Association between smoking and alcohol drinking and benign adrenal tumors: a Mendelian randomization study.

BACKGROUND: In recent years, the detection rate of adrenal tumors has increased, but it is unclear whether smoking and alcohol drinking are risk factors for benign adrenal tumors. The objective of this study is to employ Mendelian randomization (MR) analysis to explore the causal relationship between smoking, alcohol drinking and susceptibility to benign adrenal tumors. METHODS: We acquired large-scale data from publicly accessible databases on genome-wide association studies (GWAS) pertaining to smoking, alcohol drinking and benign adrenal tumors. A total of 11 sets of instrumental variables (IVs) and 281 associated single nucleotide polymorphic (SNP) loci were identified. The Mendelian randomization analyses were conducted using inverse variance weighting (IVW), MR-Egger regression and weighted median estimation (WME) methods, in addition to sensitivity analyses. RESULTS: There is no causal relationship between smoking status, alcohol drinking status, alcohol intake frequency, alcohol taken with meals, alcohol consumption and benign adrenal tumors, while pack years of smoking and cigarettes per day are risk factors for benign adrenal tumors. The IVW analysis revealed that both the pack years of smoking and cigarettes per day were positively associated with an increased risk of benign adrenal tumors (OR = 2.853, 95%CI = 1.384-5.878, p = 0.004; OR = 1.543, 95%CI = 1.147-2.076, p = 0.004). Two SNPs (rs8042849 in the analysis of pack years of smoking and rs8034191 in the analysis of cigarettes per day) significantly drove the observed causal effects. CONCLUSION: Two-sample Mendelian randomization analysis showed a causal effect between smoking but not alcohol consumption and benign adrenal tumors.

Chronic kidney disease and functional impairment in a longitudinal study of older adults in China.

OBJECTIVES: To examine the associations of chronic kidney disease (CKD) with dynamic functional impairment among older Chinese adults. DESIGN: This was a prospective longitudinal study. SETTING: Data were derived from the Chinese Longitudinal Healthy Longevity Study. PARTICIPANTS: All adults aged ≥60 years were potentially eligible. This study included 2970 participants. PRIMARY OUTCOME MEASURES: CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Functional performances included instrumental activities of daily living (IADL) and basic activities of daily living (BADL), which were measured using six daily activities, including eating, dressing, transferring, using the toilet, bathing and continence, and eight daily activities, including visiting neighbours, shopping, cooking, washing clothes, walking 1 km, lifting 5 kg, crouching and standing up three times and taking public transportation, respectively. RESULTS: This study included 2970 participants, including 988 (33.60%) participants with CKD. Participants with CKD had higher IADL scores than those without CKD (ß=0.895, 95% CI: 0.761 to 1.029). Furthermore, there was a significant linear trend in the association of CKD severity with the IADL score (p<0.001). Similarly, CKD was significantly associated with higher BADL scores (ß=0.067, 95% CI: 0.017 to 0.118). However, only participants with moderate and advanced CKD had a higher BADL score (ß=0.088 and 0.152, 95% CI: 0.006 to 0.171 and 0.019 to 0.286, respectively). CONCLUSIONS: CKD was associated with worse functional impairment. Furthermore, there was a significant linear trend in the association of the severity of CKD with the IADL score. However, only participants with moderate and advanced CKD had higher BADL scores.

