Background AKI is often iatrogenic and potentially preventable. Reduced renal NAD+ is reported to increase the susceptibility of AKI. The present study explored the predictive value of urinary de novo NAD+ synthetic metabolites for AKI using two independent cohorts. Methods The expression of de novo NAD+ synthetic enzymes in human kidney was examined by immunohistochemistry and single-cell transcriptomes. Urine samples were collected from two independent cohorts: methotrexate cohort with high-dose methotrexate treatment for lymphoma (n = 189) and liver transplantation cohort with orthotopic liver transplantation (n = 49). Urinary metabolomics study of NAD+ de novo synthesis was performed by LC-MS, screening for AKI predictive biomarkers. Nephroseq database and immunohistochemistry were used to analyze kidney de novo NAD+ synthetic enzymes expression in AKI susceptible condition. Results Human proximal tubule was the main structure in the kidney that expressed necessary enzymes for NAD+ de novo synthesis. In methotrexate cohort, urinary quinolinic acid (QA)/3-hydroxyanthranilic acid (3-OH AA) ratio before chemotherapy was significantly lower in those who developed AKI after chemotherapy compared with those who did not. This finding was consistent in liver transplantation cohort. The AUC of urinary QA/3-OH AA for AKI prediction was 0.749 and 0.729 in two cohorts respectively. HAAO, the enzyme catalyzing QA synthesis from 3-OH AA, decreased in AKI-susceptible diabetic kidneys. Conclusions The human proximal tubules were important source of NAD+ from the de novo pathway. Reduced urinary QA/3-OH AA ratio, which possibly suggested decreased HAAO activity, could be a potential AKI predictive biomarker.

Background: Androgen deprivation therapy (ADT) use in prostate cancer (PCa) has seen a rising trend. We investigated the relationship between ADT and adverse changes in metabolic parameters in an Asian population.Methods: This is an international prospective multicenter single-arm cohort yielded from the real-life experience of ADT in Asia (READT) registry. Consecutive ADTnaïve patients diagnosed of PCa and started on ADT were prospectively recruited from 2016 and analyzed. Baseline patient characteristics, PCa disease status, and metabolic parameters were documented. Patients were followed up at 6-month interval for up to 5 years. Metabolic parameters including body weight, lipid profiles, and glycemic profiles were recorded and analyzed.Results: 589 patients were eligible for analysis. ADT was associated with adverse glycemic profiles, being notable at 6 months upon ADT initiation and persisted beyond 1 year. Comparing to baseline, fasting glucose level and hemoglobin A1c level increased by 4.8% (p < 0.001) and 2.7% (p < 0.001), respectively. Triglycerides level was also elevated by 16.1% at 6th month and by 20.6% at 12th month compared to baseline (p < 0.001). Mean body weight was 1.09 kg above baseline at 18th month (p < 0.001). Conclusion:ADT was associated with adverse metabolic parameters in terms of glycemic profiles, lipid profiles, and body weight in the Asian population. These changes developed early in the treatment and can persist beyond the first year.

Context IDH1 is a pheochromocytoma/paraganglioma (PPGL) susceptibility gene, though its role, especially in the Chinese population, has not been characterized. Objective To determine the prevalence of somatic IDH1 hotspot variants in a large cohort of Chinese patients with PPGLs and to summarize associated phenotypes. Design Retrospective cross-sectional study. Setting Multiple tertiary-care centers in China. Participants This study was based on a main cohort of 1141 patients with PPGLs from two centers. We included 50 cases with urinary bladder paragangliomas (UBPGLs), from which 29 were part of the main cohort and 21 from other centers. Two additional cases with IDH1 hotspot variants not part of the main cohort were also included for summarizing IDH1-associated phenotypes. Main Outcome Measures Tumor DNA was sequenced by next generation sequencing analyzing a customized panel of genes. Results The overall prevalence of IDH1 hotspot variants in the main cohort was 0.5% (6/1141). Among those PPGLs without mutations in 15 common driver genes, the prevalence of IDH1 variants was 0.9% (4/455). When restricted to PGLs without mutations, the prevalence reached 4.7% (4/86). Among UBPGLs, IDH1 hotspot variants accounted for 8% (4/50). Together, all ten patients (9 PGLs and 1 PCC) with IDH1 hotspot variants, including three females with concurrent EPAS1 hotspot variants, had apparently sporadic tumors, without metastasis or recurrence. There were three patients with biochemical data, all showing a non-adrenergic phenotype. Conclusions The somatic IDH1 hotspot variants causes PPGL development in some Chinese patients, especially among those apparently sporadic PGLs with a non-adrenergic phenotype and without mutations in major PPGL driver genes.

