Circulating exosomal miR-16-5p and let-7e-5p are associated with bladder fibrosis of diabetic cystopathy.

Diabetic cystopathy (DCP) is a prevalent etiology of bladder dysfunction in individuals with longstanding diabetes, frequently leading to bladder interstitial fibrosis. Research investigating the initial pathological alterations of DCP is notably scarce. To comprehend the development of fibrosis and find effective biomarkers for its diagnosis, we prepared streptozotocin-induced long-term diabetic SD rats exhibiting a type 1 diabetes phenotype and bladder fibrosis in histology detection. After observing myofibroblast differentiation from rats' primary bladder fibroblasts with immunofluorescence, we isolated fibroblasts derived exosomes and performed exosomal miRNA sequencing. The co-differentially expressed miRNAs (DEMis) (miR-16-5p and let-7e-5p) were screened through a joint analysis of diabetic rats and long-term patients' plasma data (GES97123) downloaded from the GEO database. Then two co-DEMis were validated by quantitative PCR on exosomes derived from diabetic rats' plasma. Following with a series of analysis, including target mRNAs and transcription factors (TFs) prediction, hubgenes identification, protein-protein interaction (PPI) network construction and gene enrichment analysis, a miRNA-mediated genetic regulatory network consisting of two miRNAs, nine TFs, and thirty target mRNAs were identified in relation to fibrotic processes. Thus, circulating exosomal miR-16-5p and let-7e-5p are associated with bladder fibrosis of DCP, and the crucial genes in regulatory network might hold immense significance in studying the pathogenesis and molecular mechanisms of fibrosis, which deserves further exploration.

Novel gene signature for predicting biochemical recurrence-free survival of prostate cancer and PRAME modulates prostate cancer progression.

Biochemical recurrence (BCR) is considered as an early sign of prostate cancer (PCa) progression after initial treatment, such as radical prostatectomy and radiotherapy; hence, it is important to stratify patients at risk of BCR. In this study, we established a robust 8-gene signature (APOF, Clorf64, RPE65, SEMG1, ARHGDIG, COMP, MKI67 and PRAME) based on the PCa transcriptome profiles in the Cancer Genome Atlas (TCGA) for predicting BCR-free survival of PCa, which was further validated in the MSK-IMPACT Clinical Sequencing Cohort (MSKCC) PCa cohort. Moreover, we found that one risk-related gene (PRAME) was upregulated in tumor samples, particularly in high-risk group was well as in patients metastatic tumor and was correlated with chemotherapeutic drug response. In vitro experiments showed that knocking down PRAME reduced the proliferation, migration, and invasion of PCa cells. Therefore, our study established a new 8-gene signature that could accurately predict the BCR risk of PCa. Inhibition of PRAME attenuated the proliferation, invasion, and migration of PCa cells. These findings provide a novel tool for stratifying high-risk PCa patient and shed light on the mechanism of PCa progression.

Incidence trends and survival of metastatic prostate cancer with bone and visceral involvement: 2010-2019 surveillance, epidemiology, and end results.

Background: The incidence of prostate cancer (PCa) has continued to increase since the US Preventive Services Task Force (USPSTF) recommendations against prostate-specific antigen (PSA)-based screening for all men in 2012, approximately half of additional diagnosed cases are advanced-stage, including regional PCa and metastatic PCa (mPCa). It is very important to investigate the shift in mPCa incidence and mPCa-related mortality risk, as the survival of mPCa remains poor. Objective: To investigate the incidence temporal trend of mPCa stratified by metastatic site, including bone and visceral metastatic involvement, and potential survival improvements. Materials: Based on the recently released Surveillance, Epidemiology, and End Results (SEER) data (2010-2019), the age-adjusted incidence rates of mPCa with bone and visceral involvement with annual percentage changes (APCs) were assessed by a joinpoint regression model in men aged 45 years and older by age and race groups, and potential recent improvements in overall survival (OS) and cancer-specific survival (CSS) were estimated by the Kaplan-Meier method and Cox regression model. Results: From 2010 to 2019, a total of 19081 (84.8%) and 3413 (15.2%) mPCa patients with bone and visceral involvement, respectively, were recorded in the SEER database. Considering all races and age groups, the incidence rate of mPCa with bone metastasis remained stable during 2017-2019 (APC, 0.9%; p=0.421) after increasing during 2010-2017 (APC, 5.8%; p<0.001). For visceral metastasis, the incidence rate increased by 12.3% (p<0.001) per year from 2010-2019. Non-Hispanic Black men have higher incidence rates than other populations, and the Non-Hispanic Black to Non-Hispanic White incidence rates ratios of mPCa declined with the greater increasing pace of incidence of Non-Hispanic White men. There was a slight improvement in both OS and CSS among men with bone and visceral metastasis involvement when comparing the 2013-2016 period to the pre-2013 period. Conclusion: Our findings show that the incidence of mPCa with bone and visceral involvement has increased in recent years and that there has been a potential improvement in survival. Future efforts are still needed to watch closely if the rising incidence trends continue.

