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Treatment Plasma cell leukemia

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https://www.readbyqxmd.com/read/29339551/inhibition-of-flt3-and-pim-kinases-by-ec-70124-exerts-potent-activity-in-preclinical-models-of-acute-myeloid-leukemia
#1
Noelia Puente-Moncada, Paula Costales, Isaac Antolín, Luz Elena Núñez, Patricia Oro, Maria Ana Hermosilla, Jhudit Perez-Escuredo, Nicolas Rios-Lombardia, Ana M Sanchez-Sanchez, Elisa Luño, Carmen Rodriguez, Vanesa Martin, Francisco Moris
Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29333561/pharmacokinetics-of-the-b-cell-lymphoma-2-bcl-2-inhibitor-venetoclax-in-female-subjects-with-systemic-lupus-erythematosus
#2
Mukul Minocha, Jiewei Zeng, Jeroen K Medema, Ahmed A Othman
BACKGROUND AND OBJECTIVE: Venetoclax is an oral selective Bcl-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion. Mechanistic and preclinical evidence warranted evaluation of venetoclax for the treatment of systemic lupus erythematosus (SLE). This work characterized the pharmacokinetics of venetoclax in female subjects with SLE. METHODS: Single (10-500 mg) and multiple (30-600 mg) escalating doses of venetoclax or matching placebo were evaluated using randomized, double-blind, placebo-controlled designs (6 active and 2 placebo per dose with 73 unique SLE patients enrolled, 25 of whom enrolled twice)...
January 15, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29332353/aesculetin-6-7-dihydroxycoumarin-exhibits-potent-and-selective-antitumor-activity-in-human-acute-myeloid-leukemia-cells-thp-1-via-induction-of-mitochondrial-mediated-apoptosis-and-cancer-cell-migration-inhibition
#3
Jian Gong, Wei-Guo Zhang, Xiao-Fen Feng, Mei-Juan Shao, Chao Xing
PURPOSE: The main target of the present research was to examine the antitumor properties of aesculetin in human acute myeloid leukemia cancer cells (THP-1) and peripheral blood mono-nucleated cells (PBMCs) (used as normal cell line model) along with the determination of its effects on induction of apoptosis, inhibition of cancer cell migration and changes in Bcl-2/Bax protein expressions. METHODS: MTT colorimetric bioassay was performed to study the impact of this natural compound on cytotoxicity of both cell types...
November 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/29217783/somatic-stat3-mutations-in-the-felty-syndrome-an-implication-for-a-common-pathogenesis-with-large-granular-lymphocyte-leukemia
#4
Paula Savola, Oscar Brück, Thomas Olson, Tiina Kelkka, Markku J Kauppi, Panu E Kovanen, Soili Kytölä, Tuulikki Sokka-Isler, Thomas P Loughran, Marjatta Leirisalo-Repo, Satu Mustjoki
Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. We now aimed to study whether these mutations can also be detected in Felty syndrome, which would imply for a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome...
December 7, 2017: Haematologica
https://www.readbyqxmd.com/read/29216917/unexpected-profile-of-sphingolipid-contents-in-blood-and-bone-marrow-plasma-collected-from-patients-diagnosed-with-acute-myeloid-leukemia
#5
Marzena Wątek, Bonita Durnaś, Tomasz Wollny, Marcin Pasiarski, Stanisław Góźdź, Michał Marzec, Anna Chabowska, Przemysław Wolak, Małgorzata Żendzian-Piotrowska, Robert Bucki
BACKGROUND: Impaired apoptotic pathways in leukemic cells enable them to grow in an uncontrolled way. Moreover, aberrations in the apoptotic pathways are the main factor of leukemic cells drug resistance. METHODS: To assess the presence of potential abnormalities that might promote dysfunction of leukemic cells growth, HPLC system was used to determine sphingosine (SFO), sphinganine (SFA), sphingosine-1-phosphate (S1P) and ceramide (CER) concentration in the blood collected from patients diagnose with acute myeloblastic leukemia (AML; n = 49) and compare to values of control (healthily) group (n = 51)...
