Nonantibiotic prophylaxis for urinary tract infections: a network meta-analysis of randomized controlled trials.

OBJECTIVE: Recent guidelines indicated that, in addition to antibiotics, nonantibiotic interventions serve as available preventive options for urinary tract infections (UTIs). This study aimed to compare the efficacy and safety of various nonantibiotic interventions in preventing UTIs. METHODS: The authors systematically searched databases for eligible studies. The inclusion criteria encompassed randomized controlled trials (RCTs) focusing on one or more nonantibiotic interventions for UTI prevention, with the incidence of UTIs being a key outcome measure. Subgroup analyses were performed according to age, sex, and follow-up. RESULTS: 50 RCTs comprising 10,495 subjects and investigating 14 interventions, were included. Nearly 80% of the RCTs utilized double-blind or triple-blind designs. In the whole group, D-mannose (risk ratio [RR] 0.34, 0.21 to 0.56), vaccine (RR 0.65, 0.52 to 0.82), probiotics (RR 0.69, 0.50 to 0.94), cranberry (RR 0.72, 0.60 to 0.87), and triple therapy (cranberry plus probiotics plus vitamin A) (RR 0.27, 0.09 to 0.87), exhibited a significant reduction in UTI incidence compared to the placebo. Probiotics (RR 0.50, 0.28 to 0.89) were the most effective in the nonadult group, while vitamin D (RR 0.46, 0.27 to 0.81) showed the highest efficacy in the long follow-up group (≥ 1 year). There was no significant difference in the incidence of adverse events between the interventions and the placebo group. CONCLUSIONS: D-mannose, triple therapy, vaccine, probiotics, and cranberry serve as potential nonantibiotic intervention options for clinical UTI prevention.

Diagnostic accuracy of interleukin-6 in multiple diseases: An umbrella review of meta-analyses.

Objective: This review aims to conduct a comprehensive study of the diagnostic accuracy of interleukin-6 (IL-6) for multiple diseases by utilizing existing systematic reviews and meta-analyses. Methods: We performed a thorough search of Embase, Web of Science, PubMed, and Cochrane Database of Systematic Reviews up to April 2023 to gather meta-analyses that investigate the diagnostic accuracy of IL-6. To assess the methodological quality of the studies, we employed the Assessing the Methodological Quality of Systematic Reviews-2 and Grading of Recommendations, Assessment, Development and Evaluation criteria. Results: We included 34 meta-analyses out of the 3024 articles retrieved from the search. These meta-analyses covered 9 categories of diseases of the International Classification of Diseases-11. Studies rated as "Critically Low" or "Very Low" in the quality assessment process were excluded, resulting in a total of 6 meta-analyses that encompassed sepsis, colorectal cancer, tuberculous pleural effusion (TPE), endometriosis, among others. Among these diseases, IL-6 demonstrated a relatively high diagnostic potential in accurately identifying TPE and endometriosis. Conclusions: IL-6 exhibited favorable diagnostic accuracy across multiple diseases, suggesting its potential as a reliable diagnostic biomarker in the near future. Substantial evidence supported its high diagnostic accuracy, particularly in the cases of TPE and endometriosis.

Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

BACKGROUND AND OBJECTIVE: We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. METHODS: Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. RESULTS: We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. CONCLUSIONS: Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

Efficacy and Safety of Adeno-Associated Virus-Based Clinical Gene Therapy for Hemophilia: A Systematic Review and Meta-Analysis.