Association between metabolically healthy obesity and kidney stones: results from the 2011-2018 National Health and Nutrition Examination Survey.

Introduction: The risk of kidney stones in metabolically healthy obesity (MHO) individuals is largely unexplored. This study using percent body fat (%BF) to categorize obesity, to investigate the association between MHO as well as other metabolic syndrome-obesity combined phenotypes and kidney stones in a national representative population. Materials and methods: This cross-sectional study included 4,287 participants in the National Health and Nutrition Examination Survey from 2011 to 2018. Metabolically healthy status was defined as not having any component of metabolic syndrome or insulin resistance. Obesity was identified by %BF, which was measured and assessed by dual-energy x-ray absorptiometry (DXA) scan. Participants were cross-classified by metabolic health and obesity status. The outcome was self-report kidney stones. Multivariable logistic regression model was used to examine the association between MHO and kidney stones. Results: A total of 358 participants had kidney stones [weighted prevalence (SE): 8.61% (0.56%)]. The weighted prevalence (SE) of kidney stones in MHN, MHOW, and MHO groups was 3.13% (1.10%), 4.97% (1.36%), and 8.55% (2.09%), respectively. After adjusting for age, sex, race and ethnicity, education level, smoking status, alcohol consumption, physical activity, daily water intake, CKD stage 3-5, and hyperuricemia, MHO individuals (OR: 2.90, 95% CI: 1.18, 7.0) had a significantly higher risk of kidney stones than those with metabolically healthy normal weight. In metabolically healthy participants, a 5% increment in %BF was associated with a significantly higher risk of kidney stones (OR: 1.60, 95% CI: 1.20, 2.14). Furthermore, a nonlinear dose-response relationship between %BF and the kidney stones was observed in metabolically healthy participants (P for non-linearity = 0.046). Conclusion: Using %BF to define obesity, MHO phenotype was significantly associated with higher risks of kidney stones, suggesting that obesity can independently contribute to kidney stones in the absence of metabolic abnormalities and insulin resistance. Regarding kidney stones prevention, MHO individuals might still benefit from lifestyle interventions aimed at healthy body composition maintenance.

Individualized prognosis stratification in muscle invasive bladder cancer: A pairwise TP53-derived transcriptome signature.

TP53 is the most frequently mutated gene in muscle invasive bladder cancer (MIBC) and there are two gene signatures regarding TP53 developed for MIBC prognosis. However, they are limited to immune genes only and unable to be used individually across platforms due to their quantitative manners. We used 827 gene expression profiles from seven MIBC cohorts with varied platforms to build a pairwise TP53-derived transcriptome signature, 13 gene pairs (13-GPs). Since the 13-GPs model is a single sample prognostic predictor, it can be applied individually in practice and is applicable to any gene-expression platforms without specific normalization requirements. Survival difference between high-risk and low-risk patients stratified by the 13-GPs test was statistically significant (HR range: 2.26-2.76, all P < .0001). Discovery and validation sets showed that the 13-GPs was an independent prognostic factor after adjusting other clinical features (HR range: 2.21-2.82, all P < .05). Moreover, it was a potential supplement to the consensus molecular classification of MIBC to further stratify the LumP subtype (patients with better prognoses). High- and low-risk patients by the 13-GPs model presented distinct immune microenvironment and DDR mutation rates, suggesting that it might have the potential for immunotherapy. Being a general approach to other cancer types, this study demonstrated how we integrated gene variants with pairwise gene panels to build a single sample prognostic test in translational oncology.

MUC20 as a novel prognostic biomarker in ccRCC correlating with tumor immune microenvironment modulation.

