PEP and TasP Awareness among Italian MSM, PLWHA, and High-Risk Heterosexuals and Demographic, Behavioral, and Social Correlates

Post-exposure prophylaxis (PEP) has been proposed as a strategy to prevent the acquisition of HIV infection after certain high-risk exposures, and treatment as prevention (TasP) is also being advocated as a means to reduce sexual transmission of HIV. The aim of this study was to investigate the prevalence of PEP and TasP awareness and their demographic, behavioral, and social correlates in Italy. We conducted a cross-sectional survey of 1,028 high-risk heterosexual men and women, 1,874 non-HIV positive MSM (men who have sex with men), and 694 people living with HIV/AIDS (PLWHA). The majority of the participants was aware of PEP and unaware of TasP. MSM were less knowledgeable about PEP and TasP than were PLWHA and more knowledgeable about PEP and TasP than were high-risk heterosexual participants. The variables most consistently associated with PEP and TasP awareness were contact with HIV/AIDS organizations, HIV testing, and HIV stigma. A positive relationship between unprotected sexual intercourse and PEP and TasP awareness was found among high risk heterosexual participants, while this association was not significant among MSM and PLWHA. Because PEP and TasP are currently recommended, effective educational and dissemination strategies are needed to increase the level of knowledge about PEP and TasP

Somatic genome editing with the RCAS-TVA-CRISPR-Cas9 system for precision tumor modeling

To accurately recapitulate the heterogeneity of human diseases, animal models require to recreate multiple complex genetic alterations. Here, we combine the RCAS-TVA system with the CRISPR-Cas9 genome editing tools for precise modeling of human tumors. We show that somatic deletion in neural stem cells of a variety of known tumor suppressor genes (Trp53, Cdkn2a, and Pten) leads to high-grade glioma formation. Moreover, by simultaneous delivery of pairs of guide RNAs we generate different gene fusions with oncogenic potential, either by chromosomal deletion (Bcan-Ntrk1) or by chromosomal translocation (Myb-Qk). Lastly, using homology-directed-repair, we also produce tumors carrying the homologous mutation to human BRAF V600E, frequently identified in a variety of tumors, including different types of gliomas. In summary, we have developed an extremely versatile mouse model for in vivo somatic genome editing, that will elicit the generation of more accurate cancer models particularly appropriate for pre-clinical testing.A.C.-G is recipient of a Severo-Ochoa PhD fellowship. C.M. and V.M. are recipients of a "La Caixa "PhD fellowship. We thank A.J. Schuhmacher for the initial assistance with the intracranial injections in adult mice and C.S. Clemente-Troncone for the technical support. We thank Carmen Blanco, David Olmeda, and Marisol Soengas for sharing reagents and Orlando Dominguez for the help with the design of the BRAF high- throughput sequencing. We sincerely thank Dr. José Luis Rodríguez Peralto (Hospital U. 12 de Octubre Madrid) for the BRAF V600 IHCs staining. This research was supported by funds from the Acción Estratégica en Salud Spanish National Research and Development Plan, Instituto de Salud Carlos III (ISCIII), cofounder by FEDER (ERDF) (PI14/01884) to S.R.-P., by a 017 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation and a grant from the Seve Ballesteros Foundation to M.S.S

Sexuality education in Italy 2016-2020: a national survey investigating coverage, content and evaluation of school-based educational activities

Comprehensive sexuality education is an important means of promoting sexual well-being amongst young people and is key to preventing sexually transmitted infections (STIs). However, sexuality education is not currently included in the formal curriculum in Italian schools. The aim of this study was to develop an inventory of schoolbased sexuality education (SBSE) activities carried out by external providers and implemented in Italy from 2016 to 2020. A desk review and survey were carried out. In the desk review online documents on STI prevention were analysed. The survey investigated the providers, objectives, content and methods used to implement SBSE activities in secondary schools. Findings revealed a highly heterogeneous situation in terms of geographical coverage, service providers, objectives and evaluation. Some SBSE activities were classified as adopting a comprehensive approach to sexuality education, while the majority focused on STI prevention, and many were single-session activities. Although most activities were said to have been evaluated no results were available. The data showed that SBSE is not systematically and equally delivered across Italy. Action is needed to provide young people with evidence-based, age-appropriate and accurate education about sexual and reproductive health and wellbeing

MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas.

