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关键词： epithelial‐   to‐   mesenchymal transition   gene expression   genomic alteration   melanoma subtypes   phenotypic switching  

摘要： Melanoma represents the deadliest skin cancer. Recent therapeutic developments, including targeted and immune therapies have revolutionized clinical management and improved patient outcome. This progress was achieved by rigorous molecular and functional studies followed by robust clinical trials. The identification of key genomic alterations and gene expression profiles have propelled the understanding of distinct characteristics within melanoma subtypes. The aim of this review is to summarize and highlight the main genetic and epigenetic findings of melanomas and highlight their pathological and therapeutic importance.

关键词： Aging   Age-related diseases   Senescence   Senolytic   Senomorphic  

摘要： The review aims to summarize and discuss the current knowledge on targeting senescent cells to reduce the risk of age-related diseases in animal models and human studies. The role of cellular senescence in aging and the major age-related diseases -including Alzheimer's disease, atherosclerosis, and type 2 diabetes- as well as the use of senotherapeutic strategies in both experimental and preclinical studies, will be described. A large number of molecules, including synthetic agents and natural compounds, have been proposed for anti-senescence activities. Research on senotherapeutics, which includes senolytic and senomorphic, has a growing interest, and their safety and reliability as anti-aging drugs have been tested in clinical trials. Initial findings suggest that the senotherapeutic approach may be translatable to humans. Due to the lack of evidence, caution must be used against senolytic agents due to their potential side-effects. In this context, natural senolytic compounds should have the advantage of low toxicity and potentially more useful in humans, although the mechanisms of action need to be defined.

关键词： B cell development   RAG1   Immunoglobulin   Microplastics   Rainbow trout   Phagocytosis  

摘要： Environmental microplastic pollution (including polystyrene, PS) may have detrimental effects on the health of aquatic organisms. Accumulation of PS microplastics has been reported to affect innate immune cells and inflammatory responses in fish. To date, knowledge on effects of microplastics on the antibody response is still very limited. Here, we investigated effects of small (0.8-20 mu m) PS microplastics on the abundance of B lineage cells in primary cultures of developing immune cells from the anterior kidney of rainbow trout. Both purchased PS microbeads and PS microparticles generated from consumer products were used as microplastic sources. We first show that rainbow trout phagocytic B cells efficiently took up small (0.83-3.1 mu m) PS microbeads within hours of exposure. In addition, our data revealed that PS microplastic exposure most significantly decreased the abundance of a population of non-phagocytic developing B cells, using both flow cytometry and RT-qPCR. PS microplastics-induced loss of developing B cells further correlated with reduced gene expression of RAG1 and the membrane form of immunoglobulin heavy chains mu and tau. Based on the induced loss of developing B cells observed in our in vitro studies, we speculate that in vivo, chronic PS microplastic-exposure may lead to suboptimal IgM/IgT levels in response to pathogens in teleost species. Considering the highly conserved nature of vertebrate B lymphopoiesis it is likely that PS microplastics will similarly reduce antibody responses in higher vertebrate species, including humans. Further, RAG1 provides an effective biomarker to determine effects of PS microplastics on B cell development in teleost species.

