The long noncoding RNA glycoLINC assembles a lower glycolytic metabolon to promote glycolysis.

Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first example of a lncRNA-facilitated metabolon.

A genomic and epigenomic atlas of prostate cancer in Asian populations.

Prostate cancer is the second most common cancer in men worldwide1. Over the past decade, large-scale integrative genomics efforts have enhanced our understanding of this disease by characterizing its genetic and epigenetic landscape in thousands of patients2,3. However, most tumours profiled in these studies were obtained from patients from Western populations. Here we produced and analysed whole-genome, whole-transcriptome and DNA methylation data for 208 pairs of tumour tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer. Systematic comparison with published data from 2,554 prostate tumours revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of Western cohorts: specifically, 41% of tumours contained mutations in FOXA1 and 18% each had deletions in ZNF292 and CHD1. Alterations of the genome and epigenome were correlated and were predictive of disease phenotype and progression. Coding and noncoding mutations, as well as epimutations, converged on pathways that are important for prostate cancer, providing insights into this devastating disease. These discoveries underscore the importance of including population context in constructing comprehensive genomic maps for disease.

Unraveling CCL20's role by regulating Th17 cell chemotaxis in experimental autoimmune prostatitis.

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.

4-Octyl itaconate alleviates experimental autoimmune prostatitis by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway.

BACKGROUND: Chronic prostatitis demonstrates a prevalence rate of nearly 5%-10% among young and middle-aged individuals, significantly affecting their daily lives. Researchers have obtained significant outcomes investigating the anti-inflammatory properties of itaconic acid (IA) and its derivative, 4-Octyl itaconate (4-OI), against diverse chronic inflammatory disorders, such as osteoarthritis and airway inflammation. Nevertheless, whether IA can also exert anti-inflammatory effects in chronic prostatitis requires extensive research and validation. METHODS: Human prostate tissues obtained through transurethral prostate resection (TURP) from individuals were divided into three groups based on different levels of inflammation using hematoxylin and eosin staining (H&E). Subsequently, immunohistochemistry (IHC) was employed to detect the expression of immune-responsive gene 1 (IRG-1) in these different groups. The animal experiment of this study induced experimental autoimmune prostatitis (EAP) in nonobese diabetic mice through intradermal prostate antigen injection and complete Freund's adjuvant. Then, the experimental group received intraperitoneal injections of different doses of 4-OI, while the control group received injections of saline. Western blot (WB), H&E staining, and TUNEL staining helped analyze the prostate tissues, while enzyme-linked immunosorbent assay (ELISA) helped evaluate serum inflammatory factors. Reactive oxygen species, superoxide dismutase (SOD), and malondialdehyde (MDA) were assessed for oxidative stress across experimental groups. RESULTS: IHC analysis of human prostate tissue depicts that IRG-1 expression enhances as prostate inflammation worsens, highlighting the critical role of IA in human prostatitis. The application of 4-OI increased Nrf2/HO-1 expression while inhibited NLRP3 expression following the WB results, and its application resulted in a decrease in cell pyroptosis in prostate tissue, demonstrated by the results of TUNEL staining. Administering a Nrf2 inhibitor ML385 1 h before intraperitoneal injection of 50 mg/kg 4-OI reversed the previous conclusion, further confirming the above conclusion from another perspective. Meanwhile, the ELISA results of serum inflammatory factors (IL-1ß, IL-6, and TNF-α), as well as the measurements of oxidative stress markers MDA and SOD, further confirmed the specific anti-inflammatory effects of 4-OI in EAP. CONCLUSIONS: The present study indicates that 4-OI can alleviates EAP by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway, which may facilitate a novel approach toward prostatitis treatment.

Sodium butyrate alleviates experimental autoimmune prostatitis by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway.

BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) leads to severe discomfort in males and loss of sperm quality. Current therapeutic options have failed to achieve satisfactory results. Sodium butyrate (NaB) plays a beneficial role in reducing inflammation, increasing antioxidant capacities, and improving organ dysfunction; additionally NaB has good safety prospects and great potential for clinical application. The purpose of the current research was to study the effect of NaB on CP/CPPS and the underlying mechanisms using a mouse model of experimental autoimmune prostatitis (EAP) mice. METHODS: The EAP mouse model was successfully established by subcutaneously injecting a mixture of prostate antigen and complete Freund's adjuvant. Then, EAP mice received daily intraperitoneal injections of NaB (100, 200, or 400 mg/kg/day) for 16 days, from Days 26 to 42. We then explored anti-inflammatory potential mechanisms of NaB by studying the effects of Nrf2 inhibitor ML385 and HO-1 inhibitor zinc protoporphyrin on prostate inflammation and pelvic pain using this model. On Day 42, hematoxylin-eosin staining and dihydroethidium staining were used to evaluate the histological changes and oxidative stress levels of prostate tissues. Chronic pelvic pain was assessed by applying Von Frey filaments to the lower abdomen. The levels of inflammation-related cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor were detected by enzyme-linked immunosorbent assay. The regulation of Nrf2/HO-1 signaling pathway and the expression of NLRP3 inflammasome-related protein in EAP mice were detected by western blot analysis assay. RESULTS: Compared with the EAP group, chronic pain development, histological manifestations, and cytokine levels showed that NaB reduced the severity of EAP. NaB treatment could inhibit NLRP3 inflammasome activation. Mechanism studies showed that NaB intervention could alleviate oxidative stress in EAP mice through Nrf2/HO-1 signal pathway. Nrf2/HO-1 pathway inhibitors can inhibit NaB -mediated oxidative stress. The inhibitory effect of NaB on the activation of NLRP3 inflammasome and anti-inflammatory effect can also be blocked by Nrf2/HO-1 pathway. CONCLUSIONS: NaB treatment can alleviates prostatic inflammation and pelvic pain associated with EAP by inhibiting oxidative stress and NLRP3 inflammasome activation via the Nrf2/HO-1 pathway. NaB has the potential as an effective agent in the treatment of EAP.

Effect of preservation fluid contamination and associated possible donor-derived infections on early postoperative prognosis in kidney transplant recipients.

BACKGROUND: The study aims to analyze the epidemiology of preservation fluid (PF) contamination and investigate the impact of PF contamination and possible donor-derived infections(p-DDI) on early postoperative prognosis in kidney transplant (KT) recipients. METHODS: A total of 256 PF samples were collected for microbiological evaluation from all KT recipients who received deceased donor donations in our hospital from June 2018 to August 2022. Data on the baseline and clinical characteristics of these PF corresponding to recipients and donors were extracted from the electronic medical record. It mainly included the early postoperative complications and prognosis of KT recipients. RESULTS: From June 2018 to August 2022, 597 kidney transplants were performed in our center, with 260 recipients receiving kidney transplantation from donation after citizens' death. A total of 256 samples of PF were collected, of which 64.5% (165/256) were culture positive, and 24.6% (63/165) of the culture-positive PF were polymicrobial contamination. A total of 238 strains were isolated, of which coagulase-negative staphylococci (CoNS) had the highest proportion of 34.0% (81/238), followed by Klebsiella pneumoniae with 20.6% (49/238) and Escherichia coli with 8.8% (21/238). Recipients with culture-positive PF had a significantly higher incidence of postoperative infection (55.8% vs. 20.9%, P < 0.001) and DGF (38.2% vs. 24.2%, P = 0.023). In addition, the incidence of p-DDI was 12.9% (33/256). CRKP was the most common pathogen causing p-DDI. The recipients who developed p-DDI had a higher rate of graft loss (9.1% vs. 0.4%, P < 0.001), mortality (12.1% vs. 3.1%, P = 0.018), and longer postoperative hospital stay (30 days (19.5-73.5) vs. (22 days (18-32), P < 0.05) compared with recipients who did not develop p-DDI. CONCLUSIONS: Culture-positive PF is potentially significant for KT recipients, and p-DDI may increase the risk of poor prognosis for recipients. Prophylactic anti-infective treatment should be actively performed for highly virulent or multidrug-resistant (MDR) pathogens (especially Carbapenem-resistant Klebsiella pneumoniae, CRKP) in PF to avoid the occurrence of p-DDI.

Dual deficiency of melatonin and dihydrotestosterone promotes stromal cell damage and mediates prostatitis via the cGAS-STING pathway in sleep-deprived mice.

