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The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)–GATA-binding protein 3 (GATA3)–enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK–GATA3–ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. Significance: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK–GATA3–ECHS1 pathway as a potential therapeutic target and prognostic biomarker.

Epithelial-to-mesenchymal transition (EMT) is important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC.

The epidermal growth factor receptor (EGFR) family members EGFR and HER2 play pivotal roles in oncogenesis and tumor progression. Anticancer drugs targeting EGFR and HER2 have been developed. Long noncoding RNAs (lncRNAs) have been reported to regulate cancer development and progression through signaling pathways. However, lncRNAs that regulate EGFR and HER2 expression remain unknown. Here, we show that lncRNA myosin light chain kinase-antisense RNA 1 (MYLK-AS1) promotes EGFR and HER2 expression and activates their downstream signaling pathway. MYLK-AS1 increases hepatocellular carcinoma (HCC) cell proliferation, migration, and invasion in vitro. Consistently, MYLK-AS1 knockdown hinders tumor growth in vivo. Mechanistically, MYLK-AS1 enhances HCC cell proliferation, migration, and invasion through stimulating the EGFR/HER2-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In addition, MYLK-AS1 is overexpressed in HCC patients and negatively correlated with HCC prognosis. Thus, MYLK-AS1 is an upstream regulator of EGFR/HER2, and acts as an oncogene, suggesting an additional target for cancer therapeutics.

Objective: Increasing evidence indicates that RAD50, which is involved in the repair process of DNA double-strand break (DSB), is also involved in cancer outcomes. However, its role in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. This study was designed to investigate the expression of RAD50 and its prognostic value in HBV-related HCC patients. Methods: 107 and 100 patients with HBV-related HCC from the Affiliated Hospital of Youjiang Medical University of Nationalities (AHYMUN) and the Affiliated Hospital of Nantong University (AHNU), respectively, were enrolled in the study. The distribution of the categorical clinical-pathological data and the levels of RAD50 expression were compared with a χ2 test. Immunohistochemistry (IHC) staining of RAD50 was performed. A partial likelihood test based on univariate and multivariate Cox regression analysis was developed to address the influence of independent factors on disease-free survival (DFS) and overall survival (OS). The Oncomine online database was used to analyse and validate the differential expression of RAD50. The Kaplan-Meier method and a log-rank test were performed to assess the influence of RAD50 on survival at different levels. Results: RAD50 was highly expressed in HCC tissues compared to normal tissues and was significantly correlated with OS in the Cancer Genome Atlas (TCGA) cohort. The validation analysis indicated that significantly increased levels of RAD50 were expressed in HCC tissues in the two independent cohorts. In addition, HCC patients with elevated RAD50 expression levels showed poor OS and DFS in the AHYMUN cohort and decreased OS and DFS in the AHNTU cohort. Conclusion: In conclusion, our study reveals that elevated RAD50 expression is significantly correlated with cancer progression and poor survival in HBV-related HCC patients. These data suggest that RAD50 may act as an oncogene and may serve as a promising target for the therapy of HBV-related HCC patients.

Clear cell renal cell carcinoma (ccRCC) is one of the most common cancers worldwide. Despite intense efforts to elucidate its pathogenesis, the molecular mechanisms and genetic characteristics of this cancer remain unknown. In this study, three expression profile data sets (GSE15641, GSE16441 and GSE66270) were integrated to identify candidate genes that could elucidate functional pathways in ccRCC. Expression data from 63 ccRCC tumors and 54 normal samples were pooled and analyzed. The GSE profiles shared 379 differentially expressed genes (DEGs), including 249 upregulated genes, and 130 downregulated genes. A protein-protein interaction network (PPI) was constructed and analyzed using STRING and Cytoscape. Functional and signaling pathways of the shared DEGs with significant p values were identified. Kaplan-Meier plots of integrated expression scores were used to analyze survival outcomes. These suggested that FN1, ICAM1, CXCR4, TYROBP, EGF, CAV1, CCND1 and PECAM1/CD31 were independent prognostic factors in ccRCC. Finally, to investigate early events in renal cancer, we screened for the hub genes CCND1 and PECAM1/CD31. In summary, integrated bioinformatics analysis identified candidate DEGs and pathways in ccRCC that could improve our understanding of the causes and underlying molecular events of ccRCC. These candidate genes and pathways could be therapeutic targets for ccRCC.

BACKGROUND The serine peptidase inhibitor Kazal type 13 (SPINK13) gene has tumor suppressor activity, but its role in renal cell carcinoma (RCC) remains unknown. This study aimed to investigate mRNA expression of SPINK13 in clear cell renal cell carcinoma (CCRCC) in human tissue and to use bioinformatics data to investigate the role of SPINK13 expression as a clinicopathological and prognostic biomarker for patients with CCRCC. MATERIAL AND METHODS Patients with CCRCC (N=533) with available RNA sequence data from The Cancer Genome Atlas (TCGA)-CCRCC database were analyzed with patients who had a tissue diagnosis of CCRCC (N=305) at the Fudan University Shanghai Cancer Center (FUSCC). Differential transcriptional and proteome expression profiles were obtained from the ONCOMINE cancer microarray database, TCGA, and the Human Protein Atlas (HPA) database. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) measured SPINK13 mRNA expression in 305 samples of CCRCC tissue from the FUSCC. The effects of clinicopathological parameters on progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier and log-rank test. RESULTS Transcriptional and proteome expression of SPINK13 were significantly increased CCRCC tissue samples. Increased SPINK13 mRNA expression was significantly associated with reduced PFS and OS in 838 patients with CCRCC patients from the two independent cohorts, the FUSCC and the TCGA-CCRCC cohorts (p

Intratumoral fibrosis is a frequent histologic finding in highly vascularized clear cell renal cell carcinoma (ccRCC). Here, we investigated the expression of a family of collagen-modifying enzymes, procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 (PLOD1/2/3), in ccRCC tissues and assessed the prognostic value of wild-type and genetically mutated PLOD1/2/3 for ccRCC patients. Normal kidney and ccRCC mRNA and protein expression datasets were obtained from Oncomine, The Cancer Genome Atlas, and Human Protein Atlas databases. Associations between PLOD1/2/3 expression, clinicopathological variables, and patient survival were evaluated using Cox regression and Kaplan–Meier analyses. PLOD1/2/3 mRNA and protein expression levels were significantly elevated in ccRCC tissues compared with normal kidney. Increased PLOD1/2/3 mRNA expression was significantly associated with advanced tumor stage, high pathological grade, and shorter progression-free and overall survival (all p

