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Open AccessFeature PaperReview
Emerging Roles of Post-Translational Modifications in Nucleotide Excision Repair
Cells 2020, 9(6), 1466; https://doi.org/10.3390/cells9061466 (registering DOI) - 15 Jun 2020
Abstract
Nucleotide excision repair (NER) is a versatile DNA repair pathway which can be activated in response to a broad spectrum of UV-induced DNA damage, such as bulky adducts, including cyclobutane-pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4PPs). Based on the genomic position of the [...] Read more.
Nucleotide excision repair (NER) is a versatile DNA repair pathway which can be activated in response to a broad spectrum of UV-induced DNA damage, such as bulky adducts, including cyclobutane-pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4PPs). Based on the genomic position of the lesion, two sub-pathways can be defined: (I) global genomic NER (GG-NER), involved in the ablation of damage throughout the whole genome regardless of the transcription activity of the damaged DNA locus, and (II) transcription-coupled NER (TC-NER), activated at DNA regions where RNAPII-mediated transcription takes place. These processes are tightly regulated by coordinated mechanisms, including post-translational modifications (PTMs). The fine-tuning modulation of the balance between the proteins, responsible for PTMs, is essential to maintain genome integrity and to prevent tumorigenesis. In this review, apart from the other substantial PTMs (SUMOylation, PARylation) related to NER, we principally focus on reversible ubiquitylation, which involves E3 ubiquitin ligase and deubiquitylase (DUB) enzymes responsible for the spatiotemporally precise regulation of NER. Full article
(This article belongs to the Special Issue Molecular Role of PARP in Health and Disease 2020)
Open AccessReview
Ubiquilin Networking in Cancers
Cancers 2020, 12(6), 1586; https://doi.org/10.3390/cancers12061586 (registering DOI) - 15 Jun 2020
Abstract
Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. [...] Read more.
Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. For decades, researchers have been attempting to uncover a puzzle and understand the role of UBQLNs in human cancers, particularly in the modulation of oncogene’s stability and nucleotide excision repair. In this review, we summarize the UBQLNs’ genetic variants that are associated with the most common cancers and also discuss their reliability as a prognostic marker. Moreover, we provide an overview of the UBQLNs networks that are relevant to cancers in different ways, including cell cycle, apoptosis, epithelial-mesenchymal transition, DNA repairs and miRNAs. Finally, we include a future prospective on novel ubiquilin-based cancer therapies. Full article
(This article belongs to the Special Issue Ubiquitin-Related Cancer)
Open AccessFeature PaperArticle
EDMD-Causing Emerin Mutant Myogenic Progenitors Exhibit Impaired Differentiation Using Similar Mechanisms
Cells 2020, 9(6), 1463; https://doi.org/10.3390/cells9061463 (registering DOI) - 15 Jun 2020
Abstract
Mutations in the gene encoding emerin (EMD) cause Emery–Dreifuss muscular dystrophy (EDMD1), an inherited disorder characterized by progressive skeletal muscle wasting, irregular heart rhythms and contractures of major tendons. The skeletal muscle defects seen in EDMD are caused by failure of [...] Read more.
Mutations in the gene encoding emerin (EMD) cause Emery–Dreifuss muscular dystrophy (EDMD1), an inherited disorder characterized by progressive skeletal muscle wasting, irregular heart rhythms and contractures of major tendons. The skeletal muscle defects seen in EDMD are caused by failure of muscle stem cells to differentiate and regenerate the damaged muscle. However, the underlying mechanisms remain poorly understood. Most EDMD1 patients harbor nonsense mutations and have no detectable emerin protein. There are three EDMD-causing emerin mutants (S54F, Q133H, and D95–99) that localize correctly to the nuclear envelope and are expressed at wildtype levels. We hypothesized these emerin mutants would share in the disruption of key molecular pathways involved in myogenic differentiation. We generated myogenic progenitors expressing wildtype emerin and each EDMD1-causing emerin mutation (S54F, Q133H, D95–99) in an emerin-null (EMD−/y) background. S54F, Q133H, and D95–99 failed to rescue EMD−/y myogenic differentiation, while wildtype emerin efficiently rescued differentiation. RNA sequencing was done to identify pathways and networks important for emerin regulation of myogenic differentiation. This analysis significantly reduced the number of pathways implicated in EDMD1 muscle pathogenesis. Full article
(This article belongs to the collection Lamins and Laminopathies)
Open AccessArticle
Just Don’t Fall: An AI Agent’s Learning Journey Towards Posture Stabilisation
AI 2020, 1(2), 286-298; https://doi.org/10.3390/ai1020019 (registering DOI) - 15 Jun 2020
Abstract
Learning to maintain postural balance while standing requires a significant, fine coordination effort between the neuromuscular system and the sensory system. It is one of the key contributing factors towards fall prevention, especially in the older population. Using artificial intelligence (AI), we can [...] Read more.