PURPOSE: Prostatitis is a highly prevalent condition that seriously affects men's physical and mental health. Although epidemiological investigations have provided evidence of a correlation between insufficient sleep and prostatitis, the pathogenesis of prostatitis remains unclear. We sought to identify the underlying mechanism involved and identify a promising therapeutic target. METHODS: Sleep deprivation (SD) was utilized to establish a mouse model of insufficient sleep in a special device. Prostatitis was observed at different time points post-SD. The degree of prostatitis was evaluated by pathological section and behavioural tests. Using immunofluorescence, western blot, and proteomic analyses, the underlying mechanism of SD-related prostatitis was investigated, and the development and therapeutic target of prostatitis were elucidated. RESULTS: SD, as an initial pathological trigger, resulted in a reduction in dihydrotestosterone and melatonin levels. Proteomic analysis revealed that the cGAS-STING pathway may play a significant role in inducing prostatitis. The subsequent results illustrated that the dual reduction in dihydrotestosterone and melatonin led to an accumulation of reactive oxygen species and the release of mitochondrial DNA (mt-DNA). The accumulation of mt-DNA activated the cGAS-STING pathway, which recruited inflammatory cells into the prostatic stroma through the secretion of interferon-ß. Consequently, an inflammatory microenvironment was formed, ultimately promoting the development of prostatitis. Notably, mice with SD-induced prostatitis gradually recovered to a normal state within 7 days of recovery sleep. However, after being subjected to SD again, these mice tended to have a more pronounced manifestation of prostatitis within a shorter timeframe, which suggested that prostatitis is prone to relapse. CONCLUSIONS: The cGAS-STING pathway activated by dual deficiency of dihydrotestosterone and melatonin plays a comprehensive inflammatory role in SD-related prostatitis. This research provides valuable insights into the pathogenesis, therapeutic targets, and prevention strategies of prostatitis.

PEGylated Manganese-Zinc Ferrite Nanocrystals Combined with Intratumoral Implantation of Micromagnets Enabled Synergetic Prostate Cancer Therapy via Ferroptotic and Immunogenic Cell Death.

Therapeutic efficacy for prostate cancer is highly restricted by insufficient drug accumulation and the resistance to apoptosis and immunogenic cell death (ICD). Although enhanced permeability and retention (EPR) effect of magnetic nanomaterials could benefit from external magnetic field, it falls off rapidly with increased distance from magnet surface. Considering the deep location of prostate in pelvis, the improvement of EPR effect by external magnetic field is limited. In addition, apoptosis resistance and cGAS-STING pathway inhibition-related immunotherapy resistance are major obstacles to conventional therapy. Herein, the magnetic PEGylated manganese-zinc ferrite nanocrystals (PMZFNs) are designed. Instead of providing external magnet, micromagnets into tumor tissues are intratumorally implanted to actively attract and retain intravenously-injected PMZFNs. As a result, PMZFNs accumulate in prostate cancer with high efficacy, depending on the established internal magnetic field, which subsequently elicit potent ferroptosis and the activation of cGAS-STING pathway. Ferroptosis not only directly suppresses prostate cancer but also triggers burst release of cancer-associated antigens and consequently initiates ICD against prostate cancer, where activated cGAS-STING pathway further amplifies the efficacy of ICD by generating interferon-ß. Collectively, the intratumorally implanted micromagnets confer a durable EPR effect of PMZFNs, which eventually achieve the synergetic tumoricidal efficacy with negligible systemic toxicity.

Fabrication and application of a wireless high-definition endoscopic system in urological surgeries.