Accumulation of nucleotide building blocks prior to and during S phase facilitates DNA duplication. Herein, we find that the anaphase-promoting complex/cyclosome (APC/C) synchronizes ribose-5-phosphate levels and DNA synthesis during the cell cycle. In late G1 and S phases, transketolase-like 1 (TKTL1) is overexpressed and forms stable TKTL1-transketolase heterodimers that accumulate ribose-5-phosphate. This accumulation occurs by asymmetric production of ribose-5-phosphate from the non-oxidative pentose phosphate pathway and prevention of ribose-5-phosphate removal by depleting transketolase homodimers. In the G2 and M phases after DNA synthesis, expression of the APC/C adaptor CDH1 allows APC/CCDH1 to degrade D-box-containing TKTL1, abrogating ribose-5-phosphate accumulation by TKTL1. TKTL1-overexpressing cancer cells exhibit elevated ribose-5-phosphate levels. The low CDH1 or high TKTL1-induced accumulation of ribose-5-phosphate facilitates nucleotide and DNA synthesis as well as cell cycle progression in a ribose-5-phosphate-saturable manner. Here we reveal that the cell cycle control machinery regulates DNA synthesis by mediating ribose-5-phosphate sufficiency.

To observe the effect of electroacupuncture (EA) on the expression of NF-κB p65 in hippocampus and the morphology of hippocampus in rats with chronic fatigue syndrome (CFS), so as to explore its mechanism in improving cognitive dysfunction of CFS.Forty-eight SD rats were randomly divided into control, model, EA and inhibitor groups (After mode-ling, the general status score was increased （EA can improve the cognitive function in CFS rats, which may be associated with its effect in inhibiting the expression of NF-κB and reducing the inflammation response in hippocampus.

Traditionally, clear cell papillary renal cell carcinoma (ccpRCC) was considered to share similar molecular and histological characteristics with clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC). Here we aimed to identify somatic and germline variants of ccpRCC. For this purpose, we conducted whole-exome sequencing to detect somatic variants in the tissues of 18 patients with pathologically confirmed ccpRCC, who underwent surgical treatment at Fudan University Shanghai Cancer Center. Targeted sequencing was conducted to detect germline variants in paired tumor or normal tissues or blood. Somatic and germline variants of ccRCC and Renal cell carcinoma included in The Cancer Genome Atlas data and other published data were analyzed as well. The molecular profiles of ccpRCC, ccRCC and pRCC were compared. Among the 387 somatic variants identified, TCEB1 (3/18) and VHL (3/18) variants occurred at the highest frequencies. Germline mutation detection showed that nine variants associated with Fanconi anemia (VAFAs) pathway (FANCA, 6/18; FANCI, 3/18) were identified in 18 ccpRCC patients. Among ccpRCC patients with VAFAs, five out of eight patients had second primary malignancy or family history of cancer. Somatic variants characteristics may distinguish ccpRCC from ccRCC or pRCC and germline VAFAs may be a molecular characterization of ccpRCC. Compared with ccRCC or pRCC, ccpRCC patients may be significantly correlated with higher risk of developing second primary malignancy.

Summary Elevation in homocysteine (Hcy) level is associated with insulin resistance; however, the causality between them and the underlying mechanism remain elusive. Here, we show that Hcy induces insulin resistance and causes diabetic phenotypes by protein cysteine-homocysteinylation (C-Hcy) of the pro-insulin receptor (pro-IR). Mechanistically, Hcy reacts and modifies cysteine-825 of pro-IR in the endoplasmic reticulum (ER) and abrogates the formation of the original disulfide bond. C-Hcy impairs the interaction between pro-IR and the Furin protease in the Golgi apparatus, thereby hindering the cleavage of pro-IR. In mice, an increase in Hcy level decreases the mature IR level in various tissues, thereby inducing insulin resistance and the type 2 diabetes phenotype. Furthermore, inhibition of C-Hcy in vivo and in vitro by overexpressing protein disulfide isomerase rescues the Hcy-induced phenotypes. In conclusion, C-Hcy in the ER can serve as a potential pharmacological target for developing drugs to prevent insulin resistance and increase insulin sensitivity.

To construct a robust genomic classifier for high-risk sporadic type 2 papillary renal cell carcinoma (sPRCC2) and identify potential therapeutic targets. A cohort from The Cancer Genome Atlas and two datasets from Gene Expression Omnibus were examined. Common differentially expressed genes were screened, and the ConsensusClusterPlus package was used to identify potential high-risk molecular subtypes of sPRCC2. Targeting protein for Xklp2 (TPX2) expression was used to simulate the classifier according to the logistic model. Ninety-two samples from Fudan University Shanghai Cancer Center (FUSCC) were obtained, and TPX2 immunostaining was performed to validate the predictive ability of the genomic classifier. Retrospective analysis was used to compare drug efficacy between the groups. High-risk sPRCC2 had worse overall (hazard ratio [HR] = 7.804) and disease-free survival (HR = 8.777) than low-risk sPRCC2, and the tumor and lymph node stages were significantly higher in high-risk sPRCC2. Gene set enrichment analysis revealed significant enrichment of genes in the mammalian target of rapamycin (mTOR) complex 1 signaling pathway in the high-risk group. In the FUSCC cohort, high-risk sPRCC2 (high TPX2 expression) was significantly correlated with worse overall and progression-free survival. Retrospective analysis indicated that mTOR inhibitor (everolimus) had greater efficacy in the high-risk group than in the low-risk group (overall response rate: 28.6% vs. 16.7%) and that everolimus had greater efficacy than sunitinib in the high-risk group (overall response rate: 28.6% vs. 20%). This study successfully constructed a genomic classifier for identifying high-risk sPRCC2. mTOR inhibitors may have good efficacy in patients with high-risk sPRCC2.

Renal cell carcinoma (RCC) is among the top 10 malignant carcinomas1. Clear cell (cc)RCC, accounting for ~ 75% of RCC cases, is an aggressive histological RCC subtype. In the last decade, large-scale multiomics studies have profoundly enhanced our understanding of this disease2,3. However, despite the differences of genomic alterations between Western and Eastern ccRCC4,5, these studies mostly focused on patients in Western populations. Here we conducted a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. Genomic analysis revealed unique genetic features of Chinese ccRCC and distinct mutation patterns associated with copy number alterations. Based on proteomic profiles, ccRCC showed extensive metabolic dysregulation, especially in one-carbon metabolism. We classified ccRCC into three subtypes (GP1–3), among which the most aggressive GP1 exhibited dominant immune response, metastasis, and metabolic imbalance, linking the proteomic features, genomic alterations, and clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT) and NNMT mediated protein homocysteinylation were identified as a poor prognosis indicator and a drug target for GP1, respectively. We demonstrated that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes tumor growth in ccRCC. Treatment of N-acetyl-cysteine (NAC), an inhibitor of homocysteinylation, markedly reduced the NNMT overexpression induced radioresistance of tumor cells. This study provided valuable insights into the biological underpinnings and prognosis assessment of ccRCC, revealing a targetable metabolic vulnerability.

