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https://www.readbyqxmd.com/read/27913523/advances-and-practical-use-of-monoclonal-antibodies-in-multiple-myeloma-therapy
#1
Hans C Lee, Donna M Weber
The use of proteasome inhibitors and immunomodulatory agents in the treatment of myeloma have resulted in significant improvements in patient outcomes over the last decade. Although these agents now form the backbone of current myeloma treatment regimens both in the frontline and in a relapsed setting, drug resistance remains an inevitable challenge that most patients will encounter during their disease course. Hence, new treatment strategies continue to be explored, and the recent regulatory approvals of the monoclonal antibodies (mAbs) daratumumab (DARA) and elotuzumab (ELO), which target the plasma cell surface proteins CD38 and signaling lymphocytic activation molecule F7 (SLAMF7), respectively, have heralded the long-awaited era of antibody-based approaches in the treatment of myeloma...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913521/sequencing-of-nontransplant-treatments-in-multiple-myeloma-patients-with-active-disease
#2
Andrew J Yee, Noopur S Raje
The approval of several different classes of drugs in recent years has resulted in a dramatic expansion of treatment options for multiple myeloma patients, improving both survival and quality of life. Lenalidomide and bortezomib are now core components of treatment both at time of diagnosis and at relapse. Next-generation immunomodulatory drugs, like pomalidomide, and newer proteasome inhibitors like carfilzomib and ixazomib are available for use at relapse. Drugs with novel mechanisms of action such as the histone deacetylase inhibitor panobinostat and the monoclonal antibodies targeting SLAMF7 (elotuzumab) and CD38 (daratumumab) are significant steps forward...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27910963/daratumumab-monoclonal-antibody-therapy-to-treat-multiple-myeloma
#3
C Xia, M Ribeiro, S Scott, S Lonial
Daratumumab (Darzalex[TM]) is a human monoclonal antibody (MAb) that targets CD38; a surface protein highly expressed across multiple myeloma (MM) cells. Preclinical studies have shown daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis upon secondary crosslinking and immunomodulatory effects via a decrease in immune suppressive cells. Daratumumab has a favorable toxicity profile and encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) and stem cell transplant have already failed...
October 2016: Drugs of Today
https://www.readbyqxmd.com/read/27903712/the-myeloma-stem-cell-concept-revisited-from-phenomenology-to-operational-terms
#4
REVIEW
Hans Erik Johnsen, Martin Bøgsted, Alexander Schmitz, Julie Støve Bødker, Tarec Christoffer El-Galaly, Preben Johansen, Peter Valent, Niklas Zojer, Els Van Valckenborgh, Karin Vanderkerken, Mark van Duin, Pieter Sonneveld, Martin Perez-Andres, Alberto Orfao, Karen Dybkær
The concept of the myeloma stem cell may have important therapeutic implications, yet its demonstration has been hampered by a lack of consistency in terms and definitions. Here, we summarize the current documentation and propose single-cell in vitro studies for future translational studies. By the classical approach, a CD19(-)/CD45(low/-)/CD38(high)/CD138(+) malignant plasma cell, but not the CD19(+)/CD38(low/-) memory B cell compartment, is enriched for tumorigenic cells that initiate myeloma in xenografted immunodeficient mice, supporting that myeloma stem cells are present in the malignant PC compartment...
December 2016: Haematologica
https://www.readbyqxmd.com/read/27896689/pharmacokinetics-of-daratumumab-following-intravenous-infusion-in-relapsed-or-refractory-multiple-myeloma-after-prior-proteasome-inhibitor-and-immunomodulatory-drug-treatment
#5
Pamela L Clemens, Xiaoyu Yan, Henk M Lokhorst, Sagar Lonial, Nedjad Losic, Imran Khan, Richard Jansson, Tahamtan Ahmadi, Kristen Lantz, Honghui Zhou, Thomas Puchalski, Xu Steven Xu
Daratumumab is a CD38 monoclonal antibody recently approved for the treatment of multiple myeloma (MM). We report daratumumab pharmacokinetic data from GEN501, a phase I/II dose-escalation (0.005-24 mg/kg) and dose-expansion (8 or 16 mg/kg) study, and SIRIUS, a phase II study (8 or 16 mg/kg), in relapsed or refractory MM. Noncompartmental analysis was conducted to characterize daratumumab pharmacokinetics, and, in both studies, daratumumab exhibited nonlinear pharmacokinetic characteristics. Decreasing daratumumab clearance with increasing dose suggests saturation of target-mediated clearance at higher dose levels, whereas decreasing clearance over time with repeated dosing may be due to tumor burden reductions as CD38-positive cells are eliminated...
