Studio del background genetico determinante la progressione dell’ infezione da HIV:confronto tra una coorte di individui sieropositivi e individui “HIV Esposti Sieronegativi (HESN) “ Role of genetic factors in the progression of HIV infection: comparison of a cohort of HIV-positive individuals and subjects "HIV exposed seronegative (HESN)"

Riassunto: Il virus HIV, isolato per la prima volta più di trent’anni fa, è stato decritto in molti suoi aspetti morfologici e patogenetici. Una rilevanza sempre maggiore è stata conferita al rapporto virus-ospite e soprattutto ai meccanismi di difesa contro l’infezione. Grazie a queste indagini, è stato possibile individuare gruppi di pazienti che riescono a controllare l’infezione anche per molti anni. Questi soggetti costituiscono il gruppo dei “Long Term Non Progressor” (LTNP). Tra gli LTNP è possibile individuare un sottogruppo definito “Elite Controller” (EC) che, oltre ad un valore di linfociti CD4+ nella norma, presenta bassi livelli plasmatici di HIV RNA anche a distanza di anni dall’infezione. Inoltre sono stati osservati soggetti che, nonostante ripetute esposizioni al virus, non presentano infezione da HIV. Questi soggetti definiti HIV Exposed Seronegative (HESN), non evidenziano siero-conversione e nel loro plasma non sono rivelabili né acido nucleico né antigeni virali. Questi soggetti sono caratterizzati da peculiarità immunologiche che evidenziano una risposta specifica del sistema immunitario nei confronti del virus HIV. Con il progredire degli studi sul genoma umano sono stati identificati loci che comprendono geni in grado di modulare molti meccanismi di immunità virus specifici. E’ in questo ambito che si inserisce lo studio e la caratterizzazione della risposta immunitaria contro agenti infettivi virali descrivendo i geni coinvolti in questi processi per cercare di capire le ragioni alla base della differenza tra risposte immunitarie contro lo stesso agente patogeno. I metodi di studio utilizzati sono sia l’approccio del gene candidato che lo studio di associazione Gene Wide (GWAS). Grazie a questi due metodi sono stati individuati molti geni che in determinate varianti o associati in aplotipi contribuiscono allo stato di HESN. In particolare , in questo studio sono stati presi in considerazione cinque geni che rivestono un ruolo determinante per la risposta immunitaria: MX2, TLR3, APOBEC3H, ERAP2, RAC2. Nel nostro studio la frequenza di queste varianti geniche è stata valutata in una coorte di 101 pazienti HESN e in una di 79 pazienti sieropositivi. Nel gruppo dei soggetti HESN il 30,70% possiede due varianti protettive su quattro, il 69,30% ne possiede una o nessuna. Nella coorte di pazienti HIV+ l’1,26%( un solo paziente) possiede quattro varianti protettive, un altro 1,26% ne possiede tre, il 15,20% presenta due varianti protettive, il restante 82,28% una o nessuna.Successivamente abbiamo determinato se vi sia una qualche associazione tra ognuna di queste varianti e i dati clinici (sesso, periodo di infezione HIV, fattore di rischio, presenza o meno di livello di CD4+>500, ultima VL rilevabile, tempo di soppressione della VL,evoluzione clinica, assunzione di terapia, aderenza alla terapia HAART) e di laboratorio (Linfociti CD4+ Basali, ultimi CD4+, nadir CD4+, VL basale, anni di terapia) dei pazienti sieropositivi. Infine abbiamo creato quattro sottogruppi di sieropositivi in base al numero di varianti protettive possedute e abbiamo calcolato anche in questo caso il grado di associazione con i dati clinici e di laboratorio. Dall’analisi statistica, al momento, è emersa una probabilità di correlazione superiore al 95% tra sesso femminile e TLR3(p=0,02), tra assenza di evoluzione clinica e ERAP2(p=0,01). L’esiguo numero di soggetti osservati non consente di effettuare al momento correlazioni tra le caratteristiche genetiche esaminate e l’evoluzione dell’infezione da HIV nella popolazione esaminata senza ulteriori prove. Tuttavia questi dati preliminari suggeriscono la necessità di approfondire queste ipotesi di studio. Le variabili individuali, l’estrema diversità tra i pazienti, il relativo piccolo numero di soggetti esaminati possono impattare su questi risultati. Anche la terapia HAART e l’insorgenza di farmacoresistenze può impattare sulla