Evaluation of Whole-Tumor Texture Analysis Based on MRI Diffusion Kurtosis and Biparametric VI-RADS Model for Staging and Grading Bladder Cancer.

BACKGROUND: to evaluate the feasibility of texture analysis (TA) based on diffusion kurtosis imaging (DKI) in staging and grading bladder cancer (BC) and to compare it with apparent diffusion coefficient (ADC) and biparametric vesical imaging reporting and data system (VI-RADS). MATERIALS AND METHODS: In this retrospective study, 101 patients with pathologically confirmed BC underwent MRI with multiple-b values ranging from 0 to 2000 s/mm2. ADC- and DKI-derived parameters, including mean kurtosis (MK) and mean diffusivity (MD), were obtained. First-order texture histogram parameters of MK and MD, including the mean; 5th, 25th, 50th, 75th, and 90th percentiles; inhomogeneity; skewness: kurtosis; and entropy; were extracted. The VI-RADS score was evaluated based on the T2WI and DWI. The Mann-Whitney U-test was used to compare the texture parameters and ADC values between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), as well as between low and high grades. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of each significant parameter and their combinations. RESULTS: The NMIBC and low-grade group had higher MDmean, MD5th, MD25th, MD50th, MD75th, MD90th, and ADC values than those of the MIBC and the high-grade group. The NMIBC and low-grade group yielded lower MKmean, MK25th, MK50th, MK75th, and MK90th than the MIBC and high-grade group. Among all histogram parameters, MD75th and MD90th yielded the highest AUC in differentiating MIBC from NMIBC (both AUCs were 0.87), while the AUC for ADC was 0.86. The MK75th and MK90th had the highest AUC (both 0.79) in differentiating low- from high-grade BC, while ADC had an AUC of 0.68. The AUC (0.92) of the combination of DKI histogram parameters (MD75th, MD90th, and MK90th) with biparametric VI-RADS in staging BC was higher than that of the biparametric VI-RADS (0.89). CONCLUSIONS: Texture-analysis-derived DKI is useful in evaluating both the staging and grading of bladder cancer; in addition, the histogram parameters of the DKI (MD75th, MD90th, and MK90th) can provide additional value to VI-RADS.

Vitamins and minerals, education, and self-care need during preconception to 1000 days of life in Southeast Asia: An expert panel opinion.

Addressing maternal malnutrition and its drivers is paramount in Southeast Asia. This article summarizes the key clinical learnings and evidence-based opinions from the experts to understand the need for vitamins and minerals supplementation, education, and self-care from preconception to the first 1000 days of life, which warranted further attention since COVID-19 pandemic. Evidence describing the importance of vitamins and minerals during preconception, pregnancy, and lactation stages was identified using literature databases. A pre-meeting survey was conducted to determine the current practices and challenges in Southeast Asia. Based on the literature review and clinical experience, experts defined the topics, and an online meeting was held on 13th July 2021. During the meeting, nine experts from Southeast Asia provided evidence-based opinion on the vitamins and minerals supplementation, education, and self-care need during preconception, pregnancy, and lactation stages. The expert opinions underpin maternal malnutrition as a prevalent issue and discuss appropriate interventions and prevention strategies for women in Southeast Asia. The recent pandemic further impacted nutrition status, pregnancy, and neonatal health outcomes. The expert panel emphasized a need to improve existing inadequacies in education, self-care, and social support, and discussed the role of policymakers in addressing the barriers to dietary changes. As inadequacies in regular vitamins and minerals supplementation, education, and self-care for women of reproductive age implicate maternal and child health outcomes, there is an urgent need for addressing malnutrition concerns in this population. Thus, a strong partnership between policymakers, healthcare professionals, and other relevant sectors is required.

Will repeat resection after initial transurethral en bloc resection benefit patients with high-risk non-muscle-invasive bladder cancer? A propensity score matching analysis.

