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Early identification of allograft vasculopathy and the concomitant elimination of adverse risk factors is essential for improving the long-term prognosis of heart transplant (HTx) recipients with underlying cardiovascular disease (CVD). The major aim of this pilot study was to conduct a non-invasive imaging evaluation of the HTx patient microcirculation by employing nailfold video-capillaroscopy (NVC) in a well-characterized patient and control cohort, and to correlate these data with endothelial cell function, accompanied by studies of traditional cardiovascular risk factors and non-HLA antibodies in HTx recipients. Ten patients undergoing HTx (mean age of 38 ± 14 years) were recruited for the study and compared to a control group of 12 well-matched healthy volunteers (mean age 35 ± 5 years) with normal body mass index (BMI). Detailed medical records were collected from all individuals. NVC was performed using CapillaryScope 200 MEDL4N microscope. For functional readout and correlation analysis, endothelial cell network formation in conjunction with measurements of patient serum levels of vascular endothelial growth factor (VEGF) and non-HLA autoantibodies directed against the angiotensin II type-1-receptor (anti-AT1R-Ab), endothelin-1 type-A-receptor (anti-ETAR-Ab), protease-activated receptor-1 (anti-PAR-1-Ab), and VEGF-A (anti-VEGF-A-Ab) were studied. Our NVC analysis found that the average apical loop diameter of nailfold capillaries was significantly increased in HTx recipients (p = 0.001). In addition, HTx patients with more prominent changes in capillaroscopic patterns were characterized by the presence of traditional cardiovascular risk factors, and HTx patients had increased levels of anti-AT1R-ab, anti-ETAR-ab, and anti-VEGF-A-Ab (p = 0.017, p = 0.025, and p = 0.003, respectively). Capillary diameters most strongly correlated with elevated serum levels of troponin T and triglycerides (R = 0.69, p = 0.028 and R = 0.81, p = 0.004, respectively). In conclusion, we found that an abnormal NVC pattern in HTx patients is associated with traditional CVD risk factors and that NVC is a useful non-invasive tool to conveniently monitor changes in the microvasculature of HTx patients.

Phytoplankton patterns have been observed widely in aquatic systems. Although pattern formation has been investigated based on many PDEs, discrete models on aquatic systems can provide more complex dynamics. A discrete toxic-phytoplankton–zooplankton model is studied in this paper, with the consideration of Allee effect and cross-diffusion. Focusing on Allee effect coefficient, flip and Neimark–Sacker bifurcation analyses are carried out. And focusing on cross-diffusion coefficient, Turing bifurcation analyses are carried out. Parameter conditions and bifurcation diagram of these bifurcations are obtained correspondingly. Numerical simulations are then performed which are consistent with results of theoretical analysis. Irregular patterns can be formed by flip bifurcation. Spirals can be formed by Neimark–Sacker bifurcation. Spots and stripes can be formed by Turing bifurcation. When Turing and flip, or Turing and Neimark–Sacker bifurcations both occur, special patterns can be obtained.

Background Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma. Immunotherapy, especially anti-PD-1, is becoming a pillar of ccRCC treatment. However, precise biomarkers and robust models are needed to select the appropriate patients for immunotherapy.MethodsA total of 831 ccRCC transcriptomic profiles were obtained from 6 datasets. Unsupervised clustering was performed to identify the immune subtypes among ccRCC samples based on immune cell enrichment scores. Weighted correlation network analysis (WGCNA) was used to identify hub genes distinguishing subtypes and related to prognosis. A machine learning model was established by random forest algorithm, and employed to an open and free online website to predict the immune subtype. ResultsIn the identified immune subtypes, subtype2 was enriched in immune cell enrichment scores and immunotherapy biomarkers. WGCNA analysis identified 4 hub genes related to immune subtype, CTLA4, FOXP3, IFNG, and CD19. The random forest model was constructed by mRNA expression of these four hub genes, and the value of areas under the curve of the receiver operating characteristic (AUC) was 0.78. Subtype2 patients in the independent validation cohort had a better drug response and prognosis for immunotherapy treatment. Moreover, an open and free website was developed by the random forest model (https://immunotype.shinyapps.io/ISPRF/). ConclusionsThe current study constructs a model and provides a free online website that could identify suitable ccRCC patients for immunotherapy, and it is an important step forward to personalized treatment.