Clinical trials of adeno-associated virus (AAV)-based gene therapy have made remarkable progress in recent years. We aimed to perform a systematic review and meta-analysis of the literature to assess the efficacy and safety of AAV-based gene therapy for hemophilia. We systematically searched the Web of Science, Embase, PubMed, and the Cochrane Database of Systematic Reviews databases, for clinical trials involving patients diagnosed with hemophilia and treated with AAV-mediated gene therapy. Data on the annualized bleeding rate (ABR), annualized infusion rate (AIR), the incidence of treatment-related adverse events (TRAEs), severe adverse events (SAEs), and alanine aminotransferase (ALT) elevation were extracted as our outcomes. A total of 12 articles from 11 clinical trials were selected from 868 articles for meta-analysis. Pooled analyses showed that AAV-based gene therapy in hemophilia patients reduced the number of bleeding events and the number of factor infusion events by an approximate average of 7 per year and 103 per year, respectively. Eighty percent, 18%, and 63% of hemophilia patients had elevated TRAE, SAE, and ALT levels, respectively. Moreover, subgroup analysis found a significant reduction in ABR and AIR 2-3 years after the therapy. Additional findings that were not pooled including coagulation factor activity are presented in the accompanying tables. Our analysis supported the efficacy and safety of AAV-mediated gene therapy for hemophilia, providing evidence for its application as a therapeutic option for widespread clinical use in hemophilia patients in the future.

ADP-dependent glucokinase controls metabolic fitness in prostate cancer progression.

BACKGROUND: Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment. METHODS: The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays. RESULTS: ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa. CONCLUSIONS: In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.

Adjuvant chemoradiotherapy vs chemotherapy for resectable biliary tract cancer: a propensity score matching analysis based on the SEER database.

BACKGROUND: Although the role of adjuvant chemotherapy (CT) for resectable biliary tract cancer (BTC) is gradually recognized, the benefit of adjuvant chemoradiotherapy (CRT) is still controversial. Our study is designed to compare the prognosis of CRT versus CT in BCT patients. METHODS: Clinicopathologic characteristics of patients with operable gallbladder cancer (GBCA), intrahepatic bile duct cancer (IHBDC), or extrahepatic bile duct cancer (EHBDC) were obtained from the Surveillance, Epidemiology and End Results (SEER) database (2004-2015). Univariate and multivariate analyses were performed to identify prognostic factors for overall survival (OS). Selection bias were reduced by propensity-score matching (PSM). Kaplan-Meier analysis was used to estimate the survival time. RESULTS: Within 922 patients, 53.9% received adjuvant CRT, and 46.1% received adjuvant CT. Multivariate analysis showed age, primary tumor site, T stage, N stage, tumor size, number of removed lymph nodes, and treatment were independent risk factors for OS. Similar improvement of CRT on survival was identified by PSM in the matched cohort compared with CT (28.0 months vs. 25.0 months, p = 0.033), particularly in GBCA cohort (25.0 months vs. 19.0 months, p = 0.003). Subgroup analysis indicated CRT improved outcomes of patients with age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph node diseases. CONCLUSION: Adjuvant CRT correlated with improved survival in patients with resected BTC compared with adjuvant CT, particularly in GBCAs. In addition, patients with age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph node diseases may receive more benefits from adjuvant CRT.

Construction of PANoptosis signature: Novel target discovery for prostate cancer immunotherapy.

PANoptosis pathway gene sets encompassing pyroptosis, apoptosis, and necroptosis were identified from the MSigDB database. We analyzed the perturbations and crosstalk in the PANoptosis pathway in prostate adenocarcinoma (PRAD), including gene mutation, transcription, methylation, and clinical features. By constructing a PANoptosis signature, we accurately predicted the prognosis and immunotherapeutic response of PRAD patients. We further explored the molecular features and immunological roles of the signature, dividing patients into high- and low-score groups. Notably, the high-score group correlated with better survival outcomes and immunotherapeutic responses, as well as a higher mutation frequency and enrichment score in the PANoptosis and HALLMARK pathways. The PANoptosis signature also enhanced overall antitumor immunity, promoted immune cell infiltration, upregulated immune checkpoint regulators, and revealed the cold tumor characteristics of PRAD. We also identified potential drug targets based on the PANoptosis signature. These findings lead the way in identifying novel prognostic markers and therapeutic targets for patients with PRAD.

