Childhood and adulthood severe stressful experiences and biomarkers related to glucose metabolism: a possible association?

Background: No study investigated the association between stress exposure in different stages of life and metabolic dysfunction.Aim: We explore the association between stress exposure and several biomarkers related to glucose metabolism (insulin, c-peptide, GIP, GLP-1, glucagon) in a group of 72 healthy individuals.Method: We used the Childhood Experience of Care and Abuse-Questionnaire (CECA-Q) and a modified version of the Life Events Scale to define exposure to stress, according to four categories: no exposure to childhood trauma (CT) nor to stressful life events (SLEs) (46%), only to CT (25%), only to SLEs (21%), to both (8%).Results: We found that c-peptide (p = 0.006) and insulin (p = 0.002) levels differed among the four categories: 0.77 ng/ml (SD 0.27) and 0.21 ng/ml (SD 0.06) for none, 0.77 (SD 0.37) and 0.20 (SD 0.08) for only SLEs, 0.88 (SD 0.39) and 0.27 (SD 0.12) for only CT, 1.33 (SD 0.57) and 0.40 (SD 0.28) for both, respectively. The highest levels of biomarkers were found in subjects exposed to both CT and SLEs.Conclusion: Our preliminary results seem to suggest that CT might be specifically associated with a dysfunction of glucose metabolism, which might increase the risk of poorer health outcomes in adulthood. This association seems to be even stronger in individuals additionally exposed to SLEs in adulthood. In conclusion, if confirmed in other studies, subjects exposed to both CT and SLEs appear the most vulnerable individuals, for whom preventative interventions, such as healthy lifestyle education programs, might ameliorate the risk of developing metabolic abnormalities

Lipid nanoparticle-mediated messenger RNA delivery for ex vivo engineering of natural killer cells

Natural killer (NK) cells participate in the immune system by eliminating cancer and virally infected cells through germline-encoded surface receptors. Their independence from prior activation as well as their significantly lower toxicity have placed them in the spotlight as an alternative to T cells for adoptive cell therapy (ACT). Engineering NK cells with mRNA has shown great potential in ACT by enhancing their tumor targeting and cytotoxicity. However, mRNA transfection of NK cells is challenging, as the most common delivery methods, such as electroporation, show limitations. Therefore, an alternative non-viral delivery system that enables high mRNA transfection efficiency with preservation of the cell viability would be beneficial for the development of NK cell therapies. In this study, we investigated both polymeric and lipid nanoparticle (LNP) formulations for eGFP-mRNA delivery to NK cells, based on a dimethylethanolamine and diethylethanolamine polymeric library and on different ionizable lipids, respectively. The mRNA nanoparticles based on cationic polymers showed limited internalization by NK cells and low transfection efficiency. On the other hand, mRNA-LNP formulations were optimized by tailoring the lipid composition and the microfluidic parameters, resulting in a high transfection efficiency (∼100%) and high protein expression in NK cells. In conclusion, compared to polyplexes and electroporation, the optimized LNPs show a greater transfection efficiency and higher overall eGFP expression, when tested in NK (KHYG-1) and T (Jurkat) cell lines, and cord blood-derived NK cells. Thus, LNP-based mRNA delivery represents a promising strategy to further develop novel NK cell therapies

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial

Background and purpose Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. Methods This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. Results Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. Conclusions The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation

Amyotrophic Lateral Sclerosis Multiprotein Biomarkers in Peripheral Blood Mononuclear Cells

Amyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms

Aquileia. Fondi Cossar. Volume 3.3. Tomo 1 – I materiali ceramici e Tomo 2 - L’instrumentum, i materiali vitrei, metallici e gli elementi architettonici.

I due tomi di questo volume raccolgono gli studi condotti da una nutrita serie di specialisti su gran parte delle classi di reperti recuperati durante queste indagini archeologiche condotte nel sito e divenuti oggetto di approfondita analisi negli anni seguenti l’impegno sul campo

Aquileia. Fondi Cossar. 3.3. - Tomo I – I materiali ceramici. Tomo II - L'instrumentum, il materiale vitreo, metallico e gli elementi decorativo-architettonici

Il volume costituisce l'edizione sistematica di alcune classi di materiali ceramici, vitrei, metallici e lapidei recuperati nel corso delle indagini condotte tra il 2009 e il 2015 presso i fondi Cossar di Aquileia. Lo scavo ha riguardato una domus romana (domus di Tito Macro) vissuta tra il I sec. a.C. e il V sec. d.C

Introduzione

Le brevi note di questa Introduzione costituiscono una premessa alla lettura dei due tomi che compongono il volume 3.3 della serie dedicata all’edizione sistematica delle ricerche archeologiche condotte presso i fondi Cossar di Aquileia dall’Università degli studi di Padova tra il 2009 e il 2015

Gortina IX.1 e Gortina IX.2. Il Teatro del Pythion. Scavi e ricerche 2001-2013

Il volume costituisce l'edizione sistematica dello scavo del Teatro del Santuario di Apollo Pythios della citt\ue0 antica di Gortina di Creta. Lo scavo si \ue8 svolto dal 2001 al 2013 sulla base degli accordi di cooperazione internazionale tra l'Universit\ue0 di Padova e la Scuola archeologica italiana di Atene. L'intervento ha rimesso in luce l'edificio per spettacoli per oltre la sua met\ue0, concentrandosi particolarmente sulla parte orientale del complesso direttamente connessa al tempio di Apollo che costituiva il cuore del relativo santuario. L'edizione presenta nel primo volume i dati di scavo, discussi a partire dalle evidenze stratigrafiche e letti attraverso interpretazione delle fabbriche come espressione della cultura architettonica romana in Grecia; nel primo volume la trattazione \ue8 anche concentrata sui diversi contesti e sui relativi reperti, che hanno consentito di proporre analisi cronologiche di particolare dettaglio. Nel secondo volume sono valutati nel dettaglio i reperti rinvenuti secondo la suddivisione per classi e per centri di produzione, affrontando anche l'interpretazione storica integrata dei manufatti visti nel pi\uf9 ampio scenario mediterraneo. Sono inoltre presentati studi archeologici e archeometrici sulle strutture e sui materiali rinvenuti. Grazie alla lettura integrata di tutti questi dati si \ue8 potuto concludere che l'edificio venne costruito in et\ue0 adrianea come luogo assembleare posto nell'ambito del pi\uf9 ampio santuario di Apollo Pythios, che divenne dalla tarda et\ue0 ellenistica anche sede del Koinon dei Cretesi. \uc8 probabile che l'edificio abbia cos\uec assunto anche le funzioni di sede assembleare della federazione delle citt\ue0 cretesi. Il teatro presenta una morfologia architettonica tipicamente latina e costituisce uno dei molti segni monumentali che documentano la piena romanizzazione del centro greco. Nell'edizione sono presentati anche i dati sull'abbandono dell'edificio, trasformato in stalla, e sul suo rovinoso crollo avvenuto nel terremoto del 365 d.C

La ceramica con ingobbio rosso dallo scavo del teatro del Pythion a Gortyna (Creta)

Il contributo illustra una specifica classe ceramica rinvenuta negli scavi condotti presso il Teatro del Pythion di Gortyna di Cret