Background Heterogeneous nuclear ribonucleoprotein F (hnRNP-F) has been implicated in multiple cancers, suggesting its role in tumourigenesis, but the potential oncogenic role and mechanism of hnRNP-F in bladder cancer (BC) remain incompletely understood. Methods HnRNP-F was identified by proteomic methods. A correlation of hnRNP-F expression with prognosis was analysed in 103 BC patients. Then, we applied in vitro and in vivo methods to reveal the behaviours of hnRNP-F in BC tumourigenesis. Furthermore, the interaction between hnRNP-F and Snail1 mRNA was examined by RNA immunoprecipitation (RIP), and Snail1 mRNA stability was measured after treatment with actinomycin D. Finally, the binding domain between hnRNP-F and Snail1 mRNA was verified by constructing Snail1 mRNA truncations and mutants. Finding HnRNP-F is significantly upregulated in BC tissue, and its increased expression is associated with a poor prognosis in BC patients. HnRNP-F is necessary for tumour growth, inducing epithelial-mesenchymal transition (EMT) and metastasis in BC. The changes in Snail1 expression were positively correlated with hnRNP-F at both the mRNA and protein levels when hnRNP-F was silenced or enhanced, suggesting that Snail1 is likely a downstream target of hnRNP-F that mediates its effects on enhancing invasion, metastasis and EMT in BC. The overexpression of hnRNP-F caused an increase in the stability of Snail1 mRNA. Our RNA chip analysis revealed that hnRNP-F could combine with Snail1 mRNA, and we further demonstrated that hnRNP-F could directly bind to the 3′ untranslated region (3′ UTR) of Snail1 mRNA to enhance its stability. Interpretation Our findings suggest that hnRNP-F mediates the stabilization of Snail1 mRNA by binding to its 3′ UTR, subsequently regulating EMT., Graphical abstract Unlabelled Image

Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs. In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1–ERK1/2–AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis.

Background. Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc). Autoantibodies (Abs) against endothelial cell antigens have been implicated in SSc and SRC. However, their detailed roles remain poorly defined. Pro-inflammatory cytokine interleukin-6 (IL-6) has been found to be increased in SSc, but its role in SRC is unclear. Here, we aimed to determine how the autoantibodies from patients with SSc and SRC affect IL-6 secretion by micro-vascular endothelial cells (HMECs). Methods. Serum IgG fractions were isolated from either SSc patients with SRC (n = 4) or healthy individuals (n = 4) and then each experiment with HMECs was performed with SSc-IgG from a separate patient or separate healthy control. IL-6 expression and release by HMECs was assessed by quantitative reverse transcription and quantitative PCR (RT-qPCR) and immunoassays, respectively. The mechanisms underlying the production of IL-6 were analyzed by transient HMEC transfections with IL-6 promoter constructs, electrophoretic mobility shift assays, Western blots and flow cytometry. Results. Exposure of HMECs to IgG from SSc patients, but not from healthy controls, resulted in a time- and dose-dependent increase in IL-6 secretion, which was associated with increased AKT, p70S6K, and ERK1/2 signalling, as well as increased c-FOS/AP-1 transcriptional activity. All these effects could be reduced by the blockade of the endothelial PAR-1 receptor and/or c-FOS/AP-1silencing. Conclusions. Autoantibodies against PAR-1 found in patients with SSc and SRC induce IL-6 production by endothelial cells through signalling pathways controlled by the AP-1 transcription factor. These observations offer a greater understanding of adverse endothelial cell responses to autoantibodies present in patients with SRC.

