Electrospun nanofibrous mats loaded with gemcitabine and cisplatin suppress bladder tumor growth by improving the tumor immune microenvironment.

The perplexing issues related to positive surgical margins and the considerable negative consequences associated with systemic chemotherapy have posed ongoing challenges for clinicians, especially when it comes to addressing bladder cancer treatment. The current investigation describes the production of nanocomposites loaded with gemcitabine (GEM) and cisplatin (CDDP) through the utilization of electrospinning technology. In vitro and in vivo studies have provided evidence of the strong effectiveness in suppressing tumor advancement while simultaneously reducing the accumulation of chemotherapy drugs within liver and kidney tissues. Mechanically, the GEM and CDDP-loaded electrospun nanocomposites could effectively eliminate myeloid-derived suppressor cells (MDSCs) in tumor tissues, and recruit CD8+ T cells and NKp46+ NK cells to kill tumor cells, which can also effectively inhibit tumor microvascular formation. Our investigation into the impact of localized administration of chemotherapy through GEM and CDDP-loaded electrospun nanocomposites on the tumor microenvironment will offer novel insights for tackling tumors.

Impaired TFEB-mediated autophagy-lysosome fusion promotes tubular cell cycle G2/M arrest and renal fibrosis by suppressing ATP6V0C expression and interacting with SNAREs.

Increasing evidence suggests that autophagy plays a major role during renal fibrosis. Transcription factor EB (TFEB) is a critical regulator of autophagy- and lysosome-related gene transcription. However, the pathophysiological roles of TFEB in renal fibrosis and fine-tuned mechanisms by which TFEB regulates fibrosis remain largely unknown. Here, we found that TFEB was downregulated in unilateral ureteral obstruction (UUO)-induced human and mouse fibrotic kidneys, and kidney-specific TFEB overexpression using recombinant AAV serotype 9 (rAAV9)-TFEB in UUO mice alleviated renal fibrosis pathogenesis. Mechanically, we found that TFEB's prevention of extracellular matrix (ECM) deposition depended on autophagic flux integrity and its subsequent blockade of G2/M arrest in tubular cells, rather than the autophagosome synthesis. In addition, we together RNA-seq with CUT&Tag analysis to determine the TFEB targeted gene ATP6V0C, and revealed that TFEB was directly bound to the ATP6V0C promoter only at specific site to promote its expression through CUT&Run-qPCR and luciferase reporter assay. Interestingly, TFEB induced autophagic flux integrity, mainly dependent on scaffold protein ATP6V0C-mediated autophagosome-lysosome fusion by bridging with STX17 and VAMP8 (major SNARE complex) by co-immunoprecipitation analysis, rather than its mediated lysosomal acidification and degradation function. Moreover, we further investigated the underlying mechanism behind the low expression of TEFB in UUO-induced renal fibrosis, and clearly revealed that TFEB suppression in fibrotic kidney was due to DNMT3a-associated TFEB promoter hypermethylation by utilizing methylation specific PCR (MSP) and bisulfite-sequencing PCR (BSP), which could be effectively recovered by 5-Aza-2'-deoxycytidine (5A-za) to alleviate renal fibrosis pathogenesis. These findings reveal for the first time that impaired TFEB-mediated autophagosome-lysosome fusion disorder, tubular cell G2/M arrest and renal fibrosis appear to be sequentially linked in UUO-induced renal fibrosis and suggest that DNMT3a/TFEB/ATP6V0C may serve as potential therapeutic targets to prevent renal fibrosis.

Analysis of risk factors affecting the postoperative drainage after a laparoscopic partial nephrectomy: a retrospective study.

