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https://www.readbyqxmd.com/read/27883945/recent-advances-in-the-treatment-of-lower-risk-non-del-5q-myelodysplastic-syndromes-mds
#1
REVIEW
Antonio Almeida, Pierre Fenaux, Alan F List, Azra Raza, Uwe Platzbecker, Valeria Santini
Patients with lower-risk myelodysplastic syndromes (MDS) are affected primarily by symptoms of chronic anemia and fatigue rather than progression to acute myeloid leukemia. Severe thrombocytopenia, although less common in lower-risk MDS, is associated with increased risk of bleeding. For anemic patients, the principal aim of treatment is to improve anemia and decrease red blood cell transfusions. For transfusion-dependent patients with lower-risk MDS without chromosome 5q deletion [non-del(5q) MDS], there are limited effective treatments...
November 13, 2016: Leukemia Research
https://www.readbyqxmd.com/read/27857975/two-different-tales-of-atg7-clinical-relevance-to-myelodysplastic-syndromes
#2
Abdullah M Ali, Azra Raza
Somatic mutations in U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1) are associated with various cancers including myelodysplastic syndrome (MDS). Mutant U2AF1 promotes malignant transformation by inhibiting autophagy, partly as a result of alterations in the 3' tail of ATG7. This results in altered mitochondrial function, increased reactive oxygen species production, and genomic instability.
2016: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/27622333/physiologic-expression-of-sf3b1-k700e-causes-impaired-erythropoiesis-aberrant-splicing-and-sensitivity-to-therapeutic-spliceosome-modulation
#3
Esther A Obeng, Ryan J Chappell, Michael Seiler, Michelle C Chen, Dean R Campagna, Paul J Schmidt, Rebekka K Schneider, Allegra M Lord, Lili Wang, Rutendo G Gambe, Marie E McConkey, Abdullah M Ali, Azra Raza, Lihua Yu, Silvia Buonamici, Peter G Smith, Ann Mullally, Catherine J Wu, Mark D Fleming, Benjamin L Ebert
More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1(K700E). Sf3b1(K700E) mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1(K700E) myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3' splice-site selection associated with increased nonsense-mediated decay...
September 12, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27565427/distribution-and-clinical-significance-of-hepatitis-b-virus-genotypes-in-pakistan
#4
Majid Mahmood, Muhammad Asim Anwar, Azra Khanum, Nasib Zaman, Abida Raza
BACKGROUND: Hepatitis B virus (HBV) genotype and its role in disease progression and patients' response to antiviral treatment, is not well studied in Pakistan. This comprehensive study was aimed to determine the distribution of HBV genotypes in Pakistan and their possible association with phases of HBV infection. METHODS: A total of 840 HBsAg positive samples was collected and tested for HBV DNA quantity. Samples below 100 IU/ml were excluded from the study. A total of 715 samples representing all the six parts of the country were genotyped by type specific primer PCR method...
August 26, 2016: BMC Gastroenterology
https://www.readbyqxmd.com/read/27555985/therapy-associated-myeloid-dysplasia-in-a-long-surviving-patient-with-pancreatic-cancer
#5
Jillian Suzukida, Kristin Kaley, Azra Raza, Muhammad W Saif
Pancreatic cancer remains a diagnosis of poor prognosis with a median survival time of four-six months in patients with advanced stage of the disease. Although, with the development of novel chemotherapy agents some patients are able to live a little longer if they respond to therapy. However, long-term complications of chemotherapy or radiotherapy are not known due to the short survival period of patients with pancreatic cancer. We present a case of a 55-year-old-woman who developed therapy-related myelodysplastic syndrome (t-MDS) during a survival of approximately eight years during which she received multiple chemotherapies and radiation therapy...
2016: Curēus
https://www.readbyqxmd.com/read/27184077/u2af35-s34f-promotes-transformation-by-directing-aberrant-atg7-pre-mrna-3-end-formation
#6
Sung Mi Park, Jianhong Ou, Lynn Chamberlain, Tessa M Simone, Huan Yang, Ching-Man Virbasius, Abdullah M Ali, Lihua Julie Zhu, Siddhartha Mukherjee, Azra Raza, Michael R Green
Recurrent mutations in the splicing factor U2AF35 are found in several cancers and myelodysplastic syndrome (MDS). How oncogenic U2AF35 mutants promote transformation remains to be determined. Here we derive cell lines transformed by the oncogenic U2AF35(S34F) mutant and identify aberrantly processed pre-mRNAs by deep sequencing. We find that in U2AF35(S34F)-transformed cells the autophagy-related factor 7 (Atg7) pre-mRNA is abnormally processed, which unexpectedly is not due to altered splicing but rather selection of a distal cleavage and polyadenylation (CP) site...
