102 research outputs found
Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder
Mammalian microRNAs are emerging as key regulators of the development and function of the immune system. Here, we report a strong but transient induction of miR-155 in mouse bone marrow after injection of bacterial lipopolysaccharide (LPS) correlated with granulocyte/monocyte (GM) expansion. Demonstrating the sufficiency of miR-155 to drive GM expansion, enforced expression in mouse bone marrow cells caused GM proliferation in a manner reminiscent of LPS treatment. However, the miR-155âinduced GM populations displayed pathological features characteristic of myeloid neoplasia. Of possible relevance to human disease, miR-155 was found to be overexpressed in the bone marrow of patients with certain subtypes of acute myeloid leukemia (AML). Furthermore, miR-155 repressed a subset of genes implicated in hematopoietic development and disease. These data implicate miR-155 as a contributor to physiological GM expansion during inflammation and to certain pathological features associated with AML, emphasizing the importance of proper miR-155 regulation in developing myeloid cells during times of inflammatory stress
The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2
Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701
Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts
Use of Center for International Blood & Marrow Transplant Research (CIBMTR) Special Interim Audit (SIA) to Design a 1:1 Physician Guided Review Process with Data Control Coordinators (DCCs)
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Preliminary Results from a Phase I Study of RevlimidÂź (Lenalidomide) in Combination with VidazaÂź (Azacitidine) in Patients with Advanced Myelodysplastic Syndromes (MDS)
Abstract
Background: Early MDS becomes more advanced as immature myeloid cells proliferate, angiogenesis increases, genetic lesions accumulate, and tumor suppressor genes become inactivated through hypermethylation. Progression to acute myeloid leukemia (AML) may be prevented by targeting these defects through combination therapy, using an immunomodulatory, anti-angiogenic agent, lenalidomide (LEN), and a hypomethylating drug, azacitidine (AZA).
Methods: We conducted a multicenter, Phase I trial in patients (pts) with advanced MDS (IPSS score â„1.5, or FAB or WHO classification with â„5% myeloblasts) starting in 6/06, with results reported through 7/07. Pts were enrolled using a â3+3â design (See Table), and could not receive LEN or AZA previously. Cycles lasted 28 days, to a maximum of 7 cycles of therapy. The primary endpoint was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs, defined as Grade 3/4 non-hematologic toxicity or >50% neutrophil (ANC) or platelet (plt) drop without recovery by Day 56) of the combination. A secondary endpoint was response as defined by the Modified International Working Group.
Dose Level AZA Schedule LEN Schedule 1 75 mg/m2 SC days 1â5 5 mg PO days 1â14 2 75 mg/m2 SC days 1â5 5 mg PO days 1â21 3 75 mg/m2 SC days 1â5 10 mg PO days 1â21 4 50 mg/m2 SC days 1â5, 8â12 5 mg PO days 1â14 5 50 mg/m2 SC days 1â5, 8â12 5 mg PO days 1â21 6 50 mg/m2 SC days 1â5, 8â12 10 mg PO days 1â21
Results: Seven patients have been enrolled, 6 are evaluable for toxicity data. Median age was 64 years (range 52â70), 1 pt was female, and median follow-up is 5.5 months (range 1.5â13). All pts had RAEB-2; IPSS scores were 1.5 (4), 2.0 (2), and 3.0 (1), with IPSS cytogenetic risk categories of poor (1), intermediate (1), and good (5). No pt had a del (5q) lesion. Median time from MDS diagnosis was 3.5 wks (range 2â106). No DLTs occurred in Dose Levels 1 or 2, and MTD has not yet been reached. Grade 1/2 non-hematologic toxicities (n=6) included fatigue (4), injection site reaction (6), rash (3), pruritis (3), constipation or diarrhea (6), dizziness (1), and mucositis (1). Grade 3/4 non-hematologic toxicities included febrile neutropenia (1). Median ANC drop was 16.4% and plt drop was 10.4%. Although one patient was delayed 1 week in starting cycle 2 for neutropenia, there were no dose-reductions for toxicities. Four pts are evaluable for response: 2 had a complete response, 1 an erythroid response, and 1 progressive disease.
Conclusions: The combination of LEN and AZA is well-tolerated and early results suggest efficacy in advanced MDS. Responses and toxicity data from higher Dose Levels will be presented
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Hepatitis C virus infection in acquired aplastic anemia
Hepatitisâassociated aplastic anemia (HAAA) is an uncommon disorder that usually is not due to hepatitis A or B virus infection. Hepatitis C virus (HCV) seropositivity is infrequently observed in aplastic anemia (AA) patients who have not been extensively transfused. However, HCV seropositivity may not be detected until several weeks or months after viral infection and AA patients may exhibit defective humoral immunity. Therefore, we evaluated sera from AA patients for the presence of HCV viremia using a reverse transcriptase polymerase chain reaction (RTâPCR) based assay and several serologic assays for HCV antibodies. Serum samples from 90 AA patients who presented to the UCLA Medical Center between March 1984 and February 1990 were analyzed. Overall, 17 patients were found to have HCV viremia by RTâPCR assay, of whom 14 had a positive secondâgeneration HCV enzyme immunoassay (EIAâ2) and only 6 were EIAâ1 reactive. The frequency of HCV viremia increased with the duration of time between diagnosis and sample procurement, and the number of blood products transfused prior to sampling (P = 0.026). No patient who received fewer than 20 U of blood products or who was sampled less than 20 days after diagnosis had a positive HCV RTâPCR result. Of four patients with hepatitisâassociated AA (HAAA), one who was sampled 23 days after diagnosis had hepatitis C viremia and a reactive EIAâ2 assay. Therefore, the high frequency of HCV viremia in this patient population is most likely due to transfusion with contaminated blood products prior to the introduction of routine blood donor screening for HCV. Am. J. Hematol. 58:122â126, 1998. © 1998 WileyâLiss, Inc
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An interferon-Îł activation sequence mediates the transcriptional regulation of the IgG Fc receptor type IC gene by interferon-Îł
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