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Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe.
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Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe.

Haematologica. 2017 Jan 19;:

Authors: Maitra P, Caughey M, Robinson L, Desai PC, Jones S, Nouraie M, Gladwin MT, Hinderliter A, Cai J, Ataga KI

Abstract
Although recent studies show an improved survival of children with sickle cell disease in the US and Europe, mortality remains high for adult patients. This study was conducted to evaluate the factors associated with mortality in adult patients following the approval of hydroxyurea. We first evaluated the association between selected variables and mortality at an academic center (UNC cohort). Data sources were then searched for publications from 1998 to June, 2016, with meta-analysis of eligible studies conducted in North America and Europe to evaluate the associations of selected variables with mortality in adult patients. Nine studies, combined with the UNC cohort (total: 3257 patients) met the eligibility criteria. Mortality was significantly associated with age (per 10-year increase in age) (7 studies, 2,306 participants; hazard ratio: 1.28; 95% confidence interval: 1.10-1.50), tricuspid regurgitant jet velocity ≥ 2.5 m/s (5 studies, 1,577 participants; hazard ratio: 3.03; 95% confidence interval: 2.0 - 4.60), reticulocyte count (3 studies, 1,050 participants; hazard ratio: 1.05; 95% confidence interval: 1.01-1.10), log(N-terminal-pro-brain natriuretic peptide) (3 studies, 800 participants; hazard ratio: 1.68; 95% confidence interval: 1.48 - 1.90), and fetal hemoglobin (7 studies, 2,477 participants; hazard ratio: 0.97; 95% confidence interval: 0.94-1.0). This study identifies variables associated with mortality in adult patients with sickle cell disease in the hydroxyurea era.

PMID: 28104703 [PubMed - as supplied by publisher]




IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.
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IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.

Haematologica. 2017 Jan 19;:

Authors: Betts BC, Pidala J, Kim J, Mishra A, Nishihori T, Perez L, Ochoa-Bayona JL, Khimani F, Walton K, Bookout R, Nieder M, Khaira DK, Davila M, Alsina M, Field T, Ayala E, Locke FL, Riches M, Kharfan-Dabaja M, Fernandez H, Anasetti C

Abstract
Graft-versus-host disease remains a major cause of transplant-related mortality. Interleukin-2 plus sirolimus synergistically reduces acute graft-versus-host disease in rodents and promotes regulatory T-cells. This phase II trial tested the hypothesis that interleukin-2 would facilitate STAT5 phosphorylation in donor T-cells, expand regulatory T-cells, and ameliorate graft-versus-host disease. Between 4/16/2014-12/19/2015, 20 patients received interleukin-2 (200,000IU/m2 thrice weekly, days 0 to +90) with sirolimus (5-14ng/ml) and tacrolimus (3-7ng/ml) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation. The study was designed to capture an increase in regulatory T-cells from 16.0% to >23.2% at day +30. Interleukin-2/sirolimus/tacrolimus significantly increased regulatory T-cells at day +30 compared to our published data with sirolimus/tacrolimus (23.8% versus 16.0%, P=0.0016; 0.052 k/ul versus 0.037 k/ul, P=0.0163), achieving the primary study endpoint. However, adding interleukin-2 to sirolimus/tacrolimus led to a fall in regulatory T-cells by day +90 and did not reduce acute or chronic graft-versus-host disease. Patients who discontinued interleukin-2 before day +100 showed a suggestion toward less grade II-IV acute graft-versus-host disease (16.7% versus 50%, P=0.1475). We surmise that the reported accumulation of interleukin-2 receptors in circulation over time may neutralize interleukin-2, lead to progressive loss of regulatory T-cells, and offset its clinical efficacy. The amount of phospho-STAT3+ CD4+ T-cells correlated with donor T-cell activation and acute graft-versus-host incidence despite early T-cell STAT5 phosphorylation by interleukin-2. Optimizing interleukin-2 dosing and overcoming cytokine sequestration by soluble interleukin-2 receptor may sustain lasting regulatory T-cells after allogeneic transplantation. However, an approach to target STAT3 is needed to enhance graft-versus-host disease prevention (NCT01927120).

PMID: 28104702 [PubMed - as supplied by publisher]




Prospective study of thrombosis and thrombospondin-1 expression in Chuvash polycythemia.
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Prospective study of thrombosis and thrombospondin-1 expression in Chuvash polycythemia.

Haematologica. 2017 Jan 19;:

Authors: Sergueeva A, Miasnikova G, Shah BN, Song J, Lisina E, Okhotin DJ, Nouraie M, Nekhai S, Ammosova T, Niu XM, Prchal JT, Zhang X, Gordeuk VR

PMID: 28104701 [PubMed - as supplied by publisher]




Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mTOR kinase inhibitors in aggressive B-cell lymphomas.
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Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mTOR kinase inhibitors in aggressive B-cell lymphomas.

Haematologica. 2017 Jan 19;:

Authors: Bi C, Zhang X, Lu T, Zhang X, Wang X, Meng B, Zhang H, Wang P, Vose JM, Chan WC, McKeithan TW, Fu K

Abstract
Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in eukaryotes. The second generation of mTOR kinase inhibitors (TORKi), directly targeting the mTOR catalytic site, are more effective than rapamycin and its analogs in cancer treatment, particularly in inducing apoptosis. However, the mechanism underlying the cytotoxic effect of TORKi remains elusive. Herein, we demonstrated that TORKi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP activation. Knocking out Rictor, a key component of mTORC2, or inhibiting p70S6K has little effect on TORKi-induced apoptosis. Conversely, increasing the eIF4E:4EBP ratio by either overexpressing eIF4E or knocking out 4EBP1/2 protected lymphoma cells from TORKi-induced cytotoxicity. Furthermore, down-regulation of MCL1 expression plays an important role in TORKi-induced apoptosis whereas BCL-2 overexpression confers resistance to TORKi treatment. We further showed that the therapeutic effect of TORKi in aggressive B-cell lymphomas can be predicted by BH3 profiling and improved by combining with pro-apoptotic drugs, especially BCL-2 inhibitors, both in vitro and in vivo. Taken together, this study provides mechanistic insight in TORKi cytotoxicity and identified a potential way to optimize its efficacy in clinical treatment of aggressive B-cell lymphoma.

PMID: 28104700 [PubMed - as supplied by publisher]