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The tumor microenvironment (TME) affects the biologic malignancy of clear cell renal cell carcinoma (ccRCC). The influence of the 5-methylcytosine (m 5 C) epigenetic modification on the TME is unknown. We comprehensively assessed m 5 C modification patterns of 860 ccRCC samples (training, testing, and real-world validation cohorts) based on 17 m 5 C regulators and systematically integrated the modification patterns with TME cell-infiltrating characterizations. Our results identified distinct m 5 C modification clusters with gradual levels of immune cell infiltration. The distinct m 5 C modification patterns differ in clinicopathological features, genetic heterogeneity, patient prognosis, and treatment responses of ccRCC. An elevated m 5 C score, characterized by malignant biologic processes of tumor cells and suppression of immunity response, implies an immune-desert TME phenotype and is associated with dismal prognosis of ccRCC. Activation of exhausted T cells and effective immune infiltration were observed in the low m 5 C score cluster, reflecting a noninflamed and immune-excluded TME phenotype with favorable survival and better responses to immunotherapy. Together, these findings provide insights into the regulation mechanisms of DNA m 5 C methylation modification patterns on the tumor immune microenvironment. Comprehensive assessment of tumor m 5 C modification patterns may enhance our understanding of TME cell-infiltrating characterizations and help establish precision immunotherapy strategies for individual ccRCC patients.

To investigate the correlation between serum sex hormone levels and clear cell renal cell carcinoma(ccRCC). The clinical data of male patients diagnosed with ccRCC and with simple renal cysts in our hospital from 2017 to 2023 were collected. The basic clinical data and serum sex hormone levels, including luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol(E 2 ), prolactin (PRL), progesterone(P), and testosterone (T), were compared between patients with ccRCC and patients with simple renal cysts. A total of 56 male patients with ccRCC and 82 male patients with simple renal cyst were included in the study. There was no significant difference in age, height, weight, BMI, LH, PRL, P and T between patients with ccRCC and simple renal cyst. The levels of E 2 and FSH in patients with ccRCC were lower than those in patients with simple renal cysts, and the differences were statistically significant ( p  = 0.024, p  = 0.001, respectively). Logistic regression analysis showed that E 2 level was negatively correlated with ccRCC (OR = 0.968, p  = 0.027). The serum E 2 and FSH levels in patients with ccRCC are significantly lower than those in patients with simple renal cysts, and E 2 is negatively correlated with ccRCC, suggesting that E 2 and FSH may play a role in the occurrence and progression of ccRCC. The study implied the potential estrogen-based therapeutic strategies in ccRCC and further study is needed to explore its mechanism.

The pioneering work from Lieping Chen’s laboratory identified Siglec‐15 as a novel tumor immune suppressor, while the regulatory mechanisms underlying the broad upregulation of Siglec‐15 in human cancers remain obscure. Here we found that long non–coding RNA (lncRNA) LINC00973 was higher in Siglec‐15‐positive clear‐cell renal cell carcinoma (ccRCC), and LINC00973 positively regulated Siglec‐15 expression at transcriptional level. This effect was evidently dependent on miR‐7109‐3p (designated as miR‐7109 hereafter), and we provided evidence that Siglec‐15 is a direct target of miR‐7109. Through sponging miR‐7109, LINC00973 functioned as competing endogenous RNA (ceRNA) to control cell surface abundance of Siglec‐15, and, consequently, was involved in cancer immune suppression. We further demonstrated that LINC00973 and miR‐7109 expression in ccRCC antagonistically influenced immune activation of co–cultured Jurkat cells. Our study highlighted the importance of LINC00973‐miR‐7109‐Siglec‐15 in immune evasion in ccRCC, which offers significant opportunity for both therapeutic intervention and diagnostic/prognostic exploitations. Through sponging miR‐7109, LINC00973 functioned as competing endogenous RNA (ceRNA) to control cell surface abundance of Siglec‐15, and, consequently, was involved in cancer immune suppression. LINC00973 and miR‐7109 expression in ccRCC antagonistically influenced immune activation of co–cultured Jurkat cells.