OBJECTIVE: To introduce a wireless high-definition endoscopic system (WHES) and compare it with a Storz high-definition (HD) system for image resolution, colour resolution, weight, and costs. MATERIALS AND METHODS: The WHES incorporated a portable light-emitting diode light source and a wireless camera module, which can be compatible with different types of endoscopes. Images were wirelessly transmitted to a monitor or mobile platform such as smartphone through a receiver. The International Standards Organization 12233 resolution chart image was used for the comparison of image resolution and Munsell Colour Checker Chart for colour resolution. In all, 38 endourologists used a Likert questionnaire to blindly evaluate cystoscopic images from a patient with haematuria. The surgical team was asked about the overall performance of the WHES in 20 laparoscopic adrenalectomies using a unvalidated subjective survey. RESULTS: There was no difference in image resolution between the two systems (5.82 vs 5.89 line pairs/mm). Without lens and respective light sources, there were better purple (ΔE = 21.48 vs 28.73), blue (ΔE = 34.88 vs 38.6) and red colour resolution (ΔE = 29.01 vs 35.45) for the WHES camera (P < 0.05), but orange (ΔE = 43.45 vs 36.52) and yellow (ΔE = 52.7 vs 35.93) resolutions were better for the Storz HD camera (P < 0.05). Comparing the WHES to a Storz laparoscopic system, the Storz system still had better resolution of orange and yellow, while the resolution of purple, blue, and red was similar for the two systems. The expert comments on resolution, brightness, and colour for cystoscopy were not statistically different, but the ergonomics score for the WHES was higher (3.7 vs 3.33, P = 0.038). The overall cost of the WHES was $23 000-25 000 compared with $45 000-50 000 for a Storz system. There were 100% general satisfaction for the WHES in the survey. CONCLUSION: We developed a new WHES that provides the same resolution images as a Storz laparoscopic system and acceptable colour resolution with the advantages of wireless connection, small volume, low cost, portability, and high-speed wireless transmission.

Nomogram for predicting risk factors of fever in patients with negative preoperative urine culture after retrograde intrarenal surgery.

PURPOSE: To determine the risk factors for postoperative fever after retrograde intrarenal surgery (RIRS) in patients with negative preoperative urine culture (UC), and to establish a nomogram for predicting postoperative fever based on these risk factors. METHODS: This study collected 322 patients with negative UC who received RIRS at the First Affiliated Hospital of Anhui Medical University from March 2019 to May 2022. The study population was divided into a fever group and a non-fever group. The risk factors of postoperative fever were determined by univariate and multivariate logistic regression analyses, and a nomogram was established. The nomogram was evaluated in terms of differentiation, calibration, and clinical practicability. RESULTS: In this study, 47 (14.6%) patients developed a fever after surgery. Multivariate logistic regression analysis showed that for patients with negative preoperative urine culture, urinary leucocyte esterase (P = 0.005), operative time (P = 0.019), and intraoperative hypotension (P = 0.028) were independent risk factors of postoperative fever, and a nomogram was constructed according to the above variables. The area under the curve (AUC) calculated by receiver operating characteristic (ROC) analysis was 0.807 (95% CI 0.739-0.876), indicating good discrimination. The calibration curves showed good consistency, and the clinical decision curve analysis (DCA) showed the clinical applicability of the model. CONCLUSIONS: For patients with negative preoperative urine culture, urine leukocyte esterase, operative time, and intraoperative hypotension are independent risk factors of postoperative fever. The new nomogram can better assess the risk of infection in patients with negative UC after RIRS.

Overexpression of DDX49 in prostate cancer is associated with poor prognosis.

BACKGROUND: There is increasing evidence that DEAD-box helicases (DDX) can act either as promoters or suppressors in various cancer types. Nevertheless, the function of DDX49 in prostate cancer (PCa) is unknown. This study reveals the prognostic and predictive value of DDX49 in PCa. METHODS: First, we evaluated the expression of DDX49 between PCa and normal tissues based on TCGA and GEO databases. Univariate and multivariate regression analyses were conducted to reveal the risk factors for PCa recurrence. A K-M curve was employed to assess the relationship between DDX49 and recurrence-free survival. In vitro, DDX49 expression was evaluated in PCa and normal prostate cell lines. Furthermore, we constructed a shDDX49 lentivirus to knock down the expression of DDX49. Celigo® Image Cytometer and MTT assay were performed to analyse cell proliferation in PC-3 cells. Cell cycle distribution was detected with flow cytometry analysis. Apoptosis affected by the lack of DDX49 was metred with the PathScan® Stress and Apoptosis Signalling Antibody Array Kit. RESULTS: This study shows a high increase in DDX49 in PCa tissues in comparison with normal tissues and that increased DDX49 indicates a poor prognosis among PCa patients. Meanwhile, DDX49 knockdown suppressed the proliferation and migration of PC-3 cells, causing cell cycle arrest in the G1 phase. Stress and apoptosis pathway analysis revealed that the phosphorylation of HSP27, p53, and SAPK/JNK was reduced in the DDX49 knockdown group compared with the control group. CONCLUSIONS: In summary, these results suggest that high expression of DDX49 predicts a poor prognosis among PCa patients. Downregulation of DDX49 can suppress cell proliferation, block the cell cycle, and facilitate cell apoptosis. Therefore, knockdown of DDX49 is a promising novel therapy for treating patients with PCa.

