Deregulation of apoptosis in acute myeloid leukemia.

Apoptosis, or programmed cell death, is central to the development and homeostasis of the hematopoietic system. Dysregulation of apoptosis plays an important role in the development of a variety of human pathologies, including cancer, autoimmune diseases and neurodegenerative disorders. Particularly, studies carried out in the last years have shown that leukemia cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells over their normal counterpart. Furthermore, abnormalities in the apoptotic response also play a role in the development of drug resistance by leukemic cells. The identification of the different components of the apoptotic pathways has enabled the detection of various biochemical defects present in leukemic cells compared to their normal counterpart. These defects contribute to the survival advantage of the leukemic clone over the normal hematopoietic cells and are also frequently associated with a low rate of response to standard chemotherapy treatment and with poor survival. Furthermore, these findings have also lead to the identification of many potential apoptotic targets for the development of new drugs targeting anti-apoptotic molecules abnormally expressed or regulated in leukemic cells. Many of these drugs restore the sensitivity of leukemic cells to apoptotic stimuli and some of them are under investigation at a clinical level

Périgord black truffle genome uncovers evolutionary origins and mechanisms of symbiosis

LetterInternational audienceThe Périgord black truffle ($Tuber\ melanosporum$ Vittad.) and the Piedmont white truffle dominate today's truffle market. The hypogeous fruiting body of $T.\ melanosporum$ is a gastronomic delicacy produced by an ectomycorrhizal symbiont endemic to calcareous soils in southern Europe. The worldwide demand for this truffle has fuelled intense efforts at cultivation. Identification of processes that condition and trigger fruit body and symbiosis formation, ultimately leading to efficient crop production, will be facilitated by a thorough analysis of truffle genomic traits. In the ectomycorrhizal $Laccaria\ bicolor$, the expansion of gene families may have acted as a 'symbiosis toolbox'. This feature may however reflect evolution of this particular taxon and not a general trait shared by all ectomycorrhizal species. To get a better understanding of the biology and evolution of the ectomycorrhizal symbiosis, we report here the sequence of the haploid genome of $T.\ melanosporum$, which at $\sim$125 megabases is the largest and most complex fungal genome sequenced so far. This expansion results from a proliferation of transposable elements accounting for $\sim$58% of the genome. In contrast, this genome only contains $\sim$7,500 protein-coding genes with very rare multigene families. It lacks large sets of carbohydrate cleaving enzymes, but a few of them involved in degradation of plant cell walls are induced in symbiotic tissues. The latter feature and the upregulation of genes encoding for lipases and multicopper oxidases suggest that $T.\ melanosporum$ degrades its host cell walls during colonization. Symbiosis induces an increased expression of carbohydrate and amino acid transporters in both $L.\ bicolor$ and $T.\ melanosporum$, but the comparison of genomic traits in the two ectomycorrhizal fungi showed that genetic predispositions for symbiosis $-$'the symbiosis toolbox'$-$ evolved along different ways in ascomycetes and basidiomycete

Transcriptional silencing of the ETS1 oncogene contributes to human granulocytic differentiation

Ets-1 is a widely expressed transcription factor implicated in several biological processes including hematopoiesis, where it contributes to the regulation of cellular differentiation. The functions of Ets-1 are regulated by transcription factors as well as by phosphorylation events: phosphorylation of threonine 38 activates Ets-1, whereas phosphorylation of a cluster of serines within exon VII reduces DNA binding activity. This study focuses on the role of Ets-1 during granulocytic differentiation of NB4 promyelocytic and HL60 myeloblastic leukemia cell lines induced by all-trans retinoic acid

Erythropoietin, hemoglobin and endothelial progenitor cell levels in patients with acute myocardial infarction

We investigated whether changes in plasmatic erythropoietin (Epo) levels in patients with acute myocardial infarction (AMI) reflect changes in hemoglobin (Hb) levels. We studied plasma Epo levels and their relation with Hb and endothelial progenitors in patients with AMI and in patients with unstable angina (UAP). The number of endothelial progenitors was higher in patients with LVEF>40 than in those with LVEF<40

Diphtheria toxin fused to variant human interleukin-3 induces cytotoxicity of blasts from patients with acute myeloid leukemia according to the level of interleukin-3 receptor expression

Leukemic blasts from patients with acute myeloid leukemia (AML) frequently express high levels of the interleukin-3 receptor α chain (IL-3Rα). In the present study, we have explored the sensitivity of primary leukemic blasts obtained from 34 patients with AML to a diphtheria toxin (DT) composed of the catalytic and translocation domains of DT (DT388) fused to IL-3 (DT388IL-3) and to DT388 fused to a variant IL-3 with increased binding affinity (DT388IL-3[K116W]). On a molar basis, DT388IL-3[K116W] was significantly more active than DT388IL-3 in mediating leukemic cell killing. The rate of cell killing induced by the 2 DT/IL-3 fusion proteins was significantly correlated with the level of IL-3Rα/IL-3Rβ expressed on leukemic blasts. These observations support a potential use of DT388IL-3[K116W] in the treatment of refractory AMLs and provide a simple biochemical parameter for the selection of eligible patients. (Blood. 2005;106:2527-2529

