Insight into the molecular pathophysiology of myelodysplastic syndromes: targets for novel therapy

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor-alpha, interferon-gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1 genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B, EZH2, ASXL1). In addition, abnormalities in regulatory T-cell dynamics and atypical interactions between the bone marrow microenvironment, stroma and progenitor cells, and abnormal maintenance of telomeres are also notable contributors to the complex pathogenesis of MDS. These pathways represent potential targets for novel therapies. Specific therapies include drugs targeting aberrant DNA methylation and chromatin remodeling, modulating/activating the immune system to enhance tumor-specific cellular immune responses and reduce anomalous cytokine signaling, and blocking abnormal interaction between hematopoietic progenitors and stromal cells

Sazonalidade em índices de preços : o caso do IPC-FIPE

This article exams the issue of seasonal adjustment of price indices. This subject has been discussed frequently but consensus has yet to be reached. The case studied here is the Consumer Price Index elaborated by Pipe (CPI-Fipe), commonly used for indexation. The period analysed is Jan/80 to Dec/94. Using two alternative methodologies X-ll procedure and Structural Models for Time Series eleven seasonal items were identified. When the seasonal effects are considered together, it is observed that they cancel each other out. Thus, no seasonal pattern is transfered to the general index. Due to this result, seasonal adjustment of the CPI-Fipe is unnecessary.Este artigo aborda a questao do ajustamento sazonal de índices de preços, assunto frequentemente discutido mas sobre o qual não existe consenso. Estuda-se o caso concreto do IPC-Fipe, índice largamente usado como indexador. O período considerado estende-se de janeiro de 1980 a dezembro de 1994. Utilizando duas metodologias alternativas método X-11 e Modelos Estruturais de Séries de Tempo foram identificados onze itens do IPC-Fipe com comportamento sazonal. Quando se agrupam os efeitos sazonais desses itens, observa-se que eles se compensam, não transferindo, dessa forma, nenhum padrão de sazonalidade para o índice geral. Por esse resultado, o ajustamento sazonal do IPC-Fipe não é necessário

A inovação induzida e os limites a modernização na agricultura brasileira.

A agricultura brasileira vem sustentando taxas anuais de crescimento do produto superiores a 5% ao ano ao longo das duas últimas décadas. Esse ritmo de crescimento tem se mantido bastante estável no tempo, sendo mesmo superior as taxas verificadas na maioria dos demais países

Increasing the germination percentage of a declining native orchid (Himantoglossum adriaticum) by pollen transfer and outbreeding between populations

The declining native orchid Himantoglossum adriaticum H. Baumann is a European endemic of priority interest (92/43/ EEC, Annex II). Northern Italian populations of H. adriaticum are small and isolated, with depressed seed set. Given the important implications for plant population conservation, we tested the hypothesis that artificial pollen transfer (hand-pollination) and outbreeding between populations increases fruit set and seed germination percentage. The background fruit set and in vitro germination rates were determined for ten reference populations. An artificial cross-pollination experiment included (a) pollen transfer from one large population to two small and isolated populations; (b) pollen transfer between two small but not isolated populations; (c) within-population pollen transfer (control). All seeds were sown on a modified Malmgren's medium and cultured in a controlled environment. Germination percentage was compared using a Kruskal-Wallis anova. The background fruit set (mean = 18%) and germination (<5%) rates were consistently low across populations. Fruit set after hand-pollination was consistently 100%. Pollen transfer from the largest population to smaller populations resulted in an increase in total germination ranging from 0.9% to 2.9%. The largest increase in germination occurred between small-sized and less isolated populations (from 1.7% to 5.1%). The results of pollen transfer between the small populations are particularly encouraging, as the mean increase in germination was almost four times that of the control. Outbreeding can be considered a valuable tool to increase genetic flow and germination in natural populations, limit the accumulation of detrimental effects on fitness driven by repeated breeding with closely-related individuals, thereby increasing the possibility of conservation of rare or endangered species

Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells

AbstractT-cell recovery following myeloablative preparatory regimens and cord blood transplantation in adult patients gen erally occurs between 1 and 3 years following allogeneic bone marrow transplantation. T-cell reconstitution may involve thymic education of donor-derived precursors or peripheral expansion of mature T-cells transferred in the graft. We measured quantitative and qualitative immunologic reconstitution, T-cell receptor spectratyping, and T-cell receptor excision circle (TREC) levels in adult recipients of umbilical cord blood transplants following a novel nonmyeloablative regimen. These results were compared to previously published results of similar patients receiving a myeloablative regimen and cord blood stem cells. With small numbers of patients treated so far, T-cells (CD3+) reached normal levels in adults 6 to 12 months following nonmyeloablative transplantation compared with 24 months in adults receiving a myeloablative regimen. At 12 months after transplantation, the numbers of phenotypically naive (CD45RA) T-cells were higher in those receiving the nonmyeloablative regimen. The T-cell repertoire in cord blood recipients treated with a nonmyeloablative regimen was markedly more diverse and robust compared with the repertoire in those receiving the myeloablative regimen at similar time points. TRECs (which are generated within the thymus and identify new thymic emigrants and those that have not divided) were detected 12 months after transplantation in the nonmyeloablative recipients, whereas TRECs were not detected in adults until 18 to 24 months in those receiving myeloablative regimens. Thus, in adults receiving a nonmyeloablative preparatory regimen, the quantitative and qualitative recovery of T-cells occurs through rapid peripheral expansion. The ability of patients receiving a nonmyeloablative regimen to recover within a few months suggests that the peripheral niches in which T-cells can proliferate are preserved in these patients compared to those receiving ablative regimens. Moreover, the presence of TREC-positive cells within 1 year suggests that thymic recovery is likewise accelerated in non myeloablative compared to myeloablative regimens.Biol Blood Marrow Transplant 2002;8(5):249-56

Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia

PURPOSE: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. METHODS: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. RESULTS: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 (P \u3c .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). CONCLUSION: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation

Volume Assessment in Mechanically Ventilated Critical Care Patients Using Bioimpedance Vectorial Analysis, Brain Natriuretic Peptide, and Central Venous Pressure

Purpose. Strategies for volume assessment of critically ill patients are limited, yet early goal-directed therapy improves outcomes. Central venous pressure (CVP), Bioimpedance Vectorial Analysis (BIVA), and brain natriuretic peptide (BNP) are potentially useful tools. We studied the utility of these measures, alone and in combination, to predict changing oxygenation. Methods. Thirty-four mechanically ventilated patients, 26 of whom had data beyond the first study day, were studied. Relationships were assessed between CVP, BIVA, BNP, and oxygenation index (O2I) in a cross-sectional (baseline) and longitudinal fashion using both univariate and multivariable modeling. Results. At baseline, CVP and O2I were positively correlated (R = 0.39; P = .021), while CVP and BIVA were weakly correlated (R = −0.38; P = .025). The association between slopes of variables over time was negligible, with the exception of BNP, whose slope was correlated with O2I (R = 0.40; P = .044). Comparing tertiles of CVP, BIVA, and BNP slopes with the slope of O2I revealed only modest agreement between BNP and O2I (kappa = 0.25; P = .067). In a regression model, only BNP was significantly associated with O2I; however, this was strengthened by including CVP in the model. Conclusions. BNP seems to be a valuable noninvasive measure of volume status in critical care and should be assessed in a prospective manner