Fast Detection of a BRCA2 Large Genomic Duplication by Next Generation Sequencing as a Single Procedure: A Case Report.

The aim of this study was to verify the reliability of a next generation sequencing (NGS)-based method as a strategy to detect all possible BRCA mutations, including large genomic rearrangements. Genomic DNA was obtained from a peripheral blood sample provided by a patient from Southern Italy with early onset breast cancer and a family history of diverse cancers. BRCA molecular analysis was performed by NGS, and sequence data were analyzed using two software packages. Comparative genomic hybridization (CGH) array was used as confirmatory method. A novel large duplication, involving exons 4–26, of BRCA2 was directly detected in the patient by NGS workflow including quantitative analysis of copy number variants. The duplication observed was also found by CGH array, thus confirming its extent. Large genomic rearrangements can affect the BRCA1/2 genes, and thus contribute to germline predisposition to familial breast and ovarian cancers. The frequency of these mutations could be underestimated because of technical limitations of several routinely used molecular analysis, while their evaluation should be included also in these molecular testing. The NGS-based strategy described herein is an effective procedure to screen for all kinds of BRCA mutations

Gli inibitori della Neprilisina nei pazienti affetti da Malattia Renale Cronica e Sindrome Cardio-Renale

I pazienti affetti da malattia renale cronica (CKD) presentano una maggiore incidenza di eventi cardiovascolari (acuti e cronici) che, a loro volta, comportano un rischio aumentato di progressione verso la malattia renale cronica terminale (end \u2013 stage renal disease \u2013 ESRD) L\u2019inibizione della neprilisina, oltre ad offrire un nuovo target terapeutico nei pazienti affetti da scompenso cardiaco, potrebbero rappresentare una strategia di potenziale miglioramento negli outcomes, sia cardio-vascolari che renali, dei pazienti affetti da CKD. L\u2019inibizione della neprilisina, favorendo una maggiore biodisponibilit\ue0 dei peptidi natriuretici atriali, determina un incremento della diuresi e della natriuresi, oltre ad esercitare un\u2019azione di inibizione del sistema renina \u2013 angiotensina \u2013 aldosterone (RAAS). L\u2019inibizione del RAAS, a sua volta, genera una serie di controregolazioni in grado di bilanciarne gli effetti sfavorevoli in corso di CKD e di insufficienza cardiaca (HF). L\u2019idea del blocco della neprilisina non \ue8 recentissima, ma i primi farmaci impiegati, essendo molecole di associazione con antagonisti dell\u2019angiotensina II (ARBs), risultavano gravati da un\u2019incidenza inammissibile di angioedema. Tra le molecole di ultima generazione in grado di esercitare un\u2019azione inibente specifica sul recettore della neprilisina e su quello dell\u2019angiotensina II, grazie alla associazione con il valsartan, vi \ue8 l\u2019LCZ696 (sacubitril/valsartan) che ha mostrato evidenti benefici sia nel trattamento dell\u2019ipertensione arteriosa che nell\u2019insufficienza cardiaca.Patients with chronic kidney disease (CKD) have a higher incidence of cardiovascular (acute and chronic) events, which in turn have an increased risk of progression to end-stage renal disease (ESRD) Inhibition of neprilysin, in addition to offering a new therapeutic target in patients with heart failure, could represent a potential improvement strategy in cardiovascular and renal outcome of patients with CKD. Inhibition of neprilysin by inhibiting the breakdown of natriuretic peptides, increases their bioavailability resulting in an increase in diuresis and sodium excretion and, in addition to exerting an inhibition of the renin-angiotensin-aldosterone (RAAS) system. Inhibition of RAAS, in turn, generates a series of counter-regulations that can balance the adverse effects present in CKD and heart failure (HF). The idea of blocking neprilysin is not very recent, but the first drugs used as inhibitors had an inadmissible incidence of angioedema. Among the latest generation molecules that can perform a specific inhibitory action on the neprilysin receptor and, at the same time, on the angiotensin II receptor thanks to the association with valsartan there is the LCZ696 (sacubitril / valsartan). This drug has shown promising benefits both in the treatment arterial hypertension and heart failure. It is hoped that equally positive effects may occur in CKD patients, particularly those with macroproteinuria

Gli inbitori della neprilisina nei pazienti affetti da malattia renale cronica sindrome cardio-renale

