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Abstract Background Certain occupations may predispose individuals to urolithiasis, a multi-factorial disease. The study aimed to evaluate the prevalence and related factors of nephrolithiasis in medical staff in Qingdao, China. Methods Physical examination results of 5115 in-service medical staff aged 22–60 years old were retrospectively analyzed. Multivariable logistic regression analysis and stratified analyses by age and gender were applied to explore the related factors of nephrolithiasis in these medical staff. Results The overall nephrolithiasis prevalence in medical staff in Qingdao, China was 4.65%. Doctors were more prone to nephrolithiasis than nurses (5.63% vs. 3.96%, P = 0.013) and the peak prevalence (6.69%) was observed in medical staff working in the emergency department (ED). Male gender (OR = 1.615, 95% CI = 1.123–2.323, P = 0.010), overweight or obesity (OR = 1.674, 95% CI = 1.266–2.214, P

CDC42 controls intestinal epithelial (IEC) stem cell (IESC) division. How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear. We utilized models of inflammatory bowel diseases (IBD), colorectal cancer, aging, and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia. Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer. Cdc42 floxed mice were crossed with Villin-Cre, Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2, or Bmi1-CreERT2 mice to generate Cdc42 deficient mice. Irradiation, colitis, aging, and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation, IESC/progenitor regenerative capacity, and IEC repair. Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival; in contrast, lower levels of CDC42 were found in the inflamed IBD colon. Colonic Cdc42 depletion significantly reduced Lgr5+ IESCs, increased progenitors' hyperplasia, and induced mucosal inflammation, which led to crypt dysplasia. Colonic Cdc42 depletion markedly enhanced irradiation- or chemical-induced colitis. Depletion or inhibition of Cdc42 reduced colonic Lgr5+ IESC regeneration. In conclusion, depletion of Cdc42 reduces the IESC regeneration and IEC repair, leading to prolonged mucosal inflammation. Constitutive monogenic loss of Cdc42 induces mucosal inflammation, which could result in intestinal neoplasia in the context of aging.

Abstract Background Cancer-associated fibroblasts (CAFs), the predominant stromal cell of tumor microenvironment (TME), play an important role in tumor progression and immunoregulation by remodeling extracellular matrix (ECM) and secreting cytokines. However, little is known about the details of the underlying mechanism in bladder cancer. Methods Bioinformatics analysis was performed to analyze the prognostic value of CAFs and CXCL12 using GEO, TCGA and SRA databases. The effects of CXCL12 on bladder cancer progression were investigated through in vitro and in vivo assays. The biological mechanism of the effect of CXCL12 on PDL1 were investigated using western blotting, immunoprecipitation, RT-PCR, immunofluorescence, mass spectrometry, protein stability, and flow cytometry. Results The results demonstrated that CAFs-derived CXCL12 promoted cancer cell migration and invasion and upregulated PDL1. Mechanistically, upon binding to its specific receptor, CXCL12 activated the downstream JAK2/STAT3 pathway and rapidly up-regulated the expression of deubiquitinase CYLD. CYLD deubiquitinated P62 causing P62 accumulation, which in turn inhibited the autophagic degradation of PDL1. In vivo experiments demonstrated that blocking CXCL12 inhibited tumor growth, reduced tumor PDL1 expression and increased immune cell infiltration. Conclusions This study revealed a novel mechanism for the role of CXCL12 in P62-mediated PDL1 autophagic regulation. Combined application of CXCL12 receptor blocker and PD1/PDL1 blocker can more effectively inhibit PDL1 expression and enhance antitumor immune response. Targeting CAFs-derived CXCL12 may provide an effective strategy for immunotherapy in bladder cancer.

Muscle-invasive urothelial cancer (MUC), characterized by high aggressiveness and significant heterogeneity, is currently lacking highly precise individualized treatment options. We used a computational pipeline to synthesize multiomics data from MUC patients using 10 clustering algorithms, which were then combined with 10 machine learning algorithms to identify molecular subgroups of high resolution and develop a robust consensus machine learning-driven signature (CMLS). Through multiomics clustering, we identified three cancer subtypes (CSs) that are related to prognosis, with CS2 exhibiting the most favorable prognostic outcome. Subsequent screening enabled identification of 12 hub genes that constitute a CMLS with robust predictive power for prognosis. The low-CMLS group exhibited a more favorable prognosis and greater responsiveness to immunotherapy and was more likely to exhibit the “hot tumor” phenotype. The high-CMLS group had a poor prognosis and lower likelihood of benefitting from immunotherapy, but dasatinib and romidepsin may serve as promising treatments for them. Comprehensive analysis of multiomics data can offer important insights and further refine the molecular classification of MUC. Identification of CMLS represents a valuable tool for early prediction of patient prognosis and for screening potential candidates likely to benefit from immunotherapy, with broad implications for clinical practice.

BackgroundDermatomyositis (DM) is prone to nasopharyngeal carcinoma (NPC), but the mechanism is unclear. This study aimed to explore the potential pathogenesis of DM and NPC.MethodsThe datasets GSE46239, GSE142807, GSE12452, and GSE53819 were downloaded from the GEO dataset. The disease co-expression module was obtained by R-package WGCNA. We built PPI networks for the key modules. ClueGO was used to analyze functional enrichment for the key modules. DEG analysis was performed with the R-package "limma". R-package "pROC" was applied to assess the diagnostic performance of hub genes. MiRNA-mRNA networks were constructed using MiRTarBase and miRWalk databases.ResultsThe key modules that positively correlated with NPC and DM were found. Its intersecting genes were enriched in the negative regulation of viral gene replication pathway. Similarly, overlapping down-regulated DEGs in DM and NPC were also enriched in negatively regulated viral gene replication. Finally, we identified 10 hub genes that primarily regulate viral biological processes and type I interferon responses. Four key genes (GBP1, IFIH1, IFIT3, BST2) showed strong diagnostic performance, with AUC>0.8. In both DM and NPC, the expression of key genes was correlated with macrophage infiltration level. Based on hub genes' miRNA-mRNA network, hsa-miR-146a plays a vital role in DM-associated NPC.ConclusionsOur research discovered pivot genes between DM and NPC. Viral gene replication and response to type I interferon may be the crucial bridge between DM and NPC. By regulating hub genes, MiR-146a will provide new strategies for diagnosis and treatment in DM complicated by NPC patients. For individuals with persistent viral replication in DM, screening for nasopharyngeal cancer is necessary.

Summary: Background: Accurate stratification of recurrence risk for bladder cancer (BCa) is essential for precise individualized therapy. This study aimed to develop and validate a model for predicting the risk of recurrence in BCa patients postoperatively using 3-phase enhanced CT images. Methods: We retrospectively enrolled 874 BCa patients across four centers between January 2006 and December 2021. Patients from one center were used as training set, while the remaining patients went into the validation set. We trained a deep learning (DL) model based on convolutional neural networks using 3-phase enhanced CT images. The resulting prediction scores were entered into Cox regression analysis to obtain DL scores and construct a DL signature. DL scores and clinical features were then used as deep learning radioclinical signature. The predictive performance of DL signature was assessed according to concordance index and area under curve compared with deep learning radioclinical signature, clinical model and a widely accepted staging grading system. Recurrence-free survival (RFS) and overall survival (OS) were also predicted in order to further assess survival benefits. Findings: DL signature showed strong power for predicting recurrence (concordance index, 0.869; area under curve, 0.889) in validation set, outperforming other models and system. In addition, we divided RFS and OS into high and low risk groups by selecting appropriate cutoff values for DL signature, and calculated cumulative recurrence risk rates for both groups. Interpretation: Our proposed DL signature shows promising potential as clinical aid for predicting postoperative recurrence risk in BCa and for stratifying the risk of RFS and OS, which can be applied to guide personalized precision therapy. Funding: There are no sources of funding for this manuscript.