Clear cell renal clear cell carcinoma (ccRCC) is resistant to most chemotherapeutic drugs and the molecular mechanisms have not been fully revealed. Genomic instability and the abnormal activation of bypass DNA repair pathway is the potential cause of tumor resistance to radiotherapy and chemotherapy. IQ-motif GTPase activating protein 3 (IQGAP3) regulates cell migration and intercellular adhesion. This study aims to analysis the effects of IQGAP3 expression on cell survival, genome stability and clinical prognosis in ccRCC. Multiple bioinformatics analysis based on TCGA database and IHC analysis on clinical specimens were included. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) were used to determine protein expression level. MTT assay and 3D spheroid cell growth assay were used to assess cell proliferation and drug resistance in RNAi transfected ccRCC cells. Cell invasion capacity was evaluated by transwell assay. The influence of IQGAP3 on genome instability was revealed by micronuclei number and H2AX recruitment test. The highly expressed IQGAP3 in multiple subtypes of renal cell carcinoma has a clear prognostic value. Deletion of IQGAP3 inhibits cell growth in 3D Matrigel. IQGAP3 depletion lso increases accumulated DNA damage, and improves cell sensitivity to ionizing radiation and chemotherapeutic drugs. Therefore, targeting DNA damage repair function of IQGAP3 in tumorigenesis can provide ideas for the development of new targets for early diagnosis.

Introduction To explore whether there is a relationship between perirenal fat area (PFA) and the pathological types of renal cell carcinoma (RCC). Methods Two hundred ninety-seven cases of RCC patients were included in our study, which is a retrospective analysis. Based on pathological type, we divided the 297 RCC patients into two groups: the clear cell renal cell carcinoma (ccRCC) group (236 cases) and the non-clear cell renal cell carcinoma (non-ccRCC) group (61 cases). Computed tomography (CT) images at the renal vein level were used to measure PFA. A multivariate logistic regression model was employed to examine the connection between various pathological types of RCC and PFA. Results Significant differences were observed between ccRCC and non-ccRCC patients in PFA ( P  = 0.007), contralateral PFA ( P  = 0.011), weight ( P  = 0.002), BMI ( P  < 0.001), pathological stage 1 ( P  = 0.010), and pathological stage 2 ( P  = 0.002). To study the link between pathological subtypes and PFA, a multivariate logistic regression model was employed. Stratifying patients by tumor location in the kidney, the multivariate logistic regression analysis showed that when the tumor is located outside the polar lines of the kidney (OPLK), for every 1 cm 2 increase in PFA, the probability of developing ccRCC increases by 5% [1.05 (1.01, 1.10) P  = 0.0153]. Furthermore, after stratifying patients by tumor location and pathological stage, it was found that in T1 stage patients with tumors located OPLK, for every 1 cm 2 increase in PFA, the probability of developing ccRCC increases by 6% [1.06 (1.01, 1.11) P  = 0.0300]. Conclusion When the tumor is located OPLK in T1 stage patients, PFA is positively correlated with ccRCC. Perirenal adipose tissue may be a risk factor for ccRCC.

Background Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types. Results We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8 + T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number. Conclusions Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.

To evaluate the expression of Von Hippel Lindau (VHL) gene in diagnosed cases of renal cell carcinoma. This cross sectional study was conducted in department of Pathology, Basic Medical Sciences Institute, JPMC, Karachi, from January 2007 to December 2012. Paraffin embedded blocks of 30 cases of radical nephrectomy specimens diagnosed as renal cell carcinoma including CCRCC 21 (70%) CCPRCC, 3 (10%), PRCC 2 (6.79%), hybrid tumor 4 (13.3%), chromophobe tumor (0%) processed for VHL gene expression on Polymerase Chain Reaction. All the 30 cases previously diagnosed as renal cell carcinoma were processed on PCR, VHL gene mutations were seen in 20 (95.23%) of CCRCC while a single case was negative for VHL mutations. All CCPRCC were negative for VHL mutation. Among the hybrid tumor 03 cases with foci of clear cells show VHL mutation while a single case showing combination of clear cells and chromophobe cells was negative for mutation. Both the cases of PRCC were positive for mutation. Exon 3 mutation at base pair 194 seen in 8 (32%) cases and Exon 2 mutation at base pair 150-159 seen in 17 (68%) cases. None of the cases showed Exon 1 mutation. The present study shows that majority of CCRCC showed VHL mutation including the hybrid tumor with clear cell component in our population.