December 8, 2017: Lipids in Health and Disease
https://www.readbyqxmd.com/read/29202792/the-cc-chemokine-ligand-ccl-1-upregulated-by-the-viral-transactivator-tax-can-be-downregulated-by-minocycline-possible-implications-for-long-term-treatment-of-htlv-1-associated-myelopathy-tropical-spastic-paraparesis
#6
Mineki Saito, Hiroe Sejima, Tadasuke Naito, Hiroshi Ushirogawa, Toshio Matsuzaki, Eiji Matsuura, Yuetsu Tanaka, Tatsufumi Nakamura, Hiroshi Takashima
BACKGROUND: Chemokine (C-C motif) ligand 1 (CCL1) is produced by activated monocytes/ macrophages and T-lymphocytes, and acts as a potent attractant for Th2 cells and a subset of T-regulatory (Treg) cells. Previous reports have indicated that CCL1 is overexpressed in adult T-cell leukemia cells, mediating an autocrine anti-apoptotic loop. Because CCL1 is also known as a potent chemoattractant that plays a major role in inflammatory processes, we investigated the role of CCL1 in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP)...
December 4, 2017: Virology Journal
https://www.readbyqxmd.com/read/29182633/extensive-virologic-and-immunologic-characterization-in-an-hiv-infected-individual-following-allogeneic-stem-cell-transplant-and-analytic-cessation-of-antiretroviral-therapy-a-case-study
#7
Nathan W Cummins, Stacey Rizza, Mark R Litzow, Stephane Hua, Guinevere Q Lee, Kevin Einkauf, Tae-Wook Chun, Frank Rhame, Jason V Baker, Michael P Busch, Nicolas Chomont, Patrick G Dean, Rémi Fromentin, Ashley T Haase, Dylan Hampton, Sheila M Keating, Steven M Lada, Tzong-Hae Lee, Sekar Natesampillai, Douglas D Richman, Timothy W Schacker, Stephen Wietgrefe, Xu G Yu, Joseph D Yao, John Zeuli, Mathias Lichterfeld, Andrew D Badley
BACKGROUND: Notwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia. METHODS AND FINDINGS: We prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells...
November 2017: PLoS Medicine
https://www.readbyqxmd.com/read/29178667/comprehensive-review-of-post-organ-transplant-hematologic-cancers
#8
Vikas R Dharnidharka
A higher risk for a variety of cancers is among the major complications of post-transplant immunosuppression. In this part of a continuing series on cancers post-transplant, this review focuses on the hematologic cancers after solid organ transplant. Post-transplant lymphoproliferative disorders (PTLDs), which comprise the great majority of hematologic cancers, represent a spectrum of conditions that include, but are not limited to, the Hodgkin and non-Hodgkin lymphomas. The oncogenic Epstein-Barr virus is a key pathogenic driver in many PTLD cases, through known and unknown mechanisms...
November 25, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/29174474/iron-overload-in-hematological-disorders
#9
REVIEW
Eitan Fibach, Eliezer A Rachmilewitz
While most common symptom of impairment of iron homeostasis is iron deficiency anemia, some hematological disorders are associated with iron overload (IO). These disorders are related mainly to chronic severe hemolytic anemia, where red blood cells (RBC) or their precursors are destroyed prematurely (hemolyzed), leading to anemia that cannot be compensated by increased production of new RBC. In such cases, IO is mainly due to repeated RBC transfusions and/or increased uptake of iron in the gastrointestinal tract...
December 2017: La Presse Médicale
https://www.readbyqxmd.com/read/29168399/vacuolar-atpase-as-a-possible-therapeutic-target-in-human-acute-myeloid-leukemia
#10
Elise Aasebø, Sushma Bartaula-Brevik, Maria Hernandez-Valladares, Øystein Bruserud
V-ATPase is a proton pump expressed both in the membrane of intracellular organelles (e.g. endosomes, lysosomes, Golgi structures) and the plasma membrane. It is an important regulator of organellar functions, intracellular molecular trafficking, intercellular communication and intracellular signaling. It is therefore considered as a possible therapeutic target in the treatment of human malignancies. Areas covered: Relevant publications were identified through literature searches in the PubMed database. We searched for original articles and reviews describing the possible importance of V-ATPase for leukemogenesis and chemosensitivity in human myeloid cells, especially acute myeloid leukemia (AML) cells...