Neutrophil infiltration is a hallmark of peritoneal inflammation, but mechanisms regulating neutrophil recruitment in patients with peritoneal dialysis (PD)-related peritonitis are not fully defined. We examined 104 samples of PD effluent collected during acute peritonitis for correspondence between a broad range of soluble parameters and neutrophil counts. We observed an association between peritoneal IL-17 and neutrophil levels. This relationship was evident in effluent samples with low but not high IFN-γ levels, suggesting a differential effect of IFN-γ concentration on neutrophil infiltration. Surprisingly, there was no association of neutrophil numbers with the level of CXCL1, a key IL-17-induced neutrophil chemoattractant. We investigated therefore the production of CXCL1 by human peritoneal mesothelial cells (HPMCs) under in vitro conditions mimicking clinical peritonitis. Stimulation of HPMCs with IL-17 increased CXCL1 production through induction of transcription factor SP1 and activation of the SP1-binding region of the CXCL1 promoter. These effects were amplified by TNFα. In contrast, IFN-γ dose-dependently suppressed IL-17-induced SP1 activation and CXCL1 production through a transcriptional mechanism involving STAT1. The SP1-mediated induction of CXCL1 was also observed in HPMCs exposed to PD effluent collected during peritonitis and containing IL-17 and TNFα, but not IFN-γ. Supplementation of the effluent with IFN-γ led to a dose-dependent activation of STAT1 and a resultant inhibition of SP1-induced CXCL1 expression. Transmesothelial migration of neutrophils in vitro increased upon stimulation of HPMCs with IL-17 and was reduced by IFN-γ. In addition, HPMCs were capable of binding CXCL1 at their apical cell surface. These observations indicate that changes in relative peritoneal concentrations of IL-17 and IFN-γ can differently engage SP1-STAT1, impacting on mesothelial cell transcription of CXCL1, whose release and binding to HPMC surface may determine optimal neutrophil recruitment and retention during peritonitis. © 2020 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Eliminating cancer stem cells (CSCs) is a key issue in eradicating tumor. The streptavidin-granulocyte-macrophage-colony stimulating factor (SA-GM-CSF) surface-modified bladder CSCs vaccine previously developed using our protein-anchor technology could effectively induce specific immune response for eliminating CSCs. However, program death receptor-1 (PD-1)/program death ligand 1 (PD-L1) signaling in tumor microenvironment results in tumor-adaptive immune resistance. Although the CSCs vaccine could increase the number of CD8+ T cells, a part of these CD8+ T cells expressed PD-1. Moreover, the CSCs vaccine upregulated the PD-L1 expression of tumor cells, resulting in immune resistance. Adding PD-1 blockade to the CSCs vaccine therapy increased the population of CD4+ , CD8+ and CD8+ IFN-γ+ but not CD4+ Foxp3+ T cells and induced the highest production of IFN-γ. PD-1 blockade could effectively enhance the functions of tumor-specific T lymphocytes generated by the CSCs vaccine. This combination therapy improved the cure rate among mice and effectively protected the mice against a second CSCs cell challenge, but not a RM-1 cell challenge. These results indicate that PD-1 blockade combined with the GM-CSF-modified CSCs vaccine effectively induced a strong and specific antitumor immune response against bladder cancer.

Program death receptor-1 (PD-1)/program death ligand 1 (PD-L1) signaling plays an important role in tumor adaptive immune resistance. The streptavidin-granulocyte-macrophage colony stimulating factor (SA-GM-CSF) surface-modified tumor cells vaccine developed through our novel protein-anchor technology could significantly promote the activation of dendritic cells. Although GM-CSF vaccine could significantly increase the number of tumor-specific CD8+T-cells, the majority of these CD8+T-cells expressed PD-1. Moreover, GM-CSF vaccine up-regulated the PD-L1 expression of tumor cells, resulting in immune resistance. Adding PD-1/PD-L1 blockade to GM-CSF vaccine therapy could significantly increase the population of CD4+ T, CD8+ T and CD8+ IFN-γ+ T but not CD4+ Foxp3+ T-cells and induced the highest production of IFN-γ. PD-1/PD-L1 blockade could effectively rescue the tumor-specific T lymphocytes generated by the GM-CSF vaccine, resulting in consistent tumor rejection. Taken together, PD-1/PD-L1 blockade combined with SA-GM-CSF-modified vaccine could effectively induce a strong specific antitumor immune response against prostate cancer.