The effect of bladder function on the efficacy of transurethral prostatectomy in patients with benign prostatic hyperplasia: a retrospective, single-center study.

We investigated the impact and predictive value of bladder function in patients with benign prostatic hyperplasia (BPH) on the efficacy of transurethral prostatectomy. Symptomatic, imaging, and urodynamic data of patients who underwent transurethral prostatectomy at West China Hospital of Sichuan University (Chengdu, China) from July 2019 to December 2021 were collected. Follow-up data included the quality of life (QoL), International Prostate Symptom Score (IPSS), and IPSS storage and voiding (IPSS-s and IPSS-v). Moreover, urinary creatinine (Cr), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and prostaglandin estradiol (PGE2) were measured in 30 patients with BPH and 30 healthy participants. Perioperative indicators were determined by subgroup analyses and receiver operating characteristic (ROC) curve analysis. Among the 313 patients with BPH included, patients with severe micturition problems had more improvements but higher micturition grades postoperatively than those with moderate symptoms. Similarly, good bladder sensation, compliance, and detrusor contractility (DC) were predictors of low postoperative IPSS and QoL. The urinary concentrations of BDNF/Cr, NGF/Cr, and PGE2/Cr in patients were significantly higher than those in healthy participants (all P < 0.001). After evaluation, only DC was significantly related to both urinary indicators and postoperative recovery of patients. Patients with good DC, as predicted by urinary indicators, had lower IPSS and IPSS-v than those with reduced DC at the 1st month postoperatively (both P < 0.05). In summary, patients with impaired bladder function had poor recovery. The combined levels of urinary BDNF/Cr, NGF/Cr, and PGE2/Cr in patients with BPH may be valid predictors of preoperative bladder function and postoperative recovery.

Clinical benefit and safety associated with mRNA vaccines for advanced solid tumors: A meta-analysis.

Tumor mRNA vaccines have been developed for over 20 years. Whether mRNA vaccines could promote a clinical benefit to advanced cancer patients is highly unknown. PubMed and Embase were retrieved from January 1, 2000 to January 4, 2023. Random effects models were employed. Clinical benefit (objective response rate [ORR], disease control rate [DCR], 1-year/2-year progression-free survival [PFS], and overall survival [OS]) and safety (vaccine-related grade 3-5 adverse events [AEs]) were evaluated. Overall, 984 patients (32 trials) were enrolled. The most typical cancer types were melanoma (13 trials), non-small cell lung cancer (5 trials), renal cell carcinoma (4 trials), and prostate adenocarcinoma (4 trials). The pooled ORR and DCR estimates were 10.0% (95%CI, 4.6-17.0%) and 34.6% (95%CI, 24.1-45.9%). The estimates for 1-year and 2-year PFS were 38.4% (95%CI, 24.8-53.0%) and 20.0% (95%CI, 10.4-31.7%), respectively. The estimates for 1-year and 2-year OS were 75.3% (95%CI, 62.4-86.3%) and 45.5% (95%CI, 34.0-57.2%), respectively. The estimate for vaccine-related grade 3-5 AEs was 1.0% (95%CI, 0.2-2.4%). Conclusively, mRNA vaccines seem to demonstrate modest clinical response rates, with acceptable survival rates and rare grade 3-5 AEs.

RNA m6A modification in prostate cancer: A new weapon for its diagnosis and therapy.

Prostate cancer (PCa) is the most common malignant tumor and the second leading cause of cancer-related mortality in men worldwide. Despite significant advances in PCa therapy, the underlying molecular mechanisms have yet to be fully elucidated. Recently, epigenetic modification has emerged as a key player in tumor progression, and RNA-based N6-methyladenosine (m6A) epigenetic modification was found to be crucial. This review summarizes comprehensive state-of-art mechanisms underlying m6A modification, its implication in the pathogenesis, and advancement of PCa in protein-coding and non-coding RNA contexts, its relevance to PCa immunotherapy, and the ongoing clinical trials for PCa treatment. This review presents potential m6A-based targets and paves a new avenue for diagnosing and treating PCa, providing new guidelines for future related research through a systematic review of previous results.