Summary: ALDH1A1 is one of the classical stem cell markers for bladder cancer. Lysine 2-hydroxyisobutyrylation (Khib) is a newfound modification to modulate the protein expression, and the underlying mechanisms of how ALDH1A1 was regulated by Khib modification in bladder cancer remains unknown. Here, ALDH1A1 showed a decreased K260hib modification, as identified by protein modification omics in bladder cancer. Decreasing ALDH1A1 expression significantly suppressed the proliferation, migration and invasion of bladder cancer cells. Moreover, K260hib modification is responsible for the activity of ALDH1A1 in bladder cancer, which is regulated by HDAC2/3. Higher K260hib modification on ALDH1A1 promotes protein degradation through chaperone-mediated autophagy (CMA), and ALDH1A1 K260hib could sensitize bladder cancer cells to chemotherapeutic drugs. Higher ALDH1A1 expression with a lower K260hib modification indicates a poor prognosis in patients with bladder cancer. Overall, we demonstrated that K260hib of ALDH1A1 can be used as a potential therapeutic target for bladder cancer treatment.

BackgroundLow-intensity pulsed ultrasound (LIPUS) is a highly promising therapeutic method that has been widely used in rehabilitation, orthopedics, dentistry, urology, gynecology, and other multidisciplinary disease diagnoses and treatments. It has attracted extensive attention worldwide. However, there is currently a lack of comprehensive and systematic research on the current status and future development direction of the LIPUS field. Therefore, this study comprehensively analyzed LIPUS-related reports from the past decade using bibliometrics methods, and further conducted research specifically focusing on its application in endocrine and metabolic diseases.MethodsWe downloaded LIPUS literature from 2012 to 2022 reported in the Web of Science Core Collection Science Citation Index-Expanded and Social Sciences Citation Index, and used bibliometric analysis software such as VOSviewer and CiteSpace to execute the analysis and visualize the results.ResultsWe searched for 655 English articles published on LIPUS from 2012 to 2022. China had the highest number of published articles and collaborations between China and the United States were the closest in this field. Chongqing Medical University was the institution with the highest output, and ULTRASOUND IN MEDICINE AND BIOLOGY was the journal with the most related publications. In recent years, research on the molecular mechanisms of LIPUS has continued to deepen, and its clinical applications have also continued to expand. The application of LIPUS in major diseases such as oxidative stress, regeneration mechanism, and cancer is considered to be a future research direction, especially in the field of endocrinology and metabolism, where it has broad application value.ConclusionGlobal research on LIPUS is expected to continue to increase, and future research will focus on its mechanisms of action and clinical applications. This study comprehensively summarizes the current development status and global trends in the field of LIPUS, and its research progress in the field of endocrine and metabolic diseases, providing valuable reference for future research in this field.

This study summarizes the latest achievements, challenges, and future research directions in deep learning technologies for the diagnosis of renal cell carcinoma (RCC). This is the first review of deep learning in RCC applications. This review aims to show that deep learning technologies hold great promise in the field of RCC diagnosis, and we look forward to more research results to meet us for the mutual benefit of renal cell carcinoma patients. Medical imaging plays an important role in the early detection of renal cell carcinoma (RCC), as well as in the monitoring and evaluation of RCC during treatment. The most commonly used technologies such as contrast enhanced computed tomography (CECT), ultrasound and magnetic resonance imaging (MRI) are now digitalized, allowing deep learning to be applied to them. Deep learning is one of the fastest growing fields in the direction of medical imaging, with rapidly emerging applications that have changed the traditional medical treatment paradigm. With the help of deep learning-based medical imaging tools, clinicians can diagnose and evaluate renal tumors more accurately and quickly. This paper describes the application of deep learning-based imaging techniques in RCC assessment and provides a comprehensive review.

Abstract Abdominal aortic aneurysm (AAA) represents the serious vascular degenerative disorder, which causes high incidence and mortality. Alpha-ketoglutarate (AKG), a crucial metabolite in the tricarboxylic acid (TCA) cycle, has been reported to exert significant actions on the oxidative stress and inflammation. However, its role in AAA still remains elusive. Herein, we examined the effects of AKG on the formation of AAA. The study established an elastase-induced mouse abdominal aortic aneurysms model as well as a TNF-α-mediated vascular smooth muscle cells (VSMCs) model, respectively. We displayed that AKG pre-treatment remarkably prevented aneurysmal dilation assessed by diameter and volume and reduced aortic rupture. In addition, it was also observed that AKG treatment suppressed the development of AAA by attenuating the macrophage infiltration, elastin degradation and collagen fibers remodeling. In vitro, AKG potently decreased TNF-α-induced inflammatory cytokines overproduction, more apoptotic cells and excessive superoxide. Mechanistically, we discovered that upregulation of vpo1 in AAA was significantly suppressed by AKG treatment. By exploring the RNA-seq data, we found that AKG ameliorates AAA mostly though inhibiting oxidative stress and the inflammatory response. PXDN overexpression neutralized the inhibitory effects of AKG on ROS generation and inflammatory reaction in MOVAS. Furthermore, AKG treatment suppressed the expression of p-ERK1/2, 3-Cl Tyr in vivo and in vitro. ERK activator disrupted the protective of AKG on TNF-α-induced VSMCs phenotypic switch. Conclusively, AKG can serve as a beneficial therapy for AAA through regulating PXDN/HOCL/ERK signaling pathways.

Abstract Metabolic reprogramming and immune escape play a major role in tumorigenesis. Increasing number of studies have shown that reprogramming of glutamine metabolism is a putative determinant of the anti-tumor immune response in the tumor microenvironment (TME). Usually, the predatory uptake of glutamine by tumor cells in the TME results in the limited utilization of glutamine by immune cells and affects the anti-tumor immune response. The cell-programmed glutamine partitioning also affects the anti-tumor immune response. However, the reprogramming of glutamine metabolism in tumors modulates immune escape by regulating tumor PD-L1 expression. Likewise, the reprogramming of glutamine metabolism in the immune cells also affects their immune function. Additionally, different types of glutamine metabolism inhibitors extensively regulate the immune cells in the TME while suppressing tumor cell proliferation. Herein, we discuss how metabolic reprogramming of tumor and immune cells regulates anti-tumor immune responses, as well as functional changes in different immune cells in the context of targeting tumor glutamine metabolism, which can better explain the potential of targeting glutamine metabolism in combination with immunotherapy for cancer. Video abstract

Severe Acute Respiratory Syndrome Coronavirus 2, which is quickly spreading around the world and causes coronavirus disease 2019, may attack the urogenital system. We thought that a summary of the current literature about urogenital disease associated with the virus would be useful for physicians treating patients with coronavirus disease 2019. PubMed was com-prehensively screened for studies published from 2019 to 2020. Studies of coronavirus disease 2019 patients with kidney dis-ease, reproductive system diseases, or urological cancer were included. Through reviewing current literature, we summarized that acute kidney injury is a risk factor for patients with coronavirus disease 2019 and is related to their survival. A diagnosis of chronic kidney disease increases the risk of infection. The therapy for kidney transplant patients should be cautious and implemented on a case-by-case basis. When the public health burden is too heavy to bear, a rational selection of treatment for patients with urological cancer is vital. The male reproductive system is at high risk of being attacked by the virus, which may cause damage to reproductive function, and the long-term effects require further study. So, the complications associated with the urogenital system should not be ignored during the course of infection treatment and more robust evidence of long-term effects on the urogenital system will be proposed as more studies are published.