Purpose: This study aimed to identify the potential prognostic role of HK3 and provide clues about glycolysis and the microenvironmental characteristics of ccRCC. Methods: Based on the Cancer Genome Atlas (TCGA, n = 533) and Gene expression omnibus (GEO) (n = 127) databases, real-world (n = 377) ccRCC cohorts, and approximately 15,000 cancer samples, the prognostic value and immune implications of HK3 were identified. The functional effects of HK3 in ccRCC were analyzed in silico and in vitro. Results: The large-scale findings suggested a significantly higher HK3 expression in ccRCC tissues and the predictive efficacy of HK3 for tumor progression and a poor prognosis. Next, the subgroup survival and Cox regression analyses showed that HK3 serves as a promising and independent predictive marker for the prognosis and survival of patients with ccRCC from bioinformatic databases and real-world cohorts. Subsequently, we found that HK3 could be used to modulate glycolysis and the malignant behaviors of ccRCC cells. The comprehensive results suggested that HK3 is highly correlated with the abundance of immune cells, and specifically stimulates the infiltration of monocytes/macrophages presenting surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, restrains the immune escape of tumor cells, and prompts the immune-rejection microenvironment of ccRCC. Conclusion: In conclusion, the large-scale data first revealed that HK3 could affect glycolysis, promote malignant biologic processes, and predict the aggressive progression of ccRCC. HK3 may stimulate the abundance of infiltrating monocytes/macrophages presenting surface markers and regulate the key molecular subgroups of immune checkpoint molecules of exhaustive T cells, thus inducing the microenvironmental characteristics of active anti-tumor immune responses.

Purpose: This study aims to identify potential prognostic role of ccRCC and provide clues for glycolysis and the benefits of immune checkpoint therapies (ICTs) of ccRCC. Methods: Based on TCGA (n=533), GEO (n=118), real-world (n=377) ccRCC cohorts, and approximately 15,000 cancer samples, prognostic value of HK3 was identified using survival, Cox regression and ROC analysis. Afterwards, functional effects of HK3 in ccRCC were analyzed in silico and in vivo. Results: The large-scale findings suggested significantly higher HK3 expression in ccRCC tissues and the predictive efficacy of HK3 for tumor progression and poor prognosis. Next, the subgroup survival and Cox regression analysis found that HK3 serves as a promising and independent marker predicting prognosis and survival of ccRCC patients from bioinformatics and real-world cohorts. Subsequently, we found that HK3 could modulate malignant behaviors of ccRCC cells. Additionally, the comprehensive results suggested that HK3 highly correlated with abundance of immune cells, and specifically stimulates the infiltration of monocyte/macrophage surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, affects the immune escape process of cancers and predicts outcomes for ccRCC patients receiving ICT. Conclusion: In conclusion, the large-scale data first revealed that HK3 could predict aggressive progression and poor prognosis of ccRCC, and improve predictive outcomes for ccRCC patients receiving ICT. HK3 activated ccRCC microenvironment stimulates the abundance of monocyte/macrophage surface markers infiltration, and may regulate the key molecular subgroups immune checkpoint molecules of exhaustive T cells, promoting the formation of tumor immune escape in cancers. Funding Statement: This work is supported by Grants from National Key Research and Development Project (No.2019YFC1316000), the Natural Science Foundation of Shanghai (No.20ZR1413100) and Shanghai Municipal Health Commission Project (2020CXJQ03) Declaration of Interests: The author reports no conflicts of interest in this work. Ethics Approval Statement: The Ethics approval and participation consent of this study was approved and agreed by the ethics committee of Fudan University Shanghai Cancer Center (Shanghai, China).

Background: Meningioma is one of the most common tumors of central nervous system. Although genetic alterations have been linked to elevated risk of malignancy for meningioma patients, the incongruence between clinical outcomes and WHO grade classification still exist. Therefore, large-scale genome-wide expression profiles identifying reliable biomarkers remains incompletely investigated. Methods: In order to identify genes related to invasion and metastasis process in meningiomas, genome-wide profiles in 145 meningioma patients were identified using microarray datasets GSE12530, GSE16581 and GSE43290 from the Gene Expression Synthesis (GEO) database based on differential tissues expression. Protein-protein interaction (PPI) network were constructed and functional annotations of DEGs were evaluated using R software. In addition, differential expression and prognostic value of CLU on meningioma was evaluated using immunohistochemistry in WHO grade II-III meningioma from AHYMUN, a real-world cohort. Results: A total of 58 DEGs were significantly associated with malignant behaviours of meningioma. Next, CLU were identified as hub gene in the PPI network, showing markedly prognostic implications in 67 meningioma patients. Expression level of CLU significantly climbed with elevated WHO risk classification. Interestingly, 40 genes were screened according to differential CLU expression. Additionally, significant high expression level of CLU were found in meningiomas tissue than normal tissues, predicting significant poor prognosis for 100 meningiomas patients from AHYMUN cohort. Conclusion: In conclusion, this study first reveals novel role of CLU using genome-wide expression profiles in high-risk WHO grade of meningioma and significant prognostic value based on large-scale cohorts. This work laid the foundation for the targeted molecular therapies and provided new insights into the treatment and prognostic srategies of meningiomas.

The research progress of acupuncture analgesia in recent years is analyzed to summarize the analgesic mechanism of acupuncture on neuropathic pain. The analgesic mechanism of acupuncture on neuropathic pain is discussed from peripheral level and central level, including peripheral sensitization and immune inflammatory response, changes of ion channel, central sensitization, regulation of cell signal pathway, activation of spinal glial cells, etc. It is suggested that the focus of future research should include conducting in-vitro studies with the help of multi-omics technology to detect the changes of metabolic substances and signal pathway molecules in patients with neuropathic pain before and after acupuncture to further clarify the mechanism of acupuncture analgesia.

Background: Early biochemical recurrence (BCR) was considered as a sign for clinical recurrence and metastasis of prostate cancer (PCa). The purpose of the present study was to identify a lncRNA-based nomogram that can predict BCR of PCa accurately. Materials and methods: Bioinformatics analysis, such as propensity score matching (PSM) and differentially expressed genes (DEGs) analyses were used to identify candidate lncRNAs for further bioinformatics analysis. LASSO Cox regression model was used to select the most significant prognostic lncRNAs and construct the lncRNAs signature for predicting BCR in discovery set. Additionally, a nomogram based on our lncRNAs signature was also formulated. Both lncRNAs signature and nomogram were validated in test set. GSEA was carried out to identify various gene sets which share a common biological function, chromosomal location, or regulation. Results: A total of 457 patients with sufficient BCR information were included in our analysis. Finally, a five lncRNAs signature significantly associated with BCR was identified in discovery set (HR=0.44, 95%CI: 0.27-0.72, C-index = 0.63) and validated in test set (HR=0.22, 95%CI: 0.09-0.56, C-index = 0.65). Additionally, the lncRNAs-based nomogram showed significant performance for predicting BCR in both discovery set (C-index = 0.74) and test set (C-index = 0.78). Conclusion: In conclusion, our lncRNAs-based nomogram is a reliable prognostic tool for BCR in PCa patients. In addition, the present study put forward the direction for the further investigation on the mechanism of PCa progression.