November 23, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29163182/the-natural-antiangiogenic-compound-ad0157-induces-caspase-dependent-apoptosis-in-human-myeloid-leukemia-cells
#11
Melissa García-Caballero, Beatríz Martínez-Poveda, Miguel A Medina, Ana R Quesada
Evasion of apoptosis is a hallmark of cancer especially relevant in the development and the appearance of leukemia drug resistance mechanisms. The development of new drugs that could trigger apoptosis in aggressive hematological malignancies, such as AML and CML, may be considered a promising antileukemic strategy. AD0157, a natural marine pyrrolidinedione, has already been described as a compound that inhibits angiogenesis by induction of apoptosis in endothelial cells. The crucial role played by defects in the apoptosis pathways in the pathogenesis, progression and response to conventional therapies of several forms of leukemia, moved us to analyze the effect of this compound on the growth and death of leukemia cells...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29146910/an-unexpected-protein-interaction-promotes-drug-resistance-in-leukemia
#12
Aaron Pitre, Yubin Ge, Wenwei Lin, Yao Wang, Yu Fukuda, Jamshid Temirov, Aaron H Phillips, Jennifer L Peters, Yiping Fan, Jing Ma, Amanda Nourse, Chandrima Sinha, Hai Lin, Richard Kriwacki, James R Downing, Tanja A Gruber, Victoria E Centonze, Anjaparavanda P Naren, Taosheng Chen, John D Schuetz
The overall survival of patients with acute myeloid leukemia (AML) is poor and identification of new disease-related therapeutic targets remains a major goal for this disease. Here we show that expression of MPP1, a PDZ-domain-containing protein, highly correlated with ABCC4 in AML, is associated with worse overall survival in AML. Murine hematopoietic progenitor cells overexpressing MPP1 acquired the ability to serially replate in methylcellulose culture, a property crucially dependent upon ABCC4. The highly conserved PDZ-binding motif of ABCC4 is required for ABCC4 and MPP1 to form a protein complex, which increased ABCC4 membrane localization and retention, to enhance drug resistance...
November 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29119293/asparaginase-erwinia-chrysanthemi-effectively-depletes-plasma-glutamine-in-adult-patients-with-relapsed-refractory-acute-myeloid-leukemia
#13
Ashkan Emadi, Jennie Y Law, Erin T Strovel, Rena G Lapidus, Linda J B Jeng, Myounghee Lee, Miriam G Blitzer, Brandon A Carter-Cooper, Danielle Sewell, Isabella Van Der Merwe, Sunita Philip, Mohammad Imran, Stephen L Yu, Hongxia Li, Philip C Amrein, Vu H Duong, Edward A Sausville, Maria R Baer, Amir T Fathi, Zeba Singh, Søren M Bentzen
Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 μmol/L in patients with relapsed or refractory (R/R) AML...
November 8, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29108331/the-role-of-frontline-autologous-stem-cell-transplantation-for-primary-plasma-cell-leukemia-a-retrospective-multicenter-study-kmm160
#14
Sung-Hoon Jung, Je-Jung Lee, Kihyun Kim, Cheolwon Suh, Dok Hyun Yoon, Chang-Ki Min, Sang Kyun Sohn, Chul Won Choi, Ho Sup Lee, Hyo Jung Kim, Ho-Jin Shin, Soo-Mee Bang, Sung-Soo Yoon, Seong Kyu Park, Ho-Young Yhim, Min Kyoung Kim, Jae-Cheol Jo, Yeung-Chul Mun, Jae Hoon Lee, Jin Seok Kim
Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell neoplasm, with rapidly progressing clinical course. We evaluated the treatment status and survival outcomes of 69 Korean patients with pPCL. Of them, 59 patients were treated; 15 (25.4%) were treated initially with novel agent-based regimens with upfront autologous stem cell transplantation (ASCT), 7 (11.9%) with conventional chemotherapy with upfront ASCT, 21 (35.6%) with novel agent-based regimens only, and 16 (27.1%) were treated with conventional chemotherapy alone...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29099493/pharmacodynamics-and-proteomic-analysis-of-acalabrutinib-therapy-similarity-of-on-target-effects-to-ibrutinib-and-rationale-for-combination-therapy
#15
V K Patel, B Lamothe, M L Ayres, J Gay, J Cheung, K Balakrishnan, C Ivan, J Morse, M Nelson, M J Keating, W G Wierda, J R Marszalek, V Gandhi
Acalabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, is associated with high overall response rates and durable remission in previously treated chronic lymphocytic leukemia (CLL), however, complete remissions were limited. To elucidate on-target and pharmacodynamic effects of acalabrutinib, we evaluated several laboratory endpoints, including proteomic changes, chemokine modulation, and impact on cell migration. Pharmacological profiling of samples from acalabrutinib-treated CLL patients was used to identify strategies for achieving deeper responses, and to identify additive/synergistic combination regimens...