Vitamin E intake and multiple health outcomes: an umbrella review.

Background: The benefits of vitamin E (VE) for multiple health outcomes have been well evaluated in many recent studies. Objective: The purpose of this umbrella review was to conduct a systematic evaluation of the possible associations between VE intake and various health outcomes. Methods: We systematically searched various databases, such as PubMed, Embase, and the Web of Science, to identify related meta-analyses of observational studies and randomized trials. We estimated the effect size of each association by using the random or fixed effects models and the 95% confidence intervals. We used standard approaches to evaluate the quality of the articles (AMSTAR) and classified the evidence into different levels of quality (GRADE). Results: A total of 1,974 review articles were searched, and 27 articles with 28 health outcomes were yielded according to our exclusion criteria. The intake of VE was inversely associated with the risk of breast cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, cervical neoplasms, cardiovascular disease, Parkinson's disease, depression, age-related cataracts, metabolic syndrome, and fracture. Overall, most of the quality of the evidence was low or very low. Three outcomes (stroke, age-related cataracts, obesity) were identified as having a "moderate" level of quality. The AMSTAR scores for all health outcomes ranged from 5 to 10. Conclusion: Our study revealed that VE intake is beneficially related to multiple health outcomes. However, future studies on recommended doses and recommended populations of VE are also needed. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022339571.

Advances in tumor nanotechnology: theragnostic implications in tumors via targeting regulated cell death.

Cell death constitutes an indispensable part of the organismal balance in the human body. Generally, cell death includes regulated cell death (RCD) and accidental cell death (ACD), reflecting the intricately molecule-dependent process and the uncontrolled response, respectively. Furthermore, diverse RCD pathways correlate with multiple diseases, such as tumors and neurodegenerative diseases. Meanwhile, with the development of precision medicine, novel nano-based materials have gradually been applied in the clinical diagnosis and treatment of tumor patients. As the carrier, organic, inorganic, and biomimetic nanomaterials could facilitate the distribution, improve solubility and bioavailability, enhance biocompatibility and decrease the toxicity of drugs in the body, therefore, benefiting tumor patients with better survival outcomes and quality of life. In terms of the most studied cell death pathways, such as apoptosis, necroptosis, and pyroptosis, plenty of studies have explored specific types of nanomaterials targeting the molecules and signals in these pathways. However, no attempt was made to display diverse nanomaterials targeting different RCD pathways comprehensively. In this review, we elaborate on the potential mechanisms of RCD, including intrinsic and extrinsic apoptosis, necroptosis, ferroptosis, pyroptosis, autophagy-dependent cell death, and other cell death pathways together with corresponding nanomaterials. The thorough presentation of RCD pathways and diverse nano-based materials may provide a wider cellular and molecular landscape of tumor diagnosis and treatments.

Carrot and carotene and multiple health outcomes: an umbrella review of the evidence.

In recent years, the benefits of carrots and carotene in different areas of health have been examined. The purpose of this umbrella review was to identify the associations between carrots and carotene and multiple health outcomes. The review considered evidence from meta-analyses of interventional and observational studies of carrots and carotene and any health outcome. We comprehensively searched Web of Science, PubMed, and Embase. For each association, we estimated the summary effect size using random and fixed effects models and the 95% confidence interval. A total of 1329 studies were searched, and 30 meta-analyses with 26 health outcomes were identified that met the eligibility criteria. Carrot intake was associated with a lower risk of multiple cancer outcomes including breast cancer, lung cancer, pancreatic cancer, gastric cancer, urothelial cancer, and prostate cancer. Carotene intake was associated with a lower risk of fracture, age-related cataract, sunburn, Alzheimer's disease, breast cancer, lung cancer, pancreatic cancer, gastric cancer, esophageal cancer, prostate cancer, and head and neck cancer (HNC). Serum carotene was inversely associated with all-cause mortality, breast cancer, and lung cancer. Our study revealed that carrot or carotene intake could reduce the risk of various negative health outcomes. © 2023 Society of Chemical Industry.