May 19, 2016: Molecular Cell
https://www.readbyqxmd.com/read/26990290/activity-of-the-oral-mitogen-activated-protein-kinase-kinase-inhibitor-trametinib-in-ras-mutant-relapsed-or-refractory-myeloid-malignancies
#7
Gautam Borthakur, Leslie Popplewell, Michael Boyiadzis, James Foran, Uwe Platzbecker, Norbert Vey, Roland B Walter, Rebecca Olin, Azra Raza, Aristoteles Giagounidis, Aref Al-Kali, Elias Jabbour, Tapan Kadia, Guillermo Garcia-Manero, John W Bauman, Yuehui Wu, Yuan Liu, Dan Schramek, Donna S Cox, Paul Wissel, Hagop Kantarjian
BACKGROUND: RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias. METHODS: This phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3)...
June 15, 2016: Cancer
https://www.readbyqxmd.com/read/26944474/prospective-international-validation-of-the-quality-of-life-in-myelodysplasia-scale-qualms
#8
Gregory A Abel, Fabio Efficace, Rena J Buckstein, Sara Tinsley, Joseph G Jurcic, Yolanda Martins, David P Steensma, Corey D Watts, Azra Raza, Stephanie J Lee, Alan F List, Robert J Klaassen
Disease-specific measures of quality of life can improve assessment of disease-related symptoms and psychosocial sequelae. We report on the development and validation of the Quality of Life in Myelodysplasia Scale (QUALMS), a 38-item assessment tool for patients with myelodysplastic syndromes (MDS). In 2014-2015, a multi-center cohort of patients with myelodysplasia completed the QUALMS, as well as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the Functional Assessment of Cancer Therapy Anemia Scale (FACT-An); a second administration was undertaken three to six months later...
June 2016: Haematologica
https://www.readbyqxmd.com/read/26627506/bacteraemia-caused-by-escherichia-coli-in-cancer-patients-at-a-specialist-center-in-pakistan
#9
Azra Parveen, Faisal Sultan, Aun Raza, Waleed Zafar, Summiya Nizamuddin, Amjad Mahboob, Saliha Saleem, Syed Hammad Nazeer
OBJECTIVE: To analyse the antimicrobial susceptibility patterns of Escherichia coli bacteraemia among cancer patients, and to assess the risk factors and outcomes of multidrug-resistant Escherichia coli bacteraemia. METHODS: The retrospective study was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, and comprised medical records of patients with Escherichia coli bacteraemia presenting between December 2012 and November 2013. Multivariable logistic regression analyses were used to determine the factors associated with the development and 30-day mortality of multidrug-resistant Escherichia coli bacteraemia...
December 2015: JPMA. the Journal of the Pakistan Medical Association
https://www.readbyqxmd.com/read/26261309/disease-associated-mutation-in-srsf2-misregulates-splicing-by-altering-rna-binding-affinities
#10
Jian Zhang, Yen K Lieu, Abdullah M Ali, Alex Penson, Kathryn S Reggio, Raul Rabadan, Azra Raza, Siddhartha Mukherjee, James L Manley
Serine/arginine-rich splicing factor 2 (SRSF2) is an RNA-binding protein that plays important roles in splicing of mRNA precursors. SRSF2 mutations are frequently found in patients with myelodysplastic syndromes and certain leukemias, but how these mutations affect SRSF2 function has only begun to be examined. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease to introduce the P95H mutation to SRSF2 in K562 leukemia cells, generating an isogenic model so that splicing alterations can be attributed solely to mutant SRSF2...
August 25, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25616577/efficacy-safety-and-survival-with-ruxolitinib-in-patients-with-myelofibrosis-results-of-a-median-3-year-follow-up-of-comfort-i
#11
Srdan Verstovsek, Ruben A Mesa, Jason Gotlib, Richard S Levy, Vikas Gupta, John F DiPersio, John V Catalano, Michael W N Deininger, Carole B Miller, Richard T Silver, Moshe Talpaz, Elliott F Winton, Jimmie H Harvey, Murat O Arcasoy, Elizabeth O Hexner, Roger M Lyons, Azra Raza, Kris Vaddi, William Sun, Wei Peng, Victor Sandor, Hagop Kantarjian
In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib...
April 2015: Haematologica
https://www.readbyqxmd.com/read/25285531/a-multicenter-phase-i-ii-study-of-obatoclax-mesylate-administered-as-a-3-or-24-hour-infusion-in-older-patients-with-previously-untreated-acute-myeloid-leukemia
#12
RANDOMIZED CONTROLLED TRIAL
Aaron D Schimmer, Azra Raza, Thomas H Carter, David Claxton, Harry Erba, Daniel J DeAngelo, Martin S Tallman, Carolyn Goard, Gautam Borthakur
PURPOSE: An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (≥ 70 yr) with untreated acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: Phase I evaluated the safety of obatoclax infused for 3 hours on 3 consecutive days (3 h × 3 d) in 2-week cycles. Initial obatoclax dose was 30 mg/day (3 h × 3 d; n = 3). Obatoclax was increased to 45 mg/day (3 h × 3 d) if ≤ 1 patient had a dose-limiting toxicity (DLT) and decreased to 20 mg/day (3 h × 3 d) if DLT occurred in ≥ 2 patients...
