Cancers Latest open access articles published in Cancers at http://www.ynsqex.icu/journal/cancers http://www.ynsqex.icu/journal/cancers MDPI en Creative Commons Attribution (CC-BY) MDPI support@mdpi.com Cancers, Vol. 12, Pages 2253: MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies http://www.ynsqex.icu/2072-6694/12/8/2253 The MDM2 gene is amplified in dedifferentiated liposarcoma (DDLPS). Treatment with MDM2 antagonists is a promising strategy to treat DDLPS; however, drug resistance is a major limitation when these drugs are used as a single agent. This study examined the impact of MDM2 antagonists on the mitogen-activated protein kinase (MAPK) pathway in DDLPS and investigated the potential synergistic activity of a MAPK kinase (MEK) inhibitor in combination with MDM2 antagonists. We identified a synergistic effect and identified the mechanism behind it. Combination effects of MDM2 antagonists and a MEK inhibitor were analyzed in a patient-derived xenograft mouse model and in DDLPS and leiomyosarcoma cell lines using different cell proliferation assays and immunoblot analysis. MDM2 antagonist (RG7388)-resistant IB115 [P4] cells and p53-silenced DDLPS cells were also established to understand the importance of functional p53. We found that MDM2 antagonists induced an upregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) in DDLPS cells. The upregulation of p-ERK occurred due to mitochondrial translocation of p53, which resulted in increased production of reactive oxygen species, causing the activation of receptor tyrosine kinases (RTKs). Activated RTKs led to the activation of the downstream MEK/ERK signaling pathway. Treatment with a MEK inhibitor resulted in decreased expression of p-ERK, causing significant anti-tumor synergy when combined with MDM2 antagonists. Our results provide a framework for designing clinical studies of combination therapies in DDLPS patients. Cancers, Vol. 12, Pages 2253: MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies

Cancers doi: 10.3390/cancers12082253

Authors: Shomereeta Roy Audrey Laroche-Clary Stephanie Verbeke Marie-Alix Derieppe Antoine Italiano

The MDM2 gene is amplified in dedifferentiated liposarcoma (DDLPS). Treatment with MDM2 antagonists is a promising strategy to treat DDLPS; however, drug resistance is a major limitation when these drugs are used as a single agent. This study examined the impact of MDM2 antagonists on the mitogen-activated protein kinase (MAPK) pathway in DDLPS and investigated the potential synergistic activity of a MAPK kinase (MEK) inhibitor in combination with MDM2 antagonists. We identified a synergistic effect and identified the mechanism behind it. Combination effects of MDM2 antagonists and a MEK inhibitor were analyzed in a patient-derived xenograft mouse model and in DDLPS and leiomyosarcoma cell lines using different cell proliferation assays and immunoblot analysis. MDM2 antagonist (RG7388)-resistant IB115 [P4] cells and p53-silenced DDLPS cells were also established to understand the importance of functional p53. We found that MDM2 antagonists induced an upregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) in DDLPS cells. The upregulation of p-ERK occurred due to mitochondrial translocation of p53, which resulted in increased production of reactive oxygen species, causing the activation of receptor tyrosine kinases (RTKs). Activated RTKs led to the activation of the downstream MEK/ERK signaling pathway. Treatment with a MEK inhibitor resulted in decreased expression of p-ERK, causing significant anti-tumor synergy when combined with MDM2 antagonists. Our results provide a framework for designing clinical studies of combination therapies in DDLPS patients.

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MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies Shomereeta Roy Audrey Laroche-Clary Stephanie Verbeke Marie-Alix Derieppe Antoine Italiano doi: 10.3390/cancers12082253 Cancers 2020-08-12 Cancers 2020-08-12 12 8 Article 2253 10.3390/cancers12082253 http://www.ynsqex.icu/2072-6694/12/8/2253
Cancers, Vol. 12, Pages 2252: Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer http://www.ynsqex.icu/2072-6694/12/8/2252 Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC. Cancers, Vol. 12, Pages 2252: Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

Cancers doi: 10.3390/cancers12082252

Authors: Elizabeth Varghese Samson Mathews Samuel Alena Lí?ková Marek Samec Peter Kubatka Dietrich Büsselberg

Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC.

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Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer Elizabeth Varghese Samson Mathews Samuel Alena Lí?ková Marek Samec Peter Kubatka Dietrich Büsselberg doi: 10.3390/cancers12082252 Cancers 2020-08-12 Cancers 2020-08-12 12 8 Review 2252 10.3390/cancers12082252 http://www.ynsqex.icu/2072-6694/12/8/2252
Cancers, Vol. 12, Pages 2251: Neoadjuvant Systemic Treatment of Primary Angiosarcoma http://www.ynsqex.icu/2072-6694/12/8/2251 Angiosarcoma is an extremely rare and aggressive malignancy. Standard of care of localized tumors includes surgery ± radiation. Despite this multimodal treatment, >50% of the angiosarcoma patients develop local or distant recurrent disease. The role of neoadjuvant systemic therapy is still controversial and we therefore performed a systematic review of the literature to define the role of neoadjuvant systemic therapy based on available evidence. We focused on the effects of neoadjuvant systemic therapy on: 1. The success of surgical resection and 2. the long-term survival. All articles published before October 2019 on Ovid Medline, Ovid Embase, Cochrane library and Scopus were evaluated. Eighteen case reports and six retrospective cohort studies were included. There were no randomized controlled trials. This literature showed a beneficial role of neoadjuvant chemotherapy on downsizing of the tumor resulting in an improvement of the resection margins, especially in patients with cardiac or cutaneous angiosarcoma. However, no definitive conclusions on survival can be drawn based on the available literature lacking any prospective randomized studies in this setting. We advise that neoadjuvant chemotherapy should be considered, since this could lead to less mutilating resections and a higher rate of free resection margins. An international angiosarcoma registry could help to develop guidelines for this rare disease. Cancers, Vol. 12, Pages 2251: Neoadjuvant Systemic Treatment of Primary Angiosarcoma

Cancers doi: 10.3390/cancers12082251

Authors: Kimberley M. Heinhuis Nikki S. IJzerman Winette T. A. van der Graaf Jan Martijn Kerst Yvonne Schrage Jos H. Beijnen Neeltje Steeghs Winan J. van Houdt

Angiosarcoma is an extremely rare and aggressive malignancy. Standard of care of localized tumors includes surgery ± radiation. Despite this multimodal treatment, >50% of the angiosarcoma patients develop local or distant recurrent disease. The role of neoadjuvant systemic therapy is still controversial and we therefore performed a systematic review of the literature to define the role of neoadjuvant systemic therapy based on available evidence. We focused on the effects of neoadjuvant systemic therapy on: 1. The success of surgical resection and 2. the long-term survival. All articles published before October 2019 on Ovid Medline, Ovid Embase, Cochrane library and Scopus were evaluated. Eighteen case reports and six retrospective cohort studies were included. There were no randomized controlled trials. This literature showed a beneficial role of neoadjuvant chemotherapy on downsizing of the tumor resulting in an improvement of the resection margins, especially in patients with cardiac or cutaneous angiosarcoma. However, no definitive conclusions on survival can be drawn based on the available literature lacking any prospective randomized studies in this setting. We advise that neoadjuvant chemotherapy should be considered, since this could lead to less mutilating resections and a higher rate of free resection margins. An international angiosarcoma registry could help to develop guidelines for this rare disease.

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Neoadjuvant Systemic Treatment of Primary Angiosarcoma Kimberley M. Heinhuis Nikki S. IJzerman Winette T. A. van der Graaf Jan Martijn Kerst Yvonne Schrage Jos H. Beijnen Neeltje Steeghs Winan J. van Houdt doi: 10.3390/cancers12082251 Cancers 2020-08-12 Cancers 2020-08-12 12 8 Review 2251 10.3390/cancers12082251 http://www.ynsqex.icu/2072-6694/12/8/2251
Cancers, Vol. 12, Pages 2250: Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms http://www.ynsqex.icu/2072-6694/12/8/2250 Hematopoiesis is a highly regulated and complex process involving hematopoietic stem cells (HSCs), cell surface adhesion molecules, and cytokines as well as cells of the hematopoietic niche in the bone marrow (BM). Myeloproliferative neoplasms (MPNs) are characterized by clonal expansion of HSCs involving one or more blood cell lineages. Philadelphia-negative MPNs (Ph-neg MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In nearly all patients with Ph-neg MPN, mutations in the genes encoding janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) can be detected and, together with additional mutations in epigenetic modifier genes, these genetic aberrations contribute to the clonal expansion of the cells. In addition to these intracellular changes in the malignant clone, inflammatory processes involving both the clonal and the non-clonal cells contribute to the signs and symptoms of the patients, as well as to progression of the disease to myelofibrosis (MF) or acute leukemia, and to thrombotic complications. This contribution has been corroborated in preclinical studies including mouse models and patient-derived iPS cells, and in clinical trials, using anti-inflammatory drugs such as JAK inhibitors and steroids, or immunomodulatory drugs such as IMiDs and interferon-alpha (IFNa), all of which change the (im)balance of circulating inflammatory factors (e.g., TNFa, IL-1b, and TGFβ) in MPN. Currently, allogeneic hematopoietic (stem) cell transplantation (allo-HCT) remains the only curative treatment for Ph-neg MPN and is the treatment of choice in intermediate-2 and high-risk MF. HCT can reverse inflammatory changes induced by MPN as well as fibrosis in a large proportion of patients, but it also induces itself profound changes in inflammatory cells and cytokines in the patient, which may help to eradicate the disease but also in part cause significant morbidity (e.g., by graft-versus-host disease). In this review, we focus on the contribution of aberrant inflammation to disease pathogenesis in Ph-neg MPN as well as the current understanding of its alterations after allogeneic HCT. Cancers, Vol. 12, Pages 2250: Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms

Cancers doi: 10.3390/cancers12082250

Authors: Nicolas Chatain Steffen Koschmieder Edgar Jost

Hematopoiesis is a highly regulated and complex process involving hematopoietic stem cells (HSCs), cell surface adhesion molecules, and cytokines as well as cells of the hematopoietic niche in the bone marrow (BM). Myeloproliferative neoplasms (MPNs) are characterized by clonal expansion of HSCs involving one or more blood cell lineages. Philadelphia-negative MPNs (Ph-neg MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In nearly all patients with Ph-neg MPN, mutations in the genes encoding janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) can be detected and, together with additional mutations in epigenetic modifier genes, these genetic aberrations contribute to the clonal expansion of the cells. In addition to these intracellular changes in the malignant clone, inflammatory processes involving both the clonal and the non-clonal cells contribute to the signs and symptoms of the patients, as well as to progression of the disease to myelofibrosis (MF) or acute leukemia, and to thrombotic complications. This contribution has been corroborated in preclinical studies including mouse models and patient-derived iPS cells, and in clinical trials, using anti-inflammatory drugs such as JAK inhibitors and steroids, or immunomodulatory drugs such as IMiDs and interferon-alpha (IFNa), all of which change the (im)balance of circulating inflammatory factors (e.g., TNFa, IL-1b, and TGFβ) in MPN. Currently, allogeneic hematopoietic (stem) cell transplantation (allo-HCT) remains the only curative treatment for Ph-neg MPN and is the treatment of choice in intermediate-2 and high-risk MF. HCT can reverse inflammatory changes induced by MPN as well as fibrosis in a large proportion of patients, but it also induces itself profound changes in inflammatory cells and cytokines in the patient, which may help to eradicate the disease but also in part cause significant morbidity (e.g., by graft-versus-host disease). In this review, we focus on the contribution of aberrant inflammation to disease pathogenesis in Ph-neg MPN as well as the current understanding of its alterations after allogeneic HCT.

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Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms Nicolas Chatain Steffen Koschmieder Edgar Jost doi: 10.3390/cancers12082250 Cancers 2020-08-12 Cancers 2020-08-12 12 8 Review 2250 10.3390/cancers12082250 http://www.ynsqex.icu/2072-6694/12/8/2250
Cancers, Vol. 12, Pages 2249: The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer http://www.ynsqex.icu/2072-6694/12/8/2249 Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients. Cancers, Vol. 12, Pages 2249: The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer

Cancers doi: 10.3390/cancers12082249

Authors: Fiorenza Gianì Veronica Vella Dario Tumino Pasqualino Malandrino Francesco Frasca

Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients.

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The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer Fiorenza Gianì Veronica Vella Dario Tumino Pasqualino Malandrino Francesco Frasca doi: 10.3390/cancers12082249 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Review 2249 10.3390/cancers12082249 http://www.ynsqex.icu/2072-6694/12/8/2249
Cancers, Vol. 12, Pages 2248: Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression http://www.ynsqex.icu/2072-6694/12/8/2248 It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma, an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state by modulating the expression of the master regulator of melanocyte homeostasis, microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF expression and is associated with a differentiated/proliferative melanoma cell state. On the other hand, ZEB1 is correlated with low MITF expression and a more invasive, stem cell-like and therapy-resistant cell state. This intrinsic balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target for melanoma patients. In this review, we will summarise what is known on the functional mechanisms of these transcription factors. Moreover, we will look specifically at their roles during melanocyte-lineage development and homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2 in the melanoma context and link this to the ‘phenotype-switching’ model of melanoma cellular plasticity. Cancers, Vol. 12, Pages 2248: Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression

Cancers doi: 10.3390/cancers12082248

Authors: Kenneth Bruneel Jeroen Verstappe Niels Vandamme Geert Berx

It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma, an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state by modulating the expression of the master regulator of melanocyte homeostasis, microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF expression and is associated with a differentiated/proliferative melanoma cell state. On the other hand, ZEB1 is correlated with low MITF expression and a more invasive, stem cell-like and therapy-resistant cell state. This intrinsic balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target for melanoma patients. In this review, we will summarise what is known on the functional mechanisms of these transcription factors. Moreover, we will look specifically at their roles during melanocyte-lineage development and homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2 in the melanoma context and link this to the ‘phenotype-switching’ model of melanoma cellular plasticity.

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Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression Kenneth Bruneel Jeroen Verstappe Niels Vandamme Geert Berx doi: 10.3390/cancers12082248 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Review 2248 10.3390/cancers12082248 http://www.ynsqex.icu/2072-6694/12/8/2248
Cancers, Vol. 12, Pages 2247: A Multi-Analyte Approach for Improved Sensitivity of Liquid Biopsies in Prostate Cancer http://www.ynsqex.icu/2072-6694/12/8/2247 Novel androgen receptor (AR) signaling inhibitors have improved the treatment of castration-resistant prostate cancer (CRPC). Nonetheless, the effect of these drugs is often time-limited and eventually most patients become resistant due to various AR alterations. Although liquid biopsy approaches are powerful tools for early detection of such therapy resistances, most assays investigate only a single resistance mechanism. In combination with the typically low abundance of circulating biomarkers, liquid biopsy assays are therefore informative only in a subset of patients. In this pilot study, we aimed to increase overall sensitivity for tumor-related information by combining three liquid biopsy approaches into a multi-analyte approach. In a cohort of 19 CRPC patients, we 1) enumerated and characterized circulating tumor cells (CTCs) by mRNA-based in situ padlock probe analysis, 2) used RT-qPCR to detect cancer-associated transcripts (e.g., AR and AR-splice variant 7) in lysed whole blood, and 3) conducted shallow whole-genome plasma sequencing to detect AR amplification. Although 44–53% of patient samples were informative for each assay, a combination of all three approaches led to improved diagnostic sensitivity, providing tumor-related information in 89% of patients. Additionally, distinct resistance mechanisms co-occurred in two patients, further reinforcing the implementation of multi-analyte liquid biopsy approaches. Cancers, Vol. 12, Pages 2247: A Multi-Analyte Approach for Improved Sensitivity of Liquid Biopsies in Prostate Cancer

Cancers doi: 10.3390/cancers12082247

Authors: Hofmann Sallinger Haudum Smolle Heitzer Moser Novy Gesson Kroneis Bauernhofer El-Heliebi

Novel androgen receptor (AR) signaling inhibitors have improved the treatment of castration-resistant prostate cancer (CRPC). Nonetheless, the effect of these drugs is often time-limited and eventually most patients become resistant due to various AR alterations. Although liquid biopsy approaches are powerful tools for early detection of such therapy resistances, most assays investigate only a single resistance mechanism. In combination with the typically low abundance of circulating biomarkers, liquid biopsy assays are therefore informative only in a subset of patients. In this pilot study, we aimed to increase overall sensitivity for tumor-related information by combining three liquid biopsy approaches into a multi-analyte approach. In a cohort of 19 CRPC patients, we 1) enumerated and characterized circulating tumor cells (CTCs) by mRNA-based in situ padlock probe analysis, 2) used RT-qPCR to detect cancer-associated transcripts (e.g., AR and AR-splice variant 7) in lysed whole blood, and 3) conducted shallow whole-genome plasma sequencing to detect AR amplification. Although 44–53% of patient samples were informative for each assay, a combination of all three approaches led to improved diagnostic sensitivity, providing tumor-related information in 89% of patients. Additionally, distinct resistance mechanisms co-occurred in two patients, further reinforcing the implementation of multi-analyte liquid biopsy approaches.

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A Multi-Analyte Approach for Improved Sensitivity of Liquid Biopsies in Prostate Cancer Hofmann Sallinger Haudum Smolle Heitzer Moser Novy Gesson Kroneis Bauernhofer El-Heliebi doi: 10.3390/cancers12082247 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Article 2247 10.3390/cancers12082247 http://www.ynsqex.icu/2072-6694/12/8/2247
Cancers, Vol. 12, Pages 2244: Histopathologic Response Is a Positive Predictor of Overall Survival in Patients Undergoing Neoadjuvant/Perioperative Chemotherapy for Locally Advanced Gastric or Gastroesophageal Junction Cancers—Analysis from a Large Single Center Cohort in Germany http://www.ynsqex.icu/2072-6694/12/8/2244 There is conflicting evidence regarding the efficacy of neoadjuvant/perioperative chemotherapy (NCT) for gastro-esophageal cancer (GEC) on overall survival. This study aimed to analyze the outcomes of multimodal treatments in a large single center cohort. We performed a retrospective analysis of patients treated with NCT, followed by intended curative oncological surgery for locally advanced gastric cancer. Uni- and multivariate regression analysis were performed to identify the predictors of overall survival. From over 3000 patients, 702 eligible patients were analyzed. In the univariate analysis clinical stage, application of preoperative PLF, requirement of surgical extension, UICC-stage, grading, R-status, Lauren histotype, and HPR were the prognostic survival factors. In multivariate analysis PLF regimen, UICC-stages, R-status, Lauren histotype, and histopathologic regression (HPR) were significant predictors of overall survival. Overall HPR-rate was 26.9%. HPR was highest in the cT2cN0 stage (55.9%), and lowest in the cT3/4 cN+ stage (21.6%). FLOT demonstrated the highest HPR (37.5%). Independent predictors for HPR were the clinical stage and grading. Kaplan Meier analyses demonstrated significant survival benefits for the responding patients (p < 0.0001). HPR after NCT was an important prognostic factor to predict overall survival for locally advanced GEC. FLOT should be the preferred regimen in patients undergoing NCT ahead of surgery. Cancers, Vol. 12, Pages 2244: Histopathologic Response Is a Positive Predictor of Overall Survival in Patients Undergoing Neoadjuvant/Perioperative Chemotherapy for Locally Advanced Gastric or Gastroesophageal Junction Cancers—Analysis from a Large Single Center Cohort in Germany

Cancers doi: 10.3390/cancers12082244

Authors: Schirren Novotny Friess Reim

There is conflicting evidence regarding the efficacy of neoadjuvant/perioperative chemotherapy (NCT) for gastro-esophageal cancer (GEC) on overall survival. This study aimed to analyze the outcomes of multimodal treatments in a large single center cohort. We performed a retrospective analysis of patients treated with NCT, followed by intended curative oncological surgery for locally advanced gastric cancer. Uni- and multivariate regression analysis were performed to identify the predictors of overall survival. From over 3000 patients, 702 eligible patients were analyzed. In the univariate analysis clinical stage, application of preoperative PLF, requirement of surgical extension, UICC-stage, grading, R-status, Lauren histotype, and HPR were the prognostic survival factors. In multivariate analysis PLF regimen, UICC-stages, R-status, Lauren histotype, and histopathologic regression (HPR) were significant predictors of overall survival. Overall HPR-rate was 26.9%. HPR was highest in the cT2cN0 stage (55.9%), and lowest in the cT3/4 cN+ stage (21.6%). FLOT demonstrated the highest HPR (37.5%). Independent predictors for HPR were the clinical stage and grading. Kaplan Meier analyses demonstrated significant survival benefits for the responding patients (p < 0.0001). HPR after NCT was an important prognostic factor to predict overall survival for locally advanced GEC. FLOT should be the preferred regimen in patients undergoing NCT ahead of surgery.

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Histopathologic Response Is a Positive Predictor of Overall Survival in Patients Undergoing Neoadjuvant/Perioperative Chemotherapy for Locally Advanced Gastric or Gastroesophageal Junction Cancers—Analysis from a Large Single Center Cohort in Germany Schirren Novotny Friess Reim doi: 10.3390/cancers12082244 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Article 2244 10.3390/cancers12082244 http://www.ynsqex.icu/2072-6694/12/8/2244
Cancers, Vol. 12, Pages 2246: Association of a Palliative Surgical Approach to Stage IV Pancreatic Neuroendocrine Neoplasms with Survival: A Systematic Review and Meta-Analysis http://www.ynsqex.icu/2072-6694/12/8/2246 The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, Cochrane Library, Web of Science and SCOPUS databases up to January 2020 and used the Newcastle–Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5661 articles were screened. In 10 studies, 5551 unique patients with stage IV PanNEN and unresectable metastases were included. The five-year OS for PanNEN patients undergoing PPTR in stage IV was 56.6% vs. 23.9% in the non-surgically treated patients (random effects relative risk (RR): 1.70; 95% CI: 1.53–1.89). Adjusted analysis of pooled hazard ratios (HR) confirmed longer OS in PanNEN patients undergoing PPTR (random effects HR: 2.67; 95% CI: 2.24–3.18). Cumulative OS analysis confirmed an attenuated survival benefit over time. The complication rate of PPTR was as high as 27%. In conclusion, PPTR may exert a survival benefit in stage IV PanNEN. However, the included studies were subject to selection bias, and special consideration should be given to PPTR anchored to a multimodal treatment strategy. Further longitudinal studies are warranted, with long-term follow-up addressing the survival outcomes associated with surgery in stage IV disease. Cancers, Vol. 12, Pages 2246: Association of a Palliative Surgical Approach to Stage IV Pancreatic Neuroendocrine Neoplasms with Survival: A Systematic Review and Meta-Analysis

Cancers doi: 10.3390/cancers12082246

Authors: Marina Tsoli Maria-Eleni Spei G?ran Wallin Gregory Kaltsas Kosmas Daskalakis

The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, Cochrane Library, Web of Science and SCOPUS databases up to January 2020 and used the Newcastle–Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5661 articles were screened. In 10 studies, 5551 unique patients with stage IV PanNEN and unresectable metastases were included. The five-year OS for PanNEN patients undergoing PPTR in stage IV was 56.6% vs. 23.9% in the non-surgically treated patients (random effects relative risk (RR): 1.70; 95% CI: 1.53–1.89). Adjusted analysis of pooled hazard ratios (HR) confirmed longer OS in PanNEN patients undergoing PPTR (random effects HR: 2.67; 95% CI: 2.24–3.18). Cumulative OS analysis confirmed an attenuated survival benefit over time. The complication rate of PPTR was as high as 27%. In conclusion, PPTR may exert a survival benefit in stage IV PanNEN. However, the included studies were subject to selection bias, and special consideration should be given to PPTR anchored to a multimodal treatment strategy. Further longitudinal studies are warranted, with long-term follow-up addressing the survival outcomes associated with surgery in stage IV disease.

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Association of a Palliative Surgical Approach to Stage IV Pancreatic Neuroendocrine Neoplasms with Survival: A Systematic Review and Meta-Analysis Marina Tsoli Maria-Eleni Spei G?ran Wallin Gregory Kaltsas Kosmas Daskalakis doi: 10.3390/cancers12082246 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Review 2246 10.3390/cancers12082246 http://www.ynsqex.icu/2072-6694/12/8/2246
Cancers, Vol. 12, Pages 2245: Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients http://www.ynsqex.icu/2072-6694/12/8/2245 Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors. Cancers, Vol. 12, Pages 2245: Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

Cancers doi: 10.3390/cancers12082245

Authors: Pau Riera Benjamín Rodríguez-Santiago Adriana Lasa Lidia Gonzalez-Quereda Berta Martín Juliana Salazar Ana Sebio Anna C. Virgili Jordi Minguillón Cristina Camps Jordi Surrallés David Páez

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors.

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Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients Pau Riera Benjamín Rodríguez-Santiago Adriana Lasa Lidia Gonzalez-Quereda Berta Martín Juliana Salazar Ana Sebio Anna C. Virgili Jordi Minguillón Cristina Camps Jordi Surrallés David Páez doi: 10.3390/cancers12082245 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Article 2245 10.3390/cancers12082245 http://www.ynsqex.icu/2072-6694/12/8/2245
Cancers, Vol. 12, Pages 2243: Genomic Mapping Identifies Mutations in RYR2 and AHNAK as Associated with Favorable Outcome in Basal-Like Breast Tumors Expressing PD1/PD-L1 http://www.ynsqex.icu/2072-6694/12/8/2243 Treatment with anti-PD-L1 antibodies has shown efficacy in basal-like breast cancer. In this context, identification of pre-activated immune tumors is a main goal. Here we explore mutations in PD1 and PD-L1 high-expressing tumors to identify genomic correlates associated with outcome. To do so, RNA-seq and mutation data from 971 breast cancer patients from the TCGA dataset were used to identify most prevalent mutations in patients with high levels of PD1 and PD-L1. Transcriptomic signatures associated with the selected mutations were identified and analyzed in terms of outcome and immune cell infiltration. We identified co-occurrent mutations in RYR2 and AHNAK in 8% and 5% of basal-like tumors respectively, which conferred good prognosis in patients with high expression of PD1 and PD-L1 genes. The transcriptomic signature associated with these mutations, composed of CXCL9, GBP5, C1QA, IL2RG, CSF2RB, IDO1 and LAG3 genes, also conferred good prognosis and correlated with immune infiltrations within the tumors. The joint signature classified patients with favorable relapse-free survival (HR: 0.28; CI: 0.2–0.38; p = 1.7 × 10−16) and overall survival (HR: 0.18; CI: 0.09–0.34; p = 6.8 × 10−9), showing a stronger prediction capacity than previous reported signatures. In conclusion, we describe two novel mutations and their transcriptomic signature, both associated with a favorable outcome and immune infiltrates in PD1 and PD-L1 high-expressing basal-like tumors. Cancers, Vol. 12, Pages 2243: Genomic Mapping Identifies Mutations in RYR2 and AHNAK as Associated with Favorable Outcome in Basal-Like Breast Tumors Expressing PD1/PD-L1

Cancers doi: 10.3390/cancers12082243

Authors: Francisco J. Cimas Arancha Manzano Mariona Baliu-Piqué Elena García-Gil Pedro Pérez-Segura ádám Nagy Atanasio Pandiella Balázs Gy?rffy Alberto Ocana

Treatment with anti-PD-L1 antibodies has shown efficacy in basal-like breast cancer. In this context, identification of pre-activated immune tumors is a main goal. Here we explore mutations in PD1 and PD-L1 high-expressing tumors to identify genomic correlates associated with outcome. To do so, RNA-seq and mutation data from 971 breast cancer patients from the TCGA dataset were used to identify most prevalent mutations in patients with high levels of PD1 and PD-L1. Transcriptomic signatures associated with the selected mutations were identified and analyzed in terms of outcome and immune cell infiltration. We identified co-occurrent mutations in RYR2 and AHNAK in 8% and 5% of basal-like tumors respectively, which conferred good prognosis in patients with high expression of PD1 and PD-L1 genes. The transcriptomic signature associated with these mutations, composed of CXCL9, GBP5, C1QA, IL2RG, CSF2RB, IDO1 and LAG3 genes, also conferred good prognosis and correlated with immune infiltrations within the tumors. The joint signature classified patients with favorable relapse-free survival (HR: 0.28; CI: 0.2–0.38; p = 1.7 × 10−16) and overall survival (HR: 0.18; CI: 0.09–0.34; p = 6.8 × 10−9), showing a stronger prediction capacity than previous reported signatures. In conclusion, we describe two novel mutations and their transcriptomic signature, both associated with a favorable outcome and immune infiltrates in PD1 and PD-L1 high-expressing basal-like tumors.

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Genomic Mapping Identifies Mutations in RYR2 and AHNAK as Associated with Favorable Outcome in Basal-Like Breast Tumors Expressing PD1/PD-L1 Francisco J. Cimas Arancha Manzano Mariona Baliu-Piqué Elena García-Gil Pedro Pérez-Segura ádám Nagy Atanasio Pandiella Balázs Gy?rffy Alberto Ocana doi: 10.3390/cancers12082243 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Article 2243 10.3390/cancers12082243 http://www.ynsqex.icu/2072-6694/12/8/2243
Cancers, Vol. 12, Pages 2242: High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG) http://www.ynsqex.icu/2072-6694/12/8/2242 By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p < 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies. Cancers, Vol. 12, Pages 2242: High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG)

Cancers doi: 10.3390/cancers12082242

Authors: Silvia Salmoiraghi Roberta Cavagna Pamela Zanghì Chiara Pavoni Anna Michelato Ksenija Buklijas Lara Elidi Tamara Intermesoli Federico Lussana Elena Oldani Chiara Caprioli Paola Stefanoni Giacomo Gianfaldoni Ernesta Audisio Elisabetta Terruzzi Lorella De Paoli Erika Borlenghi Irene Cavattoni Daniele Mattei Annamaria Scattolin Monica Tajana Fabio Ciceri Elisabetta Todisco Leonardo Campiotti Paolo Corradini Nicola Fracchiolla Renato Bassan Alessandro Rambaldi Orietta Spinelli

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p < 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

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High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG) Silvia Salmoiraghi Roberta Cavagna Pamela Zanghì Chiara Pavoni Anna Michelato Ksenija Buklijas Lara Elidi Tamara Intermesoli Federico Lussana Elena Oldani Chiara Caprioli Paola Stefanoni Giacomo Gianfaldoni Ernesta Audisio Elisabetta Terruzzi Lorella De Paoli Erika Borlenghi Irene Cavattoni Daniele Mattei Annamaria Scattolin Monica Tajana Fabio Ciceri Elisabetta Todisco Leonardo Campiotti Paolo Corradini Nicola Fracchiolla Renato Bassan Alessandro Rambaldi Orietta Spinelli doi: 10.3390/cancers12082242 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Article 2242 10.3390/cancers12082242 http://www.ynsqex.icu/2072-6694/12/8/2242
Cancers, Vol. 12, Pages 2241: Laryngeal Compartmentalization Does Not Affect the Prognosis of T3-T4 Laryngeal Cancer Treated by Upfront Total Laryngectomy http://www.ynsqex.icu/2072-6694/12/8/2241 A picture is emerging in which advanced laryngeal cancers (LCs) are potentially not homogeneous and may be characterized by subpopulations which, if identified, could allow selection of patients amenable to organ preservation treatments in contrast to those to be treated with total laryngectomy (TL). This work aims to analyze a multicentric cohort of T3-T4a LCs treated by upfront TL, investigating the clinical and pathological features that can best predict oncologic outcomes. A total of 149 previously untreated patients who underwent TL for T3-T4a LC at four institutions were analyzed. Survival and disease-control were considered as the main outcomes. A secondary end-point was the identification of covariates associated with nodal status, investigating also the tumor thickness. T and N categories were significantly associated with both overall and disease-specific survival. The number of positive nodes and tracheal involvement were associated with loco-regional failure; post-cricoid area invasion and extra-nodal extension with distant failure. Posterior laryngeal compartment involvement was not a significant prognostic feature, by either univariable and multivariable analyses. These results support the conclusion that laryngeal compartmentalization has no impact on survival in patients treated by upfront TL and the current TNM staging system remains a robust prognosticator in advanced LC. Cancers, Vol. 12, Pages 2241: Laryngeal Compartmentalization Does Not Affect the Prognosis of T3-T4 Laryngeal Cancer Treated by Upfront Total Laryngectomy

Cancers doi: 10.3390/cancers12082241

Authors: Filippo Marchi Francesco Missale Claudio Sampieri Marta Filauro Andrea Iandelli Giampiero Parrinello Fabiola Incandela Ludwig E. Smeele Michiel W. M. van den Brekel Francesca Del Bon Piero Nicolai Cesare Piazza Giorgio Peretti

A picture is emerging in which advanced laryngeal cancers (LCs) are potentially not homogeneous and may be characterized by subpopulations which, if identified, could allow selection of patients amenable to organ preservation treatments in contrast to those to be treated with total laryngectomy (TL). This work aims to analyze a multicentric cohort of T3-T4a LCs treated by upfront TL, investigating the clinical and pathological features that can best predict oncologic outcomes. A total of 149 previously untreated patients who underwent TL for T3-T4a LC at four institutions were analyzed. Survival and disease-control were considered as the main outcomes. A secondary end-point was the identification of covariates associated with nodal status, investigating also the tumor thickness. T and N categories were significantly associated with both overall and disease-specific survival. The number of positive nodes and tracheal involvement were associated with loco-regional failure; post-cricoid area invasion and extra-nodal extension with distant failure. Posterior laryngeal compartment involvement was not a significant prognostic feature, by either univariable and multivariable analyses. These results support the conclusion that laryngeal compartmentalization has no impact on survival in patients treated by upfront TL and the current TNM staging system remains a robust prognosticator in advanced LC.

