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The prognosis of acute myeloid leukemia (AML) in elderly (≥65 years) patients is poor and treatment remains non-consensual especially for those who are not eligible for intensive therapies. Our group has shown that in vitro the iron chelator deferasirox (DFX) synergizes with vitamin D (VD) to promote monocyte differentiation in primary AML cells. Herein, we present results from a retrospective case-control study in which the association of DFX (1-2 g/d) and 25-hydroxycholecalciferol (100,000 IU/week) (DFX/VD) was proposed to patients following demethylating agents failure. Median survival of patients treated with DFX/VD combination (n = 17) was significantly increased in comparison with matched patients receiving best supportive care (BSC) alone (n = 13) (10.4 versus 4 months respectively). In addition, the only factor associated to an increased overall survival in DFX/VD-treated patients was serum VD levels. We conclude that DFX/VD treatment correlated with increased overall survival of AML patients in this retrospective cohort of elderly patients.

Leishmania parasites are able to secure their survival and propagation within their host by altering signalling pathways involved in the ability of macrophages to kill pathogens or to engage adaptive immune system. An important step in this immune evasion process is the activation of host protein tyrosine phosphatase SHP-1 by Leishmania. SHP-1 has been shown to directly inactivate JAK2 and Erk1/2 and to play a role in the negative regulation of several transcription factors involved in macrophage activation. These signalling alterations contribute to the inactivation of critical macrophage functions (e.g., Nitric oxide, IL-12, and TNF-α). Additionally, to interfere with IFN-γ receptor signalling, Leishmania also alters several LPS-mediated responses. Recent findings from our laboratory revealed a pivotal role for SHP-1 in the inhibition of TLR-induced macrophage activation through binding to and inactivating IL-1-receptor-associated kinase 1 (IRAK-1). Furthermore, we identified the binding site as an evolutionarily conserved ITIM-like motif, which we named kinase tyrosine-based inhibitory motif (KTIM). Collectively, a better understanding of the evasion mechanisms utilized by Leishmania parasite could help to develop more efficient antileishmanial therapies in the near future.

O estudo tem como objetivo analisar o grau de isolamento de lagos naturais de salinidades e pHs muito diferenciados na região da Baixa Nhecolândia, porção sul do Pantanal Matogrossense, onde há o maior campo de lagos na zona tropical do planeta. Esta questão é essencial no contexto daquele ambiente, uma vez que a origem das diferentes águas é ainda controversa. Os sólidos dissolvidos totais, indicados pela condutividade elétrica indicam as variações de salinidade. Como a possibilidade de evaporação ou precipitação diferenciada entre os lagos foi descartada, pois os lagos estão próximos e em uma região plana, as brutais diferenças de salinidade ou estariam associadas a processos atuais, como diferentes graus de isolamento entre os lagos e o freático ou a pouco prováveis eventos do passado. Para testar a primeira hipótese foram analisadas as razões dos isótopos estáveis de Oxigênio e Deutério, uma vez que o fracionamento isotópico na evaporação enriquece a água líquida em 18O e D. A correlação encontrada entre as razões isotópicas e a condutividade elétrica é exponencial, indicando não apenas que o isolamento do freático cresce com a salinidade como que a partir de salinidades intermediárias já existe um importante isolamento dos lagos. Apresenta-se ainda dados de variação sazonal do nível da água de 14 lagos que mostram quedas mais erráticas nos lagos hipossalinos, o que foi interpretado como evidência de maior troca de água entre estes lagos e o freático.

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06 × 10⁻⁶, OR = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21 × 10⁻⁵. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⁻³, OR = 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⁻³, OR = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10⁻⁴, OR = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⁻¹³, OR= 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.

BACKGROUND: The D-mannose binding lectin ArtinM is known to recruit neutrophils, to degranulate mast cells and may have potential therapeutic applications. However, the effect of ArtinM on mast cell recruitment has not been investigated. METHODOLOGY: Male Wistar rats were injected i.p. with ArtinM or ConA (control). The ability of the lectin to degranulate peritoneal and mesenteric mast cells was examined. Recruitment of mast cells to the peritoneal cavity and mesentery after ArtinM injection was examined with or without depletion of peritoneal mast cells by distilled water. RESULTS: ArtinM degranulated both peritoneal and mesentery mast cells in vitro. Three days after i.p. injection of the lectin there were reduced numbers of mast cells in the peritoneal lavage, while at 7 days post injection of ArtinM, the number of peritoneal mast cells was close to control values. Since immature mast cells are recruited from the bone marrow, the effect of the lectin on bone marrow mast cells was examined. Injection of ArtinM resulted in an increased number of mast cells in the bone marrow. To determine if degranulation of mast cells in the peritoneal cavity was required for the increase in bone marrow mast cells, the peritoneal cavity was depleted of mast cells with ultrapure water. Exposure to ArtinM increased the number of mast cells in the bone marrow of rats depleted of peritoneal mast cells. CONCLUSIONS: The ArtinM induced recruitment of mast cells from the bone marrow to the peritoneal cavity may partially explain the therapeutic actions of ArtinM.

Le lymphome de la zone marginale ganglionnaire est un lymphome B à petites cellules relativement rare. L'hétérogénéité de la présentation histologique et l'absence de marqueur immunohistochimique ou moléculaire spécifique rendent son diagnostic difficile. Nodal marginal zone lymphoma is a rare non-Hodgkin B-cell lymphoma. The heterogeneity of morphology and the absence of specific immuno-histochemical or molecular markers make its diagnosis often challenging. [ABSTRACT FROM AUTHOR]

La tolérance rénale des anticancéreux est un problème lié à la fois à la toxicité intrinsèque de certaines chimiothérapies anticancéreuses et au terrain représenté par le patient cancéreux lui-même. Le patient atteint de cancer est, en effet, exposé à tous les types d'atteinte rénale (obstructive, fonctionnelle, organique secondaire aux traitements, à la radiothérapie, à une glomérulopathie paranéoplasique, à une microangiopathie thrombotique, etc.). L'indice thérapeutique des anticancéreux est souvent faible et les doses prescrites élevées pour obtenir une efficacité optimale sur la cellule cancéreuse. L'amélioration de la tolérance passe par la meilleure adaptation des doses, elle-même conditionnée par l'évaluation correcte de la fonction rénale. La prévention reste indispensable, d'autant que la mortalité associée à l'insuffisance rénale aiguë est très élevée. The renal toxicity of anticancer drugs is a clinical challenge because of the intrinsic toxicity of some anticancer drugs and because the cancer itself. Indeed, cancer patients are exposed to all types of renal disorders (obstructive, functional, organic because of radiotherapy, paraneoplastic glomerulopathy, thrombotic microangiopathy...). The therapeutic index of anticancer drugs is often narrow and the doses used for optimal efficacy are high. Improving safety requires a better dose adjustment, which depends on the correct evaluation of the renal function. Prevention remains important as the mortality associated with acute renal failure is very high. [ABSTRACT FROM AUTHOR]