I pazienti affetti da malattia renale cronica (CKD) presentano una maggiore incidenza di eventi cardiovascolari (acuti e cronici) che, a loro volta, comportano un rischio aumentato di progressione verso la malattia renale cronica terminale (end \u2013 stage renal disease \u2013 ESRD) L\u2019inibizione della neprilisina, oltre ad offrire un nuovo target terapeutico nei pazienti affetti da scompenso cardiaco, potrebbero rappresentare una strategia di potenziale miglioramento negli outcomes, sia cardio-vascolari che renali, dei pazienti affetti da CKD. L\u2019inibizione della neprilisina, favorendo una maggiore biodisponibilit\ue0 dei peptidi natriuretici atriali, determina un incremento della diuresi e della natriuresi, oltre ad esercitare un\u2019azione di inibizione del sistema renina \u2013 angiotensina \u2013 aldosterone (RAAS). L\u2019inibizione del RAAS, a sua volta, genera una serie di controregolazioni in grado di bilanciarne gli effetti sfavorevoli in corso di CKD e di insufficienza cardiaca (HF). L\u2019idea del blocco della neprilisina non \ue8 recentissima, ma i primi farmaci impiegati, essendo molecole di associazione con antagonisti dell\u2019angiotensina II (ARBs), risultavano gravati da un\u2019incidenza inammissibile di angioedema. Tra le molecole di ultima generazione in grado di esercitare un\u2019azione inibente specifica sul recettore della neprilisina e su quello dell\u2019angiotensina II, grazie alla associazione con il valsartan, vi \ue8 l\u2019LCZ696 (sacubitril/valsartan) che ha mostrato evidenti benefici sia nel trattamento dell\u2019ipertensione arteriosa che nell\u2019insufficienza cardiaca.

Hepatitis C Virus Infection Increases the Risk of Developing Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Background and Rationale: Chronic kidney disease and hepatitis C virus are prevalent in the general population worldwide, and controversy exists about the impact of HCV infection on the development and progression of kidney disease. Design: A systematic review of the published medical literature was made to assess whether positive anti-HCV serologic status plays an independent impact on the development of chronic kidney disease in the adult general population. We used a random-effects model to generate a summary estimate of the relative risk of chronic kidney disease (defined by reduced glomerular filtration rate or detectable proteinuria) with HCV across the published studies. Meta-regression and stratified analysis were also conducted. Results: Twenty-three studies (n\ua0=\ua02,842,421 patients) were eligible, and separate meta-analyses were performed according to the outcome. Pooling results of longitudinal studies (n\ua0=\ua09; 1,947,034 unique patients) demonstrated a relationship between positive HCV serologic status and increased incidence of chronic kidney disease, the summary estimate for adjusted hazard ratio was 1.43 (95\ua0% confidence interval 1.23; 1.63, P\ua0=\ua00.0001), and between-studies heterogeneity was noted (P value by Q test <0.0001). The risk of the incidence of chronic kidney disease associated with HCV, in the subset of Asian surveys, was 1.31 (95\ua0% confidence interval 1.16; 1.45) without heterogeneity (P value by Q test\ua0=\ua00.6). HCV positive serology was an independent risk factor for proteinuria; adjusted odds ratio, 1.508 (95\ua0% confidence intervals 1.19; 1.89, P\ua0=\ua00.0001) (n\ua0=\ua06 studies; 107,356 unique patients). Conclusions: HCV infection is associated with an increased risk of developing chronic kidney disease in the adult general population

Il ruolo della ricerca scientifica ambientale nella pianificazione energetica

La pianificazione energetica e i processi di Decision Making debbono inglobare le conoscenze scientifico ambientali per garantire uno sviluppo economico garantendo il rispetto dell'ambiente. Nel lavoro vengono presentate velocemente le principali metodologie di analisi termodinamiche usate nella modellistica ambientale insieme ad alcuni esempi di ricerca scientifica appositamente sviluppati per i decisori politic

Intragenic deletion in macrod2: A family with complex phenotypes including microcephaly, intellectual disability, polydactyly, renal and pancreatic malformations

Diagnosing a complex genetic syndrome and correctly assigning the concomitant phenotypic traits to a well-defined clinical form is often a medical challenge. In this work, we report the analysis of a family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly in the proband, with the aim of adding new aspects for obtaining a clear diagnosis. We performed array-comparative genomic hybridization and quantitative reverse transcriptase PCR (qRT-PCR) analyses. We identified a deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) in several members of the family. This gene is actually not associated with a specific syndrome but with congenital anomalies of multiple organs. qRT-PCR showed higher levels of a MACROD2 mRNA isoform in the individuals carrying the deletion. Our results, together with other data reported in the literature, support the hypothesis that the deletion in MACROD2 can affect correct embryonic development and that the presence of another associated event, such as epigenetic modifications at the MACROD2 locus, can influence the level of severity of the pathology