Dasatinib-Loaded Erythrocytes Trigger Apoptosis in Untreated Chronic Myelogenous Leukemic Cells

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A novel thrombopoietin ( THPO

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A novel thrombopoietin ( THPO ) mutation altering mRNA splicing in a case of familial thrombocytosis

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Autophagy inhibition cooperates with erlotinib to induce glioblastoma cell death.

International audienceGliomas are the most common malignant primary brain tumors in adults. The median survival never exceeds 12 months, owing to inherent resistance to both radio and chemotherapies. Epidermal Growth Factor Receptor (EGFR) is amplified, overexpressed, and/or mutated in glioblastomas (GBM), making it a rational for therapy. Erlotinib, an EGFR kinase inhibitor is strongly associated with clinical response in several cancers. Inhibition of cell proliferation and induction of apoptosis by erlotinib were investigated in U87-MG and DBTRG-05MG, two human glioblastoma cell lines. The expression of several apoptosis-related proteins was investigated in these cell lines and in tumoral tissue from glioblastomas. Both cell lines expressed wild-type EGFR but were deficient for PTEN. Erlotinib induced a marked accumulation of the BIM protein, but the activation of caspase-3 machinery was missing, regardless of the decrease in XIAP. Moreover, in U87-MG, erlotinib promoted accumulation of αB-crystallin a small heat shock protein capable to impair caspase activation. DBTRG-05MG was found deficient for procaspase 3 and constitutively overexpressed αB-crystallin. Similarly, deficiencies in PTEN and procaspase 3 were constantly found in samples from glioblastoma samples, while αB-crystallin expression was inconsistent. In cell lines, high concentrations of erlotinib induced cell death through a caspase independent process and an autophagic process was evidenced in U87-MG. Inhibition of autophagy induced a marked increase in the death-inducing activity of erlotinib. These results confirm that glioblastoma cell lines exhibit several anti-apoptotic mechanisms, and underline that EGFR targeted therapy must be associated to other inhibitors to achieve an antitumoral effect

<i>TP53</i> alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma

<div><p>Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with <i>TP53</i> alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. <i>TP53</i> status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. <i>TP53</i> mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case. Interestingly, <i>TP53</i> mutations were both detected in sequential unselected blood mononuclear cells and in skin specimens. Cytogenetic analysis of blood specimens of 32 patients with SS showed a <i>TP53</i> deletion in 27 cases (84%). Altogether 29 out of 35 cases exhibited <i>TP53</i> mutation and/or deletion (83%). No difference in prognosis was observed according to <i>TP53</i> status while patients with secondary SS had a worse prognosis than patients with primary SS. Interestingly, patients with <i>TP53</i> alterations displayed a younger age and the presence of <i>TP53</i> alteration at initial diagnosis stage supports a pivotal oncogenic role for <i>TP53</i> mutation in SS as well as in erythrodermic MF making <i>TP53</i> assessment an ancillary method for the diagnosis of patients with erythroderma as patients with inflammatory dermatoses did not display <i>TP53</i> alteration.</p></div

Clinical and biological features of patients with primary Sézary Syndrome (SS) or with past-history of Mycosis Fungoides (MF) at secondary SS stage.

<p>Clinical and biological features of patients with primary Sézary Syndrome (SS) or with past-history of Mycosis Fungoides (MF) at secondary SS stage.</p

Schematic representation of somatic mutations identified in <i>TP53</i> by targeted deep sequencing (n = 35).

<p>Mutation sites were marked and amino acid changes were indicated. Colors and shapes indicated the kind of mutation and the presence in the COSMIC database.</p

Clinical data and somatic alterations of <i>TP53</i> gene in Sézary syndrome.

<p>Age at diagnosis (years), Clinical status means survival time in months after diagnosis of Sézary syndrome until the death or last clinical status, ⱡ data determined by fluorescence <i>in situ</i> hybridization, ¥ data determined by quantitative fluorescence <i>in situ</i> hybridization.</p