BackgroundEpithelial-mesenchymal transition (EMT), one leading reason of the dismal prognosis of bladder cancer (BLCA), is closely associated with tumor invasion and metastasis. We aimed to develop a novel immune−related gene signature based on different EMT and metabolic status to predict the prognosis of BLCA.MethodsGene expression and clinical data were obtained from TCGA and GEO databases. Patients were clustered based on EMT and metabolism scores calculated by ssGSEA. The immune-related differentially expressed genes (DEGs) between the two clusters with the most obvious differences were used to construct the signature by LASSO and Cox analysis. Time-dependent receiver operating characteristic (ROC) curves and Kaplan–Meier curves were utilized to evaluate the gene signature in training and validation cohorts. Finally, the function of the signature genes AHNAK and NFATC1 in BLCA cell lines were explored by cytological experiments.ResultsBased on the results of ssGSEA, TCGA patients were divided into three clusters, among which cluster 1 and cluster 3 had completely opposite EMT and metabolic status. Patients in cluster 3 had a significantly worse clinical prognosis than cluster 1. Immune-related DEGs were selected between the two clusters to construct the predictive signature based on 14 genes. High-risk patients had poorer prognosis, lower proportions of CD8+ T cells, higher EMT and carbohydrate metabolism, and less sensitivity to chemotherapy and immunotherapy. Overexpression of AHNAK or NFATC1 promoted the proliferation, migration and invasion of T24 and UMUC3 cells. Silencing ANHAK or NFATC1 could effectively inhibit EMT and metabolism in T24 and UMUC3 cells.ConclusionThe established immune signature may act as a promising model for generating accurate prognosis for patients and predicting their EMT and metabolic status, thus guiding the treatment of BLCA patients.

Abstract Understanding maturation pathways of broadly neutralizing antibodies (bnAbs) against HIV‐1 can be highly informative for HIV‐1 vaccine development. A lineage of J038 bnAbs is now obtained from a long‐term SHIV‐infected macaque. J038 neutralizes 54% of global circulating HIV‐1 strains. Its binding induces a unique “up” conformation for one of the V2 loops in the trimeric envelope glycoprotein and is heavily dependent on glycan, which provides nearly half of the binding surface. Their unmutated common ancestor neutralizes the autologous virus. Continuous maturation enhances neutralization potency and breadth of J038 lineage antibodies via expanding antibody‐Env contact areas surrounding the core region contacted by germline‐encoded residues. Developmental details and recognition features of J038 lineage antibodies revealed here provide a new pathway for elicitation and maturation of V2‐targeting bnAbs.

Abstract Background Bladder cancer (BLCA) is a common malignant tumor of urinary system with high morbidity and mortality. In recent years, immunotherapy has played a significant role in the treatment of BLCA. Tumor mutation burden (TMB) has been reported to be a powerful biomarker for predicting tumor prognosis and efficacy of immunotherapy. Our study aimed to explore the relationship between TMB, prognosis and immune infiltration to identify the key genes in BLCA. Methods Clinical information, somatic mutation and gene expression data of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high and low TMB groups according to their calculated TMB scores. Gene Set Enrichment Analysis (GSEA) was performed to screen for significantly enriched pathways. Differentially expressed genes (DEGs) between the two groups were identified. Univariate Cox analysis and Kaplan-Meier survival analysis were applied for screening key genes. Immune infiltration was performed for TMB groups and NTRK3. Results Higher TMB scores were related with poor survival in BLCA. After filtering, 36 DEGs were identified. NTRK3 had the highest hazard ratio and significant prognostic value. Co-expressed genes of NTRK3 were mainly involved in several pathways, including DNA replication, basal transcription factors, complement and coagulation cascades, and ribosome biogenesis in eukaryotes. There was a significant correlation among TMB scores, NTRK3 expression and immune infiltration. Conclusions Our results suggest that NTRK3 is a TMB-related prognostic biomarker, which lays the foundation for further research on the immunomodulatory effect of NTRK3 in BLCA.

Abstract Background Inflammatory response biomarkers have been studied as promising prognostic factors in renal cell carcinoma, but few studies have focused on papillary renal cell carcinoma (PRCC). This study was performed to evaluate the prognostic value of the preoperative neutrophil-to-lymphocyte ratio (NLR) in PRCC patients. Methods In total, 122 postoperative PRCC patients selected from 366 non-clear cell renal cell carcinoma patients were enrolled from our institution between 2012 and 2020. The optimal cutoff value of the NLR was assessed by receiver operating characteristic (ROC) curve analysis, and the Kaplan–Meier method and Cox's proportional hazards regression models were performed to analyze the association of the NLR with overall survival (OS). In addition, the potential of tumor-node-metastasis (TNM) stage, the NLR and an NLR-TNM system to predict survival were compared with ROC curves, and clinical usefulness of the predicting models were assessed by decision curve analysis. Results A threshold value of 2.39 for the NLR for OS analysis was determined by ROC curve analysis. An NLR ≥ 2.39 was associated with a more advanced TNM stage (P

Bladder cancer is one of the concerning malignancies worldwide, which is lacking effective targeted therapy. Gene therapy is a potential approach for bladder cancer treatment. While, a safe and effective targeted gene delivery system is urgently needed for prompting the bladder cancer treatment in vivo. In this study, we confirmed that the bladder cancer had CD44 overexpression and small interfering RNAs (siRNA) with high interfere to Bcl2 oncogene were designed and screened. Then hyaluronic acid dialdehyde (HAD) was prepared in an ethanol-water mixture and covalently conjugated to the chitosan nanoparticles (CS-HAD NPs) to achieve CD44 targeted siRNA delivery. The in vitro and in vivo evaluations indicated that the siRNA-loaded CS-HAD NPs (siRNA@CS-HAD NPs) were approximately 100 nm in size, with improved stability, high siRNA encapsulation efficiency and low cytotoxicity. CS-HAD NPs could target to CD44 receptor and deliver the therapeutic siRNA into T24 bladder cancer cells through a ligand-receptor-mediated targeting mechanism and had a specific accumulation capacity in vivo to interfere the targeted oncogene Bcl2 in bladder cancer. Overall, a CD44 targeted gene delivery system based on natural macromolecules was developed for effective bladder cancer treatment, which could be more conducive to clinical application due to its simple preparation and high biological safety.