Studio di coorte sull’incidenza dei decubiti al calcagno in pazienti immobilizzati da gesso agli arti inferiori presso l’Istituto Ortopedico Rizzoli e dei possibili fattori di rischio

Introduzione. La lesione da decubito, in particolare al calcagno, può rappresentare una complicanza da immobilizzazione per apparecchio gessato. Obiettivo. Indagare l’incidenza delle complicanze cutanee tardive (in particolare la lesione da decubito al calcagno) da apparecchio gessato e valutare eventuali fattori di rischio. Materiali e metodi. Sono stati monitorati per 16 mesi tutti i pazienti consecutivi, provenienti da tre reparti, a cui veniva applicato un apparecchio gessato agli arti inferiori. I fattori di rischio sono stati identificati dall’infermiere addetto al confezionamento del gesso e la gravità della lesione stadiata con la scala NPUAP, al momento dell’asportazione del gesso, dall’infermiere del reparto o dell’ambulatorio. Risultati. Sono stati arruolati 216 pazienti. Il 17.6% (38/216) ha avuto una lesione da decubito: 16/124 (13%) nei reparti ortopedici e 22/92 (24%) nei reparti oncologici. Sono risultati fattori di rischio all’analisi multivariata, l’essere sottoposti a trattamenti con farmaci antiblastici (p=0.033; OR=2.61) (la sola patologia oncologica non aumentava il rischio rispetto alla popolazione ortopedica generale); l’avere la cute arrossata prima dell’applicazione dell’apparecchio gessato (p=0.001; OR=4.44) e l’avere accusato disturbi dopo l’applicazione (p=0.000; OR=7.86). Le lesioni erano prevalentemente di 1° grado e solo il 2.4% (6/216) erano di II grado o superiore. L’estensione e la durata del gesso, il materiale con cui viene confezionato, e l’aver subito un intervento chirurgico non sono risultati fattori di rischio statisticamente significativi. Conclusioni. Le lesioni da decubito da gesso sono una complicanza relativamente frequente in particolare in alcune popolazioni a rischio che devono tenere immobilizzati gli arti inferiori. La conoscenza del rischio di base e l’identificazione di specifici fattori di rischio possono permettere l’identificazione e lo studio di misure preventive per migliorare l’assistenza a questa specifica popolazione

New data from the Italian National Register of Congenital Coagulopathies, 2016 Annual Survey

In Italy, the National Register of Congenital Coagulopathies (NRCC) collects epidemiological and therapeutic data from patients affected by haemophilia A (HA), haemophilia B (HB), von Willebrand's disease (vWD) and other rare coagulation disorders. Here we present data from the 2016 annual survey

Podocalyxin is expressed in normal and leukemic monocytes

We have investigated the expression of podocalyxin in primary cultures of leukemic blast cells from 73 patients with acute mycloid leukemia. Podocalyxin was expressed at moderate levels in 15 patients and at high levels in 13 patients. The analysis of membrane markers showed that Podocalyxin expression in leukemic blasts was associated with a monocytic immunophenotype. Cases of podocalyxin-positive acute myelogenous leukemia had high blastcell counts at diagnosis and elevated CD123, CD135, VLA-4 and CXCR4 expression, features associated with poor prognosis. Podocalyxin expression in leukemic blasts was coupled with the concomitant expression of VEGF-RI, -R2, -R3 and Tie-2, the capacity to release VEGF-A and angiopoictin1 and the ability to differentiate into endothelial cells under appropriate culture conditions. These findings show that podocalyxin is a marker of acute myeloid leukemia with a monocytic phenotype and suggest that podocalyxin-positive cases of acute myeloid leukemia originate from the malignant transformation of progenitors common to the mycloid and endothelial lineages. These observations suggest a possible relationship between the monocytic lineage and podocytes. (c) 2006 Elsevier Inc. All rights reserved

A small molecule Smac mimic potentiates TRAIL-mediated cell death of ovarian cancer cells

Objectives.: Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (Smac) has been described to sensitize for apoptosis. We have explored the proapoptotic activity of a small molecule mimic of Smac/DIABLO on ovarian cancer cell lines (A2780 cells and its chemoresistant derivatives A2780/ADR and A2780/DDP), cancer cell lines and in primary ovarian cancer cells. Methods.: The effects of a small molecule mimic of Smac/DIABLO on ovarian cancer cell lines and primary ovarian cancer cells were determined by cell proliferation, apoptosis and biochemical assays. Results.: This compound added alone elicited only a weak proapoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or agonistic TRAILR2 antibody (Lexatumumab) in inducing apoptosis of ovarian cancer cells. Conclusions.: These observations suggest that small molecule mimic of Smac/DIABLO could be useful for the development of experimental strategies aiming to treat ovarian cancer. Interestingly, in addition to its well known proapoptotic effects, Smac/DIABLO elicited a significant increase of pro-caspase-3 levels. © 2007 Elsevier Inc. All rights reserved