risposta immunitaria e sulla replicazione virale. La multifattorialità del fenomeno di resistenza all’HIV deve tener conto di un più ampio di numero di geni coinvolti nella risposta immunitaria e della loro espressione. Per questo motivo sono necessari ulteriori studi per una maggiore comprensione di questo fenomeno. ABSTRACT: The HIV virus, isolated for the first time more than thirty years ago, has been described in many morphological and pathogenic aspects. More and more importance was given to the virus-host relationship and especially the mechanisms of defense against infection. Thanks to these investigations, it was possible to identify groups of patients that are able to control the infection even for many years. These individuals constitute the group of "Long Term Non Progressor" (LTNP). Among the LTNP is possible to identify a subgroup defined "Elite Controller" (EC), which, in addition to a value of CD4 + lymphocytes in the standard, has low levels of plasma HIV RNA even after decades after infection. Moreover, subjects were observed that, despite repeated exposure to the virus, does not have HIV infection. These subjects defined HIV Exposed seronegative (HESN), do not undergo seroconversion and in their plasma are not detectable nucleic acid nor viral antigens. These subjects are characterized by immunological peculiarity that show a specific response of immune system against the HIV virus. With the progress of studies on the human genome were identified loci that include genes that can modulate several mechanisms of virus-specific immunity. The study and the characterization of the immune response against viral infectious agents fits into this context and describes the genes involved in these processes trying to understand the reasons for the difference between immune response against the same pathogen. The study methods used are either the candidate gene approach that the study of Gene Wide Association (GWAS). Thanks to these two methods have been identified many genes that in specific single variants or associated in haplotypes contribute to the state of HESN. In particular, in this study were considered five genes that play a key role for the regulation of immune response : MX2, TLR3, APOBEC3H, ERAP2, RAC2. In our study the frequency of these gene variants was evaluated in a cohort of 101 subjects HESN and one of 79 HIV-positive patients. In the group of subjects HESN 30,70% has two protective variants of four, the 69,30% has one or none. In the cohort of HIV-positive patients, 1,26% (one patient) has four protective variants, another 1,26% owns three, the 15,20% has two protective variants, the remaining 82,28% one or none. We then determined whether there is any association between each of these variants and clinical data (gender, period of HIV infection, risk factor, level of CD4 +> 500 num/mm3, last VL detectable, time suppression of VL, evolution clinic, taking HAART therapy, adherence to HAART) and laboratory (CD4 + basal, last CD4 +, CD4 + nadir, VL baseline, years of therapy) of seropositive patients. Finally, we have created four subgroups of HIV-positive according to the number of protective variants owned and we have also calculated in this case the degree of association with clinical and laboratory data. From the statistical analysis, at the time, there was a probability of greater than 95% correlation between female gender and TLR3 (p=0,02) and between the clinical evolution and ERAP2 (p=0,01). In the population examinated at the moment, the small number of subjects observed is unable to make correlation between the genetic characteristics studied and the evolution of HIV infection without further testing. However, these preliminary data suggests the need for further study of this hypothesis. Individual variables, the extreme diversity among patients, the relative small number of examinees may impact on these results. Even HAART therapy and the onset of drug resistance can impact the immune response and viral replication. The multifactorial nature of the phenomenon of resistance to HIV must take account of a larger number of genes involved in the immune response and their expression. For this reason, further studies are needed for a better understanding of this phenomenon