Abstract Programmed death receptor-ligand 1 (PD-L1) plays a crucial role in immune evasion by tumour cells. Most tumour cells exhibit energy dependency and acquire energy from glycolysis. However, the relationship between glucose metabolism and PD-L1 expression remains unclear. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glucose deficiency and recovery, and PD-L1 could inversely regulate glycolysis. In addition, the possible signalling pathways activated by a low level of glucose to regulate PD-L1 were tested experimentally. The results showed that glucose deficiency could upregulate PD-L1 expression in two renal cancer cell lines, 786-O and OS-RC-2. Although the native levels of PD-L1 differed in the two cell lines, the upregulated PD-L1 expression was repristinated after glucose recovery. Moreover, epidermal growth factor receptor (EGFR) expression was upregulated in both cell lines with glucose deficiency. The use of an EGFR inhibitor reversed the upregulation of PD-L1 expression induced by glucose deficiency and inhibited the phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2). EGFR activated by epidermal growth factor (EGF) induced PD-L1 expression and ERK1/2 phosphorylation. Furthermore, an ERK1/2 inhibitor inhibited the phosphorylation of c-Jun and decreased the elevated PD-L1 expression induced by glucose deficiency. In addition, this study also showed that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFK-2/FBPase 3 or PFKFB3) mediated upregulation of the level of glycolysis to improve the adverse environment through PD-L1 induction. Therefore, glucose metabolism can regulate the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal cancer, and elevated PD-L1 can also regulate glycolysis by improving the expression of PFKFB3. The findings of this study could provide a new multiple target treatment for renal cell carcinoma (RCC) therapy.

Compared with the traditional fixed relay assisted communication network, the mobile relay assisted wireless communication network has greater communication coverage and better flexibility. It enables to extend the lifetime of a communication system and improve the throughput of uses. Due to the time-varying nature of the actual communication environment and the existence of various interferences, there are uncertain factors in the communication channel that affect the quality of service of users. In this paper, we study the energy efficiency maximization problem based on power control, mobile relay selection, and subcarrier allocation under uncertain channel. The proposed mobile relay selection and subcarrier allocation algorithm improves the energy efficiency of the system while ensuring the normal communication of mobile users. Probabilistic constraints are introduced into the optimization problem to describe the uncertain channel, and after the mathematical transformation, it becomes a solvable form. The subcarrier allocation algorithm and distributed robust power control algorithm are also presented. Simulation results show that the improved system energy efficiency has been achieved and the proposed algorithm behaves better scalability and robustness under dynamic communication environment.

Current studies indicated that immune-associated genes (IAGs) have important roles in the occurrence and development of bladder cancer (BC). The current work aims to identify the prognostic values of IAGs in BC and establish a prognostic signature based on IAGs. RNA sequencing data and protein expression data were used to identify differentially expressed IAGs in BC. An IAGs based signature was further constructed and the prognostic and predictive values of the signature were evaluated by survival analysis and nomogram. RNA isolation and reverse transcription-quantitative PCR (RT-qPCR) were further performed to investigate the expression levels of IAGs in BC cells and were used to explore the relationship between IAGs and M2 tumour-associated macrophages (TAMs) secreted transforming growth factor-β1 (TGF-β1) in BC cells. We selected five IAGs to develop an IAGs signature model, which were significantly related to survival outcomes of BC patients. RT-qPCR showed that five IAGs were significantly differentially expressed and three IAGs were positively correlated with M2 TAMs secreted TGF-β1 in T24 cells. We identified and validated an IAGs based signature to predict the prognosis of BC patients. Furthermore, M2 TAMs may promote the expression of IAGs in BC via the TGF-β1 signalling pathway.

Bromodomain-containing protein 4 (BRD4), the core component of transcriptional regulatory elements, plays a significant role in tumorigenesis and aggressiveness. However, the mechanisms regulating the functions of BRD4 in bladder cancer (BC) still remain elusive. Herein, we identify one exonic circular RNA (circRNA) generated from NR3C1 gene (circNR3C1) as a regulator of BRD4/C-myc complex. Our previous study indicated that BRD4 and C-myc promoter region form a complex, allowing C-myc to function as a transcription factor for BC progression. In the present study, mechanism studies reveal that circNR3C1 could interact with BRD4 protein, dissociating the formation of BRD4/C-myc complex. In vivo, ectopic expression of C-myc partly reverses the tumorigenesis of xenografts circNR3C1-induced in nude mice. Conclusively, these results demonstrate that circNR3C1 inhibits BC progression through acting as endogenous blocker of BRD4/C-myc complex.

Abstract Background Bladder cancer (BC) is a commonly diagnosed malignant tumor in the urinary system, with a high morbidity and a high recurrence rate. Current studies indicated that metabolism-associated genes (MAGs) having critical roles in the etiology of BC. The present study aims to identify differentially expressed MAGs and construct a MAGs based prognostic risk signature for BC by using The Cancer Genome Atlas (TCGA) database and proteomics data. Methods RNA-sequence data from the TCGA database and proteomics data from our BC samples were used to identify differentially expressed MAGs and construct a MAGs based prognostic signature in BC. Subsequently, survival analysis and nomogram were used to evaluate the prognostic and predictive value of the MAGs based signature in BC. RNA isolation and reverse transcription‑quantitative PCR (RT-qPCR) were further performed to investigate the expression levels of MAGs in BC cells and explore the relationship between MAGs and M2 tumor associated macrophages (TAMs) secreted transforming growth factor-β1 (TGF-β1) in BC cells. Results A total of 23 differentially expressed MAGs were identified and five MAGs were finally used to construct a MAGs based signature. Survival analysis revealed that the MAGs based signature was closely correlated with the survival outcomes of patients with BC. A nomogram with the MAGs based signature risk score and clinical features was also constructed to facilitate the individualized prediction of BC patients. RT-qPCR showed that five MAGs were significantly differentially expressed and the expression levels of three MAGs were positively correlated with M2 TAMs secreted TGF-β1 in T24 cells. Conclusions Our study identified novel prognostic MAGs and constructed a MAGs based signature, which can be used as an independent factor in evaluating the prognosis of patients with BC. Furthermore, M2 TAMs may promote the expression of MAGs via the TGF-β1 signaling pathway in the microenvironment of BC. Further clinical trials and experimental explorations are needed to validate our observations in BC.

Summary: Here, we evaluated the immune properties of the HLA-A2 restricted CD8+ T cell epitopes containing mutations from B.1.1.7, and furthermore performed a comprehensive analysis of the SARS-CoV-2 specific CD8+ T cell responses from COVID-19 convalescent patients and SARS-CoV-2 vaccinees recognizing the ancestral Wuhan strain compared to B.1.1.7. First, most of the predicted CD8+ T cell epitopes showed proper binding with HLA-A2, whereas epitopes from B.1.1.7 had lower binding capability than those from the ancestral strain. In addition, these peptides could effectively induce the activation and cytotoxicity of CD8+ T cells. Our results further showed that at least two site mutations in B.1.1.7 resulted in a decrease in CD8+ T cell activation and a possible immune evasion, namely A1708D mutation in ORF1ab1707-1716 and I2230T mutation in ORF1ab2230-2238. Our current analysis provides information that contributes to the understanding of SARS-CoV-2-specific CD8+ T cell responses elicited by infection of mutated strains or vaccination.

