Treatment personalization in gastrointestinal neuroendocrine tumors

The clinical scenario of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is continuously changing due to significant improvements in the definition of their molecular landscapes and the introduction of innovative therapeutic approaches. Many efforts are currently employed in the integration of the genetics/epigenetics and clinical information. This is leading to an improvement of tumor classification, prognostic stratification and ameliorating the management of patients based on a personalized approach

The antigen CD300e drives T cell inflammation in adipose tissue and elicits an antibody response predictive of the insulin sensitivity recovery in obese patients

Obesity and insulin resistance (IR), the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation. Bariatric surgery leads to a considerable reduction in the adipose tissue mass and systemic inflammation along with a reduction of IR, with a whole-body metabolic improvement. However, a sizable portion of people experience an IR relapse within few years of remission. Numerous studies have attempted to explore the best clinical predictors of the improvement of insulin sensitivity and the maintenance of glucose homeostasis after bariatric surgery, but no simple fasting blood test has been found to be effective in predicting the short and long-term beneficial effects on glycaemia. With the present study, we investigated T-cell and antibody responses against CD300e, an antigen highly expressed in the adipose tissue of patients with obesity before the bariatric surgery-induced weight loss. We found both in fat tissue and in peripheral blood anti-CD300e-specific T helper 1 responses. Moreover, we evidenced in the sera of individuals with obesity an antibody response towards CD300e and revealed the existence of a significant correlation between the level of antibodies before surgery and the maintenance of glucose control after the intervention

A Novel Loss of Function Melanocortin-4-Receptor Mutation (MC4R-F313Sfs*29) in Morbid Obesity

CONTEXT: Melanocortin receptor-4 (MC4R) gene mutations are associated with early-onset severe obesity and the identification of potential pathological variants is crucial for the clinical management of patients with obesity.OBJECTIVE: To explore whether and how a novel heterozygous MC4R variant (MC4R-F313Sfs*29), identified in a young boy (BMI 38.8kg/m 2) during a mutation analysis conducted in a cohort of patients with obesity, plays a determinant pathophysiological role in the obesity development.DESIGN SETTING AND PATIENTS: The genetic screening was carried out in a total of 209 unrelated patients with obesity (BMI ≥ 35 kg/m 2). Structural and functional characterization of the F313Sfs*29-mutated MC4R was performed using computational approaches and in vitro, using HEK293 cells transfected with genetically-encoded biosensors for cAMP and Ca 2+.RESULTS: The F313Sfs*29 was the only variant identified. In vitro experiments showed that HEK293 cells transfected with the mutated form of MC4R did not increase intracellular cAMP or Ca 2+ levels after the stimulation with a specific agonist in comparison with HEK293 cells transfected with the wild type form of MC4R (∆R/R0= -90%±8%; p<0,001). In silico modelling showed that the F313Sfs*29 mutation causes a major reorganization cytosolic domain of the MC4R, thus reducing the affinity of the putative GalphaS binding site.CONCLUSIONS: The newly discovered F313Sfs*29 variant of MC4R may be involved in the impairment of alpha-MSH-induced cAMP and Ca 2+ signaling, blunting intracellular G protein mediated signal transduction. This alteration might have led to the dysregulation of satiety signaling, resulting in hyperphagia and early onset of obesity

Exercise training induces mitochondrial biogenesis and glucose uptake in subcutaneous adipose tissue through eNOS-dependent mechanisms.

Insulin resistance and obesity are associated with a reduction of mitochondrial content in various tissues of mammals. Moreover, a reduced nitric oxide (NO) bioavailability impairs several cellular functions, including mitochondrial biogenesis and insulin-stimulated glucose uptake, two important mechanisms of body adaptation in response to physical exercise. Although these mechanisms have been thoroughly investigated in skeletal muscle and heart, few studies have focused on the effects of exercise on mitochondria and glucose metabolism in adipose tissue. In this study, we compared the in vivo effects of chronic exercise in subcutaneous adipose tissue of wild-type (WT) and endothelial NO synthase (eNOS) knockout (eNOS(-/-)) mice after a swim training period. We then investigated the in vitro effects of NO on mouse 3T3-L1 and human subcutaneous adipose tissue-derived adipocytes after a chronic treatment with an NO donor: diethylenetriamine-NO (DETA-NO). We observed that swim training increases mitochondrial biogenesis, mitochondrial DNA content, and glucose uptake in subcutaneous adipose tissue of WT but not eNOS(-/-) mice. Furthermore, we observed that DETA-NO promotes mitochondrial biogenesis and elongation, glucose uptake, and GLUT4 translocation in cultured murine and human adipocytes. These results point to the crucial role of the eNOS-derived NO in the metabolic adaptation of subcutaneous adipose tissue to exercise training

Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism.

Endurance exercise training increases cardiac energy metabolism through poorly understood mechanisms. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) in cardiomyocytes contributes to cardiac adaptation. Here we demonstrate that the NO donor diethylenetriamine-NO (DETA-NO) activated mitochondrial biogenesis and function, as assessed by upregulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (Tfam) expression, and by increased mitochondrial DNA content and citrate synthase activity in primary mouse cardiomyocytes. DETA-NO also induced mitochondrial biogenesis and function and enhanced both basal and insulin-stimulated glucose uptake in HL-1 cardiomyocytes. The DETA-NO-mediated effects were suppressed by either PGC-1α or Tfam small-interference RNA in HL-1 cardiomyocytes. Wild-type and eNOS(-/-) mice were subjected to 6 wk graduated swim training. We found that eNOS expression, mitochondrial biogenesis, mitochondrial volume density and number, and both basal and insulin-stimulated glucose uptake were increased in left ventricles of swim-trained wild-type mice. On the contrary, the genetic deletion of eNOS prevented all these adaptive phenomena. Our findings demonstrate that exercise training promotes eNOS-dependent mitochondrial biogenesis in heart, which behaves as an essential step in cardiac glucose transport