C-peptide: a predictor of cardiovascular mortality in subjects with established atherosclerotic disease

Aim: Insulin resistance and type 2 diabetes are independent risk factors for cardiovascular diseases. Levels of C-peptide are increased in these patients and its role in the atherosclerosis progression was studied in vitro and in vivo over the past years. To evaluate the possible use of C-peptide as cardiovascular biomarkers, we designed an observational study in which we enrolled patients with mono- or poly-vascular atherosclerotic disease. Methods: We recruited 431 patients with stable atherosclerosis and performed a yearly follow-up to estimate the cardiovascular and total mortality and cardiovascular events. Results: We performed a mean follow-up of 56months on 268 patients. A multivariate Cox analysis showed that C-peptide significantly increased the risk of cardiovascular mortality [Hazard Ratio: 1.29 (95% confidence interval: 1.02-1.65, p<0.03513)] after adjustment for age, sex, diabetes treatment, estimated glomerular filtration rate and known diabetes status. Furthermore, levels of C-peptide were significantly correlated with metabolic parameters and atherogenic factors. Conclusion: C-peptide was associated with cardiovascular mortality independently of known diabetes status in a cohort of patients with chronic atherosclerotic disease. Future studies using C-peptide into a reclassification approach might be undertaken to consider its potential as a cardiovascular disease biomarker

Alterations in Rev-ERBα/BMAL1 ratio and glycated hemoglobin in rotating shift workers: the EuRhythDia study

Objective: To detect premature gluco-metabolic defects among night shift workers with disturbances in circadian rhythms. Design and methods: We performed a hypothesis-generating, cross-sectional analysis of anthropometric, metabolic, lipid, and inflammation parameters, comparing active (a-NSW, n = 111) and former (f-NSW, n = 98) rotating night shift workers with diurnal workers (controls, n = 69). All participants were hospital nurses. We also evaluated the Pittsburgh Sleep Quality Index (PSQI) and assessed expression of transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs), as indicators of the molecular clock. Results: Both a-NSW and f-NSW participants had significantly higher glycated hemoglobin (HbA1c) and white blood cell counts (WBC) (p &lt; 0.001 for both), PSQI global score (p = 0.001) and diastolic blood pressure levels (p = 0.024) compared with controls. Expression of REV-ERBα/BMAL1 RNA in PBMC was significantly higher in a-NSW (p = 0.05) than in f-NSW or control participants. Multivariate regression analysis showed that working status and PSQI were independent determinants of higher HbA1c levels (p &lt; 0.001). Conclusions: We demonstrated that young, healthy night shift workers show subclinical abnormalities in HbA1c and changes in peripheral clock gene expression

Autoantibodies against the glial glutamate transporter GLT1/EAAT2 in Type 1 diabetes mellitus-Clues to novel immunological and non-immunological therapies

: Islet cell surface autoantibodies were previously found in subjects with type 1 diabetes mellitus (T1DM), but their target antigens and pathogenic mechanisms remain elusive. The glutamate transporter solute carrier family 1, member 2 (GLT1/EAAT2) is expressed on the membrane of pancreatic β-cells and physiologically controls extracellular glutamate concentrations thus preventing glutamate-induced β-cell death. We hypothesized that GLT1 could be an immunological target in T1DM and that autoantibodies against GLT1 could be pathogenic. Immunoprecipitation and ELISA experiments showed that sera from T1DM subjects recognized GLT1 expressed in brain, pancreatic islets, and GLT1-transfected COS7-cell extracts. We validated these findings in two cohorts of T1DM patients by quantitative immunofluorescence assays. Analysis of the combined data sets indicated the presence of autoantibodies against GLT1 in 32 of the 87 (37%) T1DM subjects and in none of healthy controls (n&nbsp;=&nbsp;64) (p&nbsp;&lt;&nbsp;0.0001). Exposure of pancreatic βTC3 cells and human islets to purified IgGs from anti-GLT1 positive sera supplemented with complement resulted in plasma membrane ruffling, cell lysis and death. The cytotoxic effect was prevented when sera were depleted from IgGs. Furthermore, in the absence of complement, 6 out of 16 (37%) anti-GLT1 positive sera markedly reduced GLT1 transport activity in βTC3 cells by inducing GLT1 internalization, also resulting in β-cell death. In conclusion, we provide evidence that GLT1 is a novel T1DM autoantigen and that anti-GLT1 autoantibodies cause β-cell death through complement-dependent and independent mechanisms. GLT1 seems an attractive novel therapeutic target for the prevention of β-cell death in individuals with diabetes and prediabetes

ITCH E3 ubiquitin ligase downregulation compromises hepatic degradation of branched-chain amino acids