Abstract Background The gut microbiota was shown to play a crucial role in the development of vascular dysfunction, and the bacterial composition differed between healthy controls and coronary artery disease patients. The goal of this study was to investigate how the gut microbiota affects host metabolic homeostasis at the organism scale. Methods We colonized germ-free C57BL/6 J mice with faeces from healthy control donors (Con) and coronary artery disease (CAD) patients and fed both groups a high fat diet for 12 weeks. We monitored cholesterol and vascular function in the transplanted mice. We analysed bile acids profiles and gut microbiota composition. Transcriptome sequencing and flow cytometry were performed to evaluate inflammatory and immune response. Results CAD mice showed increased reactive oxygen species generation and intensive arterial stiffness. Microbiota profiles in recipient mice clustered according to the microbiota structure of the human donors. Clostridium symbiosum and Eggerthella colonization from CAD patients modulated the secondary bile acids pool, leading to an increase in lithocholic acid and keto-derivatives. Subsequently, bile acids imbalance in the CAD mice inhibited hepatic bile acids synthesis and resulted in elevated circulatory cholesterol. Moreover, the faecal microbiota from the CAD patients caused a significant induction of abnormal immune responses at both the transcriptome level and through the enhanced secretion of cytokines. In addition, microbes belonging to CAD promoted intestinal inflammation by contributing to lamina propria Th17/Treg imbalance and worsened gut barrier permeability. Conclusions In summary, our findings elucidated that the gut microbiota impacts cholesterol homeostasis by modulating bile acids. In addition, the CAD-associated bacterial community was shown to function as an important regulator of systemic inflammation and to influence arterial stiffness.

Abstract Background Breast cancer is one of the most common tumors for women globally. Various miRNAs have been reported to play a crucial role in breast cancer, however the clinical significance of miR-1908-3p in breast cancer remains unclear. The present study aimed to explore the role of miR-1908-3p in breast cancer. Methods The expression of miR-1908-3p was detected in 50 pairs of breast cancer tissues and adjacent normal tissues, 60 breast cancer patient serum and 60 healthy volunteer serum. The functional roles of miR-1908-3p in breast cancer cells such as proliferation, migration and invasion were evaluated using CCK8, SRB, wound healing and transwell chambers. In addition, bioinformatics tools were used to identify potential targets of miR-1908-3p. Results The results showed that the expression of miR-1908-3p were increased in breast cancer tissues and serum compared with normal breast tissues and serum of healthy volunteers respectively. Furthermore, the young breast cancer patients and HER2-positive patients had a higher level of tissues’ miR-1908-3p than elder breast cancer patients and HER2-negative patients, respectively. The young breast cancer patients had a higher level of serum miR-1908-3p than elder breast cancer patients, ROC analysis suggested that miR-1908-3p had the potential as a promising serum diagnostic biomarker of breast cancer. Up-regulation of miR-1908-3p promoted the cells proliferation, migration and invasion while knockdown of miR-1908-3p inhibited these processes in breast cancer cell MCF-7 and MDA-MB-231. The potential target genes of miR-1908-3p in breast cancer included ID4, LTBP4, GPM6B, RGMA, EFCAB1, ALX4, OSR1 and PPARA. Higher expression of these eight genes correlated with a better prognosis for breast cancer patients. Conclusions These results suggest that miR-1908-3p may exert its oncogenic functions via suppression of these eight genes in breast cancer.

DDX20 (DEAD-box polypeptide 20) is implicated in many cellular processes involving alteration of RNA secondary structure. The role of DDX20 in gastric cancer is still unknown. In the research, the expression of DDX20 and the functional roles of DDX20 in gastric cancer were detected. The increased DDX20 expression in gastric cancer tissue compared with normal gastric tissue was observed. Functional experiments indicated that DDX20 promoted gastric cancer MGC-803 and AGS cells growth, migration, and invasion in vitro. Surprisingly, survival analysis showed that high expression of DDX20 is a favorable prognostic factor for patients with gastric cancer. In addition, enrichment analysis revealed that there is a positive correlation between DDX20 expression and T cell activation in gastric cancer. but not in normal gastric tissues. Furthermore, we found that DDX20 expression level has significant positive correlations with activated CD8 + T cells and activated CD4 + T cells in gastric cancer. Therefore, we hypothesize that the prognostic role of DDX20 in gastric cancer patients may be due to patients with high DDX20 expression contained better immune activation. Taken together, these findings suggest that DDX20 can promote the progression of gastric cancer in vitro and its prognostic value in gastric cancer may be related to many factors, including immune activation.

Superhydrophobic surfaces integrated with liquid self-repelling property have great application potential, nevertheless, it remains a major challenge for simultaneously achieving super-robust feature and extreme superhydrophobicity. In this work, a super-robust self-healing superhydrophobic coating containing cyclic olefin copolymer (COC), fluorinated alkyl silane (FAS) and polytetrafluoroethylene (PTFE) nanoparticles, is prepared by a convenient one-step wet-chemical coating method. The treated fabric has water contact angle of 168˚and sliding angle of 3˚. The coating demonstrates excellent endurance to various severe damages, e.g., repeated washing, abrasion, boiling water, strong UV irradiation, extremely high and low temperature. It also shows self-healing capability from physical/chemcial damages. Benefitting from the triboelectric negative features of COC and PTFE, this coating shows triboelectrification induced water self-repellence after rubbing with a polyamide (Nylon) fabric, water droplets can jump/move off the tribo-charged area. Moreover, this self-repelling feature works with many different aqueous liquids, such as NaCl, strong acid and alkali. Such a robust superhydrophobic coating can be applied onto many other substrates, such as cotton fabric, glass and cotton, and the treated substrates also exhibited liquid self-repellent properties after rubbing with a Nylon fabric. This triboelectrification enhanced superhydrophobic coating might shed light on developing energy-efficient liquid self-removing surfaces for various applications.

The tumor microenvironment (TME) is mainly composed of tumor cells, tumor-infiltrating immune cells, and stromal components. It plays an essential role in the prognosis and therapeutic response of patients. Nonetheless, the TME landscape of urothelial cancer (UC) has not been fully elucidated. In this study, we systematically analyzed several UC cohorts, and three types of TME patterns (stromal-activation subtype, immune-enriched subtype and immune-suppressive subtype) were defined. The tumor microenvironment signature (TMSig) was constructed by modified Lasso penalized regression. Patients were stratified into high- and low-TMSig score groups. The low-score group had a better prognosis (p < 0.0001), higher M1 macrophage infiltration (p < 0.01), better response to immunotherapy (p < 0.05), and more similar molecular characteristics to the luminal (differentiated) subtype. The accuracy of the TMSig for predicting the immunotherapy response was also verified in three independent cohorts. We highlighted that the TMSig is an effective predictor of patient prognosis and immunotherapy response. Quantitative evaluation of a single sample is valuable for us to combine histopathological and molecular characteristics to comprehensively evaluate the status of the patient. Targeted macrophage treatment has great potential for the individualized precision therapy of UC patients.

Few studies have reported whether nutrients in the tumor microenvironment can regulate the expression of PD-L1. Since tumor cells are often situated in a low-glutamine environment, we investigated PD-L1 expression under glutamine deprivation in bladder cancer cells. PD-L1 expression and the activation of the EGFR/MEK/ERK/c-Jun signaling pathway under glutamine deprivation were investigated by qPCR, Western blot, and immunofluorescence analyses. C-Jun-mediated transcriptional regulation of the PD-L1 gene was assessed by ChIP. PD-L1 expression and activation of the EGFR/MEK/ERK/c-Jun signaling pathway were assessed in T24 cells, TCCSUP cells and BALB/c mice with or without glutamine supplementation. Additionally, the impact of PD-L1 expression under glutamine deprivation on the function of T cells was investigated by ELISA. The expression of PD-L1 and EGFR/MEK/ERK/c-Jun pathway activation were elevated by glutamine deprivation, and c-Jun was enriched in the enhancer region of PD-L1. The expression of PD-L1 was considerably impaired by inhibiting the EGFR/MEK/ERK/c-Jun pathway and was elevated by activating this signaling pathway. In addition, the elevated PD-L1 expression and MEK/ERK/c-Jun signaling pathway activation were reduced by glutamine supplementation in vitro and in vivo. PD-L1 upregulation by glutamine deprivation in bladder cancer cells could reduce IFN-γ production by T cells. The expression of PD-L1 was upregulated under glutamine deprivation through the EGFR/MEK/ERK/c-Jun pathway to impair T cell function.

Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.

Abnormal aromatase (CYP19A1) expression may participate in prostate cancer (PCa) carcinogenesis. However, the results of studies on the CYP19A1 gene polymorphisms and PCa are conflicting. This meta-analysis aimed to systematically evaluate the associations between the CYP19A1 Arg264Cys polymorphism and the (TTTA)n repeat polymorphism and PCa. Electronic databases (PubMed, EmBase, ScienceDirect, and Cochrane Library) were comprehensively searched to identify eligible studies. The strength of the association between the Arg264Cys polymorphism and PCa was assessed by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) in allelic, dominant, recessive, homozygous, and heterozygous genetic models. To analyze the impact of the (TTTA)n repeat polymorphism, we sequentially took the N-repeat allele (where N equals 7,8,10,11,12, and 13) as the minor allele and the sum of all the other alleles as the major allele. The ORs and 95% CIs were calculated in the allelic model; this analysis was performed individually for each repeat number. Pooled estimates of nine studies addressing the Arg264Cys polymorphism indicated that this polymorphism was not associated with PCa risk in the overall population or in the Caucasian or Asian subgroups. The 8-repeat allele in the (TTTA)n repeat polymorphism increased PCa risk in the overall population (OR = 1.34, 95% CI = 1.14–1.58, p = .001) and in the subgroup with population-based (PB) controls (OR = 1.41, 95% CI = 1.13–1.74, p = .002) as well as in the subgroup using capillary electrophoresis to identify this polymorphism (OR = 1.34, 95% CI = 1.09–1.65, p = .006).The meta-analysis indicated that the CYP19A1 (TTTA)n repeat polymorphism, but not the Arg264Cys polymorphism, may affect PCa risk.

Abstract Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune disease whose onset and progression are affected by genetic and environmental factors. The purpose of this study is to identify the influence of gut microbiota in the pathogenesis of SLE, and to investigate the mechanism involved. Methods Fecal microbiota from C57/BL6 mice and SLE prone mice were examined using next-generation sequencing (NGS). Germ free mice were given fecal microbiota transplantation (FMT), and their gut microbiome and gene expression in recipients’ colons were examined by NGS. The anti-double stranded DNA (anti-dsDNA) antibodies in recipients were determined using an enzyme-linked immunosorbent assay (ELISA). The immune cell profiles of mice were analyzed by flow cytometry at the 3rd week after FMT, and the expression of genes associated with SLE after FMT was determined using quantitative real-time PCR (qRT-PCR). Results The fecal microbiota of SLE mice had lower community richness and diversity than healthy mice. Fecal microbiota of recipient mice were similar to their donors. Fecal microbiome from SLE mice could lead to a significant increase of anti-dsDNA antibodies and promote the immune response in recipient mice. Our results also indicated that fecal microbiome from SLE mice resulted in significant changes in the distribution of immune cells and upregulated expression of certain lupus susceptibility genes. Conclusions SLE is associated with alterations of gut microbiota. Fecal microbiome from SLE mice can induce the production of anti-dsDNA antibodies in germ free mice and stimulate the inflammatory response, and alter the expression of SLE susceptibility genes in these mice.

Abstract Background Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease. We examined the effect of gut microbiota in a mouse model of RA that develops atherosclerosis. Methods We created three groups of K/BxN female mice that were positive for the anti‐glucose‐6‐phosphate isomerase (GPI) antibody: control diet (CD), high fat diet (HFD), and HFD with hydroxychloroquine (HFD + HCQ). Serological tests were used to detect the serum levels of total cholesterol (TCHO), low‐density lipoprotein cholesterol (LDL‐C), triglyceride (TG), high‐density lipoprotein cholesterol (HDL‐C), anti‐GPI antibody titers, and serum cytokines. Atherosclerotic plaque was determined by histological analysis, and gut microbiota were determined by 16sV4 sequencing. Results Relative to mice given the CD, those receiving the HFD had increased serum levels of LDL‐C, TCHO, and TG, decreased serum levels of HDL‐C, increased atherosclerotic lesions in the aortic root, and altered gut microbiota. Addition of HCQ to HFD decreased the serum levels of LDL‐C, TCHO, and TG, increased serum levels of HDL‐C, and decreased the atherosclerotic lesions in the aortic root. Mice receiving HFD + HCQ also had the greatest bacterial diversity among the three experimental groups. Moreover, HCQ treatment significantly increased the abundance of Akkermansia and Parabacteroides, and decreased the abundance of Clostridium sensu stricto cluster 1, and therefore may be responsible for the reduced RA‐associated atherosclerosis and dyslipidemia. Conclusion Our mouse model of RA indicated that HFD increased ankle width and aggravated atherosclerosis and dyslipidemia, and that HCQ alleviated the dyslipidemia and atherosclerosis, but had no effect on ankle width.

Abstract Background Coronary artery disease (CAD) is associated with gut microbiota alterations in different populations. Gut microbe-derived metabolites have been proposed as markers of major adverse cardiac events. However, the relationship between the gut microbiome and the different stages of CAD pathophysiology remains to be established by a systematic study. Results Based on multi-omic analyses (sequencing of the V3-V4 regions of the 16S rRNA gene and metabolomics) of 161 CAD patients and 40 healthy controls, we found that the composition of both the gut microbiota and metabolites changed significantly with CAD severity. We identified 29 metabolite modules that were separately classified as being positively or negatively correlated with CAD phenotypes, and the bacterial co-abundance group (CAG) with characteristic changes at different stages of CAD was represented by Roseburia, Klebsiella, Clostridium IV and Ruminococcaceae. The result revealed that certain bacteria might affect atherosclerosis by modulating the metabolic pathways of the host, such as taurine, sphingolipid and ceramide, and benzene metabolism. Moreover, a disease classifier based on differential levels of microbes and metabolites was constructed to discriminate cases from controls and was even able to distinguish stable coronary artery disease from acute coronary syndrome accurately. Conclusion Overall, the composition and functions of the gut microbial community differed from healthy controls to diverse coronary artery disease subtypes. Our study identified the relationships between the features of the gut microbiota and circulating metabolites, providing a new direction for future studies aiming to understand the host–gut microbiota interplay in atherosclerotic pathogenesis.