PURPOSE: To evaluate the efficacy of repeat transurethral resection on restaging, preventing tumor recurrence and progression in high-risk non-muscle invasive bladder cancer patients who received initial en bloc resection. METHODS AND PATIENTS: We reviewed retrospectively the clinical records of 330 consecutive patients who received en bloc resection for non-muscle invasive bladder cancer. Eligible patients with and without repeat transurethral resection were matched 1:1 by propensity score. Important covariates were balanced between the two groups. We compared the recurrence-free survival, progression-free survival, recurrence rate, and progression rate between groups. And the perioperative results regarding residual tumors and the safety of the repeat resection were also evaluated. RESULTS: Finally, there are 245 patients included in our analysis with a median follow-up duration of 19 months (range 3-50). Detrusor muscle presented in 244 (99.6%) specimens at initial en bloc resection. And among them, 30 (12.2%) patients had undergone a repeat resection and 215 (87.8%) did not. After 1:1 propensity score matching, 30 pairs were further analyzed.No case of upstaging was identified in repeat resection. During the follow-up, recurrence was observed in 5 (16.7%) and 7 (23.3%) patients in reresection group and non-reresection group, respectively. And progression was found only in 1 (3.3%) patient in each group. The 1-year recurrence-free survival estimates were comparable (86.7% vs 83.3%, p = 0.86) between groups. CONCLUSION: Our study demonstrates that repeat resection after initial transurethral en bloc resection for bladder tumor appears not to improve staging accuracy, recurrence, and progression.

Oncolytic Viruses for the Treatment of Bladder Cancer: Advances, Challenges, and Prospects.

Bladder cancer is one of the most prevalent cancers. Despite recent advancements in bladder cancer therapy, new strategies are still required for improving patient outcomes, particularly for those who experienced Bacille Calmette-Guerin failure and those with locally advanced or metastatic bladder cancer. Oncolytic viruses are either naturally occurring or purposefully engineered viruses that have the ability to selectively infect and lyse tumor cells while avoiding harming healthy cells. In light of this, oncolytic viruses serve as a novel and promising immunotherapeutic strategy for bladder cancer. A wide diversity of viruses, including adenoviruses, herpes simplex virus, coxsackievirus, Newcastle disease virus, vesicular stomatitis virus, alphavirus, and vaccinia virus, have been studied in many preclinical and clinical studies for their potential as oncolytic agents for bladder cancer. This review aims to provide an overview of the advances in oncolytic viruses for the treatment of bladder cancer and highlights the challenges and research directions for the future.

Cancer stem/progenitor signatures refine the classification of clear cell renal cell carcinoma with stratified prognosis and decreased immunotherapy efficacy.

Recent studies suggest that cancer stemness drives the acquired drug resistance process in cancer therapy. The complementary information provided by multi-omics data can help us to gain a deeper understanding of this process. This study aims to elucidate the impact of cancer stemness on the frontline treatment of clear cell renal cell carcinoma (ccRCC). Consensus clustering based on stem/progenitor signatures refined 3 subgroups in 1,730 tumor samples. We identified master regulons that regulate cancer stemness phenotypes, including key transcription factors, DNA methyltransferases, and promoter methylation probes. In addition, we compared the clinicopathological traits, genomic heterogeneity, cancer hallmarks, tumor microenvironment (TME), and oncological prognosis of the stemness subgroups. Cancer stemness was correlated with reduced efficiency of immune checkpoint blockade therapy. Cancer stemness profoundly affects the prognosis and treatment outcome of ccRCC by increasing genomic instability, tumor-associated malignant events, and immunosuppressive factors. For clinical application, we established and validated a 243-gene signature from stem/progenitor-related genes to distinguish anti-PD-1 outcomes. Overall, this presented study suggested that cancer stemness leads to adaptive resistance to anti-PD-1 treatment in CD8+ T-infiltrated ccRCC and provides a new reference for strategy development to further improve immunotherapy response rates.

Statin Use Is Associated with Better Prognosis of Patients with Prostate Cancer after Definite Therapies: A Systematic Review and Meta-Analysis of Cohort Studies.

