Autologous hematopoietic stem cell transplantation (AHSCT) increases C-peptide levels and induces insulin independence in patients with type 1 diabetes. This study aimed to investigate how clinical outcomes may associate with the immunological status, especially concerning the balance between immunoregulation and autoreactivity. Twenty-one type 1 diabetes patients were monitored after AHSCT and assessed every 6 months for duration of insulin independence, C-peptide levels, frequencies of islet-specific autoreactive CD8+ T cells (CTL), regulatory lymphocyte subsets, thymic function, and T-cell repertoire diversity. In median follow-up of 78 (range 15–106) months, all patients became insulin-independent, resuming insulin after median of 43 (range 6–100) months. Patients were retrospectively divided into short- or prolonged-remission groups, according to duration of insulin independence. For the entire follow-up, CD3+CD4+ T-cell numbers remained lower than baseline in both groups, whereas CD3+CD8+ T-cell levels did not change, resulting in a CD4/CD8 ratio inversion. Memory CTL comprehended most of T cells detected on long-term follow-up of patients after AHSCT. B cells reconstituted to baseline levels at 2–3 months post-AHSCT in both patient groups. In the prolonged-remission-group, baseline islet-specific T-cell autoreactivity persisted after transplantation, but regulatory T cell counts increased. Patients with lower frequencies of autoreactive islet-specific T cells remained insulin-free longer and presented greater C-peptide levels than those with lower frequencies of these cells. Therefore, immune monitoring identified a subgroup of patients with superior clinical outcome of AHSCT. Our study shows that improved immunoregulation may balance autoreactivity endorsing better metabolic outcomes in patients with lower frequencies of islet-specific T cells. Development of new strategies of AHSCT is necessary to increase frequency and function of T and B regulatory cells and decrease efficiently autoreactive islet-specific T and B memory cells in type 1 diabetes patients undergoing transplantation.

SummarySome cases of T-cell acute lymphoblastic leukaemia (ALL) express markers found in natural-killer (NK) cells, such as CD56 and CD16. Out of 84 T-cell ALL cases diagnosed at our Institution, CD56 and/or CD16 was detected in 24 (28AE5%), which we designated T/NK-ALL group. Clinical features, laboratory characteristics, survival and expression of cytotoxic molecules were compared in T/NK-ALL and T-ALL patients. Significant differences were observed regarding age (24AE9 vs. 16AE4 years in T/NK-ALL and T-ALL, respectively, P = 0AE006) and platelet counts (177 · 10 9 /l vs. 75 · 10 9 /l in T/NK-ALL and T-ALL, respectively, P = 0AE03). Immunophenotypic analysis demonstrated that CD34, CD45RA and CD33 were more expressed in T/NK-ALL patients, whereas CD8 and terminal deoxynucleotidyl transferase were more expressed in T-ALL patients (P < 0AE05). The mean overall survival (863 vs. 1869 d, P = 0AE02) and disease-free survival (855 vs. 2095 d, P = 0AE002) were shorter in patients expressing CD56/CD16. However, multivariate analysis identified CD56/CD16 as an independent prognostic factor only for DFS. Cytotoxic molecules were highly expressed in T/NK-ALL compared to T-ALL. Perforin, granzyme B and TIA-1 were detected in 12/17, 4/17 and 7/ 24 T/NK-ALL patients and in 1/20, 0/20 and 1/20 T-ALL respectively (P < 0AE001, P = 0AE036 and P = 0AE054). Therefore, the presence of CD56/ CD16 was associated with distinct clinical features and expression of cytotoxic molecules in the blasts.