Learning to maintain postural balance while standing requires a significant, fine coordination effort between the neuromuscular system and the sensory system. It is one of the key contributing factors towards fall prevention, especially in the older population. Using artificial intelligence (AI), we can similarly teach an agent to maintain a standing posture, and thus teach the agent not to fall. In this paper, we investigate the learning progress of an AI agent and how it maintains a stable standing posture through reinforcement learning. We used the Deep Deterministic Policy Gradient method (DDPG) and the OpenSim musculoskeletal simulation environment based on OpenAI Gym. During training, the AI agent learnt three policies. First, it learnt to maintain the Centre-of-Gravity and Zero-Moment-Point in front of the body. Then, it learnt to shift the load of the entire body on one leg while using the other leg for fine tuning the balancing action. Finally, it started to learn the coordination between the two pre-trained policies. This study shows the potentials of using deep reinforcement learning in human movement studies. The learnt AI behaviour also exhibited attempts to achieve an unplanned goal because it correlated with the set goal (e.g., walking in order to prevent falling). The failed attempts to maintain a standing posture is an interesting by-product which can enrich the fall detection and prevention research efforts. Full article
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Open AccessReview
Titanium Alloys for Dental Implants: A Review
Prosthesis 2020, 2(2), 100-116; https://doi.org/10.3390/prosthesis2020011 (registering DOI) - 15 Jun 2020
Abstract
The topic of titanium alloys for dental implants has been reviewed. The basis of the review was a search using PubMed, with the large number of references identified being reduced to a manageable number by concentrating on more recent articles and reports of [...] Read more.
The topic of titanium alloys for dental implants has been reviewed. The basis of the review was a search using PubMed, with the large number of references identified being reduced to a manageable number by concentrating on more recent articles and reports of biocompatibility and of implant durability. Implants made mainly from titanium have been used for the fabrication of dental implants since around 1981. The main alloys are so-called commercially pure titanium (cpTi) and Ti-6Al-4V, both of which give clinical success rates of up to 99% at 10 years. Both alloys are biocompatible in contact with bone and the gingival tissues, and are capable of undergoing osseointegration. Investigations of novel titanium alloys developed for orthopaedics show that they offer few advantages as dental implants. The main findings of this review are that the alloys cpTi and Ti-6Al-4V are highly satisfactory materials, and that there is little scope for improvement as far as dentistry is concerned. The conclusion is that these materials will continue to be used for dental implants well into the foreseeable future. Full article
(This article belongs to the Special Issue Prosthesis and Prosthetic Materials)
Open AccessProtocol
The Political Economy of Tobacco in Mozambique and Zimbabwe: A Triangulation Mixed Methods Protocol
Int. J. Environ. Res. Public Health 2020, 17(12), 4262; https://doi.org/10.3390/ijerph17124262 (registering DOI) - 15 Jun 2020
Abstract
Changing global markets have generated a dramatic shift in tobacco consumption from high-income countries (HICs) to low- and middle-income countries (LMICs); by 2030, more than 80% of the disease burden from tobacco use will fall on LMICs. Propelling this shift, opponents of tobacco [...] Read more.