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Laryngeal Compartmentalization Does Not Affect the Prognosis of T3-T4 Laryngeal Cancer Treated by Upfront Total Laryngectomy Filippo Marchi Francesco Missale Claudio Sampieri Marta Filauro Andrea Iandelli Giampiero Parrinello Fabiola Incandela Ludwig E. Smeele Michiel W. M. van den Brekel Francesca Del Bon Piero Nicolai Cesare Piazza Giorgio Peretti doi: 10.3390/cancers12082241 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Article 2241 10.3390/cancers12082241 http://www.ynsqex.icu/2072-6694/12/8/2241
Cancers, Vol. 12, Pages 2240: Aerobic Exercise-Induced Changes in Cardiorespiratory Fitness in Breast Cancer Patients Receiving Chemotherapy: A Systematic Review and Meta-Analysis http://www.ynsqex.icu/2072-6694/12/8/2240 While performing aerobic exercise during chemotherapy has been proven feasible and safe, the efficacy of aerobic training on cardiorespiratory fitness (CRF) in women with breast cancer undergoing chemotherapy has not yet been systematically assessed. Therefore, the objective of this work was to determine (a) the efficacy of aerobic training to improve CRF; (b) the role of aerobic training intensity (moderate or vigorous) on CRF response; (c) the effect of the aerobic training mode (continuous or interval) on changes in CRF in women with breast cancer (BC) receiving chemotherapy. A systematic review and meta-analysis were conducted as per PRISMA guidelines, and randomized controlled trials comparing usual care (UC) and aerobic training in women with BC undergoing chemotherapy were eligible. The results suggest that increases in CRF are favored by (a) aerobic training when compared to usual care; (b) vigorous-intensity aerobic exercise (64–90% of maximal oxygen uptake, VO2max) when compared to moderate-intensity aerobic exercise (46–63% of VO2max); and (c) both continuous and interval aerobic training are effective at increasing the VO2max. Aerobic training improves CRF in women with BC undergoing chemotherapy. Notably, training intensity significantly impacts the VO2max response. Where appropriate, vigorous intensity aerobic training should be considered for women with BC receiving chemotherapy. Cancers, Vol. 12, Pages 2240: Aerobic Exercise-Induced Changes in Cardiorespiratory Fitness in Breast Cancer Patients Receiving Chemotherapy: A Systematic Review and Meta-Analysis

Cancers doi: 10.3390/cancers12082240

Authors: Guilherme Maginador Manoel E. Lixandr?o Henrique I. Bortolozo Felipe C. Vechin Luís O. Sarian Sophie Derchain Guilherme D. Telles Eva Zopf Carlos Ugrinowitsch Miguel S. Concei??o

While performing aerobic exercise during chemotherapy has been proven feasible and safe, the efficacy of aerobic training on cardiorespiratory fitness (CRF) in women with breast cancer undergoing chemotherapy has not yet been systematically assessed. Therefore, the objective of this work was to determine (a) the efficacy of aerobic training to improve CRF; (b) the role of aerobic training intensity (moderate or vigorous) on CRF response; (c) the effect of the aerobic training mode (continuous or interval) on changes in CRF in women with breast cancer (BC) receiving chemotherapy. A systematic review and meta-analysis were conducted as per PRISMA guidelines, and randomized controlled trials comparing usual care (UC) and aerobic training in women with BC undergoing chemotherapy were eligible. The results suggest that increases in CRF are favored by (a) aerobic training when compared to usual care; (b) vigorous-intensity aerobic exercise (64–90% of maximal oxygen uptake, VO2max) when compared to moderate-intensity aerobic exercise (46–63% of VO2max); and (c) both continuous and interval aerobic training are effective at increasing the VO2max. Aerobic training improves CRF in women with BC undergoing chemotherapy. Notably, training intensity significantly impacts the VO2max response. Where appropriate, vigorous intensity aerobic training should be considered for women with BC receiving chemotherapy.

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Aerobic Exercise-Induced Changes in Cardiorespiratory Fitness in Breast Cancer Patients Receiving Chemotherapy: A Systematic Review and Meta-Analysis Guilherme Maginador Manoel E. Lixandr?o Henrique I. Bortolozo Felipe C. Vechin Luís O. Sarian Sophie Derchain Guilherme D. Telles Eva Zopf Carlos Ugrinowitsch Miguel S. Concei??o doi: 10.3390/cancers12082240 Cancers 2020-08-11 Cancers 2020-08-11 12 8 Review 2240 10.3390/cancers12082240 http://www.ynsqex.icu/2072-6694/12/8/2240
Cancers, Vol. 12, Pages 2239: Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience http://www.ynsqex.icu/2072-6694/12/8/2239 Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting. We evaluated all consecutive patients undergoing cytoreduction for platinum-resistance over an 8-year period (2010–2018) in two different centers. Fifty patients (median age 52.5 years, range 34–75) were included; the median number of previous chemotherapy lines was three (range 1–7) and the median number of previous surgeries was one (range 1–4). Completeness of cytoreduction (CC = 0) was achieved in 22 patients (44%). Rates of major operative morbidity and 30-day mortality were 38% and 8%, respectively. Median follow-up was 35 months. The absence of tumor residual (CC = 0) was associated with a significantly better overall survival (OS) compared to the CC > 0 subgroup (median OS 32.9 months (95% CI 21.6–44.2) vs. 4.8 months (95% CI n.a.–9.8), hazard ratio (HR) 4.21 (95% CI 2.07–8.60), p < 0.001). Optimal cytoreduction is feasible and associated with promising OS in selected, heavily pre-treated PROCs. Further prospective studies are required to better define the role of surgery in platinum-resistant disease. Cancers, Vol. 12, Pages 2239: Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience

Cancers doi: 10.3390/cancers12082239

Authors: Valentina Tuninetti Marilena Di Napoli Eleonora Ghisoni Furio Maggiorotto Manuela Robella Giulia Scotto Gaia Giannone Margherita Turinetto Dimitris Siatis Riccardo Ponzone Marco Vaira Michele De Simone Cono Scaffa Sandro Pignata Stefano Greggi Massimo Di Maio Giorgio Valabrega

Few retrospective studies have shown a benefit in selected patients affected by heavily pre-treated, platinum-resistant ovarian carcinomas (PROCs) who have undergone cytoreduction at relapse. However, the role of tertiary and quaternary cytoreductive surgery is not fully defined. Our aim was to evaluate survival and surgical morbidity and mortality after maximal cytoreduction in this setting. We evaluated all consecutive patients undergoing cytoreduction for platinum-resistance over an 8-year period (2010–2018) in two different centers. Fifty patients (median age 52.5 years, range 34–75) were included; the median number of previous chemotherapy lines was three (range 1–7) and the median number of previous surgeries was one (range 1–4). Completeness of cytoreduction (CC = 0) was achieved in 22 patients (44%). Rates of major operative morbidity and 30-day mortality were 38% and 8%, respectively. Median follow-up was 35 months. The absence of tumor residual (CC = 0) was associated with a significantly better overall survival (OS) compared to the CC > 0 subgroup (median OS 32.9 months (95% CI 21.6–44.2) vs. 4.8 months (95% CI n.a.–9.8), hazard ratio (HR) 4.21 (95% CI 2.07–8.60), p < 0.001). Optimal cytoreduction is feasible and associated with promising OS in selected, heavily pre-treated PROCs. Further prospective studies are required to better define the role of surgery in platinum-resistant disease.

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Cytoreductive Surgery for Heavily Pre-Treated, Platinum-Resistant Epithelial Ovarian Carcinoma: A Two-Center Retrospective Experience Valentina Tuninetti Marilena Di Napoli Eleonora Ghisoni Furio Maggiorotto Manuela Robella Giulia Scotto Gaia Giannone Margherita Turinetto Dimitris Siatis Riccardo Ponzone Marco Vaira Michele De Simone Cono Scaffa Sandro Pignata Stefano Greggi Massimo Di Maio Giorgio Valabrega doi: 10.3390/cancers12082239 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Article 2239 10.3390/cancers12082239 http://www.ynsqex.icu/2072-6694/12/8/2239
Cancers, Vol. 12, Pages 2232: Altered Organelle Calcium Transport in Ovarian Physiology and Cancer http://www.ynsqex.icu/2072-6694/12/8/2232 Calcium levels have a huge impact on the physiology of the female reproductive system, in particular, of the ovaries. Cytosolic calcium levels are influenced by regulatory proteins (i.e., ion channels and pumps) localized in the plasmalemma and/or in the endomembranes of membrane-bound organelles. Imbalances between plasma membrane and organelle-based mechanisms for calcium regulation in different ovarian cell subtypes are contributing to ovarian pathologies, including ovarian cancer. In this review, we focused our attention on altered calcium transport and its role as a contributor to tumor progression in ovarian cancer. The most important proteins described as contributing to ovarian cancer progression are inositol trisphosphate receptors, ryanodine receptors, transient receptor potential channels, calcium ATPases, hormone receptors, G-protein-coupled receptors, and/or mitochondrial calcium uniporters. The involvement of mitochondrial and/or endoplasmic reticulum calcium imbalance in the development of resistance to chemotherapeutic drugs in ovarian cancer is also discussed, since Ca2+ channels and/or pumps are nowadays regarded as potential therapeutic targets and are even correlated with prognosis. Cancers, Vol. 12, Pages 2232: Altered Organelle Calcium Transport in Ovarian Physiology and Cancer

Cancers doi: 10.3390/cancers12082232

Authors: Laura Caravia Cristina Elena Staicu Beatrice Mihaela Radu Carmen Elena Condrat Drago? Cre?oiu Nicolae Bacalba?a Nicolae Suciu Sanda Maria Cre?oiu Silviu Cristian Voinea

Calcium levels have a huge impact on the physiology of the female reproductive system, in particular, of the ovaries. Cytosolic calcium levels are influenced by regulatory proteins (i.e., ion channels and pumps) localized in the plasmalemma and/or in the endomembranes of membrane-bound organelles. Imbalances between plasma membrane and organelle-based mechanisms for calcium regulation in different ovarian cell subtypes are contributing to ovarian pathologies, including ovarian cancer. In this review, we focused our attention on altered calcium transport and its role as a contributor to tumor progression in ovarian cancer. The most important proteins described as contributing to ovarian cancer progression are inositol trisphosphate receptors, ryanodine receptors, transient receptor potential channels, calcium ATPases, hormone receptors, G-protein-coupled receptors, and/or mitochondrial calcium uniporters. The involvement of mitochondrial and/or endoplasmic reticulum calcium imbalance in the development of resistance to chemotherapeutic drugs in ovarian cancer is also discussed, since Ca2+ channels and/or pumps are nowadays regarded as potential therapeutic targets and are even correlated with prognosis.

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Altered Organelle Calcium Transport in Ovarian Physiology and Cancer Laura Caravia Cristina Elena Staicu Beatrice Mihaela Radu Carmen Elena Condrat Drago? Cre?oiu Nicolae Bacalba?a Nicolae Suciu Sanda Maria Cre?oiu Silviu Cristian Voinea doi: 10.3390/cancers12082232 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Review 2232 10.3390/cancers12082232 http://www.ynsqex.icu/2072-6694/12/8/2232
Cancers, Vol. 12, Pages 2235: Single-Cell RNA-seq Reveals Obesity-Induced Alterations in the Brca1-Mutated Mammary Gland Microenvironment http://www.ynsqex.icu/2072-6694/12/8/2235 Clinical and experimental studies have shown that obesity increases the development and progression of breast cancer. The impact of obesity on the tumor microenvironment plays an important role in tumorigenesis, yet the precise mechanisms underlying obesity-mediated effects on cell-to-cell communication within the tumor microenvironment have been difficult to define. In this study, we conducted single-cell RNA sequencing (scRNA-seq) studies to investigate the impact of high-fat diet (HFD)-induced obesity on transcriptomic landscapes of stromal and immune cells in mammary glands of Brca1−/−; p53+/− mice, an animal breast cancer model. Hierarchical clustering and gene pathway enrichment analyses of scRNA-seq data showed that five different subtypes of stromal fibroblasts existed in mouse Brca1-mutated mammary glands. HFD-induced obesity led to upregulated expression of extracellular matrix (ECM) genes (Col3a1, Col6a3, Eln, and Sparc) and downregulated expression of immunoregulatory genes (Iigp1 and Cxcl10) in these stromal subtype cells. These findings, taken together, suggest that obesity alters the ECM composition and immune ecosystem through modulating the functionality of mammary stromal fibroblasts. Moreover, scRNA-seq analysis of mammary immune cells indicated that HFD-induced obesity promoted the generation and/or recruiting of pro-tumorigenic M2 macrophages in mammary glands. Our studies provide new insight into a mechanistic paradigm wherein obesity modulates the functions of stromal and immune cells to create the tumorigenic microenvironment for promoting breast tumorigenesis. Cancers, Vol. 12, Pages 2235: Single-Cell RNA-seq Reveals Obesity-Induced Alterations in the Brca1-Mutated Mammary Gland Microenvironment

Cancers doi: 10.3390/cancers12082235

Authors: Pang-Kuo Lo Yuan Yao Qun Zhou

Clinical and experimental studies have shown that obesity increases the development and progression of breast cancer. The impact of obesity on the tumor microenvironment plays an important role in tumorigenesis, yet the precise mechanisms underlying obesity-mediated effects on cell-to-cell communication within the tumor microenvironment have been difficult to define. In this study, we conducted single-cell RNA sequencing (scRNA-seq) studies to investigate the impact of high-fat diet (HFD)-induced obesity on transcriptomic landscapes of stromal and immune cells in mammary glands of Brca1−/−; p53+/− mice, an animal breast cancer model. Hierarchical clustering and gene pathway enrichment analyses of scRNA-seq data showed that five different subtypes of stromal fibroblasts existed in mouse Brca1-mutated mammary glands. HFD-induced obesity led to upregulated expression of extracellular matrix (ECM) genes (Col3a1, Col6a3, Eln, and Sparc) and downregulated expression of immunoregulatory genes (Iigp1 and Cxcl10) in these stromal subtype cells. These findings, taken together, suggest that obesity alters the ECM composition and immune ecosystem through modulating the functionality of mammary stromal fibroblasts. Moreover, scRNA-seq analysis of mammary immune cells indicated that HFD-induced obesity promoted the generation and/or recruiting of pro-tumorigenic M2 macrophages in mammary glands. Our studies provide new insight into a mechanistic paradigm wherein obesity modulates the functions of stromal and immune cells to create the tumorigenic microenvironment for promoting breast tumorigenesis.

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Single-Cell RNA-seq Reveals Obesity-Induced Alterations in the Brca1-Mutated Mammary Gland Microenvironment Pang-Kuo Lo Yuan Yao Qun Zhou doi: 10.3390/cancers12082235 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Article 2235 10.3390/cancers12082235 http://www.ynsqex.icu/2072-6694/12/8/2235
Cancers, Vol. 12, Pages 2231: Utility of Circulating Tumor DNA for Detection and Monitoring of Endometrial Cancer Recurrence and Progression http://www.ynsqex.icu/2072-6694/12/8/2231 Despite the increasing incidence of endometrial cancer (EC) worldwide and the poor overall survival of patients who recur, no reliable biomarker exists for detecting and monitoring EC recurrence and progression during routine follow-up. Circulating tumor DNA (ctDNA) is a sensitive method for monitoring cancer activity and stratifying patients that are likely to respond to therapy. As a pilot study, we investigated the utility of ctDNA for detecting and monitoring EC recurrence and progression in 13 patients, using targeted next-generation sequencing (tNGS) and personalized ctDNA assays. Using tNGS, at least one somatic mutation at a variant allele frequency (VAF) > 20% was detected in 69% (9/13) of patient tumors. The four patients with no detectable tumor mutations at >20% VAF were whole exome sequenced, with all four harboring mutations in genes not analyzed by tNGS. Analysis of matched and longitudinal plasma DNA revealed earlier detection of EC recurrence and progression and dynamic kinetics of ctDNA levels reflecting treatment response. We also detected acquired high microsatellite instability (MSI-H) in ctDNA from one patient whose primary tumor was MSI stable. Our study suggests that ctDNA analysis could become a useful biomarker for early detection and monitoring of EC recurrence. However, further research is needed to confirm these findings and to explore their potential implications for patient management. Cancers, Vol. 12, Pages 2231: Utility of Circulating Tumor DNA for Detection and Monitoring of Endometrial Cancer Recurrence and Progression

Cancers doi: 10.3390/cancers12082231

Authors: Moss Gorsia Collins Sandhu Foreman Gore Wood Kent Silcock Guttery

Despite the increasing incidence of endometrial cancer (EC) worldwide and the poor overall survival of patients who recur, no reliable biomarker exists for detecting and monitoring EC recurrence and progression during routine follow-up. Circulating tumor DNA (ctDNA) is a sensitive method for monitoring cancer activity and stratifying patients that are likely to respond to therapy. As a pilot study, we investigated the utility of ctDNA for detecting and monitoring EC recurrence and progression in 13 patients, using targeted next-generation sequencing (tNGS) and personalized ctDNA assays. Using tNGS, at least one somatic mutation at a variant allele frequency (VAF) > 20% was detected in 69% (9/13) of patient tumors. The four patients with no detectable tumor mutations at >20% VAF were whole exome sequenced, with all four harboring mutations in genes not analyzed by tNGS. Analysis of matched and longitudinal plasma DNA revealed earlier detection of EC recurrence and progression and dynamic kinetics of ctDNA levels reflecting treatment response. We also detected acquired high microsatellite instability (MSI-H) in ctDNA from one patient whose primary tumor was MSI stable. Our study suggests that ctDNA analysis could become a useful biomarker for early detection and monitoring of EC recurrence. However, further research is needed to confirm these findings and to explore their potential implications for patient management.

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Utility of Circulating Tumor DNA for Detection and Monitoring of Endometrial Cancer Recurrence and Progression Moss Gorsia Collins Sandhu Foreman Gore Wood Kent Silcock Guttery doi: 10.3390/cancers12082231 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Brief Report 2231 10.3390/cancers12082231 http://www.ynsqex.icu/2072-6694/12/8/2231
Cancers, Vol. 12, Pages 2230: Interplay of tRNA-Derived Fragments and T Cell Activation in Breast Cancer Patient Survival http://www.ynsqex.icu/2072-6694/12/8/2230 Effector CD8+ T cell activation and its cytotoxic function are positively correlated with improved survival in breast cancer. tRNA-derived fragments (tRFs) have recently been found to be involved in gene regulation in cancer progression. However, it is unclear how interactions between expression of tRFs and T cell activation affect breast cancer patient survival. We used Kaplan–Meier survival and multivariate Cox regression models to evaluate the effect of interactions between expression of tRFs and T cell activation on survival in 1081 breast cancer patients. Spearman correlation analysis and weighted gene co-expression network analysis were conducted to identify genes and pathways that were associated with tRFs. tRFdb-5024a, 5P_tRNA-Leu-CAA-4-1, and ts-49 were positively associated with overall survival, while ts-34 and ts-58 were negatively associated with overall survival. Significant interactions were detected between T cell activation and ts-34 and ts-49. In the T cell exhaustion group, patients with a low level of ts-34 or a high level of ts-49 showed improved survival. In contrast, there was no significant difference in the activation group. Breast cancer related pathways were identified for the five tRFs. In conclusion, the identified five tRFs associated with overall survival may serve as therapeutic targets and improve immunotherapy in breast cancer. Cancers, Vol. 12, Pages 2230: Interplay of tRNA-Derived Fragments and T Cell Activation in Breast Cancer Patient Survival

Cancers doi: 10.3390/cancers12082230

Authors: Nayang Shan Ningshan Li Qile Dai Lin Hou Xiting Yan Amei Amei Lingeng Lu Zuoheng Wang

Effector CD8+ T cell activation and its cytotoxic function are positively correlated with improved survival in breast cancer. tRNA-derived fragments (tRFs) have recently been found to be involved in gene regulation in cancer progression. However, it is unclear how interactions between expression of tRFs and T cell activation affect breast cancer patient survival. We used Kaplan–Meier survival and multivariate Cox regression models to evaluate the effect of interactions between expression of tRFs and T cell activation on survival in 1081 breast cancer patients. Spearman correlation analysis and weighted gene co-expression network analysis were conducted to identify genes and pathways that were associated with tRFs. tRFdb-5024a, 5P_tRNA-Leu-CAA-4-1, and ts-49 were positively associated with overall survival, while ts-34 and ts-58 were negatively associated with overall survival. Significant interactions were detected between T cell activation and ts-34 and ts-49. In the T cell exhaustion group, patients with a low level of ts-34 or a high level of ts-49 showed improved survival. In contrast, there was no significant difference in the activation group. Breast cancer related pathways were identified for the five tRFs. In conclusion, the identified five tRFs associated with overall survival may serve as therapeutic targets and improve immunotherapy in breast cancer.

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Interplay of tRNA-Derived Fragments and T Cell Activation in Breast Cancer Patient Survival Nayang Shan Ningshan Li Qile Dai Lin Hou Xiting Yan Amei Amei Lingeng Lu Zuoheng Wang doi: 10.3390/cancers12082230 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Article 2230 10.3390/cancers12082230 http://www.ynsqex.icu/2072-6694/12/8/2230
Cancers, Vol. 12, Pages 2233: PCR-Free Detection of Long Non-Coding HOTAIR RNA in Ovarian Cancer Cell Lines and Plasma Samples http://www.ynsqex.icu/2072-6694/12/8/2233 Long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is one of the promising biomarkers that has widely been used in determining the stages of many cancers, including ovarian cancer. In cancer diagnostics, the two key analytical challenges for detecting long non-coding RNA biomarkers are i) the low concentration levels (nM to fM range) in which they are found and ii) the analytical method where broad dynamic range is required (four to six orders of magnitude) due to the large variation in expression levels for different HOTAIR RNAs. To meet these challenges, we report on a biosensing platform for the visual (colorimetric) estimation and subsequent electrochemical quantification of ovarian-cancer-specific HOTAIR using a screen-printed gold electrode (SPE-Au). Our assay utilizes a two-step strategy that involves (i) magnetic isolation and purification of target HOTAIR sequences and (ii) subsequent detection of isolated sequences using a sandwich hybridization coupled with horseradish peroxidase (HRP)-catalyzed reaction of 3,3′,5,5′-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide. The assay achieved a detection limit of 1.0 fM HOTAIR in spiked buffer samples with excellent reproducibility (% RSD ≤ 5%, for n = 3). It was successfully applied to detect HOTAIR in cancer cell lines and a panel of plasma samples derived from patients with ovarian cancer. The analytical performance of the method was validated with standard RT-qPCR. We believe that the proof of concept assay reported here may find potential use in routine clinical settings for the screening of cancer-related lncRNAs. Cancers, Vol. 12, Pages 2233: PCR-Free Detection of Long Non-Coding HOTAIR RNA in Ovarian Cancer Cell Lines and Plasma Samples

Cancers doi: 10.3390/cancers12082233

Authors: Narshone Soda Muhammad Umer Navid Kashaninejad Surasak Kasetsirikul Richard Kline Carlos Salomon Nam-Trung Nguyen Muhammad J. A. Shiddiky

Long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is one of the promising biomarkers that has widely been used in determining the stages of many cancers, including ovarian cancer. In cancer diagnostics, the two key analytical challenges for detecting long non-coding RNA biomarkers are i) the low concentration levels (nM to fM range) in which they are found and ii) the analytical method where broad dynamic range is required (four to six orders of magnitude) due to the large variation in expression levels for different HOTAIR RNAs. To meet these challenges, we report on a biosensing platform for the visual (colorimetric) estimation and subsequent electrochemical quantification of ovarian-cancer-specific HOTAIR using a screen-printed gold electrode (SPE-Au). Our assay utilizes a two-step strategy that involves (i) magnetic isolation and purification of target HOTAIR sequences and (ii) subsequent detection of isolated sequences using a sandwich hybridization coupled with horseradish peroxidase (HRP)-catalyzed reaction of 3,3′,5,5′-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide. The assay achieved a detection limit of 1.0 fM HOTAIR in spiked buffer samples with excellent reproducibility (% RSD ≤ 5%, for n = 3). It was successfully applied to detect HOTAIR in cancer cell lines and a panel of plasma samples derived from patients with ovarian cancer. The analytical performance of the method was validated with standard RT-qPCR. We believe that the proof of concept assay reported here may find potential use in routine clinical settings for the screening of cancer-related lncRNAs.

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PCR-Free Detection of Long Non-Coding HOTAIR RNA in Ovarian Cancer Cell Lines and Plasma Samples Narshone Soda Muhammad Umer Navid Kashaninejad Surasak Kasetsirikul Richard Kline Carlos Salomon Nam-Trung Nguyen Muhammad J. A. Shiddiky doi: 10.3390/cancers12082233 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Article 2233 10.3390/cancers12082233 http://www.ynsqex.icu/2072-6694/12/8/2233
Cancers, Vol. 12, Pages 2234: Association of the Metabolic Score Using Baseline FDG-PET/CT and dNLR with Immunotherapy Outcomes in Advanced NSCLC Patients Treated with First-Line Pembrolizumab http://www.ynsqex.icu/2072-6694/12/8/2234 Background: We aimed to assess the clinical utility of a previously published score combining the total metabolic tumor volume (TMTV) on baseline FDG-PET/CT and pretreatment derived from the neutrophils to lymphocytes ratio (dNLR) for prognostication in NSCLC patients undergoing first-line immunotherapy (IT). Methods: In this multicenter retrospective study, 63 advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) ≥50%, who underwent FDG-PET/CT before first-line IT, treated from January 2017 to September 2019, were enrolled. Associations between this score and the progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and overall response rate (ORR) were evaluated. Results: The median (m) PFS and mOS were 7.7 (95% CI 4.9–10.6) and 12.1 (8.6–15.6) months, respectively, and DCR and ORR were 65% and 58%, respectively. mOS was 17.9 months (14.6 not reached) for the good group versus 13.8 (95%CI 8.4–18.9) and 6.6 (CI 2.0–11.2) months for the intermediate and poor groups, respectively. mPFS was 15.1 (95%CI 12.1–20.0) months for the good group versus 5.2 (1.9–8.5) and 1.9 (95%CI 1.3–2.5) months for the intermediate and poor groups, respectively. The poor prognosis group was associated with DCR and ORR (p < 0.05). Conclusions: The metabolic score combining TMTV on the baseline FDG-PET/CT scan and pretreatment dNLR was associated with the survival and response in a cohort of advanced NSCLC patients with ≥50% PD-L1 receiving frontline IT. Cancers, Vol. 12, Pages 2234: Association of the Metabolic Score Using Baseline FDG-PET/CT and dNLR with Immunotherapy Outcomes in Advanced NSCLC Patients Treated with First-Line Pembrolizumab

Cancers doi: 10.3390/cancers12082234

Authors: Romain-David Seban Jean-Baptiste Assié Etienne Giroux-Leprieur Marie-Ange Massiani Michael Soussan Gérald Bonardel Christos Chouaid Margot Playe Lucas Goldfarb Boris Duchemann Laura Mezquita Nicolas Girard Laurence Champion

Background: We aimed to assess the clinical utility of a previously published score combining the total metabolic tumor volume (TMTV) on baseline FDG-PET/CT and pretreatment derived from the neutrophils to lymphocytes ratio (dNLR) for prognostication in NSCLC patients undergoing first-line immunotherapy (IT). Methods: In this multicenter retrospective study, 63 advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) ≥50%, who underwent FDG-PET/CT before first-line IT, treated from January 2017 to September 2019, were enrolled. Associations between this score and the progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and overall response rate (ORR) were evaluated. Results: The median (m) PFS and mOS were 7.7 (95% CI 4.9–10.6) and 12.1 (8.6–15.6) months, respectively, and DCR and ORR were 65% and 58%, respectively. mOS was 17.9 months (14.6 not reached) for the good group versus 13.8 (95%CI 8.4–18.9) and 6.6 (CI 2.0–11.2) months for the intermediate and poor groups, respectively. mPFS was 15.1 (95%CI 12.1–20.0) months for the good group versus 5.2 (1.9–8.5) and 1.9 (95%CI 1.3–2.5) months for the intermediate and poor groups, respectively. The poor prognosis group was associated with DCR and ORR (p < 0.05). Conclusions: The metabolic score combining TMTV on the baseline FDG-PET/CT scan and pretreatment dNLR was associated with the survival and response in a cohort of advanced NSCLC patients with ≥50% PD-L1 receiving frontline IT.

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Association of the Metabolic Score Using Baseline FDG-PET/CT and dNLR with Immunotherapy Outcomes in Advanced NSCLC Patients Treated with First-Line Pembrolizumab Romain-David Seban Jean-Baptiste Assié Etienne Giroux-Leprieur Marie-Ange Massiani Michael Soussan Gérald Bonardel Christos Chouaid Margot Playe Lucas Goldfarb Boris Duchemann Laura Mezquita Nicolas Girard Laurence Champion doi: 10.3390/cancers12082234 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Article 2234 10.3390/cancers12082234 http://www.ynsqex.icu/2072-6694/12/8/2234
Cancers, Vol. 12, Pages 2236: Predicting Peritoneal Dissemination of Gastric Cancer in the Era of Precision Medicine: Molecular Characterization and Biomarkers http://www.ynsqex.icu/2072-6694/12/8/2236 Gastric cancer (GC) is a leading cause of worldwide cancer-related death. Being a highly heterogeneous disease, the current treatment of GC has been suboptimal due to the lack of subtype-dependent therapies. Peritoneal dissemination (PD) is a common pattern of GC metastasis associated with poor prognosis. Therefore, it is urgently necessary to identify patients at high risk of PD. PD is found to be associated with Lauren diffuse type GC. Molecular profiling of GC, especially diffuse type GC, has been utilized to identify molecular alterations and has given rise to various molecular classifications, shedding light on the underlying mechanism of PD and enabling identification of patients at higher PD risk. In addition, a series of diagnositc and prognostic biomarkers of PD from serum, peritoneal lavages and primary GCs have been reported. This comprehensive review summarizes findings on the multi-omic characteristics of diffuse type GC, the clinical significance of updating molecular classifications of GC in association with PD risk and research advances in PD-associated biomarkers. Cancers, Vol. 12, Pages 2236: Predicting Peritoneal Dissemination of Gastric Cancer in the Era of Precision Medicine: Molecular Characterization and Biomarkers

Cancers doi: 10.3390/cancers12082236

Authors: Chen Zhou Wang Zhuo Ding Lu Wu Xu Teng

Gastric cancer (GC) is a leading cause of worldwide cancer-related death. Being a highly heterogeneous disease, the current treatment of GC has been suboptimal due to the lack of subtype-dependent therapies. Peritoneal dissemination (PD) is a common pattern of GC metastasis associated with poor prognosis. Therefore, it is urgently necessary to identify patients at high risk of PD. PD is found to be associated with Lauren diffuse type GC. Molecular profiling of GC, especially diffuse type GC, has been utilized to identify molecular alterations and has given rise to various molecular classifications, shedding light on the underlying mechanism of PD and enabling identification of patients at higher PD risk. In addition, a series of diagnositc and prognostic biomarkers of PD from serum, peritoneal lavages and primary GCs have been reported. This comprehensive review summarizes findings on the multi-omic characteristics of diffuse type GC, the clinical significance of updating molecular classifications of GC in association with PD risk and research advances in PD-associated biomarkers.

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Predicting Peritoneal Dissemination of Gastric Cancer in the Era of Precision Medicine: Molecular Characterization and Biomarkers Chen Zhou Wang Zhuo Ding Lu Wu Xu Teng doi: 10.3390/cancers12082236 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Review 2236 10.3390/cancers12082236 http://www.ynsqex.icu/2072-6694/12/8/2236
Cancers, Vol. 12, Pages 2237: Cancer Management during COVID-19 Pandemic: Is Immune Checkpoint Inhibitors-Based Immunotherapy Harmful or Beneficial? http://www.ynsqex.icu/2072-6694/12/8/2237 The coronavirus disease 2019 (COVID-19) is currently representing a global health threat especially for fragile individuals, such as cancer patients. It was demonstrated that cancer patients have an increased risk of developing a worse symptomatology upon severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2) infection, often leading to hospitalization and intensive care. The consequences of this pandemic for oncology are really heavy, as the entire healthcare system got reorganized. Both oncologists and cancer patients are experiencing rescheduling of treatments and disruptions of appointments with a concurrent surge of fear and stress. In this review all the up-to-date findings, concerning the association between COVID-19 and cancer, are reported. A remaining very debated question regards the use of an innovative class of anti-cancer molecules, the immune checkpoint inhibitors (ICIs), given their modulating effects on the immune system. For that reason, administration of ICIs to cancer patients represents a question mark during this pandemic, as its correlation with COVID-19-associated risks is still under investigation. Based on the mechanisms of action of ICIs and the current evidence, we suggest that ICIs not only can be safely administered to cancer patients, but they might even be beneficial in COVID-19-positive cancer patients, by exerting an immune-stimulating action. Cancers, Vol. 12, Pages 2237: Cancer Management during COVID-19 Pandemic: Is Immune Checkpoint Inhibitors-Based Immunotherapy Harmful or Beneficial?

Cancers doi: 10.3390/cancers12082237

Authors: Silvia Vivarelli Luca Falzone Caterina Maria Grillo Giuseppa Scandurra Francesco Torino Massimo Libra

The coronavirus disease 2019 (COVID-19) is currently representing a global health threat especially for fragile individuals, such as cancer patients. It was demonstrated that cancer patients have an increased risk of developing a worse symptomatology upon severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2) infection, often leading to hospitalization and intensive care. The consequences of this pandemic for oncology are really heavy, as the entire healthcare system got reorganized. Both oncologists and cancer patients are experiencing rescheduling of treatments and disruptions of appointments with a concurrent surge of fear and stress. In this review all the up-to-date findings, concerning the association between COVID-19 and cancer, are reported. A remaining very debated question regards the use of an innovative class of anti-cancer molecules, the immune checkpoint inhibitors (ICIs), given their modulating effects on the immune system. For that reason, administration of ICIs to cancer patients represents a question mark during this pandemic, as its correlation with COVID-19-associated risks is still under investigation. Based on the mechanisms of action of ICIs and the current evidence, we suggest that ICIs not only can be safely administered to cancer patients, but they might even be beneficial in COVID-19-positive cancer patients, by exerting an immune-stimulating action.

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Cancer Management during COVID-19 Pandemic: Is Immune Checkpoint Inhibitors-Based Immunotherapy Harmful or Beneficial? Silvia Vivarelli Luca Falzone Caterina Maria Grillo Giuseppa Scandurra Francesco Torino Massimo Libra doi: 10.3390/cancers12082237 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Review 2237 10.3390/cancers12082237 http://www.ynsqex.icu/2072-6694/12/8/2237
Cancers, Vol. 12, Pages 2238: Selectins: An Important Family of Glycan-Binding Cell Adhesion Molecules in Ovarian Cancer http://www.ynsqex.icu/2072-6694/12/8/2238 Ovarian cancer is the most lethal gynecological malignancy worldwide. Unlike most other tumor types that metastasize via the vasculature, ovarian cancer metastasizes predominantly via the transcoelomic route within the peritoneal cavity. As cancer metastasis accounts for the majority of deaths, there is an urge to better understand its determinants. In the peritoneal cavity, tumor-mesothelial adhesion is an important step for cancer dissemination. Selectins are glycan-binding molecules that facilitate early steps of this adhesion cascade by mediating heterotypic cell-cell interaction under hydrodynamic flow. Here, we review the function and regulation of selectins in peritoneal carcinomatosis of ovarian cancer, and highlight how dysregulation of selectin ligand biogenesis affects disease outcome. Further, we will introduce the latest tools in studying selectin-glycan interaction. Finally, an overview of potential therapeutic intervention points that may lead to the development of efficacious therapies for ovarian cancer is provided. Cancers, Vol. 12, Pages 2238: Selectins: An Important Family of Glycan-Binding Cell Adhesion Molecules in Ovarian Cancer

Cancers doi: 10.3390/cancers12082238

Authors: Ayon A. Hassan Margarita Artemenko Maggie K.S. Tang Alice S.T. Wong

Ovarian cancer is the most lethal gynecological malignancy worldwide. Unlike most other tumor types that metastasize via the vasculature, ovarian cancer metastasizes predominantly via the transcoelomic route within the peritoneal cavity. As cancer metastasis accounts for the majority of deaths, there is an urge to better understand its determinants. In the peritoneal cavity, tumor-mesothelial adhesion is an important step for cancer dissemination. Selectins are glycan-binding molecules that facilitate early steps of this adhesion cascade by mediating heterotypic cell-cell interaction under hydrodynamic flow. Here, we review the function and regulation of selectins in peritoneal carcinomatosis of ovarian cancer, and highlight how dysregulation of selectin ligand biogenesis affects disease outcome. Further, we will introduce the latest tools in studying selectin-glycan interaction. Finally, an overview of potential therapeutic intervention points that may lead to the development of efficacious therapies for ovarian cancer is provided.