Broaden Horizons: The Advancement of Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating disease that induces mental stress, lower urinary symptoms, and pelvic pain, therefore resulting in a decline in quality of life. The present diagnoses and treatments still lead to unsatisfactory outcomes, and novel diagnostic and therapeutic modalities are needed. Although our understanding of the etiology and pathophysiology of IC/BPS is growing, the altered permeability of the impaired urothelium, the sensitized nerves on the bladder wall, and the chronic or intermittent sensory pain with inaccurate location, as well as pathologic angiogenesis, fibrosis, and Hunner lesions, all act as barriers to better diagnoses and treatments. This study aimed to summarize the comprehensive information on IC/BPS research, thereby promoting the progress of IC/BPS in the aspects of diagnosis, treatment, and prognosis. According to diverse international guidelines, the etiology of IC/BPS is associated with multiple factors, while the presence of Hunner lesions could largely distinguish the pathology, diagnosis, and treatment of non-Hunner lesions in IC/BPS patients. On the basis of the diagnosis of exclusion, the diverse present diagnostic and therapeutic procedures are undergoing a transition from a single approach to multimodal strategies targeting different potential phenotypes recommended by different guidelines. Investigations into the mechanisms involved in urinary symptoms, pain sensation, and bladder fibrosis indicate the pathophysiology of IC/BPS for further potential strategies, both in diagnosis and treatment. An overview of IC/BPS in terms of epidemiology, etiology, pathology, diagnosis, treatment, and fundamental research is provided with the latest evidence. On the basis of shared decision-making, a multimodal strategy of diagnosis and treatment targeting potential phenotypes for individual patients with IC/BPS would be of great benefit for the entire process of management. The complexity and emerging evidence on IC/BPS elicit more relevant studies and research and could optimize the management of IC/BPS patients.

SR9009 inhibits lethal prostate cancer subtype 1 by regulating the LXRα/FOXM1 pathway independently of REV-ERBs.

Perturbations of the circadian clock are linked to multiple diseases, including cancers. Pharmacological activation of REV-ERB nuclear receptors, the core components of the circadian clock, has antitumor effects on various malignancies, while the impact of SR9009 on prostate cancer (PCa) remains unknown. Here, we found that SR9009 was specifically lethal to PCa cell lines but had no cytotoxic effect on prostate cells. SR9009 significantly inhibited colony formation, the cell cycle, and cell migration and promoted apoptosis in PCa cells. SR9009 treatment markedly inhibited prostate cancer subtype 1 (PCS1), the most lethal and aggressive PCa subtype, through FOXM1 pathway blockade, while it had no impacts on PCS2 and PCS3. Seven representative genes, including FOXM1, CENPA, CENPF, CDK1, CCNB1, CCNB2, and BIRC5, were identified as the shared genes involved in the FOXM1 pathway and PCS1. All of these genes were upregulated in PCa tissues, associated with worse clinicopathological outcomes and downregulated after SR9009 treatment. Nevertheless, knockdown or knockout of REV-ERB could not rescue the anticancer effect of SR9009 in PCa. Further analysis confirmed that it was LXRα rather than REV-ERBs which has been activated by SR9009. The expression levels of these seven genes were changed correspondingly after LXRα knockdown and SR9009 treatment. An in vivo study validated that SR9009 restrained tumor growth in 22RV1 xenograft models and inhibited FOXM1 and its targeted gene expression. In summary, SR9009 can serve as an effective treatment option for highly aggressive and lethal PCS1 tumors through mediating the LXRα/FOXM1 pathway independently of REV-ERBs.