Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

Inactivating Tp53 mutations are frequent genetic lesions in human tumors that harbor genomic instability, including B lineage lymphomas with IG translocations. Antigen receptor genes are assembled and modified in developing lymphocytes by RAG/AID-initiated genomic rearrangements that involve the induction of DNA double strand breaks (DSBs). Although TP53 inhibits the persistence of DSBs and induces apoptosis to protect cells from genomic instability and transformation, the development of spontaneous tumors harboring clonal translocations has not been reported in mice that only lack wild-type Tp53 protein or express Tp53 mutants. Tp53-deficient (Tp53-/-) mice succumb to T lineage lymphomas lacking clonal translocations but develop B lymphoid tumors containing immunoglobulin (Ig) translocations upon combined inactivation of DSB repair factors, RAG mutation or AID overexpression; mice expressing apoptosis-defective Tp53 mutants develop B cell lymphomas that have not been characterized for potential genomic instability. As somatic rather than germline inactivating mutations of TP53 are typically associated with human cancers and Tp53 deletion has cellular context dependent effects upon lymphocyte transformation, we generated mice with conditional Tp53 deletion in lineage-committed B lymphocytes to avoid complications associated with defective Tp53 responses during embryogenesis and/or in multi-lineage potential cells and, thereby, directly evaluate the potential physiological role of Tp53 in suppressing translocations in differentiated cells. These mb1-cre:Tp53flox/flox mice succumbed to lymphoid tumors containing Ig gene rearrangements and immuno-phenotypes characteristic of B cells from various developmental stages. Most mb1-cre:Tp53flox/flox tumors harbored clonal translocations, including Igh/c-myc or other oncogenic translocations generated by the aberrant repair of RAG/AID-generated DSBs. Our data indicate that Tp53 serves critical functions in B lineage lymphocytes to prevent transformation caused by translocations in cell populations experiencing physiological levels of RAG/AID-initiated DSB intermediates, and provide evidence that the somatic TP53 mutations found in diffuse large B-cell lymphoma and Burkitt's lymphoma may contribute to the development of these human malignancies

Performance assessment across different care settings of a heart failure hospitalisation risk-score for type 2 diabetes using administrative claims

Predicting the risk of cardiovascular complications, in particular heart failure hospitalisation (HHF), can improve the management of type 2 diabetes (T2D). Most predictive models proposed so far rely on clinical data not available at the higher Institutional level. Therefore, it is of interest to assess the risk of HHF in people with T2D using administrative claims data only, which are more easily obtainable and could allow public health systems to identify high-risk individuals. In this paper, the administrative claims of > 175,000 patients with T2D were used to develop a new risk score for HHF based on Cox regression. Internal validation on the administrative data cohort yielded satisfactory results in terms of discrimination (max AUROC = 0.792, C-index = 0.786) and calibration (Hosmer-Lemeshow test p value < 0.05). The risk score was then tested on data gathered from two independent centers (one diabetes outpatient clinic and one primary care network) to demonstrate its applicability to different care settings in the medium-long term. Thanks to the large size and broad demographics of the administrative dataset used for training, the proposed model was able to predict HHF without significant performance loss concerning bespoke models developed within each setting using more informative, but harder-to-acquire clinical variables

Tutti uguali, Tutti diversi. Convegno sulle disabilit\ue0 sensoriali

La disabilit\ue0 sensoriale viene analizzata attraverso l'analisi delle seguenti aree/problema: sociale e formativa, medico-riabilitativa e educativa