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Selectins: An Important Family of Glycan-Binding Cell Adhesion Molecules in Ovarian Cancer Ayon A. Hassan Margarita Artemenko Maggie K.S. Tang Alice S.T. Wong doi: 10.3390/cancers12082238 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Review 2238 10.3390/cancers12082238 http://www.ynsqex.icu/2072-6694/12/8/2238
Cancers, Vol. 12, Pages 2229: Identification of Cancer-Associated Circulating Cells in Anal Cancer Patients http://www.ynsqex.icu/2072-6694/12/8/2229 Whilst anal cancer accounts for less than 1% of all new cancer cases, incidence rates have increased by up to 70% in the last 30 years with the majority of cases driven by human papilloma virus (HPV) infection. Standard treatment for localised anal cancer is chemoradiotherapy (CRT). Localised progression is the predominant pattern of relapse but well under 50% of cases are salvaged by surgery, predominantly because confirming recurrence within post-radiation change is very challenging. Identifying cancer-associated circulating cells (CCs) in peripheral blood could offer a corroborative method of monitoring treatment efficacy and identifying relapse early. To study this, nucleated cells were isolated from the blood of patients with anal cancer prior to, during, and after CRT and processed through the Amnis® ImageStream®X Mk II Imaging Flow Cytometer, without prior enrichment, using Pan-cytokeratin (PCK), CD45 antibodies and making use of the DNA dye DRAQ5. Analysis was undertaken using IDEAS software to identify those cells that were PCK-positive and DRAQ5-positive as well as CD45-negative; these were designated as CCs. CCs were identified in 7 of 8 patients; range 60–876 cells per mL of blood. This first report of the successful identification of CCs in anal cancer patients raises the possibility that liquid biopsies will find a future role as a prognostic/diagnostic tool in this patient group. Cancers, Vol. 12, Pages 2229: Identification of Cancer-Associated Circulating Cells in Anal Cancer Patients

Cancers doi: 10.3390/cancers12082229

Authors: Thomas J. Carter Jeyarooban Jeyaneethi Juhi Kumar Emmanouil Karteris Rob Glynne-Jones Marcia Hall

Whilst anal cancer accounts for less than 1% of all new cancer cases, incidence rates have increased by up to 70% in the last 30 years with the majority of cases driven by human papilloma virus (HPV) infection. Standard treatment for localised anal cancer is chemoradiotherapy (CRT). Localised progression is the predominant pattern of relapse but well under 50% of cases are salvaged by surgery, predominantly because confirming recurrence within post-radiation change is very challenging. Identifying cancer-associated circulating cells (CCs) in peripheral blood could offer a corroborative method of monitoring treatment efficacy and identifying relapse early. To study this, nucleated cells were isolated from the blood of patients with anal cancer prior to, during, and after CRT and processed through the Amnis® ImageStream®X Mk II Imaging Flow Cytometer, without prior enrichment, using Pan-cytokeratin (PCK), CD45 antibodies and making use of the DNA dye DRAQ5. Analysis was undertaken using IDEAS software to identify those cells that were PCK-positive and DRAQ5-positive as well as CD45-negative; these were designated as CCs. CCs were identified in 7 of 8 patients; range 60–876 cells per mL of blood. This first report of the successful identification of CCs in anal cancer patients raises the possibility that liquid biopsies will find a future role as a prognostic/diagnostic tool in this patient group.

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Identification of Cancer-Associated Circulating Cells in Anal Cancer Patients Thomas J. Carter Jeyarooban Jeyaneethi Juhi Kumar Emmanouil Karteris Rob Glynne-Jones Marcia Hall doi: 10.3390/cancers12082229 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Article 2229 10.3390/cancers12082229 http://www.ynsqex.icu/2072-6694/12/8/2229
Cancers, Vol. 12, Pages 2228: Design and Testing of a Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA http://www.ynsqex.icu/2072-6694/12/8/2228 Detection of melanoma-associated mutations using circulating tumor DNA (ctDNA) from plasma is a potential alternative to using genomic DNA from invasive tissue biopsies. In this study, we developed a custom melanoma next-generation sequencing (NGS) panel which includes 123 amplicons in 30 genes covering driver and targetable mutations and alterations associated with treatment resistance. Analysis of a cohort of 74 stage III and IV treatment-naïve melanoma patients revealed that sensitivity of ctDNA detection was influenced by the amount of circulating-free DNA (cfDNA) input and stage of melanoma. At the recommended cfDNA input quantity of 20 ng (available in 28/74 patients), at least one cancer-associated mutation was detected in the ctDNA of 84% of stage IV patients and 47% of stage III patients with a limit of detection for mutant allele frequency (MAF) of 0.2%. This custom melanoma panel showed significant correlation with droplet digital PCR (ddPCR) and provided a more comprehensive melanoma mutation profile. Our custom panel could be further optimized by replacing amplicons spanning the TERT promoter, which did not perform well due to the high GC content. To increase the detection rate to 90% of stage IV melanoma and decrease the sensitivity to 0.1% MAF, we recommend increasing the volume of plasma to 8 mL to achieve minimal recommended cfDNA input and the refinement of poorly performing amplicons. Our panel can also be expanded to include new targetable and treatment resistance mutations to improve the tracking of treatment response and resistance in melanoma patients treated with systemic drug therapies. Cancers, Vol. 12, Pages 2228: Design and Testing of a Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

Cancers doi: 10.3390/cancers12082228

Authors: Russell J. Diefenbach Jenny H. Lee Alexander M. Menzies Matteo S. Carlino Georgina V. Long Robyn P. M. Saw Julie R. Howle Andrew J. Spillane Richard A. Scolyer Richard F. Kefford Helen Rizos

Detection of melanoma-associated mutations using circulating tumor DNA (ctDNA) from plasma is a potential alternative to using genomic DNA from invasive tissue biopsies. In this study, we developed a custom melanoma next-generation sequencing (NGS) panel which includes 123 amplicons in 30 genes covering driver and targetable mutations and alterations associated with treatment resistance. Analysis of a cohort of 74 stage III and IV treatment-naïve melanoma patients revealed that sensitivity of ctDNA detection was influenced by the amount of circulating-free DNA (cfDNA) input and stage of melanoma. At the recommended cfDNA input quantity of 20 ng (available in 28/74 patients), at least one cancer-associated mutation was detected in the ctDNA of 84% of stage IV patients and 47% of stage III patients with a limit of detection for mutant allele frequency (MAF) of 0.2%. This custom melanoma panel showed significant correlation with droplet digital PCR (ddPCR) and provided a more comprehensive melanoma mutation profile. Our custom panel could be further optimized by replacing amplicons spanning the TERT promoter, which did not perform well due to the high GC content. To increase the detection rate to 90% of stage IV melanoma and decrease the sensitivity to 0.1% MAF, we recommend increasing the volume of plasma to 8 mL to achieve minimal recommended cfDNA input and the refinement of poorly performing amplicons. Our panel can also be expanded to include new targetable and treatment resistance mutations to improve the tracking of treatment response and resistance in melanoma patients treated with systemic drug therapies.

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Design and Testing of a Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA Russell J. Diefenbach Jenny H. Lee Alexander M. Menzies Matteo S. Carlino Georgina V. Long Robyn P. M. Saw Julie R. Howle Andrew J. Spillane Richard A. Scolyer Richard F. Kefford Helen Rizos doi: 10.3390/cancers12082228 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Article 2228 10.3390/cancers12082228 http://www.ynsqex.icu/2072-6694/12/8/2228
Cancers, Vol. 12, Pages 2227: Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer http://www.ynsqex.icu/2072-6694/12/8/2227 Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response. Cancers, Vol. 12, Pages 2227: Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer

Cancers doi: 10.3390/cancers12082227

Authors: Juan M. Sendoya Soledad Iseas Mariana Coraglio Mariano Golubicki Juan Robbio Ruben Salanova Mirta Kujaruk Vanesa Mikolaitis Mariana Rizzolo Gonzalo Ruiz Ana Cabanne Ubaldo Gualdrini Guillermo Mendez Stella Hirmas Cecilia Rotondaro Julieta Viglino Martín Eleta Elmer Fernandez Martín Abba Osvaldo Podhajcer Enrique Roca Andrea S Llera

Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.

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Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer Juan M. Sendoya Soledad Iseas Mariana Coraglio Mariano Golubicki Juan Robbio Ruben Salanova Mirta Kujaruk Vanesa Mikolaitis Mariana Rizzolo Gonzalo Ruiz Ana Cabanne Ubaldo Gualdrini Guillermo Mendez Stella Hirmas Cecilia Rotondaro Julieta Viglino Martín Eleta Elmer Fernandez Martín Abba Osvaldo Podhajcer Enrique Roca Andrea S Llera doi: 10.3390/cancers12082227 Cancers 2020-08-10 Cancers 2020-08-10 12 8 Article 2227 10.3390/cancers12082227 http://www.ynsqex.icu/2072-6694/12/8/2227
Cancers, Vol. 12, Pages 2225: Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome http://www.ynsqex.icu/2072-6694/12/8/2225 Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56–2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67–4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44–2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26–5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk. Cancers, Vol. 12, Pages 2225: Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome

Cancers doi: 10.3390/cancers12082225

Authors: María Dolores Picó Ana Beatriz Sánchez-Heras Adela Castillejo Mar Giner-Calabuig Miren Alustiza Ariadna Sánchez Leticia Moreira María Pellise Antoni Castells Gemma Llort Carmen Yagüe Teresa Ramon y Cajal Alexandra Gisbert-Beamud Joaquin Cubiella Laura Rivas Maite Herraiz Catalina Garau Inmaculada Salces Marta Carrillo-Palau Luis Bujanda Adriá López-Fernández Cristina Alvarez-Urturi María Jesús López Cristina Alenda Pedro Zapater Francisco Javier Lacueva Francesc Balaguer Jose-Luis Soto óscar Murcia Rodrigo Jover

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56–2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67–4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44–2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26–5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.

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Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome María Dolores Picó Ana Beatriz Sánchez-Heras Adela Castillejo Mar Giner-Calabuig Miren Alustiza Ariadna Sánchez Leticia Moreira María Pellise Antoni Castells Gemma Llort Carmen Yagüe Teresa Ramon y Cajal Alexandra Gisbert-Beamud Joaquin Cubiella Laura Rivas Maite Herraiz Catalina Garau Inmaculada Salces Marta Carrillo-Palau Luis Bujanda Adriá López-Fernández Cristina Alvarez-Urturi María Jesús López Cristina Alenda Pedro Zapater Francisco Javier Lacueva Francesc Balaguer Jose-Luis Soto óscar Murcia Rodrigo Jover doi: 10.3390/cancers12082225 Cancers 2020-08-09 Cancers 2020-08-09 12 8 Article 2225 10.3390/cancers12082225 http://www.ynsqex.icu/2072-6694/12/8/2225
Cancers, Vol. 12, Pages 2226: Understanding the Role of Innate Immune Cells and Identifying Genes in Breast Cancer Microenvironment http://www.ynsqex.icu/2072-6694/12/8/2226 The innate immune system is the first line of defense against invading pathogens and has a major role in clearing transformed cells, besides its essential role in activating the adaptive immune system. Macrophages, dendritic cells, NK cells, and granulocytes are part of the innate immune system that accumulate in the tumor microenvironment such as breast cancer. These cells induce inflammation in situ by secreting cytokines and chemokines that promote tumor growth and progression, in addition to orchestrating the activities of other immune cells. In breast cancer microenvironment, innate immune cells are skewed towards immunosuppression that may lead to tumor evasion. However, the mechanisms by which immune cells could interact with breast cancer cells are complex and not fully understood. Therefore, the importance of the mammary tumor microenvironment in the development, growth, and progression of cancer is widely recognized. With the advances of using bioinformatics and analyzing data from gene banks, several genes involved in NK cells of breast cancer individuals have been identified. In this review, we discuss the activities of certain genes involved in the cross-talk among NK cells and breast cancer. Consequently, altering tumor immune microenvironment can make breast tumors more responsive to immunotherapy. Cancers, Vol. 12, Pages 2226: Understanding the Role of Innate Immune Cells and Identifying Genes in Breast Cancer Microenvironment

Cancers doi: 10.3390/cancers12082226

Authors: Israa Shihab Bariaa A. Khalil Noha Mousaad Elemam Ibrahim Y. Hachim Mahmood Yaseen Hachim Rifat A. Hamoudi Azzam A. Maghazachi

The innate immune system is the first line of defense against invading pathogens and has a major role in clearing transformed cells, besides its essential role in activating the adaptive immune system. Macrophages, dendritic cells, NK cells, and granulocytes are part of the innate immune system that accumulate in the tumor microenvironment such as breast cancer. These cells induce inflammation in situ by secreting cytokines and chemokines that promote tumor growth and progression, in addition to orchestrating the activities of other immune cells. In breast cancer microenvironment, innate immune cells are skewed towards immunosuppression that may lead to tumor evasion. However, the mechanisms by which immune cells could interact with breast cancer cells are complex and not fully understood. Therefore, the importance of the mammary tumor microenvironment in the development, growth, and progression of cancer is widely recognized. With the advances of using bioinformatics and analyzing data from gene banks, several genes involved in NK cells of breast cancer individuals have been identified. In this review, we discuss the activities of certain genes involved in the cross-talk among NK cells and breast cancer. Consequently, altering tumor immune microenvironment can make breast tumors more responsive to immunotherapy.

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Understanding the Role of Innate Immune Cells and Identifying Genes in Breast Cancer Microenvironment Israa Shihab Bariaa A. Khalil Noha Mousaad Elemam Ibrahim Y. Hachim Mahmood Yaseen Hachim Rifat A. Hamoudi Azzam A. Maghazachi doi: 10.3390/cancers12082226 Cancers 2020-08-09 Cancers 2020-08-09 12 8 Review 2226 10.3390/cancers12082226 http://www.ynsqex.icu/2072-6694/12/8/2226
Cancers, Vol. 12, Pages 2224: TERT Promoter Mutation as an Independent Prognostic Marker for Poor Prognosis MAPK Inhibitors-Treated Melanoma http://www.ynsqex.icu/2072-6694/12/8/2224 Although the development of mitogen-activated protein kinase (MAPK) inhibitors has greatly improved the prognosis of BRAFV600 cutaneous melanomas, the identification of molecular indicators for mutated patients at risk of early progression remains a major issue. Using an amplicon-based next-generation-sequencing (NGS) assay that targets cancer-related genes, we investigated co-occurring alterations in 89 melanoma samples. We analyzed both their association with clinicopathological variables and clinical significance in terms of progression-free survival (PFS) and overall survival (OS) according to BRAF genotyping. Among co-occurring mutations, TERT promoter was the most frequently mutated gene. Although no significant difference in PFS was observed in the presence or absence of co-occurring alterations to BRAFV600, there was a trend of longer PFS for patients harboring TERT c.-124C>T mutation. Of most interest, this mutation is an independent marker of good prognosis in subgroups of patients with poor prognosis (presence of brain metastasis and elevated level of lactate dehydrogenase, LDH). Moreover, combination of elevated LDH level, presence of brain metastasis, and TERT c.-124C>T mutation was identified as the best fit model for predicting clinical outcome. Our work revealed the potential interest of c.-124C>T status determination in order to refine the prognosis of BRAFV600 melanoma under mitogen-activated protein kinase (MAPK) inhibitors. Cancers, Vol. 12, Pages 2224: TERT Promoter Mutation as an Independent Prognostic Marker for Poor Prognosis MAPK Inhibitors-Treated Melanoma

Cancers doi: 10.3390/cancers12082224

Authors: Pauline Blateau Etienne Coyaud Estelle Laurent Benoit Béganton Vincent Ducros Géraldine Chauchard Julie A. Vendrell Jér?me Solassol

Although the development of mitogen-activated protein kinase (MAPK) inhibitors has greatly improved the prognosis of BRAFV600 cutaneous melanomas, the identification of molecular indicators for mutated patients at risk of early progression remains a major issue. Using an amplicon-based next-generation-sequencing (NGS) assay that targets cancer-related genes, we investigated co-occurring alterations in 89 melanoma samples. We analyzed both their association with clinicopathological variables and clinical significance in terms of progression-free survival (PFS) and overall survival (OS) according to BRAF genotyping. Among co-occurring mutations, TERT promoter was the most frequently mutated gene. Although no significant difference in PFS was observed in the presence or absence of co-occurring alterations to BRAFV600, there was a trend of longer PFS for patients harboring TERT c.-124C>T mutation. Of most interest, this mutation is an independent marker of good prognosis in subgroups of patients with poor prognosis (presence of brain metastasis and elevated level of lactate dehydrogenase, LDH). Moreover, combination of elevated LDH level, presence of brain metastasis, and TERT c.-124C>T mutation was identified as the best fit model for predicting clinical outcome. Our work revealed the potential interest of c.-124C>T status determination in order to refine the prognosis of BRAFV600 melanoma under mitogen-activated protein kinase (MAPK) inhibitors.

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TERT Promoter Mutation as an Independent Prognostic Marker for Poor Prognosis MAPK Inhibitors-Treated Melanoma Pauline Blateau Etienne Coyaud Estelle Laurent Benoit Béganton Vincent Ducros Géraldine Chauchard Julie A. Vendrell Jér?me Solassol doi: 10.3390/cancers12082224 Cancers 2020-08-09 Cancers 2020-08-09 12 8 Article 2224 10.3390/cancers12082224 http://www.ynsqex.icu/2072-6694/12/8/2224
Cancers, Vol. 12, Pages 2223: Antibody-Drug Conjugates: A Promising Novel Therapy for the Treatment of Ovarian Cancer http://www.ynsqex.icu/2072-6694/12/8/2223 Antibody-drug conjugates (ADCs) represent a novel and promising therapeutic strategy for the treatment of cancer patients. ADCs target antigens highly expressed on the membrane surface of tumor cells to selectively deliver a cytotoxic drug. Ovarian tumors differentially express tumor-specific antigens, which can be used to guide ADCs. This strategy allows for optimizing tumor targeting while minimizing systemic toxicity compared to classical chemotherapeutic agents. ADCs can be improved by using a cleavable linker allowing the delivery of the toxic payload in surrounding cells not expressing the target protein, therefore acting on heterogeneous tumors with different cell populations. Currently, more than 15 ADCs are under preclinical investigation in ovarian cancer, and some of them have already been tested in early-phase clinical trials with promising results. In this review, we summarize the mechanism of action and the toxicity profile of ADCs and discuss the latest preclinical discoveries and forthcoming applications in ovarian cancer. Cancers, Vol. 12, Pages 2223: Antibody-Drug Conjugates: A Promising Novel Therapy for the Treatment of Ovarian Cancer

Cancers doi: 10.3390/cancers12082223

Authors: Aranzazu Manzano Alberto Oca?a

Antibody-drug conjugates (ADCs) represent a novel and promising therapeutic strategy for the treatment of cancer patients. ADCs target antigens highly expressed on the membrane surface of tumor cells to selectively deliver a cytotoxic drug. Ovarian tumors differentially express tumor-specific antigens, which can be used to guide ADCs. This strategy allows for optimizing tumor targeting while minimizing systemic toxicity compared to classical chemotherapeutic agents. ADCs can be improved by using a cleavable linker allowing the delivery of the toxic payload in surrounding cells not expressing the target protein, therefore acting on heterogeneous tumors with different cell populations. Currently, more than 15 ADCs are under preclinical investigation in ovarian cancer, and some of them have already been tested in early-phase clinical trials with promising results. In this review, we summarize the mechanism of action and the toxicity profile of ADCs and discuss the latest preclinical discoveries and forthcoming applications in ovarian cancer.

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Antibody-Drug Conjugates: A Promising Novel Therapy for the Treatment of Ovarian Cancer Aranzazu Manzano Alberto Oca?a doi: 10.3390/cancers12082223 Cancers 2020-08-09 Cancers 2020-08-09 12 8 Review 2223 10.3390/cancers12082223 http://www.ynsqex.icu/2072-6694/12/8/2223
Cancers, Vol. 12, Pages 2222: Modeling the Diversity of Epithelial Ovarian Cancer through Ten Novel Well Characterized Cell Lines Covering Multiple Subtypes of the Disease http://www.ynsqex.icu/2072-6694/12/8/2222 Cancer cell lines are amongst the most important pre-clinical models. In the context of epithelial ovarian cancer, a highly heterogeneous disease with diverse subtypes, it is paramount to study a wide panel of models in order to draw a representative picture of the disease. As this lethal gynaecological malignancy has seen little improvement in overall survival in the last decade, it is all the more pressing to support future research with robust and diverse study models. Here, we describe ten novel spontaneously immortalized patient-derived ovarian cancer cell lines, detailing their respective mutational profiles and gene/biomarker expression patterns, as well as their in vitro and in vivo growth characteristics. Eight of the cell lines were classified as high-grade serous, while two were determined to be of the rarer mucinous and clear cell subtypes, respectively. Each of the ten cell lines presents a panel of characteristics reflective of diverse clinically relevant phenomena, including chemotherapeutic resistance, metastatic potential, and subtype-associated mutations and gene/protein expression profiles. Importantly, four cell lines formed subcutaneous tumors in mice, a key characteristic for pre-clinical drug testing. Our work thus contributes significantly to the available models for the study of ovarian cancer, supplying additional tools to better understand this complex disease. Cancers, Vol. 12, Pages 2222: Modeling the Diversity of Epithelial Ovarian Cancer through Ten Novel Well Characterized Cell Lines Covering Multiple Subtypes of the Disease

Cancers doi: 10.3390/cancers12082222

Authors: Alexandre Sauriol Kayla Simeone Lise Portelance Liliane Meunier Kim Leclerc-Desaulniers Manon de Ladurantaye Meriem Chergui Jennifer Kendall-Dupont Kurosh Rahimi Euridice Carmona Diane M. Provencher Anne-Marie Mes-Masson

Cancer cell lines are amongst the most important pre-clinical models. In the context of epithelial ovarian cancer, a highly heterogeneous disease with diverse subtypes, it is paramount to study a wide panel of models in order to draw a representative picture of the disease. As this lethal gynaecological malignancy has seen little improvement in overall survival in the last decade, it is all the more pressing to support future research with robust and diverse study models. Here, we describe ten novel spontaneously immortalized patient-derived ovarian cancer cell lines, detailing their respective mutational profiles and gene/biomarker expression patterns, as well as their in vitro and in vivo growth characteristics. Eight of the cell lines were classified as high-grade serous, while two were determined to be of the rarer mucinous and clear cell subtypes, respectively. Each of the ten cell lines presents a panel of characteristics reflective of diverse clinically relevant phenomena, including chemotherapeutic resistance, metastatic potential, and subtype-associated mutations and gene/protein expression profiles. Importantly, four cell lines formed subcutaneous tumors in mice, a key characteristic for pre-clinical drug testing. Our work thus contributes significantly to the available models for the study of ovarian cancer, supplying additional tools to better understand this complex disease.

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Modeling the Diversity of Epithelial Ovarian Cancer through Ten Novel Well Characterized Cell Lines Covering Multiple Subtypes of the Disease Alexandre Sauriol Kayla Simeone Lise Portelance Liliane Meunier Kim Leclerc-Desaulniers Manon de Ladurantaye Meriem Chergui Jennifer Kendall-Dupont Kurosh Rahimi Euridice Carmona Diane M. Provencher Anne-Marie Mes-Masson doi: 10.3390/cancers12082222 Cancers 2020-08-08 Cancers 2020-08-08 12 8 Article 2222 10.3390/cancers12082222 http://www.ynsqex.icu/2072-6694/12/8/2222
Cancers, Vol. 12, Pages 2219: Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells http://www.ynsqex.icu/2072-6694/12/8/2219 (1) Background: The hedgehog (HH) signaling pathway is a key regulator of embryonic patterning, tissue regeneration, stem cell renewal, and cancer growth. The smoothened (SMO) protein regulates the HH signaling pathway and has demonstrated oncogenic activity. (2) Methods: To clarify the role of the HH signaling pathway in tumorigenesis, the expression profile of key HH signaling molecules, including SMO, PTCH1, GLI1, GLI2, and GLI3, were determined in 33 cancer cell lines and normal prostate cells and tissues. We performed a computational analysis of the upstream region of the SMO gene to identify the regulatory elements. (3) Results: Three potential CpG islands and several putative SMO promoter elements were identified. Luciferase reporter assays mapped key SMO promoter elements, and functional binding sites for SP1, AP1, CREB, and AP-2α transcription factors in the core SMO promoter region were confirmed. A hypermethylated SMO promoter was identified in several cancer cell lines suggesting an important role for epigenetic silencing of SMO expression in certain cancer cells. (4) Discussion: These results have important implications for our understanding of regulatory mechanisms controlling HH pathway activity and the molecular basis of SMO gene function. Moreover, this study may prove valuable for future research aimed at producing therapeutic downregulation of SMO expression in cancer cells. Cancers, Vol. 12, Pages 2219: Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells

Cancers doi: 10.3390/cancers12082219

Authors: Hong Lou Hongchuan Li Andrew R. Huehn Nadya I. Tarasova Bahara Saleh Stephen K. Anderson Michael Dean

(1) Background: The hedgehog (HH) signaling pathway is a key regulator of embryonic patterning, tissue regeneration, stem cell renewal, and cancer growth. The smoothened (SMO) protein regulates the HH signaling pathway and has demonstrated oncogenic activity. (2) Methods: To clarify the role of the HH signaling pathway in tumorigenesis, the expression profile of key HH signaling molecules, including SMO, PTCH1, GLI1, GLI2, and GLI3, were determined in 33 cancer cell lines and normal prostate cells and tissues. We performed a computational analysis of the upstream region of the SMO gene to identify the regulatory elements. (3) Results: Three potential CpG islands and several putative SMO promoter elements were identified. Luciferase reporter assays mapped key SMO promoter elements, and functional binding sites for SP1, AP1, CREB, and AP-2α transcription factors in the core SMO promoter region were confirmed. A hypermethylated SMO promoter was identified in several cancer cell lines suggesting an important role for epigenetic silencing of SMO expression in certain cancer cells. (4) Discussion: These results have important implications for our understanding of regulatory mechanisms controlling HH pathway activity and the molecular basis of SMO gene function. Moreover, this study may prove valuable for future research aimed at producing therapeutic downregulation of SMO expression in cancer cells.

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Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells Hong Lou Hongchuan Li Andrew R. Huehn Nadya I. Tarasova Bahara Saleh Stephen K. Anderson Michael Dean doi: 10.3390/cancers12082219 Cancers 2020-08-08 Cancers 2020-08-08 12 8 Article 2219 10.3390/cancers12082219 http://www.ynsqex.icu/2072-6694/12/8/2219
Cancers, Vol. 12, Pages 2221: Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction http://www.ynsqex.icu/2072-6694/12/8/2221 RNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include Numb, APC, and P21WAF-1, key regulators of Notch/Wnt signaling and cell cycle progression, respectively. In this study, we aim to identify small molecule inhibitors of MSI1–mRNA interactions, which could block the growth of cancer cells with high levels of MSI1. Using a fluorescence polarization (FP) assay, we screened small molecules from several chemical libraries for those that disrupt the binding of MSI1 to its consensus RNA. One cluster of hit compounds is the derivatives of secondary metabolites from Aspergillus nidulans. One of the top hits, Aza-9, from this cluster was further validated by surface plasmon resonance and nuclear magnetic resonance spectroscopy, which demonstrated that Aza-9 binds directly to MSI1, and the binding is at the RNA binding pocket. We also show that Aza-9 binds to Musashi-2 (MSI2) as well. To test whether Aza-9 has anti-cancer potential, we used liposomes to facilitate Aza-9 cellular uptake. Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines. In conclusion, we identified a series of potential lead compounds for inhibiting MSI1/2 function, while establishing a framework for identifying small molecule inhibitors of RNA binding proteins using FP-based screening methodology. Cancers, Vol. 12, Pages 2221: Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction

Cancers doi: 10.3390/cancers12082221

Authors: Lan Lan Jiajun Liu Minli Xing Amber R. Smith Jinan Wang Xiaoqing Wu Carl Appelman Ke Li Anuradha Roy Ragul Gowthaman John Karanicolas Amber D. Somoza Clay C. C. Wang Yinglong Miao Roberto De Guzman Berl R. Oakley Kristi L. Neufeld Liang Xu

RNA-binding protein Musashi-1 (MSI1) is a key regulator of several stem cell populations. MSI1 is involved in tumor proliferation and maintenance, and it regulates target mRNAs at the translational level. The known mRNA targets of MSI1 include Numb, APC, and P21WAF-1, key regulators of Notch/Wnt signaling and cell cycle progression, respectively. In this study, we aim to identify small molecule inhibitors of MSI1–mRNA interactions, which could block the growth of cancer cells with high levels of MSI1. Using a fluorescence polarization (FP) assay, we screened small molecules from several chemical libraries for those that disrupt the binding of MSI1 to its consensus RNA. One cluster of hit compounds is the derivatives of secondary metabolites from Aspergillus nidulans. One of the top hits, Aza-9, from this cluster was further validated by surface plasmon resonance and nuclear magnetic resonance spectroscopy, which demonstrated that Aza-9 binds directly to MSI1, and the binding is at the RNA binding pocket. We also show that Aza-9 binds to Musashi-2 (MSI2) as well. To test whether Aza-9 has anti-cancer potential, we used liposomes to facilitate Aza-9 cellular uptake. Aza-9-liposome inhibits proliferation, induces apoptosis and autophagy, and down-regulates Notch and Wnt signaling in colon cancer cell lines. In conclusion, we identified a series of potential lead compounds for inhibiting MSI1/2 function, while establishing a framework for identifying small molecule inhibitors of RNA binding proteins using FP-based screening methodology.

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Identification and Validation of an Aspergillus nidulans Secondary Metabolite Derivative as an Inhibitor of the Musashi-RNA Interaction Lan Lan Jiajun Liu Minli Xing Amber R. Smith Jinan Wang Xiaoqing Wu Carl Appelman Ke Li Anuradha Roy Ragul Gowthaman John Karanicolas Amber D. Somoza Clay C. C. Wang Yinglong Miao Roberto De Guzman Berl R. Oakley Kristi L. Neufeld Liang Xu doi: 10.3390/cancers12082221 Cancers 2020-08-08 Cancers 2020-08-08 12 8 Article 2221 10.3390/cancers12082221 http://www.ynsqex.icu/2072-6694/12/8/2221
Cancers, Vol. 12, Pages 2220: Does the Use of Proton Pump Inhibitors Increase the Risk of Pancreatic Cancer? A Systematic Review and Meta-Analysis of Epidemiologic Studies http://www.ynsqex.icu/2072-6694/12/8/2220 Background: One of the most frequently used medications for treating gastrointestinal disorders is proton pump inhibitor (PPI), which reportedly has potential adverse effects. Although the relationship between the use of PPIs and the risk of pancreatic cancer has been extensively investigated, the results remain inconsistent. Hence, this meta-analysis aimed to evaluate such relationship. Methods: We searched for literature and subsequently included 10 studies (seven case–control and three cohort studies; 948,782 individuals). The pooled odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer were estimated using a random-effects model. We also conducted sensitivity analysis and subgroup analysis. Results: The pooled OR of the meta-analysis was 1.698 (95% CI: 1.200–2.402, p = 0.003), with a substantial heterogeneity (I2 = 98.75%, p < 0.001). Even when studies were excluded one by one, the pooled OR remained statistically significant. According to the stratified subgroup analyses, PPI use, and pancreatic cancer incidence were positively associated, regardless of the study design, quality of study, country, and PPI type. Conclusion: PPI use may be associated with the increased risk of pancreatic cancer. Hence, caution is needed when using PPIs among patients with a high risk of pancreatic cancer. Cancers, Vol. 12, Pages 2220: Does the Use of Proton Pump Inhibitors Increase the Risk of Pancreatic Cancer? A Systematic Review and Meta-Analysis of Epidemiologic Studies

Cancers doi: 10.3390/cancers12082220

Authors: Hee-Eun Hong A-Sol Kim Mi-Rae Kim Hae-Jin Ko Min Kyu Jung

Background: One of the most frequently used medications for treating gastrointestinal disorders is proton pump inhibitor (PPI), which reportedly has potential adverse effects. Although the relationship between the use of PPIs and the risk of pancreatic cancer has been extensively investigated, the results remain inconsistent. Hence, this meta-analysis aimed to evaluate such relationship. Methods: We searched for literature and subsequently included 10 studies (seven case–control and three cohort studies; 948,782 individuals). The pooled odds ratio (OR) and 95% confidence intervals (CI) for pancreatic cancer were estimated using a random-effects model. We also conducted sensitivity analysis and subgroup analysis. Results: The pooled OR of the meta-analysis was 1.698 (95% CI: 1.200–2.402, p = 0.003), with a substantial heterogeneity (I2 = 98.75%, p < 0.001). Even when studies were excluded one by one, the pooled OR remained statistically significant. According to the stratified subgroup analyses, PPI use, and pancreatic cancer incidence were positively associated, regardless of the study design, quality of study, country, and PPI type. Conclusion: PPI use may be associated with the increased risk of pancreatic cancer. Hence, caution is needed when using PPIs among patients with a high risk of pancreatic cancer.

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Does the Use of Proton Pump Inhibitors Increase the Risk of Pancreatic Cancer? A Systematic Review and Meta-Analysis of Epidemiologic Studies Hee-Eun Hong A-Sol Kim Mi-Rae Kim Hae-Jin Ko Min Kyu Jung doi: 10.3390/cancers12082220 Cancers 2020-08-08 Cancers 2020-08-08 12 8 Article 2220 10.3390/cancers12082220 http://www.ynsqex.icu/2072-6694/12/8/2220
Cancers, Vol. 12, Pages 2218: Autocrine Signaling of NRP1 Ligand Galectin-1 Elicits Resistance to BRAF-Targeted Therapy in Melanoma Cells http://www.ynsqex.icu/2072-6694/12/8/2218 Melanoma cells addicted to mutated BRAF oncogene activity can be targeted by specific kinase inhibitors until they develop resistance to therapy. We observed that the expression of Galectin-1 (Gal-1), a soluble ligand of Neuropilin-1 (NRP1), is upregulated in melanoma tumor samples and melanoma cells resistant to BRAF-targeted therapy. We then demonstrated that Gal-1 is a novel driver of resistance to BRAF inhibitors in melanoma and that its activity is linked to the concomitant upregulation of the NRP1 receptor observed in drug-resistant cells. Mechanistically, Gal-1 sustains increased expression of NRP1 and EGFR in drug-resistant melanoma cells. Moreover, consistent with its role as a NRP1 ligand, Gal-1 negatively controls p27 levels, a mechanism previously found to enable EGFR upregulation in cancer cells. Finally, the combined treatment with a Gal-1 inhibitor and a NRP1 blocking drug enabled resistant melanoma cell resensitization to BRAF-targeted therapy. In summary, we found that the activation of Galectin-1/NRP1 autocrine signaling is a new mechanism conferring independence from BRAF kinase activity to oncogene-addicted melanoma cells. Cancers, Vol. 12, Pages 2218: Autocrine Signaling of NRP1 Ligand Galectin-1 Elicits Resistance to BRAF-Targeted Therapy in Melanoma Cells

Cancers doi: 10.3390/cancers12082218

Authors: Sabrina Rizzolio Simona Corso Silvia Giordano Luca Tamagnone

Melanoma cells addicted to mutated BRAF oncogene activity can be targeted by specific kinase inhibitors until they develop resistance to therapy. We observed that the expression of Galectin-1 (Gal-1), a soluble ligand of Neuropilin-1 (NRP1), is upregulated in melanoma tumor samples and melanoma cells resistant to BRAF-targeted therapy. We then demonstrated that Gal-1 is a novel driver of resistance to BRAF inhibitors in melanoma and that its activity is linked to the concomitant upregulation of the NRP1 receptor observed in drug-resistant cells. Mechanistically, Gal-1 sustains increased expression of NRP1 and EGFR in drug-resistant melanoma cells. Moreover, consistent with its role as a NRP1 ligand, Gal-1 negatively controls p27 levels, a mechanism previously found to enable EGFR upregulation in cancer cells. Finally, the combined treatment with a Gal-1 inhibitor and a NRP1 blocking drug enabled resistant melanoma cell resensitization to BRAF-targeted therapy. In summary, we found that the activation of Galectin-1/NRP1 autocrine signaling is a new mechanism conferring independence from BRAF kinase activity to oncogene-addicted melanoma cells.

