-Dual nucleoside therapy for HIV infection: analysis of results and factors influencing viral response and long term efficacy.

We performed a retrospective analysis of our experience with dual nucleoside regimens to look for predictors of long term benefit. We evaluated a cohort of 68 HIV-infected patients treated at 3 Italian hospital-based facilities. The results were analysed using univariate and multivariate statistical analyses. Fourty-three males and 25 females were treated for 22 ± 14 months. Sixty three patients (92.6%) suffered no or low-grade side-effects. Thirty-four patients (50 %) reached a viral load 150/μl pre-treatment viremia 1,500/μl, and no previous exposure to NRTI. Total lymphocyte counts and CD4+ T-cells showed a significant correlation. Dual NRTI regimens may be still considered for patients unable to tolerate HAART regimens and presenting with favourable predictors of response

Reprogramming the assembly of unmodified DNA with a small molecule

The ability of DNA to store and encode information arises from base pairing of the four-letter nucleobase code to form a double helix. Expanding this DNA ‘alphabet’ by synthetic incorporation of new bases can introduce new functionalities and enable the formation of novel nucleic acid structures. However, reprogramming the self-assembly of existing nucleobases presents an alternative route to expand the structural space and functionality of nucleic acids. Here we report the discovery that a small molecule, cyanuric acid, with three thymine-like faces reprogrammes the assembly of unmodified poly(adenine) (poly(A)) into stable, long and abundant fibres with a unique internal structure. Poly(A) DNA, RNA and peptide nucleic acid all form these assemblies. Our studies are consistent with the association of adenine and cyanuric acid units into a hexameric rosette, which brings together poly(A) triplexes with a subsequent cooperative polymerization. Fundamentally, this study shows that small hydrogen-bonding molecules can be used to induce the assembly of nucleic acids in water, which leads to new structures from inexpensive and readily available materials

May some HCV genotype 1 patients still benefit from dual therapy? The role of very early HCV kinetics

When treating HCV patients with conventional dual therapy in the current context of rapidly evolving HCV therapy, outcome prediction is crucial and HCV kinetics, as early as 48 hours after the start of treatment, may play a major role. We aimed at clarifying the role of HCV very early kinetics. We consecutively enrolled mono-infected HCV patients at 7 treatment sites in Central Italy and evaluated the predictive value of logarithmic decay of HCV RNA 48 hours after the start of dual therapy (Delta48). Among the 171 enrolled patients, 144 were evaluable for early and sustained virological response (EVR, SVR) prediction; 108 (75.0%) reached EVR and 84 (58.3%) reached SVR. Mean Delta48 was 1.68±1.22 log10 IU/ml, being higher in patients with SVR and EVR. Those genotype-1 patients experiencing a Delta48 >2 logs showed a very high chance of success (100% positive predictive value), even in the absence of rapid virological response (RVR). Evaluation of very early HCV kinetics helped identify a small but significant proportion of genotype-1 patients (close to 10%) in addition to those identified with RVR, who could be treated with dual therapy in spite of not reaching RVR. In the current European context, whereby sustainability of HCV therapy is a crucial issue, conventional dual therapy may still play a reasonable role in patients with good tolerance and early prediction of success

High seroprevalence of HCV in the Abruzzo Region, Italy: results on a large sample from opt-out pre-surgical screening

Available estimates of the prevalence of chronic HCV infection in Italy are quite conflicting, varying from 1.5 to 22.5%, with an apparent north to south gradient. As Direct Acting Antivirals are expensive, both National and local governmental Agencies are in urgent need of detailed and reliable estimates of HCV patients to be treated, nationwide and in each district. We investigated the prevalence of anti-HCV antibodies in a large unselected sample of surgical patients providing consent to in-hospital opt-out pre-surgical HCV screening, at two hospitals from the Abruzzo Region, Italy

TAF5L and TAF6L Maintain Self-Renewal of Embryonic Stem Cells via the MYC Regulatory Network

Self-renewal and pluripotency of the embryonic stem cell (ESC) state are established and maintained by multiple regulatory networks that comprise transcription factors and epigenetic regulators. While much has been learned regarding transcription factors, the function of epigenetic regulators in these networks is less well defined. We conducted a CRISPR-Cas9-mediated loss-of-function genetic screen that identified two epigenetic regulators, TAF5L and TAF6L, components or co-activators of the GNAT-HAT complexes for the mouse ESC (mESC) state. Detailed molecular studies demonstrate that TAF5L/TAF6L transcriptionally activate c-Myc and Oct4 and their corresponding MYC and CORE regulatory networks. Besides, TAF5L/TAF6L predominantly regulate their target genes through H3K9ac deposition and c-MYC recruitment that eventually activate the MYC regulatory network for self-renewal of mESCs. Thus, our findings uncover a role of TAF5L/TAF6L in directing the MYC regulatory network that orchestrates gene expression programs to control self-renewal for the maintenance of mESC state.Davide Seruggia, Martin Oti, Pratibha Tripathi, Matthew C. Canver, Lucy LeBlanc, Dafne C. Di Giammartino, Michael J. Bullen, Christian M. Nefzger, Yu Bo Yang Sun, Rick Farouni, Jose M. Polo, Luca Pinello, Effie Apostolou, Jonghwan Kim, Stuart H. Orkin, and Partha Pratim Da