Purpose: Laparoscopic partial nephrectomy (LPN) remains the most commonly used measure for treating localized renal cell cancer (RCC) with an increasing incidence of RCC ever since the 1990s. This study aimed to identify risk factors that affect the postoperative time of drainage and total drainage volume after LPN. Method: The clinical data of 612 RCC patients who received LPN from January 2012 to December 2022 in our hospital, including the postoperative drainage time and total drainage volume, were retrospectively analyzed. Univariable and multivariable linear regression and correlation analyses were used to identify the correlations between 21 factors, which include gender, age, history of alcohol consumption, family history of RCC, body weight, body mass index (BMI), and operation time, postoperative drainage time, and total drainage volume. Results: The mean time of drainage was 3.52 ± 0.71 days (range: 2 to 8 days), with an average total drainage volume of 259.83 ± 72.64 mL (range: 50 to 620 mL). Both univariable and multivariable linear regression analyses revealed several statistically significant associations. Gender (p = 0.04), age (p = 0.008), smoking history (p < 0.001), diabetes (p = 0.032), operation time (p = 0.014), and BMI (p = 0.023) were identified as significant factors associated with the time of drainage. On the other hand, age (p = 0.008), smoking history (p < 0.001), diabetes (p = 0.006), and BMI (p = 0.016) emerged as independent risk factors influencing the total drainage volume. Conclusion: The duration of postoperative drainage was found to be associated with gender, age, smoking history, diabetes, operation time, and BMI. In contrast, the total drainage volume was primarily influenced by age, smoking history, diabetes, and high BMI following LPN. For patients with these conditions, meticulous attention to hemostasis and bleeding control is crucial during the perioperative period.

Frailty as a risk marker of adverse lower urinary symptom outcomes in patients with benign prostatic hyperplasia undergoing transurethral resection of prostate.

Purpose: Lower urinary symptoms (LUTS) may persist in a proportion of patients with benign prostatic hyperplasia (BPH) following transurethral resection of prostate (TURP), which is a major cause of reduced quality-of-life. We aimed to investigate the effect of frailty on LUTS in patients with BPH treated with TURP. Methods: We longitudinally evaluated LUTS and health-related quality-of-life (HRQOL) in patients with BPH treated with TURP from February 2019 and January 2022 using International Prostate Symptom Score (IPSS) and Short Form-8 (SF-8), respectively. Patients were divided into frail and non-frail groups according to the Fried phenotype (FP). The primary purpose was comparing the outcomes of LUTS and HRQOL between two groups. Secondary purposes were investigating the frailty as a preoperative predictor of postoperative adverse LUTS outcomes following TURP using logistic regression analysis. A 1:2 propensity score matching (PSM) was performed to reduce the effects of selection bias and potential confounders. Results: Of the 567 patients enrolled, 495 (87.3%) patients were non-frail (FP = 0-2), and the remaining 72 (12.7%) patients were classified into the frail group. There were no significant differences in body mass index (BMI), urine white blood cell (UWBC), creatinine, prostate-specific antigen (PSA) and prostate volume in both groups at baseline (all p > 0.05). However, patients with frailty were older, higher comorbidity rates, lower peak flow rates and lower HRQOL. In the frail group, although LUTS and HRQOL at 6 months following TURP improved significantly compared to those at baseline, it did not show a significant improvement compared with the non-frail group (both p < 0.001). Moreover, multivariable logistic regression analysis demonstrated that preoperative frailty was significantly associated with poor LUTS improvement in both the entire cohort and PSM subset (both p < 0.05), whereas age and comorbidities were not after PSM analysis. Conclusion: In patients with frail or non-frail, TURP for BPH provides overall good results. However, frail individuals are at higher risk of postoperative adverse LUTS outcomes. Frailty has the potential to be a strong objective tool for risk stratification and should be considered during the perioperative evaluation.

Qualification of Necroptosis-Related lncRNA to Forecast the Treatment Outcome, Immune Response, and Therapeutic Effect of Kidney Renal Clear Cell Carcinoma.

