Tumour necrosis as assessed with 18 F-FDG PET is a potential prognostic marker in diffuse large B cell lymphoma independent of MYC rearrangements

Objectives: MYC gene rearrangements in diffuse large B cell lymphomas (DLBCLs) result in high proliferation rates and are associated with a poor prognosis. Strong proliferation is associated with high metabolic demand and tumour necrosis. The aim of this study was to investigate differences in the presence of necrosis and semiquantitative 18 F-FDG PET metrics between DLBCL cases with or without a MYC rearrangement. The prognostic impact of necrosis and semiquantitative 18 F-FDG PET parameters was investigated in an explorative survival analysis. Methods: Fluorescence in situ hybridisation analysis for MYC rearrangements, visual assesment, semiquantitative analysis of 18 F-FDG PET scans and patient survival analysis were performed in 61 DLBCL patients, treated at a single referral hospital between 2008 and 2015. Results: Of 61 tumours, 21 (34%) had a MYC rearrangement (MYC + ). MYC status was neither associated with the presence of necrosis on 18 F-FDG PET scans (necrosis PET ; p = 1.0) nor associated with the investigated semiquantitative parameters maximum standard uptake value (SUV max ; p = 0.43), single highest SUV max (p = 0.49), metabolic active tumour volume (MATV; p = 0.68) or total lesion glycolysis (TLG; p = 0.62). A multivariate patient survival analysis of the entire cohort showed necrosis PET as an independent prognostic marker for disease-specific survival (DSS) (HR = 13.9; 95% CI 3.0–65; p = 0.001). Conclusions: MYC rearrangements in DLBCL have no influence on the visual parameter necrosis PET or the semi-quantiative parameters SUV max , MATV and TLG. Irrespective of MYC rearrangements, necrosis PET is an independent, adverse prognostic factor for DSS. Key Points: • Retrospective analysis indicates that MYC rearrangement is not associated with necrosis on 18 F-FDG PET (necrosis PET ) scans or semiquantitative 18 F-FDG PET parameters. • Necrosis PET is a potential independent adverse prognostic factor for disease-specific survival in patients with DLBCL and is not influenced by the presence of MYC rearrangements

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction: DEFINE-HF

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), yet underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between SGLT2i treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. Methods: Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction (DEFINE-HF) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry-based profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis (PCA)-defined metabolite clusters that changed differentially with treatment, and also examined the relationship between change in metabolite clusters with change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Models were adjusted for relevant clinical covariates, and nominal p\u3c0.05 with FDR-adjusted p-value\u3c0.10 were used to determine statistical significance. Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short/medium-chain acylcarnitine PCA metabolite clusters compared with placebo (nominal p=0.01, FDR-adjusted p-value=0.08 for both clusters). However, ketosis (Β-hydroxybutyrate levels \u3e 500 μM), was infrequently achieved (3 [2.5%] in dapagliflozin arm vs. 1 [0.9%] in placebo arm), and supraphysiologic levels were not observed. Conversely, increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in KCCQ scores (i.e. worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of SGLT2i in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with SGLT2i in patients with HFrEF. Reassuringly, only physiologic levels of ketosis were observed. Additionally, we identified several metabolic biomarkers associated with adverse HFrEF outcomes

Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 x 10(-10)), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.Peer reviewe

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus

BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.Peer reviewe

Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D

Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D