Changing global markets have generated a dramatic shift in tobacco consumption from high-income countries (HICs) to low- and middle-income countries (LMICs); by 2030, more than 80% of the disease burden from tobacco use will fall on LMICs. Propelling this shift, opponents of tobacco control have successfully asserted that tobacco is essential to the economic livelihoods of smallholder tobacco farmers and the economy of tobacco-growing countries. This nexus of economic, agricultural and public health policymaking is one of the greatest challenges facing tobacco control efforts, especially in LMICs. To date, there is a lack of comparative, individual level evidence about the actual livelihoods of tobacco-growing farmers and the political economic context driving tobacco production. This comparative evidence is critically important to identify similarities and differences across contexts and to provide local evidence to inform policies and institutional engagement. Our proposed four-year project will examine the economic situation of smallholder farmers in two major tobacco-growing LMICs—Mozambique and Zimbabwe—and the political economy shaping farmers’ livelihoods and tobacco control efforts. We will collect and analyze the existing data and policy literature on the political economy of tobacco in these two countries. We will also implement household-level economic surveys of nationally representative samples of farmers. The surveys will be complimented with focus group discussions with farmers across the major tobacco-growing regions. Finally, we will interview key informants in these countries in order to illuminate the policy context in which tobacco production is perpetuated. The team will develop country-level reports and policy briefs that will inform two sets of dissemination workshops in each country with relevant stakeholders. We will also conduct workshops to present our findings to the survey and focus group participants, and other members of these tobacco-growing communities, so they can directly benefit from the research to which they are contributing. Full article
Open AccessFeature PaperArticle
Defective TiO2 Core-Shell Magnetic Photocatalyst Modified with Plasmonic Nanoparticles for Visible Light-Induced Photocatalytic Activity
Catalysts 2020, 10(6), 672; https://doi.org/10.3390/catal10060672 (registering DOI) - 15 Jun 2020
Abstract
In the presented work, for the first time, the metal-modified defective titanium(IV) oxide nanoparticles with well-defined titanium vacancies, was successfully obtained. Introducing platinum and copper nanoparticles (NPs) as surface modifiers of defective d-TiO2 significantly increased the photocatalytic activity in both UV-Vis and [...] Read more.
In the presented work, for the first time, the metal-modified defective titanium(IV) oxide nanoparticles with well-defined titanium vacancies, was successfully obtained. Introducing platinum and copper nanoparticles (NPs) as surface modifiers of defective d-TiO2 significantly increased the photocatalytic activity in both UV-Vis and Vis light ranges. Moreover, metal NPs deposition on the magnetic core allowed for the effective separation and reuse of the nanometer-sized photocatalyst from the suspension after the treatment process. The obtained Fe3O4@SiO2/d-TiO2-Pt/Cu photocatalysts were characterized by X-ray diffractometry (XRD) and specific surface area (BET) measurements, UV-Vis diffuse reflectance spectroscopy (DR-UV/Vis), X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM). Further, the mechanism of phenol degradation and the role of four oxidative species (h+, e, OH, and O2) in the studied photocatalytic process were investigated. Full article
(This article belongs to the Special Issue Plasmonic Photocatalysts)
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Open AccessReview
Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics
Cancers 2020, 12(6), 1579; https://doi.org/10.3390/cancers12061579 (registering DOI) - 15 Jun 2020
Abstract
Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs [...] Read more.
Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future. Full article
(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)
Open AccessArticle
Changes in the Abundance of Danish Orchids over the Past 30 Years
Diversity 2020, 12(6), 244; https://doi.org/10.3390/d12060244 (registering DOI) - 15 Jun 2020
Abstract
Orchid abundance data collected over the past 30 years (1987–2016) from 440 sites within the National Orchid Monitoring Program were analyzed to quantify the population trends of orchids in Denmark, and the underlying reasons for the observed population trends were analyzed and discussed. [...] Read more.
