Identification of a cancer-associated fibroblast signature for predicting prognosis and immunotherapeutic responses in bladder urothelial carcinoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are the most important cellular components in bladder urothelial carcinoma (BLCA) and are involved in the development and immunosuppression of BLCA. Therefore, we aimed to construct a CAF-associated signature for predicting the prognosis and immunotherapy response in patients with BLCA. METHODS: CAF infiltration and stromal score were quantified using two algorithms. Weighted gene co-expression network analysis (WGCNA) was performed to identify the CAF-associated modules and hub genes. Univariate Cox and Least Absolute Shrinkage and Selection Operator regression analyses were used for constructing CAF signatures and calculating CAF scores. The ability of the CAF signature to predict prognosis and response to immunotherapy was validated using the data from three cohorts. RESULTS: WGCNA identified two CAF-associated modules and constructed a CAF signature containing 27 genes. In all three cohorts, patients with high CAF scores had markedly worse prognoses than those with low CAF scores, and CAF scores were independent risk factors. In addition, patients with high CAF scores did not respond to immunotherapy, whereas those with lower CAF scores responded to immunotherapy. CONCLUSION: CAF signature can be used to predict prognosis and immunotherapy response to guide individualized treatment planning in patients with BLCA.

Erectile Dysfunction and Obstructive Sleep Apnea: A Review.

Erectile dysfunction (ED) is a disease with a wide scope of etiologies. Obstructive sleep apnea (OSA) is considered one of the risk factors for ED and is less studied. A growing lot of evidence show an association between OSA and ED. This study provides an updated review of the relationship between ED and OSA and the possible physiological mechanisms of ED in patients with OSA based on the current evidence. In clinical interviews, patients with ED may benefit from a sleep evaluation. However, further clinical investigations and more basic research are needed to illustrate the relationship between ED and OSA.

Diagnostic significance of miRNAs as potential biomarkers for human renal cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Numerous studies have explored miRNAs as potential diagnostic biomarkers in patients with renal cell carcinoma (RCC). However, its diagnostic accuracy remains controversial. RESEARCH DESIGN AND METHODS: PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, China Science and Technology Journal, and Wanfang Databases were searched according to inclusion/exclusion criteria. The quality of the studies was assessed using the QUADAS-2 scale. The combined sensitivity, specificity, positive/negative likelihood ratios, diagnostic odds ratio, and area under the curve (AUC) of the summary receiver operating characteristic (SROC) were calculated using a bivariate mixed-effect model. RESULTS: Of the 16 studies included, 20 diagnostic tests were assessed. Results are presented with a corresponding 95% confidence interval in brackets: for miR-210, the combined sensitivity was 0.78 (0.68-0.85), specificity 0.71 (0.61-0.79), and AUC 0.81 (0.77-0.8); for miR-378, combined sensitivity 0.78 (0.68-0.86), specificity 0.79 (0.64-0.89), and AUC 0.85 (0.81-0.88); for miR-1233, combined sensitivity 0.86 (0.80-0.90), specificity 0.80 (0.36-0.96), and AUC 0.86 (0.83-0.89); for miR-21, combined sensitivity 0.84 (0.78-0.89), specificity 0.79 (0.55-0.92), and AUC 0.87 (0.84-0.89). CONCLUSIONS: This meta-analysis suggests that miR-210, miR-378, miR-1233, and miR-21 have high accuracy in diagnosing RCC.

An Unfolded Protein Response Related Signature Could Robustly Predict Survival Outcomes and Closely Correlate With Response to Immunotherapy and Chemotherapy in Bladder Cancer.

Background: The unfolded protein response (UPR) plays a significant role in maintaining protein hemostasis in tumor cells, which are crucial for tumor growth, invasion, and resistance to therapy. This study aimed to develop a UPR-related signature and explore its correlation with immunotherapy and chemotherapy in bladder cancer. Methods: The differentially expressed UPR-related genes were put into Lasso regression to screen out prognostic genes, which constituted the UPR signature, and were incorporated into multivariate Cox regression to generate risk scores. Subsequently, the predictive performance of this signature was estimated by receiver operating characteristic (ROC) curves. The CIBERSORTx, the maftool, and Gene set enrichment analysis (GSEA) were applied to explore infiltrated immune cells, tumor mutational burden (TMB), and enriched signaling pathways in both risk groups, respectively. Moreover, The Cancer Immunome Atlas (TCIA) and Genomics of Drug Sensitivity in Cancer (GDSC) databases were used to predict responses to chemotherapy and immunotherapy. Results: Twelve genes constituted the UPR-related signature. Patients with higher risk scores had worse overall survival (OS) in training and three validation sets. The UPR-related signature was closely correlated with clinicopathologic parameters and could serve as an independent prognostic factor. M0 macrophages showed a significantly infiltrated difference in both risk groups. TMB analysis showed that the risk score in the wild type and mutation type of FGFR3 was significantly different. GSEA indicated that the immune-, extracellular matrix-, replication and repair associated pathways belonged to the high risk group and metabolism-related signal pathways were enriched in the low risk group. Prediction of immunotherapy and chemotherapy revealed that patients in the high risk group might benefit from chemotherapy, but had a worse response to immunotherapy. Finally, we constructed a predictive model with age, stage, and UPR-related risk score, which had a robustly predictive performance and was validated in GEO datasets. Conclusion: We successfully constructed and validated a novel UPR-related signature in bladder cancer, which could robustly predict survival outcomes and closely correlate with the response to immunotherapy and chemotherapy in bladder cancer.