November 29, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27895173/human-regulatory-t-cells-mediate-transcriptional-modulation-of-dendritic-cell-function
#6
Emily Mavin, Lindsay Nicholson, Syed Rafez Ahmed, Fei Gao, Anne Dickinson, Xiao-Nong Wang
Regulatory T cells (Treg) attenuate dendritic cell (DC) maturation and stimulatory function. Current knowledge on the functional impact of semimature DC is limited to CD4(+) T cell proliferation and cytokine production. Little is known about the molecular basis underpinning the functional effects of Treg-treated DC (Treg-DC). We present novel evidence that Treg-DC skewed CD4(+) naive T cell polarization toward a regulatory phenotype and impaired CD8(+) T cell allo-reactive responses, including their ability to induce target tissue damage in a unique in vitro human graft-versus-host disease skin explant model...
November 28, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27890934/egr2-mutations-define-a-new-clinically-aggressive-subgroup-of-chronic-lymphocytic-leukemia
#7
E Young, D Noerenberg, L Mansouri, V Ljungström, M Frick, L-A Sutton, S J Blakemore, J Galan-Sousa, K Plevova, P Baliakas, D Rossi, R Clifford, D Roos-Weil, V Navrkalova, B Dörken, C A Schmitt, K E Smedby, G Juliusson, B Giacopelli, J S Blachly, C Belessi, P Panagiotidis, N Chiorazzi, F Davi, A W Langerak, D Oscier, A Schuh, G Gaidano, P Ghia, W Xu, L Fan, O A Bernard, F Nguyen-Khac, L Rassenti, J Li, T J Kipps, K Stamatopoulos, S Pospisilova, T Zenz, C C Oakes, J C Strefford, R Rosenquist, F Damm
Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27881669/aerobic-exercise-in-humans-mobilizes-hsc-in-an-intensity-dependent-manner
#8
Jeff M Baker, Joshua P Nederveen, Gianni Parise
Hematopoietic stem and progenitor cells are necessary to maintain, repair, and reconstitute the hematopoietic blood cell system. Mobilization of these cells from bone marrow to blood can be greatly increased under certain conditions, one such being exercise. The purpose of this study was to identify the importance of exercise intensity in hematopoietic mobilization, to better understand the mobilization kinetics post exercise, and to determine if exercise is capable of mobilizing several specific populations of hematopoietic cells that have clinical relevance in a transplant setting...
November 23, 2016: Journal of Applied Physiology
https://www.readbyqxmd.com/read/27878389/spleen-atrophy-related-immune-system-changes-attributed-to-infection-of-angiostrongylus-cantonensis-in-mouse-model
#9
Zhen Liu, Yu Wu, Ying Feng, Feng Wu, Rui-Feng Liu, Li-Fu Wang, Jin-Yi Liang, Jia-Hua Liu, Xi Sun, Zhong-Dao Wu
The spleen is one of the most important peripheral immune organs, which is frequently affected in infectious diseases. Infectious diseases can induce splenic alterations including splenic atrophy and functional alteration, while splenic atrophy may in turn interferes with recovery of infectious diseases. Angiostrongyliasis is an infectious disease by Angiostrongylus cantonensis (A. cantonensis), which invade non-permissive hosts, such as humans and mice, to cause severe damage to the central nervous system (CNS) and acute inflammatory response...
November 22, 2016: Parasitology Research
https://www.readbyqxmd.com/read/27872867/bone-marrow-mesenchymal-stem-cells-enhance-the-differentiation-of-human-switched-memory-b-lymphocytes-into-plasma-cells-in-serum-free-medium
#10
Guillaume Bonnaure, Catherine Gervais-St-Amour, Sonia Néron
The differentiation of human B lymphocytes into plasma cells is one of the most stirring questions with regard to adaptive immunity. However, the terminal differentiation and survival of plasma cells are still topics with much to be discovered, especially when targeting switched memory B lymphocytes. Plasma cells can migrate to the bone marrow in response to a CXCL12 gradient and survive for several years while secreting antibodies. In this study, we aimed to get closer to niches favoring plasma cell survival...