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Autocrine Signaling of NRP1 Ligand Galectin-1 Elicits Resistance to BRAF-Targeted Therapy in Melanoma Cells Sabrina Rizzolio Simona Corso Silvia Giordano Luca Tamagnone doi: 10.3390/cancers12082218 Cancers 2020-08-08 Cancers 2020-08-08 12 8 Article 2218 10.3390/cancers12082218 http://www.ynsqex.icu/2072-6694/12/8/2218
Cancers, Vol. 12, Pages 2217: Donor-Site Morbidity after Fibula Transplantation in Head and Neck Tumor Patients: A Split-Leg Retrospective Study with Focus on Leg Stability and Quality of Life http://www.ynsqex.icu/2072-6694/12/8/2217 The free fibula flap has been one of the most important microvascular grafts for orofacial reconstruction for more than 30 years. The complication rates at the donor-site reported in literature are considered to be low, but the published data vary greatly in some cases. In particular, restrictions in the stability and balance of the involved leg and their effects on the quality of life have been described very inconsistently to date. Therefore, this study mainly focuses on the stability and balance of the affected leg in a split-leg design. Between December 2014 and January 2018, out of 119 subjects who underwent mainly jaw ablative tumor surgery and reconstruction using a fibula flap, 68 subjects were examined for donor site morbidity. Besides reporting general types of complications, two specific test procedures were used. The Star Excursion Balance Test (SEBT) as a practical test for ankle function and the Foot and Ankle Disability Index (FADI) as a questionnaire in order to assess quality of life, depending on the lower leg function. SEBT revealed an average of 55.3 cm with the operated leg as the supporting leg, which corresponds to 95.5% of 57.9 cm achieved with the healthy leg as the supporting leg. An average FADI score of 89.4% was recorded. SEBT and FADI seem to be suitable methods of examination for subjects post fibular transplantation and pointed out minimal limitations of the involved legs in comparison to the unaffected legs. These limitations were clinically not relevant and they had minor influence on the subjects’ quality of life and their daily activities. Cancers, Vol. 12, Pages 2217: Donor-Site Morbidity after Fibula Transplantation in Head and Neck Tumor Patients: A Split-Leg Retrospective Study with Focus on Leg Stability and Quality of Life

Cancers doi: 10.3390/cancers12082217

Authors: Sameh Attia Jonas Diefenbach Daniel Schmermund Sebastian B?ttger J?rn Pons-Kühnemann Christine Scheibelhut Christian Heiss Hans-Peter Howaldt

The free fibula flap has been one of the most important microvascular grafts for orofacial reconstruction for more than 30 years. The complication rates at the donor-site reported in literature are considered to be low, but the published data vary greatly in some cases. In particular, restrictions in the stability and balance of the involved leg and their effects on the quality of life have been described very inconsistently to date. Therefore, this study mainly focuses on the stability and balance of the affected leg in a split-leg design. Between December 2014 and January 2018, out of 119 subjects who underwent mainly jaw ablative tumor surgery and reconstruction using a fibula flap, 68 subjects were examined for donor site morbidity. Besides reporting general types of complications, two specific test procedures were used. The Star Excursion Balance Test (SEBT) as a practical test for ankle function and the Foot and Ankle Disability Index (FADI) as a questionnaire in order to assess quality of life, depending on the lower leg function. SEBT revealed an average of 55.3 cm with the operated leg as the supporting leg, which corresponds to 95.5% of 57.9 cm achieved with the healthy leg as the supporting leg. An average FADI score of 89.4% was recorded. SEBT and FADI seem to be suitable methods of examination for subjects post fibular transplantation and pointed out minimal limitations of the involved legs in comparison to the unaffected legs. These limitations were clinically not relevant and they had minor influence on the subjects’ quality of life and their daily activities.

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Donor-Site Morbidity after Fibula Transplantation in Head and Neck Tumor Patients: A Split-Leg Retrospective Study with Focus on Leg Stability and Quality of Life Sameh Attia Jonas Diefenbach Daniel Schmermund Sebastian B?ttger J?rn Pons-Kühnemann Christine Scheibelhut Christian Heiss Hans-Peter Howaldt doi: 10.3390/cancers12082217 Cancers 2020-08-08 Cancers 2020-08-08 12 8 Article 2217 10.3390/cancers12082217 http://www.ynsqex.icu/2072-6694/12/8/2217
Cancers, Vol. 12, Pages 2216: Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues http://www.ynsqex.icu/2072-6694/12/8/2216 Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding “splicing and myeloproliferative neoplasms”. We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies. Cancers, Vol. 12, Pages 2216: Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Cancers doi: 10.3390/cancers12082216

Authors: Marie Hautin Clélia Mornet Aurélie Chauveau Delphine Bernard Laurent Corcos Eric Lippert

Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding “splicing and myeloproliferative neoplasms”. We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies.

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Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues Marie Hautin Clélia Mornet Aurélie Chauveau Delphine Bernard Laurent Corcos Eric Lippert doi: 10.3390/cancers12082216 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Review 2216 10.3390/cancers12082216 http://www.ynsqex.icu/2072-6694/12/8/2216
Cancers, Vol. 12, Pages 2215: Role of Chemokines in the Biology of Cholangiocarcinoma http://www.ynsqex.icu/2072-6694/12/8/2215 Cholangiocarcinoma (CCA), a heterogeneous tumor with poor prognosis, can arise at any level in the biliary tree. It may derive from epithelial cells in the biliary tracts and peribiliary glands and possibly from progenitor cells or even hepatocytes. Several risk factors are responsible for CCA onset, however an inflammatory milieu nearby the biliary tree represents the most common condition favoring CCA development. Chemokines play a key role in driving the immunological response upon liver injury and may sustain tumor initiation and development. Chemokine receptor-dependent pathways influence the interplay among various cellular components, resulting in remodeling of the hepatic microenvironment towards a pro-inflammatory, pro-fibrogenic, pro-angiogenic and pre-neoplastic setting. Moreover, once tumor develops, chemokine signaling may influence its progression. Here we review the role of chemokines in the regulation of CCA development and progression, and the modulation of angiogenesis, metastasis and immune control. The potential role of chemokines and their receptors as possible biomarkers and/or therapeutic targets for hepatobiliary cancer is also discussed. Cancers, Vol. 12, Pages 2215: Role of Chemokines in the Biology of Cholangiocarcinoma

Cancers doi: 10.3390/cancers12082215

Authors: Alessandra Caligiuri Mirella Pastore Giulia Lori Chiara Raggi Giovanni Di Maira Fabio Marra Alessandra Gentilini

Cholangiocarcinoma (CCA), a heterogeneous tumor with poor prognosis, can arise at any level in the biliary tree. It may derive from epithelial cells in the biliary tracts and peribiliary glands and possibly from progenitor cells or even hepatocytes. Several risk factors are responsible for CCA onset, however an inflammatory milieu nearby the biliary tree represents the most common condition favoring CCA development. Chemokines play a key role in driving the immunological response upon liver injury and may sustain tumor initiation and development. Chemokine receptor-dependent pathways influence the interplay among various cellular components, resulting in remodeling of the hepatic microenvironment towards a pro-inflammatory, pro-fibrogenic, pro-angiogenic and pre-neoplastic setting. Moreover, once tumor develops, chemokine signaling may influence its progression. Here we review the role of chemokines in the regulation of CCA development and progression, and the modulation of angiogenesis, metastasis and immune control. The potential role of chemokines and their receptors as possible biomarkers and/or therapeutic targets for hepatobiliary cancer is also discussed.

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Role of Chemokines in the Biology of Cholangiocarcinoma Alessandra Caligiuri Mirella Pastore Giulia Lori Chiara Raggi Giovanni Di Maira Fabio Marra Alessandra Gentilini doi: 10.3390/cancers12082215 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Review 2215 10.3390/cancers12082215 http://www.ynsqex.icu/2072-6694/12/8/2215
Cancers, Vol. 12, Pages 2214: Renal Cell Tumors: Uncovering the Biomarker Potential of ncRNAs http://www.ynsqex.icu/2072-6694/12/8/2214 Renal cell tumors (RCT) remain as one of the most common and lethal urological tumors worldwide. Discrimination between (1) benign and malignant disease, (2) indolent and aggressive tumors, and (3) patient responsiveness to a specific therapy is of major clinical importance, allowing for a more efficient patient management. Nonetheless, currently available tools provide limited information and novel strategies are needed. Over the years, a putative role of non-coding RNAs (ncRNAs) as disease biomarkers has gained relevance and is now one of the most prolific fields in biological sciences. Herein, we extensively sought the most significant reports on ncRNAs as potential RCTs’ diagnostic, prognostic, predictive, and monitoring biomarkers. We could conclude that ncRNAs, either alone or in combination with currently used clinical and pathological parameters, might represent key elements to improve patient management, potentiating the implementation of precision medicine. Nevertheless, most ncRNA biomarkers require large-scale validation studies, prior to clinical implementation. Cancers, Vol. 12, Pages 2214: Renal Cell Tumors: Uncovering the Biomarker Potential of ncRNAs

Cancers doi: 10.3390/cancers12082214

Authors: Gon?alo Outeiro-Pinho Daniela Barros-Silva Margareta P. Correia Rui Henrique Carmen Jerónimo

Renal cell tumors (RCT) remain as one of the most common and lethal urological tumors worldwide. Discrimination between (1) benign and malignant disease, (2) indolent and aggressive tumors, and (3) patient responsiveness to a specific therapy is of major clinical importance, allowing for a more efficient patient management. Nonetheless, currently available tools provide limited information and novel strategies are needed. Over the years, a putative role of non-coding RNAs (ncRNAs) as disease biomarkers has gained relevance and is now one of the most prolific fields in biological sciences. Herein, we extensively sought the most significant reports on ncRNAs as potential RCTs’ diagnostic, prognostic, predictive, and monitoring biomarkers. We could conclude that ncRNAs, either alone or in combination with currently used clinical and pathological parameters, might represent key elements to improve patient management, potentiating the implementation of precision medicine. Nevertheless, most ncRNA biomarkers require large-scale validation studies, prior to clinical implementation.

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Renal Cell Tumors: Uncovering the Biomarker Potential of ncRNAs Gon?alo Outeiro-Pinho Daniela Barros-Silva Margareta P. Correia Rui Henrique Carmen Jerónimo doi: 10.3390/cancers12082214 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Review 2214 10.3390/cancers12082214 http://www.ynsqex.icu/2072-6694/12/8/2214
Cancers, Vol. 12, Pages 2213: Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α http://www.ynsqex.icu/2072-6694/12/8/2213 Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1α on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ERα. HNF1α mutated HCA (H-HCA) significantly overexpressed SigR1 compared to all other HCA subtypes. HNF1 knockout mice showed an increase in SigR1 expression. Overexpressing SigR1 in cellular models increases proliferation rate and storage of lipid droplets, which phenocopies the H-HCA phenotype. SigR1 is involved in hepatocyte proliferation and steatosis and may play an important role in the control of the H-HCA phenotype. Cancers, Vol. 12, Pages 2213: Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α

Cancers doi: 10.3390/cancers12082213

Authors: Laure Villemain Sylvie Prigent Aurélie Abou-Lovergne Laura Pelletier Magali Chiral Marco Pontoglio Fabienne Foufelle Stefano Caruso Raphael Pineau Sandra Rebouissou Eric Chevet Jessica Zucman-Rossi Laurent Combettes

Sigma receptor 1 (SigR1) is an endoplasmic reticulum resident integral membrane protein whose functions remain unclear. Although the liver shows the highest expression of SigR1, its role in this organ is unknown. SigR1 is overexpressed in many cancers and its expression is correlated to hormonal status in hormone-dependent cancers. To better understand the role of SigR1 in hepatocytes we focused our work on the regulation of its expression in tumoral liver. In this context, hepatocellular adenomas, benign hepatic tumors associated with estrogen intake are of particular interest. The expression of SigR1 mRNA was assessed in hepatocellular adenoma (HCA) patients using qPCR. The impact of estrogen on the expression of SigR1 was studied in vivo (mice) and in vitro (HepG2 and Huh7 cells). The effect of HNF1α on the expression of SigR1 was studied in vivo by comparing wild type mice to HNF1 knockout mice. Estrogen enhanced SigR1 expression through its nuclear receptor ERα. HNF1α mutated HCA (H-HCA) significantly overexpressed SigR1 compared to all other HCA subtypes. HNF1 knockout mice showed an increase in SigR1 expression. Overexpressing SigR1 in cellular models increases proliferation rate and storage of lipid droplets, which phenocopies the H-HCA phenotype. SigR1 is involved in hepatocyte proliferation and steatosis and may play an important role in the control of the H-HCA phenotype.

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Sigma 1 Receptor is Overexpressed in Hepatocellular Adenoma: Involvement of ERα and HNF1α Laure Villemain Sylvie Prigent Aurélie Abou-Lovergne Laura Pelletier Magali Chiral Marco Pontoglio Fabienne Foufelle Stefano Caruso Raphael Pineau Sandra Rebouissou Eric Chevet Jessica Zucman-Rossi Laurent Combettes doi: 10.3390/cancers12082213 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Article 2213 10.3390/cancers12082213 http://www.ynsqex.icu/2072-6694/12/8/2213
Cancers, Vol. 12, Pages 2211: The Use of Artificial Intelligence in the Differentiation of Malignant and Benign Lung Nodules on Computed Tomograms Proven by Surgical Pathology http://www.ynsqex.icu/2072-6694/12/8/2211 The purpose of this work was to evaluate the performance of an existing commercially available artificial intelligence (AI) software system in differentiating malignant and benign lung nodules. The AI tool consisted of a vessel-suppression function and a deep-learning-based computer-aided-detection (VS-CAD) analyzer. Fifty patients (32 females, mean age 52 years) with 75 lung nodules (47 malignant and 28 benign) underwent low-dose computed tomography (LDCT) followed by surgical excision and the pathological analysis of their 75 nodules within a 3 month time frame. All 50 cases were then processed by the AI software to generate corresponding VS images and CAD outcomes. All 75 pathologically proven lung nodules were well delineated by vessel-suppressed images. Three (6.4%) of the 47 lung cancer cases, and 11 (39.3%) of the 28 benign nodules were ignored and not detected by the AI without showing a CAD analysis summary. The AI system/radiologists produced a sensitivity and specificity (shown in %) of 93.6/89.4 and 39.3/82.1 in distinguishing malignant from benign nodules, respectively. AI sensitivity was higher than that of radiologists, though not statistically significant (p = 0.712). Specificity obtained by the radiologists was significantly higher than that of the VS-CAD AI (p = 0.003). There was no significant difference between the malignant and benign lesions with respect to age, gender, pure ground-glass pattern, the diameter and location of the nodules, or nodules <6 vs. ≥6 mm. However, more part-solid nodules were proven to be malignant than benign (90.9% vs. 9.1%), and more solid nodules were proven to be benign than malignant (86.7% vs. 13.3%) with statistical significance (p = 0.001 and <0.001, respectively). A larger cohort and prospective study are required to validate the AI performance. Cancers, Vol. 12, Pages 2211: The Use of Artificial Intelligence in the Differentiation of Malignant and Benign Lung Nodules on Computed Tomograms Proven by Surgical Pathology

Cancers doi: 10.3390/cancers12082211

Authors: Yung-Liang Wan Pei-Kwei Tsay Kuang-Tse Pan Nguyen Ngoc Trang Patricia Wanping Wu Pei-Ching Huang Wen-Yu Chuang Ching-Yang Wu ShihChung Benedict Lo

The purpose of this work was to evaluate the performance of an existing commercially available artificial intelligence (AI) software system in differentiating malignant and benign lung nodules. The AI tool consisted of a vessel-suppression function and a deep-learning-based computer-aided-detection (VS-CAD) analyzer. Fifty patients (32 females, mean age 52 years) with 75 lung nodules (47 malignant and 28 benign) underwent low-dose computed tomography (LDCT) followed by surgical excision and the pathological analysis of their 75 nodules within a 3 month time frame. All 50 cases were then processed by the AI software to generate corresponding VS images and CAD outcomes. All 75 pathologically proven lung nodules were well delineated by vessel-suppressed images. Three (6.4%) of the 47 lung cancer cases, and 11 (39.3%) of the 28 benign nodules were ignored and not detected by the AI without showing a CAD analysis summary. The AI system/radiologists produced a sensitivity and specificity (shown in %) of 93.6/89.4 and 39.3/82.1 in distinguishing malignant from benign nodules, respectively. AI sensitivity was higher than that of radiologists, though not statistically significant (p = 0.712). Specificity obtained by the radiologists was significantly higher than that of the VS-CAD AI (p = 0.003). There was no significant difference between the malignant and benign lesions with respect to age, gender, pure ground-glass pattern, the diameter and location of the nodules, or nodules <6 vs. ≥6 mm. However, more part-solid nodules were proven to be malignant than benign (90.9% vs. 9.1%), and more solid nodules were proven to be benign than malignant (86.7% vs. 13.3%) with statistical significance (p = 0.001 and <0.001, respectively). A larger cohort and prospective study are required to validate the AI performance.

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The Use of Artificial Intelligence in the Differentiation of Malignant and Benign Lung Nodules on Computed Tomograms Proven by Surgical Pathology Yung-Liang Wan Pei-Kwei Tsay Kuang-Tse Pan Nguyen Ngoc Trang Patricia Wanping Wu Pei-Ching Huang Wen-Yu Chuang Ching-Yang Wu ShihChung Benedict Lo doi: 10.3390/cancers12082211 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Article 2211 10.3390/cancers12082211 http://www.ynsqex.icu/2072-6694/12/8/2211
Cancers, Vol. 12, Pages 2212: Neoadjuvant Intraperitoneal Chemotherapy in Patients with Pseudomyxoma Peritonei—A Novel Treatment Approach http://www.ynsqex.icu/2072-6694/12/8/2212 Neoadjuvant intravenous chemotherapy in patients with pseudomyxoma peritonei (PMP) has not shown convincing results. The effectiveness of neoadjuvant intraperitoneal (IP) chemotherapy has never been reported. This prospective, non-randomized phase II study included patients with PMP treated between May 2017 and December 2018, who were not considered suitable for primary cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The majority of patients were treated with laparoscopic HIPEC (oxaliplatin 200 mg/m2, 60 min, 43 °C). IP chemotherapy was started 2 weeks after docetaxel 40 mg/m2 + cisplatin 40 mg/m2, accompanied by oral S1 (tegafur, gimeracil, and oteracil) (50 mg/m2) for 14 days, followed by one week rest. Clinical parameters and complications were recorded. In total, 22/27 patients qualified for CRS and HIPEC after neoadjuvant treatment. A complete cytoreduction (Completeness of cytoreduction Score 0/1) could be achieved in 54.5%. The postoperative morbidity rate was 13.6% and mortality was rate 4.5%. In total, 20/22 patients had major pathological tumor responses. The mean drop in CEA was 28.2% and in the peritoneal carcinomatosis index (PCI) was 2.6. Positive or suspicious cytology turned negative in 69.2% of patients. Thus, for PMP patients who were not amenable for primary surgery, the majority received complete cytoreduction after treatment with neoadjuvant IP chemotherapy, with satisfying tumor regression and with low complication rates. The oncological benefit in terms of survival with this new treatment regimen needs to be proven. Cancers, Vol. 12, Pages 2212: Neoadjuvant Intraperitoneal Chemotherapy in Patients with Pseudomyxoma Peritonei—A Novel Treatment Approach

Cancers doi: 10.3390/cancers12082212

Authors: Aruna Prabhu Andreas Brandl Satoshi Wakama Shouzou Sako Haruaki Ishibashi Akiyoshi Mizumoto Nobuyuki Takao Kousuke Noguchi Shunsuke Motoi Masumi Ichinose Yang Liu Yutaka Yonemura

Neoadjuvant intravenous chemotherapy in patients with pseudomyxoma peritonei (PMP) has not shown convincing results. The effectiveness of neoadjuvant intraperitoneal (IP) chemotherapy has never been reported. This prospective, non-randomized phase II study included patients with PMP treated between May 2017 and December 2018, who were not considered suitable for primary cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The majority of patients were treated with laparoscopic HIPEC (oxaliplatin 200 mg/m2, 60 min, 43 °C). IP chemotherapy was started 2 weeks after docetaxel 40 mg/m2 + cisplatin 40 mg/m2, accompanied by oral S1 (tegafur, gimeracil, and oteracil) (50 mg/m2) for 14 days, followed by one week rest. Clinical parameters and complications were recorded. In total, 22/27 patients qualified for CRS and HIPEC after neoadjuvant treatment. A complete cytoreduction (Completeness of cytoreduction Score 0/1) could be achieved in 54.5%. The postoperative morbidity rate was 13.6% and mortality was rate 4.5%. In total, 20/22 patients had major pathological tumor responses. The mean drop in CEA was 28.2% and in the peritoneal carcinomatosis index (PCI) was 2.6. Positive or suspicious cytology turned negative in 69.2% of patients. Thus, for PMP patients who were not amenable for primary surgery, the majority received complete cytoreduction after treatment with neoadjuvant IP chemotherapy, with satisfying tumor regression and with low complication rates. The oncological benefit in terms of survival with this new treatment regimen needs to be proven.

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Neoadjuvant Intraperitoneal Chemotherapy in Patients with Pseudomyxoma Peritonei—A Novel Treatment Approach Aruna Prabhu Andreas Brandl Satoshi Wakama Shouzou Sako Haruaki Ishibashi Akiyoshi Mizumoto Nobuyuki Takao Kousuke Noguchi Shunsuke Motoi Masumi Ichinose Yang Liu Yutaka Yonemura doi: 10.3390/cancers12082212 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Article 2212 10.3390/cancers12082212 http://www.ynsqex.icu/2072-6694/12/8/2212
Cancers, Vol. 12, Pages 2210: Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors http://www.ynsqex.icu/2072-6694/12/8/2210 The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics. Cancers, Vol. 12, Pages 2210: Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors

Cancers doi: 10.3390/cancers12082210

Authors: Shu-Chun Chang Wayne Hsu Emily Chia-Yu Su Chin-Sheng Hung Jeak Ling Ding

The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics.

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Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors Shu-Chun Chang Wayne Hsu Emily Chia-Yu Su Chin-Sheng Hung Jeak Ling Ding doi: 10.3390/cancers12082210 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Article 2210 10.3390/cancers12082210 http://www.ynsqex.icu/2072-6694/12/8/2210
Cancers, Vol. 12, Pages 2209: Therapeutic Potential of Chemically Modified miR-489 in Triple-Negative Breast Cancers http://www.ynsqex.icu/2072-6694/12/8/2209 Triple-negative breast cancers (TNBCs) lack ER, PR and her2 receptors that are targets of common breast cancer therapies with poor prognosis due to their high rates of metastasis and chemoresistance. Based on our previous studies that epigenetic silencing of a potential metastasis suppressor, arrestin domain-containing 3 (ARRDC3), is linked to the aggressive nature of TNBCs, we identified a sub-group of tumor suppressing miRNAs whose expressions were significantly up-regulated by ARRDC3 over-expression in TNBC cells. Among these tumor suppressing miRs, we found that miR-489 is most anti-proliferative in TNBC cells. miR-489 also blocked DNA damaging responses (DDRs) in TNBC cells. To define the mechanism by which miR-489 inhibits TNBC cell functions, we screened the potential target genes of miR-489 and identified MDC-1 and SUZ-12 as novel target genes of miR-489 in TNBC cells. To further exploit the therapeutic potentials of miR-489 in TNBC models, we chemically modified the guide strand of miR-489 (CMM489) by replacing Uracil with 5-fluorouracil (5-FU) so that tumor suppressor (miR-489) and DNA damaging (5-FU) components are combined into a single agent as a novel drug candidate for TNBCs. Our studies demonstrated that CMM489 shows superior effects over miR-489 or 5-FU in inhibition of TNBC cell proliferation and tumor progression, suggesting its therapeutic efficacy in TNBC models. Cancers, Vol. 12, Pages 2209: Therapeutic Potential of Chemically Modified miR-489 in Triple-Negative Breast Cancers

Cancers doi: 10.3390/cancers12082209

Authors: Young Hwa Soung Heesung Chung Cecilia Yan Andrew Fesler Hyungjin Kim Eok-Soo Oh Jingfang Ju Jun Chung

Triple-negative breast cancers (TNBCs) lack ER, PR and her2 receptors that are targets of common breast cancer therapies with poor prognosis due to their high rates of metastasis and chemoresistance. Based on our previous studies that epigenetic silencing of a potential metastasis suppressor, arrestin domain-containing 3 (ARRDC3), is linked to the aggressive nature of TNBCs, we identified a sub-group of tumor suppressing miRNAs whose expressions were significantly up-regulated by ARRDC3 over-expression in TNBC cells. Among these tumor suppressing miRs, we found that miR-489 is most anti-proliferative in TNBC cells. miR-489 also blocked DNA damaging responses (DDRs) in TNBC cells. To define the mechanism by which miR-489 inhibits TNBC cell functions, we screened the potential target genes of miR-489 and identified MDC-1 and SUZ-12 as novel target genes of miR-489 in TNBC cells. To further exploit the therapeutic potentials of miR-489 in TNBC models, we chemically modified the guide strand of miR-489 (CMM489) by replacing Uracil with 5-fluorouracil (5-FU) so that tumor suppressor (miR-489) and DNA damaging (5-FU) components are combined into a single agent as a novel drug candidate for TNBCs. Our studies demonstrated that CMM489 shows superior effects over miR-489 or 5-FU in inhibition of TNBC cell proliferation and tumor progression, suggesting its therapeutic efficacy in TNBC models.

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Therapeutic Potential of Chemically Modified miR-489 in Triple-Negative Breast Cancers Young Hwa Soung Heesung Chung Cecilia Yan Andrew Fesler Hyungjin Kim Eok-Soo Oh Jingfang Ju Jun Chung doi: 10.3390/cancers12082209 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Article 2209 10.3390/cancers12082209 http://www.ynsqex.icu/2072-6694/12/8/2209
Cancers, Vol. 12, Pages 2208: Electroporation-Based Treatments in Urology http://www.ynsqex.icu/2072-6694/12/8/2208 The observation that an application of a pulsed electric field (PEF) resulted in an increased permeability of the cell membrane has led to the discovery of the phenomenon called electroporation (EP). Depending on the parameters of the electric current and cell features, electroporation can be either reversible or irreversible. The irreversible electroporation (IRE) found its use in urology as a non-thermal ablative method of prostate and renal cancer. As its mechanism is based on the permeabilization of cell membrane phospholipids, IRE (as well as other treatments based on EP) provides selectivity sparing extracellular proteins and matrix. Reversible EP enables the transfer of genes, drugs, and small exogenous proteins. In clinical practice, reversible EP can locally increase the uptake of cytotoxic drugs such as cisplatin and bleomycin. This approach is known as electrochemotherapy (ECT). Few in vivo and in vitro trials of ECT have been performed on urological cancers. EP provides the possibility of transmission of genes across the cell membrane. As the protocols of gene electrotransfer (GET) over the last few years have improved, EP has become a well-known technique for non-viral cell transfection. GET involves DNA transfection directly to the cancer or the host skin and muscle tissue. Among urological cancers, the GET of several plasmids encoding prostate cancer antigens has been investigated in clinical trials. This review brings into discussion the underlying mechanism of EP and an overview of the latest progress and development perspectives of EP-based treatments in urology. Cancers, Vol. 12, Pages 2208: Electroporation-Based Treatments in Urology

Cancers doi: 10.3390/cancers12082208

Authors: Aleksander Kie?bik Wojciech Szlasa Jolanta Saczko Julita Kulbacka

The observation that an application of a pulsed electric field (PEF) resulted in an increased permeability of the cell membrane has led to the discovery of the phenomenon called electroporation (EP). Depending on the parameters of the electric current and cell features, electroporation can be either reversible or irreversible. The irreversible electroporation (IRE) found its use in urology as a non-thermal ablative method of prostate and renal cancer. As its mechanism is based on the permeabilization of cell membrane phospholipids, IRE (as well as other treatments based on EP) provides selectivity sparing extracellular proteins and matrix. Reversible EP enables the transfer of genes, drugs, and small exogenous proteins. In clinical practice, reversible EP can locally increase the uptake of cytotoxic drugs such as cisplatin and bleomycin. This approach is known as electrochemotherapy (ECT). Few in vivo and in vitro trials of ECT have been performed on urological cancers. EP provides the possibility of transmission of genes across the cell membrane. As the protocols of gene electrotransfer (GET) over the last few years have improved, EP has become a well-known technique for non-viral cell transfection. GET involves DNA transfection directly to the cancer or the host skin and muscle tissue. Among urological cancers, the GET of several plasmids encoding prostate cancer antigens has been investigated in clinical trials. This review brings into discussion the underlying mechanism of EP and an overview of the latest progress and development perspectives of EP-based treatments in urology.

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Electroporation-Based Treatments in Urology Aleksander Kie?bik Wojciech Szlasa Jolanta Saczko Julita Kulbacka doi: 10.3390/cancers12082208 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Review 2208 10.3390/cancers12082208 http://www.ynsqex.icu/2072-6694/12/8/2208
Cancers, Vol. 12, Pages 2207: Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity http://www.ynsqex.icu/2072-6694/12/8/2207 Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets. Cancers, Vol. 12, Pages 2207: Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Cancers doi: 10.3390/cancers12082207

Authors: Ji-Yong Sung Hee-Woong Lim Je-Gun Joung Woong-Yang Park

Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.

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Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity Ji-Yong Sung Hee-Woong Lim Je-Gun Joung Woong-Yang Park doi: 10.3390/cancers12082207 Cancers 2020-08-07 Cancers 2020-08-07 12 8 Article 2207 10.3390/cancers12082207 http://www.ynsqex.icu/2072-6694/12/8/2207
Cancers, Vol. 12, Pages 2206: Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma http://www.ynsqex.icu/2072-6694/12/8/2206 Chromosome instability (CIN), the hallmarks of cancer, reflects ongoing chromosomal changes caused by chromosome segregation errors and results in whole chromosomal or segmental aneuploidy. In multiple myeloma (MM), CIN contributes to the acquisition of tumor heterogeneity, and thereby, to disease progression, drug resistance, and eventual treatment failure; however, the underlying mechanism of CIN in MM remains unclear. Faithful chromosomal segregation is tightly regulated by a series of mitotic checkpoint proteins, such as budding uninhibited by benzimidazoles 1 (BUB1). In this study, we found that BUB1 was overexpressed in patient-derived myeloma cells, and BUB1 expression was significantly higher in patients in an advanced stage compared to those in an early stage. This suggested the involvement of aberrant BUB1 overexpression in disease progression. In human myeloma-derived cell lines (HMCLs), BUB1 knockdown reduced the frequency of chromosome segregation errors in mitotic cells. In line with this, partial knockdown of BUB1 showed reduced variations in chromosome number compared to parent cells in HMCLs. Finally, BUB1 overexpression was found to promote the clonogenic potency of HMCLs. Collectively, these results suggested that enhanced BUB1 expression caused an increase in mitotic segregation errors and the resultant emergence of subclones with altered chromosome numbers and, thus, was involved in CIN in MM. Cancers, Vol. 12, Pages 2206: Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma

Cancers doi: 10.3390/cancers12082206

Authors: Yuto Fujibayashi Reiko Isa Daichi Nishiyama Natsumi Sakamoto-Inada Norichika Kawasumi Junko Yamaguchi Saeko Kuwahara-Ota Yayoi Matsumura-Kimoto Taku Tsukamoto Yoshiaki Chinen Yuji Shimura Tsutomu Kobayashi Shigeo Horiike Masafumi Taniwaki Hiroshi Handa Junya Kuroda

Chromosome instability (CIN), the hallmarks of cancer, reflects ongoing chromosomal changes caused by chromosome segregation errors and results in whole chromosomal or segmental aneuploidy. In multiple myeloma (MM), CIN contributes to the acquisition of tumor heterogeneity, and thereby, to disease progression, drug resistance, and eventual treatment failure; however, the underlying mechanism of CIN in MM remains unclear. Faithful chromosomal segregation is tightly regulated by a series of mitotic checkpoint proteins, such as budding uninhibited by benzimidazoles 1 (BUB1). In this study, we found that BUB1 was overexpressed in patient-derived myeloma cells, and BUB1 expression was significantly higher in patients in an advanced stage compared to those in an early stage. This suggested the involvement of aberrant BUB1 overexpression in disease progression. In human myeloma-derived cell lines (HMCLs), BUB1 knockdown reduced the frequency of chromosome segregation errors in mitotic cells. In line with this, partial knockdown of BUB1 showed reduced variations in chromosome number compared to parent cells in HMCLs. Finally, BUB1 overexpression was found to promote the clonogenic potency of HMCLs. Collectively, these results suggested that enhanced BUB1 expression caused an increase in mitotic segregation errors and the resultant emergence of subclones with altered chromosome numbers and, thus, was involved in CIN in MM.