With the ever-growing concern about environmental conservation, green production and water-based nanofibers have attracted more and more interest from both academic and industrial fields; nevertheless, the stabilization process of water-based nanofibers is primarily relying on the application of organic solvent-based crosslinking agents. In this work, we develop a green approach to fabricate water-resistant polyvinyl alcohol (PVA) nanofibers by using a water-based epoxy compound, N1, N6-bis(oxiran-2-ylmethyl) hexane-1,6-diamine (EH), as the crosslinker. This EH/sodium carbonate/sodium bicarbonate (CBS) solution system can break down large aggregates of PVA molecules into small ones and promote the uniform distribution of EH in the solution, resulting in the improved stability of crosslinked PVA nanofibers. We firstly report that the uniform dispersion of crosslinking agents in the electrospinning solution plays a vital role in improving the stability of spinning solutions and the water resistance of crosslinked PVA nanofibers by comparing crosslinking performances between water-based epoxy and conventional water-based blocked isocyanate (BI). This work could open up a novel strategy and green approach for the stabilization of water-based nanofibers.

Hepatoblastoma (HB) is the most common malignant tumor in the liver of infants and young children. The incidence rate varies among different populations. However, genetic differences in HB patients with different epidemiological and ancestral backgrounds have not been found. In this study, we aim to analyze data from 16 patients treated at our center and collected published data from whole-exome sequencing studies on HB, and to explore the genetic differences between races. Data from a total of 75 HB patients of three races (24 Asian, 37 Caucasian and 14 Hispanic) were analyzed. We identified 16 genes with recurrent somatic mutations and 7 core pathway modules. Among them, the Wnt/β-catenin pathway had the highest mutation rate, and the mutation frequency in Caucasians and Hispanics was approximately twice as high as that in Asians. In addition, this study compared the characteristics of gene mutations between patients who underwent preoperative chemotherapy and those who did not and found that there was no significant difference in gene mutations between the two groups. We also preliminarily verified the function of cancer-associated candidate genes (CTNNB1 and KMT2D). In conclusion, we found ethnic differences in HB biology at the genomic level, which expands our understanding of the genetics of HB in children.

Abstract With the improvements in relevant policies, laws, and regulations regarding drug clinical trials in China, the quantity and quality of drug clinical trials have gradually improved, and the development prospects of drug clinical trials for endocrine disorders and metabolism and nutrition disorders are promising. Based on information from the clinical trials from the online drug clinical trial registration platform of the National Medical Products Administration, we aimed to review and evaluate the development of clinical trials of drugs for endocrine disorders and metabolism and nutrition disorders in mainland China from 2010 to 2019, as well as the trends over time. A total of 861 trials were carried out on 254 types of drugs for endocrine disorders and metabolism and nutrition disorders, among which 531 (61.67%) involved endocrine disorders, and 330 (38.33%) addressed metabolism and nutrition disorders. The annual number of clinical trials has been increasing gradually, with a significant increase in 2017. Among them, the proportion of clinical trials with Chinese epidemiological characteristics was relatively large (Wu, Annual Report on Development Health Management and Health Industry in China, 2018). The largest number of trials were for diabetes drugs (55.63%), followed by trials of drugs for hyperlipidemia (19.4%) and those for hyperuricemia (7.9%). It was found that the geographical area of the leading units also showed obvious unevenness according to the analysis of the test unit data. Based on the statistics and evaluation of the data, comprehensive information is provided to support the cooperation of global pharmaceutical R&D companies and research units in China and the development of international multicenter clinical trials in China. This work additionally provides clinical trial units with a self‐evaluation of scientific research competitiveness and hospital development strategies. At the same time, it provides a reference with basic data for sponsors and stakeholders in these trials to determine their development strategy goals.

BackgroundClear cell renal cell carcinoma (ccRCC) is one of the most common types of malignant adult kidney cancer, and its incidence and mortality are not optimistic. It is well known that tumor-related protein markers play an important role in cancer detection, prognosis prediction, or treatment selection, such as carcinoembryonic antigen (CEA), programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4), so a comprehensive analysis was performed in this study to explore the prognostic value of protein expression in patients with ccRCC.Materials and MethodsProtein expression data were obtained from The Cancer Proteome Atlas (TCPA), and clinical information were downloaded from The Cancer Genome Atlas (TCGA). We selected 445 patients with complete information and then separated them into a training set and testing set. We performed univariate, least absolute shrinkage and selection operator (LASSO) Cox analyses to find prognosis-related proteins (PRPs) and constructed a protein signature. Then, we used stratified analysis to fully verify the prognostic significance of the prognostic-related protein signature score (PRPscore). Besides, we also explored the differences in immunotherapy response and immune cell infiltration level in high and low score groups. The consensus clustering analysis was also performed to identify potential cancer subgroups.ResultsFrom the training set, a total of 233 PRPs were selected, and a seven-protein signature was constructed, including ACC1, AR, MAPK, PDK1, PEA15, SYK, and BRAF. Based on the PRPscore, patients could be divided into two groups with significantly different overall survival rates. Univariate and multivariate Cox regression analyses proved that this signature was an independent prognostic factor for patients (P < 0.001). Moreover, the signature showed a high ability to distinguish prognostic outcomes among subgroups, and the low score group had a better prognosis (P < 0.001) and better immunotherapy response (P = 0.003) than the high score group.ConclusionWe constructed a novel protein signature with robust predictive power and high clinical value. This will help to guide the disease management and individualized treatment of ccRCC patients.

ObjectivesTo evaluate copy number alterations (CNAs) in genes associated with penile cancer (PeC) and determine their correlation and prognostic ability with PeC.MethodsWhole-exome sequencing was performed for tumor tissue and matched normal DNA of 35 patients diagnosed with penile squamous cell carcinoma from 2011 to 2016. Somatic CNAs were detected using the Genome Analysis Toolkit (GATK). Retrospective clinical data were collected and analyzed. All the data were statistically analyzed using SPSS 16.0 software. The cancer-specific survival rates were estimated by Kaplan-Meier curves and compared with the log-rank test.ResultsCNAs in the MYCN gene was detected in 19 (amplification: 54.29%) patients. Other CNAs gene targets were FAK (amplification: 45.72%, deletion: 8.57%), TP53 (amplification: 2.86%, deletion: 51.43%), TRKA (amplification: 34.29%, deletion: 2.86%), p75NTR (amplification: 5.71%, deletion: 42.86%), Miz-1 (amplification: 14.29%, deletion: 20.00%), Max (amplification: 17.14%, deletion: 2.86%), Bmi1 (amplification:14.29%, deletion: 48.57%), and MDM2 (amplification: 5.71%, deletion: 45.72%). The CNAs in MYCN and FAK correlated significantly with patient prognosis (P

Although bisphenol A (BPA) has been associated with impaired spermatogenesis, the mechanisms remain unclear. Tight junction occludin plays important roles in spermatogenesis. The objective of the present study was to explore the effects of BPA exposure in adolescent mice. Male mice were orally treated with low-dose (0.05 mg/kg/d), middle-dose (5.0 mg/kg/d), or high-dose (50 mg/kg/d) BPA in corn oil from postnatal day (PND) 35 to 65. Animals were killed on PND 65 and PND 125. On PND 65, the sperm count, sperm motility, and the expression of occludin showed a dose-related decline. On PND 125, the sperm count, sperm motility, and the expression of occludin were in recovery. However, there remained significant decreases in these parameters in the 50 mg/kg/d group on PND 125 compared with the control. The dose-related effects on the measured parameters and occludin expression suggest an early suppressive or damaging effect on the blood–testis barrier followed by recovery after dosing ceased. At a BPA dose of 50 mg/kg/d, recovery did not occur, suggesting that higher doses of BPA may cause irreversible damage to reproduction in male mice.

