Helicobacter pylori and Epstein-Barr virus infection in gastric diseases: Correlation with IL-10 and IL1RN polymorphism.

Introduction: Helicobacter pylori and Epstein-Barr virus (EBV) infection have recently 23 been shown to be associated with gastric diseases. Polymorphisms in genes encoding 24 cytokines such as interleukin 10 (IL-10) and interleukin 1 Receptor (IL-1RN) influence 25 cytokine secretion levels and appear to contribute to the risk of developing gastroduodenal 26 diseases. 27 To our knowledge, this is the first preliminary study to address the association of 28 coinfection with H. pylori and EBV and their correlation with genetic predisposition in the 29 development of gastric diseases. 30 Methods: Gastric biopsy samples of 96 patients with different gastric diseases were used. 31 Results: Our results showed that the rate of co-infection was higher in patients with 32 gastric cancer than in patients with normal gastric mucosa, active chronic gastritis and 33 MALT lymphoma. As regards the characterization of H. pilory strains, the 34 polymorphism s1m1i1 of vacA gene was more frequent in patients with MALT 35 Lymphoma in comparison to others, while the polymorphism s2m2i2 was most 36 frequent in patients with normal gastric mucosa. In addition, patients who tested 37 positivefor the cagA gene were more frequently those affected with gastric cancer than 38 those with inactive chronic gastritis. Similarly, the patients with oipA gene ON were more 39 frequently those with gastric cancer than those with inactive chronic gastritis. 40 Conclusion: According to our analysis, there was no correlation between coinfection 41 and polymorphisms in genes encoding IL-10 and IL-1RN. We conclude that various 42 factors can be involved in the development of gastric diseases

Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype–phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges. Methods and results: We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype–phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants. Conclusions: Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context

Prediction and visualization data for the interpretation of sarcomeric and non-sarcomeric DNA variants found in patients with hypertrophic cardiomyopathy

AbstractGenomic technologies are redefining the understanding of genotype–phenotype relationships and over the past decade, many bioinformatics algorithms have been developed to predict functional consequences of single nucleotide variants. This article presents the data from a comprehensive computational workflow adopted to assess the biomedical impact of the DNA variants resulting from the experimental study “Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy” (Bottillo et al., 2016) [1]. Several different independently methods were employed to predict the functional consequences of alleles that result in amino acid substitutions, to study the effect of some DNA variants over the splicing process and to investigate the impact of a sequence variant with respect to the evolutionary conservation

Identification of a variant hotspot in "MYBPC3" and of a novel "CSRP3" autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy

INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands. OBJECTIVES This study aimed to assess the genetic background of HCM in a cohort of Polish patients. PATIENTS AND METHODS Twenty‑nine Polish patients were analyzed by a next‑generation sequencing panel including 404 cardiovascular genes. RESULTS Pathogenic variants were found in 41% of the patients, with ultra‑rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3. CONCLUSIONS This report expands the mutational spectrum and the inheritance pattern of HCM

Functional characterization of a novel truncating mutation in Lamin A/C gene in a family with a severe cardiomyopathy with conduction defects

Background/Aims: Truncating LMNA gene mutations occur in many inherited cardiomyopathy cases, but the molecular mechanisms involved in the disease they cause have not yet been systematically investigated. Here, we studied a novel frameshift LMNA variant (p.D243Gfs*4) identified in three members of an Italian family co-segregating with a severe form of cardiomyopathy with conduction defects. Methods: HEK293 cells and HL-1 cardiomyocytes were transiently transfected with either Lamin A or D243Gfs*4 tagged with GFP (or mCherry). D243Gfs*4 expression, cellular localization and its effects on diverse cellular mechanisms were evaluated with western blotting, laser-scanning confocal microscopy and video-imaging analysis in single cells. Results: When expressed in HEK293 cells, GFP- (or mCherry)-tagged LMNA D243Gfs*4 colocalized with calnexin within the ER. ER mislocalization of LMNA D243Gfs*4 did not significantly induce ER stress response, abnormal Ca2+ handling and apoptosis when compared with HEK293 cells expressing another truncated mutant of LMNA (R321X) which similarly accumulates within the ER. Of note, HEK293-LMNA D243Gfs*4 cells showed a significant reduction of connexin 43 (CX43) expression level, which was completely rescued by activation of the WNT/β-catenin signaling pathway. When expressed in HL-1 cardiomyocytes, D243Gfs*4 significantly impaired the spontaneous Ca2+ oscillations recorded in these cells as result of propagation of the depolarizing waves through the gap junctions between non-transfected cells surrounding a cell harboring the mutation. Furthermore, mCh-D243Gfs*4 HL-1 cardiomyocytes showed reduced CX43-dependent Lucifer Yellow (LY) loading and propagation. Of note, activation of β-catenin rescued both LY loading and LMNA D243Gfs*4 -HL-1 cells spontaneous activity propagation. Conclusion: Overall, the present results clearly indicate the involvement of the aberrant CX43 expression/activity as a pathogenic mechanism for the conduction defects associated to this LMNA truncating alteration