Background: Kidney renal clear cell carcinoma (KIRC) is considered as a highly immune infiltrative tumor. Necroptosis is an inflammatory programmed cell death associated with a wide range of diseases. Long noncoding RNAs (lncRNAs) play important roles in gene regulation and immune function. lncRNA associated with necroptosis could systematically explore the prognostic value, regulate tumor microenvironment (TME), etc. Method: The patients' data was collected from TCGA datasets. We used the univariate Cox regression (UCR) to select prediction lncRNAs that are related to necroptosis. Meanwhile, risk models were constructed using LASSO Cox regression (LCR). Kaplan-Meier (KM) analysis, accompanied with receiver operating characteristic (ROC) curves, was performed to assess the independent risk factors of different clinical characteristics. The evaluated factors are age, gender, disease staging, grade, and their related risk score. Databases such as Gene Ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and Gene set enrichment analysis (GSEA) were used to search the probable biological characteristics that could influence the risk groups, containing signaling pathway and immue-related pathways. The single-sample gene set enrichment analysis (ssGSEA) was chosen to perform gene set variation analysis (GSVA), and the GSEABase package was selected to detect the immune and inflammatory infiltration profiles. The TIDE and IC50 evaluation were used to estimate the effectiveness of clinical treatment on KIRC. Results: Based on the above analysis, we have got a conclusion that patients who show high risk had higher immune infiltration, immune checkpoint expression, and poorer prognosis. We identified 19 novel prognostic necroptosis-related lncRNAs, which could offer opinions for a deeper study of KIRC. Conclusion: The risk model we constructed makes it possible to predict the prognosis of KIRC patients and offers directions for further research on the prognostication and treatment strategies for KIRC.

A Multilayer Nanofibrous Mat for the Topical Chemotherapy of the Positive Margin in Bladder Cancer.

Treatment of positive margins after solid tumor resection remains a significant challenge for clinicians. Owing to unique structural features, electrospun nanofibrous mats are promised to be an implantable antitumor system through the delivery of active agents in a controlled manner. In this study, we utilized sequential electrospinning to fabricate a multilayer mat in which gemcitabine (GEM) and cisplatin (CDDP) were electrospun individually in distinct layers. By designing the structure, the multilayer mat could deliver antitumor agents sustainedly and prolong the release of GEM, which is loaded in the inner layer. In vitro assays show that the multilayer mats effectively inhibit bladder cancer (BC) cells and elevate apoptosis. In animal models of BC, the implantable drug-loaded fibrous mat can effectively treat positive margins and prevent local recurrence. Moreover, the local delivery of GEM and CDDP significantly lowers liver toxicity compared with systemic chemotherapy. In summary, a multilayer nanofibrous mat is developed for the localized and controlled delivery of GEM, dramatically improving the treatment of residual tumors and preventing BC recurrence. Impact statement The designed multilayer nanofibrous mats can achieve two chemotherapeutic drugs (gemcitabine and cisplatin) co-loading and time-programmed sustained release, significantly improving our previous study. The antitumor effect of the drug-loaded mat in vivo and in vitro was sufficiently demonstrated. We expect to bring a new strategy of topical chemotherapy for treating positive surgical margins in bladder cancer.

Tislelizumab in combination with gemcitabine plus cisplatin chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer: a retrospective study.

BACKGROUND: Combining immune checkpoint inhibitors with chemotherapy can synergistically improve antitumor activity and are generally well tolerated. Recently, the efficacy and safety of combination therapy has been demonstrated for many cancers, including urothelial carcinomas. The aim of this retrospective pilot study was to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer. METHODS: We conducted a retrospective analysis of 31 patients with locally advanced or metastatic bladder cancer from December 2020 to January 2022 with an Eastern Cooperative Oncology Group performance status of 0/1. Of the 31 patients, 14 patients received tislelizumab (200 mg i.v. every 3 weeks, Q3W) plus 21 days cycles of chemotherapy (gemcitabine, 1000 mg/m2 i.v. on days 1 and 8 of each cycle + cisplatin, 70 mg/m2 i.v. on day 2 of each cycle) (TGC) treatment and 17 patients received gemcitabine plus cisplatin chemotherapy (GC) treatment. All patients treated with bladder cytoreductive surgery and were treated for four 21 days cycles until disease progression or intolerable treatment-related adverse events (TRAEs). The objective progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and TRAEs were recorded and reviewed. RESULTS: As of the cut-off date (March 25, 2022), PFS, OS, ORR, DCR, CBR and TRAEs were evaluated in 14 patients receiving combination therapy and 17 patients in the chemotherapy alone group. The median PFS was 36.0 [95% confidence interval (CI) 33.1-38.9] weeks in the TGC group and 29.0 (95% CI 25.4-32.6) weeks in the GC group [hazard ratio (HR) 0.15 (95% CI 0.04-0.55)]. In the GC group, the median OS was 48.0 (95% CI 39.7-56.3) weeks; the median OS was not yet mature for the TGC group [HR 0.26 (95% CI 0.07-0.94)]. Treatment with TGC resulted in improved DCR (TGC 71.4%; GC 65.0%) and CBR (TGC 64.3%; GC 52.9%) compared with GC. However, although higher incidences of grade ≥ 3 TRAEs were observed with TGC compared with GC (35.7% vs 23.5%), the difference was not statistically significant (p = 0.47). CONCLUSION: This study suggested that TGC provided survivors of locally advanced or metastatic bladder cancer with encouraging antitumor activity and was generally well tolerated.