Objective: Growing evidence has proved obesity one of the confirmed important etiologic indicators for renal cell carcinoma (RCC). CD36 is underpinned to be involved in adipose absorption, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the mRNA expression of CD36 in anthropometric measures of adipose tissue and defining its value in predicting prognosis in ccRCC patients. Methods: Real-Time qPCR gene expression analysis was detected from 367 paired ccRCC and adjacent normal tissues. Distributions of categorical clinical-pathological data together with levels of CD36 expression were compared with χ2-test in a contingency table. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured by magnetic resonance imaging (MRI) and identified at the level of the umbilicus. Pearson's correlation coefficient was utilized to quantify relations between body mass index (BMI), VAT%, SAT and CD36 expression respectively. Partial likelihood test from univariate and multivariate Cox regression analysis were developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess the survival benefits between discrete levels. Results: In the current study, CD36 mRNA was demonstrated highly expressed in ccRCC compared with normal tissues. In addition, CD36 mRNA expression was significantly increased in patients with advanced TNM stage (p=0.003, p

INTRODUCTION AND OBJECTIVE:Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 ...

Background: Specific lifestyle factors including tobacco-exposure are vital etiologic factors for renal cell carcinoma (RCC), F2R Like Thrombin/Trypsin Receptor 3 (F2RL3) is associated with smoking but it is unknown whether its expression translate into poor survival of clear cell RCC (ccRCC). In the current study, the expression profiling and prognostic value of F2RL3 in Chinese patients with ccRCC were investigated. Methods: Using Quantitative PCR analysis and immunohistochemistry, the relative expression levels of F2RL3 in 367 paired ccRCC and adjacent normal tissues were calculated. Cox regression analysis was used to identify independent prognostic factors and Kaplan-Meier analysis and a log-rank test were employed to evaluate the prognostic value of F2RL3. Results: We observed that high expression of F2RL3 mRNA and protein were strongly correlated with shorten progression-free survival (PFS) of ccRCC with hazard ratios (HR; 95% confidence interval (CI)) of 2.060 (1.410-3.009) and 1.657 (1.193-2.300), respectively, as well as with poor overall survival (OS) with HRs (95%CI) of 2.826 (1.713-4.662) and 1.712 (1.140-2.569), respectively. After adjustment for confounding factors including smoking status, elevated HRs (95%CI) of 2.113 (1.445-3.089) and 1.692 (1.218-2.352) were presented for PFS, respectively, and 2.936 (1.777-4.851) and 1.811 (1.203-2.725) were present for OS, respectively. Meanwhile, increased F2RL3 mRNA and protein level were reported to significantly associate with smoking-exposure and well-known prognostic factors (higher TNM stage and ISUP grade). Conclusion: These findings suggested that F2RL3 mRNA and protein level in ccRCC is a robust predictor of poorly prognostic phenotype. Exploring the causal relevance of F2RL3 in ccRCC development further warrants in the future study.

Human cytomegalovirus (CMV) has been linked to the pathogenesis of elevated arterial blood pressure (BP). Our study aimed to determine the association between anti-CMV titers and arterial BP in the Kazakh and Han Chinese populations. Kazakh and Han (n = 800 each) (age, ≥18 years) subjects from Xinjiang, China were examined for anti-CMV immunoglobulin (Ig)G titers using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. The highest anti-CMV titer tertiles determined within gender and ethnicity groups were compared against the two lower tertiles and seronegative samples. Multivariate linear regression analysis revealed that anti-CMV titers were independent determinants for elevated systolic (p = 0.006) BP in Kazakh women and inversely associated with systolic (p = 0.004) and mean arterial (p = 0.019) BP in Han women. The association between CMV infection and/or resulting immune response and BP elevation differed by sex and ethnicity. In Kazakh women, they were associated with elevated BP and the opposite was true among Han women.

Clear cell renal cell carcinoma (ccRCC) is the most common adult renal neoplasm and its incidence continues to increase. Collagen is the most abundant extracellular matrix protein in stroma, and contributes to the development and progression of ccRCC. We examined the human collagen type XXIII α1 chain (COL23A1) expression in ccRCC and the relationship between COL23A1 and patients’ survival. We found COL23A1 mRNA was elevated in tumor compared with adjacent normal tissues, which was further validated by TCGA cohort. IHC results from 151 ccRCC cases suggested that high COL23A1 expression correlated with larger tumor size (P = 0.017) and advanced T stage (P = 0.011). The overall survival (OS) was shorter for ccRCC patients with high COL23A1 expression (P = 0.002). In multivariate analysis, high COL23A1 expression was an independent prognostic factor of OS (HR: 3.024, P = 0.017). Furthermore, COL23A1 knockdown repressed proliferation of ccRCC cell lines by blocking cell cycle progression. Cell adhesion and migration capacity was also downregulated by knockdown of COL23A1. Our data indicate that COL23A1 may be a novel prognostic indicator in ccRCC and might be a specific and accessible biomarker as well as a potential new target for clinical diagnosis of ccRCC.

Background : This study aims to identify potential biomarkers with prognostic value in papillary renal cell carcinoma (PRCC) by combining protein interaction networks with gene expression profiles from multiply cohorts. Methods : Two microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified based on standardized labeling information. The protein-protein interaction network (PPI) and functional annotations of DEGs was established and the modules were analyzed by using STRING and Cytoscape. Survival analysis of significant DEGs was analyzed by Kaplan-Meier comprehensive expression score in the Cancer Genome Atlas (TCGA) cohort. Receiver operating characteristic (ROC) curves were constructed to describe binary classifier value of genes using area under the curve (AUC) score. Additionally, immunohistochemical staining of PTTG1 protein was performed, and survival analysis was validated in Fudan University Shanghai Cancer Center (FUSCC) cohort. Results : A total of 473 DEGs and 38 functionally related hub genes were identified as candidate prognostic biomarkers. Eight genes, including BUB1B , CCNB1 , CCNB2 , MAD2L1 , TTK , CDC20 , PTTG1 and MCM, enrichment with cell cycle process were identified for further analysis. Statistical analysis of TCGA cohort indicates that expression level of the eight genes was higher in PRCC tumor tissues and was negatively correlated with patient's outcome. Significantly elevated PTTG1 expression and its negative correlativity with patient's outcome was validated in FUSCC cohorts. Conclusions : Expression levels of eight hub genes have strong prognostic value and may help better understand the potential carcinogenesis and develop targeted therapy strategies for PRCC.