Heterogeneous nuclear ribonucleoprotein F (hnRNP-F) is crucial for gene expression and signal transduction as a tumor-promoting molecule with the ability to promote cell proliferation in various cancers. However, the role and mechanism of hnRNP-F in bladder cancer (BC) remain unclear. Therefore, we investigated the effect of hnRNP-F on the proliferation of BC cells and the potential mechanism. In this study, hnRNP-F was found to be upregulated in BC tissues and cells by western blotting. The knockdown of hnRNP-F could inhibit proliferation and delay cell cycle progression in EJ and UMUC-3 cells. Mechanistically, hnRNP-F was shown to bind to Targeting protein for Xenopus kinesin-like protein 2 (TPX2) by mass spectrometry and coimmunoprecipitation. Furthermore, Pearson correlation analysis showed that the expression of hnRNP-F was positively associated with that of TPX2 in BC tissues (P

Objective: To investigate the relationship between vitamin D status, using circulating 25-hydroxyvitamin D [25 (OH) D], and renal cell carcinoma (RCC) risk in a case-control study, because the association between the two is unclear in China. Materials and Methods: A total of 135 incident RCC cases were matched with 135 controls by age and sex. The blood samples were collected on the first day of hospitalization before surgery to measure plasma 25 (OH) D. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) with adjustment for several confounders (e.g. age, gender, smoking and season of blood draw). Furthermore, the association of RCC with 25 (OH) D in units of 10 ng / mL as a continuous variable were also examined. Results: The average plasma 25 (OH) D concentrations in RCC were significantly lower compared with those of the controls (21.5 ± 7.4 ng / mL vs. 24.1 ± 6.6 ng / mL, respectively; P = 0.003). In the adjusted model, inverse associations were observed between circulating 25 (OH) D levels and RCC risk for 25 (OH) D insufficiency (20-30 ng / mL) with OR of 0.50 (95% CI: 0.29-0.88; P = 0.015) and a normal 25 (OH) D level (≥ 30 ng / mL) with OR of 0.30 (95% CI: 0.13-0.72; P = 0.007), compared with 25 (OH) D deficiency (< 20 ng / mL). Furthermore, results with 25 (OH) D as a linear variable indicated that each 10 ng / mL increment of plasma 25 (OH) D corresponded to a 12% decrease in RCC risk. Conclusions: This case-control study on a Chinese Han population supports the protective effect of a higher circulating concentration of 25 (OH) against RCC, whether the confounding factors are adjusted or not.

Background: Heterogeneous nuclear ribonucleoprotein F (HnRNP-F) has previously been implicated in multiple cancers, suggesting its roles in tumorigenesis, but the potential oncogenic role and mechanism of hnRNP-F in bladder cancer (BC) remains incompletely understood. Methods: HnRNP-F was identified by proteomic methods. A correlation of hnRNP-F expression with the prognosis was analyzed in103 BC patients. Then, we applied in vitro and in vivo methods to reveal the behaviors of hnRNP-F in BC tumorigenesis. Furthermore, the interaction between hnRNP-F and Snail mRNA was examined by RNA immunopreciptiation (RIP), and Snail mRNA stability was measured after treatment with actinomycin D. Finally, the binding domain between hnRNP-F and Snail mRNA was tested through Snail mRNA truncations and mutants. Finding: HnRNP-F is significantly up-regulated in BC tissue, and its increased expression is associated with poor prognosis in BC patients. HnRNP-F was necessary for tumor growth, inducing Epithelial-mesenchymal transition (EMT) and metastasis in BC. The changes of Snail expression were positively consistent with hnRNP-F in both mRNA and protein levels when hnRNP-F was silenced or enhanced, suggesting that Snail is likely to be the downstream target of hnRNP-F that mediates its effects on enhancing invasion, metastasis and EMT in BC. Overexpression of hnRNP-F caused an increase in the stability of the Snail mRNA was enhanced. Our RNA chip analysis revealed that hnRNP-F could combine with the Snail mRNA, and we further demonstrated that hnRNP-F could directly bind to the 3'untranslated region (3'UTR) of Snail mRNA to enhance its stability. Interpretation: Our findings suggest that hnRNP-F mediates the stabilization of Snail mRNA via binding to its 3'UTR, subsequently regulating EMT. Funding Statement: This study was supported by Natural Science Foundation Committee of China (NSFC 81802941) (F.L.), and the Natural Science Foundation of Guangdong Province of China (2018A0303130287) (F.L.). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All patients were given written informed consent and all procedures were approved by bioethics committee of the authors' hospital.

