Overexpressed TP73 induces apoptosis in medulloblastoma

Abstract Background Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth. Methods We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the ΔNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and ΔNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and ΔNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods. Results Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated ΔNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or ΔNp73 induced apoptosis under basal growth conditions in vitro and sensitized them to cell death in response to chemotherapeutic agents. Conclusion These results indicate that primary medulloblastomas express significant levels of TP73 isoforms, and suggest that they can modulate the survival and genotoxic responsiveness of medulloblastomas cells

Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases

In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies

Knowledge translation strategies for dissemination with a focus on healthcare recipients: an overview of systematic reviews

Background While there is an ample literature on the evaluation of knowledge translation interventions aimed at healthcare providers, managers, and policy-makers, there has been less focus on patients and their informal caregivers. Further, no overview of the literature on dissemination strategies aimed at healthcare users and their caregivers has been conducted. The overview has two specific research questions: (1) to determine the most effective strategies that have been used to disseminate knowledge to healthcare recipients, and (2) to determine the barriers (and facilitators) to dissemination of knowledge to this group. Methods This overview used systematic review methods and was conducted according to a pre-defined protocol. A comprehensive search of ten databases and five websites was conducted. Both published and unpublished reviews in English, Spanish, or Portuguese were included. A methodological quality assessment was conducted; low-quality reviews were excluded. A narrative synthesis was undertaken, informed by a matrix of strategy by outcome measure. The Health System Evidence taxonomy for “consumer targeted strategies” was used to separate strategies into one of six categories. Results We identified 44 systematic reviews that describe the effective strategies to disseminate health knowledge to the public, patients, and caregivers. Some of these reviews also describe the most important barriers to the uptake of these effective strategies. When analyzing those strategies with the greatest potential to achieve behavioral changes, the majority of strategies with sufficient evidence of effectiveness were combined, frequent, and/or intense over time. Further, strategies focused on the patient, with tailored interventions, and those that seek to acquire skills and competencies were more effective in achieving these changes. In relation to barriers and facilitators, while the lack of health literacy or e-literacy could increase inequities, the benefits of social media were also emphasized, for example by widening access to health information for ethnic minorities and lower socioeconomic groups. Conclusions Those interventions that have been shown to be effective in improving knowledge uptake or health behaviors should be implemented in practice, programs, and policies—if not already implemented. When implementing strategies, decision-makers should consider the barriers and facilitators identified by this overview to ensure maximum effectiveness