Feasibility of a home-based computerized cognitive training for pediatric patients with congenital or acquired brain damage: An explorative study

Pediatric brain damage is associated with various cognitive deficits. Cognitive rehabilitation may prevent and reduce cognitive impairment. In recent years, home-based computerized cognitive training (CCT) has been introduced in clinical practice to increase treatment opportunities for patients (telerehabilitation). However, limited research has been conducted thus far on investigating the effects of remote CCT for the juvenile population in contexts other than English-speaking countries. The aim of the present study was to investigate the feasibility of a home-based CCT in a group of Italian adolescents with brain damage. A commercially available CCT (Lumosity) developed in the English language was used due to the lack of telerehabilitation programs in the Italian language that allow stimulation of multiple cognitive domains and, at the same time, remote automatic collection of data. Thus, this investigation provides information on the possibility of introducing CCT programs available in foreign languages in countries with limited investment in the telerehabilitation field

Remote Technology-Based Training Programs for Children with Acquired Brain Injury: A Systematic Review and a Meta-Analytic Exploration

Introduction. Multidisciplinary rehabilitation interventions are considered to be a need for children with acquired brain injury (ABI), in order to remediate the important sequelae and promote adjustment. Technology-based treatments represent a promising field inside the rehabilitation area, as they allow delivering interventions in ecological settings and creating amusing exercises that may favor engagement. In this work, we present an overview of remote technology-based training programs (TP) addressing cognitive and behavioral issues delivered to children with ABI and complement it with the results of a meta-analytic exploration. Evidence Acquisition. We performed the review process between January and February 2019. 32 studies were included in the review, of which 14 were further selected to be included in the meta-analysis on TP efficacy. Evidence Synthesis. Based on the review process, the majority of TP addressing cognitive issues and all TP focusing on behavioral issues were found to be effective. Two meta-analytic models examining the means of either cognitive TP outcomes or behavioral TP outcomes as input outcome yielded a nonsignificant effect size for cognitive TP and a low-moderate effect size for behavioral TP. Additional models on outcomes reflecting the greatest beneficial effects of TP yielded significant moderate effect sizes for both types of TP. Nevertheless, consistent methodological heterogeneity was observed, pointing to cautious interpretation of findings. A subgroup analysis on visuospatial skill outcomes showed a smaller yet significant effect size of cognitive TP, with low heterogeneity, providing a more reliable estimation of overall cognitive TP effects. Conclusions. Promising results on remote cognitive and behavioral TP efficacy emerged both at the review process and at the meta-analytic investigation. Nevertheless, the high heterogeneity that emerged across studies prevents us from drawing definite conclusions. Further research is needed to identify whether specific training characteristics and population subgroups are more likely to be associated with greater training efficacy

ADAM10 new selective inhibitors reduce NKG2D ligand release sensitizing Hodgkin lymphoma cells to NKG2D-mediated killing

Hodgkin lymphoma (HL) resistant to conventional therapies is increasing, making of interest the search for new schemes of treatment. Members of the “A Disintegrin And Metalloproteases” (ADAMs) family, mainly ADAM10 or ADAM17, have been proposed as therapeutic targets in solid tumors and some ADAMs inhibitors have been shown to exert antitumor effects. We have previously described an overexpression of ADAM10 in HL, together with increased release of NKG2D ligands (NKG2D-L) and reduced activation of effector T lymphocytes with anti-lymphoma capacity. Aim of the present work was to verify whether inhibition of ADAM10 in HL cells could restore the triggering of NKG2D-dependent anti-lymphoma T cell response. As no selective ADAM10 blockers have been reported so far, we synthesized the two hydroxamate compounds LT4 and MN8 with selectivity for ADAM10 over metalloproteases (MMPs), LT4 showing higher specificity for ADAM10 over ADAM17. We show that (i) HL lymph nodes (LN) and cultured HL cells express high levels of the mature active membrane form of ADAM10; (ii) ADAM10 is the major sheddase for the NKG2D-L in HL cells; (iii) the new LT4 and MN8 compounds strongly reduce the shedding of NKG2D-L by HL cell lines and enhance the binding of NKG2D receptor; (iv) of note, these new ADAM10 inhibitors increase the sensitivity of HL cell lines to NKG2D-dependent cell killing exerted by natural killer and γδ T cells. Overall, the biologic activity of LT4 and MN8 appears to be more potent than that of the commercial inhibitor GI254023X

Feasibility and Acceptability of a Real-Time Telerehabilitation Intervention for Children and Young Adults with Acquired Brain Injury During the COVID-19 Pandemic: An Experience Report

This study examined the feasibility and acceptability of a telerehabilitation intervention during the COVID-19 pandemic in a sample of children and young adults with Acquired Brain Injury (ABI). Thirteen patients and/or their families agreed to participate in the speech and neuropsychological telerehabilitation sessions. The treatment was synchronous, patient centered and aimed at improving specific abilities. Sessions were held twice a week over a 10-week period. Two questionnaires were completed both by parents and therapists to assess feasibility and acceptability. Neither technical issues nor clinical obstacles were found. The quality of the therapeutic relationship played a key role in the intervention. Synchronous telerehabilitation provided several advantages both for patients and therapists. Moreover, the patient centered intervention eased the burden of the caregivers at a time of high stress. The real-time telerehabilitation treatments were deemed suitable for children and young adults with ABI. Further studies are needed to support the use of telerehabilitation as an integral part of their standard care

A multi-organ-on-chip to recapitulate the infiltration and the cytotoxic activity of circulating NK cells in 3D matrix-based tumor model

