Liefu Ye

Introduction: LINC00887 plays critical roles in tumor biology, from oncogenesis to metastasis and drug resistance, while the specific mechanism in ccRCC remains unclear. We analyzed the expression profiles of LINC00887 and UPF1 and assessed their correlation with glycolytic activity and M2 macrophage infiltration. Methods: Here, we performed scRNA-seq to identify distinct UPF1 expression profiles and found significant pathways. A suite of assay kits was utilized to evaluate glycolytic metabolism. Glycolytic gene expression at the mRNA and protein levels was quantified via qRT-PCR and immunoblot. Macrophage polarization and CD8 ⁺ T cells were analyzed via flow cytometry, and CD8 ⁺ T cell cytotoxicity was quantified with an LDH release assay. Orthotopic tumor models were built for validation. Results: We found that highly expressed LINC00887 induced M2 macrophage polarization by activating aerobic glycolysis and promoting lactate buildup. Mechanistically, suppression of UPF1 expression promoted malignant progression of ccRCC. Additionally, UPF1 was found to be negatively correlated with aerobic glycolysis, repressing glycolytic activity and M2 macrophage polarization while bolstering the tumor-killing potential of CD8 ⁺ T cells. Conclusion: In summary, LINC00887, through the inhibition of UPF1, escalates glycolytic activity in ccRCC and induces M2 macrophage polarization, impairing the effectiveness of CD8 ⁺ T cells in combating the tumor.

Pelvic floor disorders, including pelvic organ prolapse and urinary incontinence, represent a common health burden with substantial clinical comorbidity, but their shared genetic architecture remains incompletely understood. We performed a multi-trait genomic analysis of six pelvic-floor-related phenotypes using publicly available GWAS summary statistics from FinnGen R12 and the GWAS Catalog, with Pan-UKBB summary statistics used only for cross-ancestry validation. Linkage disequilibrium score regression and Genomic Structural Equation Modeling identified two broad latent genetic dimensions: a structural factor related to anatomical prolapse and a functional factor related to urinary and bowel dysfunction. MAGMA gene-based analysis identified 267 significant genes enriched for extracellular matrix organization and urogenital developmental pathways, including WNT4, LOXL1, ESR1, WT1, HNF1B, and FGFR2. An exploratory network-informed machine-learning framework incorporating protein-protein interaction topology improved gene prioritization over a baseline Random Forest model and highlighted biologically plausible hub genes. Cross-ancestry analysis of Pan-UKBB female genital prolapse supported directional portability of European-discovered signals and identified WNT4 as a directionally concordant locus. These findings provide a systems-level map of pelvic-floor-related genetic architecture and prioritize candidate genes for future functional validation.

Bladder cancer remains a clinically challenging malignancy, with increasing evidence suggesting that chronic bladder inflammation, such as interstitial cystitis (IC), may contribute to its development. However, the molecular mechanisms linking inflammation to tumorigenesis are poorly understood. Here, we identify coiled-coil domain-containing 8 (CCDC8) as a potential oncogenic factor in bladder cancer. Transcriptomic analysis revealed that CCDC8 is dysregulated in both IC and bladder cancer, with overexpression confirmed in tumor tissues and cell lines. Elevated CCDC8 expression was significantly associated with advanced tumor stage, lymph node metastasis, and poor prognosis, particularly in patients harboring wild-type TP53. Functional studies demonstrated that CCDC8 promotes tumor cell proliferation, migration, and survival in vitro, and enhances tumor growth in vivo. Mechanistically, CCDC8 interacts with the E3 ubiquitin ligase scaffold protein CUL7, facilitating proteasome-dependent degradation of P53, thereby suppressing its downstream effectors such as P21 and BAX. Pharmacological inhibition of neddylation with MLN4924 restored P53 levels and reversed the oncogenic effects of CCDC8 both in vitro and in vivo. Together, these findings highlight a novel mechanism of P53 regulation in bladder cancer, position CCDC8 as a potential biomarker and therapeutic target, and suggest a molecular link between chronic bladder inflammation and malignant transformation.

