GALNT2 mRNA levels are associated with serum triglycerides in humans

Atherogenic dyslipidemia, characterized by high triglycerides (TG) and low high density lipoprotein (HDL)-cholesterol levels, is a feature of patients with insulin resistance, obesity, and type 2 diabetes (T2D) [1] and plays a major role in shaping the risk of cardiovascular disease. Both TG and HDL-cholesterol serum concentrations are under the control of both environmental factors and up to 95 genetic loci, unraveled by a very large genome-wide association study (GWAs) in approximately 100,000 individuals [2]. Among these loci is GALNT2, which encode for ppGal-NAc-T2, involved in O-linked glycosylation. Similarly, studies in rodents have shown that liver GALNT2 expression modulates HDL-cholesterol concentrations [2]. Based on such studies, it is conceivable that GALNT2 expression changes play a role on TG and/or HDL-cholesterol levels. To gain further insights about this hypothesis, GALNT2 expression was measured in peripheral white blood cells (PWBC), from 224 individuals with a wide range of TG and HDL-cholesterol levels, as well as other metabolic parameters and clinical conditions

Suggestive evidence of a multi-cytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals

In cells and tissues resistin affects IL-1β, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMA IR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p < 0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p < 0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p < 0.001) and both associated with cardiovascular risk factors (all p < 0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI = 1.10-1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE

The PPARγ2 P12A polymorphism is not associated with all-cause mortality in patients with type 2 diabetes mellitus

The high mortality risk of patients with type 2 diabetes mellitus may well be explained by the several comorbidities and/or complications. Also the intrinsic genetic component predisposing to diabetes might have a role in shaping the risk of diabetes-related mortality. Among type 2 diabetes mellitus SNPs, rs1801282 is of particular interest because (i) it is harbored by peroxisome proliferator-activated receptor-γ2 (PPARγ2), which is the target for thiazolidinediones which are used as antidiabetic drugs, decreasing all-cause mortality in type 2 diabetes mellitus, and (ii) it is associated with insulin resistance and related traits, risk factors for overall mortality in type 2 diabetes mellitus. We investigated the role of PPARγ2 P12A, according to a dominant model (PA + AA vs. PP individuals) on incident all-cause mortality in three cohorts of type 2 diabetes mellitus, comprising a total of 1672 patients (462 deaths) and then performed a meta-analysis of ours and all available published data. In the three cohorts pooled and analyzed together, no association between PPARγ2 P12A and all-cause mortality was observed (HR 1.02, 95 % CI 0.79–1.33). Similar results were observed after adjusting for age, sex, smoking habits, and BMI (HR 1.09, 95 % CI 0.83–1.43). In a meta-analysis of ours and all studies previously published (n = 3241 individuals; 666 events), no association was observed between PPARγ2 P12A and all-cause mortality (HR 1.07, 95 % CI 0.85–1.33). Results from our individual samples as well as from our meta-analysis suggest that the PPARγ2 P12A does not significantly affect all-cause mortality in patients with type 2 diabetes mellitus

Lice (Haematopinus tuberculatus) in water buffalo farms from central Italy

The aim of the present study was to obtain information about the presence and distribution of the suckling louse Haematopinus tuberculatus in water buffalo farms in central Italy. The survey was carried out on 127 farms (epidemiological units), selected using a grid approach within a Geographical Information System, followed by proportional allocation. In each farm 6 buffaloes were examined in order to detect the louse presence. Parasitological examinations were performed on each buffalo at predilection sites. A total of 762 water buffaloes were examined. H. tuberculatus was found in the 11.0% (14/127) of the farms and in the 4.5% (34/762) of the animals. The presence H. tuberculatus should be routinely considered because it is a cause of serious health, production and economic damages in intensive breeding buffaloes

Cheetah:a computational toolkit for cybergenetic control

Abstract Advances in microscopy, microfluidics, and optogenetics enable single-cell monitoring and environmental regulation and offer the means to control cellular phenotypes. The development of such systems is challenging and often results in bespoke setups that hinder reproducibility. To address this, we introduce Cheetah, a flexible computational toolkit that simplifies the integration of real-time microscopy analysis with algorithms for cellular control. Central to the platform is an image segmentation system based on the versatile U-Net convolutional neural network. This is supplemented with functionality to robustly count, characterize, and control cells over time. We demonstrate Cheetah’s core capabilities by analyzing long-term bacterial and mammalian cell growth and by dynamically controlling protein expression in mammalian cells. In all cases, Cheetah’s segmentation accuracy exceeds that of a commonly used thresholding-based method, allowing for more accurate control signals to be generated. Availability of this easy-to-use platform will make control engineering techniques more accessible and offer new ways to probe and manipulate living cells

Serum Resistin, Cardiovascular Disease and All-Cause Mortality in Patients with Type 2 Diabetes