Objective: Although the prognostic effect of statins on patients with prostate cancer (PCa) has been frequently evaluated, a consistent result is still lacking. We aimed to evaluate the association between statin use and mortality among patients with PCa after definite therapies. Methods: A systematic search of PubMed and other databases for cohort studies about the effect of statins on patients with PCa was performed until April 2022. Meta-analysis was performed using R software version 4.1.2. Results: 24 cohort studies involving 369, 206 participants were finally included. We found statin use significantly reduced the risk of prostate cancer-specific mortality (PCSM) with a pooled hazard ratio (pHR) = 0.76 (95% CI: 0.69-0.84, 18 studies), especially for postdiagnostic statin users: pHR = 0.81 (95% CI: 0.77-0.85) and patients who accepted androgen deprivation therapy (ADT): pHR = 0.69 (95% CI: 0.59-0.81). Statin use was also associated with a 24% reduction in the risk of all-cause mortality (ACM): pHR = 0.76 (95% CI: 0.68-0.85, 17 studies), especially for postdiagnostic statin users: pHR = 0.81 (95% CI: 0.78-0.85) and patients treated with ADT: pHR = 0.72 (95% CI: 0.63-0.82) or radiotherapy (RT): pHR = 0.68 (95% CI: 0.50-0.93). Conclusion: In conclusion, the use of statins could promote the prognosis of patients with PCa, especially for postdiagnostic users. For patients who received either ADT or radical prostatectomy (RP), statin use could decrease the PCSM. As for those who received either ADT or RT, statin use could decrease the ACM.

A Systematic Review on the Role of Repeat Transurethral Resection after Initial en Bloc Resection for Non-Muscle Invasive Bladder Cancer.

International guidelines recommend repeat transurethral resection of bladder tumors (reTURB) for selected patients with high-risk non-muscle invasive bladder cancer to remove possible residual tumors, restage tumors and improve the therapeutic outcome. However, most evidence supporting the benefits of reTURB is from conventional TURB. The role of reTURB in patients receiving initial En bloc resection of bladder tumor (ERBT) is still unknown. PubMed, Embase, Web of Science, The Cochrane Library, and China National Knowledge Infrastructure (CNKI) were systematically searched. Finally, this systematic review and meta-analysis included twelve articles, including 539 patients. The rates of residual tumor and tumor upstaging detected by reTURB after ERBT were 5.9% (95%CI, 2.0%-11.1%) and 0.0% (95%CI, 0.0%-0.5%), respectively. Recurrence-free survival, tumor recurrence and progression were comparable between patients with and without reTURB after initial ERBT. The pooled hazard ratios of 1-year, 2-year, 3-year and 5-year recurrence-free survival were 0.74 (95%CI, 0.36-1.51; p = 0.40), 0.76 (95%CI, 0.45-1.26; p = 0.28), 0.83 (95%CI, 0.53-1.32; p = 0.43) and 0.83 (95%CI, 0.56-1.23; p = 0.36), respectively. The pooled relative risks of recurrence and progression were 0.87 (95%CI, 0.64-1.20; p = 0.40) and 1.11 (95%CI, 0.54-2.32; p = 0.77), respectively. Current evidence demonstrates that reTURB after ERBT for bladder cancer can detect relatively low rates of residual tumor and tumor upstaging and appears not to improve either recurrence or progression.

Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma.

Accumulating evidence has suggested the impact of senescence on tumor progression, but no report has yet described how senescence shapes the tumor microenvironment of clear cell renal cell carcinoma (ccRCC). The objective of this study was to delineate the senescence features of ccRCC and its role in shaping the tumor microenvironment through a comprehensive analysis of multiple datasets, including 2,072 ccRCC samples. Unsupervised consensus clustering identified three senescence subtypes, and we found that the senescence-activated subtype survived the worst, even in the condition of targeted therapy and immunotherapy. The activated senescence program was correlated to increased genomic instability, unbalanced PBMR1/BAP1 mutations, elevated immune cell infiltration, and enhanced immune inhibitory factors (cancer-associated fibroblasts, immune suppression, immune exclusion, and immune exhaustion signaling). A senescence score based on nine senescence-related genes (i.e., P3H1, PROX1, HJURP, HK3, CDKN1A, AR, VENTX, MAGOHB, and MAP2K6) was identified by adaptive lasso regression and showed robust prognostic predictive power in development and external validation cohorts. Notably, we found that the senescence score was correlated to immune suppression, and the low-score subgroup was predicted to respond to anti-PD-1 therapy, whereas the high-score subgroup was predicted to respond to Sunitinib/Everolimus treatment. Collectively, senescence acted as an active cancer hallmark of ccRCC, shaped the immune microenvironment, and profoundly affected tumor prognosis and drug treatment response.