关键词： Glycemic variability   Insulin therapy   Sympathovagal effects  

摘要： Aims/Introduction This study compares the effects of two different insulin regimens - basal versus bolus insulin - on metabolic and cardiovascular autonomic function in Japanese participants with type 2 diabetes. Materials and Methods Participants were randomly assigned to groups for therapy with insulin glulisine (IGlu) or insulin glargine (IGla). The primary efficacy end-point was glycemic variability, including M-values, mean of glucose levels, and a blood glucose profile of seven time points before and after the intervention. The secondary end-points included pleiotropic effects, including endothelial and cardiac autonomic nerve functions. Results Blood glucose levels at all time points significantly decreased in both groups. Post-lunch, post-dinner, and bedtime blood glucose levels were significantly lower in the IGlu group than in the IGla group. Nadir fasting blood glucose levels at the end-point were significantly lower in the IGla group than in the IGlu group. The M-value and mean blood glucose levels were significantly decreased from baseline in both groups, although the former was significantly lower in the IGlu group than in the IGla group. IGla, but not IGlu, was found to elevate 24-h parasympathetic tone, especially during night-time, and it decreased 24-h sympathetic nerve activity, especially at dawn. Conclusions Both IGlu and IGla regimens reduced glucose variability, with IGlu bringing a greater reduction in M-value. IGla, but not IGlu, increased parasympathetic tone during night-time and decreased sympathetic nerve activity at dawn. These findings shed light on the previously unrecognized role of night-time basal insulin supplementation on sympathovagal activity in type 2 diabetes patients.

关键词： Diabetic retinopathy   Maximum principal curvature   Hessian matrix   Squeeze-excitation   Bottleneck   Convolutional neural network  

摘要： Diabetic retinopathy is ophthalmological distress, diabetic patients suffer due to clots, lesions, or haemorrhage formation in the light-sensitive region of the retina. Blocking of vessels leads, due to the increase of blood sugar leads to the formation of new vessel growth, which gives rise to mesh-like structures. Assessing the branching retinal vasculature is an important aspect for ophthalmologists for efficient diagnosis. The fundus scans of the eye are first subjected to pre-processing, followed by segmentation. To extract the branching blood vessels, the technique of maximal principal curvature has been applied, which utilizes the maximum Eigenvalues of the Hessian matrix. Adaptive histogram equalization and the morphological opening, are performed post to that, to enhance and eliminate falsely segmented regions. The proliferation of optical nerves was observed much greater in diabetic or affected patients than in healthy ones. We have used a convolution neural network (CNN) to train the classifier for performing classification. The CNN, constructed for classification, comprises a combination of squeeze and excitation and bottleneck layers, one for each class, and a convolution and pooling layer architecture for classification between the two classes. For the performance evaluation of the proposed algorithm, we use the dataset DIARETDB1 (standard Diabetic Retinopathy Dataset) and the dataset provided by a medical institution, comprised of fundus scans of both affected and normal retinas. Experimental results show that the proposed algorithm provides improved results, when compared to traditional schemes. The model yielded an accuracy of 98.7 % and a precision of 97.2 % while evaluated on the DIARETDB1 dataset.

关键词： DM   liver   hepatocytes   insulin-positive cells   Pdx1   MafA   Ngn3  

摘要： Due to a high occurrence of diabetes mellitus (DM) and its complications, insulin-positive cells detected in different organs are of great interest as they can probably partially compensate for insulin deficiency in DM. The development of pancreatic beta-cells is regulated by the consecutive expression of transcription factors, among which Pdx1, MafA and Ngn3 are most extensively explored. Specifically, these factors have been reported to be able to transdifferentiate a broad variety of cell types into insulin-positive cells. The goal of this study was to characterize insulin-positive (insulin(+)) cells in the liver and to evaluate the expression of transcription factors Pdx1, MafA and Ngn3 involved in their differentiation in an alloxan-induced rat model of type 1 DM (T1DM) and streptozotocin-nicotinamide-induced rat model of type 2 DM (T2DM). Experiments were carried out on male Wistar rats. In experimental animals, plasma levels of glucose, glycosylated hemoglobin and insulin were determined. The oral glucose tolerance test was performed and the insulin resistance index (HOMA-IR) was calculated. The expression of Pdx1(+), MafA(+) and Ngn3(+) was investigated immunohistochemically. Insulin(+), Pdx1(+), MafA(+) and Ngn3(+) cells were detected in the liver both of healthy animals and those with experimental models of T1DM and T2DM. The largest number of insulin(+) cells was found in animals with streptozotocin-nicotinamide-induced T2DM, wherein cells were localized throughout the hepatic lobule. In an alloxan-induced model of T1DM, these cells were detected mainly at the periphery of the hepatic lobule. The number of Pdx1(+), Mafa(+) and Ngn3(+) hepatic cells was different in intact animals vs. those with experimental DM. A correlation was established between the number of Ngn3(+) cells and insulin(+) cells in alloxan-induced DM, as well as between the number of MafA(+) cells and insulin(+) cells in both types of experimental DM. Thus, in rats with both experimental