The success of immunotherapeutic approaches strictly depends on the immune cells interaction with cancer cells. While conventional in vitro cell cultures under-represent the complexity and dynamic crosstalk of the tumor microenvironment, animal models do not allow deciphering the anti-tumor activity of the human immune system. Therefore, the development of reliable and predictive preclinical models has become crucial for the screening of immune-therapeutic approaches. We here present an organ-on-chip organ on chips (OOC)-based approach for recapitulating the immune cell Natural Killer (NK) migration under physiological fluid flow, infiltration within a 3D tumor matrix, and activation against neuroblastoma cancer cells in a humanized, fluid-dynamic environment. Circulating NK cells actively initiate a spontaneous "extravasation " process toward the physically separated tumor niche, retaining their ability to interact with matrix-embedded tumor cells, and to display a cytotoxic effect (tumor cell apoptosis). Since NK cells infiltration and phenotype is correlated with prognosis and response to immunotherapy, their phenotype is also investigated: most importantly, a clear decrease in CD16-positive NK cells within the migrated and infiltrated population is observed. The proposed immune-tumor OOC-based model represents a promising approach for faithfully recapitulating the human pathology and efficiently employing the immunotherapies testing, eventually in a personalized perspective. An immune-organ on chip to recapitulate the tumor-mediated infiltration of circulating immune cells within 3D tumor model

Road traffic pollution and childhood leukemia: a nationwide case-control study in Italy

Background The association of childhood leukemia with traffic pollution was considered in a number of studies from 1989 onwards, with results not entirely consistent and little information regarding subtypes. Aim of the study We used the data of the Italian SETIL case-control on childhood leukemia to explore the risk by leukemia subtypes associated to exposure to vehicular traffic. Methods We included in the analyses 648 cases of childhood leukemia (565 Acute lymphoblastic–ALL and 80 Acute non lymphoblastic-AnLL) and 980 controls. Information on traffic exposure was collected from questionnaire interviews and from the geocoding of house addresses, for all periods of life of the children. Results We observed an increase in risk for AnLL, and at a lower extent for ALL, with indicators of exposure to traffic pollutants. In particular, the risk was associated to the report of closeness of the house to traffic lights and to the passage of trucks (OR: 1.76; 95% CI 1.03–3.01 for ALL and 6.35; 95% CI 2.59–15.6 for AnLL). The association was shown also in the analyses limited to AML and in the stratified analyses and in respect to the house in different period of life. Conclusions Results from the SETIL study provide some support to the association of traffic related exposure and risk for AnLL, but at a lesser extent for ALL. Our conclusion highlights the need for leukemia type specific analyses in future studies. Results support the need of controlling exposure from traffic pollution, even if knowledge is not complete

Prognostic factors of lung cancer in lymphoma survivors (the LuCiLyS study)

Background Second cancer is the leading cause of death in lymphoma survivors, with lung cancer representing the most common solid tumor. Limited information exists about the treatment and prognosis of second lung cancer following lymphoma. Herein, we evaluated the outcome and prognostic factors of Lung Cancer in Lymphoma Survivors (the LuCiLyS study) to improve the patient selection for lung cancer treatment. Methods This is a retrospective multicentre study including consecutive patients treated for lymphoma disease that subsequently developed non-small cell lung cancer (NSCLC). Data regarding lymphoma including age, symptoms, histology, disease stage, treatment received and lymphoma status at the time of lung cancer diagnosis, and data on lung carcinoma as age, smoking history, latency from lymphoma, symptoms, histology, disease stage, treatment received, and survival were evaluated to identify the significant prognostic factors for overall survival. Results Our study population included 164 patients, 145 of which underwent lung cancer resection. The median overall survival was 63 (range, 58–85) months, and the 5-year survival rate 54%. At univariable analysis no-active lymphoma (HR: 2.19; P=0.0152); early lymphoma stage (HR: 1.95; P=0.01); adenocarcinoma histology (HR: 0.59; P=0.0421); early lung cancer stage (HR: 3.18; P<0.0001); incidental diagnosis of lung cancer (HR: 1.71; P<0.0001); and lung cancer resection (HR: 2.79; P<0.0001) were favorable prognostic factors. At multivariable analysis, no-active lymphoma (HR: 2.68; P=0.004); early lung cancer stage (HR: 2.37; P<0.0001); incidental diagnosis of lung cancer (HR: 2.00; P<0.0001); and lung cancer resection (HR: 2.07; P<0.0001) remained favorable prognostic factors. Patients with non-active lymphoma (n=146) versus those with active lymphoma (n=18) at lung cancer diagnosis presented better median survival (64 vs. 37 months; HR: 2.4; P=0.02), but median lung cancer specific survival showed no significant difference (27 vs. 19 months; HR: 0.3; P=0.17). Conclusions The presence and/or a history of lymphoma should not be a contraindication to resection of lung cancer. Inclusion of lymphoma survivors in a lung cancer-screening program may lead to early detection of lung cancer, and improve the survival