Downregulated calmodulin expression contributes to endothelial cell impairment in diabetes.

Endothelial dysfunction, a central hallmark of cardiovascular pathogenesis in diabetes mellitus, is characterized by impaired endothelial nitric oxide synthase (eNOS) and NO bioavailability. However, the underlying mechanisms remain unclear. Here in this study, we aimed to identify the role of calmodulin (CaM) in diabetic eNOS dysfunction. Human umbilical vein endothelial cells and murine endothelial progenitor cells (EPCs) treated with high glucose (HG) exhibited downregulated CaM mRNA/protein and vascular endothelial growth factor (VEGF) expression with impeded eNOS phosphorylation and cell migration/tube formation. These perturbations were reduplicated in CALM1-knockdown cells but prevented in CALM1-overexpressing cells. EPCs from type 2 diabetes animals behaved similarly to HG-treated normal EPCs, which could be rescued by CALM1-gene transduction. Consistently, diabetic animals displayed impaired eNOS phosphorylation, endothelium-dependent dilation, and CaM expression in the aorta, as well as deficient physical interaction of CaM and eNOS in the gastrocnemius. Local CALM1 gene delivery into a diabetic mouse ischemic hindlimb improved the blunted limb blood perfusion and gastrocnemius angiogenesis, and foot injuries. Diabetic patients showed insufficient foot microvascular autoregulation, eNOS phosphorylation, and NO production with downregulated CaM expression in the arterial endothelium, and abnormal CALM1 transcription in genome-wide sequencing analysis. Therefore, our findings demonstrated that downregulated CaM expression is responsible for endothelium dysfunction and angiogenesis impairment in diabetes, and provided a novel mechanism and target to protect against diabetic endothelial injury.

A real-world study of socioeconomic factors with survival in adults aged 18-64 years with renal cell carcinoma.

Aim: To evaluate the impact of socioeconomic factors (SEFs) on survival of renal cell carcinoma (RCC) patients. Materials & methods: RCC patients diagnosed between 2007 and 2015 were collected from the SEER database. The crude and multivariate Cox regression analysis was used to identify the independent prognostic factors and quantity the mortality risks for overall survival (OS). Results: Three SEFs including marital status, insurance status and median household income were identified as prognostic factors for OS. SEF-stage was built based on the three SEFs. Moreover, the SEF-stage 1 had superior OS than SEF-stage 2 within the respective American Joint Committee on Cancer stages. Conclusion: The SEF-stage was an independently prognostic factor for OS in RCC. Incorporation of SEF-stage into the American Joint Committee on Cancer staging system might be beneficial for better survival prediction and clinical management. However, further studies were needed to validate these findings in other populations.

Marital status and survival in patients with soft tissue sarcoma: A population-based, propensity-matched study.

BACKGROUND: Marital status serves as an independent prognostic factor for survival in a variety of cancers. However, its prognostic impact on soft tissue sarcoma (STS) has not yet been established. OBJECTIVE: To investigate the impact of marital status on survival outcomes among STS patients. METHODS: A total of 18 013 STS patients diagnosed between 2004 and 2015 were extracted from Surveillance, Epidemiology, and End Results (SEER) database. The marital status was classified into married, divorced, widowed, and single. Kaplan-Meier analysis and multivariate Cox proportional hazards regression analysis were conducted to establish the impact of marital status on the overall survival (OS) and cancer-specific survival (CSS). Subgroup analyses were conducted based on age, SEER historic stage and surgery condition. Propensity score matching (PSM) was used to perform a 1:1 matched-pair analysis to minimize the group differences caused by covariates. RESULTS: Married patients enjoyed better 5-year overall survival (OS) and 5-year cancer-specific survival (CSS), compared with patients who were divorced, widowed, and single, respectively. Multivariate Cox proportional hazards regression analysis revealed that marital status was an independent prognostic and protective factor for survival among STS patients, and unmarried status was associated with higher mortality hazards for both OS and CSS. Additionally, widowed individuals had the highest risks of overall and cancer-specific mortality compared to other unmarried groups. In the subgroup analyses, similar associations were also found. Furthermore, marital status still remained an independent prognostic and protective factor for both OS and CSS even in 1:1 matched-pair analysis. CONCLUSIONS: Marital status was an independent prognostic and protective factor for survival for STS patients. Widowed patients suffered the highest death risks among the unmarried groups.