Feasibility and safety of bipolar-plasmakinetic transurethral enucleation and resection of the prostate in day surgery mode. / åŒæžç­‰ç¦»å­ç»å°¿é“å‰åˆ—è ºå‰œåˆ‡æ—¥é—´æ‰‹æœ¯ä¸´åºŠå®žè·µ.

OBJECTIVES: To evaluate the feasibility and safety of bipolar-plasmakinetic transurethral enucleation and resection of the prostate (B-TUERP) in day surgery. METHODS: From January 2021 to August 2022, 34 patients with benign prostatic hyperplasia (BPH) underwent B-TUERP in day surgery in the First Affiliated Hospital of Anhui Medical University. Patients completed the screening and anesthesia evaluation before admission and received the standard surgery which implements "anatomical enucleation of the prostate" and "absolute bleeding control" on the same day of admission, and by the same doctor. Bladder irrigation was stopped, catheter was removed and the discharge evaluation was performed on the first day after operation. The baseline data, perioperative conditions, time of recovery, treatment outcomes, hospitalization costs, and postoperative complications were analyzed. RESULTS: All operations were successfully conducted. The average age of the patients was (62.2±7.8) years, average prostate volume was (50.2±29.3) mL. The average operation time was (36.5±19.1) min, the average hemoglobin and blood sodium were decreased by (16.2±7.1) g/L and (2.2±2.0) mmol/L, respectively. The average postoperative length of hospital stay, and total length of hospital stay were (17.7±2.2) and (20.8±2.1) h, respectively, and the average hospitalization cost was (13 558±2320) CNY. All patients were discharged on the day after surgery except for one patient who was transferred to a general ward. Three patients received indwelling catheterization after catheter removal. The 3-month follow-up results showed a substantial improvement in the International Prostate Symptom Score, quality of life score and maximum urinary flow rate (all P<0.01). Three patients experienced temporary urinary incontinence, 1 patient experienced urinary tract infection, 4 patients were diagnosed with urethral stricture and 2 patients experienced bladder neck contracture. No complications above Clavien grade Ⅱ occurred. CONCLUSIONS: The preliminary results showed that B-TUERP ambulatory surgery is a safe, feasible, economical and effective treatment for appropriately selected patients with BPH.

Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial.

BACKGROUND: Rezvilutamide, a novel androgen-receptor inhibitor with low blood-brain barrier penetration, has shown potent antitumour activity against metastatic castration-resistant prostate cancer. In this study, we aimed to evaluate the efficacy and safety of rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) for high-volume, metastatic, hormone-sensitive prostate cancer. METHODS: CHART is a randomised, open-label, phase 3 study done at 72 hospitals in China, Poland, Czech Republic, and Bulgaria. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had high-volume metastatic, hormone-sensitive prostate cancer. Previous chemotherapy or other localised treatment for prostate cancer were not allowed. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. Randomisation was done via an interactive response technology system (block size of four) and stratified according to ECOG performance status and presence of visceral metastasis (excluding lymph nodes). Herein, we present the results of the preplanned interim analyses for the two co-primary endpoints of radiographic progression-free survival assessed by a blinded independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study medication. This study is ongoing, but is closed to recruitment. This trial is registered with ClinicalTrials.gov, NCT03520478. FINDINGS: Between June 28, 2018, and Aug 6, 2020, 792 patients were screened and 654 patients were randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). At the preplanned interim analysis for radiographic progression-free survival (data cutoff May 16, 2021), the median follow-up duration was 21·2 months (IQR 16·6-25·8). Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached-not reached] vs 25·1 months [95% CI 15·7-not reached]; hazard ratio [HR] 0·44 [95% CI 0·33-0·58]; p<0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0-33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44-0·77]; p=0·0001; median overall survival was not reached [95% CI not reached-not reached] vs not reached [36·2-not reached]). The most common grade 3 or worse adverse events of any cause in the safety population were hypertension (26 [8%] of 323 patients in the rezvilutamide group vs 24 [7%] of 324 patients in the bicalutamide group), hypertriglyceridaemia (24 [7%] vs seven [2%]), increased weight (20 [6%] vs 12 [4%]), anaemia (12 [4%] vs 16 [5%]), and hypokalaemia (11 [3%] vs four [1%]). Serious adverse events were reported in 90 (28%) of 323 patients in the rezvilutamide group and 69 (21%) of 324 patients in the bicalutamide group. No treatment-related deaths occurred in patients in the rezvilutamide group; one treatment-related death of unknown specific cause (<1%) occurred in the bicalutamide group. INTERPRETATION: In the two interim analyses, rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival compared with bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, with a tolerable safety profile. FUNDING: Jiangsu Hengrui Pharmaceuticals.