The Geriatric G8 Score Is Associated with Survival Outcomes in Older Patients with Advanced Prostate Cancer in the ADHERE Prospective Study of the Meet-URO Network

Introduction: Androgen receptor pathway inhibitors (ARPIs) have been increasingly offered to older patients with prostate cancer (PC). However, prognostic factors relevant to their outcome with ARPIs are still little investigated. Methods and Materials: The Meet-URO network ADHERE was a prospective multicentre observational cohort study evaluating and monitoring adherence to ARPIs metastatic castrate-resistant PC (mCRPC) patients aged ≥70. Cox regression univariable and multivariable analyses for radiographic progression-free (rPFS) and overall survival (OS) were performed. Unsupervised median values and literature-based thresholds where available were used as cut-offs for quantitative variables. Results: Overall, 234 patients were enrolled with a median age of 78 years (73–82); 86 were treated with abiraterone (ABI) and 148 with enzalutamide (ENZ). With a median follow-up of 15.4 months (mo.), the median rPFS was 26.0 mo. (95% CI, 22.8–29.3) and OS 48.8 mo. (95% CI, 36.8–60.8). At the MVA, independent prognostic factors for both worse rPFS and OS were Geriatric G8 assessment ≤ 14 (p < 0.001 and p = 0.004) and PSA decline ≥50% (p < 0.001 for both); time to castration resistance ≥ 31 mo. and setting of treatment (i.e., post-ABI/ENZ) for rPFS only (p < 0.001 and p = 0.01, respectively); age ≥78 years for OS only (p = 0.008). Conclusions: Baseline G8 screening is recommended for mCRPC patients aged ≥70 to optimise ARPIs in vulnerable individuals, including early introduction of palliative care

AGILE detection of extreme gamma-ray activity from the blazar PKS 1510-089 during March 2009. Multifrequency analysis

We report on the extreme gamma-ray activity from the FSRQ PKS 1510-089 observed by AGILE in March 2009. In the same period a radio-to-optical monitoring of the source was provided by the GASP-WEBT and REM. Moreover, several Swift ToO observations were triggered, adding important information on the source behaviour from optical/UV to hard X-rays. We paid particular attention to the calibration of the Swift/UVOT data to make it suitable to the blazars spectra. Simultaneous observations from radio to gamma rays allowed us to study in detail the correlation among the emission variability at different frequencies and to investigate the mechanisms at work. In the period 9-30 March 2009, AGILE detected an average gamma-ray flux of (311+/-21)x10^-8 ph cm^-2 s^-1 for E>100 MeV, and a peak level of (702+/-131)x10^-8 ph cm^-2 s^-1 on daily integration. The gamma-ray activity occurred during a period of increasing activity from near-IR to UV, with a flaring episode detected on 26-27 March 2009, suggesting that a single mechanism is responsible for the flux enhancement observed from near-IR to UV. By contrast, Swift/XRT observations seem to show no clear correlation of the X-ray fluxes with the optical and gamma-ray ones. However, the X-ray observations show a harder photon index (1.3-1.6) with respect to most FSRQs and a hint of harder-when-brighter behaviour, indicating the possible presence of a second emission component at soft X-ray energies. Moreover, the broad band spectrum from radio-to-UV confirmed the evidence of thermal features in the optical/UV spectrum of PKS 1510-089 also during high gamma-ray state. On the other hand, during 25-26 March 2009 a flat spectrum in the optical/UV energy band was observed, suggesting an important contribution of the synchrotron emission in this part of the spectrum during the brightest gamma-ray flare, therefore a significant shift of the synchrotron peak.Comment: 13 pages, 7 figures, 3 tables. Accepted for publication in Astronomy and Astrophysic

Multiwavelength observations of 3C 454.3. III. Eighteen months of AGILE monitoring of the "Crazy Diamond"