关键词： Tim-3   Primary biliary cholangitis   NK cells   CXCR1   CXCR3  

摘要： Tim-3, which is expressed on a variety of innate immune cells including NK cells, plays a key role in many autoimmune diseases. However, the immunomodulatory actions of Tim-3 on NK cells in primary biliary cholangitis (PBC) remain uncertain. Using a murine model of PBC we evaluated the expression of Tim-3 and its ligand Gal-9 in peripheral blood, liver, and spleen. Additionally, we studied Tim-3 regulation of chemokine receptors (CXCR1 and CXCR3) in vitro. Flow cytometric analysis indicated large numbers of infiltrating NK cells in the liver which exhibited high expression of Tim-3 and CXCR3. Moreover, we found overexpression of CXCR1 in liver tissue and liver-derived NK cells in PBC mice. We also observed lower levels of soluble Tim-3 in the serum of PBC mice. In vitro experiments with liver-derived NK cells from PBC mice indicated that CXCR3 was up-regulated by treatment with recombinant mouse TIM-3 Fc (rmTim-3 Fc) to activate the Tim-3 pathway. Furthermore, stimulating normal mouse spleen NK cells with poly I:C resulted in elevated expression of CXCR1 and interferon-. release. Nonetheless, adding rmTim-3 Fc or rmGal-9 significantly down-regulated CXCR1 expression and IFN-. release in NK cells activated by poly I:C, proposing a means to exploit the Tim-3 pathway to reverse responses in NK cells. In conclusion, our data demonstrate that dysregulation of Tim-3/Gal-9 is involved in modulating the local immune microenvironment in PBC mice. Our findings highlight the potential of Tim-3 pathway to modulate chemokine responses in NK cells during autoimmunity.

关键词： A-type granite   Sr-Nd-Pb-Hf isotopes   Petrogenesis   LYRB   Crust-mantle interaction  

摘要： Many late Mesozoic granites within the Lower Yangtze River Belt (LYRB), eastern China, are defined as A-types based on their geochemical characteristics, although their petrogenesis is unclear. We present an integrated study combining geochronology, whole-rock geochemistry, Sr, Nd, Pb and zircon Hf isotopes andmineral chemistry for a lithologically-diverse suite of A-type granitoids at Bashan. The Bashan complex in the Chizhou area is composed of quartz monzonite, quartz syenite, syenogranite and alkali-feldspar granite. Zircon U\\Pb geochronology indicates that these intrusive rocks formed at 126-123 Ma. The quartz monzonites have intermediate SiO2 (60.5-63.1 wt%) and high Na2O + K2O (8.66-9.83 wt%) contents, arc-like trace element compositions, enriched whole-rock Sr, Nd and zircon Hf isotopes ((87Sr/86Sr) i = 0.7082-0.7091;eNd(t) = -6.9 to -7.1;eHf (t) = -5.3 to -8.2) and high radiogenic Pb isotopes (Pb-206/Pb-204(t) = 18.581-18.792). They are inferred to have been derived from partial melting of an enriched lithospheric mantle source, followed by fractional crystallisation and limited crustal contamination. The quartz syenites show high SiO2 (65.9-69.8 wt%) and Na2O+ K2O (11.3-12.3 wt%) contents, low MgO (0.14-0.23 wt%) contents, high 104 * Ga/Al (2.34-3.61) values, arc-like trace element compositions, and whole-rock Nd and Pb and zircon Hf isotopic compositions (epsilon(Nd)(t) = -6.8 to -7.0;epsilon(Hf)(t) = -7.3 to -12.3;Pb-206/Pb-204(t) = 18.559-18.970) similar to the quartz monzonite, suggesting that they were derived through fractional crystallisation of the quartz monzonite, with some crustal assimilation. The quartzmonzonite has higher Ti-in-zircon temperatures (TTi- in-Zrn= 696-832 degrees C) and lower zircon saturation temperatures (TZr= 772-818 degrees C) and oxygen fugacities (.FMQ=+1.8 to +2.8) than the quartz syenite (TTi- in-Zrn= 623-805 degrees C;TZr= 856-909 degrees C;.FMQ = +3.5 to +4.8), indicating that the zircons from the quartz syenite cryst