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Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma Yuto Fujibayashi Reiko Isa Daichi Nishiyama Natsumi Sakamoto-Inada Norichika Kawasumi Junko Yamaguchi Saeko Kuwahara-Ota Yayoi Matsumura-Kimoto Taku Tsukamoto Yoshiaki Chinen Yuji Shimura Tsutomu Kobayashi Shigeo Horiike Masafumi Taniwaki Hiroshi Handa Junya Kuroda doi: 10.3390/cancers12082206 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Article 2206 10.3390/cancers12082206 http://www.ynsqex.icu/2072-6694/12/8/2206
Cancers, Vol. 12, Pages 2205: Engineering a Humanised Niche to Support Human Haematopoiesis in Mice: Novel Opportunities in Modelling Cancer http://www.ynsqex.icu/2072-6694/12/8/2205 Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the combination of an orthotopic humanised tissue-engineered bone construct (ohTEBC) with patient-specific bone marrow (BM) cells to create a humanised bone marrow (hBM) niche capable of supporting the engraftment of human haematopoietic cells. Results showed that this model supports the engraftment of human CD34+ cells from a healthy BM with human haematopoietic cells migrating into the mouse BM, human BM compartment, spleen and peripheral blood. We compared these results with the engraftment capacity of human CD34+ cells obtained from patients with multiple myeloma (MM). We demonstrated that CD34+ cells derived from a diseased BM had a reduced engraftment potential compared to healthy patients and that a higher cell dose is required to achieve engraftment of human haematopoietic cells in peripheral blood. Finally, we observed that hematopoietic cells obtained from the mobilised peripheral blood of patients yields a higher number of CD34+, overcoming this problem. In conclusion, this humanised mouse model has potential as a unique and patient-specific pre-clinical platform for the study of tumour–microenvironment interactions, including human bone and haematopoietic cells, and could, in the future, serve as a drug testing platform. Cancers, Vol. 12, Pages 2205: Engineering a Humanised Niche to Support Human Haematopoiesis in Mice: Novel Opportunities in Modelling Cancer

Cancers doi: 10.3390/cancers12082205

Authors: Alvaro Sanchez-Herrero Isabel A. Calvo Maria Flandes-Iparraguirre Marietta Landgraf Christoph A. Lahr Abbas Shafiee Froilán Granero-Molto Borja Saez Manuel M. Mazo Bruno Paiva Elena de Juan Pardo Andrew Nicol Felipe Prosper Laura J. Bray Jacqui A. McGovern

Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the combination of an orthotopic humanised tissue-engineered bone construct (ohTEBC) with patient-specific bone marrow (BM) cells to create a humanised bone marrow (hBM) niche capable of supporting the engraftment of human haematopoietic cells. Results showed that this model supports the engraftment of human CD34+ cells from a healthy BM with human haematopoietic cells migrating into the mouse BM, human BM compartment, spleen and peripheral blood. We compared these results with the engraftment capacity of human CD34+ cells obtained from patients with multiple myeloma (MM). We demonstrated that CD34+ cells derived from a diseased BM had a reduced engraftment potential compared to healthy patients and that a higher cell dose is required to achieve engraftment of human haematopoietic cells in peripheral blood. Finally, we observed that hematopoietic cells obtained from the mobilised peripheral blood of patients yields a higher number of CD34+, overcoming this problem. In conclusion, this humanised mouse model has potential as a unique and patient-specific pre-clinical platform for the study of tumour–microenvironment interactions, including human bone and haematopoietic cells, and could, in the future, serve as a drug testing platform.

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Engineering a Humanised Niche to Support Human Haematopoiesis in Mice: Novel Opportunities in Modelling Cancer Alvaro Sanchez-Herrero Isabel A. Calvo Maria Flandes-Iparraguirre Marietta Landgraf Christoph A. Lahr Abbas Shafiee Froilán Granero-Molto Borja Saez Manuel M. Mazo Bruno Paiva Elena de Juan Pardo Andrew Nicol Felipe Prosper Laura J. Bray Jacqui A. McGovern doi: 10.3390/cancers12082205 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Article 2205 10.3390/cancers12082205 http://www.ynsqex.icu/2072-6694/12/8/2205
Cancers, Vol. 12, Pages 2204: Isolation of Two Novel Human Anti-CTLA-4 mAbs with Intriguing Biological Properties on Tumor and NK Cells http://www.ynsqex.icu/2072-6694/12/8/2204 The cytotoxic T lymphocyte-antigen 4 (CTLA-4) has been considered an IC exclusively expressed on T cells, where it counteracts the co-stimulatory CD28 receptor, by competing for its binding to CD-80 and CD-86. We recently found that it is expressed also on tumor and NK cells, suggesting other possible unknown roles of CTLA-4. To shed light on these novel aspects of CTLA-4, we used Ipilimumab, the first FDA approved human antibody targeting CTLA-4, in parallel studies with two novel human mAbs we isolated by using an efficient phage display selection strategy on live activated lymphocytes and purified mouse and human CTLA-4. The selection for cross-reactive mAbs was guaranteed by a high throughput sequencing to identify the sequences commonly enriched by two parallel pannings on human and mouse CTLA-4. Two isolated antibodies were found to bind with high affinity to both human and mouse CTLA-4 and lymphocytes, showing nanomolar or sub-nanomolar Kd values. They were able to kill Treg cells by ADCC, and to activate both human and mouse PBMCs, by strongly increasing cytokines secretion. Interestingly, they activated NK cells, exhibited cytotoxicity against cancer cells by inducing ADCC and inhibited tumor cell growth by affecting CTLA-4 downstream pathways in a similar fashion to CD-80 and CD-86 ligands and differently from Ipilimumab. Moreover, the novel mAbs showed a reduced ability to interfere in the binding of CD-80 ligands to CTLA-4 on T cells with respect to Ipilimumab, suggesting that they could allow for anti-tumor effects without the irAEs associated with the potent antagonistic activity of Ipilimumab. Cancers, Vol. 12, Pages 2204: Isolation of Two Novel Human Anti-CTLA-4 mAbs with Intriguing Biological Properties on Tumor and NK Cells

Cancers doi: 10.3390/cancers12082204

Authors: Margherita Passariello Cinzia Vetrei Emanuele Sasso Guendalina Froechlich Chiara Gentile Anna Morena D'Alise Nicola Zambrano Elisa Scarselli Alfredo Nicosia Claudia De Lorenzo

The cytotoxic T lymphocyte-antigen 4 (CTLA-4) has been considered an IC exclusively expressed on T cells, where it counteracts the co-stimulatory CD28 receptor, by competing for its binding to CD-80 and CD-86. We recently found that it is expressed also on tumor and NK cells, suggesting other possible unknown roles of CTLA-4. To shed light on these novel aspects of CTLA-4, we used Ipilimumab, the first FDA approved human antibody targeting CTLA-4, in parallel studies with two novel human mAbs we isolated by using an efficient phage display selection strategy on live activated lymphocytes and purified mouse and human CTLA-4. The selection for cross-reactive mAbs was guaranteed by a high throughput sequencing to identify the sequences commonly enriched by two parallel pannings on human and mouse CTLA-4. Two isolated antibodies were found to bind with high affinity to both human and mouse CTLA-4 and lymphocytes, showing nanomolar or sub-nanomolar Kd values. They were able to kill Treg cells by ADCC, and to activate both human and mouse PBMCs, by strongly increasing cytokines secretion. Interestingly, they activated NK cells, exhibited cytotoxicity against cancer cells by inducing ADCC and inhibited tumor cell growth by affecting CTLA-4 downstream pathways in a similar fashion to CD-80 and CD-86 ligands and differently from Ipilimumab. Moreover, the novel mAbs showed a reduced ability to interfere in the binding of CD-80 ligands to CTLA-4 on T cells with respect to Ipilimumab, suggesting that they could allow for anti-tumor effects without the irAEs associated with the potent antagonistic activity of Ipilimumab.

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Isolation of Two Novel Human Anti-CTLA-4 mAbs with Intriguing Biological Properties on Tumor and NK Cells Margherita Passariello Cinzia Vetrei Emanuele Sasso Guendalina Froechlich Chiara Gentile Anna Morena D'Alise Nicola Zambrano Elisa Scarselli Alfredo Nicosia Claudia De Lorenzo doi: 10.3390/cancers12082204 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Article 2204 10.3390/cancers12082204 http://www.ynsqex.icu/2072-6694/12/8/2204
Cancers, Vol. 12, Pages 2203: Targeting NF-κB Signaling for Multiple Myeloma http://www.ynsqex.icu/2072-6694/12/8/2203 Multiple myeloma (MM) is the second most common hematologic malignancy in the world. Even though survival rates have significantly risen over the past years, MM remains incurable, and is also far from reaching the point of being managed as a chronic disease. This paper reviews the evolution of MM therapies, focusing on anti-MM drugs that target the molecular mechanisms of nuclear factor kappa B (NF-κB) signaling. We also provide our perspectives on contemporary research findings and insights for future drug development. Cancers, Vol. 12, Pages 2203: Targeting NF-κB Signaling for Multiple Myeloma

Cancers doi: 10.3390/cancers12082203

Authors: Ada Hang-Heng Wong Eun Myoung Shin Vinay Tergaonkar Wee-Joo Chng

Multiple myeloma (MM) is the second most common hematologic malignancy in the world. Even though survival rates have significantly risen over the past years, MM remains incurable, and is also far from reaching the point of being managed as a chronic disease. This paper reviews the evolution of MM therapies, focusing on anti-MM drugs that target the molecular mechanisms of nuclear factor kappa B (NF-κB) signaling. We also provide our perspectives on contemporary research findings and insights for future drug development.

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Targeting NF-κB Signaling for Multiple Myeloma Ada Hang-Heng Wong Eun Myoung Shin Vinay Tergaonkar Wee-Joo Chng doi: 10.3390/cancers12082203 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2203 10.3390/cancers12082203 http://www.ynsqex.icu/2072-6694/12/8/2203
Cancers, Vol. 12, Pages 2201: High-Risk Human Papillomavirus and Tobacco Smoke Interactions in Epithelial Carcinogenesis http://www.ynsqex.icu/2072-6694/12/8/2201 Cervical, anogenital, and some head and neck cancers (HNC) are etiologically associated with high-risk human papillomavirus (HR-HPV) infection, even though additional cofactors are necessary. Epidemiological studies have established that tobacco smoke (TS) is a cofactor for cervical carcinogenesis because women who smoke are more susceptible to cervical cancer when compared to non-smokers. Even though such a relationship has not been established in HPV-related HNC, a group of HPV positive patients with this malignancy are smokers. TS is a complex mixture of more than 4500 chemical compounds and approximately 60 of them show oncogenic properties such as benzo[α]pyrene (BaP) and nitrosamines, among others. Some of these compounds have been evaluated for carcinogenesis through experimental settings in collaboration with HR-HPV. Here, we conducted a comprehensive review of the suggested molecular mechanisms involved in cooperation with both HR-HPV and TS for epithelial carcinogenesis. Furthermore, we propose interaction models in which TS collaborates with HR-HPV to promote epithelial cancer initiation, promotion, and progression. More studies are warranted to clarify interactions between oncogenic viruses and chemical or physical environmental factors for epithelial carcinogenesis. Cancers, Vol. 12, Pages 2201: High-Risk Human Papillomavirus and Tobacco Smoke Interactions in Epithelial Carcinogenesis

Cancers doi: 10.3390/cancers12082201

Authors: Francisco Aguayo Juan P. Mu?oz Francisco Perez-Dominguez Diego Carrillo-Beltrán Carolina Oliva Gloria M. Calaf Rances Blanco Daniela Nu?ez-Acurio

Cervical, anogenital, and some head and neck cancers (HNC) are etiologically associated with high-risk human papillomavirus (HR-HPV) infection, even though additional cofactors are necessary. Epidemiological studies have established that tobacco smoke (TS) is a cofactor for cervical carcinogenesis because women who smoke are more susceptible to cervical cancer when compared to non-smokers. Even though such a relationship has not been established in HPV-related HNC, a group of HPV positive patients with this malignancy are smokers. TS is a complex mixture of more than 4500 chemical compounds and approximately 60 of them show oncogenic properties such as benzo[α]pyrene (BaP) and nitrosamines, among others. Some of these compounds have been evaluated for carcinogenesis through experimental settings in collaboration with HR-HPV. Here, we conducted a comprehensive review of the suggested molecular mechanisms involved in cooperation with both HR-HPV and TS for epithelial carcinogenesis. Furthermore, we propose interaction models in which TS collaborates with HR-HPV to promote epithelial cancer initiation, promotion, and progression. More studies are warranted to clarify interactions between oncogenic viruses and chemical or physical environmental factors for epithelial carcinogenesis.

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High-Risk Human Papillomavirus and Tobacco Smoke Interactions in Epithelial Carcinogenesis Francisco Aguayo Juan P. Mu?oz Francisco Perez-Dominguez Diego Carrillo-Beltrán Carolina Oliva Gloria M. Calaf Rances Blanco Daniela Nu?ez-Acurio doi: 10.3390/cancers12082201 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2201 10.3390/cancers12082201 http://www.ynsqex.icu/2072-6694/12/8/2201
Cancers, Vol. 12, Pages 2202: Body Mass Index and Total Symptom Burden in Myeloproliferative Neoplasms Discovery of a U-shaped Association http://www.ynsqex.icu/2072-6694/12/8/2202 Elevated body mass index (BMI) is a global health problem, leading to enhanced mortality and the increased risk of several cancers including essential thrombocythemia (ET), a subtype of the Philadelphia-chromosome negative myeloproliferative neoplasms (MPN). Furthermore, evidence states that BMI is associated with the severity of symptom burden among cancer patients. MPN patients often suffer from severe symptom burden. The purpose of this study was to examine whether deviations from a normal BMI in an MPN population are associated with higher symptom burden and reduced quality of life (QoL). A combined analysis of two large cross-sectional surveys, the Danish Population-based Study, MPNhealthSurvey (n = 2044), and the international Fatigue Study (n = 1070), was performed. Symptoms and QoL were assessed using the validated Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Analysis of covariance was used to estimate the effects of different BMI categories on symptom scores while adjusting for age, sex, and MPN subtype. A U-shaped association between BMI and Total Symptom Burden was observed in both datasets with significantly higher mean scores for underweight and obese patients relative to normal weight (mean difference: underweight 5.51 (25.8%), p = 0.006; obese 5.70 (26.6%) p < 0.001). This is an important finding, as BMI is a potentially modifiable factor in the care of MPN patients. Cancers, Vol. 12, Pages 2202: Body Mass Index and Total Symptom Burden in Myeloproliferative Neoplasms Discovery of a U-shaped Association

Cancers doi: 10.3390/cancers12082202

Authors: Sarah Friis Christensen Robyn Marie Scherber Nana Brochmann Martin Goros Jonathan Gelfond Christen Lykkegaard Andersen Esben Meulengracht Flachs Ruben Mesa

Elevated body mass index (BMI) is a global health problem, leading to enhanced mortality and the increased risk of several cancers including essential thrombocythemia (ET), a subtype of the Philadelphia-chromosome negative myeloproliferative neoplasms (MPN). Furthermore, evidence states that BMI is associated with the severity of symptom burden among cancer patients. MPN patients often suffer from severe symptom burden. The purpose of this study was to examine whether deviations from a normal BMI in an MPN population are associated with higher symptom burden and reduced quality of life (QoL). A combined analysis of two large cross-sectional surveys, the Danish Population-based Study, MPNhealthSurvey (n = 2044), and the international Fatigue Study (n = 1070), was performed. Symptoms and QoL were assessed using the validated Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). Analysis of covariance was used to estimate the effects of different BMI categories on symptom scores while adjusting for age, sex, and MPN subtype. A U-shaped association between BMI and Total Symptom Burden was observed in both datasets with significantly higher mean scores for underweight and obese patients relative to normal weight (mean difference: underweight 5.51 (25.8%), p = 0.006; obese 5.70 (26.6%) p < 0.001). This is an important finding, as BMI is a potentially modifiable factor in the care of MPN patients.

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Body Mass Index and Total Symptom Burden in Myeloproliferative Neoplasms Discovery of a U-shaped Association Sarah Friis Christensen Robyn Marie Scherber Nana Brochmann Martin Goros Jonathan Gelfond Christen Lykkegaard Andersen Esben Meulengracht Flachs Ruben Mesa doi: 10.3390/cancers12082202 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Article 2202 10.3390/cancers12082202 http://www.ynsqex.icu/2072-6694/12/8/2202
Cancers, Vol. 12, Pages 2200: Combination of Peri-Tumoral and Intra-Tumoral Radiomic Features on Bi-Parametric MRI Accurately Stratifies Prostate Cancer Risk: A Multi-Site Study http://www.ynsqex.icu/2072-6694/12/8/2200 Background: Prostate cancer (PCa) influences its surrounding habitat, which tends to manifest as different phenotypic appearances on magnetic resonance imaging (MRI). This region surrounding the PCa lesion, or the peri-tumoral region, may encode useful information that can complement intra-tumoral information to enable better risk stratification. Purpose: To evaluate the role of peri-tumoral radiomic features on bi-parametric MRI (T2-weighted and Diffusion-weighted) to distinguish PCa risk categories as defined by D’Amico Risk Classification System. Materials and Methods: We studied a retrospective, HIPAA-compliant, 4-institution cohort of 231 PCa patients (n = 301 lesions) who underwent 3T multi-parametric MRI prior to biopsy. PCa regions of interest (ROIs) were delineated on MRI by experienced radiologists following which peri-tumoral ROIs were defined. Radiomic features were extracted within the intra- and peri-tumoral ROIs. Radiomic features differentiating low-risk from: (1) high-risk (L-vs.-H), and (2) (intermediate- and high-risk (L-vs.-I + H)) lesions were identified. Using a multi-institutional training cohort of 151 lesions (D1, N = 116 patients), machine learning classifiers were trained using peri- and intra-tumoral features individually and in combination. The remaining 150 lesions (D2, N = 115 patients) were used for independent hold-out validation and were evaluated using Receiver Operating Characteristic (ROC) analysis and compared with PI-RADS v2 scores. Results: Validation on D2 using peri-tumoral radiomics alone resulted in areas under the ROC curve (AUCs) of 0.84 and 0.73 for the L-vs.-H and L-vs.-I + H classifications, respectively. The best combination of intra- and peri-tumoral features resulted in AUCs of 0.87 and 0.75 for the L-vs.-H and L-vs.-I + H classifications, respectively. This combination improved the risk stratification results by 3–6% compared to intra-tumoral features alone. Our radiomics-based model resulted in a 53% accuracy in differentiating L-vs.-H compared to PI-RADS v2 (48%), on the validation set. Conclusion: Our findings suggest that peri-tumoral radiomic features derived from prostate bi-parametric MRI add independent predictive value to intra-tumoral radiomic features for PCa risk assessment. Cancers, Vol. 12, Pages 2200: Combination of Peri-Tumoral and Intra-Tumoral Radiomic Features on Bi-Parametric MRI Accurately Stratifies Prostate Cancer Risk: A Multi-Site Study

Cancers doi: 10.3390/cancers12082200

Authors: Ahmad Algohary Rakesh Shiradkar Shivani Pahwa Andrei Purysko Sadhna Verma Daniel Moses Ronald Shnier Anne-Maree Haynes Warick Delprado James Thompson Sreeharsha Tirumani Amr Mahran Ardeshir R Rastinehad Lee Ponsky Phillip D. Stricker Anant Madabhushi

Background: Prostate cancer (PCa) influences its surrounding habitat, which tends to manifest as different phenotypic appearances on magnetic resonance imaging (MRI). This region surrounding the PCa lesion, or the peri-tumoral region, may encode useful information that can complement intra-tumoral information to enable better risk stratification. Purpose: To evaluate the role of peri-tumoral radiomic features on bi-parametric MRI (T2-weighted and Diffusion-weighted) to distinguish PCa risk categories as defined by D’Amico Risk Classification System. Materials and Methods: We studied a retrospective, HIPAA-compliant, 4-institution cohort of 231 PCa patients (n = 301 lesions) who underwent 3T multi-parametric MRI prior to biopsy. PCa regions of interest (ROIs) were delineated on MRI by experienced radiologists following which peri-tumoral ROIs were defined. Radiomic features were extracted within the intra- and peri-tumoral ROIs. Radiomic features differentiating low-risk from: (1) high-risk (L-vs.-H), and (2) (intermediate- and high-risk (L-vs.-I + H)) lesions were identified. Using a multi-institutional training cohort of 151 lesions (D1, N = 116 patients), machine learning classifiers were trained using peri- and intra-tumoral features individually and in combination. The remaining 150 lesions (D2, N = 115 patients) were used for independent hold-out validation and were evaluated using Receiver Operating Characteristic (ROC) analysis and compared with PI-RADS v2 scores. Results: Validation on D2 using peri-tumoral radiomics alone resulted in areas under the ROC curve (AUCs) of 0.84 and 0.73 for the L-vs.-H and L-vs.-I + H classifications, respectively. The best combination of intra- and peri-tumoral features resulted in AUCs of 0.87 and 0.75 for the L-vs.-H and L-vs.-I + H classifications, respectively. This combination improved the risk stratification results by 3–6% compared to intra-tumoral features alone. Our radiomics-based model resulted in a 53% accuracy in differentiating L-vs.-H compared to PI-RADS v2 (48%), on the validation set. Conclusion: Our findings suggest that peri-tumoral radiomic features derived from prostate bi-parametric MRI add independent predictive value to intra-tumoral radiomic features for PCa risk assessment.

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Combination of Peri-Tumoral and Intra-Tumoral Radiomic Features on Bi-Parametric MRI Accurately Stratifies Prostate Cancer Risk: A Multi-Site Study Ahmad Algohary Rakesh Shiradkar Shivani Pahwa Andrei Purysko Sadhna Verma Daniel Moses Ronald Shnier Anne-Maree Haynes Warick Delprado James Thompson Sreeharsha Tirumani Amr Mahran Ardeshir R Rastinehad Lee Ponsky Phillip D. Stricker Anant Madabhushi doi: 10.3390/cancers12082200 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Article 2200 10.3390/cancers12082200 http://www.ynsqex.icu/2072-6694/12/8/2200
Cancers, Vol. 12, Pages 2199: Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma http://www.ynsqex.icu/2072-6694/12/8/2199 The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters ≤4 tumor cells) and PDC (clusters ≥5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (≤4), grade-2 (5–9), or grade-3 (≥10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months; p = 0.007) in the lower stage (stages I–II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages. Cancers, Vol. 12, Pages 2199: Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma

Cancers doi: 10.3390/cancers12082199

Authors: Sun-Young Jun Joon-Yong Chung Nara Yoon Eun Sun Jung Young-Ha Oh Seung-Mo Hong

The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters ≤4 tumor cells) and PDC (clusters ≥5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (≤4), grade-2 (5–9), or grade-3 (≥10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months; p = 0.007) in the lower stage (stages I–II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages.

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Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma Sun-Young Jun Joon-Yong Chung Nara Yoon Eun Sun Jung Young-Ha Oh Seung-Mo Hong doi: 10.3390/cancers12082199 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Article 2199 10.3390/cancers12082199 http://www.ynsqex.icu/2072-6694/12/8/2199
Cancers, Vol. 12, Pages 2197: Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer http://www.ynsqex.icu/2072-6694/12/8/2197 Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, and targeting of antioxidant enzymes as therapeutic approaches for cancer treatment. It also highlights the need for additional studies to investigate the role and regulation of these antioxidant enzymes in cancer. The focus of this review is on glutathione peroxidase 3 (GPx3), a selenoprotein, and the only extracellular GPx of a family of oxidoreductases that catalyze the detoxification of hydro- and soluble lipid hydroperoxides by reduced glutathione. In addition to summarizing the biochemical function, regulation, and disease associations of GPx3, we specifically discuss the role and regulation of systemic and tumor cell expressed GPx3 in cancer. From this it is evident that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein. Further studies are needed to examine how loss or gain of GPx3 specifically affects oxidant scavenging and redox signaling in the extracellular tumor microenvironment, and how GPx3 might be targeted for therapeutic intervention. Cancers, Vol. 12, Pages 2197: Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Cancers doi: 10.3390/cancers12082197

Authors: Caroline Chang Beth L. Worley Rébécca Pha?ton Nadine Hempel

Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, and targeting of antioxidant enzymes as therapeutic approaches for cancer treatment. It also highlights the need for additional studies to investigate the role and regulation of these antioxidant enzymes in cancer. The focus of this review is on glutathione peroxidase 3 (GPx3), a selenoprotein, and the only extracellular GPx of a family of oxidoreductases that catalyze the detoxification of hydro- and soluble lipid hydroperoxides by reduced glutathione. In addition to summarizing the biochemical function, regulation, and disease associations of GPx3, we specifically discuss the role and regulation of systemic and tumor cell expressed GPx3 in cancer. From this it is evident that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein. Further studies are needed to examine how loss or gain of GPx3 specifically affects oxidant scavenging and redox signaling in the extracellular tumor microenvironment, and how GPx3 might be targeted for therapeutic intervention.

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Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer Caroline Chang Beth L. Worley Rébécca Pha?ton Nadine Hempel doi: 10.3390/cancers12082197 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2197 10.3390/cancers12082197 http://www.ynsqex.icu/2072-6694/12/8/2197
Cancers, Vol. 12, Pages 2196: Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells http://www.ynsqex.icu/2072-6694/12/8/2196 Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action. Cancers, Vol. 12, Pages 2196: Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

Cancers doi: 10.3390/cancers12082196

Authors: Lauralie Peronne Eric Denarier Ankit Rai Renaud Prudent Audrey Vernet Peggy Suzanne Sacnicté Ramirez-Rios Sophie Michallet Mélanie Guidetti Julien Vollaire Daniel Lucena-Agell Anne-Sophie Ribba Véronique Josserand Jean-Luc Coll Patrick Dallemagne J. Fernando Díaz María ángela Oliva Karin Sadoul Anna Akhmanova Annie Andrieux Laurence Lafanechère

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

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Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells Lauralie Peronne Eric Denarier Ankit Rai Renaud Prudent Audrey Vernet Peggy Suzanne Sacnicté Ramirez-Rios Sophie Michallet Mélanie Guidetti Julien Vollaire Daniel Lucena-Agell Anne-Sophie Ribba Véronique Josserand Jean-Luc Coll Patrick Dallemagne J. Fernando Díaz María ángela Oliva Karin Sadoul Anna Akhmanova Annie Andrieux Laurence Lafanechère doi: 10.3390/cancers12082196 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Article 2196 10.3390/cancers12082196 http://www.ynsqex.icu/2072-6694/12/8/2196
Cancers, Vol. 12, Pages 2198: Key MicroRNA’s and Their Targetome in Adrenocortical Cancer http://www.ynsqex.icu/2072-6694/12/8/2198 Adrenocortical Carcinoma (ACC) is a rare but aggressive malignancy with poor prognosis and limited response to available systemic therapies. Although complete surgical resection gives the best chance for long-term survival, ACC has a two-year recurrence rate of 50%, which poses a therapeutic challenge. High throughput analyses focused on characterizing the molecular signature of ACC have revealed specific micro-RNAs (miRNAs) that are associated with aggressive tumor phenotypes. MiRNAs are small non-coding RNA molecules that regulate gene expression by inhibiting mRNA translation or degrading mRNA transcripts and have been generally implicated in carcinogenesis. This review summarizes the current insights into dysregulated miRNAs in ACC tumorigenesis, their known functions, and specific targetomes. In addition, we explore the possibility of particular miRNAs to be exploited as clinical biomarkers in ACC and as potential therapeutics. Cancers, Vol. 12, Pages 2198: Key MicroRNA’s and Their Targetome in Adrenocortical Cancer

Cancers doi: 10.3390/cancers12082198

Authors: Marthe Chehade Martyn Bullock Anthony Glover Gyorgy Hutvagner Stan Sidhu

Adrenocortical Carcinoma (ACC) is a rare but aggressive malignancy with poor prognosis and limited response to available systemic therapies. Although complete surgical resection gives the best chance for long-term survival, ACC has a two-year recurrence rate of 50%, which poses a therapeutic challenge. High throughput analyses focused on characterizing the molecular signature of ACC have revealed specific micro-RNAs (miRNAs) that are associated with aggressive tumor phenotypes. MiRNAs are small non-coding RNA molecules that regulate gene expression by inhibiting mRNA translation or degrading mRNA transcripts and have been generally implicated in carcinogenesis. This review summarizes the current insights into dysregulated miRNAs in ACC tumorigenesis, their known functions, and specific targetomes. In addition, we explore the possibility of particular miRNAs to be exploited as clinical biomarkers in ACC and as potential therapeutics.

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Key MicroRNA’s and Their Targetome in Adrenocortical Cancer Marthe Chehade Martyn Bullock Anthony Glover Gyorgy Hutvagner Stan Sidhu doi: 10.3390/cancers12082198 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2198 10.3390/cancers12082198 http://www.ynsqex.icu/2072-6694/12/8/2198
Cancers, Vol. 12, Pages 2195: Menopausal Hormone Therapy and Risk of Endometrial Cancer: A Systematic Review http://www.ynsqex.icu/2072-6694/12/8/2195 Background: Menopausal hormone therapy (MHT) is an appropriate treatment for women with the climacteric syndrome. The estrogen component of MHT effectively alleviates climacteric symptoms but also stimulates the endometrium and thus may increase the risk of endometrial cancer (EC). Materials and Methods: We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify controlled and uncontrolled clinical trials reporting on the prevalence and/or incidence of EC among women using MHT. Results: 31 publications reporting on 21,306 women with EC diagnosed during or after MHT were identified. A significantly reduced risk of EC among continuous-combined (cc)MHT users with synthetic progestins (SPs) was demonstrated in 10/19 studies with odds ratios (ORs)/hazard ratios (HRs) between 0.24 and 0.71. Only one study documented an increased risk of EC among long-term users (≥10 years), not confirmed in three other sub-group analyses of women with ≥6, ≥5, and >10 years of ccMHT use. A significantly increased risk of EC among users of sequential-combined (sc)MHT with SPs was demonstrated in 6/12 studies with ORs/HRs between 1.38 and 4.35. Number of days of progestin per month was a significant modulator of EC risk. A decreased risk of EC was seen in obese women. Two studies documented an increased risk of EC among users of cc/scMHT with micronized progesterone. A significantly increased risk of EC among estrogen-only MHT users was demonstrated in 9/12 studies with ORs/HRs between 1.45 and 4.46. The adverse effect of estrogen-only MHT was greatest among obese women. Conclusion: ccMHT with SPs reduces the risk of EC, whereas estrogen-only MHT increases the risk. scMHT with SPs and cc/scMHT with micronized progesterone increase the risk of EC depending on type of progestin, progestin dosage, and duration of MHT use. Cancers, Vol. 12, Pages 2195: Menopausal Hormone Therapy and Risk of Endometrial Cancer: A Systematic Review

Cancers doi: 10.3390/cancers12082195

Authors: Clemens B. Tempfer Ziad Hilal Peter Kern Ingolf Juhasz-Boess Günther A. Rezniczek

Background: Menopausal hormone therapy (MHT) is an appropriate treatment for women with the climacteric syndrome. The estrogen component of MHT effectively alleviates climacteric symptoms but also stimulates the endometrium and thus may increase the risk of endometrial cancer (EC). Materials and Methods: We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify controlled and uncontrolled clinical trials reporting on the prevalence and/or incidence of EC among women using MHT. Results: 31 publications reporting on 21,306 women with EC diagnosed during or after MHT were identified. A significantly reduced risk of EC among continuous-combined (cc)MHT users with synthetic progestins (SPs) was demonstrated in 10/19 studies with odds ratios (ORs)/hazard ratios (HRs) between 0.24 and 0.71. Only one study documented an increased risk of EC among long-term users (≥10 years), not confirmed in three other sub-group analyses of women with ≥6, ≥5, and >10 years of ccMHT use. A significantly increased risk of EC among users of sequential-combined (sc)MHT with SPs was demonstrated in 6/12 studies with ORs/HRs between 1.38 and 4.35. Number of days of progestin per month was a significant modulator of EC risk. A decreased risk of EC was seen in obese women. Two studies documented an increased risk of EC among users of cc/scMHT with micronized progesterone. A significantly increased risk of EC among estrogen-only MHT users was demonstrated in 9/12 studies with ORs/HRs between 1.45 and 4.46. The adverse effect of estrogen-only MHT was greatest among obese women. Conclusion: ccMHT with SPs reduces the risk of EC, whereas estrogen-only MHT increases the risk. scMHT with SPs and cc/scMHT with micronized progesterone increase the risk of EC depending on type of progestin, progestin dosage, and duration of MHT use.

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Menopausal Hormone Therapy and Risk of Endometrial Cancer: A Systematic Review Clemens B. Tempfer Ziad Hilal Peter Kern Ingolf Juhasz-Boess Günther A. Rezniczek doi: 10.3390/cancers12082195 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2195 10.3390/cancers12082195 http://www.ynsqex.icu/2072-6694/12/8/2195
Cancers, Vol. 12, Pages 2194: Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses http://www.ynsqex.icu/2072-6694/12/8/2194 The myeloproliferative neoplasms (MPNs) are acquired hematological stem cell neoplasms characterized by driver mutations in JAK2, CALR, or MPL. Additive mutations may appear in predominantly epigenetic regulator, RNA splicing and signaling pathway genes. These molecular mutations are a hallmark of diagnostic, prognostic, and therapeutic assessment in patients with MPNs. Over the past decade, next generation sequencing (NGS) has identified multiple somatic mutations in MPNs and has contributed substantially to our understanding of the disease pathogenesis highlighting the role of clonal evolution in disease progression. In addition, disease prognostication has expanded from encompassing only clinical decision making to include genomics in prognostic scoring systems. Taking into account the decreasing costs and increasing speed and availability of high throughput technologies, the integration of NGS into a diagnostic, prognostic and therapeutic pipeline is within reach. In this review, these aspects will be discussed highlighting their role regarding disease outcome and treatment modalities in patients with MPNs. Cancers, Vol. 12, Pages 2194: Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses

Cancers doi: 10.3390/cancers12082194

Authors: Vibe Skov

The myeloproliferative neoplasms (MPNs) are acquired hematological stem cell neoplasms characterized by driver mutations in JAK2, CALR, or MPL. Additive mutations may appear in predominantly epigenetic regulator, RNA splicing and signaling pathway genes. These molecular mutations are a hallmark of diagnostic, prognostic, and therapeutic assessment in patients with MPNs. Over the past decade, next generation sequencing (NGS) has identified multiple somatic mutations in MPNs and has contributed substantially to our understanding of the disease pathogenesis highlighting the role of clonal evolution in disease progression. In addition, disease prognostication has expanded from encompassing only clinical decision making to include genomics in prognostic scoring systems. Taking into account the decreasing costs and increasing speed and availability of high throughput technologies, the integration of NGS into a diagnostic, prognostic and therapeutic pipeline is within reach. In this review, these aspects will be discussed highlighting their role regarding disease outcome and treatment modalities in patients with MPNs.

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Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses Vibe Skov doi: 10.3390/cancers12082194 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2194 10.3390/cancers12082194 http://www.ynsqex.icu/2072-6694/12/8/2194
Cancers, Vol. 12, Pages 2193: Immune-Modulating Effects of Conventional Therapies in Colorectal Cancer http://www.ynsqex.icu/2072-6694/12/8/2193 Biological heterogeneity and low inherent immunogenicity are two features that greatly impact therapeutic management and outcome in colorectal cancer. Despite high local control rates, systemic tumor dissemination remains the main cause of treatment failure and stresses the need for new developments in combined-modality approaches. While the role of adaptive immune responses in a small subgroup of colorectal tumors with inherent immunogenicity is indisputable, the challenge remains in identifying the optimal synergy between conventional treatment modalities and immune therapy for the majority of the less immunogenic cases. In this context, cytotoxic agents such as radiation and certain chemotherapeutics can be utilized to enhance the immunogenicity of an otherwise immunologically silent disease and enable responsiveness to immune therapy. In this review, we explore the immunological characteristics of colorectal cancer, the effects that standard-of-care treatments have on the immune system, and the opportunities arising from combining immune checkpoint-blocking therapy with immune-modulating conventional treatments. Cancers, Vol. 12, Pages 2193: Immune-Modulating Effects of Conventional Therapies in Colorectal Cancer

Cancers doi: 10.3390/cancers12082193

Authors: Erta Kalanxhi Sebastian Meltzer Anne Hansen Ree

Biological heterogeneity and low inherent immunogenicity are two features that greatly impact therapeutic management and outcome in colorectal cancer. Despite high local control rates, systemic tumor dissemination remains the main cause of treatment failure and stresses the need for new developments in combined-modality approaches. While the role of adaptive immune responses in a small subgroup of colorectal tumors with inherent immunogenicity is indisputable, the challenge remains in identifying the optimal synergy between conventional treatment modalities and immune therapy for the majority of the less immunogenic cases. In this context, cytotoxic agents such as radiation and certain chemotherapeutics can be utilized to enhance the immunogenicity of an otherwise immunologically silent disease and enable responsiveness to immune therapy. In this review, we explore the immunological characteristics of colorectal cancer, the effects that standard-of-care treatments have on the immune system, and the opportunities arising from combining immune checkpoint-blocking therapy with immune-modulating conventional treatments.