Background Increasing evidence indicates that RAD50, which is involved in the DNA double-strand break (DSB) repair process, is also involved in cancer outcomes. However, its role in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) remains unclear.Aim This study was designed to investigate the expression of RAD50 and its prognostic value in HCC patients.Method A total of 207 patientswith HBV-associated HCCfrom two cohorts (107 and 100 patientsfrom the Affiliated Hospital of Youjiang Medical University of Nationalities and the Affiliated Hospital of Nantong University, respectively) were enrolled in the current study.The distribution of the categorical clinical-pathological data and the levels of RAD50 expression were compared with a χ 2 test. IHC staining of RAD50 was performed.A partial likelihood test based onunivariate and multivariate Cox regression analysis was developed to address the influence of independent factors on disease-free survival (DFS) and overall survival (OS). The Oncomine online database was used to analyse and validate the differential expression of RAD50. The Kaplan-Meier method and a log-rank test were performed to assess the influence of RAD50 on survival at different levels.Results RAD50 was highly expressed in HCC tissues compared to normal tissues and was significantly correlated with OS in the TCGA cohort. The validation analysis indicated that significantly increased levels of RAD50 were expressed in HCC tissues in the two independent cohorts, AHYMUN and AHNTU. In addition, HCC patients with elevated RAD50 expression levels showed poor OS and DFSin the AHYMUN cohort and decreased OS and DF Sin the AHNTU cohort. Furthermore, four datasets obtained from the Oncomine database validated the analysis of the differential expression of RAD50 in HCC tumours and normal tissues.Discussion In our study, we demonstrated that RAD50 was positively correlated with poor prognosis in HCC patients in the TCGA cohort. Our study also suggested that increased RAD50 expression in HBV-related HCC is a marker of poor prognosis. In this study, the analysis of the data form the two cohorts supported our hypothesis and clearly demonstrated thehigh expression of RAD50 in tumour tissues from HCC patients, which results inincreases in the HCC recurrence rate and poor overall survival.

Objective The purpose of this study was to explore the composition of tumor-infiltrating immune cells (TIIC) and prognostic significance of tumor-infiltrating mast cells (TIMC) in adrenocortical carcinoma (ACC). Methods The gene expression profiles of ACC were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE90713, GSE12368). The abundance of TIICs in ACC samples was calculated by CIBERSORT algorithm and immunohistochemistry was used to identify mast cells of 39 tumor samples from Fudan University Shanghai Cancer Center (FUSCC). Differentially expressed genes (DEGs) were analyzed by LIMMA package using R software. Survival analysis was analyzed by Kaplan-Meier method and Cox regression models. Results The abundance of mast cells (p = .008) was positively correlated with ACC patients’ outcome in TCGA cohort and was also positively correlated with both overall survival (p

BACKGROUND This study aimed to evaluate the factors associated with a survival benefit for patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib, with and without cytoreductive nephrectomy (CN). MATERIAL AND METHODS This retrospective clinical study included 118 patients with mRCC who were treated with CN and sunitinib (CN-sunitinib) (N=70) and with sunitinib-alone (N=48). Categorical clinicopathological variables were compared with hypothesis tests using contingency tables and a chi-squared test. Independent indicators for progression-free survival (PFS) and overall survival (OS) were analyzed with univariate and multivariate Cox regression models. The Kaplan-Meier method and log-rank test were used to evaluate patient survival. RESULTS The median PFS and OS for the 118 patients were 8.38 and 15.48 months, respectively. There were no significant differences between the CN-sunitinib group and the sunitinib-alone group for either PFS (7.2 months vs. 11.6 months; P=0.525) or OS (16.7 months vs. 15.2 months; P=0.839). Stratification of patients based on clinicopathological characteristics showed that CN was significantly associated with reduced PFS and OS for patients with lymph node metastasis (PFS, P

Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in clear cell renal cell carcinoma (ccRCC). This study categorized ccRCC cases into high and low score groups based on their immune/stromal scores generated by the ESTIMATE algorithm, and identified an association between these scores and prognosis. Differentially expressed tumor environment (TME)-related genes extracted from common upregulated components in immune and stromal scores were described using functional annotations and protein-protein interaction (PPI) networks. Most PPIs were selected for further prognostic investigation. Many additional previously neglected signatures, including AGPAT9, AQP7, HMGCS2, KLF15, MLXIPL, PPARGC1A, exhibited significant prognostic potential. In addition, multivariate Cox analysis indicated that MIXIPL and PPARGC1A were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort. External prognostic validation of MIXIPL and PPARGC1A was undertaken in 380 ccRCC cases from a real-world cohort. These findings indicate the relevance of monitoring and manipulation of the microenvironment for ccRCC prognosis and precision immunotherapy.

OBJECTIVE Serine palmitoyltransferase, long chain base subunit 1 (SPTLC1) catalyzes the first step in sphingolipid synthesis and has been implicated in the progression of various cancers. However, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Here, we investigated the expression and prognostic value of SPTLC1 in ccRCC. METHODS Three ccRCC patient cohorts were studied. ccRCC and adjacent normal kidney tissue samples were obtained from 183 patients at the Fudan University Shanghai Cancer Center (FUSCC) and subjected to immunohistochemical staining and quantitative reverse-transcription polymerase chain reaction to evaluate SPTLC1 protein and messenger RNA (mRNA) expression. Two validation cohorts consisting of mRNA and clinicopathological data sets from patients with ccRCC were obtained from the Cancer Genome Atlas (TCGA, n = 429) and Oncomine (n = 178) databases. Associations between low and high SPTLC1 mRNA and protein expression and survival were evaluated using the Kaplan-Meier method and log-rank test. Independent prognostic factors were identified using univariate and multivariate Cox regression analysis. RESULTS SPTLC1 mRNA or protein were expressed at significantly lower levels in ccRCC tissues compared with normal kidney tissues in all three patient cohorts (P

INTRODUCTION AND OBJECTIVES:To evaluate the role of cytoreductive nephrectomy (CN), which was an indispensable treatment in metastasis renal cell carcinoma (mRCC), compared with cytokine treatment,...

INTRODUCTION AND OBJECTIVES:Growing evidence has proved obesity one of the confirmed important etiologic indicators for renal cell carcinoma (RCC). CD36 is underpinned to be involved in adipose abs...