Establishment of a five-enzalutamide-resistance-related-gene-based classifier for recurrence-free survival predicting of prostate cancer.

To identify prostate cancer (PCa) patients with a high risk of recurrence is critical before delivering adjuvant treatment. We developed a classifier based on the Enzalutamide treatment resistance-related genes to assist the currently available staging system in predicting the recurrence-free survival (RFS) prognosis of PCa patients. We overlapped the DEGs from two datasets to obtain a more convincing Enzalutamide-resistance-related-gene (ERRG) cluster. The five-ERRG-based classifier obtained good predictive values in both the training and validation cohorts. The classifier precisely predicted RFS of patients in four cohorts, independent of patient age, pathological tumour stage, Gleason score and PSA levels. The classifier and the clinicopathological factors were combined to construct a nomogram, which had an increased predictive accuracy than that of each variable alone. Besides, we also compared the differences between high- and low-risk subgroups and found their differences were enriched in cancer progression-related pathways. The five-ERRG-based classifier is a practical and reliable predictor, which adds value to the existing staging system for predicting the RFS prognosis of PCa after radical prostatectomy, enabling physicians to make more informed treatment decisions concerning adjuvant therapy.

CXCR3 antagonist AMG487 ameliorates experimental autoimmune prostatitis by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation.

BACKGROUND: Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease that is characterized by infiltrating inflammatory cells in the prostate and pelvic or by perineal pain. Receptor CXCR3modulates immune and inflammatory responses; however, the effects of CXCR3 antagonist AMG487 in the context of CP/CPPS are unknown. Therefore, we investigated the effect of AMG487 in experimental autoimmune prostatitis (EAP) mice and explored the potential functional mechanisms. METHODS: The EAP model was induced by intradermally injecting a mixture of prostate antigens and complete Freund's adjuvant on Days 0 and 28. To evaluate the effect of AMG487 on EAP mice, treatment with AMG487 and vehicle solution was conducted for the indicated period. Then, procedures were performed, including behavioral test, to evaluate the pain response to stimulation before the mice were killed and a histological assessment to evaluate the inflammation after the mice were killed. Immunofluorescence, flow cytometry, and Western blot assay were used to analyze the functional phenotype and regulation mechanism of AMG487 on T helper type 1 (Th1) cells and macrophages. RESULTS: We found high expression of CXCR3 in human benign prostate tissues with inflammation and EAP mice. The elevated CXCR3 in prostate tissues correlates with the severity of inflammation. CXCR3 antagonist AMG487 treatment ameliorated the inflammatory changes and the pelvic pain of EAP mice. AMG487 inhibits Th1 cell differentiation through the IL-12/STAT4pathway and inhibits pro-inflammatory M1 macrophages through the lipopolysaccharide/NF-κB p65signaling. AMG487 could inhibit the secretion of inflammatory mediators in EAP mice. CONCLUSION: CXCR3 antagonist AMG487 could ameliorate the inflammatory changes and the pelvic pain of EAP mice by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation. Thus, the results imply that AMG487 has the potential as an effective therapeutic agent in the prevention and treatment of EAP.