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Immune-Modulating Effects of Conventional Therapies in Colorectal Cancer Erta Kalanxhi Sebastian Meltzer Anne Hansen Ree doi: 10.3390/cancers12082193 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2193 10.3390/cancers12082193 http://www.ynsqex.icu/2072-6694/12/8/2193
Cancers, Vol. 12, Pages 2192: First-Line Treatment for Primary Breast Diffuse Large B-Cell Lymphoma Using Immunochemotherapy and Central Nervous System Prophylaxis: A Multicenter Phase 2 Trial http://www.ynsqex.icu/2072-6694/12/8/2192 There are limited data from prospective controlled trials regarding optimal treatment strategies in patients with primary breast diffuse large B-cell lymphoma (DLBCL). In this phase 2 study (NCT01448096), we examined the efficacy and safety of standard immunochemotherapy and central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX). Thirty-three patients with newly diagnosed primary breast DLBCL received six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and four fixed doses of IT-MTX (12 mg). The median age was 50 years (range, 29–75), and all patients were females. According to the CNS-International Prognostic Index, most patients (n = 28) were categorized as the low-risk group. Among the 33 patients, 32 completed R-CHOP, and 31 completed IT-MTX as planned. With a median follow-up of 46.1 months (interquartile range (IQR), 31.1–66.8), the 2-year progression-free and overall survival rates were 81.3% and 93.5%, respectively. Six patients experienced treatment failures, which included the CNS in four patients (two parenchyma and two leptomeninges) and breast in two patients (one ipsilateral and one contralateral). The 2-year cumulative incidence of CNS relapse was 12.5%. Although standard R-CHOP and IT-MTX without routine radiotherapy show clinically meaningful survival outcomes, this strategy may not be optimal for reducing CNS relapse and warrants further investigation. Cancers, Vol. 12, Pages 2192: First-Line Treatment for Primary Breast Diffuse Large B-Cell Lymphoma Using Immunochemotherapy and Central Nervous System Prophylaxis: A Multicenter Phase 2 Trial

Cancers doi: 10.3390/cancers12082192

Authors: Ho-Young Yhim Dok Hyun Yoon Seok Jin Kim Deok-Hwan Yang Hyeon-Seok Eom Kyoung Ha Kim Yong Park Jin Seok Kim Hyo Jung Kim Cheolwon Suh Won Seog Kim Jae-Yong Kwak

There are limited data from prospective controlled trials regarding optimal treatment strategies in patients with primary breast diffuse large B-cell lymphoma (DLBCL). In this phase 2 study (NCT01448096), we examined the efficacy and safety of standard immunochemotherapy and central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX). Thirty-three patients with newly diagnosed primary breast DLBCL received six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and four fixed doses of IT-MTX (12 mg). The median age was 50 years (range, 29–75), and all patients were females. According to the CNS-International Prognostic Index, most patients (n = 28) were categorized as the low-risk group. Among the 33 patients, 32 completed R-CHOP, and 31 completed IT-MTX as planned. With a median follow-up of 46.1 months (interquartile range (IQR), 31.1–66.8), the 2-year progression-free and overall survival rates were 81.3% and 93.5%, respectively. Six patients experienced treatment failures, which included the CNS in four patients (two parenchyma and two leptomeninges) and breast in two patients (one ipsilateral and one contralateral). The 2-year cumulative incidence of CNS relapse was 12.5%. Although standard R-CHOP and IT-MTX without routine radiotherapy show clinically meaningful survival outcomes, this strategy may not be optimal for reducing CNS relapse and warrants further investigation.

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First-Line Treatment for Primary Breast Diffuse Large B-Cell Lymphoma Using Immunochemotherapy and Central Nervous System Prophylaxis: A Multicenter Phase 2 Trial Ho-Young Yhim Dok Hyun Yoon Seok Jin Kim Deok-Hwan Yang Hyeon-Seok Eom Kyoung Ha Kim Yong Park Jin Seok Kim Hyo Jung Kim Cheolwon Suh Won Seog Kim Jae-Yong Kwak doi: 10.3390/cancers12082192 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Article 2192 10.3390/cancers12082192 http://www.ynsqex.icu/2072-6694/12/8/2192
Cancers, Vol. 12, Pages 2191: Development of [18F]ICMT-11 for Imaging Caspase-3/7 Activity during Therapy-Induced Apoptosis http://www.ynsqex.icu/2072-6694/12/8/2191 Insufficient apoptosis is a recognised hallmark of cancer. A strategy to quantitatively measure apoptosis in vivo would be of immense value in both drug discovery and routine patient management. The first irreversible step in the apoptosis cascade is activation of the “executioner” caspase-3 enzyme to commence cleavage of key structural proteins. One strategy to measure caspase-3 activity is Positron Emission Tomography using isatin-5-sulfonamide radiotracers. One such radiotracer is [18F]ICMT-11, which has progressed to clinical application. This review summarises the design and development process for [18F]ICMT-11, suggesting potential avenues for further innovation. Cancers, Vol. 12, Pages 2191: Development of [18F]ICMT-11 for Imaging Caspase-3/7 Activity during Therapy-Induced Apoptosis

Cancers doi: 10.3390/cancers12082191

Authors: Segundo Francisco García-Argüello Beatriz Lopez-Lorenzo Bart Cornelissen Graham Smith

Insufficient apoptosis is a recognised hallmark of cancer. A strategy to quantitatively measure apoptosis in vivo would be of immense value in both drug discovery and routine patient management. The first irreversible step in the apoptosis cascade is activation of the “executioner” caspase-3 enzyme to commence cleavage of key structural proteins. One strategy to measure caspase-3 activity is Positron Emission Tomography using isatin-5-sulfonamide radiotracers. One such radiotracer is [18F]ICMT-11, which has progressed to clinical application. This review summarises the design and development process for [18F]ICMT-11, suggesting potential avenues for further innovation.

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Development of [18F]ICMT-11 for Imaging Caspase-3/7 Activity during Therapy-Induced Apoptosis Segundo Francisco García-Argüello Beatriz Lopez-Lorenzo Bart Cornelissen Graham Smith doi: 10.3390/cancers12082191 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2191 10.3390/cancers12082191 http://www.ynsqex.icu/2072-6694/12/8/2191
Cancers, Vol. 12, Pages 2190: Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine http://www.ynsqex.icu/2072-6694/12/8/2190 Biliary tract cancers (BTCs) are a group of rare cancers that account for up to 3–5% of cancer patients worldwide. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). They are frequently diagnosed at an advanced stage when the disease is often found disseminated. A late diagnosis highly compromises surgery, the only potentially curative option. Current treatment regimens include a combination of chemotherapeutic drugs gemcitabine with cisplatin that have a limited efficiency since more than 50% of patients relapse in the first year. More recently, an inhibitor of fibroblast growth factor receptor 2 (FGFR2) was approved as a second-line treatment, based on the promising results from the NCT02924376 clinical trial. However, novel secondary treatment options are urgently needed. Recent molecular characterization of CCA and GBC highlighted the molecular heterogeneity, etiology, and epidemiology in BTC development and lead to the classification of the extrahepatic CCA into four types: metabolic, proliferating, mesenchymal, and immune type. Differences in the immune infiltration and tumor microenvironment (TME) have been described as well, showing that only a small subset of BTCs could be classified as an immune “hot” and targeted with the immunotherapeutic drugs. This recent evidence has opened a way to new clinical trials for BTCs, and new drug approvals are highly expected by the medical community. Cancers, Vol. 12, Pages 2190: Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine

Cancers doi: 10.3390/cancers12082190

Authors: Ines Malenica Matteo Donadon Ana Lleo

Biliary tract cancers (BTCs) are a group of rare cancers that account for up to 3–5% of cancer patients worldwide. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). They are frequently diagnosed at an advanced stage when the disease is often found disseminated. A late diagnosis highly compromises surgery, the only potentially curative option. Current treatment regimens include a combination of chemotherapeutic drugs gemcitabine with cisplatin that have a limited efficiency since more than 50% of patients relapse in the first year. More recently, an inhibitor of fibroblast growth factor receptor 2 (FGFR2) was approved as a second-line treatment, based on the promising results from the NCT02924376 clinical trial. However, novel secondary treatment options are urgently needed. Recent molecular characterization of CCA and GBC highlighted the molecular heterogeneity, etiology, and epidemiology in BTC development and lead to the classification of the extrahepatic CCA into four types: metabolic, proliferating, mesenchymal, and immune type. Differences in the immune infiltration and tumor microenvironment (TME) have been described as well, showing that only a small subset of BTCs could be classified as an immune “hot” and targeted with the immunotherapeutic drugs. This recent evidence has opened a way to new clinical trials for BTCs, and new drug approvals are highly expected by the medical community.

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Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine Ines Malenica Matteo Donadon Ana Lleo doi: 10.3390/cancers12082190 Cancers 2020-08-06 Cancers 2020-08-06 12 8 Review 2190 10.3390/cancers12082190 http://www.ynsqex.icu/2072-6694/12/8/2190
Cancers, Vol. 12, Pages 2189: Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo http://www.ynsqex.icu/2072-6694/12/8/2189 Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal-2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression. Cancers, Vol. 12, Pages 2189: Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo

Cancers doi: 10.3390/cancers12082189

Authors: Wan-Pei Su Wan-Jen Wang Jean-Yun Chang Pei-Chuan Ho Tsung-Yun Liu Kuang-Yu Wen Hsiang-Ling Kuo Yu-Jie Chen Shenq-Shyang Huang Dudekula Subhan Yu-An Chen Chen-Yu Lu Chia-Yun Wu Sing-Ru Lin Ming-Hui Lee Ming-Fu Chiang Chun-I Sze Nan-Shan Chang

Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal-2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression.

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Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo Wan-Pei Su Wan-Jen Wang Jean-Yun Chang Pei-Chuan Ho Tsung-Yun Liu Kuang-Yu Wen Hsiang-Ling Kuo Yu-Jie Chen Shenq-Shyang Huang Dudekula Subhan Yu-An Chen Chen-Yu Lu Chia-Yun Wu Sing-Ru Lin Ming-Hui Lee Ming-Fu Chiang Chun-I Sze Nan-Shan Chang doi: 10.3390/cancers12082189 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2189 10.3390/cancers12082189 http://www.ynsqex.icu/2072-6694/12/8/2189
Cancers, Vol. 12, Pages 2185: The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications http://www.ynsqex.icu/2072-6694/12/8/2185 Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review. Cancers, Vol. 12, Pages 2185: The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

Cancers doi: 10.3390/cancers12082185

Authors: Sheng-Kai Hsu Wen-Tsan Chang I-Ling Lin Yih-Fung Chen Nitin Balkrushna Padalwar Kai-Chun Cheng Yen-Ni Teng Chi-Huei Wang Chien-Chih Chiu

Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review.

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The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications Sheng-Kai Hsu Wen-Tsan Chang I-Ling Lin Yih-Fung Chen Nitin Balkrushna Padalwar Kai-Chun Cheng Yen-Ni Teng Chi-Huei Wang Chien-Chih Chiu doi: 10.3390/cancers12082185 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Review 2185 10.3390/cancers12082185 http://www.ynsqex.icu/2072-6694/12/8/2185
Cancers, Vol. 12, Pages 2188: YB-1 Mediates TNF-Induced Pro-Survival Signaling by Regulating NF-κB Activation http://www.ynsqex.icu/2072-6694/12/8/2188 Cell fate decisions regulating survival and death are essential for maintaining tissue homeostasis; dysregulation thereof can lead to tumor development. In some cases, survival and death are triggered by the same receptor, e.g., tumor necrosis factor (TNF)-receptor 1 (TNFR1). We identified a prominent role for the cold shock Y-box binding protein-1 (YB-1) in the TNF-induced activation and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65. In the absence of YB-1, the expression of TNF receptor-associated factor 2 (TRAF2), a central component of the TNF receptor signaling complex required for NF-κB activation, is significantly reduced. Therefore, we hypothesized that the loss of YB-1 results in a destabilization of TRAF2. Consistent with this hypothesis, we observed that YB-1-deficient cells were more prone to TNF-induced apoptotic cell death. We observed enhanced effector caspase-3 activation and could successfully rescue the cells using the pan-caspase inhibitor zVAD-fmk, but not necrostatin-1. Taken together, our results indicate that YB-1 plays a central role in promoting cell survival through NF-κB activation and identifies a novel mechanism by which enhanced YB-1 expression may contribute to tumor development. Cancers, Vol. 12, Pages 2188: YB-1 Mediates TNF-Induced Pro-Survival Signaling by Regulating NF-κB Activation

Cancers doi: 10.3390/cancers12082188

Authors: Aneri Shah Carlos Plaza-Sirvent S?nke Weinert J?rn H. Buchbinder Inna N. Lavrik Peter R. Mertens Ingo Schmitz Jonathan A. Lindquist

Cell fate decisions regulating survival and death are essential for maintaining tissue homeostasis; dysregulation thereof can lead to tumor development. In some cases, survival and death are triggered by the same receptor, e.g., tumor necrosis factor (TNF)-receptor 1 (TNFR1). We identified a prominent role for the cold shock Y-box binding protein-1 (YB-1) in the TNF-induced activation and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65. In the absence of YB-1, the expression of TNF receptor-associated factor 2 (TRAF2), a central component of the TNF receptor signaling complex required for NF-κB activation, is significantly reduced. Therefore, we hypothesized that the loss of YB-1 results in a destabilization of TRAF2. Consistent with this hypothesis, we observed that YB-1-deficient cells were more prone to TNF-induced apoptotic cell death. We observed enhanced effector caspase-3 activation and could successfully rescue the cells using the pan-caspase inhibitor zVAD-fmk, but not necrostatin-1. Taken together, our results indicate that YB-1 plays a central role in promoting cell survival through NF-κB activation and identifies a novel mechanism by which enhanced YB-1 expression may contribute to tumor development.

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YB-1 Mediates TNF-Induced Pro-Survival Signaling by Regulating NF-κB Activation Aneri Shah Carlos Plaza-Sirvent S?nke Weinert J?rn H. Buchbinder Inna N. Lavrik Peter R. Mertens Ingo Schmitz Jonathan A. Lindquist doi: 10.3390/cancers12082188 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2188 10.3390/cancers12082188 http://www.ynsqex.icu/2072-6694/12/8/2188
Cancers, Vol. 12, Pages 2187: Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia http://www.ynsqex.icu/2072-6694/12/8/2187 NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR+NKG2A−CD57+ NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed. Cancers, Vol. 12, Pages 2187: Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia

Cancers doi: 10.3390/cancers12082187

Authors: Raffaella Meazza Michela Falco Fabrizio Loiacono Paolo Canevali Mariella Della Chiesa Alice Bertaina Daria Pagliara Pietro Merli Valentina Indio Federica Galaverna Mattia Algeri Francesca Moretta Natalia Colomar-Carando Letizia Muccio Simona Sivori Andrea Pession Maria Cristina Mingari Lorenzo Moretta Alessandro Moretta Franco Locatelli Daniela Pende

NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR+NKG2A−CD57+ NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed.

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Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia Raffaella Meazza Michela Falco Fabrizio Loiacono Paolo Canevali Mariella Della Chiesa Alice Bertaina Daria Pagliara Pietro Merli Valentina Indio Federica Galaverna Mattia Algeri Francesca Moretta Natalia Colomar-Carando Letizia Muccio Simona Sivori Andrea Pession Maria Cristina Mingari Lorenzo Moretta Alessandro Moretta Franco Locatelli Daniela Pende doi: 10.3390/cancers12082187 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2187 10.3390/cancers12082187 http://www.ynsqex.icu/2072-6694/12/8/2187
Cancers, Vol. 12, Pages 2186: SARS-CoV-2 Infection and Lung Cancer: Potential Therapeutic Modalities http://www.ynsqex.icu/2072-6694/12/8/2186 Human coronaviruses, especially SARS-CoV-2, are emerging pandemic infectious diseases with high morbidity and mortality in certain group of patients. In general, SARS-CoV-2 causes symptoms ranging from the common cold to severe conditions accompanied by lung injury, acute respiratory distress syndrome in addition to other organs’ destruction. The main impact upon SARS-CoV-2 infection is damage to alveolar and acute respiratory failure. Thus, lung cancer patients are identified as a particularly high-risk group for SARS-CoV-2 infection and its complications. On the other hand, it has been reported that SARS-CoV-2 spike (S) protein binds to angiotensin-converting enzyme 2 (ACE-2), that promotes cellular entry of this virus in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2). Today, there are no vaccines and/or effective drugs against the SARS-CoV-2 coronavirus. Thus, manipulation of key entry genes of this virus especially in lung cancer patients could be one of the best approaches to manage SARS-CoV-2 infection in this group of patients. We herein provide a comprehensive and up-to-date overview of the role of ACE-2 and TMPRSS2 genes, as key entry elements as well as therapeutic targets for SARS-CoV-2 infection, which can help to better understand the applications and capacities of various remedial approaches for infected individuals, especially those with lung cancer. Cancers, Vol. 12, Pages 2186: SARS-CoV-2 Infection and Lung Cancer: Potential Therapeutic Modalities

Cancers doi: 10.3390/cancers12082186

Authors: Ishita Gupta Balsam Rizeq Eyad Elkord Semir Vranic Ala-Eddin Al Moustafa

Human coronaviruses, especially SARS-CoV-2, are emerging pandemic infectious diseases with high morbidity and mortality in certain group of patients. In general, SARS-CoV-2 causes symptoms ranging from the common cold to severe conditions accompanied by lung injury, acute respiratory distress syndrome in addition to other organs’ destruction. The main impact upon SARS-CoV-2 infection is damage to alveolar and acute respiratory failure. Thus, lung cancer patients are identified as a particularly high-risk group for SARS-CoV-2 infection and its complications. On the other hand, it has been reported that SARS-CoV-2 spike (S) protein binds to angiotensin-converting enzyme 2 (ACE-2), that promotes cellular entry of this virus in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2). Today, there are no vaccines and/or effective drugs against the SARS-CoV-2 coronavirus. Thus, manipulation of key entry genes of this virus especially in lung cancer patients could be one of the best approaches to manage SARS-CoV-2 infection in this group of patients. We herein provide a comprehensive and up-to-date overview of the role of ACE-2 and TMPRSS2 genes, as key entry elements as well as therapeutic targets for SARS-CoV-2 infection, which can help to better understand the applications and capacities of various remedial approaches for infected individuals, especially those with lung cancer.

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SARS-CoV-2 Infection and Lung Cancer: Potential Therapeutic Modalities Ishita Gupta Balsam Rizeq Eyad Elkord Semir Vranic Ala-Eddin Al Moustafa doi: 10.3390/cancers12082186 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Review 2186 10.3390/cancers12082186 http://www.ynsqex.icu/2072-6694/12/8/2186
Cancers, Vol. 12, Pages 2180: Characteristics of PSA Bounce after Radiotherapy for Prostate Cancer: A Meta-Analysis http://www.ynsqex.icu/2072-6694/12/8/2180 The rate and characteristics of prostate-specific antigen (PSA) bounce post-radiotherapy remain unclear. To address this issue, we performed a meta-analysis. Reports of PSA bounce post-radiotherapy with a cutoff of 0.2 ng/mL were searched by using Medline and Web of Science. The primary endpoint was the occurrence rate, and the secondary endpoints were bounce characteristics such as amplitude, time to occurrence, nadir value, and time to nadir. Radiotherapy modality, age, risk classification, androgen deprivation therapy, and the follow-up period were extracted as clinical variables. Meta-analysis and univariate meta-regression were performed with random-effect modeling. Among 290 search-positive studies, 50 reports including 26,258 patients were identified. The rate of bounce was 31%; amplitude was 1.3 ng/mL; time to occurrence was 18 months; nadir value was 0.5 ng/mL; time to nadir was 33 months. Univariate meta-regression analysis showed that radiotherapy modality (29.7%), age (20.2%), and risk classification (12.2%) were the major causes of heterogeneity in the rate of bounce. This is the first meta-analysis of PSA bounce post-radiotherapy. The results are useful for post-radiotherapy surveillance of prostate cancer patients. Cancers, Vol. 12, Pages 2180: Characteristics of PSA Bounce after Radiotherapy for Prostate Cancer: A Meta-Analysis

Cancers doi: 10.3390/cancers12082180

Authors: Narisa Dewi Maulany Darwis Takahiro Oike Nobuteru Kubo Soehartati A Gondhowiardjo Tatsuya Ohno

The rate and characteristics of prostate-specific antigen (PSA) bounce post-radiotherapy remain unclear. To address this issue, we performed a meta-analysis. Reports of PSA bounce post-radiotherapy with a cutoff of 0.2 ng/mL were searched by using Medline and Web of Science. The primary endpoint was the occurrence rate, and the secondary endpoints were bounce characteristics such as amplitude, time to occurrence, nadir value, and time to nadir. Radiotherapy modality, age, risk classification, androgen deprivation therapy, and the follow-up period were extracted as clinical variables. Meta-analysis and univariate meta-regression were performed with random-effect modeling. Among 290 search-positive studies, 50 reports including 26,258 patients were identified. The rate of bounce was 31%; amplitude was 1.3 ng/mL; time to occurrence was 18 months; nadir value was 0.5 ng/mL; time to nadir was 33 months. Univariate meta-regression analysis showed that radiotherapy modality (29.7%), age (20.2%), and risk classification (12.2%) were the major causes of heterogeneity in the rate of bounce. This is the first meta-analysis of PSA bounce post-radiotherapy. The results are useful for post-radiotherapy surveillance of prostate cancer patients.

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Characteristics of PSA Bounce after Radiotherapy for Prostate Cancer: A Meta-Analysis Narisa Dewi Maulany Darwis Takahiro Oike Nobuteru Kubo Soehartati A Gondhowiardjo Tatsuya Ohno doi: 10.3390/cancers12082180 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2180 10.3390/cancers12082180 http://www.ynsqex.icu/2072-6694/12/8/2180
Cancers, Vol. 12, Pages 2183: Cancer Cell Acid Adaptation Gene Expression Response Is Correlated to Tumor-Specific Tissue Expression Profiles and Patient Survival http://www.ynsqex.icu/2072-6694/12/8/2183 The acidic pH of the tumor microenvironment plays a critical role in driving cancer development toward a more aggressive phenotype, but the underlying mechanisms are unclear. To this end, phenotypic and genotypic changes induced by adaptation of cancer cells to chronic acidosis have been studied. However, the generality of acid adaptation patterns across cell models and their correlation to the molecular phenotypes and aggressiveness of human cancers are essentially unknown. Here, we define an acid adaptation expression response shared across three cancer cell models, dominated by metabolic rewiring, extracellular matrix remodeling, and altered cell cycle regulation and DNA damage response. We find that many genes which are upregulated by acid adaptation are significantly correlated to patient survival, and more generally, that there are clear correlations between acid adaptation expression response and gene expression change between normal and tumor tissues, for a large subset of cancer patients. Our data support the notion that tumor microenvironment acidity is one of the key factors driving the selection of aggressive cancer cells in human patient tumors, yet it also induces a growth-limiting genotype that likely limits cancer cell growth until the cells are released from acidosis, for instance during invasion. Cancers, Vol. 12, Pages 2183: Cancer Cell Acid Adaptation Gene Expression Response Is Correlated to Tumor-Specific Tissue Expression Profiles and Patient Survival

Cancers doi: 10.3390/cancers12082183

Authors: Jiayi Yao Dominika Czaplinska Renata Ialchina Julie Schnipper Bin Liu Albin Sandelin Stine Falsig Pedersen

The acidic pH of the tumor microenvironment plays a critical role in driving cancer development toward a more aggressive phenotype, but the underlying mechanisms are unclear. To this end, phenotypic and genotypic changes induced by adaptation of cancer cells to chronic acidosis have been studied. However, the generality of acid adaptation patterns across cell models and their correlation to the molecular phenotypes and aggressiveness of human cancers are essentially unknown. Here, we define an acid adaptation expression response shared across three cancer cell models, dominated by metabolic rewiring, extracellular matrix remodeling, and altered cell cycle regulation and DNA damage response. We find that many genes which are upregulated by acid adaptation are significantly correlated to patient survival, and more generally, that there are clear correlations between acid adaptation expression response and gene expression change between normal and tumor tissues, for a large subset of cancer patients. Our data support the notion that tumor microenvironment acidity is one of the key factors driving the selection of aggressive cancer cells in human patient tumors, yet it also induces a growth-limiting genotype that likely limits cancer cell growth until the cells are released from acidosis, for instance during invasion.

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Cancer Cell Acid Adaptation Gene Expression Response Is Correlated to Tumor-Specific Tissue Expression Profiles and Patient Survival Jiayi Yao Dominika Czaplinska Renata Ialchina Julie Schnipper Bin Liu Albin Sandelin Stine Falsig Pedersen doi: 10.3390/cancers12082183 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2183 10.3390/cancers12082183 http://www.ynsqex.icu/2072-6694/12/8/2183
Cancers, Vol. 12, Pages 2184: Conditional Probability of Survival and Prognostic Factors in Long-Term Survivors of High-Grade Serous Ovarian Cancer http://www.ynsqex.icu/2072-6694/12/8/2184 Objective: High-grade serous ovarian cancers (HGSOC) are heterogeneous, often diagnosed at an advanced stage, and associated with poor overall survival (OS, 39% at five years). There are few data about the prognostic factors of late relapses in HGSOC patients who survived ≥five years, long-term survivors (LTS). The aim of our study is to assess the probability of survival according to the already survived time from diagnosis. Methods: Data from HGSOC patients treated between 1995 and 2016 were retrospectively collected to estimate the conditional probability of survival (CPS), probability of surviving Y years after diagnosis when the patient had already survived X years, and to determine the LTS prognostic factors. The primary endpoint was OS. Results: 404 patients were included; 120 of them were LTS. Patients were aged 61 years (range: 20–89), WHO performance status 0–1 in 86.9% and 2 in 13.1%, and Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) staging III and IV in 82.7% and 17.3% patients. Breast cancer (BRCA) status was available in 116 patients (33% mutated), including 58 LTS (36% mutated). No macroscopic residual disease was observed in 58.4% patients. First-line platinum-based chemotherapy plus paclitaxel was administered in 80.4% of patients (median: six cycles (range: 1–14)). After a 9 point 3-year follow-up, median OS was four years (95% CI: 3.6–4.5). The CPS at five years after surviving one year was 42.8% (95% CI: 35.3–48.3); it increased to 81.7% (95% CI: 75.5–87.8) after four survived years. Progression-free interval>18 months was the only LTS prognostic factor in the multivariable analysis (hazard ratio (HR) = 0.23; 95% CI: 0.13–0.40; p < 0.001). Conclusion: The CPS provided relevant and encouraging clinical information on the life expectancy of HGSOC patients who already survived a period of time after diagnosis. LTS prognostic factors are useful for clinicians and patients. Cancers, Vol. 12, Pages 2184: Conditional Probability of Survival and Prognostic Factors in Long-Term Survivors of High-Grade Serous Ovarian Cancer

Cancers doi: 10.3390/cancers12082184

Authors: Michel Fabbro Pierre-Emmanuel Colombo Cristina Marinella Leaha Philippe Rouanet Sébastien Carrère Fran?ois Quenet Marian Gutowski Anne Mourregot Véronique D’Hondt Isabelle Coupier Julie Vendrell Paul Vilquin Pascal Pujol Jér?me Solassol Caroline Mollevi

Objective: High-grade serous ovarian cancers (HGSOC) are heterogeneous, often diagnosed at an advanced stage, and associated with poor overall survival (OS, 39% at five years). There are few data about the prognostic factors of late relapses in HGSOC patients who survived ≥five years, long-term survivors (LTS). The aim of our study is to assess the probability of survival according to the already survived time from diagnosis. Methods: Data from HGSOC patients treated between 1995 and 2016 were retrospectively collected to estimate the conditional probability of survival (CPS), probability of surviving Y years after diagnosis when the patient had already survived X years, and to determine the LTS prognostic factors. The primary endpoint was OS. Results: 404 patients were included; 120 of them were LTS. Patients were aged 61 years (range: 20–89), WHO performance status 0–1 in 86.9% and 2 in 13.1%, and Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) staging III and IV in 82.7% and 17.3% patients. Breast cancer (BRCA) status was available in 116 patients (33% mutated), including 58 LTS (36% mutated). No macroscopic residual disease was observed in 58.4% patients. First-line platinum-based chemotherapy plus paclitaxel was administered in 80.4% of patients (median: six cycles (range: 1–14)). After a 9 point 3-year follow-up, median OS was four years (95% CI: 3.6–4.5). The CPS at five years after surviving one year was 42.8% (95% CI: 35.3–48.3); it increased to 81.7% (95% CI: 75.5–87.8) after four survived years. Progression-free interval>18 months was the only LTS prognostic factor in the multivariable analysis (hazard ratio (HR) = 0.23; 95% CI: 0.13–0.40; p < 0.001). Conclusion: The CPS provided relevant and encouraging clinical information on the life expectancy of HGSOC patients who already survived a period of time after diagnosis. LTS prognostic factors are useful for clinicians and patients.

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Conditional Probability of Survival and Prognostic Factors in Long-Term Survivors of High-Grade Serous Ovarian Cancer Michel Fabbro Pierre-Emmanuel Colombo Cristina Marinella Leaha Philippe Rouanet Sébastien Carrère Fran?ois Quenet Marian Gutowski Anne Mourregot Véronique D’Hondt Isabelle Coupier Julie Vendrell Paul Vilquin Pascal Pujol Jér?me Solassol Caroline Mollevi doi: 10.3390/cancers12082184 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2184 10.3390/cancers12082184 http://www.ynsqex.icu/2072-6694/12/8/2184
Cancers, Vol. 12, Pages 2176: Physical Cues in the Microenvironment Regulate Stemness-Dependent Homing of Breast Cancer Cells http://www.ynsqex.icu/2072-6694/12/8/2176 Tissue-specific microenvironmental factors contribute to the targeting preferences of metastatic cancers. However, the physical attributes of the premetastatic microenvironment are not yet fully characterized. In this research, we develop a transwell-based alginate hydrogel (TAH) model to study how permeability, stiffness, and roughness of a hanging alginate hydrogel regulate breast cancer cell homing. In this model, a layer of physically characterized alginate hydrogel is formed at the bottom of a transwell insert, which is placed into a matching culture well with an adherent monolayer of breast cancer cells. We found that breast cancer cells dissociate from the monolayer and home to the TAH for continual growth. The process is facilitated by the presence of rich serum in the upper chamber, the increased stiffness of the gel, as well as its surface roughness. This model is able to support the homing ability of MCF-7 and MDA-MB-231 cells drifting across the vertical distance in the culture medium. Cells homing to the TAH display stemness phenotype morphologically and biochemically. Taken together, these findings suggest that permeability, stiffness, and roughness are important physical factors to regulate breast cancer homing to a premetastatic microenvironment. Cancers, Vol. 12, Pages 2176: Physical Cues in the Microenvironment Regulate Stemness-Dependent Homing of Breast Cancer Cells

Cancers doi: 10.3390/cancers12082176

Authors: Hsueh-Yao Chu Yin-Ju Chen Chun-Jieh Hsu Yang-Wei Liu Jeng-Fong Chiou Long-Sheng Lu Fan-Gang Tseng

Tissue-specific microenvironmental factors contribute to the targeting preferences of metastatic cancers. However, the physical attributes of the premetastatic microenvironment are not yet fully characterized. In this research, we develop a transwell-based alginate hydrogel (TAH) model to study how permeability, stiffness, and roughness of a hanging alginate hydrogel regulate breast cancer cell homing. In this model, a layer of physically characterized alginate hydrogel is formed at the bottom of a transwell insert, which is placed into a matching culture well with an adherent monolayer of breast cancer cells. We found that breast cancer cells dissociate from the monolayer and home to the TAH for continual growth. The process is facilitated by the presence of rich serum in the upper chamber, the increased stiffness of the gel, as well as its surface roughness. This model is able to support the homing ability of MCF-7 and MDA-MB-231 cells drifting across the vertical distance in the culture medium. Cells homing to the TAH display stemness phenotype morphologically and biochemically. Taken together, these findings suggest that permeability, stiffness, and roughness are important physical factors to regulate breast cancer homing to a premetastatic microenvironment.

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Physical Cues in the Microenvironment Regulate Stemness-Dependent Homing of Breast Cancer Cells Hsueh-Yao Chu Yin-Ju Chen Chun-Jieh Hsu Yang-Wei Liu Jeng-Fong Chiou Long-Sheng Lu Fan-Gang Tseng doi: 10.3390/cancers12082176 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2176 10.3390/cancers12082176 http://www.ynsqex.icu/2072-6694/12/8/2176
Cancers, Vol. 12, Pages 2181: Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition http://www.ynsqex.icu/2072-6694/12/8/2181 Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models. Cancers, Vol. 12, Pages 2181: Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition

Cancers doi: 10.3390/cancers12082181

Authors: Hugo Arasanz Carlos Hernández Ana Bocanegra Luisa Chocarro Miren Zuazo Maria Gato Karina Ausin Enrique Santamaría Joaquín Fernández-Irigoyen Gonzalo Fernandez Eva Santamaria Carlos Rodríguez Idoia Blanco-Luquin Ruth Vera David Escors Grazyna Kochan

Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.