Orchid abundance data collected over the past 30 years (1987–2016) from 440 sites within the National Orchid Monitoring Program were analyzed to quantify the population trends of orchids in Denmark, and the underlying reasons for the observed population trends were analyzed and discussed. Of the 45 monitored Danish orchids, 20 showed a significant decrease in abundance over the past 30 years (16, if only orchids with at least 50 observations each were selected), thus corroborating the previous observations of declining orchid abundances at the European scale. Generally, there was a significant negative effect of overgrowing with tall-growing herbs and shrubs on the abundance of Danish orchids, mainly caused by change of farming practices, as extensive management, such as grazing or mowing of light-open grassland areas, has decreased. Full article
(This article belongs to the Section Plant Diversity)
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Open AccessArticle
Probing the Nanostructure of Neutron-Irradiated Diamond Using Raman Spectroscopy
Nanomaterials 2020, 10(6), 1166; https://doi.org/10.3390/nano10061166 (registering DOI) - 15 Jun 2020
Abstract
Disordering of crystal lattice induced by irradiation with fast neutrons and other high-energy particles is used for the deep modification of electrical and optical properties of diamonds via significant nanoscale restructuring and defects engineering. Raman spectroscopy was employed to investigate the nature of [...] Read more.
Disordering of crystal lattice induced by irradiation with fast neutrons and other high-energy particles is used for the deep modification of electrical and optical properties of diamonds via significant nanoscale restructuring and defects engineering. Raman spectroscopy was employed to investigate the nature of radiation damage below the critical graphitization level created when chemical vapor deposition and natural diamonds are irradiated by fast neutrons with fluencies from 1 × 1018 to 3 × 1020 cm−2 and annealed at the 100–1700 °C range. The significant changes in the diamond Raman spectra versus the neutron-irradiated conditions are associated with the formation of intrinsic irradiation-induced defects that do not completely destroy the crystalline feature but decrease the phonon coherence length as the neutron dose increases. It was shown that the Raman spectrum of radiation-damaged diamonds is determined by the phonon confinement effect and that the boson peak is present in the Raman spectra up to annealing at 800–1000 °C. Three groups of defect-induced bands (first group = 260, 495, and 730 cm−1; second group = 230, 500, 530, 685, and 760 cm–1; and third group = 335, 1390, 1415, and 1740 cm−1) were observed in Raman spectra of fast-neutron-irradiated diamonds. Full article
(This article belongs to the Special Issue Carbon-Based Nanostructured Films)
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Open AccessReview
Obesity and the Impact on Cutaneous Melanoma: Friend or Foe?
Cancers 2020, 12(6), 1583; https://doi.org/10.3390/cancers12061583 (registering DOI) - 15 Jun 2020
Abstract
Excess body weight has been identified as a risk factor for many types of cancers, and for the majority of cancers, it is associated with poor outcomes. In contrast, there are cancers in which obesity is associated with favorable outcomes and this has [...] Read more.
Excess body weight has been identified as a risk factor for many types of cancers, and for the majority of cancers, it is associated with poor outcomes. In contrast, there are cancers in which obesity is associated with favorable outcomes and this has been termed the obesity paradox”. In melanoma, the connection between obesity and the increased incidence is not as strong as for other cancer types with some but not all studies showing an association. However, several recent studies have indicated that increased body mass index (BMI) improves survival outcomes in targeted and immune therapy treated melanoma patients. The mechanisms underlying how obesity leads to changes in therapeutic outcomes are not completely understood. This review discusses the current evidence implicating obesity in melanoma progression and patient response to targeted and immunotherapy, and discusses potential mechanisms underpinning these associations. Full article
(This article belongs to the Special Issue How Does Obesity Cause Cancer?)
Open AccessReview
Targeting Dendritic Cells with Antigen-Delivering Antibodies for Amelioration of Autoimmunity in Animal Models of Multiple Sclerosis and Other Autoimmune Diseases
Antibodies 2020, 9(2), 23; https://doi.org/10.3390/antib9020023 (registering DOI) - 15 Jun 2020
Abstract
The specific targeting of dendritic cells (DCs) using antigen-delivering antibodies has been established to be a highly efficient protocol for the induction of tolerance and protection from autoimmune processes in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), as well as [...] Read more.
