Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma

Anaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secondary to a transcriptional and epigenetic repressive program induced by oncogenic NPM-ALK. While inhibiting the expression of T cell molecules, NPM-ALK activates surrogate TCR signaling by directly inducing pathways downstream the TCR. CD45 is a tyrosine phosphatase that plays a central role in T cell activation by controlling the TCR signaling and regulating the cytokine responses through the JAK/STAT pathway and exists in different isoforms depending on the stage of T-cell maturation, activation and differentiation. ALK+ ALCL cells mainly express the isoform CD45RO in keeping with their mature/memory T cell phenotype. Because of its regulatory effect on the JAK/STAT pathway that is essential for ALK+ ALCL, we investigated whether CD45 expression was affected by oncogenic ALK. We found that most ALK+ ALCL cell lines express the CD45RO isoform with modest CD45RA expression and that NPM-ALK regulated the expression of these CD45 isoforms. Regulation of CD45 expression was dependent on ALK kinase activity as CD45RO expression was increased when NPM-ALK kinase activity was inhibited by treatment with ALK tyrosine kinase inhibitors (TKIs). Silencing ALK expression through shRNA or degradation of ALK by the PROTAC TL13-112 caused upregulation of CD45RO both at mRNA and protein levels with minimal changes on CD45RA, overall indicating that oncogenic ALK downregulates the expression of CD45. CD45 repression was mediated by STAT3 as demonstrated by ChIP-seq data on ALCL cells treated with the ALK-TKI crizotinib or cells treated with a STAT3 degrader. Next, we found that knocking-out CD45 with the CRISPR/Cas9 system resulted in increased resistance to ALK TKI treatment and CD45 was down-regulated in ALCL cells that developed resistance in vitro to ALK TKIs. Overall, these data suggest that CD45 expression is regulated by ALK via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment in ALCL

Modifications of auditory brainstem responses (ABR): observations in full-term and pre-term newborns

Objective: In this study, we have evaluated by means of auditory brainstem responses (ABR), in a population derived from a newborn hearing screening protocol, some aspects of maturation of the auditory pathways in the first months after birth, and the possible repercussions on early treatment. Materials and methods: In this retrospective study newborns were recruited through our hearing screening program, and an ABR evaluation was performed on 339 newborns, that had risk factors or had failed the screening, or both. Such population was divided in two groups for statistical analysis purposes: full-term and pre-term. The initial ABR was pathological in 70 infants. Results: We observed an improvement over time of the estimated hearing threshold in follow-up ABRs in 43 newborns (26 in the full-term group, mean improvement 27.9 dB SPL, and 17 in the pre-term group, mean improvement 34.6 dB SPL); such an improvement might be related to a maturation of the auditory pathways that was not complete at birth. Conclusions: The auditory system might not be completely developed at birth, and might require some months to complete; hence any early clinical approach should consider the possibility of an overtreatment, and any therapeutic strategy should only be considered once the diagnosis is certain and definitive

La lettura digitale e il web

Cosa cambia nelle abitudini di lettura di chi sceglie di leggere un ebook? In che modo l’editoria affronta i cambiamenti che il digitale porta con sé? Qual è il ruolo del web nel determinare queste trasformazioni? A queste ed altre domande un gruppo di undici book bloggers, riuniti in occasione di LibrInnovando 2011, tenta di rispondere in questo libro. A partire da un’idea di Marco Giacomello, gli autori offrono riflessioni e ricerche originali, utili tanto al lettore incuriosito dalle possibilità della lettura digitale quanto al professionista – l’editore, l’autore, il libraio – che si trova a vivere i mutamenti dell’editoria. Ma se cambiano i libri, cambia anche il modo di fare e diffondere cultura in Italia: l’ebook apre nuove possibilità di condivisione e socializzazione del sapere, che bisogna, criticamente, saper cogliere. Questo volume, parlando senza eccessivi tecnicismi e sempre con un profondo rispetto del lettore, sviluppa alcuni punti nodali e indica delle strade percorribili