2014: PloS One
https://www.readbyqxmd.com/read/25139351/inhibition-of-leukemia-cell-engraftment-and-disease-progression-in-mice-by-osteoblasts
#13
Maria Krevvata, Barbara C Silva, John S Manavalan, Marta Galan-Diez, Aruna Kode, Brya Grace Matthews, David Park, Chiyuan A Zhang, Naomi Galili, Thomas L Nickolas, David W Dempster, William Dougall, Julie Teruya-Feldstein, Aris N Economides, Ivo Kalajzic, Azra Raza, Ellin Berman, Siddhartha Mukherjee, Govind Bhagat, Stavroula Kousteni
The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival...
October 30, 2014: Blood
https://www.readbyqxmd.com/read/25052051/a-phase-ii-multicenter-open-label-study-of-obatoclax-mesylate-in-patients-with-previously-untreated-myelodysplastic-syndromes-with-anemia-or-thrombocytopenia
#14
MULTICENTER STUDY
Martha L Arellano, Gautam Borthakur, Mark Berger, Jill Luer, Azra Raza
BACKGROUND: Obatoclax mesylate is a small-molecule Bcl-2 homology domain-3 mimetic that neutralizes antiapoptotic Bcl-2-related proteins. We evaluated obatoclax in untreated MDS patients with anemia/thrombocytopenia. PATIENTS AND METHODS: Twenty-four patients with a bone marrow blast count of ≤ 10% and anemia (hemoglobin level < 10 g/dL) or thrombocytopenia (platelet count < 50 × 10(9)/L) were eligible to receive intravenous obatoclax 60 mg over 24 hours every 2 weeks...
December 2014: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/24777753/clinical-activity-and-safety-of-the-dual-pathway-inhibitor-rigosertib-for-higher-risk-myelodysplastic-syndromes-following-dna-methyltransferase-inhibitor-therapy
#15
Lewis R Silverman, Peter Greenberg, Azra Raza, Matthew J Olnes, James F Holland, Premkumar Reddy, Manoj Maniar, Francois Wilhelm
Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib...
June 2015: Hematological Oncology
https://www.readbyqxmd.com/read/24429522/leukaemogenesis-induced-by-an-activating-%C3%AE-catenin-mutation-in-osteoblasts
#16
Aruna Kode, John S Manavalan, Ioanna Mosialou, Govind Bhagat, Chozha V Rathinam, Na Luo, Hossein Khiabanian, Albert Lee, Vundavalli V Murty, Richard Friedman, Andrea Brum, David Park, Naomi Galili, Siddhartha Mukherjee, Julie Teruya-Feldstein, Azra Raza, Raul Rabadan, Ellin Berman, Stavroula Kousteni
Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression...
February 13, 2014: Nature
https://www.readbyqxmd.com/read/24227693/a-prospective-multicenter-study-of-paroxysmal-nocturnal-hemoglobinuria-cells-in-patients-with-bone-marrow-failure
#17
MULTICENTER STUDY
Azra Raza, Farhad Ravandi, Anjay Rastogi, Jeffrey Bubis, Seah H Lim, Ilene Weitz, Hugo Castro-Malaspina, Naomi Galili, Rony Abou Jawde, Andrea Illingworth
BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. METHODS: Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones...
May 2014: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/24127323/a-prospective-multicenter-study-of-paroxysmal-nocturnal-hemoglobinuria-cells-in-patients-with-bone-marrow-failure
#18
Azra Raza, Farhad Ravandi, Anjay Rastogi, Jeffrey Bubis, Seah H Lim, Ilene Weitz, Hugo Castro-Malaspina, Naomi Galili, Rony Abou Jawde, Andrea Illingworth
Background: Paroxysmal nocturnal hemoglobinuria (PNH), a rare clonal hematopoietic stem cell disorder, is characterized by chronic, uncontrolled complement activation leading to intravascular hemolysis and an inflammatory prothrombotic state. The EXPLORE study aimed to determine the prevalence of undiagnosed PNH in patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and/or other bone marrow failure (BMF) syndromes and the effect of PNH clone size on hemolysis. Methods: Patients, selected from medical office chart reviews, had blood samples collected for hematologic panel testing and for flow cytometry detection of PNH clones...
October 11, 2013: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/24064823/the-biology-and-treatment-of-myelodysplastic-syndromes
#19
REVIEW
Azra Raza, Naomi Galili
No abstract text is available yet for this article.
October 2013: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/24038026/efficacy-safety-and-survival-with-ruxolitinib-in-patients-with-myelofibrosis-results-of-a-median-2-year-follow-up-of-comfort-i
#20
RANDOMIZED CONTROLLED TRIAL
Srdan Verstovsek, Ruben A Mesa, Jason Gotlib, Richard S Levy, Vikas Gupta, John F DiPersio, John V Catalano, Michael W N Deininger, Carole B Miller, Richard T Silver, Moshe Talpaz, Elliott F Winton, Jimmie H Harvey, Murat O Arcasoy, Elizabeth O Hexner, Roger M Lyons, Ronald Paquette, Azra Raza, Kris Vaddi, Susan Erickson-Viitanen, William Sun, Victor Sandor, Hagop M Kantarjian
COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment...
December 2013: Haematologica
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