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John Byrd

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https://www.readbyqxmd.com/read/27903679/the-bruton-s-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#1
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
PURPOSE: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27892987/sweet-like-eruption-associated-with-obinutuzumab-therapy-for-chronic-lymphocytic-leukemia
#2
Abraham M Korman, Justin G Hastings, John C Byrd, Benjamin H Kaffenberger
No abstract text is available yet for this article.
November 23, 2016: JAMA Dermatology
https://www.readbyqxmd.com/read/27853650/therapeutic-cd94-nkg2a-blockade-improves-natural-killer-cell-dysfunction-in-chronic-lymphocytic-leukemia
#3
Emily M McWilliams, Jennifer M Mele, Carolyn Cheney, Elizabeth A Timmerman, Faraz Fiazuddin, Ethan J Strattan, Xiaokui Mo, John C Byrd, Natarajan Muthusamy, Farrukh T Awan
Natural killer (NK)-cell count is predictive of chronic lymphoid leukemia (CLL) disease progression and their dysfunction is well documented, but the etiology of this is currently lacking. CLL cells have been shown to over-express HLA-E, the natural ligand for NKG2A expressed on NK-cells that generates a distinct negative signal relative to direct NK-cell cytotoxicity in other disease models. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mAb), monalizumab, we explored the in vitro preclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in CLL patients...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27852036/interim-analysis-of-a-phase-i-iia-trial-assessing-e39-gm-csf-a-folate-binding-protein-vaccine-to-prevent-recurrence-in-ovarian-and-endometrial-cancer-patients
#4
Doreen O Jackson, Kevin Byrd, Timothy J Vreeland, Diane F Hale, Garth S Herbert, Julia M Greene, Erika J Schneble, John S Berry, Alfred F Trappey, G T Clifton, Mark O Hardin, Jonathan Martin, John C Elkas, Thomas P Conrads, Kathleen M Darcy, Chad A Hamilton, George L Maxwell, George E Peoples
BACKGROUND: Folate binding protein(FBP) is an immunogenic protein over-expressed in endometrial(EC) and ovarian cancer(OC). We are conducting a phase I/IIa trial of E39 (GALE 301)+GM-CSF, an HLA-A2-restricted, FBP-derived peptide vaccine to prevent recurrences in disease-free EC and OC patients. This interim analysis summarizes toxicity, immunologic responses, and clinical outcomes to date. METHODS: HLA-A2+ patients were vaccinated(VG), and HLA-A2- or -A2+ patients were followed as controls(CG)...
November 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27802969/ibrutinib-efficacy-and-tolerability-in-patients-with-relapsed-chronic-lymphocytic-leukemia-following-allogeneic-hct
#5
Christine E Ryan, Bita Sahaf, Aaron C Logan, Susan O'Brien, John C Byrd, Peter Hillmen, Jennifer R Brown, Martin J S Dyer, Anthony R Mato, Michael J Keating, Samantha Jaglowski, Fong Clow, Andrew R Rezvani, Lori Styles, Steven E Coutre, David B Miklos
Ibrutinib, a potent and irreversible small molecule inhibitor of both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplantation who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87...
November 1, 2016: Blood
https://www.readbyqxmd.com/read/27784745/mutational-landscape-and-gene-expression-patterns-in-adult-acute-myeloid-leukemias-with-monosomy-7-as-a-sole-abnormality
#6
Ann-Kathrin Eisfeld, Jessica Kohlschmidt, Krzysztof Mrozek, Stefano Volinia, James S Blachly, Deedra Nicolet, Christopher Oakes, Karl Kroll, Shelley Orwick, Andrew J Carroll, Richard M Stone, John C Byrd, Albert de la Chapelle, Clara D Bloomfield
Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML) which may give insights into the basis for its poor prognosis have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and microRNA expression profiles were also determined using paired RNA and small RNA sequencing data...