Identification of novel susceptibility factors related to CP/CPPS-like symptoms: Evidence from a multicenter case-control study.

BACKGROUND: We aimed to systematically identify novel susceptible factors related to the occurrence and development of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)-like symptoms that were not limited to lifestyles or dietary habits in Chinese population. METHODS: We recruited participants from three centers (Shanghai [northeast], Hefei [east], and Lanzhou [northwest]) from August 2020 to June 2021. Demographics, lifestyles, dietary habits, past medical history, and national institutes of health-chronic prostatitis symptom index (NIH-CPSI) were collected from the individuals via optimized questionnaires. Logistic regression analysis and multivariate adjustment models were used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) to assess the association between these variables and CP/CPPS-like symptoms. RESULTS: A total of 1851 participants were enrolled in this study (764 cases and 1087 controls). Age distributions differed between groups (median, range: 32, 18-74 vs. 29, 18-70, p < 0.001). After adjustment, physicochemical occupational hazards were identified significantly related to CP/CPPS-like symptom occurrence and development (ORoccurrence : 1.389, 95% CI: 1.031-1.870, p < 0.001; ORdevelopment : 2.222, 95% CI: 1.464-3.372, p < 0.001); besides, greater than or equal to four ejaculations per week significantly increased the likelihood of CP/CPPS-like symptoms compared with one ejaculation per week (ORoccurrence : 3.051, 95% CI: 1.598-5.827, p = 0.001). For these patients, who were easily felt gastrointestinal discomfort caused by spicy food intake, they had a higher incidence to affect with CP/CPPS-like symptoms (ORoccurrence : 2.258, 95% CI: 1.858-2.745, p < 0.001). In addition, history of drug allergy and genitourinary infections were identified as independent susceptible factors for the occurrence of CP/CPPS-like symptoms (ORoccurrence : 1.689, 95% CI: 1.007-2.834, p = 0.047; ORoccurrence : 3.442, 95% CI: 2.202-5.382, p < 0.001, respectively), while the history of rheumatic immune diseases was found tightly associated with the development of CP/CPPS-like symptoms (ORdevelopment : 2.002, 95% CI: 1.008-4.058, p = 0.048). CONCLUSION: Infection/inflammatory/immune-related disorders, novel dietary habits, and lifestyles associated with the susceptibility of CP/CPPS-like symptoms' occurrence and development are identified. Altering these irregular conditions serves as potential strategies for the treatment of patients with CP/CPPS-like symptoms.

CD274 (PD-L1) Methylation is an Independent Predictor for Bladder Cancer Patients' Survival.

This study was carried out to demonstrate the prognostic value of CD274 (PD-L1 promoter gene) methylation in bladder cancer patients. UCSC Xena database was searched for relevant information on PD-L1 (CD274) methylation and PD-L1 mRNA expression in bladder cancer. 407 bladder patients were included in our analyses. Multivariate analysis revealed that PD-L1 methylation was an independent predictor for OS (P = 0.037). Moreover, PD-L1 methylation might be a prognostic biomarker for immunotherapy response. However, PD-L1 methylation and PD-L1 mRNA expression was not statistically associated with chemotherapy response. In conclusion, PD-L1 methylation was an independent prognostic factor for bladder cancer patients.

Identification and validation of an E2F-related gene signature for predicting recurrence-free survival in human prostate cancer.

