Multitarget CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach

Cystic fibrosis (CF) is a multiorgan disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria trigger acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients’ age, and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multitarget compounds able to “kill two birds with one stone” by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as CFTR correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multidimensional structure–activity relationship (SAR) study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor, and a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs

A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor

20siopenOverexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells' membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.openFallacara, Anna Lucia; Zamperini, Claudio; Podolski-Renić, Ana; Dinić, Jelena; Stanković, Tijana; Stepanović, Marija; Mancini, Arianna; Rango, Enrico; Iovenitti, Giulia; Molinari, Alessio; Bugli, Francesca; Sanguinetti, Maurizio; Torelli, Riccardo; Martini, Maurizio; Maccari, Laura; Valoti, Massimo; Dreassi, Elena; Botta, Maurizio; Pešić, Milica; Schenone, SilviaFallacara, Anna Lucia; Zamperini, Claudio; Podolski-Renić, Ana; Dinić, Jelena; Stanković, Tijana; Stepanović, Marija; Mancini, Arianna; Rango, Enrico; Iovenitti, Giulia; Molinari, Alessio; Bugli, Francesca; Sanguinetti, Maurizio; Torelli, Riccardo; Martini, Maurizio; Maccari, Laura; Valoti, Massimo; Dreassi, Elena; Botta, Maurizio; Pešić, Milica; Schenone, Silvi

The Salmonella enterica Pan-genome

Salmonella enterica is divided into four subspecies containing a large number of different serovars, several of which are important zoonotic pathogens and some show a high degree of host specificity or host preference. We compare 45 sequenced S. enterica genomes that are publicly available (22 complete and 23 draft genome sequences). Of these, 35 were found to be of sufficiently good quality to allow a detailed analysis, along with two Escherichia coli strains (K-12 substr. DH10B and the avian pathogenic E. coli (APEC O1) strain). All genomes were subjected to standardized gene finding, and the core and pan-genome of Salmonella were estimated to be around 2,800 and 10,000 gene families, respectively. The constructed pan-genomic dendrograms suggest that gene content is often, but not uniformly correlated to serotype. Any given Salmonella strain has a large stable core, whilst there is an abundance of accessory genes, including the Salmonella pathogenicity islands (SPIs), transposable elements, phages, and plasmid DNA. We visualize conservation in the genomes in relation to chromosomal location and DNA structural features and find that variation in gene content is localized in a selection of variable genomic regions or islands. These include the SPIs but also encompass phage insertion sites and transposable elements. The islands were typically well conserved in several, but not all, isolates—a difference which may have implications in, e.g., host specificity

La cittadinanza psicologica tra ostracismo e assimilazione: Le relazioni sociali del partner straniero di coppie miste