Identification of disulfidptosis-related subtypes and development of a prognosis model based on stacking framework in renal clear cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor with an unsatisfactory prognosis. This study aims to identify the expression patterns of disulfidptosis-related genes (DRGs), develop a prognostic model, and predict immunological profiles. METHODS: First, we identified differentially expressed DRGs in TCGA-KIRC cohort and analyzed their mutational profiles, methylation levels, and interaction networks. Subsequently, we identified disulfidptosis-associated molecular subtypes and investigated their prognostic and immunological characteristics. Simultaneously, a disulfidptosis-related prognostic signature (DRPS) was developed using a two-stage stacking framework consisting of 5 machine learning models. The effect of DRPS on immune cell infiltration levels was explored using seven different algorithms, and the status and function of T cells for distinct risk-score groups were evaluated based on T cell exhaustion and dysfunction scores. Additionally, the study also examined differences in clinical characteristics and therapy efficacy between high- and low-risk groups. RESULTS: We found two disulfidptosis-associated clusters, one of which had a poor prognosis and was linked to high immune cell infiltration but impaired T cell function. DRPS showed excellent predictive performance in all four cohorts and could accurately identified disulfidptosis-related molecular subtypes. The DRPS-based risk score was positively associated with poor prognosis, malignant pathological features, high immune cell infiltration levels, and T cell exhaustion or dysfunction, and better respond to immunotherapy and targeted therapy. Additionally, we have identified a close association between ISG20 and disulfidptosis as well as tumor immunity. CONCLUSION: Our study identified distinct disulfidptosis-related subtypes in ccRCC patients, and constructed the highly accurate and robust DRPS based on an ensemble learning framework, which has critical reference value in clinical decision-making and individualized treatment. And this work also revealed ISG20 exhibits promising potential as a therapeutic target for ccRCC.

ITIH5, as a predictor of prognosis and immunotherapy response for P53-like bladder cancer, is related to cell proliferation and invasion.

p53-like bladder cancer (BLCA) is a bladder cancer subtype that is resistant to cisplatin-based chemotherapy. The ideal treatment modality for such tumors remains poorly defined, and immunotherapy seems to be a potential approach. Therefore, it is significant to understand the risk stratification of p53-like BLCA and identify novel therapeutic targets. ITIH5 is a member of the inter-α-trypsin inhibitory (ITI) gene family, and the effect of ITIH5 on p53-like BLCA remains elusive. In this study, TCGA data and in vitro experiments were used to explore the prognostic value of ITIH5 for p53-like BLCA and its effect on tumor cell proliferation, migration, and invasion. The impact of ITIH5 on the level of immune cell infiltration was explored using seven different algorithms, and the predictive value of ITIH5 on the efficacy of immunotherapy for p53-like BLCA was explored in combination with an independent immunotherapy cohort. The results showed that patients with high ITIH5 expression had a better prognosis, and overexpression of ITIH5 could inhibit the proliferation, migration, and invasion of tumor cells. Two or more algorithms consistently showed that ITIH5 promoted the infiltration of antitumor immune cells, such as B cells, CD4+ T cells, and CD8+ T cells. In addition, ITIH5 expression was positively correlated with the expression levels of many immune checkpoints, and the high ITIH5 expression group showed better response rates to PD-L1 and CTLA-4 therapies. In short, ITIH5 is a predictor of prognosis and the immunotherapy response for p53-like BLCA and is correlated with tumor immunity.

Segmental ureterectomy for high-risk ureteral carcinoma: a preliminary report.

BACKGROUND: EAU guidelines strongly recommend kidney sparing surgery (KSS) as the primary treatment option for the low-risk UTUC patients. While there are few reports involving the KSS treated for the high-risk counterparts, especially the ureteral resection. OBJECTIVE: To evaluate the effectiveness and safety of the segmental ureterectomy (SU) for the patients with high-risk ureteral carcinoma. MATERIALS AND METHODS: We included 20 patients from May 2017 to December 2021 who underwent segmental ureterectomy (SU) in Henan Provincial People's Hospital. The overall survival (OS) and progression free survival (PFS) were evaluated. Besides, the ECOG scores and postoperative complications were also included. RESULTS: As of December 2022, the mean OS was 62.1months (95%CI:55.6-68.6months) and the mean PFS was 45.0months (95%CI:35.9-54.1months). The median OS and median PFS were not reached. The 3-year OS rate was 70% and the 3-year PFS rate was 50%. The percentage of Clavien I and II complications was 15%. CONCLUSION: For the selected patients with high-risk ureteral carcinoma, the efficacy and safety of segmental ureterectomy were satisfactory. But we still need to conduct prospective or randomized study to validate the value of SU in patients with high-risk ureteral carcinoma.

Correlation between mesenchymal circulating tumor cells and prognosis of urologic malignancies: a single-center retrospective analysis.

