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Omar Abdel-Wahab

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https://www.readbyqxmd.com/read/29643185/expression-of-mutant-asxl1-perturbs-hematopoiesis-and-promotes-susceptibility-to-leukemic-transformation
#1
Reina Nagase, Daichi Inoue, Alessandro Pastore, Takeshi Fujino, Hsin-An Hou, Norimasa Yamasaki, Susumu Goyama, Makoto Saika, Akinori Kanai, Yasuyuki Sera, Sayuri Horikawa, Yasunori Ota, Shuhei Asada, Yasutaka Hayashi, Kimihito Cojin Kawabata, Reina Takeda, Hwei-Fang Tien, Hiroaki Honda, Omar Abdel-Wahab, Toshio Kitamura
Additional sex combs like 1 ( ASXL1 ) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia...
April 11, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29576046/editorial-overview-cancer-genomics-rna-metabolism-and-translation-in-cancer-pathogenesis-and-therapy
#2
EDITORIAL
Omar Abdel-Wahab, Fátima Gebauer
No abstract text is available yet for this article.
February 2018: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/29572486/setd2-linking-stem-cell-survival-and-transformation
#3
Mrinal M Patnaik, Omar Abdel-Wahab
No abstract text is available yet for this article.
March 23, 2018: Cell Research
https://www.readbyqxmd.com/read/29547721/the-dietary-supplement-chondroitin-4-sulfate-exhibits-oncogene-specific-pro-tumor-effects-on-braf-v600e-melanoma-cells
#4
Ruiting Lin, Siyuan Xia, Changliang Shan, Dong Chen, Yijie Liu, Xue Gao, Mei Wang, Hee-Bum Kang, Yaozhu Pan, Shuangping Liu, Young Rock Chung, Omar Abdel-Wahab, Taha Merghoub, Michael Rossi, Ragini R Kudchadkar, David H Lawson, Fadlo R Khuri, Sagar Lonial, Jing Chen
Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors...
March 15, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29533777/targeting-mrna-decapping-in-aml
#5
Akihide Yoshimi, Omar Abdel-Wahab
In this issue of Cancer Cell, Yamauchi et al. identify a dependency of acute myeloid leukemia (AML) on DCPS, which catalyzes the final step of 3'-to-5' mRNA decay and is implicated in numerous aspects of RNA metabolism. DCPS is targetable with a clinical inhibitor, underscoring the translational importance of this discovery.
March 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29483135/allele-specific-mechanisms-of-activation-of-mek1-mutants-determine-their-properties
#6
Yijun Gao, Matthew T Chang, Daniel McKay, Na Na, Bing Zhou, Rona D Yaeger, Neilawattie M Torres, Keven Muniz, Matthias Drosten, Mariano Barbacid, Giordano Caponigro, Darrin Stuart, Henrik Moebitz, David B Solit, Omar I Abdel-Wahab, Barry S Taylor, Zhan Yao, Neal Rosen
Mutations at multiple sites in MEK1 occur in cancer suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS-RAF dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output and often co-occur with RAS or RAF mutations. They act as amplifiers of RAF signaling. By contrast, another class of mutants delete a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity...
February 26, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29472347/single-agent-dabrafenib-for-brafv600e-mutated-histiocytosis
#7
Ankush Bhatia, Gary Ulaner, Raajit Rampal, David M Hyman, Omar Abdel-Wahab, Benjamin H Durham, Ahmet Dogan, Neval Ozkaya, Mario E Lacouture, Julio Hajdenberg, Chezi Ganzel, Eli L Diamond
No abstract text is available yet for this article.
February 22, 2018: Haematologica
https://www.readbyqxmd.com/read/29466766/recent-advances-in-the-genomics-and-therapy-of-bcr-abl1-positive-and-negative-chronic-myeloproliferative-neoplasms
#8
REVIEW
Tariq I Mughal, Jason Gotlib, Ruben Mesa, Steffen Koschmieder, H Jean Khoury, Jorge E Cortes, Tiziano Barbui, Rüdiger Hehlmann, Michael Mauro, Susanne Saussele, Jerald P Radich, Richard A Van Etten, Giuseppe Saglio, Srdnan Verstovek, Robert Peter Gale, Omar Abdel-Wahab
This review is based on the presentations and deliberations at the 7th John Goldman Chronic Myeloid Leukemia (CML) and Myeloproliferative Neoplasms (MPN) Colloquium which took place in Estoril, Portugal on the 15th October 2017, and the 11th post-ASH International Workshop on CML and MPN which took place on the 6th-7th December 2016, immediately after the 58th American Society of Hematology Annual Meeting. Rather than present a resume of the proceedings, we have elected to address some of the topical translational research and clinically relevant topics in greater detail...