Tumor microenvironment (TME) broadly participates in genesis development of clear cell renal cell carcinoma (ccRCC). To recognize the immune and stromal modulation in TME, we screened the differentially expressed TME-related genes generated by the ESTIMATE algorithm in ccRCC specimens. Following the construction of protein-protein interaction (PPI) network and univariate COX regression, mucin 20 (MUC20) was judged to be a predictive factor. Further analysis, including immunohistochemistry (IHC) showed that MUC20 was positively correlated with survival and negatively correlated with the clinicopathologic characteristics (grade, clinical and TNM stages) in ccRCC patients. Gene Set Enrichment Analysis suggested that the low-expression MUC20 group was primarily enriched in immune-related activities, inflammation and epithelial-mesenchymal transition. Based on the CIBERSORT analysis for tumor-infiltrating immune cells (TICs), MUC20 was positively correlated with CD8+ T cells and resting mast cells and negatively correlated with activated CD4+ memory T cells, Treg cells, and plasma cells, implying that MUC20 may contribute to immune component in TME. Additionally, the patients with low MUC20 expression had better response to immune checkpoint blockades (ICBs) and 17 potential anticancer drugs were screened regarding calculating IC50 value. Thus, MUC20 may contain a value of prognosis assessment for ccRCC patients and indicate the immune modulation status of TME, which provided a novel insight for comprehensive immunotherapy.

Metabolically healthy obesity is associated with increased risk of lower urinary tract symptoms secondary to benign prostatic hyperplasia: A cohort study of Chinese elderly males.

OBJECTIVES: Obesity and metabolic status are both modifiable risk factors of lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). However, the association between metabolically healthy obesity (MHO) and LUTS/BPH is largely unexplored. This study aimed to investigate the risk of LUTS/BPH among different metabolic syndrome-body mass index (MetS-BMI) phenotypes in a cohort of Chinese males. METHODS: A total of 3321 males from the China Health and Retirement Longitudinal Study (CHARLS) without history of LUTS/BPH at baseline were included into the analyses. Participants were categorized into six mutually exclusive groups according to presence or absence of MetS combined with BMI status: metabolically healthy normal weight/overweight/obesity (MHN/MHOW/MHO) and metabolically unhealthy normal weight/overweight/obesity (MUN/MUOW/MUO). Adjusted odds ratios (OR) and 95% CI of LUTS/BPH across MetS-BMI categories were estimated with multivariable logistic regression models. RESULTS: A total of 394 (11.86%) participants developed LUTS/BPH during the follow-up. After adjusting for age, educational level, smoking status, drinking status, and BMI change, the multivariable-adjusted OR (95% CI) for incident LUTS/BPH comparing MUO, MHO, MUOW, MHOW, and MUN with MHN were 1.99 (1.23-3.22), 2.04 (1.14-3.66), 1.61 (1.11-2.34), 1.45 (1.02-2.05), and 0.91 (0.54-1.56), respectively. CONCLUSIONS: MHO and MHOW were risk populations of LUTS/BPH, suggesting that overweight and obesity can independently contribute to LUTS/BPH, even among metabolically healthy individuals. These findings emphasize metabolically healthy individuals may still benefit from maintaining normal body weight to prevent LUTS/BPH. Our findings also support that those recommendations for LUTS/BPH should highlight the importance of maintaining metabolic health across all BMI groups among Chinese males.

Proteomic profiling identifies signatures associated with progression of precancerous gastric lesions and risk of early gastric cancer.

BACKGROUND: Molecular features underlining the multistage progression of gastric lesions and development of early gastric cancer (GC) are poorly understood, restricting the ability to GC prevention and management. METHODS: We portrayed proteomic landscape and explored proteomic signatures associated with progression of gastric lesions and risk of early GC. Tissue proteomic profiling was conducted for a total of 324 subjects. A case-control study was performed in the discovery stage (n=169) based on populations from Linqu, a known high-risk area for GC in China. We then conducted two-stage validation, including a cohort study from Linqu (n = 56), with prospective follow-up for progression of gastric lesions (280-473 days), and an independent case-control study from Beijing (n = 99). FINDINGS: There was a clear distinction in proteomic features for precancerous gastric lesions and GC. We derived four molecular subtypes of gastric lesions and identified subtype-S4 with the highest progression risk. We found 104 positively-associated and 113 inversely-associated proteins for early GC, with APOA1BP, PGC, HPX and DDT associated with the risk of gastric lesion progression. Integrating these proteomic signatures, the ability to predict progression of gastric lesions was significantly strengthened (areas-under-the-curve=0.88 (95%CI: 0.78-0.99) vs. 0.56 (0.36-0.76), Delong's P = 0.002). Immunohistochemistry assays and examination at mRNA level validated the findings for four proteins. INTERPRETATION: We defined proteomic signatures for progression of gastric lesions and risk of early GC, which may have translational significance for identifying particularly high-risk population and detecting GC at an early stage, improving potential for targeted GC prevention. FUNDING: The funders are listed in the Acknowledgement.

Identification and Validation of Plasma Metabolomic Signatures in Precancerous Gastric Lesions That Progress to Cancer.