The role of reactive oxygen species derived from different NADPH oxidase isoforms and mitochondria in oxalate-induced oxidative stress and cell injury.

Hyperoxaluria is a risk factor for urolithiasis and can cause renal epithelial cell injury secondary to oxidative stress. Reactive oxygen species (ROS) produced during cell damage originate from different sources and play different roles. Here, we explored the potential sources of ROS production and investigated the role of ROS from various sources in oxalate-induced oxidative stress and cell injury in normal rat kidney-52 epithelial (NRK-52E) cells. Oxalate-induced injury was assessed by lactate dehydrogenase (LDH) release experiments. 2,7-dichlorodihydrofluorescein diacetate and mitoSOX Red were used to determine the intracellular and mitochondrial ROS (mtROS) production, respectively. The expression level of Nox4, Nox2, and p22 protein was detected by Western blotting to observe the effect of oxalate on nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase (Nox). Furthermore, a specific NADPH oxidase subtype inhibitor and targeted mitochondrial antioxidants were used to preliminarily identify the role of ROS from different sources in renal tubular epithelial cell injury induced by oxalate. We found that oxalate inhibited cell viability, induced LDH release, and prompted intracellular and mitochondrial ROS (mtROS) production. Oxalate also decreased the protein expression level of Nox4 and increased the protein expression level of p22. Mitochondria were also a source of ROS production. In addition, Nox2 inhibitor or mtROS scavenging prevented oxalate-induced cell injury, reversed by an inhibitor of Nox4/1. We concluded that ROS from different sources might play different roles in oxalate-induced renal tubular epithelial cell injury. We also identified new potential targets for preventing or alleviating oxalate-induced renal tubular epithelial cell injury.

Accuracy and Challenges in the Vesical Imaging-Reporting and Data System for Staging Bladder Cancer.

BACKGROUND: The Vesical Imaging-Reporting and Data System (VI-RADS) scoring system has been widely used to stage bladder cancer (BCa) since 2018. PURPOSE: To describe the characteristics of cases with discordant T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) scores in patients with BCa and further verify the accuracy of the VI-RADS scoring system and the necessity of dynamic contrast-enhanced (DCE) sequence. STUDY TYPE: Retrospective. SUBJECTS: A total of 106 patients (include 16.5% female) with bladder cancer. SEQUENCE: T2WI (fast spin echo), DWI (echo planer imaging), and DCE (gradient echo). ASSESSMENT: Some cases are difficult to score according to the system, mainly when the T2WI (category 4) and DWI (category 2) sequence scores are discordant, termed the discordant group below. The complementary group will be termed concordant group. Each MRI sequence was reviewed respectively according to the 5-point VI-RADS scoring system by three observers. The diagnostic ability of sequences for evaluating muscle invasion by BCa was calculated using histopathology as the reference standards. STATISTICAL TESTS: Receiver operating characteristic (ROC) curve, DeLong test, intraclass correlation coefficient. A P value of 0.05 or less was considered statistically significant. RESULTS: Fourteen cases (13.2%) had discordant VI-RADS scoring system. In the discordant group, the area under the ROC curve (AUC) of DCE was 0.875, while the T2WI and DWI showed limited diagnostic performance (AUCs = 0.50). In the concordant group, there was no significant difference in diagnostic efficacy between the overall VI-RADS (AUC: 0.950) and the combination of T2WI and DWI (AUC: 0.946) (P = 0.56). Among all patients, the AUC of overall VIRADS was 0.939 with a 3 or greater cutoff value. DATA CONCLUSION: The DCE was crucial in the discordant group for evaluating muscle-invasiveness, while DCE may not be necessary for the concordant group. The VI-RADS scoring system performed with overall good diagnostic performance in evaluating muscle-invasiveness in BCa patients. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Comparison of Thulium Laser Resection of Bladder Tumors and Conventional Transurethral Resection of Bladder Tumors for Non-Muscle-Invasive Bladder Cancer.