Development of a Laser Scanning Machining System Supporting On-the-Fly Machining and Laser Power Follow-Up Adjustment.

In this study, a laser scanning machining system supporting on-the-fly machining and laser power follow-up adjustment was developed to address the increasing demands for high-speed, wide-area, and high-quality laser scanning machining. The developed laser scanning machining system is based on the two-master and multi-slave architecture with synchronization mechanism, and realizes the integrated and synchronous collaborative control of the motion stage or robot, the galvanometer scanner, and the laser over standard industrial ethernet networks. The galvanometer scanner can be connected to the industrial ethernet topology as a node, via the self-developed galvanometer scanner control gateway module, and a "one-transmission and multiple-conversion" approach is proposed to ensure real-time ability and synchronization. The proposal of a laser power follow-up adjustment approach could realize real-time synchronous modulation of the laser power, along with the motion of the galvanometer scanner, which is conducive to ensuring the machining quality. In addition, machining software was developed to realize timesaving and high-quality laser scanning machining. The feasibility and practicability of this laser scanning machining system were verified using specific cases. Results showed that the proposed system overcame the limitation of working field size and isolation between the galvanometer scanner controller with the stage motion controller, and achieved high-speed and efficient laser scanning machining for both large-area consecutively and discontinuously arrayed patterns. Moreover, the integration of laser power follow-up adjustment into the system was conducive to ensuring welding quality and inhibiting welding defects. The proposed system paves the way for high-speed, wide-area, and high-quality laser scanning machining and provides technical convenience and cost advantages for customized laser-processing applications, exhibiting great research value and application potential in the field of material processing engineering.

Clinicopathological factors associated with pathological upgrading from biopsy to prostatectomy in patients with ISUP grade group ≤2 prostate cancer.

We performed this study to investigate pathological upgrading from biopsy to prostatectomy and clinicopathological factors associated with grade group (GG) upgrading in patients with International Society of Urological Pathology (ISUP) GG 1 and 2 prostate cancer (PCa) in a Chinese cohort. We included patients diagnosed with PCa with ISUP GG 1 and 2 at biopsy, who underwent RP at our institution. Pre- and postoperative clinical variables were examined. Univariate and multivariate logistic regression analyses were conducted to identify independent factors associated with GG upgrading. Patients in GG upgraded group had higher total prostate-specific antigen (tPSA; median: 14.43 ng ml-1 vs 10.52 ng ml-1, P = 0.001) and PSA density (PSAD; median: 0.45 ng ml-2 vs 0.27 ng ml-2, P < 0.001) than those in GG nonupgraded group. Patients in upgraded group had a higher ratio for Prostate Imaging-Reporting and Data System (PI-RADS) score >3 (86.4% vs 67.9%, P < 0.001). Those with GG 1 in biopsy were more likely to experience GG upgrading after RP than those with GG 2 (71 vs 54, P = 0.016). Independent preoperative factors predicting GG upgrading were PI-RADS score >3 (odds ratio [OR]: 2.471, 95% confidence interval [CI]: 1.132-5.393; P = 0.023), higher PSAD (P = 0.001), and GG in biopsy (OR: 0.241, 95% CI: 0.123-0.471; P < 0.001). The histopathological analyses of RP specimens revealed that perineural invasion (PNI; OR: 1.839, 95% CI: 1.027-3.490; P = 0.041) was identified as an independent factor associated with GG upgrading. Our results revealed that GG in the biopsy, PSAD, PI-RADS score >3, and PNI were independent factors of GG upgrading. These factors should be considered for patients with ISUP grade ≤2 PCa.

