ASSOCIAZIONE TRA SCORE GENETICO GRS E RISCHIO DI EPATOCARCINOMA IN PAZIENTI CON CIRROSI HCV TRATTATI CON FARMACI ANTIVIRALI DIRETTI

Background and aim: Several single nucleotide polymorphisms (SNPs) have been associated with hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) cirrhotics, however their role in patients cured by direct-acting antivirals (DAA) is still undefined. We assessed the association between a genetic risk score (GRS) based on the combination of 4 SNPs (PNPLA3 rs738409, MBOAT7 rs641738, TM6SF2 rs5842926 and GCKR rs1260326) and HCC in a cohort of DAA-treated patients. Methods: Consecutive HCV cirrhotics receiving DAA between December 2014-2016 in a single Center were genotyped for the 4 SNPs. Cirrhosis was defined histologically or non-invasively (Liver stiffness measurement [LSM] 6512 kPa). HCC was diagnosed and staged according to international recommendations. Results: 509 patients were analyzed: median age 64 (28-87) years, 58% males, LSM 19.4 (12.0-75.0) kPa, 87% Child-Pugh score A (CPT) A, 11% with previous HCC history. Genotypes distribution was as follows: PNPLA3 CC (46%), CG (41%) GG (13%); MBOAT7 CC (29%), CT (49%), TT (22%); TM6SF2 CC (91%), CT (8%), TT (1%); GCKR CC (26%), CT (48%), TT (26%). Median GRS score in the overall population was 0.3 (0-1.1). Patients\u2019 demography and clinical features were similar across SNPs genotypes. Following antiviral treatment, 491 (96%) patients achieved viral eradication. During a median follow-up of 43 (3-57) months from DAA start, HCC developed in 36/452 (8%) patients without a history of HCC (de novo HCC), 4-year estimated cumulative probability of HCC being 9% (95% CI 7-12%). Male sex (Hazard Ratio [HR] 2.54; 95% CI 1.15-5.63; p=0.02), diabetes (HR 2.39; 95% CI 1.20-4.74; p=0.01), albumin (HR 0.35; 95% CI 0.19-0.64; p=0.001) and GRS score >0.6 (HR 2.30; 95% CI 1.03-5.11; p=0.04) were independently associated with de novo HCC. Indeed, 4-year cumulative rates of de novo HCC resulted 6% (95% CI 1-10%) vs. 12% (95% CI 8-16%) in males vs. females (p=0.01); 17% (95% CI 9-24%) vs. 7% (95% CI 5-10%) in diabetic vs. non-diabetic (p=0.001); 21% (95% 10-34%) vs. 7% (95% CI 4-11%) in patients with albumin 64 or >3.5 g/dl (p<0.001) and 16% (95% CI 8-28%) vs. 7% (95% CI 5-11%) in patients with a GRS score > or 640.6 (p=0.01), respectively. Main tumor features did not significantly differ according to the 4 SNPs genotypes. By combining independent risk factors for HCC, 4-year cumulative incidence resulted 20% (95% CI 12-28%) vs. 5% (95% CI 3-7%) in patients with or without two different risk factors, respectively (p<0.0001). HCC developed in 28/57 (49%) patients with a previous HCC history, corresponding to a 4-year cumulative HCC recurrence of 49% (95% CI 27-63%). At multivariate analysis, only diabetes (HR 2.77, 95% CI 1.15-6.67; p=0.02) was independently associated with recurrent HCC, while GRS score was not significant. Indeed, 4-year cumulative incidence of HCC resulted 88% (95% CI 64-100%) vs. 40% (95% CI 25-55%) in diabetic vs. non-diabetic patients, respectively (p=0.002). Conclusions: In a large, single-center cohort of consecutive HCV patients with cirrhosis who received DAA treatment, a genetic risk score was independently associated with de novo HCC, together with clinical predictors (male sex, diabetes, albumin values). Combination of clinical and genetic predictors could allow a better HCC risk stratification in HCV cirrhotic patients after viral cure, in order to develop personalized HCC surveillance programs

High Susceptibility Of Activated Lymphocytes To Oxidative Stress-induced Cell Death.