INTRODUCTION: The thulium laser resection of bladder tumors (TmLRBT) was increasingly used in the treatment of non-muscle-invasive bladder cancer (NMIBC) recently, and here we report the relevant outcomes of our institution to evaluate its efficacy and safety. METHODS: We retrospectively collected the data of NMIBC patients who underwent either TmLRBT or transurethral resection of bladder tumor (TURBT). The baseline characteristics and perioperative outcomes were compared in these 2 groups. RESULTS: The TmLRBT had a higher rate of detrusor identification than TURBT (97.4 vs. 87.6%, p = 0.001). After screening, 134 patients who underwent TmLRBT and 152 patients who received TURBT were enrolled in the analysis, and their baseline characteristics were similar. During the TURBT, 24 (15.8%) obturator nerve reflexes and 9 (5.9%) bladder perforations occurred, while none happened during the TmLRBT. After surgery, TmLRBT patients had fewer postoperative gross hematuria (38.1 vs. 96.7%, p < 0.001) and postoperative irrigation (27.6 vs. 92.7%, p < 0.001), and its irrigation duration was significantly shorter (2.3 vs. 3.3 day, p < 0.001). During the follow-up, no significant difference in the recurrence rate was detected (p = 0.315). CONCLUSIONS: TmLRBT is a safer technique than conventional TURBT in the treatment of NMIBC, and it could offer better specimens for pathologic assessment while the cancer control was not compromised.

Role of Nox4 in High Calcium-Induced Renal Oxidative Stress Damage and Crystal Deposition.

Aims: We aimed at exploring the role of nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (Nox4) in the regulation of hypercalciuria-induced renal oxidative damage and crystal depositions. Results: High calcium activated Nox4 expression through protein kinase C (PKC). Downregulation of Nox4 expression attenuated hypercalciuria-induced osteoblast-associated protein expression, oxidative stress injury, and crystal deposition in rat kidneys of 1,25-dihydroxyvitamin D3 (VitD) urolithiasis model. Further, calcium-induced activation of mitogen-activated protein kinase (MAPK), overexpression of osteoblast-associated protein, oxidative stress injury, apoptosis, and calcium salt deposition in normal rat kidney epithelial-like (NRK-52E) cells were reversed by downregulating Nox4 expression but were enhanced by upregulating Nox4 expression in vitro. Moreover, calcium-induced increases of osteoblast-associated protein expression were attenuated by the c-Jun-N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) inhibitors. Innovation: Our results demonstrated the effect of Nox4 in the pathological process of kidney stones in in vitro and in vivo studies for the first time. Calcium aggravates renal oxidative stress injury and crystal deposition by activating the Nox4-related reactive oxygen species (ROS)-ERK/JNK pathway in the rat kidney. This study is expected to provide a new theoretical basis for the prevention and treatment of kidney stones. Conclusion: Nox4-derived ROS induced by calcium through PKC caused oxidative stress damage and apoptosis in renal tubular epithelial cells; in addition, Nox4-derived ROS induced by calcium mediated abnormal activation of the bone morphogenetic protein 2 (BMP2) signaling pathway through the MAPK signaling pathway, which induced renal tubular epithelial cells to transdifferentiate into osteoblast-like cells, resulting in the formation of a kidney stone. Antioxid. Redox Signal. 36, 15-38.

Renal cell carcinoma of different pathological types in bilateral native kidneys of a kidney transplant recipient: A case report and literature review.