Background Clear cell renal cell carcinoma is susceptible to ferroptosis, and immunotherapy is recently recommended as a priority for the initial treatment of metastatic clear cell renal carcinoma. Increased ferroptosis and immune activation can synergistically reinforce each other in killing cancer cells. NCOA4 depletion can eliminate iron accumulation and thus weaken ferroptosis. Here, we aim to identify and validate the association between NCOA4 expression, clinicopathologic characteristics, and overall survival in ccRCC by using The Cancer Genome Atlas and Gene Expression Omnibus databases. We further analyze the interacted proteins of NCOA4 and infiltrated immune cells via TIMER and GEPIA databases. Methods NCOA4 expression in clear cell renal carcinoma (ccRCC) tissues and normal adjacent tissues in The Cancer Genome Atlas (TCGA) data were primarily screened, and further validated in another independent cohort from the gene expression omnibus (GEO) database and human protein atlas. The relationships of NCOA4 expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which NCOA4 interacted were also built using the online STRING website. Meanwhile, we use TIMER and GEPIA databases to investigate the relationships between NCOA4 expression and infiltrated immune cells and their corresponding gene marker sets. Results Contrast to normal tissue, NCOA4 expression was lower in ccRCC tumor tissue( p  < 0.05). Lower NCOA4 expression was closely associated with high-grade malignancy and advanced TNM stage. Univariate and multivariate analysis indicated the overall survival of ccRCC cases with low NCOA4 level is shorter than those of patients with high NCOA4 expression ( p  < 0.05). FTL and FTH1 were the important proteins interacting with NCOA4. ccRCC with NCOA4 deficiency presented the paucity of infiltrated immune cells and their matching marker sets, including CD8+ T cells. Conclusion Deficient NCOA4 expression was related to disease progression and poor prognosis, as well as impaired infiltration of immune cells in ccRCC.

Abstract Renal cell carcinomas (RCC) are well-vascularized tumors. Although clear cell RCC (CCRCC) show a characteristic vascular network, some cases show overlapping features with other RCC. We aimed to evaluate vascular architectural patterns, microvessel density (MVD), and endothelial cell density (ECD) in CCRCC compared to clear cell papillary RCC (ccpRCC). Thirty-four RCC (17 CCRCC and 17 ccpRCC) were included in the study. CD34 was used to evaluate vascular architectural patterns by microscopic estimation in all cases. CD34, ERG, and Bioquant Osteo 2019 Imaging Analysis Software were used to evaluate MVD and ECD in 17 CCRCC and 15 ccpRCC. Mean MVD was 526.63 in CCRCC vs. 426.18 in ccpRCC (p = 0.16); mean ECD was 937.50 in CCRCC vs. 1060.21 in ccpRCC (p = 0.25). CD34 highlighted four distinct vascular architectural patterns: pseudoacinar, Golgi-like, lacunae, and scattered. Lacunae and pseudoacinar was the most frequent combination in CCRCC; lacunae and Golgi-like was the predominant combination among ccpRCC. Pseudoacinar was most extensive in CCRCC and least in ccpRCC; Golgi-like was predominant in ccpRCC and uncommon in CCRCC. The extent of pseudoacinar and Golgi-like vascular architectural patterns was significantly different between CCRCC and ccpRCC (p < 0.05). Pathologists acquainted with these different vascular architectural patterns may utilize them as an additional tool in the distinction of CCRCC from ccpRCC.