The specific targeting of dendritic cells (DCs) using antigen-delivering antibodies has been established to be a highly efficient protocol for the induction of tolerance and protection from autoimmune processes in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), as well as in some other animal disease models. As the specific mechanisms of such induced tolerance are being investigated, the newly gained insights may also possibly help to design effective treatments for patients. Here we review approaches applied for the amelioration of autoimmunity in animal models based on antibody-mediated targeting of self-antigens to DCs. Further, we discuss relevant mechanisms of immunological tolerance that underlie such approaches, and we also offer some future perspectives for the application of similar methods in certain related disease settings such as transplantation. Full article
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Open AccessArticle
Cognitive, Affective, and Behavioral Constructs of COVID-19 Health Beliefs: A Comparison Between Sexual Minority and Heterosexual Individuals in Taiwan
Int. J. Environ. Res. Public Health 2020, 17(12), 4282; https://doi.org/10.3390/ijerph17124282 (registering DOI) - 15 Jun 2020
Abstract
This online survey study aimed to compare the cognitive, affective, and behavioral constructs of health beliefs related to coronavirus disease 2019 (COVID-19) between sexual minority and heterosexual individuals in Taiwan. In total, 533 sexual minority and 1421 heterosexual participants were recruited through a [...] Read more.
This online survey study aimed to compare the cognitive, affective, and behavioral constructs of health beliefs related to coronavirus disease 2019 (COVID-19) between sexual minority and heterosexual individuals in Taiwan. In total, 533 sexual minority and 1421 heterosexual participants were recruited through a Facebook advertisement. The constructs pertaining to cognition (perceived relative susceptibility to COVID-19, perceived COVID-19 severity, having sufficient knowledge and information on COVID-19, and confidence in coping with COVID-19), affect (worry toward COVID-19), and behavior (adoption of health-protective behaviors) in relation to health beliefs about COVID-19 were compared between sexual minority and heterosexual participants. The results indicated that sexual minority participants had lower perceived susceptibility to COVID-19, greater self-confidence in coping with COVID-19, and lower worry about COVID-19 and were less likely to maintain good indoor ventilation and disinfect their household than heterosexual individuals. Sexual orientation is the modifying factor for the Health Belief Model in the COVID-19 pandemic and should be taken into consideration when medical professionals establish prevention programs for COVID-19. Full article
(This article belongs to the Special Issue Research about Risk Perception in the Environmental Health Domain)
Open AccessArticle
Blood Flow Measurements Enable Optimization of Light Delivery for Personalized Photodynamic Therapy
Cancers 2020, 12(6), 1584; https://doi.org/10.3390/cancers12061584 (registering DOI) - 15 Jun 2020
Abstract
Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time [...] Read more.
Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time but may compromise treatment efficacy by inducing blood flow stasis during illumination. We developed blood-flow-informed PDT (BFI-PDT) to balance these effects. BFI-PDT uses real-time noninvasive monitoring of tumor blood flow to inform selection of irradiance, i.e. incident fluence rate, on the treated surface. BFI-PDT thus aims to conserve tumor perfusion during PDT while minimizing treatment time. Pre-clinical studies in murine tumors of radiation-induced fibrosarcoma (RIF) and a mesothelioma cell line (AB12) show that BFI-PDT preserves tumor blood flow during illumination better than standard PDT with continuous light delivery at high irradiance. Compared to standard high irradiance PDT, BFI-PDT maintains better tumor oxygenation during illumination and increases direct tumor cell kill in a manner consistent with known oxygen dependencies in PDT-mediated cytotoxicity. BFI-PDT promotes vascular shutdown after PDT, thereby depriving remaining tumor cells of oxygen and nutrients. Collectively, these benefits of BFI-PDT produce a significantly better therapeutic outcome than standard high irradiance PDT. Moreover, BFI-PDT requires ~40% less time on average to achieve outcomes that are modestly better than those with standard low irradiance treatment. This contribution introduces BFI-PDT as a platform for personalized light delivery in PDT, documents the design of a clinically-relevant instrument, and establishes the benefits of BFI-PDT with respect to treatment outcome and duration. Full article
(This article belongs to the Section Methods and Technologies Development)
Open AccessFeature PaperArticle
The Power of Three in Cannabis Shotgun Proteomics: Proteases, Databases and Search Engines
Proteomes 2020, 8(2), 13; https://doi.org/10.3390/proteomes8020013 (registering DOI) - 15 Jun 2020
Abstract
Cannabis research has taken off since the relaxation of legislation, yet proteomics is still lagging. In 2019, we published three proteomics methods aimed at optimizing protein extraction, protein digestion for bottom-up and middle-down proteomics, as well as the analysis of intact proteins for [...] Read more.