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ

EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer

Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway.This research was supported by the National Brain Tumor Society (I.K.M.), the National Institutes of Health grants 1R01NS080944-01 (I.K.M.), 1 R35 NS105109 01 (I.K.M.), and P30CA008748 (MSKCC Core Grant), the Geoffrey Beene Cancer Research Foundation (I.K.M.), the Cycle of Survival (I.K.M.), and the Seve Ballesteros Foundation (M.S.). B.O. was supported by an American–Italian Cancer Foundation fellowship and a MSKCC Brain Tumor Center grant. W.-Y.H. is the recipient of a FY15 Horizon Award from the U.S. Department of Defense (W81XWH-15-PRCRP-HA). A.C.-G. is the recipient of the Severo-Ochoa PhD fellowship. Further support was provided by the Sontag Foundation (B.S.T.). We thank all members of the Mellinghoff laboratory for helpful suggestions. We thank Dr. Fiona Ginty (Diagnostic Imaging and Biomedical Technologies, GE Global Research Center, Niskayuna, New York, USA) for assistance with multiplexed immunofluorescence. We thank A.J. Schuhmacher and C.S. Clemente-Troncone for assistance with the in vivo experiments, M. Kaufmann for assistance in the luciferase assays and N. Yannuzzi for assistance in cloning.S

PHILOS Synthesis for Proximal Humerus Fractures Has High Complications and Reintervention Rates: A Systematic Review and Meta-Analysis

Purpose: The aim of this study was to quantify the rate of complications and reinterventions in patients treated with PHILOS plate for proximal humerus fractures (PHFs) synthesis. Methods: A comprehensive literature search was performed on the PubMed, Web of Science, Embase, and Cochrane databases up to 7 October 2021. Studies describing medium and long-term complications in PHF synthesis using the PHILOS plate were included. A systematic review and meta-analysis were performed on complications and causes of reinterventions. Assessment of risk of bias and quality of evidence was performed with the Downs and Black’s “Checklist for Measuring Quality”. Results: Seventy-six studies including 4200 patients met the inclusion criteria. The complication rate was 23.8%, and the main cause was screw cut-out (4.1%), followed by avascular necrosis (AVN) (3.1%) and subacromial impingement (1.5%). In patients over 55 years, the complication rate was 29.5%. In the deltopectoral (DP) approach the complication rate was 23.8%, and in the delto-split (DS) it was 17.5%, but no difference between the two approaches was seen when considering the type of fracture. The overall reintervention rate was 10.5% in the overall population and 19.0% in older patients. Conclusions: Proximal humerus synthesis with a PHILOS plate has high complications and reintervention rates. The most frequent complication was screw cut-out, followed by humeral head AVN and subacromial impingement. These results need to be further investigated to better understand both the type of patient and fracture that is more at risk of complications and reintervention and to compare pros and cons of the PHILOS plate with respect to the other solutions to manage PHFs

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Quanto ne sai di Hiv? QuestionAids: indagine su conoscenze in materia di Hiv/Aids

Lo scopo di questo studio è stato quello di studiare il livello di conoscenze sul tema dell’Hiv/Aids e i fattori ad esso associati in termini di variabili demografiche e sociali. Sono stati coinvolti in questo studio 11.588 partecipanti di maggiore età che sono stati invitati a rispondere a domande poste tramite un quiz su un sito web. Sebbene i livelli di conoscenza riguardo l’Hiv/Aids siano risultati medio alti, si è riscontrata la presenza relativamente diffusa di miti/stereotipi riguardo l’Hiv/Aids. La maggioranza dei partecipanti ha mostrato di non essere consapevole della TasP. Le variabili associate maggiormente alle conoscenze in tema di Hiv/Aids sono state il contatto con Associazioni che si occupano di Hiv/Aids, lo stato sierologico positivo, la conoscenza di persone con Hiv/Aids, e il grado di scolarità. Il presente studio mette in luce l’esigenza di programmare interventi informativi ed educativi efficaci sulle tematiche dell’Hiv/Aids al fine di incrementare le conoscenze

The role of knowing someone living with HIV/AIDS and HIV disclosure in the HIV stigma framework: a Bayesian mediation analysis

The current study evaluated the role of knowing someone living with HIV/AIDS and disclosure of one\u2019s HIV-positive status in the HIV Stigma Framework using a Bayesian mediation analysis. We used data on 387 people living with HIV/AIDS (PLWHA) and 6074 HIV uninfected Italian participants. Knowing someone living with HIV/AIDS was negatively related to stigmatizing attitudes among HIV uninfected participants and internalized stigma among PLWHA. Internalized stigma mediated the relationship between personal knowledge of someone living with HIV/AIDS and disclosure of one\u2019s HIV-positive status. In turn, disclosure of one\u2019s HIV-positive status mediated the relationship between internalized stigma and engagement in HIV care. Undetectable viral load was predicted by internalized stigma but not by disclosure of one\u2019s HIV-positive status and enacted stigma. Among uninfected participants, stigmatizing attitudes mediated the relationship between knowledge of someone living with HIV/AIDS and HIV testing. In addition, an interaction between knowledge of someone living with HIV/AIDS and HIV testing was found such that stigmatizing attitudes did not predict HIV testing among participants who do not have a personal knowledge of someone living with HIV/AIDS