INTRODUCTION AND OBJECTIVES:Adrenal neuroblastoma (NB) is a common child malignancy that originates in the adrenal cortex. It is rare in adult. However there are also cases diagnosed or surviving i...

4550 Background: Considering the synergistic/additive effect of PD-1 blockade and angiogenesis inhibition, we conducted an open-label, multi-center phase II study of camrelizumab (an anti-PD-1 antibody) plus famitinib (a TKI against VEGFR-2, PDGFR, c-kit, and FGFR) in pts with heavily treated advanced renal cell carcinoma (RCC) and unresectable urothelial carcinoma (UC). Methods: Based on an adaptive two-stage design, 22 pts were enrolled in the RCC and UC cohort, respectively, at stage 1; if there were ≥7 responders of the 22 pts, enrollment would be extend to 33 at stage 2. Pts received famitinib 20 mg orally QD plus camrelizumab 200 mg IV Q3W. Primary endpoint was ORR per RECIST v1.1. Preliminary data at stage 1 were reported at ASCO 2020 annual meeting (#5085). More than 7 pts in each cohort had CR/PR during stage 1; enrollment of stage 2 had been completed, and the data are firstly reported here. Results: 74 pts (38 advanced RCC and 36 unresectable UC) were enrolled from Jan 23, 2019 to Dec 14, 2020. In RCC cohort, 65.8% of pts had received ≥1 prior VEGFR inhibitors. In UC cohort, all pts had progressed on or relapsed after a platinum-containing chemotherapy. As of Jan 10, 2021, median time from enrollment to data cutoff was 18.8 mos (range, 8.5-22.7) for RCC cohort and 7.0 mos (range, 0.9-23.6) for UC cohort. In RCC cohort, ORR was 63.2% (95% CI, 46.0-78.2; 24 PRs), DCR was 89.5% (95% CI, 75.9-95.8), median DOR was not reached (range 2-19+ mos), mPFS was not reached, and 12-mo OS rate was 88.0%. Most pts (92.1%) had reduction in target lesions, and median reduction was 47% from baseline. ORR was 84.6% (95% CI, 57.8-97.3; 11/13) for untreated RCC pts and 52.0% (95% CI, 31.3-72.2; 13/25) for pre-treated pts; DCR was 100% (95% CI, 77.2-100.0) and 84.0% (95% CI, 65.3-93.6), mPFS was not reached and 13.4 mos (95% CI: 4.1-21.0), respectively. In UC cohort, of the 33 pts with post-baseline efficacy evaluation, ORR was 33.3% (95% CI, 19.8-50.4; 1 CR, 10 PRs), DCR was 60.6% (95% CI, 43.7-75.3), median DOR was not reached (range 1.0+-16.7+ mos), mPFS was 6.4 mos (95% CI, 2.1-11.8), and mOS was not reached. ORR trended to be higher for bladder cancer (43.8%, 7/16) than upper tract urothelial carcinoma (25.0%, 4/16). Treatment-related AEs (TRAEs) occurred in 97.3% of 74 pts. Grade 3 or 4 TRAEs occurred in 63.5% of pts, mainly hypertension (23.4%), decreased platelet count (21.3%), proteinuria (17.0%), anemia (14.9%), and palmar-plantar erythrodysesthesia syndrome (14.9%). 1 pt died of TRAE (multiple organ dysfunction syndrome). Conclusions: Camrelizumab plus famitinib showed potent anti-tumor activity in pts with advanced RCC and UC with no new safety concerns. Additionally, promising ORR and durable DOR were observed in pts with heavily-treated RCC. These results support further investigation in these settings. Clinical trial information: NCT03827837.

e16563 Association of BMI, body composition and outcomes in Chinese patients with metastatic renal cell carcinoma treated with immunotherapy: a retrospective, multicohort analysis. Background: Obesity (body-mass index [BMI] ≥30 kg/m) is associated with a higher risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with better outcome in renal cell carcinoma (RCC) patients treated with immunotherapy. Whether BMI associate outcomes in Chinese RCC patients treated with immunotherapy considering Asian population has a lower BMI? In this study, we aimed to investigate the relationship between BMI, body composition and outcomes of Chinese patients with RCC treated with immunotherapy. Methods: We evaluated clinical data of metastatic RCC patients treated with immunotherapy from five major centers in China. Despite using the Chinese standard, only 6 people met the obese standard (BMI ≥28 kg/m, as per WHO's BMI categories), so we divided the patients into high BMI gourps (BMI ≥24.0 kg/m), and normal weight groups (BMI 18.5-23·9 kg/m). We assessed overall survival, defined as the time from treatment initiation to the date of any-cause death or of censoring on the day of the last follow-up, in high BMI patients and in patients with a normal weight. We also investigative the relationship between body composition (skeletal muscle index (SMI = skeletal muscle area/height2), skeletal muscle density (SMD), and subcutaneous adipose distribution index (SADI = subcutaneous adipose tissue area / subcutaneous adipose tissue area + visceral adipose tissue area) of each patient at the third lumbar vertebrae) and overall survival using CT or MRI scan at the treatment initiation. Results: Out of a total of 222 patients, 203 had evaluable CT or MRI radiographs, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 4 (1.7%) underwetight patients, leaving a final cohort of 199 patients from this study for our analyses. There were 79 (39.7%) high BMI patients and 120 (65.3%) normal weight patients. There was no difference in overall survival between the high BMI and normal weight groups (HR:1.36, CI 0.83-2.21). In addition, SMI and SMD were not associated with outcome of patients. Interestingly, although there was no statistical difference, subcutaneous fat was associated with better outcomes, while visceral fat was associated with poor outcomes. Thus, the combination of the two indicators, SADI, showed a significant prognostic correlation after adjustment for International Metastatic RCC Database risk score (aHR:0.314, CI 0.19-0.51). Conclusions: BMI is not a good predictor of the outcome of immunotherapy in Chinese patients with RCC. Evaluation of body composition may be a better tool for predicting prognosis in RCC patients treated with immunotherapy.

Chemokines are involved in many aspects of oncogenesis, including regulation of cancer cell growth, dissemination and host-tumor response. However, the potential of the chemokine receptors, CXCR4 and CXCR7, in serving as biomarkers in extramammary Paget's disease (EMPD) has been rarely examined. Expressions of CXCR4 and CXCR7 were evaluated in 92 EMPD specimens by immunohistochemistry. High expression of CXCR4 and CXCR7 were both correlated with regional lymph node metastasis and presence of lymphovascular invasion. High expression of CXCR7 also correlated with the depth of invasion. The prognostic value of these two chemokines were also investigated in progression-free survival (PFS) and cancer-specific survival (CSS). Both high expression of CXCR4 and CXCR7 were indicative of shorter PFS and CSS. In the combined prognostic model, concomitant high expression of CXCR4 and CXCR7 were suggestive of poor prognosis compared with the other two groups. In the multivariate analysis, depth of invasion, combined prognostic model and regional lymph node metastasis at diagnosis were the independent prognostic factors for EMPD patients for PFS, and the former two factors independently impacted CSS. Our results demonstrated that CXCR4 and CXCR7 can be used as prognostic biomarkers and prediction of aggressiveness of EMPD. Therapy targeting CXCR4 and CXCR7 may helpful to prevent EMPD progression and improve the prognosis of EMPD.