Cannabis research has taken off since the relaxation of legislation, yet proteomics is still lagging. In 2019, we published three proteomics methods aimed at optimizing protein extraction, protein digestion for bottom-up and middle-down proteomics, as well as the analysis of intact proteins for top-down proteomics. The database of Cannabis sativa proteins used in these studies was retrieved from UniProt, the reference repositories for proteins, which is incomplete and therefore underrepresents the genetic diversity of this non-model species. In this fourth study, we remedy this shortcoming by searching larger databases from various sources. We also compare two search engines, the oldest, SEQUEST, and the most popular, Mascot. This shotgun proteomics experiment also utilizes the power of parallel digestions with orthogonal proteases of increasing selectivity, namely chymotrypsin, trypsin/Lys-C and Asp-N. Our results show that the larger the database the greater the list of accessions identified but the longer the duration of the search. Using orthogonal proteases and different search algorithms increases the total number of proteins identified, most of them common despite differing proteases and algorithms, but many of them unique as well. Full article
(This article belongs to the Special Issue Proteomics: Technologies and Their Applications)
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Open AccessFeature PaperArticle
Geohydrology of a Reference Mediterranean Catchment (Cilento UNESCO Geopark, Southern Italy)
Appl. Sci. 2020, 10(12), 4117; https://doi.org/10.3390/app10124117 (registering DOI) - 15 Jun 2020
Abstract
In this paper, we studied the geo-hydrological structure and behavior of a reference catchment, located in the Cilento UNESCO Global Geopark, southern Italy, representative of the hilly, terrigenous and forested headwaters of the Mediterranean eco-region. Based on detailed hydrogeological and hydro-geomorphological surveys and [...] Read more.
In this paper, we studied the geo-hydrological structure and behavior of a reference catchment, located in the Cilento UNESCO Global Geopark, southern Italy, representative of the hilly, terrigenous and forested headwaters of the Mediterranean eco-region. Based on detailed hydrogeological and hydro-geomorphological surveys and geomorphometric analysis, starting in 2012, a hydro-chemical monitoring activity at the catchment and sub-catchment scale started, and a hydro-chemical dataset was progressively recorded at daily and sub-hourly time steps. Based on this dataset, the authors performed an original procedure to identify different runoff components, derived by applying cascade mass balance filtering. The integration of hydrological and geomorphological approaches allowed us to obtain an interesting conceptualization of the storm flow generation using hydro-chemical signatures related to different runoff components produced during the increasing–decreasing cycle of the flood event magnitude. The hydro-system activated progressively different runoff sources (i.e., groundwater, riparian corridor, hillslope and hollow) and involved various mechanisms (i.e., groundwater ridging, saturation-excess, infiltration-excess and soil pipe exfiltration). The geo-hydrological conceptualization was validated using a hysteresis Q-EC loop analysis performed on selected events that showed how hysteretic indices could be used to characterize the events in respect to their origins, mechanisms and pathways in similar catchments. Full article
(This article belongs to the Special Issue Advances in Geohydrology: Methods and Applications)
Open AccessReview
Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity
Cancers 2020, 12(6), 1576; https://doi.org/10.3390/cancers12061576 (registering DOI) - 15 Jun 2020
Abstract
Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor [...] Read more.
Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment. Full article
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