The present study provides evidence that activated spleen lymphocytes from Walker 256 tumor bearing rats are more susceptible than controls to tert-butyl hydroperoxide (t-BOOH)-induced necrotic cell death in vitro. The iron chelator and antioxidant deferoxamine, the intracellular Ca2+ chelator BAPTA, the L-type Ca2+ channel antagonist nifedipine or the mitochondrial permeability transition inhibitor cyclosporin A, but not the calcineurin inhibitor FK-506, render control and activated lymphocytes equally resistant to the toxic effects of t-BOOH. Incubation of activated lymphocytes in the presence of t-BOOH resulted in a cyclosporin A-sensitive decrease in mitochondrial membrane potential. These results indicate that the higher cytosolic Ca2+ level in activated lymphocytes increases their susceptibility to oxidative stress-induced cell death in a mechanism involving the participation of mitochondrial permeability transition.80137-4

A relative entropy rate method for path space sensitivity analysis of stationary complex stochastic dynamics

We propose a new sensitivity analysis methodology for complex stochastic dynamics based on the Relative Entropy Rate. The method becomes computationally feasible at the stationary regime of the process and involves the calculation of suitable observables in path space for the Relative Entropy Rate and the corresponding Fisher Information Matrix. The stationary regime is crucial for stochastic dynamics and here allows us to address the sensitivity analysis of complex systems, including examples of processes with complex landscapes that exhibit metastability, non-reversible systems from a statistical mechanics perspective, and high-dimensional, spatially distributed models. All these systems exhibit, typically non-gaussian stationary probability distributions, while in the case of high-dimensionality, histograms are impossible to construct directly. Our proposed methods bypass these challenges relying on the direct Monte Carlo simulation of rigorously derived observables for the Relative Entropy Rate and Fisher Information in path space rather than on the stationary probability distribution itself. We demonstrate the capabilities of the proposed methodology by focusing here on two classes of problems: (a) Langevin particle systems with either reversible (gradient) or non-reversible (non-gradient) forcing, highlighting the ability of the method to carry out sensitivity analysis in non-equilibrium systems; and, (b) spatially extended Kinetic Monte Carlo models, showing that the method can handle high-dimensional problems

Lake surface temperature [in “State of the Climate in 2017”]

Observed lake surface water temperature anomalies in 2017 are placed in the context of the recent warming observed in global surface air temperature by collating long-term in situ lake surface temperature observations from some of the world’s best-studied lakes and a satellite-derived global lake surface water temperature dataset. The period 1996–2015, 20 years for which satellite-derived lake temperatures are available, is used as the base period for all lake temperature anomaly calculations

Challenges in treating patients with inflammatory bowel disease and concurrent viral hepatitis infection

Introduction: Inflammatory bowel diseases (IBD) require long-term administration of immunomodulatory treatments to maintain disease remission. Due to the high worldwide prevalence of hepatitis B (HBV) or C (HCV) virus infections, presence of concurrent hepatitis can be a relevant clinical issue to manage when treating IBD. Areas covered: The paper summarizes epidemiological data about IBD and HBV/HCV infection and reviews current knowledge about the natural history of HBV and HCV in the IBD setting, concentrating on risk of hepatitis reactivation during immunosuppressive treatment. Most updated recommendations for management of HBV and HCV infections in IBD patients are discussed. Expert commentary: The development of new drugs for IBD with different molecular targets and the availability of potent and efficacious antiviral drugs for HBV and HCV will simplify management of hepatitis infection in IBD patients in the near future

Limited utility of ITPA deficiency to predict early anemia in HCV patients with advanced fibrosis receiving telaprevir

Background: Severe anemia is a common side effect of Pegylated Interferon + Ribavirin (PR) and Telaprevir (TVR) in hepatitis C virus (HCV) genotype 1 patients with advanced fibrosis or cirrhosis (F3-F4). Inosine triphosphatase (ITPA) genetic variants are associated with RBV- induced anemia and dose reduction. Aim: To test the association of ITPA polymorphisms rs1127354 and rs7270101 with hemoglobin (Hb) decline, need for RBV dose reduction (RBV DR), erythropoietin (EPO) support and blood transfusions during the first 12 weeks of TVR triple therapy. Materials and Methods: 69 consecutive HCV-1 patients (mean age 57 years) with F3-F4 who received PR and TVR were genotyped for ITPA polymorphisms rs1127354 and rs7270101. Estimated ITPA deficiency was graded on severity (0-3, no deficiency/mild/moderate/severe). Results: ITPA deficiency was absent in 48 patients (70%), mild in 12 (17%) and moderate in 9 patients (13%). Mean week 4 Hb decline was higher in non ITPA deficient patients (3,85 g/dL) than in mildly or moderately ITPA deficient patients (3,07 g/dL and 1,67 g/dL, p<0.0001). Grade 3-4 anemia developed in 81% non ITPA deficient patients versus 67% mild deficient and 55% moderate deficient patients (p = ns). Grade of ITPA deficiency was not associated with RbvDR (no deficiency: 60%, mild: 58%, moderate: 67%; p = ns), EPO use (no deficiency: 65%, mild: 58%, moderate:56%; p = ns) or need for blood transfusion (no deficiency: 27%, mild: 17%, moderate: 33%; p = ns). Conclusions: In patients with F3-F4 chronic hepatitis C receiving TVR based therapy, ITPA genotype does not impact on the management of early anemia. \ua9 2014 Aghemo et al

