Severe Aplastic Anemia and PNH

Severe aplastic anemia (SAA) is an autoimmune disorder (AID) due to the attack of autoreactive cytotoxic T lymphocytes to the hematopoietic component of the bone marrow

Luminescence and Charge-transfer .2. Aminomethyl Anthracene-derivatives As Fluorescent Pet (photoinduced Electron-transfer) Sensors for Protons

The importance of the modular structure 'fluor-spacer-amine' is pointed out for the design of fluorescent molecular sensors for pH according to the principle of photoinduced electron transfer (PET). Anthracen-9-yl methylamines (24) and some azacrown ether analogues (15 and 23) are examined in this context. They show pH-dependent fluorescence quantum yields describable by eqn. (5) while all other electronic spectral parameters remain essentially pH-invariant. The range of pK(a) values of these sensors are understandable in terms of macrocyclic effects and the transmission of electric fields across the anthracene short axis. Phase-shift fluorometric determination of the fluorescence lifetimes of these sensors allows the calculation of the rate constant of PET in their proton-free form to be 10(10)-10(11) s-1, with the diamines 23 and 24b exhibiting the faster rates

Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol

Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence = 6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting 472 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P = 0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P = 5.8x10(-7); odds ratio (OR) = 6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P = 0.015) and had lower risk of AAP-related complications (15% vs 43%; P = 0.13) compared with cases without this variant. Among 45 cases and 517 control

A novel non genomic glucocorticoid signaling mediated by a membrane palmitoylated glucocorticoid receptor cross talks with GnRH in gonadotrope cells

International audienceGlucocorticoid hormones (GC) are the main stress mediators associated with reproductive disorders. GC exert their effects through activation of the glucocorticoid receptor (GR) principally acting as a transcription factor. Beside well-established GR-mediated genomic actions, several lines of evidence suggest a role for rapid membrane-initiated GC signaling in gonadotrope cells triggered by a membrane-associated GR. Herein, we demonstrate the existence of a specific membrane-initiated GC signaling in L beta T2 gonadotrope cells involving two related phosphoproteins: Ca2+/Calmodulin-dependent protein kinase II (CaMKII) and synapsin-I. Within 5 min, L beta T2 cells treated with stress range of 10(-7) M Corticosterone or a membrane impermeable-GC, BSA-conjugated corticosterone, exhibited a 2-fold increase in levels of phospho-CaMKII and phospho-synapsin-I. Biochemical approaches revealed that this rapid signaling is promoted by a palmitoylated GR. Importantly, GC significantly alter GnRH-induced CaMKII phosphorylation, consistent with a novel cross-talk between the GnRH receptor and GC. This negative effect of GC on GnRH signaling was further observed on LH release by mouse pituitary explants. Altogether, our work provides new findings in GC field by bringing novel understanding on how GR integrates plasma membrane, allowing GC membrane-initiated signaling that differs in presence of GnRH to disrupt GnRH-dependent signaling and LH secretion