Rosmarinic acid ameliorates hypoxia/ischemia induced cognitive deficits and promotes remyelination.

Rosmarinic acid, a common ester extracted from Rosemary, Perilla frutescens, and Salvia miltiorrhiza Bunge, has been shown to have protective effects against various diseases. This is an investigation into whether rosmarinic acid can also affect the changes of white matter fibers and cognitive deficits caused by hypoxic injury. The right common carotid artery of 3-day-old rats was ligated for 2 hours. The rats were then prewarmed in a plastic container with holes in the lid, which was placed in 37°C water bath for 30 minutes. Afterwards, the rats were exposed to an atmosphere with 8% O2 and 92% N2 for 30 minutes to establish the perinatal hypoxia/ischemia injury models. The rat models were intraperitoneally injected with rosmarinic acid 20 mg/kg for 5 consecutive days. At 22 days after birth, rosmarinic acid was found to improve motor, anxiety, learning and spatial memory impairments induced by hypoxia/ischemia injury. Furthermore, rosmarinic acid promoted the proliferation of oligodendrocyte progenitor cells in the subventricular zone. After hypoxia/ischemia injury, rosmarinic acid reversed to some extent the downregulation of myelin basic protein and the loss of myelin sheath in the corpus callosum of white matter structure. Rosmarinic acid partially slowed down the expression of oligodendrocyte marker Olig2 and myelin basic protein and the increase of oligodendrocyte apoptosis marker inhibitors of DNA binding 2. These data indicate that rosmarinic acid ameliorated the cognitive dysfunction after perinatal hypoxia/ischemia injury by improving remyelination in corpus callosum. This study was approved by the Animal Experimental Ethics Committee of Xuzhou Medical University, China (approval No. 20161636721) on September 16, 2017.

LncRNA ADAMTS9-AS2 inhibits cell proliferation and decreases chemoresistance in clear cell renal cell carcinoma via the miR-27a-3p/FOXO1 axis.

Accumulating evidence reveals the principal role of long noncoding RNAs in the progression of clear cell renal cell carcinoma (ccRCC). However, little is known about the underlying mechanism of ADAM metallopeptidase with thrombospondin type 1 motif, 9 antisense RNA 2 (ADAMTS9-AS2) in ccRCC. Here, bioinformatics analyses verified ADAMTS9-AS2 is a long noncoding RNA and its high expression was associated with better prognosis of ccRCC. ADAMTS9-AS2 was clearly downregulated in ccRCC clinical samples and cell lines. Clinical data showed low-expressed ADAMTS9-AS2 was correlated with worse overall survival in ccRCC patients. Next, miR-27a-3p was identified as an inhibitory target of ADAMTS9-AS2 by dual-luciferase reporter and RNA immunoprecipitation assays. Both overexpressed ADAMTS9-AS2 and underexpressed miR-27a-3p in ccRCC cell lines led to the inhibition of cell proliferation and the reduction of chemoresistance. Additionally, Forkhead Box Protein O1 (FOXO1) was confirmed as the inhibitory target of miR-27a-3p. Induced by ADAMTS9-AS2 overexpression, cell proliferation and chemoresistance exhibited an obvious reduction, FOXO1 expression showed an evident increase, but all were reversed after miR-27a-3p was simultaneously overexpressed. Collectively, these results suggest ADAMTS9-AS2 inhibits the progression and impairs the chemoresistance of ccRCC via miR-27a-3p-mediated regulation of FOXO1 and may serve as a prognostic biomarker and therapeutic target for ccRCC.

Hydroxylated polychlorinated biphenyl metabolites (OH-PCBs), maternal smoking and size at birth.

In a sample of 442 births from the Child Health and Development Studies cohort, we examined associations between maternal prenatal exposure to hydroxylated polychlorinated biphenyl metabolites (OH-PCBs) and pregnancy outcomes, and whether associations were mediated by maternal thyroid hormone levels and/or modified by maternal smoking. Compared to nonsmokers, smokers had twice the mean concentration of 4-OH-CB107 (p<0.001) and lower levels of its parent compound, PCB118 (p=0.001). Among mothers who smoked, the birth weight of newborns with maternal concentrations of 4-OH-CB107 in the upper quartile was 316g lighter (95% confidence interval (CI) 566, 65) compared to those with maternal concentrations in the lowest quartile, after control for PCB118 and other potential confounders. This association was not observed for non-smoking mothers and was not mediated by maternal thyroid hormone levels. Maternal prenatal 4-OH-CB107 levels appear to be influenced by maternal smoking and contribute to lower birth weight among smokers.