Importance: Metabolic deregulation plays an important role in gastric cancer (GC) development. To date, no studies have comprehensively explored the metabolomic profiles along the cascade of gastric lesions toward GC. Objective: To draw a metabolic landscape and define metabolomic signatures associated with the progression of gastric lesions and risk of early GC. Design, Setting, and Participants: A 2-stage, population-based cohort study was initiated in 2017 in Linqu County, Shandong Province, China, a high-risk area for GC. Prospective follow-up was conducted during the validation stage (June 20, 2017, to May 27, 2020). A total of 400 individuals were included based on the National Upper Gastrointestinal Cancer Early Detection Program in China. The discovery stage involved 200 individuals with different gastric lesions or GC (high-grade intraepithelial neoplasia or invasive GC). The validation stage prospectively enrolled 152 individuals with gastric lesions who were followed up for 118 to 1063 days and 48 individuals with GC. Exposures: Metabolomic profiles and metabolite signatures were examined based on untargeted plasma metabolomics assay. Main Outcomes and Measures: The risk of GC overall and early GC (high-grade intraepithelial neoplasia), and progression of gastric lesions. Results: Of the 400 participants, 124 of 200 (62.0%) in the discovery set were men; mean (SD) age was 56.8 (7.5) years. In the validation set, 136 of 200 (68.0%) were men; mean (SD) age was 57.5 (8.1) years. Distinct metabolomic profiles were noted for gastric lesions and GC. Six metabolites, including α-linolenic acid, linoleic acid, palmitic acid, arachidonic acid, sn-1 lysophosphatidylcholine (LysoPC)(18:3), and sn-2 LysoPC(20:3) were significantly inversely associated with risk of GC overall and early GC (high-grade intraepithelial neoplasia). Among these metabolites, the first 3 were significantly inversely associated with gastric lesion progression, especially for the progression of intestinal metaplasia (α-linolenic acid: OR, 0.42; 95% CI, 0.18-0.98; linoleic acid: OR, 0.43; 95% CI, 0.19-1.00; and palmitic acid: OR, 0.32; 95% CI, 0.13-0.78). Compared with models including only age, sex, Helicobacter pylori infection, and gastric histopathologic findings, integrating these metabolites significantly improved the performance for predicting the progression of gastric lesions (area under the curve [AUC], 0.86; 95% CI, 0.70-1.00 vs AUC, 0.69; 95% CI, 0.50-0.88; P = .02) and risk of early GC (AUC, 0.83; 95% CI, 0.58-1.00 vs AUC, 0.61; 95% CI, 0.31-0.91; P = .03). Conclusions and Relevance: This study defined metabolite signatures that might serve as meaningful biomarkers for assessing high-risk populations and early diagnosis of GC, possibly advancing targeted GC prevention and control.

Microbiota alteration at different stages in gastric lesion progression: a population-based study in Linqu, China.

In addition to Helicobacter pylori (H.pylori), gastric microbiota may be involved in carcinogenesis process. However, the longitudinal study to assess changes in the gastric microbiota associated with the development of gastric carcinogenesis is still limited. The aim of this study is to explore dynamic microbial alterations in gastric cancer (GC) development based on a 4-year endoscopic follow-up cohort in Linqu County, China. Microbial alterations were investigated by deep sequencing of the microbial 16S ribosomal RNA gene in 179 subjects with various gastric lesions, and validated in paired gastric biopsies prospectively collected before and after lesion progression and in non-progression controls. Significant differences were found in microbial diversity and community structure across various gastric lesions, with 62 candidate differential taxa between at least two lesion groups. Further validations identified Helicobacter, Bacillus, Capnocytophaga and Prevotella to be associated with lesion progression-to-dysplasia (DYS)/GC (all P < 0.05), especially for subjects progressing from intestinal metaplasia (IM) to DYS/GC. The combination of the four genera in a microbial dysbiosis index showed a significant difference after lesion progression-to-DYS/GC compared to controls (P = 0.027). The panel including the four genera identified subjects after progression-to-DYS/GC with an area under the receiver-operating curve (AUC) of 0.941. Predictive significance was found before lesion progression-to-DYS/GC with an AUC = 0.776 and an even better AUC (0.927) for subjects progressing from IM to DYS/GC. Microbiota may play different roles at different stages in gastric carcinogenesis. A panel of bacterial genera associated with gastric lesions may help to assess gastric microbial dysbiosis and show potential predictive values for lesion progression. Our findings provide new clues for the microbial mechanism of H.pylori-associated carcinogenesis.