Background/Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-cancer agent due to its selective toxicity. However, many human non-small cell lung cancer (NSCLC) cells are partially resistant to TRAIL, thereby limiting its clinical application. Therefore, there is a need for the development of novel adjuvant therapeutic agents to be used in combination with TRAIL. Methods: In this study, the effect of N-acetyl-glucosamine (GlcNAc), a type of monosaccharide derived from chitosan, combined with TRAIL was evaluated in vitro and in vivo. Thirty NSCLC clinical samples were used to detect the expression of death receptor (DR) 4 and 5. After GlcNAc and TRAIL co-treatment, DR expression was determined by real-time PCR and western blotting. Cycloheximide was used to detect the protein half-life to further understand the correlation between GlcNAc and the metabolic rate of DR. Non-reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis was used to detect receptor clustering, and the localization of DR was visualized by immunofluorescence under a confocal microscope. Furthermore, a co-immunoprecipitation assay was performed to analyze the formation of death-inducing signaling complex (DISC). O-linked glycan expression levels were evaluated following DR5 overexpression and RNA interference mediated knockdown. Results: We found that the clinical samples expressed higher levels of DR5 than DR4, and GlcNAc co-treatment improved the effect of TRAIL-induced apoptosis by activating DR5 accumulation and clustering, which in turn recruited the apoptosis-initiating protease caspase-8 to form DISC, and initiated apoptosis. Furthermore, GlcNAc promoted DR5 clustering by improving its O-glycosylation. Conclusion: These results uncovered the molecular mechanism by which GlcNAc sensitizes cancer cells to TRAIL-induced apoptosis, thereby highlighting a novel effective agent for TRAIL-mediated NSCLC-targeted therapy.

Abstract The gut microbiota, the largest symbiotic ecosystem with the host, has been shown to play important roles in maintaining intestinal homeostasis. Dysbiosis of the gut microbiome is caused by the imbalance between the commensal and pathogenic microbiomes. The commensal microbiome regulates the maturation of the mucosal immune system, while the pathogenic microbiome causes immunity dysfunction, resulting in disease development. The gut mucosal immune system, which consists of lymph nodes, lamina propria and epithelial cells, constitutes a protective barrier for the integrity of the intestinal tract. The composition of the gut microbiota is under the surveillance of the normal mucosal immune system. Inflammation, which is caused by abnormal immune responses, influences the balance of the gut microbiome, resulting in intestinal diseases. In this review, we briefly outlined the interaction between the gut microbiota and the immune system and provided a reference for future studies.

Matrix metallopeptidase 9 (MMP9) was found to be associated with tumor aggressiveness. In this study, we focused on the correlation between MMP9 expression and clear cell renal carcinoma (ccRCC). Through the Gene Expression Omnibus (GEO) database, the Cancer Genome Atlas (TCGA) database and immunohistochemical (IHC) staining, we observed that compared with adjacent normal renal tissues, in ccRCC tissues the mRNA and protein levels of MMP9 were enhanced, and the mRNA levels of GTP-binding protein smg p21B(RAP1B), B rapidly accelerated fibrosarcoma (RAF), methyl ethyl ketone2 (MEK2), extracellular regulated protein kinases1 (ERK1), ERK2, v-ets avian erythroblastosis virus E26 oncogene homolog1 (ETS1) and ETS2 also increased. The Kaplan–Meier survival analysis suggested that high MMP9 expression was an unfavorable prognostic biomarker for ccRCC patients. Our results indicated that the increased expression level of MMP9 in ccRCC may be due to the activation of the Mitogen-activated protein kinases (MAPK)/ERK signaling pathway, and MMP9 may be an attractive target for ccRCC therapy.

Systemic autoimmune diseases are a group of heterogeneous disorders caused by both genetic and environmental factors. Although numerous causal genes have been identified by genome-wide association studies (GWAS), these susceptibility genes are correlated to a relatively low disease risk, indicating that environmental factors also play an important role in the pathogenesis of disease. The intestinal microbiome, as the main symbiotic ecosystem between the host and host-associated microorganisms, has been demonstrated to regulate the development of the body’s immune system and is likely related to genetic mutations in systemic autoimmune diseases. Next-generation sequencing (NGS) technology, with high-throughput capacity and accuracy, provides a powerful tool to discover genomic mutations, abnormal transcription and intestinal microbiome identification for autoimmune diseases. In this review, we briefly outlined the applications of NGS in systemic autoimmune diseases. This review may provide a reference for future studies in the pathogenesis of systemic autoimmune diseases.

Epidemiological studies have identified hyperuricemia as an independent risk factor for cardiovascular disease. However, the mechanism whereby hyperuricemia causes atherosclerosis remains unclear. The objective of the study was to establish a new rat model of hyperuricemia-induced atherosclerosis. Wistar-Kyoto rats were randomly allocated to either a normal diet (ND), high-fat diet (HFD), or high-adenine diet (HAD), followed by sacrifice 4, 8, or 12 weeks later. Serum uric acid and lipid levels were analyzed, pathologic changes in the aorta were observed by hematoxylin and eosin staining, and mRNA expression was evaluated by quantitative real-time polymerase chain reaction. Serum uric acid and TC were significantly increased in the HAD group at 4 weeks compared with the ND group, but there was no significant difference in serum uric acid between the ND and HFD groups. Aorta calcification occurred earlier and was more severe in the HAD group, compared with the HFD group. Proliferating cell nuclear antigen, monocyte chemotactic factor-1, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 mRNA levels were increased in the HFD and HAD groups compared with the ND group. This new animal model will be a useful tool for investigating the mechanisms responsible for hyperuricemia-induced atherosclerosis.

Small-diameter blood vessels (SDBVs) are still a challenging task to prepare due to the occurrence of thrombosis formation, intimal hyperplasia, and aneurysmal dilation. Electrospinning technique, as a promising tissue engineering approach, can fabricate polymer fibrous scaffolds that satisfy requirements on the construction of extracellular matrix (ECM) of native blood vessel and promote the adhesion, proliferation, and growth of cells. In this review, we summarize the polymers that are deployed for the fabrication of SDBVs and classify them into three categories, synthetic polymers, natural polymers, and hybrid polymers. Furthermore, the biomechanical properties and the biological activities of the electrospun SBVs including anti-thrombogenic ability and cell response are discussed. Polymer blends seem to be a strategic way to fabricate SDBVs because it combines both suitable biomechanical properties coming from synthetic polymers and favorable sites to cell attachment coming from natural polymers.

This study aims to determine the motivation and performance of employees at Mukhbis Jaya Konveksi in Rancamalang, Bandung Regency and to determine and analyze the effect of motivation on employee performance at Mukhbis Jaya Konveksi in Rancamalang, Bandung Regency. This research uses descriptive and verification methods with a quantitative approach. The data used are primary data and secondary data obtained from observations, interviews, questionnaires and literature studies. The population in this study were all employees at Mukhbis Jaya Konveksi in Rancamalang, Bandung Regency. The sampling technique used is a saturated sample technique where all populations are sampled. Data analysis using simple linear regression analysis using the SPSS (Statistical Program for Social Science) application. The results showed that motivation has a positive and significant effect on employee performance, but has a low level of relationship between motivation and employee performance at Mukhbis Jaya Konveksi in Rancamalang, Bandung Regency and a small coefficient of determination. Meanwhile, the remaining coefficient of determination is from other variables not examined in this study. [ABSTRACT FROM AUTHOR]