5085 Background: Camrelizumab (SHR-1210) is a humanised anti-PD-1 antibody. Famitinib malate is a tyrosine kinase inhibitor (TKI) against VEGFR-2, PDGFR, c-kit, and FGFR. This is an ongoing, open label, multi-center Phase II study to assess the preliminary efficacy and safety of camrelizumab in combination with famitinib malate in patients (pts) with genitourinary cancers and gynecologic cancers. Here we just report genitourinary cancers results. Methods: Eligible pts were aged 18 or older, who had advanced clear-cell renal-cell carcinoma with their primary tumour resected or unresectable urothelial carcinoma, had an ECOG performance status of 0-1and measurable disease. Previous system treatments were allowed (excluding prior PD-1/PD-L1 inhibitors or famitinib treatment). Famitinib 20 mg was administered orally once daily with SHR-1210 200 mg given intravenously every 3 weeks. We assessed antitumour activity and safety in all pts who received at least one dose treatment. The primary end point was objective response rate (ORR) per RECIST v1.1. Results: From 23 Jan 2019 to 24 Jun2019, 35 pts were enrolled (25 with RCC, 10 with UC). Median previous treatment line was 1 (range, 1-4), and 50.0% of pts had received ≥2 prior therapies in RCC, all pts received one or more-line therapies in UC. At the data cut-off date (Dec 31, 2019), after at least 6 months follow-up, 22 (63%) pts were still receiving study treatment. The most common reason for discontinuing treatments was disease progression (n = 10). 16 pts achieved a confirmed response, all were partial response, with 8 additional > 24 weeks stable disease. the ORR was 52.0% (13/25, 95% CI 31.3% to 72.2%) in RCC and 30.0% (3/10) in UC, the disease control rate was 84.0% (21/25) in RCC and 70.0% in UC. 13/16 confirmed PR pts were still on treatment, the median duration of response is not reached. The most common grade 3-4 treatment-related AEs (TRAEs) were hypertension (17.1%), proteinuria (11.4%), platelet count decreased (8.6%), hand-foot syndrome (8.6%) and anemia (5.7%). Immune-related adverse events were observed in 7 pts (20%) of 35 pts, 1 pt (2.9%) with grade 3 enteritis. Conclusions: The camrelizumab with famitinib combination appeared to show encouraging activity in pts with heavy-treated RCC and UC, and the safety profile of the combination seemed to be manageable and consistent with that of each drug alone. This combination represented a novel potential treatment option for these settings and warranted further investigation. Clinical trial information: NCT03827837 .

Summary: Colorectal cancer (CRC) onset is profoundly affected by Western diet. Here, we report that high-fat (HF) diet-induced, organ-specific colonic lysine homocysteinylation (K-Hcy) increase might promote CRC onset by impeding DNA damage repair. HF chow induced elevated methionyl-tRNA synthetase (MARS) expression and K-Hcy levels and DNA damage accumulation in the mouse and rat colon, resulting in a phenotype identical to that of CRC tissues. Moreover, the increased copy number of MARS, whose protein product promotes K-Hcy, correlated with increased CRC risk in humans. Mechanistically, MARS preferentially bound to and modified ataxia-telangiectasia and Rad3-related protein (ATR), inhibited ATR and its downstream effectors checkpoint kinase-1 and p53, and relieved cell-cycle arrest and decreased DNA damage-induced apoptosis by disrupting the binding of ATR-interacting protein to ATR. Inhibiting K-Hcy by targeting MARS reversed these effects and suppressed oncogenic CRC cell growth. Our study reveals a mechanism of Western-diet-associated CRC and highlights an intervention approach for reversing diet-induced oncogenic effects. : Wang et al. find that high-fat diet induces K-Hcy through elevating colonic MARS expression. They show that K-Hcy modification of ATR suppresses DNA damage repair to result in an accumulation of colonic DNA damage. Keywords: high-fat diet, lysine homocysteinylation, DNA damage repair, colorectal cancer, ataxia-telangiectasia and Rad3-related protein

Accumulation of nucleotide building blocks prior to and during S phase facilitates DNA duplication. Herein, we find that the anaphase-promoting complex/cyclosome (APC/C) synchronizes ribose-5-phosphate levels and DNA synthesis during the cell cycle. In late G1 and S phases, transketolase-like 1 (TKTL1) is overexpressed and forms stable TKTL1-transketolase heterodimers that accumulate ribose-5-phosphate. This accumulation occurs by asymmetric production of ribose-5-phosphate from the non-oxidative pentose phosphate pathway and prevention of ribose-5-phosphate removal by depleting transketolase homodimers. In the G2 and M phases after DNA synthesis, expression of the APC/C adaptor CDH1 allows APC/CCDH1 to degrade D-box-containing TKTL1, abrogating ribose-5-phosphate accumulation by TKTL1. TKTL1-overexpressing cancer cells exhibit elevated ribose-5-phosphate levels. The low CDH1 or high TKTL1-induced accumulation of ribose-5-phosphate facilitates nucleotide and DNA synthesis as well as cell cycle progression in a ribose-5-phosphate-saturable manner. Here we reveal that the cell cycle control machinery regulates DNA synthesis by mediating ribose-5-phosphate sufficiency., Ribose-5-phosphate (R5P) is required for DNA synthesis, but how this is regulated during cell cycle progression is unclear. Here the authors report that the cell cycle regulator APC/C-CDH1 synchronizes cell cycle progression with R5P-derived DNA synthesis by controlling TKTL1 stability

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Elucidating the tumorigenic mechanism of R-2-hydroxyglutarate (R-2HG) is critical for determining how NADP(+)-IDH mutations cause cancer. Here we report that R-2HG induces cancerous metabolism and apoptosis resistance through promoting hypersuccinylation. By competitive inhibition of the mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH), R-2HG preferentially induced succinyl-CoA accumulation and hypersuccinylation in the mitochondria. IDH1 mutation-bearing glioma samples and cells were hypersuccinylated in the mitochondria. IDH1 mutation or SDH inactivation resulted in hypersuccinylation, causing respiration inhibition and inducing cancerous metabolism and mitochondrial depolarization. These mitochondrial dysfunctions induced BCL-2 accumulation at the mitochondrial membrane, leading to apoptosis resistance of hypersuccinylated cells. Relief of hypersuccinylation by overexpressing the desuccinylase SIRT5 or supplementing glycine rescued mitochondrial dysfunctions, reversed BCL-2 accumulation, and slowed the oncogenic growth of hypersuccinylated IDH1(R132C)-harboring HT1080 cells. Thus, R-2HG-induced hypersuccinylation contributes to the tumorigenicity of NADP(+)-IDH mutations, suggesting the potential of hypersuccinylation inhibition as an intervention for hypersuccinylation-related tumors.