BackgroundTuberculosis is a serious public health problem worldwide. It is the leading cause of death amongst people living with HIV, and default from tuberculosis (TB) treatment in people living with HIV increases the probability of death. The aim of this study was to estimate the survival probability of people living with HIV who default treatment for TB compared to those who complete the treatment.MethodsThis was a longitudinal cohort study of people living with HIV, from June 2007 to December 2013 with two components: a retrospective (for those who started tuberculosis treatment before 2013 for whom failure (death) or censoring occurred before 2013), and prospective (those who started tuberculosis treatment at any time between 2007 and June 2013 and for whom death or censoring occurred after the beginning of 2013), at two referral hospitals for people living with HIV (Correia Picanço Hospital - HCP and at Hospital Universitário Oswaldo Cruz – HUOC), in Recife/PE. A total of 317 patients who initiated TB treatment were studied. Default from TB treatment was defined as any patient who failed to attend their pre-booked return appointment at the health center for more than 30 consecutive days, in accordance with Brazilian Ministry of Health recommendations.ResultsFrom a cohort of 2372 people living with HIV we analyzed 317 patients who had initiated TB treatment. The incidence of death was 5.6 deaths per 100 persons per year (CI 95% 4.5 to 7.08). Independent factors associated with death: default from TB treatment 3.65 HR (95% CI 2.28 to 5.83); CD4 < 200 cells/mm3 2.39 HR (95% CI 1.44 to 3.96); extrapulmonary tuberculosis 1.56 HR (95% CI 0.93 to 2.63); smoking 2.28 HR (95% CI 1.33 to 3.89); alcohol light 0.13 HR (95% CI 0.03 to 0.56).ConclusionThe probability of death in people living with HIV who default TB treatment is approximately four times greater when compared to those who do not default from treatment.

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.

Background Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is currently one of the most effective therapies in onco-hematology. For the treatment of the disease and prevention of such complications, a complex pharmacotherapeutic regimen is employed. Non-compliance is prevalent among adolescents and young adults with chronic hematological diseases, being reported by up to 50% of the patients. Objective To evaluate the results of pharmacotherapeutic follow-up on medication compliance and on the knowledge about pharmacotherapy of patients who underwent allo-HSCT. Methods A single-arm, open-label and non-randomized intervention study developed in an allo-HSCT outpatient clinic. The participants attended pharmaceutical consultations and had their knowledge about pharmacotherapy and medication compliance measured by MedTake and Brief Medication Questionnaire (BMQ), respectively. Results A total of 27 patients attended pharmaceutical consultations (4.81 consultations/patient; SD = 1.80). There was an improvement in medication compliance and in knowledge between the first and last consultations (p < 0.05). In the final consultation, 70.37% of the patients showed compliance, with a knowledge rate of 98.35% (SD = 3.63). Non-compliant individuals presented a greater tendency to hospital readmissions. There was no relationship between medication compliance and sociodemographic variables, graft-versus-host disease, and knowledge about pharmacotherapy. Conclusions Pharmacotherapeutic follow-up contributed to improving medication compliance. Knowledge about pharmacotherapy alone does not translate into behaviors, which corroborates the complexity of the biopsychosocial factors associated with medication compliance.

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Summary Despite adequate immunization and penicillin prophylaxis, bacterial infections remain a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Besides hyposplenism, inflammatory and genetic factors might modulate their susceptibility to bacterial infections. We performed a candidate gene association of single nucleotide polymorphisms (SNPs) located in Toll‐like receptor (TLR) genes, encoding prominent molecules for innate immune responses, with the occurrence of bacterial infections in patients with SCD. A cohort followed in centres in Brazil, France and Senegal (n = 430) was divided in two groups: patients who presented at least one episode of bacterial infection (n = 235) and patients who never had bacterial infections (n = 195). There were no differences in gender or age distribution among the groups. The frequency of the TLR2 rs4696480 TA genotype was significantly lower in the infected group (50% vs. 67%, odds ratio [OR] = 0·50, 95% confidence interval [CI] 0·34–0·75, P < 0·001), and the TT genotype was significantly higher in the infected group (15% vs. 5%, OR = 3·18, 95% CI 1·53–6·61, P < 0·001). Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. The rs4696480 TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and inefficient responses (TT genotype) to infectious agents in SCD settings.

Key Points• Pre-allo-HSCT ageadjusted recipient telomere length and mismatched unrelated donor predict TRM.Various pretransplant patient and disease characteristics are associated with treatmentrelated mortality (TRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).However, TRM cannot yet be satisfactorily predicted. We prospectively investigated the