Nella riflessione politica \ue8 abituale considerare l\u2019evoluzione dei progetti di cittadinanza partendo dalla stagione dei diritti civili del Settecento, passando per la cittadinanza politica dell\u2019Ottocento e approdando a quella sociale del Novecento. Dove per \u201cprogetti di cittadinanza\u201d si indicano le modalit\ue0 con cui le autorit\ue0 politiche hanno pensato e attuato l\u2019idea di cittadino. Progetti che in passato hanno avuto un ruolo centrale nella costruzione degli stati nazione, mentre oggi \ue8 in crisi la concezione della cittadinanza nazionale. Infatti, i dibattiti sul multiculturalismo e sulla globalizzazione mettono in discussione la capacit\ue0 dei singoli stati di circoscrivere i cittadini in base al luogo di nascita (il suolo) e alla parentela/lignaggio/popolazione (il sangue). Ne consegue che anche le posizioni di chi vorrebbe nel nostro Paese controbilanciare la centralit\ue0 del \u201csangue\u201d \u2013 dominante in materia di cittadinanza \u2013 dando maggiore forza al fattore \u201csuolo\u201d (pensiamo alle discussioni sui diritti della \u201cseconda generazione\u201d di migranti), paiono attestate su argomentazioni gi\ue0 superate dalla morfologia umana delle societ\ue0 contemporanee. Questo dibattito tende inoltre a ignorare la \u201ccittadinanza psicologica\u201d: un senso soggettivo di attaccamento emozionale, identificazione e partecipazione relazionale con la comunit\ue0 ospitante e con le persone che la costituiscono. Se da una parte appare scontato che la dimensione psicologica venga rafforzata dalla presenza di quella legale-politica (sia essa fondata sul sangue o sul suolo), i due aspetti non sono necessariamente sovrapponibili. Questa \u201ccittadinanza dimenticata\u201d \ue8 analizzata nel presente capitolo a livello di comunit\ue0 attraverso i rapporti di coppia. Infatti, nel nostro Paese un alto numero di migranti accede alla cittadinanza contraendo matrimonio con partner italiani; per cui il matrimonio si configura come una via privilegiata per ottenere la cittadinanza. In ogni caso, a dispetto di questa paventata scorciatoia civica, sul piano psicosociale, per i migranti il matrimonio pu\uf2 costituire una sfida ardua, perch\ue9 i processi di adattamento e inclusione da affrontare sono carichi di difficolt\ue0: soggettive, familiari, amicali e comunitarie. Infatti, i rapporti umani possono presentare varie forme di ostracismo interpersonale: per esempio, il rifiuto della famiglia del partner autoctono; l\u2019esclusione dalle amicizie; l\u2019essere ignorati dai vicini. La ricerca qui presentata analizza quindi le modalit\ue0 relazionali di inclusione/esclusione nella comunit\ue0 di residenza delle coppie miste, dedicando attenzione alle strategie messe in atto per negoziare la cittadinanza psicologica

The Social Construction of \u201cIndebt\u201d Man: Economic Crisis, Discursive Violence and the Role of Mass Media in Italy

Debt and personal indebtedness have become a global problem as consumption-driven economies have spread across the world. These days, outstanding consumer debt is a normal feature of many economies and for a large number of people, the source of great mental distress. However, an understanding of personal debt requires an understanding of the complex social systems that produce poverty. This book frames credit use as a social phenomenon, and explores the dynamic interplays between consumers who need credit and credit granting institutions. By drawing upon a range of international perspectives, this book sheds much needed light on the social and psychological factors that contribute to the growth of personal debt and its associated impact on wellbeing. In so doing, the book contributes to an understanding of why more and more people are in debt, why it is causing so much harm to so many people and exactly who is benefiting from what has become the world's number one growth industry

La violenza collettiva e il G8 di Genova. Trauma psicopolitico e terapia sociale della testimonianza

Generalmente la violenza di Stato \ue8 associata a sistemi totalitari e a dittature che violano i diritti umani. Carente \ue8 invece la letteratura scientifica in merito alla violenza di Stato esercitata in societ\ue0 democratiche. Il presente articolo cerca di colmare questa lacuna, analizzando gli eventi del G8 di Genova del 20-22 luglio 2001, durante i quali, secondo osservatori internazionali, si \ue8 verificata la pi\uf9 grave sospensione dei diritti umani in un Paese occidentale dopo la seconda guerra mondiale. Criticando la diagnosi di disturbo post-traumatico da stress (PTSD), e articolando i concetti di delegittimazione sociale, trauma psicopolitico e terapia della testimonianza, viene proposta un\u2019analisi contestuale del trauma sub\uecto dalle vittime durante le violenze del G8 di Genova

Gender and state violence at the G8 in Genoa

Psychosocial studies generally connect state violence with undemocratic and totalitarian system that trample down human rights. In fact scientific literature is poor in the state violence practiced in democratic societies. If the international observers agreed that in Genoa there has been a heavy suspension of human rights during the G8 summit, it remains to be investigated how it has concretized itself and what kind of suffering has generated. By articulating the concepts of social delegitimization and psychopolitical trauma, in this article we analyze the collective violence suffered by female protesters

Relations technique-scientifique: Les cons\ue9quences de la violence collective du sommet du G8 \ue0 G\ueanes

Rapport technique-scientifique sur la torture dans la prison de Bolzaneto. L'analyse des formes de violence et les cons\ue9quences psychologiques