Penetration Depth Prediction of Infinity Shaped Laser Scanning Welding Based on Latin Hypercube Sampling and the Neuroevolution of Augmenting Topologies.

This paper builds an infinity shaped ("∞"-shaped) laser scanning welding test platform based on a self-developed motion controller and galvanometer scanner control gateway, takes the autogenous bead-on-plate welding of 304SS with 3 mm thick specimens as the experimental objects, designs the experimental parameters by the Latin hypercube sampling method for obtaining different penetration depth welded joints, and presents a methodology based on the neuroevolution of augmenting topologies for predicting the penetration depth of "∞"-shaped laser scanning welding. Laser power, welding speed, scanning frequency, and scanning amplitude are set as the input parameters of the model, and welding depth (WD) as the output parameter of the model. The model can accurately reflect the nonlinear relationship between the main welding parameters and WD by validation. Moreover, the normalized root mean square error (NRMSE) of the welding depth is about 6.2%. On the whole, the proposed methodology and model can be employed for guiding the actual work in the main process parameters' preliminary selection and lay the foundation for the study of penetration morphology control of "∞"-shaped laser scanning welding.

Standardized Incidence Rate, Risk and Survival Outcomes of Second Primary Malignancy Among Renal Cell Carcinoma Survivors: A Nested Case-Control Study.

PURPOSE: Second primary malignancy (SPM) is challenging for treatment and long-term survival. We sought to investigate the standardized incidence rate (SIR), risk factors, and survival outcomes for SPM after renal cell carcinoma (RCC) treatment. METHOD: A nested case-control study was designed, we identified all T1-4N0-1M0 RCC patients diagnosed between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database and followed them for SPM diagnosis for up to 13 years. Patients with SPM diagnosis ≥6 months after treatment of primary T1-4N0-1M0 RCC were identified as the case cohort and SPM-free patients were the control cohort. SIRs and the excess risk were calculated. A competing risks and Cox model were used to evaluate the risk factors of SPM and overall survival (OS). RESULTS: A cohort of 6,204 RCC patients with SPM were matched with a control group of 31,020 RCC patients without SPM. The median time-to-SPM interval was 54.5 months in RCC patients with SPM diagnosis. Besides, an SPM of T3/4 or/and M1 stage diagnosis was positively associated with a longer time-to-SPM interval. SIR of SPM increased by follow-up time and decreased with age at diagnosis (Pfor all <0.001). SPM in the kidney had the highest SIR (54.6, P <0.001) among all SPMs. Prostate cancer (29.8%) in males and breast cancer (23.5%) in females were the most common SPM. Older age, black ethnicity, male sex, higher family income, papillary RCC, and lower TNM stage were significant risk factors for SPM diagnosis. The proportion of deaths from SPM exceeds that of deaths from RCC 3 years after the first RCC treatment. Patients with SPM and early time-to-SPM interval shortens the OS compared with SPM-free patients. The 5-year OS was 85.9% and 58.9% from the first RCC and the SPM diagnosis, respectively. Besides, patients with low-grade/early-stage SPM could benefit from aggressive surgical treatment for solid tumors. CONCLUSIONS: Collectively, our study described the epidemiological characteristics of SPM among RCC survivors and identified the independent predictors of the SPM diagnosis and its survival outcomes. This study highlights the importance of patient education and follow-up after the surgery for RCC.