Background Risk factors of visceral metastases in prostate cancer (PCa) patients are unclear. The aim of this study is to investigate the risk factors of developing visceral metastases at diagnosis and the impact of these risk factors on the survival of patients with visceral metastatic PCa. Methods Patients with visceral metastases at the time of diagnosis of [2010–2015] PCa were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Visceral metastatic distribution data were provided for liver, lung, and brain. The overall survival (OS) was calculated by the Kaplan-Meier method. Multivariable logistic and Cox regression models were performed to identify risk factors and analyze survival outcomes. Results A total of 13,092 eligible patients with stage IV PCa were identified from SEER database. A total of 598 patients developed visceral metastases at diagnosis among these patients. In multivariable analyses, patients with PSA >80 ng/mL had 1.545-fold higher risk of developing visceral metastases compared with those with PSA <20 ng/mL (P<0.001). The presence of bone metastasis and lymph node (LN) metastases were represented as risk factors of visceral metastases in stage IV PCa patients. Patients with two or three metastatic sites had 1.604-fold higher risk of shorter OS compared with those with one metastatic site (P<0.05). And patients with bone plus visceral metastases had 1.410-fold higher risk of shorter OS compared with those with visceral metastasis only (P<0.05). Age ≥70 had 1.621-fold higher risk of shorter OS compared with those with age <70 (P<0.05). T4 stage had 1.476-fold higher risk of shorter OS compared with those with T1 stage (P<0.05). Conclusions The incidence rate was increased among patients with visceral metastases in stage IV PCa at diagnosis. PSA over 80 ng/mL, the presence of bone metastasis and the presence of LN metastases were risk factors associated with a higher rate of development of visceral metastases in stage IV PCa patients. The presence of visceral plus bone metastases, two or three sites, age over 70, and T4 stage represent prognostic factors on survival outcomes in visceral metastatic PCa patients.

Background: Emerging evidence indicate that long noncoding RNA (lncRNA) plays an important biological role in clear cell renal cell carcinoma (ccRCC), however the clinical value of tumor mutation burden related lncRNA in ccRCC patients is unknown yet. Method: Somatic mutation profiles and lncRNA expression data of ccRCC was downloaded from TCGA database. We retrospectively analyzed lncRNA expression data and survival information from 116 patients with ccRCC between January 2013 to January 2014. Univariate and multivariate Cox regression analysis were performed to construct lncRNA signature, and the prognosis value was determined by Kaplan-Mayer and receiver operating characteristic curve (ROC) analysis. Results: Based on 160 differentially expressed TMB-related lncRNAs, two TMB-related molecular clusters with distinct immune checkpoints expression and immune cells infiltration were established for ccRCC patients. Moreover, a novel TMB-related lncRNA signature was constructed based on five lncRNAs for individualized prognosis assessment. High-risk group represents significantly worse overall survival in all cohorts. The area under ROC curve were 0.716, 0.775 and 0.744 in training cohort, testing cohort and TCGA cohort. Results of qRT-PCR successfully validated the expression levels of AP002360.3, LINC00460, AL590094.1, LINC00944 and LINC01843 in HK-2, 786-O, 769-P and ACHN cells. More importantly, the predictive performance of TMB-related lncRNA signature was successfully validated in an independent cohort of 116 ccRCC patients at our institution. Conclusion: This study successfully developed and validated a novel TMB-related lncRNA signature for individualized prognosis assessment of ccRCC patients.