MYC regulates a pan-cancer network of co-expressed oncogenic splicing factors.

MYC is dysregulated in \u3e50% of cancers, but direct targeting of MYC has been clinically unsuccessful. Targeting downstream MYC effector pathways represents an attractive alternative. MYC regulates alternative mRNA splicing, but the mechanistic links between MYC and the splicing machinery in cancer remain underexplored. Here, we identify a network of co-expressed splicing factors (SF-modules) in MYC-active breast tumors. Of these, one is a pan-cancer SF-module correlating with MYC activity across 33 tumor types. In mammary cell models, MYC activation leads to co-upregulation of pan-cancer module SFs and to changes in \u3e4,000 splicing events. In breast cancer organoids, co-overexpression of the pan-cancer SF-module induces MYC-regulated splicing events and increases organoid size and invasiveness, while knockdown decreases organoid size. Finally, we uncover a MYC-activity pan-cancer splicing signature correlating with survival across tumor types. Our findings provide insight into the mechanisms of MYC-regulated splicing and for the development of therapeutics for MYC-driven tumors

Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis

Misregulation of alternative splicing is a hallmark of human tumors, yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer and uncover differences and redundancies in their targets and biological functions. We identify splicing factors frequently altered in human breast tumors and assay their oncogenic functions using breast organoid models. We demonstrate that not all splicing factors affect mammary tumorigenesis in MCF-10A cells. Specifically, the upregulation of SRSF4, SRSF6, or TRA2beta disrupts acinar morphogenesis and promotes cell proliferation and invasion in MCF-10A cells. By characterizing the targets of these oncogenic splicing factors, we identify shared spliced isoforms associated with well-established cancer hallmarks. Finally, we demonstrate that TRA2beta is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast cancer patient survival

Counting on co-transcriptional splicing

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial Licens

An updated follow-up of chronic hepatitis C after three decades of observation in pediatric patients cured of malignancy

BACKGROUND: The aim of the study was to evaluate the clinical characteristics and the long-term outcome of chronic hepatitis C in a cohort of Caucasian children cured of pediatric malignancy. PROCEDURE: The study population included 83 consecutive patients, referred to our Center with a diagnosis of leukemia/lymphoma (50) or solid tumors (33) between 1977 and 1989 and infected with hepatitis C virus (HCV) during chemotherapy. RESULTS: At enrollment 77 subjects were HCV-RNA positive. After a median follow-up of 21 years (range 13-36), a sustained virological response (SVR) was obtained in 3 of 29 patients (10%) treated with interferon (IFN), in 1 of 3 patients (33%) treated with IFN and ribavirin, and in 5 of 11 patients (42%) treated with pegylated-IFN and ribavirin (P = 0.03). Forty-two patients remained untreated and only one (2.5%) cleared viremia. Four of 77 patients (5%) developed cirrhosis while other 4 patients died of causes not related to liver. At last follow-up, 72% of HCV-RNA positive patients had abnormal ALT. CONCLUSIONS: In patients cured of pediatric malignancy chronic hepatitis C tends to run an indolent course during childhood and adolescence but more than 70% of treated and more than 80% of untreated cases children maintained HCV viremia. Moreover, after 2-3 decades of observation, 60% of HCV-RNA positive patients had abnormal ALT and 5% had developed cirrhosis. Among treated patients, IFN or pegylated-IFN and ribavirin obtained the higher rate of HCV-RNA clearanc

Hyperbaric therapy (HT) in the treatment of hemorhragic cystitis (HC) after bone marrow transplantation

Retrospective results of hyperbaric therapy in a group of pediatric patients who underwent HSC

Design and testing of an adhesively bonded CFRP strengthening system for steel structures

In the framework of sustainable development policies, it is essential that infrastructure owners can rely on effective repair or strengthening solutions, designed and tested in relevance to actual service conditions. In the case of steel structures, fatigue damage is a major concern that can significantly affect the lifespan of the structure, and so far, there are very few operational methods capable of preventing fatigue cracks in the field. Adhesively bonded carbon fiber reinforced polymer (CFRP) composites are being successfully applied to the rehabilitation of concrete structures for more than two decades, and they are currently receiving much interest for the strengthening of steel elements, but mainly for curative purpose after severe damage has occurred. In the present study, which is part of a European project called FASSTbridge, a specific CFRP system has been developed as a preventive method against fatigue damage of steel structures. The proposed system consists of a commercially available ultra-high modulus (UHM) CFRP composite plate compatible with the stiffness of the host steel structures, which is bonded to the steel support using a novel hybrid epoxy/polyurethane adhesive. A first part of the paper presents the main specifications that should be adopted in the design of CFRP strengthening systems applied to steel structures, and that were identified from an extensive literature survey. These specifications have guided the development of the polymer adhesive and the choice of a peculiar commercial CFRP plate in the preliminary phase of the project. Experimental characterizations were then conducted (i) on the formulated hybrid polymer adhesive to optimize its curing schedule and check the previous specifications are fulfilled, and (ii) on CFRP reinforced steel specimens in order to verify the effectiveness of the proposed strengthening system. This experimental program involved both short term and durability tests that were performed by different laboratories. Such an inter-laboratory study made it possible to verify the performances of the developed strengthening system and to assess the influence of installation parameters and environmental conditions.The authors wish to acknowledge Epsilon Composite Company for supporting the study. This work is part of the FASSTBRIDGE project. This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 31109806.0008. FASSTbridge is co-funded by Funding Partners of The ERA-NET Plus Infravation and the European Commission. The Funding Partners of the Infravation 2014 Call are: MINISTERIE VAN INFRASTRUCTUUR EN MILIEU, RIJKSWATERSTAAT, BUNDESMINISTERIUM FÜR VERKEHR, BAU UND STADTENTWICKLUNG, DANISH ROAD DIRECTORATE, STATENS VEGVESEN VEGDIREKTORATET, TRAFIKVERKET – TRV, VEGAGERÐIN, MINISTERE DE L'ECOLOGIE, DU DEVELOPPEMENT DURABLE ET DE L'ENERGIE, CENTRO PARA EL DESARROLLO TECNOLOGICO INDUSTRIAL, ANAS S.p.A., NETIVEI, ISRAEL - NATIONAL TRANSPORT INFRASTRUCTURE COMPANY LTD, FEDERAL HIGHWAY ADMINISTRATION USDO