Background: High serum resistin has been associated with increased risk of cardiovascular disease in the general population, Only sparse and conflicting results, limited to Asian individuals, have been reported, so far, in type 2 diabetes. We studied the role of serum resistin on coronary artery disease, major cardiovascular events and all-cause mortality in type 2 diabetes. Methods: We tested the association of circulating resistin concentrations with coronary artery disease, major cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and all-cause mortality in 2,313 diabetic patients of European ancestry from two cross-sectional and two prospective studies. In addition, the expression of resistin gene (RETN) was measured in blood cells of 68 diabetic patients and correlated with their serum resistin levels. Results: In a model comprising age, sex, smoking habits, BMI, HbA1c, and insulin, antihypertensive and antidyslipidemic therapies, serum resistin was associated with coronary artery disease in both cross-sectional studies: OR (95%CI) per SD increment = 1.35 (1.10–1.64) and 1.99 (1.55–2.55). Additionally, serum resistin predicted incident major cardiovascular events (HR per SD increment = 1.31; 1.10–1.56) and all-cause mortality (HR per SD increment = 1.16; 1.06–1.26). Adjusting also for fibrinogen levels affected the association with coronary artery disease and incident cardiovascular events, but not that with all cause-mortality. Finally, serum resistin was positively correlated with RETN mRNA expression (rho = 0.343). Conclusions: This is the first study showing that high serum resistin (a likely consequence, at least partly, of increased RETN expression) is a risk factor for cardiovascular disease and all-cause mortality in diabetic patients of European ancestry

Accelerated hypofractionated radiotherapy as adjuvant regimen after conserving surgery for early breast cancer: interim report of toxicity after a minimum follow up of 3 years

<p>Abstract</p> <p>Background</p> <p>Accelerated hypofractionation is an attractive approach for adjuvant whole breast radiotherapy. In this study we evaluated the adverse effects at least 3 years post an accelerated hypofractionated whole breast radiotherapy schedule.</p> <p>Methods</p> <p>From October 2004 to March 2006, 39 consecutive patients aged over 18 years with pTis, pT1-2, pN0-1 breast adenocarcinoma who underwent conservative surgery were treated with an adjuvant accelerated hypofractionated radiotherapy schedule consisting of 34 Gy in 10 daily fractions over 2 weeks to the whole breast, followed after 1 week by an electron boost dose of 8 Gy in a single fraction to the tumour bed. Skin and lung radiation toxicity was evaluated daily during therapy, once a week for one month after radiotherapy completion, every 3 months for the first year and from then on every six months. In particular lung toxicity was investigated in terms of CT density evaluation, pulmonary functional tests, and clinical and radiological scoring. Paired t-test, Chi-square test and non-parametric Wilcoxon test were performed.</p> <p>Results</p> <p>After a median follow-up of 43 months (range 36-52 months), all the patients are alive and disease-free. None of the patients showed any clinical signs of lung toxicity, no CT-lung toxicity was denoted by radiologist on CT lung images acquired about 1 year post-radiotherapy, no variation of pulmonary density evaluated in terms of normalised Hounsfield numbers was evident. Barely palpable increased density of the treated breast was noted in 9 out of 39 patients (in 2 patients this toxicity was limited to the boost area) and teleangectasia (<1/cm²) limited to the boost area was evident in 2 out of 39 patients. The compliance with the treatment was excellent (100%).</p> <p>Conclusion</p> <p>The radiotherapy schedule investigated in this study (i.e 34 Gy in 3.4 Gy/fr plus boost dose of 8 Gy in single fraction) is a feasible and safe treatment and does not lead to adjunctive acute and late toxicities. A longer follow up is necessary to confirm these favourable results.</p

ENPP1 Affects Insulin Action and Secretion: Evidences from In Vitro Studies

The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities

Role of GALNT2 on Insulin Sensitivity, Lipid Metabolism and Fat Homeostasis

O-linked glycosylation, the greatest form of post-translational modifications, plays a key role in regulating the majority of physiological processes. It is, therefore, not surprising that abnormal O-linked glycosylation has been related to several human diseases. Recently, GALNT2, which encodes the GalNAc-transferase 2 involved in the first step of O-linked glycosylation, has attracted great attention as a possible player in many highly prevalent human metabolic diseases, including atherogenic dyslipidemia, type 2 diabetes and obesity, all clustered on the common ground of insulin resistance. Data available both in human and animal models point to GALNT2 as a molecule that shapes the risk of the aforementioned abnormalities affecting diverse protein functions, which eventually cause clinically distinct phenotypes (a typical example of pleiotropism). Pathways linking GALNT2 to dyslipidemia and insulin resistance have been partly identified, while those for type 2 diabetes and obesity are yet to be understood. Here, we will provide a brief overview on the present knowledge on GALNT2 function and dysfunction and propose novel insights on the complex pathogenesis of the aforementioned metabolic diseases, which all impose a heavy burden for patients, their families and the entire society