We report on 18 months of multiwavelength observations of the blazar 3C 454.3 (Crazy Diamond) carried out in July 2007-January 2009. We show the results of the AGILE campaigns which took place on May-June 2008, July-August 2008, and October 2008-January 2009. During the May 2008-January 2009 period, the source average flux was highly variable, from an average gamma-ray flux F(E>100MeV) > 200E-8 ph/cm2/s in May-June 2008, to F(E>100MeV)~80E-8 ph/cm2/s in October 2008-January 2009. The average gamma-ray spectrum between 100 MeV and 1 GeV can be fit by a simple power law (Gamma_GRID ~ 2.0 to 2.2). Only 3-sigma upper limits can be derived in the 20-60 keV energy band with Super-AGILE. During July-August 2007 and May-June 2008, RXTE measured a flux of F(3-20 keV)= 8.4E-11 erg/cm2/s, and F(3-20 keV)=4.5E-11 erg/cm2/s, respectively and a constant photon index Gamma_PCA=1.65. Swift/XRT observations were carried out during all AGILE campaigns, obtaining a F(2-10 keV)=(0.9-7.5)E-11 erg/cm2/s and a photon index Gamma_XRT=1.33-2.04. BAT measured an average flux of ~5 mCrab. GASP-WEBT monitored 3C 454.3 during the whole 2007-2008 period from the radio to the optical. A correlation analysis between the optical and the gamma-ray fluxes shows a time lag of tau=-0.4 days. An analysis of 15 GHz and 43 GHz VLBI core radio flux observations shows an increasing trend of the core radio flux, anti- correlated with the higher frequency data. The modeling SEDs, and the behavior of the long-term light curves in different energy bands, allow us to compare the jet properties during different emission states, and to study the geometrical properties of the jet on a time-span longer than one year.Comment: Accepted for publication in ApJ. Adapted Abstract. 17 pages, 19 Figures, 5 Table

INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors: a transversal challenge. The INVIDIa study

Aim: Considering the unmet need for the counseling of cancer patients treated with immune checkpoint inhibitors (CKI) about influenza vaccination, an explorative study was planned to assess flu vaccine efficacy in this population. Methods: INVIDIa was a retrospective, multicenter study, enrolling consecutive advanced cancer outpatients receiving CKI during the influenza season 2016-2017. Results: Of 300 patients, 79 received flu vaccine. The incidence of influenza syndrome was 24.1% among vaccinated, versus 11.8% of controls; odds ratio: 2.4; 95% CI: 1.23-4.59; p = 0.009. The clinical ineffectiveness of vaccine was more pronounced among elderly: 37.8% among vaccinated patients, versus 6.1% of unvaccinated, odds ratio: 9.28; 95% CI: 2.77-31.14; p < 0.0001. Conclusion: Although influenza vaccine may be clinically ineffective in advanced cancer patients receiving CKI, it seems not to negatively impact the efficacy of anticancer therapy

Heart valve calcification in patients with type 2 diabetes and nonalcoholic fatty liver disease

PurposeAortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are two powerful predictors of adverse cardiovascular outcomes in patients with type 2 diabetes, but the aetiology of valvular calcification is uncertain. Nonalcoholic fatty liver disease (NAFLD) is an emerging cardiovascular risk factor and is very common in type 2 diabetes, but whether NAFLD is associated with valvular calcification in this group of patients is presently unknown.MethodsWe undertook a cross-sectional study of 247 consecutive type 2 diabetic outpatients with no previous history of heart failure, valvular heart diseases (aortic stenosis, mitral stenosis, moderate or severe aortic and mitral regurgitation) or hepatic diseases. Presence of MAC and AVS was detected by echocardiography. NAFLD was diagnosed by ultrasonography.ResultsOverall, 139 (56.3%) patients had no heart valve calcification (HVC-0), 65 (26.3%) patients had one valve affected (HVC-1) and 43 (17.4%) patients had both valves affected (HVC-2). 175 (70.8%) patients had NAFLD and the prevalence of this disease markedly increased in patients with HVC-2 compared with either HVC-1 or HVC-0 (86.1% vs. 83.1% vs. 60.4%, respectively; p<0.001). NAFLD was significantly associated with AVS and/or MAC (unadjusted-odds ratio 3.51, 95%CI 1.89–6.51, p<0.001). Adjustments for age, sex, waist circumference, smoking, blood pressure, hemoglobin A1c, LDL-cholesterol, kidney function parameters, medication use and echocardiographic variables did not appreciably weaken this association (adjusted-odds ratio 2.70, 95%CI 1.23-7.38, p<0.01).ConclusionsOur results show that NAFLD is an independent predictor of cardiac calcification in both the aortic and mitral valves in patients with type 2 diabetes