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Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition Hugo Arasanz Carlos Hernández Ana Bocanegra Luisa Chocarro Miren Zuazo Maria Gato Karina Ausin Enrique Santamaría Joaquín Fernández-Irigoyen Gonzalo Fernandez Eva Santamaria Carlos Rodríguez Idoia Blanco-Luquin Ruth Vera David Escors Grazyna Kochan doi: 10.3390/cancers12082181 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2181 10.3390/cancers12082181 http://www.ynsqex.icu/2072-6694/12/8/2181
Cancers, Vol. 12, Pages 2182: Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma http://www.ynsqex.icu/2072-6694/12/8/2182 There is an urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations. This is often the case in patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma. Here, we analyzed data from the cutaneous melanoma The Cancer Genome Atlas Network (TCGA) transcriptomic and proteomic databases for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations. Our data indicated higher B-cell CLL/lymphoma 2 (BCL2) expression in melanoma without BRAF hotspot mutations, suggesting that BH3 mimetics, such as ABT-199 (venetoclax, a small molecule against BCL2), may be a potential therapeutic option for these patients. We explored the efficacy of combining two BH3 mimetics, ABT-199 and a myeloid cell leukemia sequence 1 (MCL1) inhibitor (S63845 or S64315/MIK665) in cutaneous, mucosal and acral melanomas, in vitro and in vivo. Our data indicate this combination induced cell death in a broad range of melanoma cell lines, including melanoma initiating cell populations, and was more potent in melanoma cells without BRAF-V600E/K mutations. Our knockdown/knockout experiments suggest that several pro-apoptotic BCL2 family members, BCL2-like 11 (apoptosis facilitator) (BIM), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) or BID, play a role in the combination-induced effects. Overall, our study supports the rationale for combining an MCL1 inhibitor with a BCL2 inhibitor as a therapeutic option in patients with advanced melanoma. Cancers, Vol. 12, Pages 2182: Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma

Cancers doi: 10.3390/cancers12082182

Authors: Nabanita Mukherjee Carol M. Amato Jenette Skees Kaleb J. Todd Karoline A. Lambert William A. Robinson Robert Van Gulick Ryan M. Weight Chiara R. Dart Richard P. Tobin Martin D. McCarter Mayumi Fujita David A. Norris Yiqun G. Shellman

There is an urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations. This is often the case in patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma. Here, we analyzed data from the cutaneous melanoma The Cancer Genome Atlas Network (TCGA) transcriptomic and proteomic databases for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations. Our data indicated higher B-cell CLL/lymphoma 2 (BCL2) expression in melanoma without BRAF hotspot mutations, suggesting that BH3 mimetics, such as ABT-199 (venetoclax, a small molecule against BCL2), may be a potential therapeutic option for these patients. We explored the efficacy of combining two BH3 mimetics, ABT-199 and a myeloid cell leukemia sequence 1 (MCL1) inhibitor (S63845 or S64315/MIK665) in cutaneous, mucosal and acral melanomas, in vitro and in vivo. Our data indicate this combination induced cell death in a broad range of melanoma cell lines, including melanoma initiating cell populations, and was more potent in melanoma cells without BRAF-V600E/K mutations. Our knockdown/knockout experiments suggest that several pro-apoptotic BCL2 family members, BCL2-like 11 (apoptosis facilitator) (BIM), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) or BID, play a role in the combination-induced effects. Overall, our study supports the rationale for combining an MCL1 inhibitor with a BCL2 inhibitor as a therapeutic option in patients with advanced melanoma.

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Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma Nabanita Mukherjee Carol M. Amato Jenette Skees Kaleb J. Todd Karoline A. Lambert William A. Robinson Robert Van Gulick Ryan M. Weight Chiara R. Dart Richard P. Tobin Martin D. McCarter Mayumi Fujita David A. Norris Yiqun G. Shellman doi: 10.3390/cancers12082182 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2182 10.3390/cancers12082182 http://www.ynsqex.icu/2072-6694/12/8/2182
Cancers, Vol. 12, Pages 2179: The Biology of Exosomes in Breast Cancer Progression: Dissemination, Immune Evasion and Metastatic Colonization http://www.ynsqex.icu/2072-6694/12/8/2179 In recent decades, the study of exosome biology has gained growing interest, representing an active area of cancer research with many potential clinical applications. Exosomes are small lipid bilayer particles released by cells with pleiotropic functions that have been reported to regulate the complex intracellular pathway involved in all steps of breast cancer development—from initiation to progression toward a metastatic dissemination. Particularly, the role of these microvesicles has been explored in metastasis, which represents the leading cause of breast cancer morbidity and mortality worldwide. Reports highlight that the plasticity of breast cancer cells, fundamental for the establishment of distant metastasis, may be in part attributed to exosome-carried signals shared between adjacent cells and long-distance cells in the body. In the present review, we will discuss the functions of exosomes in the metastatic breast cancer process and secondary site outgrowth. The possibility to decode the exosome functions in advanced diseases may offer new opportunities for early detection, molecular targeted therapies and exosome-based therapeutics in breast cancer. Cancers, Vol. 12, Pages 2179: The Biology of Exosomes in Breast Cancer Progression: Dissemination, Immune Evasion and Metastatic Colonization

Cancers doi: 10.3390/cancers12082179

Authors: Cinzia Giordano Giusi La Camera Luca Gelsomino Ines Barone Daniela Bonofiglio Sebastiano Andò Stefania Catalano

In recent decades, the study of exosome biology has gained growing interest, representing an active area of cancer research with many potential clinical applications. Exosomes are small lipid bilayer particles released by cells with pleiotropic functions that have been reported to regulate the complex intracellular pathway involved in all steps of breast cancer development—from initiation to progression toward a metastatic dissemination. Particularly, the role of these microvesicles has been explored in metastasis, which represents the leading cause of breast cancer morbidity and mortality worldwide. Reports highlight that the plasticity of breast cancer cells, fundamental for the establishment of distant metastasis, may be in part attributed to exosome-carried signals shared between adjacent cells and long-distance cells in the body. In the present review, we will discuss the functions of exosomes in the metastatic breast cancer process and secondary site outgrowth. The possibility to decode the exosome functions in advanced diseases may offer new opportunities for early detection, molecular targeted therapies and exosome-based therapeutics in breast cancer.

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The Biology of Exosomes in Breast Cancer Progression: Dissemination, Immune Evasion and Metastatic Colonization Cinzia Giordano Giusi La Camera Luca Gelsomino Ines Barone Daniela Bonofiglio Sebastiano Andò Stefania Catalano doi: 10.3390/cancers12082179 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Review 2179 10.3390/cancers12082179 http://www.ynsqex.icu/2072-6694/12/8/2179
Cancers, Vol. 12, Pages 2178: Immunoradiotherapy as an Effective Therapeutic Strategy in Lung Cancer: From Palliative Care to Curative Intent http://www.ynsqex.icu/2072-6694/12/8/2178 Lung cancer is one of the main causes of cancer-related mortality worldwide. Over the years, different therapeutic modalities have been adopted depending on tumor stage and patient characteristics, such as surgery, radiotherapy (RT), and chemotherapy. Recently, with the development of immune-checkpoint inhibitors (ICI), the treatment of metastatic and locally advanced non-small cell lung cancer (NSCLC) has experienced a revolution that has resulted in a significant improvement in overall survival with an enhanced toxicity profile. Despite this paradigm shift, most patients present some kind of resistance to ICI. In this setting, current research is shifting towards the integration of multiple therapies, with RT and ICI being one of the most promising based on the potential immunostimulatory synergy of this combination. This review gives an overview of the evolution and current state of the combination of RT and ICI and provides evidence-based data that can improve patient selection. The combination in lung cancer is a safe therapeutic approach that improves local control and progression-free survival, and it has the potential to unleash abscopal responses. Additionally, this treatment strategy seems to be able to re-sensitize select patients that have reached a state of resistance to ICI, further enabling the continuation of systemic therapy. Cancers, Vol. 12, Pages 2178: Immunoradiotherapy as an Effective Therapeutic Strategy in Lung Cancer: From Palliative Care to Curative Intent

Cancers doi: 10.3390/cancers12082178

Authors: Rodolfo Chicas-Sett Juan Zafra-Martin Ignacio Morales-Orue Juan Castilla-Martinez Miguel A. Berenguer-Frances Elisa Gonzalez-Rodriguez Delvys Rodriguez-Abreu Felipe Cou?ago

Lung cancer is one of the main causes of cancer-related mortality worldwide. Over the years, different therapeutic modalities have been adopted depending on tumor stage and patient characteristics, such as surgery, radiotherapy (RT), and chemotherapy. Recently, with the development of immune-checkpoint inhibitors (ICI), the treatment of metastatic and locally advanced non-small cell lung cancer (NSCLC) has experienced a revolution that has resulted in a significant improvement in overall survival with an enhanced toxicity profile. Despite this paradigm shift, most patients present some kind of resistance to ICI. In this setting, current research is shifting towards the integration of multiple therapies, with RT and ICI being one of the most promising based on the potential immunostimulatory synergy of this combination. This review gives an overview of the evolution and current state of the combination of RT and ICI and provides evidence-based data that can improve patient selection. The combination in lung cancer is a safe therapeutic approach that improves local control and progression-free survival, and it has the potential to unleash abscopal responses. Additionally, this treatment strategy seems to be able to re-sensitize select patients that have reached a state of resistance to ICI, further enabling the continuation of systemic therapy.

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Immunoradiotherapy as an Effective Therapeutic Strategy in Lung Cancer: From Palliative Care to Curative Intent Rodolfo Chicas-Sett Juan Zafra-Martin Ignacio Morales-Orue Juan Castilla-Martinez Miguel A. Berenguer-Frances Elisa Gonzalez-Rodriguez Delvys Rodriguez-Abreu Felipe Cou?ago doi: 10.3390/cancers12082178 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Review 2178 10.3390/cancers12082178 http://www.ynsqex.icu/2072-6694/12/8/2178
Cancers, Vol. 12, Pages 2177: Cell Motility and Cancer http://www.ynsqex.icu/2072-6694/12/8/2177 Cell migration is an essential systemic behavior, tightly regulated, of all living cells endowed with directional motility that is involved in the major developmental stages of all complex organisms such as morphogenesis, embryogenesis, organogenesis, adult tissue remodeling, wound healing, immunological cell activities, angiogenesis, tissue repair, cell differentiation, tissue regeneration as well as in a myriad of pathological conditions. However, how cells efficiently regulate their locomotion movements is still unclear. Since migration is also a crucial issue in cancer development, the goal of this narrative is to show the connection between basic findings in cell locomotion of unicellular eukaryotic organisms and the regulatory mechanisms of cell migration necessary for tumor invasion and metastases. More specifically, the review focuses on three main issues, (i) the regulation of the locomotion system in unicellular eukaryotic organisms and human cells, (ii) how the nucleus does not significantly affect the migratory trajectories of cells in two-dimension (2D) surfaces and (iii) the conditioned behavior detected in single cells as a primitive form of learning and adaptation to different contexts during cell migration. New findings in the control of cell motility both in unicellular organisms and mammalian cells open up a new framework in the understanding of the complex processes involved in systemic cellular locomotion and adaptation of a wide spectrum of diseases with high impact in the society such as cancer. Cancers, Vol. 12, Pages 2177: Cell Motility and Cancer

Cancers doi: 10.3390/cancers12082177

Authors: Ildefonso M. De la Fuente José I. López

Cell migration is an essential systemic behavior, tightly regulated, of all living cells endowed with directional motility that is involved in the major developmental stages of all complex organisms such as morphogenesis, embryogenesis, organogenesis, adult tissue remodeling, wound healing, immunological cell activities, angiogenesis, tissue repair, cell differentiation, tissue regeneration as well as in a myriad of pathological conditions. However, how cells efficiently regulate their locomotion movements is still unclear. Since migration is also a crucial issue in cancer development, the goal of this narrative is to show the connection between basic findings in cell locomotion of unicellular eukaryotic organisms and the regulatory mechanisms of cell migration necessary for tumor invasion and metastases. More specifically, the review focuses on three main issues, (i) the regulation of the locomotion system in unicellular eukaryotic organisms and human cells, (ii) how the nucleus does not significantly affect the migratory trajectories of cells in two-dimension (2D) surfaces and (iii) the conditioned behavior detected in single cells as a primitive form of learning and adaptation to different contexts during cell migration. New findings in the control of cell motility both in unicellular organisms and mammalian cells open up a new framework in the understanding of the complex processes involved in systemic cellular locomotion and adaptation of a wide spectrum of diseases with high impact in the society such as cancer.

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Cell Motility and Cancer Ildefonso M. De la Fuente José I. López doi: 10.3390/cancers12082177 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Review 2177 10.3390/cancers12082177 http://www.ynsqex.icu/2072-6694/12/8/2177
Cancers, Vol. 12, Pages 2174: Fecal microRNAs as Innovative Biomarkers of Intestinal Diseases and Effective Players in Host-Microbiome Interactions http://www.ynsqex.icu/2072-6694/12/8/2174 Over the past decade, short non-coding microRNAs (miRNAs), including circulating and fecal miRNAs have emerged as important modulators of various cellular processes by regulating the expression of target genes. Recent studies revealed the role of miRNAs as powerful biomarkers in disease diagnosis and for the development of innovative therapeutic applications in several human conditions, including intestinal diseases. In this review, we explored the literature and summarized the role of identified dysregulated fecal miRNAs in intestinal diseases, with particular focus on colorectal cancer (CRC) and celiac disease (CD). The aim of this review is to highlight one fascinating aspect of fecal miRNA function related to gut microbiota shaping and bacterial metabolism influencing. The role of miRNAs as “messenger” molecules for inter kingdom communications will be analyzed to highlight their role in the complex host-bacteria interactions. Moreover, whether fecal miRNAs could open up new perspectives to develop novel suitable biomarkers for disease detection and innovative therapeutic approaches to restore microbiota balance will be discussed. Cancers, Vol. 12, Pages 2174: Fecal microRNAs as Innovative Biomarkers of Intestinal Diseases and Effective Players in Host-Microbiome Interactions

Cancers doi: 10.3390/cancers12082174

Authors: Meysam Sarshar Daniela Scribano Cecilia Ambrosi Anna Teresa Palamara Andrea Masotti

Over the past decade, short non-coding microRNAs (miRNAs), including circulating and fecal miRNAs have emerged as important modulators of various cellular processes by regulating the expression of target genes. Recent studies revealed the role of miRNAs as powerful biomarkers in disease diagnosis and for the development of innovative therapeutic applications in several human conditions, including intestinal diseases. In this review, we explored the literature and summarized the role of identified dysregulated fecal miRNAs in intestinal diseases, with particular focus on colorectal cancer (CRC) and celiac disease (CD). The aim of this review is to highlight one fascinating aspect of fecal miRNA function related to gut microbiota shaping and bacterial metabolism influencing. The role of miRNAs as “messenger” molecules for inter kingdom communications will be analyzed to highlight their role in the complex host-bacteria interactions. Moreover, whether fecal miRNAs could open up new perspectives to develop novel suitable biomarkers for disease detection and innovative therapeutic approaches to restore microbiota balance will be discussed.

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Fecal microRNAs as Innovative Biomarkers of Intestinal Diseases and Effective Players in Host-Microbiome Interactions Meysam Sarshar Daniela Scribano Cecilia Ambrosi Anna Teresa Palamara Andrea Masotti doi: 10.3390/cancers12082174 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Review 2174 10.3390/cancers12082174 http://www.ynsqex.icu/2072-6694/12/8/2174
Cancers, Vol. 12, Pages 2175: Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery http://www.ynsqex.icu/2072-6694/12/8/2175 The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics. Cancers, Vol. 12, Pages 2175: Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery

Cancers doi: 10.3390/cancers12082175

Authors: Thomas J. Gardner Christopher M. Bourne Megan M. Dacek Keifer Kurtz Manish Malviya Leila Peraro Pedro C. Silberman Kristen C. Vogt Mildred J. Unti Renier Brentjens David Scheinberg

The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.

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Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery Thomas J. Gardner Christopher M. Bourne Megan M. Dacek Keifer Kurtz Manish Malviya Leila Peraro Pedro C. Silberman Kristen C. Vogt Mildred J. Unti Renier Brentjens David Scheinberg doi: 10.3390/cancers12082175 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Review 2175 10.3390/cancers12082175 http://www.ynsqex.icu/2072-6694/12/8/2175
Cancers, Vol. 12, Pages 2173: The Role of RNA and DNA Aptamers in Glioblastoma Diagnosis and Therapy: A Systematic Review of the Literature http://www.ynsqex.icu/2072-6694/12/8/2173 Glioblastoma (GBM) is the most lethal primary brain tumor of the central nervous system in adults. Despite advances in surgical and medical neuro-oncology, the median survival is about 15 months. For this reason, initial diagnosis, prognosis, and targeted therapy of GBM represent very attractive areas of study. Aptamers are short three-dimensional structures of single-stranded nucleic acids (RNA or DNA), identified by an in vitro process, named systematic evolution of ligands by exponential enrichment (SELEX), starting from a partially random oligonucleotide library. They bind to a molecular target with high affinity and specificity and can be easily modified to optimize binding affinity and selectivity. Thanks to their properties (low immunogenicity and toxicity, long stability, and low production variability), a large number of aptamers have been selected against GBM biomarkers and provide specific imaging agents and therapeutics to improve the diagnosis and treatment of GBM. However, the use of aptamers in GBM diagnosis and treatment still represents an underdeveloped topic, mainly due to limited literature in the research world. On these bases, we performed a systematic review aimed at summarizing current knowledge on the new promising DNA and RNA aptamer-based molecules for GBM diagnosis and treatment. Thirty-eight studies from 2000 were included and investigated. Seventeen involved the use of aptamers for GBM diagnosis and 21 for GBM therapy. Our findings showed that a number of DNA and RNA aptamers are promising diagnostic and therapeutic tools for GBM management. Cancers, Vol. 12, Pages 2173: The Role of RNA and DNA Aptamers in Glioblastoma Diagnosis and Therapy: A Systematic Review of the Literature

Cancers doi: 10.3390/cancers12082173

Authors: Silvia Nuzzo Valentina Brancato Alessandra Affinito Marco Salvatore Carlo Cavaliere Gerolama Condorelli

Glioblastoma (GBM) is the most lethal primary brain tumor of the central nervous system in adults. Despite advances in surgical and medical neuro-oncology, the median survival is about 15 months. For this reason, initial diagnosis, prognosis, and targeted therapy of GBM represent very attractive areas of study. Aptamers are short three-dimensional structures of single-stranded nucleic acids (RNA or DNA), identified by an in vitro process, named systematic evolution of ligands by exponential enrichment (SELEX), starting from a partially random oligonucleotide library. They bind to a molecular target with high affinity and specificity and can be easily modified to optimize binding affinity and selectivity. Thanks to their properties (low immunogenicity and toxicity, long stability, and low production variability), a large number of aptamers have been selected against GBM biomarkers and provide specific imaging agents and therapeutics to improve the diagnosis and treatment of GBM. However, the use of aptamers in GBM diagnosis and treatment still represents an underdeveloped topic, mainly due to limited literature in the research world. On these bases, we performed a systematic review aimed at summarizing current knowledge on the new promising DNA and RNA aptamer-based molecules for GBM diagnosis and treatment. Thirty-eight studies from 2000 were included and investigated. Seventeen involved the use of aptamers for GBM diagnosis and 21 for GBM therapy. Our findings showed that a number of DNA and RNA aptamers are promising diagnostic and therapeutic tools for GBM management.

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The Role of RNA and DNA Aptamers in Glioblastoma Diagnosis and Therapy: A Systematic Review of the Literature Silvia Nuzzo Valentina Brancato Alessandra Affinito Marco Salvatore Carlo Cavaliere Gerolama Condorelli doi: 10.3390/cancers12082173 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Review 2173 10.3390/cancers12082173 http://www.ynsqex.icu/2072-6694/12/8/2173
Cancers, Vol. 12, Pages 2172: The Impact of the Timing of Health-Related Quality of Life Assessments on the Actual Results in Glioma Patients: A Randomized Prospective Study http://www.ynsqex.icu/2072-6694/12/8/2172 Background: The aim of this study was to explore the impact of the timing of Health-Related Quality of Life (HRQoL) measurements in clinical care on the obtained HRQoL scores in glioma patients, and the association with feelings of anxiety or depression. Methods: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC)’s Quality of Life Questionnaires (QLQ-C30 and QLQ-BN20), and the Hospital Anxiety and Depression Scale (HADS) twice. All patients completed the first measurement on the day of the Magnetic Resonance Imaging (MRI) scan (t = 0), but the second measurement (t = 1) depended on randomization; Group 1 (n = 49) completed the questionnaires before and Group 2 (n = 51) after the consultation with the physician. Results: median HRQoL scale scores on t0/t1 and change scores were comparable between the two groups. Between 8–58% of patients changed to a clinically relevant extent (i.e., ≥10 points) on the evaluated HRQoL scales in about one-week time, in both directions, with only 3% of patients remaining stable in all scales. Patients with a stable role functioning had a lower HADS anxiety change score. The HADS depression score was not associated with a change in HRQoL. Conclusions: Measuring HRQoL before or after the consultation did not impact HRQoL scores on a group level. However, most patients reported a clinically relevant difference in at least one HRQoL scale between the two time points. These findings highlight the importance of standardized moments of HRQoL assessments, or patient-reported outcomes in general, during treatment and follow-up in clinical trials. Cancers, Vol. 12, Pages 2172: The Impact of the Timing of Health-Related Quality of Life Assessments on the Actual Results in Glioma Patients: A Randomized Prospective Study

Cancers doi: 10.3390/cancers12082172

Authors: Marthe C.M. Peeters Hanneke Zwinkels Johan A.F. Koekkoek Maaike J. Vos Linda Dirven Martin J.B. Taphoorn

Background: The aim of this study was to explore the impact of the timing of Health-Related Quality of Life (HRQoL) measurements in clinical care on the obtained HRQoL scores in glioma patients, and the association with feelings of anxiety or depression. Methods: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC)’s Quality of Life Questionnaires (QLQ-C30 and QLQ-BN20), and the Hospital Anxiety and Depression Scale (HADS) twice. All patients completed the first measurement on the day of the Magnetic Resonance Imaging (MRI) scan (t = 0), but the second measurement (t = 1) depended on randomization; Group 1 (n = 49) completed the questionnaires before and Group 2 (n = 51) after the consultation with the physician. Results: median HRQoL scale scores on t0/t1 and change scores were comparable between the two groups. Between 8–58% of patients changed to a clinically relevant extent (i.e., ≥10 points) on the evaluated HRQoL scales in about one-week time, in both directions, with only 3% of patients remaining stable in all scales. Patients with a stable role functioning had a lower HADS anxiety change score. The HADS depression score was not associated with a change in HRQoL. Conclusions: Measuring HRQoL before or after the consultation did not impact HRQoL scores on a group level. However, most patients reported a clinically relevant difference in at least one HRQoL scale between the two time points. These findings highlight the importance of standardized moments of HRQoL assessments, or patient-reported outcomes in general, during treatment and follow-up in clinical trials.

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The Impact of the Timing of Health-Related Quality of Life Assessments on the Actual Results in Glioma Patients: A Randomized Prospective Study Marthe C.M. Peeters Hanneke Zwinkels Johan A.F. Koekkoek Maaike J. Vos Linda Dirven Martin J.B. Taphoorn doi: 10.3390/cancers12082172 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2172 10.3390/cancers12082172 http://www.ynsqex.icu/2072-6694/12/8/2172
Cancers, Vol. 12, Pages 2171: Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia http://www.ynsqex.icu/2072-6694/12/8/2171 Background: Acute myeloid leukemia (AML) remains a major clinical challenge due to poor overall survival, which is even more dramatic in elderly patients. TIGIT, an inhibitory receptor that interacts with CD155 and CD112 molecules, is considered as a checkpoint in T and NK cell activation. This receptor shares ligands with the co-stimulatory receptor DNAM-1 and with TACTILE. The aim of this work was to analyze the expression of DNAM-1, TIGIT and TACTILE in NK cells and T cell subsets in AML patients. Methods: We have studied 36 patients at the time of diagnosis of AML and 20 healthy volunteers. The expression of DNAM-1, TIGIT and TACTILE in NK cells and T cells, according to the expression of CD3 and CD56, was performed by flow cytometry. Results: NK cells, CD56− T cells and CD56+ T (NKT-like) cells from AML patients presented a reduced expression of DNAM-1 compared with healthy volunteers. An increased expression of TIGIT was observed in mainstream CD56− T cells. No differences were observed in the expression of TACTILE. Simplified presentation of incredibly complex evaluations (SPICE) analysis of the co-expression of DNAM-1, TIGIT and TACTILE showed an increase in NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE. Low percentages of DNAM-1−TIGIT+TACTILE+ NK cells and DNAM-1− TIGIT+TACTILE+ CD56− T cells were associated with a better survival of AML patients. Conclusions: The expression of DNAM-1 is reduced in NK cells and in CD4+ and CD8+ T cells from AML patients compared with those from healthy volunteers. An increased percentage of NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE is associated with patient survival, supporting the role of TIGIT as a novel candidate for checkpoint blockade. Cancers, Vol. 12, Pages 2171: Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia

Cancers doi: 10.3390/cancers12082171

Authors: Isabel Valhondo Fakhri Hassouneh Nelson Lopez-Sejas Alejandra Pera Beatriz Sanchez-Correa Beatriz Guerrero Juan M. Bergua Maria Jose Arcos Helena Ba?as Ignacio Casas-Avilés Joaquin Sanchez-Garcia Josefina Serrano Carmen Martin Esther Duran Corona Alonso Rafael Solana Raquel Tarazona

Background: Acute myeloid leukemia (AML) remains a major clinical challenge due to poor overall survival, which is even more dramatic in elderly patients. TIGIT, an inhibitory receptor that interacts with CD155 and CD112 molecules, is considered as a checkpoint in T and NK cell activation. This receptor shares ligands with the co-stimulatory receptor DNAM-1 and with TACTILE. The aim of this work was to analyze the expression of DNAM-1, TIGIT and TACTILE in NK cells and T cell subsets in AML patients. Methods: We have studied 36 patients at the time of diagnosis of AML and 20 healthy volunteers. The expression of DNAM-1, TIGIT and TACTILE in NK cells and T cells, according to the expression of CD3 and CD56, was performed by flow cytometry. Results: NK cells, CD56− T cells and CD56+ T (NKT-like) cells from AML patients presented a reduced expression of DNAM-1 compared with healthy volunteers. An increased expression of TIGIT was observed in mainstream CD56− T cells. No differences were observed in the expression of TACTILE. Simplified presentation of incredibly complex evaluations (SPICE) analysis of the co-expression of DNAM-1, TIGIT and TACTILE showed an increase in NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE. Low percentages of DNAM-1−TIGIT+TACTILE+ NK cells and DNAM-1− TIGIT+TACTILE+ CD56− T cells were associated with a better survival of AML patients. Conclusions: The expression of DNAM-1 is reduced in NK cells and in CD4+ and CD8+ T cells from AML patients compared with those from healthy volunteers. An increased percentage of NK and T cells lacking DNAM-1 and co-expressing TIGIT and TACTILE is associated with patient survival, supporting the role of TIGIT as a novel candidate for checkpoint blockade.

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Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia Isabel Valhondo Fakhri Hassouneh Nelson Lopez-Sejas Alejandra Pera Beatriz Sanchez-Correa Beatriz Guerrero Juan M. Bergua Maria Jose Arcos Helena Ba?as Ignacio Casas-Avilés Joaquin Sanchez-Garcia Josefina Serrano Carmen Martin Esther Duran Corona Alonso Rafael Solana Raquel Tarazona doi: 10.3390/cancers12082171 Cancers 2020-08-05 Cancers 2020-08-05 12 8 Article 2171 10.3390/cancers12082171 http://www.ynsqex.icu/2072-6694/12/8/2171
Cancers, Vol. 12, Pages 2167: Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1/IRE1α Axis http://www.ynsqex.icu/2072-6694/12/8/2167 Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a consequence of high production of immunoglobulins and high rates of protein synthesis. A great deal of scientific data also evidenced that a mild activation of UPR pathway can regulate cellular differentiation. Our previous studies revealed that MM cell-derived small extracellular vesicle (MM-EV) modulated osteoclasts (OCs) function and induced OCs differentiation. Here, we investigated the role of the UPR pathway, and in particular of the IRE1α/XBP1 axis, in osteoclastogenesis induced by MM-EVs. By proteomic analysis, we identified UPR signaling molecules as novel MM-EV cargo, prompting us to evaluate the effects of the MM-EVs on osteoclastogenesis through UPR pathway. MM-EVs administration in a murine macrophage cell line rapidly induced activation of IRE1α by phosphorylation in S724; accordingly, Xbp1 mRNA splicing was increased and the transcription of NFATc1, a master transcription factor for OCs differentiation, was activated. Some of these results were also validated using both human primary OC cultures and MM-EVs from MM patients. Notably, a chemical inhibitor of IRE1α (GSK2850163) counteracted MM-EV-triggered OC differentiation, hampering the terminal stages of OCs differentiation and reducing bone resorption. Cancers, Vol. 12, Pages 2167: Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1/IRE1α Axis

Cancers doi: 10.3390/cancers12082167

Authors: Lavinia Raimondi Angela De Luca Simona Fontana Nicola Amodio Viviana Costa Valeria Carina Daniele Bellavia Stefania Raimondo Sergio Siragusa Francesca Monteleone Riccardo Alessandro Milena Fini Gianluca Giavaresi

Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a consequence of high production of immunoglobulins and high rates of protein synthesis. A great deal of scientific data also evidenced that a mild activation of UPR pathway can regulate cellular differentiation. Our previous studies revealed that MM cell-derived small extracellular vesicle (MM-EV) modulated osteoclasts (OCs) function and induced OCs differentiation. Here, we investigated the role of the UPR pathway, and in particular of the IRE1α/XBP1 axis, in osteoclastogenesis induced by MM-EVs. By proteomic analysis, we identified UPR signaling molecules as novel MM-EV cargo, prompting us to evaluate the effects of the MM-EVs on osteoclastogenesis through UPR pathway. MM-EVs administration in a murine macrophage cell line rapidly induced activation of IRE1α by phosphorylation in S724; accordingly, Xbp1 mRNA splicing was increased and the transcription of NFATc1, a master transcription factor for OCs differentiation, was activated. Some of these results were also validated using both human primary OC cultures and MM-EVs from MM patients. Notably, a chemical inhibitor of IRE1α (GSK2850163) counteracted MM-EV-triggered OC differentiation, hampering the terminal stages of OCs differentiation and reducing bone resorption.

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Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1/IRE1α Axis Lavinia Raimondi Angela De Luca Simona Fontana Nicola Amodio Viviana Costa Valeria Carina Daniele Bellavia Stefania Raimondo Sergio Siragusa Francesca Monteleone Riccardo Alessandro Milena Fini Gianluca Giavaresi doi: 10.3390/cancers12082167 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Article 2167 10.3390/cancers12082167 http://www.ynsqex.icu/2072-6694/12/8/2167
Cancers, Vol. 12, Pages 2170: Contrast-Enhanced Ultrasound (CEUS) for Follow-Up of Bosniak 2F Complex Renal Cystic Lesions—A 12-Year Retrospective Study in a Specialized European Center http://www.ynsqex.icu/2072-6694/12/8/2170 Bosniak 2F renal cystic lesions feature morphologic characteristics between Bosniak I and III categories, the majority of which remain benign. However, a minor part of Bosniak 2F lesions may progress to malignancy. The purpose of this study was to assess Bosniak 2F cystic lesions during follow-up examinations by CEUS. One-hundred-and-twelve out of 364 patients with Bosniak 2F lesions underwent follow-up CEUS examinations between February 2008 and February 2020. Twelve out of 364 patients underwent renal surgery without follow-up CEUS. The progression rate of Bosniak 2F renal lesions detected by CEUS accounted for 7.1% (8/112 patients) after a mean of 12.9 months. The first follow-up CEUS revealed 75% of progressions (6/8), the remaining 25% (2/8) of progressions were detected during second follow-up CEUS. Underlying clear-cell renal cell carcinoma was histopathologically validated in 5/8 progressive complex cystic renal lesions. Stable sonomorphologic features were observed in 92.1% (104/112 patients). CEUS depicts a promising diagnostic imaging modality in the diagnostic work-up and follow-up of complex renal cystic lesions at higher spatial and temporal resolutions than CT or MRI. Its excellent safety profile, its easy and repeatable accessibility, and low financial costs render CEUS an attractive and powerful alternative imaging tool for monitoring complex renal cystic lesions. Cancers, Vol. 12, Pages 2170: Contrast-Enhanced Ultrasound (CEUS) for Follow-Up of Bosniak 2F Complex Renal Cystic Lesions—A 12-Year Retrospective Study in a Specialized European Center

Cancers doi: 10.3390/cancers12082170

Authors: Johannes Rübenthaler Sa?a ?e?atka Matthias Frank Froelich Matthias Stechele Constantin Marschner Bastian Oliver Sabel Florian Bogner Moritz Ludwig Schnitzer Daniel Overhoff Nils Gro?e Hokamp Michael Staehler Vincent Schwarze Dirk-André Clevert

Bosniak 2F renal cystic lesions feature morphologic characteristics between Bosniak I and III categories, the majority of which remain benign. However, a minor part of Bosniak 2F lesions may progress to malignancy. The purpose of this study was to assess Bosniak 2F cystic lesions during follow-up examinations by CEUS. One-hundred-and-twelve out of 364 patients with Bosniak 2F lesions underwent follow-up CEUS examinations between February 2008 and February 2020. Twelve out of 364 patients underwent renal surgery without follow-up CEUS. The progression rate of Bosniak 2F renal lesions detected by CEUS accounted for 7.1% (8/112 patients) after a mean of 12.9 months. The first follow-up CEUS revealed 75% of progressions (6/8), the remaining 25% (2/8) of progressions were detected during second follow-up CEUS. Underlying clear-cell renal cell carcinoma was histopathologically validated in 5/8 progressive complex cystic renal lesions. Stable sonomorphologic features were observed in 92.1% (104/112 patients). CEUS depicts a promising diagnostic imaging modality in the diagnostic work-up and follow-up of complex renal cystic lesions at higher spatial and temporal resolutions than CT or MRI. Its excellent safety profile, its easy and repeatable accessibility, and low financial costs render CEUS an attractive and powerful alternative imaging tool for monitoring complex renal cystic lesions.

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Contrast-Enhanced Ultrasound (CEUS) for Follow-Up of Bosniak 2F Complex Renal Cystic Lesions—A 12-Year Retrospective Study in a Specialized European Center Johannes Rübenthaler Sa?a ?e?atka Matthias Frank Froelich Matthias Stechele Constantin Marschner Bastian Oliver Sabel Florian Bogner Moritz Ludwig Schnitzer Daniel Overhoff Nils Gro?e Hokamp Michael Staehler Vincent Schwarze Dirk-André Clevert doi: 10.3390/cancers12082170 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Article 2170 10.3390/cancers12082170 http://www.ynsqex.icu/2072-6694/12/8/2170
Cancers, Vol. 12, Pages 2169: Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells http://www.ynsqex.icu/2072-6694/12/8/2169 The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG)4 motif, which confers eIF4A dependency, was incorporated into the 5’-leader region of a luciferase-tdTomato lentiviral reporter construct. The Prestwick Chemical Library was then screened in multiple TNBC cell lines by measuring the tdTomato fluorescent intensity. We identified several cardiac glycosides as potential inhibitors of eIF4A1-mediated translation. Based on our studies, we find that cardiac glycosides inhibit the expression of eIF4A1. To identify a potential mechanism by which this was occurring, we utilized the Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our pursuits led us to the discovery that cardiac glycosides also decrease levels of c-MYC. Quantitative PCR confirmed that decreases in c-MYC and eIF4A were occurring at the transcriptional level. As such, disruption of the eIF4A1-c-MYC axis may be a viable approach in the treatment of TNBC. The novel combination of rocaglamide A and digoxin exhibited synergistic anti-cancer activity against TNBC cells in vitro. The findings in this study and others are important for formulating potential combination chemotherapies against eIF4A1 in vivo. Thus, drug repositioning may be one classical approach to successfully target eIF4A1 in TNBC patients. Cancers, Vol. 12, Pages 2169: Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells

Cancers doi: 10.3390/cancers12082169

Authors: Cory M. Howard Matthew Estrada David Terrero Amit K. Tiwari Dayanidhi Raman

The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG)4 motif, which confers eIF4A dependency, was incorporated into the 5’-leader region of a luciferase-tdTomato lentiviral reporter construct. The Prestwick Chemical Library was then screened in multiple TNBC cell lines by measuring the tdTomato fluorescent intensity. We identified several cardiac glycosides as potential inhibitors of eIF4A1-mediated translation. Based on our studies, we find that cardiac glycosides inhibit the expression of eIF4A1. To identify a potential mechanism by which this was occurring, we utilized the Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our pursuits led us to the discovery that cardiac glycosides also decrease levels of c-MYC. Quantitative PCR confirmed that decreases in c-MYC and eIF4A were occurring at the transcriptional level. As such, disruption of the eIF4A1-c-MYC axis may be a viable approach in the treatment of TNBC. The novel combination of rocaglamide A and digoxin exhibited synergistic anti-cancer activity against TNBC cells in vitro. The findings in this study and others are important for formulating potential combination chemotherapies against eIF4A1 in vivo. Thus, drug repositioning may be one classical approach to successfully target eIF4A1 in TNBC patients.