BACKGROUND: It is well-established that biochemical recurrence is detrimental to prostate cancer (PCa). In the present study, we explored the mechanisms underlying PCa progression. METHODS: Five cohorts from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were used to perform gene set variation analysis (GSVA) between nonrecurrent and recurrent PCa patients. We obtained the intersection of pathway enrichment results and extracted the corresponding gene list. LASSO Cox regression analysis was used to identify recurrence-free survival (RFS)-related significant genes and establish an RFS prediction gene signature and nomogram. MTT and colony formation assays were conducted to validate our findings. RESULTS: The E2F signaling pathway was activated in recurrent PCa patients compared to nonrecurrent patients. We established an E2F-related gene signature for RFS prediction based on the four identified E2F-related genes (CDKN2C, CDKN3, RACGAP1, and RRM2) using LASSO Cox regression in the Memorial Sloan Kettering Cancer Center (MSKCC) cohort. The risk score of each patient in MSKCC was calculated based on the expression levels of CDKN2C, CDKN3, RACGAP1, and RRM2. PCa patients with low-risk scores exhibited higher RFS than those with high-risk scores. Receiver operating characteristic (ROC) curve analysis validated the good performance and prognostic accuracy of the E2F-related gene signature, which was validated in the TCGA-prostate adenocarcinoma (TCGA-PRAD) cohort. Compared to patients with low Gleason scores and early T stages, PCa patients with high Gleason scores and advanced T stages had high-risk scores. Moreover, the E2F-related gene signature-based nomogram yielded good performance in RFS prediction. Functional experiments further confirmed these results. CONCLUSIONS: The E2F signaling pathway is associated with biochemical recurrence in PCa. Our established E2F-related gene signature and nomogram yielded good accuracy in predicting the biochemical recurrence in PCa.

Effects of iron oxide nanoparticles as T2-MRI contrast agents on reproductive system in male mice.

Iron oxide nanoparticles (IONPs)-based contrast agents are widely used for T2-weighted magnetic resonance imaging (MRI) in clinical diagnosis, highlighting the necessity and importance to evaluate their potential systematic toxicities. Although a few previous studies have documented the toxicity concerns of IONPs to major organs, limited data are available on the potential reproductive toxicity caused by IONPs, especially when administrated via intravenous injection to mimic clinical use of MRI contrast agents. Our study aimed to determine whether exposure to IONPs would affect male reproductive system and cause other related health concerns in ICR mice. The mice were intravenously injected with different concentrations IONPs once followed by routine toxicity tests of major organs and a series of reproductive function-related analyses at different timepoints. As a result, most of the contrast agents were captured by reticuloendothelial system (RES) organs such as liver and spleen, while IONPs have not presented adverse effects on the normal function of these major organs. In contrast, although IONPs were not able to enter testis through the blood testicular barrier (BTB), and they have not obviously impaired the overall testicular function or altered the serum sex hormones levels, IONPs exposure could damage Sertoli cells in BTB especially at a relative high concentration. Moreover, IONPs administration led to a short-term reduction in the quantity and quality of sperms in a dose-dependent manner, which might be attributed to the increase of oxidative stress and apoptotic activity in epididymis. However, the semen parameters have gradually returned to the normal range within 14 days after the initial injection of IONPs. Collectively, these results demonstrated that IONPs could cause reversible damage to the reproductive system of male mice without affecting the main organs, providing new guidance for the clinical application of IONPs as T2-MRI contrast agents.

hOGG1 rs1052133 Polymorphism and Prostate Cancer Risk: A Chinese Case-Control Study and Meta-Analysis.

BACKGROUND We performed a case-control study and an updated meta-analysis to assess the relationship between the hOGG1 rs1052133 polymorphism and prostate cancer (PCa) risk. MATERIAL AND METHODS We recruited 160 PCa cases and 243 healthy controls. For the meta-analysis, relevant studies were recruited from diverse databases up to April 2022. Genetic risk was evaluated by using an odds ratio (OR) with a corresponding 95% confidence interval (95% CI). The genotypes of this polymorphism were genotyped via the SNaPshot genotyping method. RESULTS In the case-control study, we failed to identify any association between the hOGG1 rs1052133 polymorphism and PCa risk. Negative results were also obtained when stratified analyses were performed based on the patient's prostatic-specific antigen (PSA) level and Gleason score, as well as tumor, node, and metastasis (TNM) stage. To enlarge the sample size, we performed a restricted updated meta-analysis by recruiting 10 case-control studies (including the current one), and the results suggested that genotypes of rs1052133 polymorphism were significantly associated with an elevated risk of PCa in 2 genetic models - the heterozygote and dominant models. In the stratification analysis by population ethnicity, a significant association of this polymorphism with susceptibility to PCa was found both in the Asian populations and White populations. CONCLUSIONS Our case-control and updated meta-analysis study suggest that the hOGG1 rs1052133 polymorphism is a susceptibility factor for PCa, but still needs to be further verified in the Chinese population.