Patients after kidney transplantation have a much higher risk of developing malignant tumors than the general population. And the native kidney is an organ relatively susceptible to malignant tumors after renal transplantation. However, the simultaneous development of bilateral renal tumors is very rare; especially the bilateral native kidneys harbor different pathological types of renal cell carcinoma (RCC). We report a case of a patient who developed malignant tumors in both native kidneys nearly 19 years after renal transplantation. This patient underwent bilateral laparoscopic radical nephrectomy, and postoperative pathological examination showed clear cell RCC on the left native kidney and papillary RCC on the right one. And the early detection and surgical treatment resulted in a good prognosis. The literature related to the diagnosis and treatment of bilateral RCC after renal transplantation is also reviewed.

Proteomic analysis reveals some common proteins in the kidney stone matrix.

BACKGROUND: Proteins are the most abundant component of kidney stone matrices and their presence may reflect the process of the stone's formation. Many studies have explored the proteomics of urinary stones and crystals. We sought to comprehensively identify the proteins found in kidney stones and to identify new, reliable biomolecules for use in nephrolithiasis research. METHODS: We conducted bioinformatics research in November 2020 on the proteomics of urinary stones and crystals. We used the ClusterProfiler R package to transform proteins into their corresponding genes and Ensembl IDs. In each study we located where proteomic results intersected to determine the 20 most frequently identified stone matrix proteins. We used the Human Protein Atlas to obtain the biological information of the 20 proteins and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis to explore their biological functions. We also performed immunohistochemistry to detect the expression of the top five stone matrix proteins in renal tissue. RESULTS: We included 19 relevant studies for analysis. We then identified 1,409 proteins in the stone matrix after the duplicates were removed. The 20 most-commonly identified stone matrix proteins were: S100A8, S100A9, uromodulin, albumin, osteopontin, lactotransferrin, vitamin K-dependent protein Z, prothrombin, hemoglobin subunit beta, myeloperoxidase, mannan-binding lectin serine protease 2, lysozyme C, complement C3, serum amyloid P-component, cathepsin G, vitronectin, apolipoprotein A-1, eosinophil cationic protein, fibrinogen alpha chain, and apolipoprotein D. GO and KEGG analysis revealed that these proteins were typically engaged in inflammation and immune response.Immunohistochemistry of the top five stone matrix proteins in renal tissue showed that the expression of S100A8, S100A9, and osteopontin increased, while uromodulin decreased in kidney stone patients. Albumin was rarely expressed in the kidney with no significant difference between healthy controls and kidney stone patients. CONCLUSION: Proteomic analysis revealed some common inflammation-related proteins in the kidney stone matrix. The role of these proteins in stone formation should be explored for their potential use as diagnostic biomarkers and therapeutic targets for urolithiasis.

The Activation of ROS/NF-κB/MMP-9 Pathway Promotes Calcium-Induced Kidney Crystal Deposition.

Idiopathic hypercalciuria is an important risk factor for the formation of calcium-containing kidney stones. Matrix metalloproteinase-9 (MMP-9) is closely related to cell and tissue remodeling and is involved in ectopic tissue calcification. However, little is known about its role in kidney stone formation. In this study, we found that the expression of MMP-9 and that of osteoblastic-related proteins was increased in normal rat kidney epithelial-like (NRK-52E) cells following treatment with a high concentration of calcium, while the knockout or overexpression of MMP-9 could, respectively, significantly inhibit or upregulate the expression of osteoblastic-related proteins and calcium crystal deposition. In addition, apoptosis and calcium crystal deposition were significantly reduced in Sprague-Dawley rats with 1,25(OH)2D3-induced hypercalciuria following MMP-9 inhibitor I treatment. Furthermore, inhibiting reactive oxygen species (ROS) production or the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway significantly reduced calcium-induced MMP-9 expression and calcium crystal deposition. In summary, our results suggested that a high calcium concentration promotes epithelial-osteoblastic transformation and calcium crystal deposition in renal tubule cells by regulating the ROS/NF-κB/MMP-9 axis and identified a novel role for MMP-9 in regulating calcium-induced calcium crystal deposition in renal tubules.

Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis.