Effectiveness of self-management training in community residents with chronic schizophrenia: a single-blind randomized controlled trial in Shanghai, China.

AIM: Evaluate the effectiveness of self-management training in community-dwelling adults with schizophrenia. METHODS: A total of 201 individuals with chronic schizophrenia (mean duration of illness of 17.4 years) were recruited and randomized into the self-management intervention group (n=103) and treatment-as-usual control group (n=98). The self-management training involved weekly group sessions for 6 months in which basic self-management skills were discussed and modelled followed by monthly group booster sessions for 24 months in which a community health worker reviewed patients' self-management checklist journals. Two psychiatrists who were blind to group assignment evaluated the symptoms and social functioning of participants at baseline and 6 months and 30 months after enrollment using the Brief Psychiatric Rating Scale (BPRS), Social Disability Screening Schedule (SDSS), and Morningside Rehabilitation Status Scale (MRSS). A total of 194 individuals (99 from the intervention group and 95 from the control group) completed the 2.5-year follow-up. Intention-to-treat analysis with the last observation carried forward method was used for analysis. RESULTS: Compared to the control group, the intervention group had lower mean scores in the BPRS, SDSS and MRSS at both follow-up points. The scores in the intervention group continued to improve during the maintenance phase of the treatment from 6 months to 30 months after enrollment. CONCLUSION: Self-management training is an effective method to improve symptoms and social functioning among individuals with chronic schizophrenia living in the community. After six months of weekly training in self-management skills, monthly booster sessions reviewing patients' daily checklist of illness-related symptoms events are sufficient to maintain the beneficial effects of the training. Further study of the long-term cost-effectiveness of this method is needed.

Effect of self-management training on adherence to medications among community residents with chronic schizophrenia: a singleblind randomized controlled trial in Shanghai, China.

BACKGROUND: Many community dwelling individuals with schizophrenia do not take medications regularly and, thus, are prone to frequent relapses. AIM: Evaluate the effectiveness of self-management training on adherence to medications and relapse among individuals with chronic schizophrenia living in the community. METHODS: A total of 201 individuals with chronic schizophrenia living in the urban and rural communities of Shanghai Municipality were randomized into a treatment as usual control group (n=98) or a selfmanagement intervention group (n=103) that received weekly self-management skills training for 6 months followed by 24 months of monthly group booster sessions in which a community health worker reviewed patients' self-management checklists. Two psychiatrists blind to the treatment status of patients, assessed adherence to medications using the Morisky Medication Adherence Scale and patients' insight into their illness using the Scale to Assess Unawareness of Mental Disorders (SAUMD) at baseline and 30 months after baseline. A total of 194 individuals (95.6%) completed the study. RESULTS: There were no differences between groups at baseline, but after 30 months the intervention group had significantly better medication compliance, significantly greater insight into their illness, and (by self-report) were using significantly higher dosages of antipsychotic medication. Only 2 (1.9%) of the 103 intervention group participants relapsed (i.e., experienced one or more re-hospitalizations) over the 30 months of follow-up, but 14 (14.3%) of the 98 control group subjects relapsed (X (2)=8.83, p=0.003). CONCLUSIONS: Given the large sample size, relatively long follow-up, randomized design, and single-blind evaluation of outcomes the dramatic reduction in relapse and improvements in medication adherence and insight identified in this study are robust findings. These results extended our previous findings, which demonstrated the benefit of self-management training on improving the symptoms and social functioning of individuals with chronic schizophrenia living in the community. Cost-benefit studies are now needed to assess the feasibility of up-scaling this self-management intervention to a wide range of communities.

A hidden Markov model for copy number variant prediction from whole genome resequencing data.

MOTIVATION: Copy Number Variants (CNVs) are important genetic factors for studying human diseases. While high-throughput whole genome re-sequencing provides multiple lines of evidence for detecting CNVs, computational algorithms need to be tailored for different type or size of CNVs under different experimental designs. RESULTS: To achieve optimal power and resolution of detecting CNVs at low depth of coverage, we implemented a Hidden Markov Model that integrates both depth of coverage and mate-pair relationship. The novelty of our algorithm is that we infer the likelihood of carrying a deletion jointly from multiple mate pairs in a region without the requirement of a single mate pairs being obvious outliers. By integrating all useful information in a comprehensive model, our method is able to detect medium-size deletions (200-2000bp) at low depth (<10× per sample). We applied the method to simulated data and demonstrate the power of detecting medium-size deletions is close to theoretical values. AVAILABILITY: A program implemented in Java, Zinfandel, is available at http://www.cs.columbia.edu/~itsik/zinfandel/