关键词： head and neck squamous cell carcinoma   human epidermal growth factor receptor 2 human papilloma virus immunotherapy oropharynx  

摘要： Background The purpose of this study is to describe human epidermal growth factor 2 (HER2) overexpression in head and neck squamous cell carcinoma (HNSCC) and re-evaluate its potential as a target for HER2-directed immunotherapies. Methods A retrospective cohort of patients with HNSCC receiving curative treatment was identified, and HER2 expression evaluated in archival tissue by immunohistochemistry and correlated with clinicopathological characteristics. HER2 expression data were also determined for HNSCC patients in The Cancer Genome Atlas. Results Nineteen percent of HNSCC and 39% of oropharyngeal HNSCC (OPSCC) were HER2 positive. HER2 expression positively correlated with nodal metastasis (p = 0.035). Patients with HER2-positive tumors had decreased overall survival (p = 0.012), including within the human papilloma virus-positive OPSCC subgroup (p = 0.007). Conclusions A substantial fraction of HNSCC overexpresses HER2 protein, suggesting it may be a suitable target for antigen-directed immunotherapy. HER2 expression and its correlation with survival vary across HNSCC subsites, making it unsuitable as a prognostic marker.

关键词： Non-small-cell lung cancer   Outcomes research  

摘要： Studies validating the prognostic accuracy of the tumor-node-metastases (TNM) classification in patients with lung cancer treated by neoadjuvant therapy are scarce. Tumor regression, particularly major pathological response (MPR), is an acknowledged prognostic factor in this setting. We aimed to validate a novel combined prognostic score. This retrospective single-center study was conducted on 117 consecutive patients with non-small cell lung cancer resected after neoadjuvant treatment at a Swiss University Cancer Center between 2000 and 2016. All cases were clinicopathologically re-evaluated. We assessed the prognostic performance of a novel prognostic score (PRSC) combining T-category, lymph node status, and MPR, in comparison with the eighth edition of the TNM classification (TNM8), the size adapted TNM8 as proposed by the International Association for the Study of Lung Cancer (IASLC) and MPR alone. The isolated ypT-category and the combined TNM8 stages accurately differentiated overall survival (OS, stage p = 0.004) and disease-free survival (DFS, stage p = 0.018). Tumor regression had a prognostic impact. Optimal cut-offs for MPR emerged as 65% for adenocarcinoma and 10% for non-adenocarcinoma and were statistically significant for survival (OS p = 0.006, DFS p < 0.001). The PRSC differentiated between three prognostic groups (OS and DFS p < 0.001), and was superior compared to the stratification using MPR alone or the TNM8 systems, visualized by lower Akaike (AIC) and Bayesian information criterion (BIC) values. In the multivariate analyses, stage III tumors (HR 4.956, p = 0.003), tumors without MPR (HR 2.432, p = 0.015), and PRSC high-risk tumors (HR 5.692, p < 0.001) had significantly increased risks of occurring death. In conclusion, we support 65% as the optimal cut-off for MPR in adenocarcinomas. TNM8 and MPR were comparable regarding their prognostic significance. The novel prognostic score performed distinctly better regarding OS and DFS.