Human cytomegalovirus (HCMV) infection, chronic inflammation and oxidative stress, the renin–angiotensin system (RAS), endothelial function, and DNA methylation play roles in the pathogenesis of essential hypertension (EH); however, the mechanism by which HCMV predisposes patients to hypertension remain unclear. Our group previously demonstrated an association between EH and HCMV infection in Kazakh Chinese. Here, we investigated the relationship between HCMV infection and other clinicopathological features in 720 Kazakh individuals with or without hypertension (n=360 each; age: 18–80). Multiple linear and logistic regression analyses were used to determine the associations between HCMV infection, clinical characteristics, and EH. Notably, patients with EH, particularly those with HCMV infection, exhibited a marked increase in tumor necrosis factor-α (TNF-α) and 8-hydroxy-2-deoxyguanosine (8-OHDG) levels, but a decrease in endothelial nitric oxide synthase (eNOS) and renin levels. Similarly, elevated TNF-α and 8-OHDG levels were independent predictors of increased HCMV antibody titers, whereas eNOS and renin were negatively correlated with the latter. Moreover, serum angiotensin-converting enzyme (sACE, ACE) methylation was increased, whereas 11-β hydroxysteroid dehydrogenase 2 (HSD11β2; HSD3B2) methylation was decreased in patients with EH who were also infected with HCMV. A positive correlation between HSD3B2 methylation and HCMV IgG titer and blood pressure was additionally observed, whereas angiotensin-converting enzyme (ACE) methylation was inversely correlated with blood pressure. Collectively, these data indicate that HCMV may contribute to EH development in the Kazakh Chinese by increasing TNF-α and 8-OHDG levels, suppressing eNOS and renin, and manipulating HSD3B2 and ACE methylation.

739 Background: Epithelial-to-mesenchymal transition (EMT) in important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). Methods: A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. Results: We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Conclusions: Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC.

736 Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) is a rare subtype of RCC which occurs predominantly in children and adolescents. Xp11.2 RCC is characterized by the gene fusions of transcription factor E3 (TFE3). Since there is a high false-positive and false-negative rate of immunohistochemistry (IHC) for TFE3 and an uncertainty of TFE3 fusion partners by fluorescence in situ hybridization (FISH), a genetic approach, such as DNA sequencing, is necessary for auxiliary diagnosis. Methods: Thirty Chinese Xp11.2 RCC patients with positive TEF3 fusion diagnosed by FISH were involved in this analysis. Formalin-fixed, paraffin-embedded (FFPE) samples were collected for a next-generation sequencing (NGS)-based 576 gene panel assay. Genomic alterations including single base substitution, copy number variations, gene fusions, and rearrangements were assessed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were also analyzed by an NGS algorithm. Results: The 30 patients in the Xp11.2 RCC cohort included 13 males and 17 females, and had a median age of 30 years. TFE3 fusions of these patients were confirmed by both FISH and NGS. Out of the 30 Xp11.2 RCC patients, 2 patients (6.7%) showed negative TFE3 IHC expression and 4 patients (13.3%) showed equivocal TFE3 IHC expression. ASPL (9/30), PRCC (5/30), PSF (5/30), and NONO (3/30) were the most common partners of TFE3 fusion in this cohort. Moreover, we identified uncommon or novel partner genes by NGS, including ZNF627 (1/30), PTPN12 (1/30), PBM10 (1/30), PARP14 (1/30), MED15 (2/30), MATR3 (1/30), LUC7L3 (1/30), KHSRP (1/30), and EWSR1 (1/30). Based on the NGS results, several actionable genomic alterations including CDKN2A, BRCA2, and ATM were found in this study. All samples were identified as microsatellite stable (MSS). The median TMB of the entire cohort was 1.35 muts/Mb (range, 0-9.2 muts/Mb). Conclusions: In summary, we identified the partner genes of TFE3 fusion in 30 Chinese Xp11.2 RCC patients by NGS. Ten uncommon or novel partner genes (33.3%) of TFE3 were identified in this study. Overall, our results provide evidence for diagnosis and therapeutic strategies for Xp11.2 RCC patients.

737 Background: Clear cell renal cell carcinoma (ccRCC) patient usually face aggressive progression when metastasis occurs. Therefore, in-depth investigation is needed to elucidate underlying mechanisms behind the metastasis of ccRCC to promote therapeutic benefits.This study aims to explore and investigate prognostic gene expression profiles based on multi-cohorts. Methods: Three microarray datasets were obtained from the Gene Expression Omnibus (GEO) database to screen and identify differentially expressed genes (DEGs) according to normalization annotation information. A total of 112 DEGs with functional enrichment were identified as candidate prognostic biomarkers. A protein–protein interaction network (PPI) of DEGs was developed, and the modules were analyzed using STRING and Cytoscape. Results: LASSO Cox regression suggested 31 significant involved genes, and 10 hub genes were identified as independent oncogenes in ccRCC patients. Distinct integrated scores of the hub genes mRNA expression showed statistical significance in predicting disease-free survival (DFS; p

Objectives To investigate the clinicopathological features, therapeutic strategies, and prognostic factors of patients with penoscrotal invasive extramammary Paget's disease (EMPD). Patients and Methods We retrospectively collected clinical, pathological, and follow-up data of 56 men with invasive penoscrotal EMPD. Histopathological features of the primary skin lesion including tumour size, surgical margin status, depth of invasion and lymphovascular invasion were examined. Results The median age was 67 years and median longest diameter of lesion was 5 cm. All patients were treated with wide surgical excision and 22 patients with clinically positive regional lymph nodes underwent therapeutic regional lymph node dissection. At the end of the study, 44.6% of patients developed distant metastasis and 39.3% of patients had died from disease. Univariate analysis showed that patients with one of the following poor prognostic factors: depth of invasion of lower dermis or deeper, presence of lymphovascular invasion and regional lymph node metastasis at diagnosis, had significantly shorter cancer-specific survival time. Multivariate analysis found that depth of invasion was the only independent prognostic factor. Conclusion The prognosis of invasive EMPD is significantly associated with depth of invasion, lymphovascular invasion and regional lymph node status. More aggressive therapy and more rigorous follow-up should be recommended for patients with these poor prognostic factors.