OBJECTIVE: To evaluate the correlation of circulating tumor cells (CTCs) and mesenchymal CTCs (M-CTCs) with clinical characteristics and survival of patients with urologic malignancies. METHODS: The clinical data of 52 patients with urinary system malignancy in Henan Provincial People's Hospital were retrospectively analyzed (40 cases of renal malignant tumor, 7 cases of prostate cancer, 3 cases of urothelial carcinoma, 1 case of testis cancer, and 1 case of penile cancer). The CTC counts of patients were collected, and the expression of epithelial-mesenchymal transition phenotype in CTCs was evaluated. The relationship of different types of CTC counts with tumor stage, location, size, metastasis, and differentiation, as well as their effect on progression-free survival (PFS) were analyzed. RESULTS: We detected CTCs in all patients with urinary system malignancy. The positive rates of epithelial CTCs (E-CTC), M-CTCs, and epithelial/mesenchymal CTCs (E/M-CTCs) were 34.62%, 26.92% and 94.23%, respectively. Total CTCs (T-CTCs), M-CTCs and E/M-CTCs were correlated with distant metastasis (Z=-3.052, -3.574, -2.898; all P<0.005). M-CTC count was correlated with lymph node metastasis (Z=-3.125; P=0.002). Furthermore, the presence of T-CTCs ≥13.5, M-CTC ≥0.5 or E/M-CTCs ≥9.5 per 5 ml of blood was correlated with worse PFS in patients with urinary system malignancy. CONCLUSIONS: M-CTC and E/M-CTC counts correlate with the prognosis of patients with urinary system malignancy. Higher M-CTC and E/M-CTC counts are risk factors for worse prognosis in patients with urinary system malignancies. All in all, M-CTC count is a valuable tumor biomarker for urologic malignancies.

LncRNA PGM5-AS1 Inhibits the Progression of Bladder Cancer by Regulating miR-587/SLIT3 Axis.

Bladder cancer (BC), as one of the most common urological malignant tumor types worldwide, places a considerable burden on the economy and patients' health. Long non-coding RNA PGM5-AS1 has been shown to be downregulated in BC, however, its exact function in BC remains unclear. This study aimed to determine the influence of PGM5-AS1 on BC and its related mechanisms. The expression of PGM5-AS1, miR-587, and slit guided ligand 3 (SLIT3) in BC tissues and cells was detected using real-time quantitative polymerase chain reaction and Western blotting. In vitro functional experiments, including CCK-8, Transwell, and Western blotting, were used to assess BC cell proliferation, migration, and the expression of apoptosis-related proteins (Bax and Bcl-2). A xenograft tumor experiment was conducted to test the role of PGM5-AS1 in BC cell growth in vivo. In addition, the relationship between PGM5-AS1, miR-587, and SLIT3 was verified using luciferase reporter and RIP assays. PGM5-AS1 and SLIT3 were expressed at low levels in BC, whereas miR-587 exhibited the opposite trend. PGM5-AS1 overexpression significantly inhibited BC cell proliferation and migration, promoted apoptosis in vitro, and alleviated tumor growth in vivo. miR-587 has been shown to be a target of PGM5-AS1, and miR-587 overexpression can reverse the inhibitory effect of PGM5-AS1 upregulation on BC cell growth. Furthermore, miR-587 directly targeted SLIT3 and negatively regulated its expression. PGM5-AS1 inhibited BC cell proliferation and migration while facilitating apoptosis through the miR-587/SLIT3 pathway. PGM5-AS1 represses BC development via the miR-587/SLIT3 axis, indicating that PGM5-AS1 may be a candidate biomarker and target for BC treatment.

Classification of Muscle Invasive Bladder Cancer to Predict Prognosis of Patients Treated with Immunotherapy.