Background: Darolutamide, a novel androgen receptor inhibitor, significantly improved outcomes in the ARASENS trial when combined with androgen deprivation therapy (ADT) and docetaxel chemotherapy for metastatic hormone-sensitive prostate cancer (mHSPC). In China, the regimen has been reimbursed since December 2023, expanding real-world accessibility. PSMA imaging–guided focal therapy enables precise localization of residual or oligometastatic lesions and may complement systemic control. Objective: To evaluate the real-world efficacy and safety of darolutamide-based triplet therapy combined with PSMA imaging–guided focal treatment in patients with mHSPC. Methods: This multicenter, retrospective study included 17 patients treated across three tertiary hospitals between June 2023 and June 2024. All patients received darolutamide (600 mg twice daily), ADT, and docetaxel (75 mg/m ² every 3 weeks for 4–6 cycles), followed 4–6 weeks later by focal therapy (surgery or radiotherapy) based on multidisciplinary team (MDT) assessment and PSMA IMAGING findings. Data collection followed STROBE recommendations. The primary endpoint was PSA90 response; secondary endpoints included PSA ≤0.2 ng/mL, PSA progression-free survival (PSA-PFS), radiographic PFS (rPFS), and safety. Results: Seventeen patients with predominantly low- to intermediate-volume metastatic disease were analyzed. The PSA90 response rate was 94.1%, and 82.4% achieved PSA ≤0.2 ng/mL. Median PSA-PFS and rPFS were not reached at a median follow-up of 16 months. The 12-/18-month PSA-PFS rates were 88% and 65%, while the corresponding rPFS rates were 94% and 76%. Grade 1–2 myelosuppression (64.7%) and fatigue (47.1%) were most common; grade 3 neutropenia occurred in two patients (11.8%) without grade ≥4 events. Focal therapy was well tolerated, with no severe complications. Conclusion: Darolutamide-based triplet therapy combined with PSMA-guided focal intervention achieved deep biochemical responses and durable disease control with manageable toxicity in real-world Chinese patients with mHSPC. The multicenter design and standardized methodology support the feasibility of this multimodal approach, which warrants validation in larger prospective studies.

Supplementary Data clean version

Mayo adhesive probability (MAP) score affects the outcomes of adrenaletomy. Aimed to determine whether the modified retroperitoneal laparoscopic adrenalectomy (MRLA) overcomes periadrenal fat adhesion compared to Classical retroperitoneal laparoscopic adrenalectomy (CRLA) to achieve better surgical outcomes. Patients admitted from January 2016 to December 2022 were retrospectively analyzed and systematically categorized into two distinct cohorts: the MRLA group and the CRLA group, based on specific criteria.The main surgical techniques modified of MRLA is third separation level: between the edge of adrenal gland and the peripheral renal fat. The baseline characteristics and perioperative data, e.g., age, gender, BMI, tumor position, tumor size (cm), MAP score, P distance (cm), perinephric stranding, and periadrenal stranding, estimated blood loss, Operating time, were analyzed, with statistical significance defined as p < 0.05. We analyzed the differences between groups using the t test. For measurement data that didn’t follow normal distribution, we described the concentration and dispersion trended using M (Q25, Q75) and analyzed the differences between groups using the M-U test. For data that met certain conditions like being linear, normal and independent, we used linear regression analysis. For binary classification of dependent variables, we used binary logistic regression analysis. A total of 731 patients underwent adrenaletomy, and 651 patients had adequate data, were available for MAP score assessment. Of these patients, 247 were in the MRLA group, whereas 404 were in the CRLA group, baseline characteristics weren’t found to be different between the two groups (p > 0.05). The MRLA group exhibited superior outcomes in terms of operating time, duration, postoperative hospital stay, estimated blood loss, and complications, in comparison to the CRLA group. Further analysis revealed that periadrenal stranding could be the underlying cause for this discrepancy. The MRLA effectively overcame the impact of adhesive periadrenal fat (APAF) compared to CRLA. We recommend to employ the MRLA for patients with preoperative CT images indicating periadrenal fat adhesion. Not applicable.

Supplementary Data clean version