Objective: Metabolic syndrome, obesity, and steatosis are characterized by a range of dysregulations including defects in ubiquitin ligase tagging proteins for degradation. The identification of novel hepatic genes associated with fatty liver disease and metabolic dysregulation may be relevant to unravelling new mechanisms involved in liver disease progression METHODS: Through integrative analysis of liver transcriptomic and metabolomic obtained from obese subjects with steatosis, we identified itchy E ubiquitin protein ligase (ITCH) as a gene downregulated in human hepatic tissue in relation to steatosis grade. Wild-type or ITCH knockout mouse models of non-alcoholic fatty liver disease (NAFLD) and obesity-related hepatocellular carcinoma were analyzed to dissect the causal role of ITCH in steatosis RESULTS: We show that ITCH regulation of branched-chain amino acids (BCAAs) degradation enzymes is impaired in obese women with grade 3 compared with grade 0 steatosis, and that ITCH acts as a gatekeeper whose loss results in elevation of circulating BCAAs associated with hepatic steatosis. When ITCH expression was specifically restored in the liver of ITCH knockout mice, ACADSB mRNA and protein are restored, and BCAA levels are normalized both in liver and plasma CONCLUSIONS: Our data support a novel functional role for ITCH in the hepatic regulation of BCAA metabolism and suggest that targeting ITCH in a liver-specific manner might help delay the progression of metabolic hepatic diseases and insulin resistance

Systematic versus on-demand early palliative care: results from a multicentre, randomised clinical trial

Background Early palliative care (EPC) in oncology has been shown to have a positive impact on clinical outcome, quality-of-care outcomes, and costs. However, the optimal way for activating EPC has yet to be defined. Methods This prospective, multicentre, randomised study was conducted on 207 outpatients with metastatic or locally advanced inoperable pancreatic cancer. Patients were randomised to receive ‘standard cancer care plus on-demand EPC’ (n&nbsp;=&nbsp;100) or ‘standard cancer care plus systematic EPC’ (n&nbsp;=&nbsp;107). Primary outcome was change in quality of life (QoL) evaluated through the Functional Assessment of Cancer Therapy – Hepatobiliary questionnaire between baseline (T0) and after 12 weeks (T1), in particular the integration of physical, functional, and Hepatic Cancer Subscale (HCS) combined in the Trial Outcome Index (TOI). Patient mood, survival, relatives' satisfaction with care, and indicators of aggressiveness of care were also evaluated. Findings The mean changes in TOI score and HCS score between T0 and T1 were −4.47 and −0.63, with a difference between groups of 3.83 (95% confidence interval [CI] 0.10–7.57) (p&nbsp;=&nbsp;0.041), and −2.23 and 0.28 (difference between groups of 2.51, 95% CI 0.40–4.61, p&nbsp;=&nbsp;0.013), in favour of interventional group. QoL scores at T1 of TOI scale and HCS were 84.4 versus 78.1 (p&nbsp;=&nbsp;0.022) and 52.0 versus 48.2 (p&nbsp;=&nbsp;0.008), respectively, for interventional and standard arm. Until February 2016, 143 (76.9%) of the 186 evaluable patients had died. There was no difference in overall survival between treatment arms. Interpretations Systematic EPC in advanced pancreatic cancer patients significantly improved QoL with respect to on-demand EPC

High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status

Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biologic foundations. We previously showed that FHC-high patients experienced prolonged overall (OS) and progression-free survival (PFS) following PD-1/PD-L1 checkpoint inhibitors. To validate our findings in patients with NSCLC, we evaluated two multicenter cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab or chemotherapy. From each cohort, 607 patients were randomly case-control matched accounting for FHC, age, performance status, and disease burden. Compared to FHC-low/negative, FHC-high patients experienced longer OS (HR 0.67 [95% CI 0.46-0.95], p\u2009=\u20090.0281), PFS (HR 0.65 [95% CI 0.48-0.89]; p\u2009=\u20090.0074) and higher disease control rates (DCR, 86.4% vs 67.5%, p\u2009=\u20090.0096), within the pembrolizumab cohort. No significant associations were found between FHC and OS/PFS/DCR within the chemotherapy cohort. We explored the association between FHC and somatic DNA damage response (DDR) gene alterations as underlying mechanism to our findings in a parallel cohort of 118 NSCLC, 16.9% of whom were FHC-high. The prevalence of\u2009 65\u20091 somatic DDR gene mutation was 20% and 24.5% (p\u2009=\u20090.6684) in FHC-high vs. FHC-low/negative, with no differences in tumor mutational burden (6.0 vs. 7.6 Mut/Mb, p\u2009=\u20090.6018) and tumor cell PD-L1 expression. FHC-high status identifies NSCLC patients with improved outcomes from pembrolizumab but not chemotherapy, independent of somatic DDR gene status. Prospective studies evaluating FHC alongside germline genetic testing are warranted