Background: Recently, immunotherapies have been approved for advanced muscle invasive bladder cancer (MIBC) treatment, but only a small fraction of MIBC patients could achieve a durable drug response. Our study is aimed at identifying tumor microenvironment (TME) subtypes that have different immunotherapy response rates. Methods: The mRNA expression profiles of MIBC samples from seven discovery datasets (GSE13507, GSE31684, GSE32548, GSE32894, GSE48075, GSE48276, and GSE69795) were analyzed to identify TME subtypes. The identified TME subtypes were then validated by an independent dataset (TCGA-MIBC). The subtype-related biomarkers were discovered using computational analyses and then utilized to establish a random forest predictive model. The associations of TME subtypes with immunotherapy therapeutic responses were investigated in a group of patients who had been treated with immunotherapy. A prognostic index model was constructed using the subtype-related biomarkers. Two nomograms were built by the subtype-related biomarkers or the clinical parameters. Results: Two TME subtypes, including ECM-enriched class (EC) and immune-enriched class (IC), were found. EC was associated with greater extracellular matrix (ECM) pathways, and IC was correlated with immune pathways, respectively. Overall survival was significantly greater for tumors classified as IC, whereas the EC subtype had a worse prognosis. A total of nine genes (AKAP12, APOL3, CXCL13, CXCL9, GBP4, LRIG1, PEG3, PODN, and PTPRD) were selected by computational analyses to construct the random forest model. The area under the curve (AUC) values for this model were 0.827 and 0.767 in the testing and external validation datasets, respectively. Therapeutic response rates were greater in IC patients than in EC patients (28 percent vs. 18 percent). Patients with a high prognostic index had a poorer prognosis than those with a low prognostic index. The nomogram constructed from nine genes and stage achieved a C-index of 0.71. Conclusion: The present investigation defined two distinct TME subtypes and developed models to assess immunotherapeutic treatment outcomes.

Microvesicles derived from human umbilical cord mesenchymal stem cells ameliorate renal ischemia-reperfusion injury via delivery of miR-21.

Microvesicles (MVs) derived from human umbilical cord mesenchymal stem cells (hUC-MSCs-MVs) and miR-21 were demonstrated to ameliorate renal ischemia-reperfusion injury (IRI). Since hUC-MSC-MVs contained a substantial quantity of miR-21, we speculated that miR-21 might account for a part of the therapeutic effects of hUC-MSCs-MVs. The human tubule epithelial (HK-2) cells were cultured under low oxygen (LO) condition to mimic a cellular IRI model. A rat model of unilateral renal IRI was established. A co-culture model of HK-2 cells and MSC-MVs was utilized to examine the therapeutic role of MSC-MVs in HK-2 cell apoptosis and mechanism. The results showed that hUC-MSCs-MVs inhibited LO-induced HK-2 cell apoptosis through transferring miR-21 to HK-2 cells. Mechanistically, miR-21 directly targeted and negatively regulated programmed cell death protein 4 (PDCD4) in HK-2 cells. Moreover, PDCD4 overexpression in HK-2 cells abrogated the hUC-MSCs-MVs-inhibited HK-2 cell apoptosis under LO condition. Additionally, the beneficial effect of MSC-MVs on rat renal IRI was partly eliminated when miR-21 was knocked down in MSCs. Taken together, MSC-MVs inhibit tubular epithelial cell apoptosis and ameliorate renal IRI, at least partially, via delivery of miR-21.

Efficacy and safety of intra-arterial chemotherapy combined with intravesical chemotherapy for high-risk non-muscle invasive bladder cancer: A protocol for a systematic review and meta-analysis.

BACKGROUND: Non-muscle invasive bladder cancer (NMIBC) is the most common bladder cancer. Many studies have reported that intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IVC) could effectively reduce the recurrence rate of NMIBC. The purpose of this study is to assess the efficacy and safety of IAC combined with IVC for patients with high-risk NMIBC. METHODS: PubMed, Cochrane Library, Medline, Embase, Web of Science, and 4 Chinese databases will be searched for eligible studies published without language restrictions from their inception up August 31, 2019. Subgroup analysis will be mainly explored in study design, types of chemotherapy drugs, and sample size. Cochrane Collaboration Risk of bias Tool will be applied in evaluating the quality of enrolled articles. Statistical analysis will be carried out by the Stata version 14.0 software. RESULTS: The primary outcome is recurrence-free survival (RFS). The secondary outcomes include overall survival (OS), progression-free survival (PFS), adverse reactions and toxicity grade coded by common toxicity criteria for adverse events. CONCLUSION: The findings of this study will provide latest evidence to verify whether IAC combined with IVC is more effective and safer than IVC alone for patients with high-risk NMIBC. PROSPERO REGISTRATION NUMBER: CRD42019146847.