February 14, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29459898/parotid-quadrantectomy-is-a-safe-management-for-localized-pleomorphic-adenoma
#9
Osama Hussein, Khaled Abdel Wahab, Omar Hamdy, Mohammad Arafa, Emad-Eldeen Hamed, Shady Awny, Sameh Roshdy, Adel Denewer, Mahmoud Mosbah
Aim: Pleomorphic adenoma is the most common benign tumor of the parotid gland and is classically treated with superficial or total parotidectomy. Less radical surgeries have been proposed to minimize the risk of facial nerve injury. The oncological safety of these procedures remains controversial. We conducted this study to evaluate the safety of superficial hemi-lobectomy (quadrantectomy). Patients and methods: Retrospective analysis was conducted on the paraffin sections of archived superficial parotidectomy specimens from 11 male and 6 female patients (median age 33 years)...
2018: Frontiers in Surgery
https://www.readbyqxmd.com/read/29457796/h3b-8800-an-orally-available-small-molecule-splicing-modulator-induces-lethality-in-spliceosome-mutant-cancers
#10
Michael Seiler, Akihide Yoshimi, Rachel Darman, Betty Chan, Gregg Keaney, Michael Thomas, Anant A Agrawal, Benjamin Caleb, Alfredo Csibi, Eckley Sean, Peter Fekkes, Craig Karr, Virginia Klimek, George Lai, Linda Lee, Pavan Kumar, Stanley Chun-Wei Lee, Xiang Liu, Crystal Mackenzie, Carol Meeske, Yoshiharu Mizui, Eric Padron, Eunice Park, Ermira Pazolli, Shouyong Peng, Sudeep Prajapati, Justin Taylor, Teng Teng, John Wang, Markus Warmuth, Huilan Yao, Lihua Yu, Ping Zhu, Omar Abdel-Wahab, Peter G Smith, Silvia Buonamici
Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells...
February 19, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29395063/the-augmented-r-loop-is-a-unifying-mechanism-for-myelodysplastic-syndromes-induced-by-high-risk-splicing-factor-mutations
#11
Liang Chen, Jia-Yu Chen, Yi-Jou Huang, Ying Gu, Jinsong Qiu, Hao Qian, Changwei Shao, Xuan Zhang, Jing Hu, Hairi Li, Shunmin He, Yu Zhou, Omar Abdel-Wahab, Dong-Er Zhang, Xiang-Dong Fu
Mutations in several general pre-mRNA splicing factors have been linked to myelodysplastic syndromes (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is involved. Here we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway...
February 1, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29192649/the-histopathology-of-erdheim-chester-disease-a-comprehensive-review-of-a-molecularly-characterized-cohort
#12
Neval Ozkaya, Marc K Rosenblum, Benjamin H Durham, Janine D Pichardo, Omar Abdel-Wahab, Meera R Hameed, Klaus J Busam, William D Travis, Eli L Diamond, Ahmet Dogan
Erdheim-Chester disease is a rare, non-Langerhans cell histiocytosis histologically characterized by multi-systemic proliferation of mature histiocytes in a background of inflammatory stroma. The disease can involve virtually any organ system; most commonly the bones, skin, retroperitoneum, heart, orbit, lung, and brain are affected. Although a histiocytic proliferation is the histological hallmark of the disease, a wide range of morphological appearances have been described as part of case studies or small series...
December 1, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29188284/vemurafenib-for-braf-v600-mutant-erdheim-chester-disease-and-langerhans-cell-histiocytosis-analysis-of-data-from-the-histology-independent-phase-2-open-label-ve-basket-study
#13
Eli L Diamond, Vivek Subbiah, A Craig Lockhart, Jean-Yves Blay, Igor Puzanov, Ian Chau, Noopur S Raje, Jurgen Wolf, Joseph P Erinjeri, Jean Torrisi, Mario Lacouture, Elena Elez, Ferran Martínez-Valle, Benjamin Durham, Maria E Arcila, Gary Ulaner, Omar Abdel-Wahab, Bethany Pitcher, Martina Makrutzki, Todd Riehl, José Baselga, David M Hyman
Importance: The histiocytic neoplasms Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are highly enriched for BRAF V600 mutations and have been previously shown to be responsive to treatment with vemurafenib, an inhibitor of the BRAF V600 kinase. However, the long-term efficacy and safety of prolonged vemurafenib use in these patients are not defined. Here we analyze the final efficacy and safety data for vemurafenib in patients with ECD and LCH enrolled in the VE-BASKET study...
March 1, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29097875/trends-and-outcomes-of-pancreaticoduodenectomy-for-periampullary-tumors-a-25-year-single-center-study-of-1000-consecutive-cases
#14
Ayman El Nakeeb, Waleed Askar, Ehab Atef, Ehab El Hanafy, Ahmad M Sultan, Tarek Salah, Ahmed Shehta, Mohamed El Sorogy, Emad Hamdy, Mohamed El Hemly, Ahmed A El-Geidi, Tharwat Kandil, Mohamed El Shobari, Talaat Abd Allah, Amgad Fouad, Mostafa Abu Zeid, Ahmed Abu El Eneen, Nabil Gad El-Hak, Gamal El Ebidy, Omar Fathy, Ahmed Sultan, Mohamed Abdel Wahab
AIM: To evaluate the evolution, trends in surgical approaches and reconstruction techniques, and important lessons learned from performing 1000 consecutive pancreaticoduodenectomies (PDs) for periampullary tumors. METHODS: This is a retrospective review of the data of all patients who underwent PD for periampullary tumor during the period from January 1993 to April 2017. The data were categorized into three periods, including early period (1993-2002), middle period (2003-2012), and late period (2013-2017)...
October 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28958291/therapeutic-targeting-of-rna-splicing-in-myelodysplasia
#15
REVIEW
Young Joon Kim, Omar Abdel-Wahab
Genomic analysis of patients with myelodysplastic syndromes (MDS) has identified that mutations within genes encoding RNA splicing factors represent the most common class of genetic alterations in MDS. These mutations primarily affect SF3B1, SRSF2, U2AF1, and ZRSR2. Current data suggest that these mutations perturb RNA splicing catalysis in a manner distinct from loss of function but how exactly the global changes in RNA splicing imparted by these mutations result in MDS is not well delineated. At the same time, cells bearing mutations in RNA splicing factors are exquisitely dependent on the presence of the remaining wild-type (WT) allele to maintain residual normal splicing for cell survival...
July 2017: Seminars in Hematology
https://www.readbyqxmd.com/read/28854169/a-somatic-mutation-in-erythro-myeloid-progenitors-causes-neurodegenerative-disease
#16
Elvira Mass, Christian E Jacome-Galarza, Thomas Blank, Tomi Lazarov, Benjamin H Durham, Neval Ozkaya, Alessandro Pastore, Marius Schwabenland, Young Rock Chung, Marc K Rosenblum, Marco Prinz, Omar Abdel-Wahab, Frederic Geissmann
The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration...
September 21, 2017: Nature
https://www.readbyqxmd.com/read/28801450/genomic-analysis-of-hairy-cell-leukemia-identifies-novel-recurrent-genetic-alterations
#17
Benjamin H Durham, Bartlomiej Getta, Sascha Dietrich, Justin Taylor, Helen Won, James M Bogenberger, Sasinya Scott, Eunhee Kim, Young Rock Chung, Stephen S Chung, Jennifer Hüllein, Tatjana Walther, Lu Wang, Sydney X Lu, Christopher C Oakes, Raoul Tibes, Torsten Haferlach, Barry S Taylor, Martin S Tallman, Michael F Berger, Jae H Park, Thorsten Zenz, Omar Abdel-Wahab
Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAF V600E mutation, whereas ∼30% of variant HCLs (vHCLs) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAF V600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 wild-type vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n = 53) and vHCL (n = 8). The most common genetic alteration in cHCL apart from BRAF V600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type BRAF , subdividing cHCL into those hemizygous versus heterozygous for the BRAF V600E mutation...
October 5, 2017: Blood
https://www.readbyqxmd.com/read/28748614/novel-activating-braf-fusion-identifies-a-recurrent-alternative-mechanism-for-erk-activation-in-pediatric-langerhans-cell-histiocytosis
#18
Sara Zarnegar, Benjamin H Durham, Pallavi Khattar, Neerav N Shukla, Ryma Benayed, Mario E Lacouture, Ehud Lavi, David C Lyden, Eli L Diamond, Ira J Dunkel, Omar Abdel-Wahab
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism...
January 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28679734/high-prevalence-of-myeloid-neoplasms-in-adults-with-non-langerhans-cell-histiocytosis
#19
Matthias Papo, Eli L Diamond, Fleur Cohen-Aubart, Jean-François Emile, Damien Roos-Weil, Nishant Gupta, Benjamin H Durham, Neval Ozkaya, Ahmet Dogan, Gary A Ulaner, Raajit Rampal, Jean-Emmanuel Kahn, Thomas Sené, Frédéric Charlotte, Baptiste Hervier, Caroline Besnard, Olivier A Bernard, Catherine Settegrana, Nathalie Droin, Zofia Hélias-Rodzewicz, Zahir Amoura, Omar Abdel-Wahab, Julien Haroche
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that most commonly affects adults and is driven by a high frequency of mutations in BRAF , MAP2K1 , and kinases promoting MAPK signaling. Because of the relative rarity of ECD, key clinical features of the disease may not be well defined. Across a multi-institutional cohort of 189 patients with ECD and ECD overlapping with Langerhans cell histiocytosis (so-called mixed histiocytosis [MH]), we identified an unexpected and heretofore undescribed frequent occurrence of myeloid neoplasms among patients with ECD and MH...
August 24, 2017: Blood
https://www.readbyqxmd.com/read/28673397/identification-and-targeting-of-kinase-alterations-in-histiocytic-neoplasms
#20
REVIEW
Neval Ozkaya, Ahmet Dogan, Omar Abdel-Wahab
Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective...
August 2017: Hematology/oncology Clinics of North America
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