BACKGROUND: The toll-like receptor 4 (TLR4) agonist, Bacille Calmette-Guérin, has exhibited gratifying effects in treating bladder cancer. The study aims to explore the expression pattern, prognostic value, and potential mechanism of TLR4 in bladder cancer. METHODS: The transcriptome file from the GSE13507 dataset in the Gene Expression Omnibus database and the promoter methylation file from the bladder cancer dataset in The Cancer Genome Atlas database were downloaded for analysis. The prognostic value of the TLRs was assessed by univariate Cox regression. Immunohistochemistry was applied to verify the expression of TLR4 in bladder cancer. The drug response is estimated through the R package "pRRophetic." The CIBERSORT algorithm was carried out to estimate the infiltrating immune cells of samples. Gene Set Enrichment Analysis (GSEA) was performed to identify the pathways involved under varied TLR4 expression levels. RESULTS: TLR4 is decreased in tumor tissues compared with surrounding tumor tissues or normal tissue, which is also positively correlated to the overall survival rate (hazard ratio [HR] = 0.38) and cancer-specific survival rate (HR = 0.15) of patients with bladder cancer. Low expression of TLR4 is observed in tumors with malignant performance (high pathological grade, higher tumor stage, and progression). Patients with low TLR4 levels are more sensitive to gemcitabine rather than cisplatin. The promoter methylation level of TLR4 is positively associated with TLR4 expression (P < 0.001). The cg14629571 methylation site largely contributes to the overall methylation level. The CIBERSORT analysis shows that high TLR4 expression is associated with lower levels of plasma cells, M0 macrophages, and M1 macrophages. The GSEA results indicate that the TGF-ß pathway and apoptosis are activated in high TLR4 bladder cancer, while G2M checkpoint and E2F targets pathways are enriched in low TLR4 bladder cancer. CONCLUSION: This research discusses the abnormal expression and prognostic value of TLR4 in bladder cancer. The TLR4 expression can effectively predict oncological outcomes and drug sensitivity of bladder cancer patients. TLR4 is also associated with infiltrating immune cell variation and cancer pathway dysregulation. The results provide a novel prognostic marker and potential drug targets for bladder cancer.

Resveratrol Attenuates Oxalate-Induced Renal Oxidative Injury and Calcium Oxalate Crystal Deposition by Regulating TFEB-Induced Autophagy Pathway.

The oxidative injury of renal tubular epithelial cells caused by inflammation and oxidative stress induced by hyperoxaluria is an important factor in the kidney calcium oxalate (CaOx) stone formation. Resveratrol (RSV) has been reported to reduce oxidative injury to renal tubular epithelial cells, and autophagy is critical for the protective effect of resveratrol. However, the protective mechanism of RSV in oxalate-induced oxidative injury of renal tubular cells and the role of autophagy in this process are still unclear. In our study, glyoxylic acid monohydrate-induced rats were treated with or without resveratrol, and it was detected that the overexpression of oxidant species, CaOx crystal deposition, apoptosis level, inflammatory cytokines and osteoblastic-associated protein expression were reversed by resveratrol. Additionally, Resveratrol pretreatment significantly reversed oxalate -induced decline in cell viability, cell damage, oxidant species overexpression, and osteogenic transformation in normal rat kidney epithelial-like (NRK-52E) cells. Furthermore, we found that RSV pretreatment promoted intracellular LC3II upregulation, p62 downregulation, and autophagosome formation, whereas 3-methyladenine treatment reduced this effect. Moreover, RSV induced the expression of transcription factor EB (TFEB) in the nucleus of NRK-52E cells in a concentration-dependent manner. After transfection of NRK-52E cells with TFEB siRNA, we showed that the RSV-induced increase in TFEB expression and autophagosome formation were inhibited. Simultaneously, RSV-induced NRK-52E cells protection was partially reversed. These results suggested that RSV regulates oxalate-induced renal inflammation, oxidative injury, and CaOx crystal deposition in vitro and in vivo through the activation of a TFEB-induced autophagy.

Application of bi-planar reduced field-of-view DWI (rFOV DWI) in the assessment of muscle-invasiveness of bladder cancer.