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Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells Cory M. Howard Matthew Estrada David Terrero Amit K. Tiwari Dayanidhi Raman doi: 10.3390/cancers12082169 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Article 2169 10.3390/cancers12082169 http://www.ynsqex.icu/2072-6694/12/8/2169
Cancers, Vol. 12, Pages 2168: Genetic Engineering of Zebrafish in Cancer Research http://www.ynsqex.icu/2072-6694/12/8/2168 Zebrafish (Danio rerio) is an excellent model to study a wide diversity of human cancers. In this review, we provide an overview of the genetic and reverse genetic toolbox allowing the generation of zebrafish lines that develop tumors. The large spectrum of genetic tools enables the engineering of zebrafish lines harboring precise genetic alterations found in human patients, the generation of zebrafish carrying somatic or germline inheritable mutations or zebrafish showing conditional expression of the oncogenic mutations. Comparative transcriptomics demonstrate that many of the zebrafish tumors share molecular signatures similar to those found in human cancers. Thus, zebrafish cancer models provide a unique in vivo platform to investigate cancer initiation and progression at the molecular and cellular levels, to identify novel genes involved in tumorigenesis as well as to contemplate new therapeutic strategies. Cancers, Vol. 12, Pages 2168: Genetic Engineering of Zebrafish in Cancer Research

Cancers doi: 10.3390/cancers12082168

Authors: Ludivine Raby Pamela V?lkel Xuefen Le Bourhis Pierre-Olivier Angrand

Zebrafish (Danio rerio) is an excellent model to study a wide diversity of human cancers. In this review, we provide an overview of the genetic and reverse genetic toolbox allowing the generation of zebrafish lines that develop tumors. The large spectrum of genetic tools enables the engineering of zebrafish lines harboring precise genetic alterations found in human patients, the generation of zebrafish carrying somatic or germline inheritable mutations or zebrafish showing conditional expression of the oncogenic mutations. Comparative transcriptomics demonstrate that many of the zebrafish tumors share molecular signatures similar to those found in human cancers. Thus, zebrafish cancer models provide a unique in vivo platform to investigate cancer initiation and progression at the molecular and cellular levels, to identify novel genes involved in tumorigenesis as well as to contemplate new therapeutic strategies.

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Genetic Engineering of Zebrafish in Cancer Research Ludivine Raby Pamela V?lkel Xuefen Le Bourhis Pierre-Olivier Angrand doi: 10.3390/cancers12082168 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2168 10.3390/cancers12082168 http://www.ynsqex.icu/2072-6694/12/8/2168
Cancers, Vol. 12, Pages 2166: Lymphotropic Viruses EBV, KSHV and HTLV in Latin America: Epidemiology and Associated Malignancies. A Literature-Based Study by the RIAL-CYTED http://www.ynsqex.icu/2072-6694/12/8/2166 The Epstein–Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations. Cancers, Vol. 12, Pages 2166: Lymphotropic Viruses EBV, KSHV and HTLV in Latin America: Epidemiology and Associated Malignancies. A Literature-Based Study by the RIAL-CYTED

Cancers doi: 10.3390/cancers12082166

Authors: Paola Chabay Daniela Lens Rocio Hassan Socorro María Rodríguez Pinilla Fabiola Valvert Gamboa Iris Rivera Fuad Huamán Garaicoa Stella Maris Ranuncolo Carlos Barrionuevo Abigail Morales Sánchez Vanesa Scholl Elena De Matteo Ma. Victoria Preciado Ezequiel M. Fuentes-Pananá

The Epstein–Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations.

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Lymphotropic Viruses EBV, KSHV and HTLV in Latin America: Epidemiology and Associated Malignancies. A Literature-Based Study by the RIAL-CYTED Paola Chabay Daniela Lens Rocio Hassan Socorro María Rodríguez Pinilla Fabiola Valvert Gamboa Iris Rivera Fuad Huamán Garaicoa Stella Maris Ranuncolo Carlos Barrionuevo Abigail Morales Sánchez Vanesa Scholl Elena De Matteo Ma. Victoria Preciado Ezequiel M. Fuentes-Pananá doi: 10.3390/cancers12082166 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2166 10.3390/cancers12082166 http://www.ynsqex.icu/2072-6694/12/8/2166
Cancers, Vol. 12, Pages 2165: Laryngeal Mid-Cord Erythroleukoplakias: How to Modulate the Transoral CO2 Laser Excisional Biopsy http://www.ynsqex.icu/2072-6694/12/8/2165 Background: The endoscopic appearance of glottic erythroleukoplakias is non-predictive of their histopathology, potentially ranging from keratosis to invasive squamous cell carcinoma (SCC). The aim of this study was to assess a comprehensive workup for the one-step diagnosis and treatment of mid-cord erythroleukoplakias, using CO2 laser excisional biopsy. Methods: We evaluated 147 untreated patients affected by 155 mid-cord erythroleukoplakias submitted to excisional biopsy by subepithelial (Type I) or subligamental cordectomy (Type II), across two academic institutions. Patients were evaluated by preoperative videolaryngostroboscopy, pre- and intraoperative videoendoscopy with biologic endoscopy (narrow band imaging, NBI, or the Storz professional image enhancement system, SPIES), either with or without intraoperative saline infusion into the Reinke’s space. Adequacy of treatment was the primary outcome. Results: The histopathologic diagnosis was keratosis in 26 (17%) cases, squamous intraepithelial neoplasia (SIN1-2) in 47 (30%), carcinoma in situ in 21 (14%), and SCC in 61 (39%) patients. The adequacy of treatment across the entire cohort was 89%. The intraoperative saline infusion procedure, facing not clearly suspicious lesions, raised the adequacy of treatment from 60% to 90% (p = 0.006). Conclusions: Excisional biopsy by Type I–II cordectomies, after a comprehensive diagnostic workup, should be accepted as an adequate and cost-effective treatment of unilateral mid-cord glottic erythroleukoplakias. Cancers, Vol. 12, Pages 2165: Laryngeal Mid-Cord Erythroleukoplakias: How to Modulate the Transoral CO2 Laser Excisional Biopsy

Cancers doi: 10.3390/cancers12082165

Authors: Francesco Mora Filippo Carta Francesco Missale Andrea Laborai Giampiero Parrinello Cesare Piazza Roberto Puxeddu Giorgio Peretti

Background: The endoscopic appearance of glottic erythroleukoplakias is non-predictive of their histopathology, potentially ranging from keratosis to invasive squamous cell carcinoma (SCC). The aim of this study was to assess a comprehensive workup for the one-step diagnosis and treatment of mid-cord erythroleukoplakias, using CO2 laser excisional biopsy. Methods: We evaluated 147 untreated patients affected by 155 mid-cord erythroleukoplakias submitted to excisional biopsy by subepithelial (Type I) or subligamental cordectomy (Type II), across two academic institutions. Patients were evaluated by preoperative videolaryngostroboscopy, pre- and intraoperative videoendoscopy with biologic endoscopy (narrow band imaging, NBI, or the Storz professional image enhancement system, SPIES), either with or without intraoperative saline infusion into the Reinke’s space. Adequacy of treatment was the primary outcome. Results: The histopathologic diagnosis was keratosis in 26 (17%) cases, squamous intraepithelial neoplasia (SIN1-2) in 47 (30%), carcinoma in situ in 21 (14%), and SCC in 61 (39%) patients. The adequacy of treatment across the entire cohort was 89%. The intraoperative saline infusion procedure, facing not clearly suspicious lesions, raised the adequacy of treatment from 60% to 90% (p = 0.006). Conclusions: Excisional biopsy by Type I–II cordectomies, after a comprehensive diagnostic workup, should be accepted as an adequate and cost-effective treatment of unilateral mid-cord glottic erythroleukoplakias.

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Laryngeal Mid-Cord Erythroleukoplakias: How to Modulate the Transoral CO2 Laser Excisional Biopsy Francesco Mora Filippo Carta Francesco Missale Andrea Laborai Giampiero Parrinello Cesare Piazza Roberto Puxeddu Giorgio Peretti doi: 10.3390/cancers12082165 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Article 2165 10.3390/cancers12082165 http://www.ynsqex.icu/2072-6694/12/8/2165
Cancers, Vol. 12, Pages 2162: Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor http://www.ynsqex.icu/2072-6694/12/8/2162 Estrogen receptors (ERs) comprise several nuclear and membrane-bound receptors with different tissue-specific functions. ERα and ERβ are two nuclear members of this family, whereas G protein-coupled estrogen receptor (GPER), ER-X, and Gq-coupled membrane estrogen receptor (Gq-mER) are membrane-bound G protein-coupled proteins. ERα participates in the development and function of several body organs such as the reproductive system, brain, heart and musculoskeletal systems. ERβ has a highly tissue-specific expression pattern, particularly in the female reproductive system, and exerts tumor-suppressive roles in some tissues. Recent studies have revealed functional links between both nuclear and membrane-bound ERs and non-coding RNAs. Several oncogenic lncRNAs and miRNAs have been shown to exert their effects through the modulation of the expression of ERs. Moreover, treatment with estradiol has been shown to alter the malignant behavior of cancer cells through functional axes composed of non-coding RNAs and ERs. The interaction between ERs and non-coding RNAs has functional relevance in several human pathologies associated with estrogen regulation, such as cancers, intervertebral disc degeneration, coronary heart disease and diabetes. In the current review, we summarize scientific literature on the role of miRNAs and lncRNAs on ER-associated signaling and related disorders. Cancers, Vol. 12, Pages 2162: Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

Cancers doi: 10.3390/cancers12082162

Authors: Mohammad Taheri Hamed Shoorei Marcel E. Dinger Soudeh Ghafouri-Fard

Estrogen receptors (ERs) comprise several nuclear and membrane-bound receptors with different tissue-specific functions. ERα and ERβ are two nuclear members of this family, whereas G protein-coupled estrogen receptor (GPER), ER-X, and Gq-coupled membrane estrogen receptor (Gq-mER) are membrane-bound G protein-coupled proteins. ERα participates in the development and function of several body organs such as the reproductive system, brain, heart and musculoskeletal systems. ERβ has a highly tissue-specific expression pattern, particularly in the female reproductive system, and exerts tumor-suppressive roles in some tissues. Recent studies have revealed functional links between both nuclear and membrane-bound ERs and non-coding RNAs. Several oncogenic lncRNAs and miRNAs have been shown to exert their effects through the modulation of the expression of ERs. Moreover, treatment with estradiol has been shown to alter the malignant behavior of cancer cells through functional axes composed of non-coding RNAs and ERs. The interaction between ERs and non-coding RNAs has functional relevance in several human pathologies associated with estrogen regulation, such as cancers, intervertebral disc degeneration, coronary heart disease and diabetes. In the current review, we summarize scientific literature on the role of miRNAs and lncRNAs on ER-associated signaling and related disorders.

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Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor Mohammad Taheri Hamed Shoorei Marcel E. Dinger Soudeh Ghafouri-Fard doi: 10.3390/cancers12082162 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2162 10.3390/cancers12082162 http://www.ynsqex.icu/2072-6694/12/8/2162
Cancers, Vol. 12, Pages 2164: Molecular Markers Guiding Thyroid Cancer Management http://www.ynsqex.icu/2072-6694/12/8/2164 The incidence of thyroid cancer is rapidly increasing, mostly due to the overdiagnosis and overtreatment of differentiated thyroid cancer (TC). The increasing use of potent preclinical models, high throughput molecular technologies, and gene expression microarrays have provided a deeper understanding of molecular characteristics in cancer. Hence, molecular markers have become a potent tool also in TC management to distinguish benign from malignant lesions, predict aggressive biology, prognosis, recurrence, as well as for identification of novel therapeutic targets. In differentiated TC, molecular markers are mainly used as an adjunct to guide management of indeterminate nodules on fine needle aspiration biopsies. In contrast, in advanced thyroid cancer, molecular markers enable targeted treatments of affected signalling pathways. Identification of the driver mutation of targetable kinases in advanced TC can select treatment with mutation targeted tyrosine kinase inhibitors (TKI) to slow growth and reverse adverse effects of the mutations, when traditional treatments fail. This review will outline the molecular landscape and discuss the impact of molecular markers on diagnosis, surveillance and treatment of differentiated, poorly differentiated and anaplastic follicular TC. Cancers, Vol. 12, Pages 2164: Molecular Markers Guiding Thyroid Cancer Management

Cancers doi: 10.3390/cancers12082164

Authors: Carolina Nylén Robert Mechera Isabella Maréchal-Ross Venessa Tsang Angela Chou Anthony J. Gill Roderick J. Clifton-Bligh Bruce G. Robinson Mark S. Sywak Stan B. Sidhu Anthony R. Glover

The incidence of thyroid cancer is rapidly increasing, mostly due to the overdiagnosis and overtreatment of differentiated thyroid cancer (TC). The increasing use of potent preclinical models, high throughput molecular technologies, and gene expression microarrays have provided a deeper understanding of molecular characteristics in cancer. Hence, molecular markers have become a potent tool also in TC management to distinguish benign from malignant lesions, predict aggressive biology, prognosis, recurrence, as well as for identification of novel therapeutic targets. In differentiated TC, molecular markers are mainly used as an adjunct to guide management of indeterminate nodules on fine needle aspiration biopsies. In contrast, in advanced thyroid cancer, molecular markers enable targeted treatments of affected signalling pathways. Identification of the driver mutation of targetable kinases in advanced TC can select treatment with mutation targeted tyrosine kinase inhibitors (TKI) to slow growth and reverse adverse effects of the mutations, when traditional treatments fail. This review will outline the molecular landscape and discuss the impact of molecular markers on diagnosis, surveillance and treatment of differentiated, poorly differentiated and anaplastic follicular TC.

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Molecular Markers Guiding Thyroid Cancer Management Carolina Nylén Robert Mechera Isabella Maréchal-Ross Venessa Tsang Angela Chou Anthony J. Gill Roderick J. Clifton-Bligh Bruce G. Robinson Mark S. Sywak Stan B. Sidhu Anthony R. Glover doi: 10.3390/cancers12082164 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2164 10.3390/cancers12082164 http://www.ynsqex.icu/2072-6694/12/8/2164
Cancers, Vol. 12, Pages 2163: The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells http://www.ynsqex.icu/2072-6694/12/8/2163 Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various solid tumors than CUR. However, the efficacy of these analogues against non-solid tumors, particularly in acute myeloid leukemia (AML), has not been fully investigated. Herein, we observed that both DMC and EF-24 significantly decrease the proportion of viable AML cells including HL-60, U937, and MV4-11, harboring different NRAS and Fms-like tyrosine kinase 3 (FLT3) statuses, and that EF-24 has a lower half maximal inhibitory concentration (IC50) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G1 population, phosphatidylserine (PS) externalization, and significant activation of extrinsic proapoptotic signaling such as caspase-8 and -3 activation. Mechanistically, p38 mitogen-activated protein kinase (MAPK) activation is critical for EF-24-triggered apoptosis via activating protein phosphatase 2A (PP2A) to attenuate extracellular-regulated protein kinase (ERK) activities in HL-60 AML cells. In the clinic, patients with AML expressing high level of PP2A have the most favorable prognoses compared to various solid tumors. Taken together, our results indicate that EF-24 is a potential therapeutic agent for treating AML, especially for cancer types that lose the function of the PP2A tumor suppressor. Cancers, Vol. 12, Pages 2163: The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells

Cancers doi: 10.3390/cancers12082163

Authors: Pei-Ching Hsiao Jer-Hwa Chang Wei-Jiunn Lee Chia-Chi Ku Meng-Ying Tsai Shun-Fa Yang Ming-Hsien Chien

Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various solid tumors than CUR. However, the efficacy of these analogues against non-solid tumors, particularly in acute myeloid leukemia (AML), has not been fully investigated. Herein, we observed that both DMC and EF-24 significantly decrease the proportion of viable AML cells including HL-60, U937, and MV4-11, harboring different NRAS and Fms-like tyrosine kinase 3 (FLT3) statuses, and that EF-24 has a lower half maximal inhibitory concentration (IC50) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G1 population, phosphatidylserine (PS) externalization, and significant activation of extrinsic proapoptotic signaling such as caspase-8 and -3 activation. Mechanistically, p38 mitogen-activated protein kinase (MAPK) activation is critical for EF-24-triggered apoptosis via activating protein phosphatase 2A (PP2A) to attenuate extracellular-regulated protein kinase (ERK) activities in HL-60 AML cells. In the clinic, patients with AML expressing high level of PP2A have the most favorable prognoses compared to various solid tumors. Taken together, our results indicate that EF-24 is a potential therapeutic agent for treating AML, especially for cancer types that lose the function of the PP2A tumor suppressor.

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The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells Pei-Ching Hsiao Jer-Hwa Chang Wei-Jiunn Lee Chia-Chi Ku Meng-Ying Tsai Shun-Fa Yang Ming-Hsien Chien doi: 10.3390/cancers12082163 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Article 2163 10.3390/cancers12082163 http://www.ynsqex.icu/2072-6694/12/8/2163
Cancers, Vol. 12, Pages 2161: A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe http://www.ynsqex.icu/2072-6694/12/8/2161 Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative—OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells. Cancers, Vol. 12, Pages 2161: A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe

Cancers doi: 10.3390/cancers12082161

Authors: Mykola Zdioruk Andrew Want Anna Mietelska-Porowska Katarzyna Laskowska-Kaszub Joanna Wojsiat Agata Klejman Ewelina U?arowska Paulina Koza Sylwia Olejniczak Stanislaw Pikul Witold Konopka Jakub Golab Urszula Wojda

Induction of mitotic catastrophe through the disruption of microtubules is an established target in cancer therapy. However, the molecular mechanisms determining the mitotic catastrophe and the following apoptotic or non-apoptotic cell death remain poorly understood. Moreover, many existing drugs targeting tubulin, such as vincristine, have reduced efficacy, resulting from poor solubility in physiological conditions. Here, we introduce a novel small molecule 2-aminoimidazoline derivative—OAT-449, a synthetic water-soluble tubulin inhibitor. OAT-449 in a concentration range from 6 to 30 nM causes cell death of eight different cancer cell lines in vitro, and significantly inhibits tumor development in such xenograft models as HT-29 (colorectal adenocarcinoma) and SK-N-MC (neuroepithelioma) in vivo. Mechanistic studies showed that OAT-449, like vincristine, inhibited tubulin polymerization and induced profound multi-nucleation and mitotic catastrophe in cancer cells. HeLa and HT-29 cells within 24 h of treatment arrested in G2/M cell cycle phase, presenting mitotic catastrophe features, and 24 h later died by non-apoptotic cell death. In HT-29 cells, both agents altered phosphorylation status of Cdk1 and of spindle assembly checkpoint proteins NuMa and Aurora B, while G2/M arrest and apoptosis blocking was consistent with p53-independent accumulation in the nucleus and largely in the cytoplasm of p21/waf1/cip1, a key determinant of cell fate programs. This is the first common mechanism for the two microtubule-dissociating agents, vincristine and OAT-449, determining the cell death pathway following mitotic catastrophe demonstrated in HT-29 cells.

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A New Inhibitor of Tubulin Polymerization Kills Multiple Cancer Cell Types and Reveals p21-Mediated Mechanism Determining Cell Death after Mitotic Catastrophe Mykola Zdioruk Andrew Want Anna Mietelska-Porowska Katarzyna Laskowska-Kaszub Joanna Wojsiat Agata Klejman Ewelina U?arowska Paulina Koza Sylwia Olejniczak Stanislaw Pikul Witold Konopka Jakub Golab Urszula Wojda doi: 10.3390/cancers12082161 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Article 2161 10.3390/cancers12082161 http://www.ynsqex.icu/2072-6694/12/8/2161
Cancers, Vol. 12, Pages 2159: The Prowess of Andrographolide as a Natural Weapon in the War against Cancer http://www.ynsqex.icu/2072-6694/12/8/2159 There has been a paradigm shift in our understanding about the multifaceted nature of cancer, and a wealth of information has revealed that single-target drugs are not good enough to provide satisfactory clinical outcomes and therapeutic effects for complex diseases which involve multiple factors. Therefore, there has been a reignition to search for natural products having premium pharmacological activities aim to efficiently target multiple deregulated cellular signaling pathways. Andrographolide, a diterpene lactone from Andrographis paniculata was brought into to the limelight because of its ability to inhibit cancer cell proliferation and induce apoptosis. Here we reviewed andrographolide on cellular pathways regulation including Wnt/β-catenin, mTOR, VEGF-mediated intracellular signaling, as well as TRAIL-mediated apoptosis to inhibit cancer development. Cancers, Vol. 12, Pages 2159: The Prowess of Andrographolide as a Natural Weapon in the War against Cancer

Cancers doi: 10.3390/cancers12082159

Authors: Ammad Ahmad Farooqi Rukset Attar Uteuliyev Yerzhan Sabitaliyevich Nada Alaaeddine Dami?o Pergentino de Sousa Baojun Xu William C. Cho

There has been a paradigm shift in our understanding about the multifaceted nature of cancer, and a wealth of information has revealed that single-target drugs are not good enough to provide satisfactory clinical outcomes and therapeutic effects for complex diseases which involve multiple factors. Therefore, there has been a reignition to search for natural products having premium pharmacological activities aim to efficiently target multiple deregulated cellular signaling pathways. Andrographolide, a diterpene lactone from Andrographis paniculata was brought into to the limelight because of its ability to inhibit cancer cell proliferation and induce apoptosis. Here we reviewed andrographolide on cellular pathways regulation including Wnt/β-catenin, mTOR, VEGF-mediated intracellular signaling, as well as TRAIL-mediated apoptosis to inhibit cancer development.

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The Prowess of Andrographolide as a Natural Weapon in the War against Cancer Ammad Ahmad Farooqi Rukset Attar Uteuliyev Yerzhan Sabitaliyevich Nada Alaaeddine Dami?o Pergentino de Sousa Baojun Xu William C. Cho doi: 10.3390/cancers12082159 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2159 10.3390/cancers12082159 http://www.ynsqex.icu/2072-6694/12/8/2159
Cancers, Vol. 12, Pages 2160: The Pathologic and Molecular Landscape of Esophageal Squamous Cell Carcinogenesis http://www.ynsqex.icu/2072-6694/12/8/2160 Esophageal squamous cell carcinoma represents the most common histotype of epithelial neoplasm occurring within esophageal mucosa worldwide. Despite the comprehensive molecular characterization of this entity, to date no significant targeted therapy has been introduced into clinical practice. In this review, we describe the molecular landscape of esophageal squamous cell carcinoma based on the most recent literature. Moreover, we focus on other rare variants and on the relationship with head and neck squamous cell carcinomas. Cancers, Vol. 12, Pages 2160: The Pathologic and Molecular Landscape of Esophageal Squamous Cell Carcinogenesis

Cancers doi: 10.3390/cancers12082160

Authors: Gianluca Businello Paola Parente Luca Mastracci Gianmaria Pennelli Giulia Traverso Massimo Milione Elena Bellan Mauro Michelotto Andromachi Kotsafti Federica Grillo Matteo Fassan

Esophageal squamous cell carcinoma represents the most common histotype of epithelial neoplasm occurring within esophageal mucosa worldwide. Despite the comprehensive molecular characterization of this entity, to date no significant targeted therapy has been introduced into clinical practice. In this review, we describe the molecular landscape of esophageal squamous cell carcinoma based on the most recent literature. Moreover, we focus on other rare variants and on the relationship with head and neck squamous cell carcinomas.

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The Pathologic and Molecular Landscape of Esophageal Squamous Cell Carcinogenesis Gianluca Businello Paola Parente Luca Mastracci Gianmaria Pennelli Giulia Traverso Massimo Milione Elena Bellan Mauro Michelotto Andromachi Kotsafti Federica Grillo Matteo Fassan doi: 10.3390/cancers12082160 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2160 10.3390/cancers12082160 http://www.ynsqex.icu/2072-6694/12/8/2160
Cancers, Vol. 12, Pages 2158: Multiple Myeloma as a Bone Disease? The Tissue Disruption-Induced Cell Stochasticity (TiDiS) Theory http://www.ynsqex.icu/2072-6694/12/8/2158 The standard model of multiple myeloma (MM) relies on genetic instability in the normal counterparts of MM cells. MM-induced lytic bone lesions are considered as end organ damages. However, bone is a tissue of significance in MM and bone changes could be at the origin/facilitate the emergence of MM. We propose the tissue disruption-induced cell stochasticity (TiDiS) theory for MM oncogenesis that integrates disruption of the microenvironment, differentiation, and genetic alterations. It starts with the observation that the bone marrow endosteal niche controls differentiation. As decrease in cellular stochasticity occurs thanks to cellular interactions in differentiating cells, the initiating role of bone disruption would be in the increase of cellular stochasticity. Thus, in the context of polyclonal activation of B cells, memory B cells and plasmablasts would compete for localizing in endosteal niches with the risk that some cells cannot fully differentiate if they cannot reside in the niche because of a disrupted microenvironment. Therefore, they would remain in an unstable state with residual proliferation, with the risk that subclones may transform into malignant cells. Finally, diagnostic and therapeutic perspectives are provided. Cancers, Vol. 12, Pages 2158: Multiple Myeloma as a Bone Disease? The Tissue Disruption-Induced Cell Stochasticity (TiDiS) Theory

Cancers doi: 10.3390/cancers12082158

Authors: Jean-Pascal Capp Régis Bataille

The standard model of multiple myeloma (MM) relies on genetic instability in the normal counterparts of MM cells. MM-induced lytic bone lesions are considered as end organ damages. However, bone is a tissue of significance in MM and bone changes could be at the origin/facilitate the emergence of MM. We propose the tissue disruption-induced cell stochasticity (TiDiS) theory for MM oncogenesis that integrates disruption of the microenvironment, differentiation, and genetic alterations. It starts with the observation that the bone marrow endosteal niche controls differentiation. As decrease in cellular stochasticity occurs thanks to cellular interactions in differentiating cells, the initiating role of bone disruption would be in the increase of cellular stochasticity. Thus, in the context of polyclonal activation of B cells, memory B cells and plasmablasts would compete for localizing in endosteal niches with the risk that some cells cannot fully differentiate if they cannot reside in the niche because of a disrupted microenvironment. Therefore, they would remain in an unstable state with residual proliferation, with the risk that subclones may transform into malignant cells. Finally, diagnostic and therapeutic perspectives are provided.

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Multiple Myeloma as a Bone Disease? The Tissue Disruption-Induced Cell Stochasticity (TiDiS) Theory Jean-Pascal Capp Régis Bataille doi: 10.3390/cancers12082158 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Perspective 2158 10.3390/cancers12082158 http://www.ynsqex.icu/2072-6694/12/8/2158
Cancers, Vol. 12, Pages 2157: MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models http://www.ynsqex.icu/2072-6694/12/8/2157 Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 17 differentially abundant metabolites across both panels (FDR < 0.05, log2 fold change < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome. Cancers, Vol. 12, Pages 2157: MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models

Cancers doi: 10.3390/cancers12082157

Authors: Andrew Patt Bryce Demoret Colin Stets Kate-Lynn Bill Philip Smith Anitha Vijay Andrew Patterson John Hays Mindy Hoang James L. Chen Ewy A. Mathé

Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 17 differentially abundant metabolites across both panels (FDR < 0.05, log2 fold change < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome.

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MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models Andrew Patt Bryce Demoret Colin Stets Kate-Lynn Bill Philip Smith Anitha Vijay Andrew Patterson John Hays Mindy Hoang James L. Chen Ewy A. Mathé doi: 10.3390/cancers12082157 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Article 2157 10.3390/cancers12082157 http://www.ynsqex.icu/2072-6694/12/8/2157
Cancers, Vol. 12, Pages 2156: Brain Metastases from Ovarian Cancer: Current Evidence in Diagnosis, Treatment, and Prognosis http://www.ynsqex.icu/2072-6694/12/8/2156 With this review, we provide the state of the art concerning brain metastases (BMs) from ovarian cancer (OC), a rare condition. Clinical, pathological, and molecular features, treatment options, and future perspectives are comprehensively discussed. Overall, a diagnosis of high-grade serous OC and an advanced disease stage are common features among patients who develop brain metastases. BRCA1 and BRCA2 gene mutations, as well as the expression of androgen receptors in the primary tumor, are emerging risk and prognostic factors which could allow one to identify categories of patients at greater risk of BMs, who could benefit from a tailored follow-up. Based on present data, a multidisciplinary approach combining surgery, radiotherapy, and chemotherapy seem to be the best approach for patients with good performance status, although the median overall survival (<1 year) remains largely disappointing. Hopefully, novel therapeutic avenues are being explored, like PARP inhibitors and immunotherapy, based on our improved knowledge regarding tumor biology, but further investigation is warranted. Cancers, Vol. 12, Pages 2156: Brain Metastases from Ovarian Cancer: Current Evidence in Diagnosis, Treatment, and Prognosis

Cancers doi: 10.3390/cancers12082156

Authors: Fulvio Borella Luca Bertero Antonio Morrone Alessandro Gambella Marialuisa Bovetti Stefano Cosma Andrea Carosso Dionyssios Katsaros Silvia Gemmiti Mario Preti Giorgio Valabrega Giulia Scotto Paola Cassoni Chiara Benedetto

With this review, we provide the state of the art concerning brain metastases (BMs) from ovarian cancer (OC), a rare condition. Clinical, pathological, and molecular features, treatment options, and future perspectives are comprehensively discussed. Overall, a diagnosis of high-grade serous OC and an advanced disease stage are common features among patients who develop brain metastases. BRCA1 and BRCA2 gene mutations, as well as the expression of androgen receptors in the primary tumor, are emerging risk and prognostic factors which could allow one to identify categories of patients at greater risk of BMs, who could benefit from a tailored follow-up. Based on present data, a multidisciplinary approach combining surgery, radiotherapy, and chemotherapy seem to be the best approach for patients with good performance status, although the median overall survival (<1 year) remains largely disappointing. Hopefully, novel therapeutic avenues are being explored, like PARP inhibitors and immunotherapy, based on our improved knowledge regarding tumor biology, but further investigation is warranted.

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Brain Metastases from Ovarian Cancer: Current Evidence in Diagnosis, Treatment, and Prognosis Fulvio Borella Luca Bertero Antonio Morrone Alessandro Gambella Marialuisa Bovetti Stefano Cosma Andrea Carosso Dionyssios Katsaros Silvia Gemmiti Mario Preti Giorgio Valabrega Giulia Scotto Paola Cassoni Chiara Benedetto doi: 10.3390/cancers12082156 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2156 10.3390/cancers12082156 http://www.ynsqex.icu/2072-6694/12/8/2156
Cancers, Vol. 12, Pages 2155: The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis http://www.ynsqex.icu/2072-6694/12/8/2155 Preclinical and/or clinical evidence has indicated a potential role of steroid hormone-mediated signaling pathways in the development of various neoplastic diseases, while precise mechanisms for the functions of specific receptors remain poorly understood. Specifically, in urothelial cancer where sex-related differences particularly in its incidence are noted, activation of sex hormone receptors, such as androgen receptor and estrogen receptor-β, has been associated with the induction of tumor development. More recently, glucocorticoid receptor has been implied to function as a suppressor of urothelial tumorigenesis. This article summarizes and discusses available data suggesting that steroid hormone receptors, including androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor and vitamin D receptor, as well as their related signals, contribute to modulating urothelial tumorigenesis. Cancers, Vol. 12, Pages 2155: The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis

Cancers doi: 10.3390/cancers12082155

Authors: Hiroki Ide Hiroshi Miyamoto

Preclinical and/or clinical evidence has indicated a potential role of steroid hormone-mediated signaling pathways in the development of various neoplastic diseases, while precise mechanisms for the functions of specific receptors remain poorly understood. Specifically, in urothelial cancer where sex-related differences particularly in its incidence are noted, activation of sex hormone receptors, such as androgen receptor and estrogen receptor-β, has been associated with the induction of tumor development. More recently, glucocorticoid receptor has been implied to function as a suppressor of urothelial tumorigenesis. This article summarizes and discusses available data suggesting that steroid hormone receptors, including androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor and vitamin D receptor, as well as their related signals, contribute to modulating urothelial tumorigenesis.

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The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis Hiroki Ide Hiroshi Miyamoto doi: 10.3390/cancers12082155 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2155 10.3390/cancers12082155 http://www.ynsqex.icu/2072-6694/12/8/2155
Cancers, Vol. 12, Pages 2154: EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment http://www.ynsqex.icu/2072-6694/12/8/2154 Transcription factors, extensively described for their role in epithelial–mesenchymal transition (EMT-TFs) in epithelial cells, also display essential functions in the melanocyte lineage. Recent evidence has shown specific expression patterns and functions of these EMT-TFs in neural crest-derived melanoma compared to carcinoma. Herein, we present an update of the specific roles of EMT-TFs in melanocyte differentiation and melanoma progression. As major regulators of phenotype switching between differentiated/proliferative and neural crest stem cell-like/invasive states, these factors appear as major drivers of intra-tumor heterogeneity and resistance to treatment in melanoma, which opens new avenues in terms of therapeutic targeting. Cancers, Vol. 12, Pages 2154: EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment

Cancers doi: 10.3390/cancers12082154

Authors: Yaqi Tang Simon Durand Stéphane Dalle Julie Caramel

Transcription factors, extensively described for their role in epithelial–mesenchymal transition (EMT-TFs) in epithelial cells, also display essential functions in the melanocyte lineage. Recent evidence has shown specific expression patterns and functions of these EMT-TFs in neural crest-derived melanoma compared to carcinoma. Herein, we present an update of the specific roles of EMT-TFs in melanocyte differentiation and melanoma progression. As major regulators of phenotype switching between differentiated/proliferative and neural crest stem cell-like/invasive states, these factors appear as major drivers of intra-tumor heterogeneity and resistance to treatment in melanoma, which opens new avenues in terms of therapeutic targeting.

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EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment Yaqi Tang Simon Durand Stéphane Dalle Julie Caramel doi: 10.3390/cancers12082154 Cancers 2020-08-04 Cancers 2020-08-04 12 8 Review 2154 10.3390/cancers12082154 http://www.ynsqex.icu/2072-6694/12/8/2154
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