// Lina Hou 1, * , Xuwei Hong 2, * , Meng Dai 1 , Pengliang Chen 2 , Hongfan Zhao 2 , Qiang Wei 2 , Fei Li 2 , Wanlong Tan 2 1 Department of Healthy Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China 2 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R.China * These authors have contributed equally to this work Correspondence to: Wanlong Tan, email: twl@smu.edu.cn Fei Li, email: feili20700338@126.com Qiang Wei, email: Qiangwei1975@163.com Keywords: smoking, bladder cancer, prognosis, surgery, meta-analysis Received: June 14, 2016 Accepted: November 12, 2016 Published: November 25, 2016 ABSTRACT There is considerable controversy regarding the association between smoking and prognosis in surgically treated bladder cancer. The present meta-analysis was performed to quantify the role of smoking status in bladder cancer recurrence, progression and patient survival by pooling the available previous data. Pubmed, Embase and the Cochrane Library databases were searched for eligible studies published prior to April 2016. Random and fixed effects models were used to calculate the summary relative risk estimates (SRRE). A total of 10,192 patients from 15 studies were included in the meta-analysis. There was evidence of positive associations between current smoking and the risk of recurrence (SRRE=1.23; 95% CI, 1.05–1.45) and mortality (SRRE=1.28; 95% CI, 1.07-1.52) in bladder cancer. Furthermore, former smoking had positive associations with bladder cancer recurrence (SRRE=1.22; 95% CI, 1.09-1.37) and mortality (SRRE=1.20; 95% CI, 1.03-1.41). However, there was no significant association between bladder cancer progression risk and current (SRRE=1.11; 95% CI, 0.71-1.75) or previous smoking (SRRE=1.16; 95% CI, 0.92-1.46). The findings indicate that current and former smoking increase the risk of recurrence and mortality in patients with bladder cancer. However, due to the nonrandomized and retrospective nature of the current study, patients may be prone to potential selection bias. Prospective and larger epidemiological studies with a longer follow-up are required to confirm these findings.

To assess a nomogram including the computed tomography (CT) score and body mass index (BMI) that was constructed to predict indolent diseases in a cohort of patients with renal masses.The data collected from patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN) between January 2012 and September 2016 were analyzed. Two urologic surgeons and a radiologist reviewed the images to determine the CT score. Postoperative pathological assessment was performed to categorize renal masses as either indolent or aggressive. The BMI and CT scores were included in the nomogram to identify the risk of indolent disease. The performance of the novel model was assessed by using discrimination, calibration plots, and decision curve analysis (DCA).Two hundred and two participants (with 202 masses) who underwent RN or PN were included; 37% of the masses were indolent. The predictive performances of the nomogram revealed areas under the curve of 0.866 for masses of all cases and 0.808 for cT1 masses without visible fat. DCA revealed that the nomogram was moderately clinically useful. The calibration plots showed a reasonable calibration and systematic overestimation of indolent disease based on nomogram predictions.The CT score nomogram discriminated well between indolent and aggressive renal masses. The model had a reasonable calibration in our cohort for discriminating indolent from aggressive lesions. Further research to validate and assess the nomogram is required.

This paper introduces a method which expands short-wave bandpass, and coat`1.54 micrometers reflection, 0.43 approximately 1.10 micrometers antireflection dichroic planar splitter' and `1.06 micrometers reflection, 0.43 approximately 0.90 micrometers antireflection dichroic cubic splitter'. The solutions to important technical problems are also presented.

This paper describes manufacture technology, specification and characteristics of lightweight metal replica mirror. Its optical quality and the measures to ensure it are also revealed. Its future application is predicted.