OBJECTIVES: To compare the image quality of the reduced field-of-view (rFOV) diffusion-weighted imaging (DWI) with the full field-of-view (fFOV) DWI in the assessment of bladder cancer (BC); and to explore the possible superiority of bi-planar (axial and sagittal) rFOV DWI over single planar fFOV DWI in predicting muscle-invasiveness of BC. MATERIALS AND METHODS: This retrospective study analyzed 61 patients with BC who underwent DWI sequences including axial fFOV DWI, axial rFOV DWI, and sagittal rFOV DWI. Qualitative and quantitative image quality assessment were compared between axial fFOV DWI and rFOV DWI sequences. The tumor with its base could be clearly displayed on DWI was defined as the evaluable lesion, and the number of evaluable lesions detected from single axial fFOV DWI, axial rFOV DWI, sagittal rFOV DWI, and bi-planar rFOV DWI sequences was recorded and compared. The apparent diffusion coefficient (ADC) was compared between non-muscular-invasive bladder cancer (NMIBC) and muscular-invasive bladder cancer (MIBC) based on the sequences of axial fFOV DWI and rFOV DWI, respectively. Vesical Imaging-Reporting and Data System (VI-RADS) was introduced to evaluate the overall risk of muscle-invasiveness of BC and receiver operating characteristic (ROC) curve analysis was applied to assess the diagnostic performance. RESULTS: The contrast-to-noise ratio (CNR) of the rFOV DWI was significantly higher than that of fFOV DWI (p < 0.01), while the signal-to-noise ratio (SNR) was significantly lower than that of fFOV DWI (p < 0.01). The subjective score of rFOV DWI was significantly higher than that of fFOV DWI (p < 0.01). The ADC value of the MIBC group was significantly lower than that of the NMIBC in both rFOV DWI and fFOV DWI (all p < 0.01). The number of evaluable lesions detected from the bi-planar rFOV DWI was significantly higher than that detected from the single axial fFOV DWI, axial rFOV DWI, and sagittal rFOV DWI (all p < 0.01). VI-RADS based on the bi-planar rFOV DWI offered high predictive power (the area under the ROC curve, 0.946) for predicting the presence of muscle-invasiveness of BC. CONCLUSION: Bi-planar rFOV DWI may provide more diagnostic confidence than the single planar DWI for predicting the presence of muscle-invasiveness in BC, with improved image quality over the fFOV DWI.

Efficacy and toxicity in scheduled intravesical gemcitabine versus Bacille Calmette-Guérin for Ta and T1 bladder cancer: a systematic review and meta-analysis.

BACKGROUND: We conducted a meta-analysis to compare the efficacy and toxicity of scheduled intravesical gemcitabine (GEM) and Bacille Calmette-Guérin (BCG) for Ta and T1 non-muscle invasive bladder cancer (NMIBC). METHODS: The database search was performed in Ovid Medline, Embase, Web of Science, Cochrane Library from the commencement of the database to July 7, 2020. Trials using immediate instillation were excluded and we present the included studies in accordance with the PRISMA 2020 reporting checklist. The data extracted was analyzed using Stata 11.0 software. RESULTS: Six studies of 466 patients comparing GEM and BCG were finally included. No significant difference was detected between GEM and BCG group in recurrence free survival [hazard ratio (HR) =0.80, 95% confidence interval (95% CI), 0.46-1.37, P=0.410], progression free survival (HR =0.82, 95% CI, 0.38-1.77, P=0.621), and total adverse events [odds ratio (OR) =0.70, 95% CI, 0.38-1.29, P=0.253). However, patients receiving GEM treatment are less likely to develop urinary adverse events, such as dysuria (OR =0.50, 95% CI, 0.29-0.87) and hematuria (OR =0.40, 95% CI, 0.18-0.91). We performed subgroup analysis and found that the effects of GEM and BCG were similar even on patients with high recurrence risk tumor. Sensitivity analysis showed the robustness of the results. DISCUSSION: Scheduled intravesical GEM instillation has a similar effect with BCG instillation in preventing NMIBC recurrence and progression, but GEM therapy causes a lower incidence of dysuria and hematuria than BCG. GEM may be an alternative therapy for BCG. However, the results should be treated with caution due to the low to moderate quality of the included studies.