November 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29066491/igm-myeloma-with-plasma-cell-leukemia-case-report-and-literature-review
#16
Saurabh Chhabra, Sandeep Jain, Amanda Fowler, Valeriy Sedov, Amarendra K Neppalli, Cynthia A Schandl, John Lazarchick
IgM multiple myeloma (MM) is a rare entity representing approximately 0.5% of all MM. It should be distinguished from malignant neoplasms of B cells with plasmacytic differentiation such as Waldenstrom macroglobulinemia (WM) and marginal zone lymphoma with plasmacytic differentiation. Plasma cell leukemia (PCL) is a rare and aggressive variant of MM characterized by the presence of circulating plasma cells. We present a case report of a patient who presented with IgM MM in primary PCL phase with high-risk cytogenetics...
September 2017: Annals of Clinical and Laboratory Science
https://www.readbyqxmd.com/read/29064593/combination-therapy-incorporating-bcl-2-inhibition-with-venetoclax-for-the-treatment-of-refractory-primary-plasma-cell-leukemia-with-t-11-14
#17
Wilson I Gonsalves, Francis K Buadi, Shaji K Kumar
Primary plasma cell leukemia (pPCL) is the most aggressive form of the plasma cell (PC) malignancy, multiple myeloma (MM). It has been commonly associated with the presence of a chromosome translocation involving the immunoglobulin heavy chain (IgH) locus on 14q32, i.e. t (11;14). Results from early phase clinical trials utilizing the selective bcl-2 inhibitor, venetoclax, as a single agent in patients with relapsed MM have had remarkable efficacy among patients with t (11;14) abnormality. The present case demonstrates the ability of a combination regimen incorporating bcl-2 inhibition with daratumumab, bortezomib, venetoclax and dexamethasone to induce a rapid and very deep hematologic response in a pPCL patient with t (11;14), even in a setting of very refractory disease...
October 24, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/29064484/jam-a-as-a-prognostic-factor-and-new-therapeutic-target-in-multiple-myeloma
#18
A G Solimando, A Brandl, K Mattenheimer, C Graf, M Ritz, A Ruckdeschel, T Stühmer, Z Mokhtari, M Rudelius, J Dotterweich, M Bittrich, V Desantis, R Ebert, P Trerotoli, M A Frassanito, A Rosenwald, A Vacca, H Einsele, F Jakob, A Beilhack
Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis...
September 28, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28978109/sorafenib-inhibits-therapeutic-induction-of-necroptosis-in-acute-leukemia-cells
#19
Friederike Feldmann, Barbara Schenk, Sofie Martens, Peter Vandenabeele, Simone Fulda
Induction of necroptosis has emerged as an alternative approach to trigger programmed cell death, in particular in apoptosis-resistant cancer cells. Recent evidence suggests that kinase inhibitors targeting oncogenic B-RAF can also affect Receptor-interacting serine/threonine-protein kinase (RIP)1 and RIP3. Sorafenib, a multi-targeting kinase inhibitor with activity against B-RAF, is used for the treatment of acute leukemia. In the present study, we therefore investigated whether Sorafenib interferes with therapeutic induction of necroptosis in acute leukemia...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28960265/cabozantinib-is-well-tolerated-in-acute-myeloid-leukemia-and-effectively-inhibits-the-resistance-conferring-flt3-tyrosine-kinase-domain-f691-mutation
#20
Amir T Fathi, Traci M Blonquist, Daniela Hernandez, Philip C Amrein, Karen K Ballen, Malgorzata McMasters, David E Avigan, Robin Joyce, Emma K Logan, Gabriela Hobbs, Andrew M Brunner, Christelle Joseph, Ashley M Perry, Meghan Burke, Tanya Behnan, Julia Foster, Meghan K Bergeron, Jenna A Moran, Aura Y Ramos, Tina T Som, Jessica Rae, Kaitlyn M Fishman, Kristin L McGregor, Christine Connolly, Donna S Neuberg, Mark J Levis
BACKGROUND: Cabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways. METHODS: Adults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy...
September 28, 2017: Cancer
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