Eosinophil Subtypes in Adults with Asthma and Adults with Chronic Obstructive Pulmonary Disease.

Rationale: There is a differential response to eosinophilic modulation between patients with asthma and those with chronic obstructive pulmonary disease (COPD). There is also evidence of different subtypes of eosinophils in murine models. However, no study has compared eosinophil subtypes in individuals with COPD and in those with asthma. Objectives: Study the differences in eosinophils subtypes based in the surface protein expression in COPD patients and asthmatic patients. Methods: We studied 10 stable subjects in each of four groups: subjects with COPD, subjects with asthma, smokers without COPD, and healthy volunteers. Subjects with COPD and those with asthma were matched by age, sex, and FEV1% predicted. The following variables were determined: anthropometrics, smoking, exacerbation history, medication use, lung function, and comorbidities. Using flow cytometry and confocal microscopy from blood samples, we determined differences in eosinophil surface proteins and classified them as 1) resident eosinophils (Siglec-8+CD62L+IL-3Rlo) or 2) inflammatory eosinophils (iEos; Siglec-8+CD62LloIL-3Rhi). IL-5 receptor was also determined. Findings were validated in 59 patients with COPD and in 17 patients with asthma. Measurements and Main Results: Patients with asthma had a higher proportion of iEos (25 ± 15%) compared with those with COPD (0.5 ± 1%), smokers without COPD (0.14 ± 0.24%), and healthy volunteers (0.67 ± 1.72%). In patients with asthma, the proportion of iEos was independent of total eosinophil number. iEos had more IL-5 receptors than resident eosinophils (777.02 ± 124.55 vs. 598.35 ± 318.69; P < 0.01). In patients with COPD, there was no relation between iEos number and inhaled corticosteroid use, disease severity, or exacerbations rate. The findings in patients with COPD and those with asthma were confirmed in validation cohorts. Conclusions: There are differences in the subtypes of circulating eosinophils between patients with asthma and those with COPD. This could have clinical implications in the interpretation of eosinophil significance and the approach to therapy in these patients.

Clinical and genetic features of congenital dyserythropoietic anemia (CDA).

INTRODUCTION: Congenital dyserythropoietic anemias (CDA) are characterized by hyporegenerative anemia with inadequate reticulocyte values, ineffective erythropoiesis, and hemolysis. Distinctive morphology of bone marrow erythroblasts and identification of causative genes allow classification into 4 types caused by variants in CDAN1, c15orf41, SEC23B, KIF23, and KLF1 genes. OBJECTIVE: Identify pathogenic variants in CDA patients. METHODS: Massive parallel sequencing with a targeted gene panel, Sanger sequencing, Comparative Genome Hybridization (CGH), and in silico predictive analysis of pathogenicity. RESULTS: Pathogenic variants were found in 21 of 53 patients studied from 44 unrelated families. Six variants were found in CDAN1: two reported, p.Arg714Trp and p.Arg725Trp and, four novel, p.Arg623Trp, p.Arg946Trp, p.Phe1125Ser and p.Ser1227Gly. Twelve variants were found in SEC23B: seven reported, p.Arg14Trp, p.Glu109Lys, p.Arg217Ter, c.835-2A>G, p.Arg535Ter, p.Arg550Ter and p.Arg718Ter and, five novel, p.Val164Leu, p.Arg190Gln, p.Gln521Ter, p.Arg546Trp, and p.Arg611Gln. The variant p.Glu325Lys in KLF1 was found in one patient and p.Tyr365Cys in ALAS2 in an other. Moreover, we identified genomic rearrangements by CGH in some SEC23B-monoallelic patients. CONCLUSIONS: New technologies for genetic studies will help to find variants in other genes, in addition to those known, that contribute to or modulate the CDA phenotype or support the correct diagnosis.

Genetic Testing at Diagnosis Has Prognostic Value in Patients with Chronic Lymphocytic Leukemia including at Early Stages.

Chronic lymphocytic leukemia (CLL) has a variable clinical evolution, with some patients living treatment-free for decades while others require therapy shortly after diagnosis. In a consecutive series of 217 CLL patients, molecular biomarkers with prognostic value (IGHV status, TP53 mutations, and cytogenetics), whose analysis is recommended prior to treatment start, were studied at diagnosis. Multivariate analyses identified prognostic variables for overall survival (OS) and time to first treatment (TTFT) and validated the CLL-IPI and IPS-E variables for all or early-stage patients (Rai 0-2/Binet A), respectively. Unmutated IGHV was associated with shorter OS and TTFT, even for early-stage patients. Lymphocyte count was not statistically significant for TTFT of early-stage patients in multivariate analysis. Our results validate the prognostic value of IGHV mutational status at diagnosis for OS and TTFT, including for early stages. Our findings suggest a role for molecular and mutational analysis at diagnosis in future prospective studies.

A case of congenital dyserythropoietic anemia type IV.

Congenital dyserythropoietic anemias (CDAs) are displayed by ineffective erythropoiesis. The wide variety of phenotypes observed in CDA patients makes differential diagnosis difficult; identification of the genetic variants is crucial in clinical management. We report the fifth case of a patient with unclassified CDAs, after genetic study, with CDA type IV.

Induction of apoptosis in leukemic cell lines treated with captopril, trandolapril and losartan: a new role in the treatment of leukaemia for these agents.

Renin-angiotensin system (RAS) in the bone marrow is related to proliferation and cellular differentiation. We investigated the effect of ACE inhibitors (ACEI) captopril (>1mM) and trandolapril (>0.05 mM) and losartan (0.2 mM) on K562 cell line and K562 transfected with c-myc, bcl-x and bcl-2 (KmycB, Kbclx and Kbcl2 respectively). RAS components, proliferation, apoptosis and c-myc expression were analyzed. ACEI and losartan inhibited cell growth, decreased c-myc expression and increased apoptosis. These effects seem to be associated to angiotensin II-induced Smad activation. This work offers a new possible line of treatment for some acute myeloid leukemias and a new area of clinical research.