October 26, 2016: Cancer Research
https://www.readbyqxmd.com/read/27780867/interferon-%C3%AE-promotes-antibody-mediated-fratricide-of-acute-myeloid-leukemia-cells
#7
Kavin Fatehchand, Elizabeth L McMichael, Brenda F Reader, Huiqing Fang, Ramasamy Santhanam, Shalini Gautam, Saranya Elavazhagan, Payal Mehta, Nathaniel J Buteyn, Giovanna Merchand-Reyes, Sumithira Vasu, Xiaokui Mo, Don M Benson, James S Blachly, William E Carson, John C Byrd, Jonathan P Butchar, Susheela Tridandapani
Acute Myeloid Leukemia (AML) is characterized by the proliferation of immature myeloid-lineage blasts. Due to its heterogeneity and to the high rate of acquired drug resistance and relapse, new treatment strategies are needed. Here, we demonstrate that IFNγ promotes AML blasts to act as effector cells within the context of antibody therapy. Treatment with IFNγ drove AML blasts toward a more differentiated state, wherein they showed increased expression of the M1-related markers HLA-DR and CD86, as well as of FcγRI, which mediates effector responses to therapeutic antibodies...
October 25, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27775550/microrna-29b-mediates-altered-innate-immune-development-in-acute-leukemia
#8
Bethany L Mundy-Bosse, Steven D Scoville, Li Chen, Kathleen McConnell, Hsiaoyin C Mao, Elshafa H Ahmed, Nicholas Zorko, Sophia Harvey, Jordan Cole, Xiaoli Zhang, Stefan Costinean, Carlo M Croce, Karilyn Larkin, John C Byrd, Sumithira Vasu, William Blum, Jianhua Yu, Aharon G Freud, Michael A Caligiuri
Natural killer (NK) cells can have potent antileukemic activity following haplo-mismatched, T cell-depleted stem cell transplantations for the treatment of acute myeloid leukemia (AML), but they are not successful in eradicating de novo AML. Here, we have used a mouse model of de novo AML to elucidate the mechanisms by which AML evades NK cell surveillance. NK cells in leukemic mice displayed a marked reduction in the cytolytic granules perforin and granzyme B. Further, as AML progressed, we noted the selective loss of an immature subset of NK cells in leukemic mice and in AML patients...
December 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27766616/genomics-of-primary-chemoresistance-and-remission-induction-failure-in-paediatric-and-adult-acute-myeloid-leukaemia
#9
Fiona C Brown, Paolo Cifani, Esther Drill, Jie He, Eric Still, Shan Zhong, Sohail Balasubramanian, Dean Pavlick, Bahar Yilmazel, Kristina M Knapp, Todd A Alonzo, Soheil Meshinchi, Richard M Stone, Steven M Kornblau, Guido Marcucci, Alan S Gamis, John C Byrd, Mithat Gonen, Ross L Levine, Alex Kentsis
Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases...
October 21, 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27760757/assessment-of-cd37-b-cell-antigen-and-cell-of-origin-significantly-improves-risk-prediction-in-diffuse-large-b-cell-lymphoma
#10
Zijun Y Xu-Monette, Ling Li, John C Byrd, Kausar J Jabbar, Ganiraju C Manyam, Charlotte Maria de Winde, Michiel van den Brand, Alexandar Tzankov, Carlo Visco, Jing Wang, Karen Dybkaer, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L Richards, Eric D Hsi, William W L Choi, Jooryung Huh, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Ben M Parsons, Jane N Winter, Michael Wang, Fredrick B Hagemeister, Miguel A Piris, J Han van Krieken, L Jeffrey Medeiros, Yong Li, Annemiek B van Spriel, Ken H Young
CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B-cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. In this study, we assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab-CHOP and 231 patients treated with CHOP chemotherapy. We found CD37 loss (CD37(-)) in ~60% of DLBCL predicted significantly decreased survival rates in R-CHOP-treated patients, independent of the International Prognostic Index (IPI), germinal-center-B-cell-like (GCB)/activated-B-cell-like (ABC) cell-of-origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37(-), including TP53 mutation, NF-κB(high), Myc(high), p-STAT3(high), survivin(high), p63(-), and BCL6 translocation...
October 19, 2016: Blood
https://www.readbyqxmd.com/read/27757311/targeting-myeloid-derived-suppressor-cells-using-a-novel-adenosine-monophosphate-activated-protein-kinase-ampk-activator
#11
Prashant Trikha, Robert L Plews, Andrew Stiff, Shalini Gautam, Vincent Hsu, David Abood, Robert Wesolowski, Ian Landi, Xiaokui Mo, John Phay, Ching-Shih Chen, John Byrd, Michael Caligiuri, Susheela Tridandapani, William Carson
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. MDSC play a critical role during tumor evasion and promote immune suppression through variety of mechanisms, such as the generation of reactive oxygen and nitrogen species (ROS and RNS) and cytokines. AMPactivated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that regulates energy homeostasis and metabolic stress. However, the role of AMPK in the regulation of MDSC function remains largely unexplored...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27756747/targeting-btk-through-microrna-in-chronic-lymphocytic-leukemia
#12
Arianna Bottoni, Lara Rizzotto, Tzung-Huei Lai, Chaomei Liu, Lisa L Smith, Rose Mantel, Sean Reiff, Dalia El-Gamal, Karilyn Larkin, Amy J Johnson, Rosa Lapalombella, Amy Lehman, William Plunkett, John C Byrd, James S Blachly, Jennifer A Woyach, Deepa Sampath
BTK is a critical mediator of survival in B cell neoplasms. While BTK inhibitors have transformed therapy in CLL, high genetic risk patients are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of miRNAs that target BTK in primary CLL cells and show that the HDAC repressor complex is recruited to these miRNA promoters to silence their expression...
October 17, 2016: Blood
https://www.readbyqxmd.com/read/27728800/a-new-role-for-lyn-in-the-cll-microenvironment
#13
Shuai Dong, John C Byrd
The role of Lyn, both a positive and a negative regulator of B and myeloid cells, in chronic lymphocytic leukemia (CLL) has not been well characterized. In this issue of Cancer Cell, Nguyen et al. demonstrated that Lyn in macrophages rather than in CLL cells is critical for the malignancy.
October 10, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27630290/assessment-of-promoter-methylation-identifies-ptch-as-a-putative-tumor-suppressor-gene-in-human-cll
#14
Ingo G H Schmidt-Wolf, Christoph Plass, John C Byrd, Kathrin Frevel, Torsten Pietsch, Andreas Waha
BACKGROUND: Chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of neoplastic lymphocytes, indicating disruption of apoptosis. PATIENTS AND METHODS: Differential methylation hybridization analysis was performed to identify novel target genes silenced by CpG island methylation in patients with CLL. RESULTS: Patched (PTCH), a tumor-suppressor gene, was found to be frequently methylated in CLL samples compared to samples derived from healthy individuals...
September 2016: Anticancer Research
https://www.readbyqxmd.com/read/27587620/nccn-guidelines-insights-non-hodgkin-s-lymphomas-version-3-2016
#15
Steven M Horwitz, Andrew D Zelenetz, Leo I Gordon, William G Wierda, Jeremy S Abramson, Ranjana H Advani, C Babis Andreadis, Nancy Bartlett, John C Byrd, Luis E Fayad, Richard I Fisher, Martha J Glenn, Thomas M Habermann, Nancy Lee Harris, Francisco Hernandez-Ilizaliturri, Richard T Hoppe, Mark S Kaminski, Christopher R Kelsey, Youn H Kim, Susan Krivacic, Ann S LaCasce, Matthew Lunning, Auayporn Nademanee, Oliver Press, Rachel Rabinovitch, Nishitha Reddy, Erin Reid, Kenneth Roberts, Ayman A Saad, Lubomir Sokol, Lode J Swinnen, Julie M Vose, Joachim Yahalom, Nadeem Zafar, Mary Dwyer, Hema Sundar, Pierluigi Porcu
Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant...
September 2016: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/27539615/individual-differences-in-physical-symptom-burden-and-psychological-responses-in-individuals-with-chronic-lymphocytic-leukemia
#16
Eleshia J Morrison, Joseph M Flynn, Jeffrey Jones, John C Byrd, Barbara L Andersen
Chronic lymphocytic leukemia (CLL) is an incurable illness, with some patients requiring no treatment until disease progression. Burden from physical symptoms has been associated with depression, anxiety, and stress in cancer patients. Additionally, patient factors, i.e., individual differences, have been associated with worse psychological outcomes. There are few psychological studies of CLL, with no examination of individual differences. A cross-sectional design studied the covariation of symptom burden with depressive and anxiety symptoms and cancer-specific stress, and tested patients' individual differences as predictors and as moderators...
December 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27476855/persistence-of-dnmt3a-r882-mutations-during-remission-does-not-adversely-affect-outcomes-of-patients-with-acute-myeloid-leukaemia
#17
Bhavana Bhatnagar, Ann-Kathrin Eisfeld, Deedra Nicolet, Krzysztof Mrózek, James S Blachly, Shelley Orwick, David M Lucas, Jessica Kohlschmidt, William Blum, Jonathan E Kolitz, Richard M Stone, Clara D Bloomfield, John C Byrd
Somatic mutation of the DNMT3A gene at the arginine R882 site is common in acute myeloid leukaemia (AML). The prognostic significance of DNMT3A R882 mutation clearance, using traditional diagnostic next generation sequencing (NGS) methods, during complete remission (CR) in AML patients is controversial. We examined the impact of clearing DNMT3A R882 mutations at diagnosis to the detectable threshold of ˂3% during CR on outcome in 56 adult AML patients. Mutational remission, defined as clearance of pre-treatment DNMT3A R882 and all other AML-associated mutations to a variant allele frequency ˂3%, occurred in 14 patients whereas persistent DNMT3A R882 mutations were observed in 42 patients...
October 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27471620/a-tec-kinase-btk-inhibitor-ibrutinib-promotes-maturation-and-activation-of-dendritic-cells
#18
Gayathri Natarajan, Steve Oghumu, Cesar Terrazas, Sanjay Varikuti, John C Byrd, Abhay R Satoskar
Ibrutinib, a BTK inhibitor, is currently used to treat various hematological malignancies. We evaluated whether ibrutinib treatment during development of murine bone marrow-derived dendritic cells (DCs) modulates their maturation and activation. Ibrutinib treatment increased the proportion of CD11c(+) DCs, upregulated the expression of MHC-II and CD80 and downregulated Ly6C expression by DCs. Additionally, ibrutinib treatment led to an increase in MHC-II(+), CD80(+) and CCR7(+) DCs but a decrease in CD86(+) DCs upon LPS stimulation...
June 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27470602/chromosome-abnormalities-at-onset-of-complete-remission-are-associated-with-worse-outcome-in-patients-with-acute-myeloid-leukemia-and-an-abnormal-karyotype-at-diagnosis-calgb-8461-alliance
#19
Christian Niederwieser, Deedra Nicolet, Andrew J Carroll, Jonathan E Kolitz, Bayard L Powell, Jessica Kohlschmidt, Richard M Stone, John C Byrd, Krzysztof Mrózek, Clara D Bloomfield
Achievement of complete remission is essential for long-term survival of acute myeloid leukemia patients. We evaluated the prognostic significance of cytogenetics at complete remission in 258 adults with de novo acute myeloid leukemia and abnormal pre-treatment karyotypes, treated on Cancer and Leukemia Group B front-line studies, with cytogenetic data at onset of morphological complete remission. Thirty-two patients had abnormal karyotypes at time of initial complete remission. Of these, 28 had at least 1 abnormality identified pre-treatment, and 4 acute myeloid leukemia-related abnormalities not detected pre-treatment...
December 2016: Haematologica
https://www.readbyqxmd.com/read/27434128/preclinical-evaluation-of-the-novel-btk-inhibitor-acalabrutinib-in-canine-models-of-b-cell-non-hodgkin-lymphoma
#20
Bonnie K Harrington, Heather L Gardner, Raquel Izumi, Ahmed Hamdy, Wayne Rothbaum, Kevin R Coombes, Todd Covey, Allard Kaptein, Michael Gulrajani, Bart Van Lith, Cecile Krejsa, Christopher C Coss, Duncan S Russell, Xiaoli Zhang, Bridget K Urie, Cheryl A London, John C Byrd, Amy J Johnson, William C Kisseberth
Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells...
2016: PloS One
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