Ancient DNA from domestic animal species remains : preliminary approaches

DNA analysis from ancient and old remains offers new tools to answer archaeozoological questions and investigate the origin of the genetic variability in domestic animal species. Molecular genetics techniques contribute to identify the species supporting classical osteological studies and to establish the relationship to modern species and breeds. Mitochondrial DNA (mtDNA) sequences are useful to reconstruct the history of maternal lineages comparing haplotype variations of present and old DNA samples. Mitochondrial data from modern cattle populations show a high diversity in Anatolia and in the Middle East supporting a near-Eastern matrilineal centre of origin. On the contrary in Europe a single family of mitochondrial haplotypes strongly dominates. A number of recent studies reported the successful recovery of ancient and old nuclear DNA (nuDNA) sequences. Such studies represent an important breakthrough, as nuDNA can be used for the characterisation of genetic loci directly involved in phenotypic traits, answering challenging questions. A bright example is offered by the study on the single nuclear exon of melanocortin type 1 receptor gene from a ca. 43,000 years old mammoth bone from Siberia, showing that mammoth populations were polymorphic with regard to hair colour, harbouring both dark and light haired animals. In contrast, these studies on ancient and old DNA sequences need great caution, due to the analytical problems caused by post-mortem damage of DNA, contamination from exogenous sources of mt- and nuDNA, and the consequent reliability of observed polymorphisms. The present research describes the preliminary analytical approach to DNA study of faunal remains (103 animal bones of different domestic species: Bos taurus 51; Ovis aries/Capra hircus 39; Sus scrofa/Sus domesticus 10; Gallus gallus 1; Equus caballus/Equus sp. 2), collected in seven archaeological sites located within the province of Trento, in the Alpine region of Trentino Alto-Adige (N-E Italy). The chosen sites, dating from the Bronze Age to the late Middle Ages, display different settlement typology and include Iron Age retic houses, votive Bronze Age contexts, a 4th century roman villa and several 13th century medieval buildings. Archaeozoological data will be collected on species, skeletal parts, age of slaughter, method of butchery, evidence of bone working and presence of paleopathologies. We describe the analytical procedure used in preparing and collecting samples and in extracting and analysing DNA from a subset of the bones previously described

From current status to optimization of HCV treatment: Recommendations from an expert panel

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper

Fyn Mediates Leptin Actions in the Thymus of Rodents

BACKGROUND:Several effects of leptin in the immune system rely on its capacity to modulate cytokine expression and apoptosis in the thymus. Surprisingly, some of these effects are dependent on signal transduction through the IRS1/PI3-kinase, but not on the activation of JAK2. Since all the well known effects of leptin in different cell types and tissues seem to be dependent on JAK2 activation, we hypothesized that, at least for the control of thymic function, another, unknown kinase could mediate the transduction of the leptin signal from the ObR towards the IRS1/PI3-kinase signaling cascade. METHODOLOGY/PRINCIPAL FINDINGS:Here, by employing immunoblot, real-time PCR and flow citometry we show that the tyrosine kinase, Fyn, is constitutively associated with the ObR in thymic cells. Following a leptin stimulus, Fyn undergoes an activating tyrosine phosphorylation and a transient association with IRS1. All these effects are independent of JAK2 activation and, upon Fyn inhibition, the signal transduction towards IRS1/PI3-kinase is abolished. In addition, the inhibition of Fyn significantly modifies the effects of leptin on thymic cytokine expression. CONCLUSION/SIGNIFICANCE:Therefore, in the thymus, Fyn acts as a tyrosine kinase that transduces the leptin signal independently of JAK2 activation, and mediates some of the immunomodulatory effects of leptin in this tissue

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes