Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

Background VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. Methods Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. Results 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1 x10(13) viral particles (vp)/patient (Part I), and 3.3x10(12) vp/patient (Part II). Fourteen patients were included in Part Ill: there were no DLTs and the RP2D was 1 x10(13) vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1x10(13) vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1 x10(13) vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon- r,soluble lymphocyte activation ne-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. Conclusions Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paditaxel plus gemcitabine to patients with pancreatic adenocarcinoma

Effects of Pin1 Loss in Hdh(Q111) Knock-in Mice

Huntington's disease (HD) is a fatal, dominantly inherited, neurodegenerative disorder due to a pathological expansion of the CAG repeat in the coding region of the HTT gene. In the quest for understanding the molecular basis of neurodegeneration, we have previously demonstrated that the prolyl isomerase Pin1 plays a crucial role in mediating p53-dependent apoptosis triggered by mutant huntingtin (mHtt) in vitro. To assess the effects of the lack of Pin1 in vivo, we have bred Pin1 knock-out mice with Hdh(Q111) knock-in mice, a genetically precise model of HD. We show that Pin1 genetic ablation modifies a portion of Hdh(Q111) phenotypes in a time-dependent fashion. As an early event, Pin1 activity reduces the DNA damage response (DDR). In midlife mice, by taking advantage of next-generation sequencing technology, we show that Pin1 activity modulates a portion of the alterations triggered by mHtt, extending the role of Pin1 to two additional Hdh(Q111) phenotypes: the unbalance in the "synthesis/concentration of hormones", as well as the alteration of "Wnt/\u3b2-catenin signaling". In aging animals, Pin1 significantly increases the number of mHtt-positive nuclear inclusions while it reduces gliosis. In summary, this work provides further support for a role of Pin1 in HD pathogenesis. \ua9 2016 Agostoni, Michelazzi, Maurutto, Carnemolla, Ciani, Vatta, Roncaglia, Zucchelli, Leanza, Mantovani, Gustincich, Santoro, Piazza, Del Sal and Persichetti

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

EuReCa ONE—27 Nations, ONE Europe, ONE Registry A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe

AbstractIntroductionThe aim of the EuReCa ONE study was to determine the incidence, process, and outcome for out of hospital cardiac arrest (OHCA) throughout Europe.MethodsThis was an international, prospective, multi-centre one-month study. Patients who suffered an OHCA during October 2014 who were attended and/or treated by an Emergency Medical Service (EMS) were eligible for inclusion in the study. Data were extracted from national, regional or local registries.ResultsData on 10,682 confirmed OHCAs from 248 regions in 27 countries, covering an estimated population of 174 million. In 7146 (66%) cases, CPR was started by a bystander or by the EMS. The incidence of CPR attempts ranged from 19.0 to 104.0 per 100,000 population per year. 1735 had ROSC on arrival at hospital (25.2%), Overall, 662/6414 (10.3%) in all cases with CPR attempted survived for at least 30 days or to hospital discharge.ConclusionThe results of EuReCa ONE highlight that OHCA is still a major public health problem accounting for a substantial number of deaths in Europe.EuReCa ONE very clearly demonstrates marked differences in the processes for data collection and reported outcomes following OHCA all over Europe. Using these data and analyses, different countries, regions, systems, and concepts can benchmark themselves and may learn from each other to further improve survival following one of our major health care events

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología

Physiologic responses of firefighter recruits during a supervised live-fire work performance test.

The aim of this research was to determine physiologic responses to typical activities of military Italian firefighters. Heart rate (HR), metabolic equivalent units (MET), skin temperature ( T.Sk.), and galvanic skin response (GSR) were measured in 13 firefighters (age = 36.3 +/- 6.9 yr; period of military fire service = 16.8 +/- 7 yr) during the acclimation phase (5 min standing, still dressed in their protective clothing), the work phase (simulated firefighting situations), and the following 24 hours. Multivariate linear step-wise regression showed that body mass index was highly correlated with mean and minimal HR values during the acclimation phase (beta 0.59, p < 0.001; beta 1.90, p = 0.003) and with mean and maximum HR values during the work phase (beta 1.08, p = 0.05; beta 1.17, p = 0.04), increasing cardiovascular stress. Firefighting tasks were associated with high energy expenditure. The minimum and mean MET values, during the acclimation phase, were significantly correlated with age (beta 0.49, p = 0.008 and beta 0.46, p < 0.01). During the work phase, maximal MET values were also strongly correlated with weight (beta 0.51, p = 0.03). No correlations between predictor and dependent variables were found for GSR; however, the high GSR levels recorded during the work phase returned to normal values only 12 hours after completion of the work phase, indicating that high levels of psychological stress remain, even after physical recovery. The data obtained in this study demonstrate that the physical fitness and anthropometric characteristics of firefighters influence the performance of firefighting tasks. These results may be useful to set up specific training that meets the real needs of firefighters in terms of physical fitness

Postural trials: expertise in rhythmic gymnastics increases control in lateral directions

ABSTRACT The purpose of this paper was to investigate if the expertise in Rhythmic Gymnastics (RG) could influence posture steadiness comparing RG gymnasts (RGG) and other sports trained subjects (Non Athletes, NA). A group of 15 high level RGG and a group of 43 female sport university students, NA, were matched in sighted and unsighted postural trials, using a force platform. Data were computed also in a Discrete Fourier Transform and an appropriate two ways variance analysis (ANOVA) with repeated measures. This study revealed the visual dependence for all thesubjects, irrespective of the groups, in their postural trials. Moreover, there were no statistically significant differences in the vision related changes, between RGG and NA groups. Nevertheless, comparing the two groups’ variables (RGG vs NA), data showed gymnasts were more instable in antero-posterior axis and students in mediolateral axis. These results suggested the expertise in RG performance was specialising gymnasts group in the lateral directions postural control. In fact they demonstrated to have a higher range of movements in antero-posterior direction, but it was only in the lowest and shortest frequencies. Furthermore, these high level gymnasts revealed to have better results than students in medium frequencies (from 0.50 to 2 seconds) periods, in which they were trained to perform in RG training routine and competition program

Forza al femminile

Scopo di questo studio è stato quello di valutare gli effetti di un programma di allenamento della forza muscolare della durata di 14 settimane in soggetti anziani di sesso femminile. 25 donne di eta compresa tra 60 e 81 anni sono state assegnate in maniera randomizzata ad un gruppo sperimentale (n=15) e ad un gruppo di controllo (n=10). Prima e dopo il programma di allenamento sono state valutate: negli arti superiori, la forza della stretta della mano (hand grip); negli arti inferiori, la forza dell'estensione della gamba sulla coscia alla leg extension (forza massima e torque), e la velocità di sviluppo della forza (RFD). I soggetti sono stati allenati 2 volte la settimana usando pesi liberi e macchine isotoniche, seguendo un programma strutturato in 3 mesocili con intensità progressivamente crescente (dal 45% al 75% di una ripetizione massima). Il livello generale di forza degli arti inferiori è migliorata maggiormente nel gruppo sperimentale rispetto al gruppo di controllo, mentre non si sono registrate variazioni significative nel livello generale di forza degli arti superior