2016: Journal of Immunology Research
https://www.readbyqxmd.com/read/27870882/immune-activation-at-sites-of-hiv-tb-co-infection-contributes-to-the-pathogenesis-of-hiv-1-disease
#11
Qinglai Meng, Ismail Sayin, David H Canaday, Harriet Mayanja-Kizza, Joy Baseke, Zahra Toossi
Systemic immune activation is critical to the pathogenesis of HIV-1 disease, and is accentuated in HIV/TB co-infected patients. The contribution of immune activation at sites of HIV/TB co-infection to viral activity, CD4 T cell count, and productive HIV-1 infection remain unclear. In this study, we measured markers of immune activation both in pleural fluid and plasma, and in T cells in pleural fluid mononuclear cell (PFMC) and peripheral blood mononuclear cell (PBMC) in HIV/TB co-infected subjects. The relationship between soluble and T cell activation markers with viral load in pleural fluid and blood CD4 T cell count were assessed...
2016: PloS One
https://www.readbyqxmd.com/read/27864418/ampk-ulk1-mediated-autophagy-confers-resistance-to-bet-inhibitor-jq1-in-acute-myeloid-leukemia-stem-cells
#12
Ji Eun Jang, Ju In Eom, Hoi Kyung Jeung, June-Won Cheong, Jung Yeon Lee, Jin Seok Kim, Yoo Hong Min
PURPOSE: Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSCs) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. EXPERIMENTAL DESIGN: We evaluated the levels of apoptosis and autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34(+)CD38(-) leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations...
November 18, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27863374/magic-year-for-multiple-myeloma-therapeutics-key-takeaways-from-the-ash-2015-annual-meeting
#13
REVIEW
Kejie Zhang, Aakash Desai, Dongfeng Zeng, Tiejun Gong, Peihua Lu, Michael Wang
Despite the availability of various anticancer agents, Multiple Myeloma (MM) remains incurable in most cases, along with high relapse rate in the patients treated with these agents. The year 2015 saw major advancements in our battle against multiple myeloma. In 2015, the U.S. Food and Drug Administration (FDA) approved three new therapies for multiple myeloma, namely Ixazomib (an oral proteasome inhibitor), Daratumumab and Elotuzumab (monoclonal antibodies against CD38 and SLAMF7 respectively). The purpose of this review is to provide a detailed analysis of these aforementioned breakthrough therapies and two other newer agents, Filanesib (kinesis spindle inhibitor) and selinexor (SINE inhibitor), presented at the 2015 annual meeting of American Society of Hematology (ASH)...
November 11, 2016: Oncotarget
https://www.readbyqxmd.com/read/27862137/t-cell-responses-and-regulation-and-the-impact-of-in-vitro-il-10-and-tgf-%C3%AE-modulation-during-treatment-of-active-tuberculosis
#14
Siri L Feruglio, Dag Kvale, Anne Ma Dyrhol-Riise
Mycobacterium tuberculosis (Mtb) is particularly challenging for the immune system being an intracellular pathogen, and a variety of T cell subpopulations are activated by the host defense mechanism. In the present study we investigated T cell responses and regulation in active TB patients with drug-sensitive Mtb (n=18) during 24 weeks of efficient anti-TB therapy. T cell activation, differentiation, regulatory T cell (Treg) subsets, Mtb induced T cell proliferation and in vitro IL-10 and TGF-β modulation were analysed by flow cytometry at baseline and after 8 and 24 weeks of therapy, while soluble cytokines in culture supernatants were analysed by a 9-plex Luminex assay...
November 18, 2016: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/27859332/patients-outcome-after-rescue-plerixafor-administration-for-autologous-stem-cell-mobilization-a-single-center-retrospective-analysis
#15
Silvia Spoerl, Robert Peter, Dagmar Wäscher, Katharina Götze, Mareike Verbeek, Christian Peschel, Angela M Krackhardt
BACKGROUND: Plerixafor is predominantly used for patients mobilizing inadequate stem cell numbers for autologous transplantation after stimulation with granulocyte-colony-stimulating factor (G-CSF). STUDY DESIGN AND METHODS: We here report on 300 patients undergoing stem cell mobilization with G-CSF, among them 36 poor mobilizers (CD34+ cell counts < 50 × 10(6) /L blood) receiving G-CSF alone and 49 receiving G-CSF in combination with plerixafor for rescue intervention...
November 18, 2016: Transfusion
https://www.readbyqxmd.com/read/27859027/clinical-implications-of-complex-pharmacokinetics-for-daratumumab-dose-regimen-in-patients-with-relapsed-refractory-multiple-myeloma
#16
Xu Steven Xu, Xiaoyu Yan, Thomas Puchalski, Sagar Lonial, Henk M Lokhorst, Peter M Voorhees, Torben Plesner, Kevin Liu, Imran Khan, Richard Jansson, Tahamtan Ahmadi, Juan Jose Perez Ruixo, Honghui Zhou, Pamela L Clemens
New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen for daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM...
November 17, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27856460/architectural-and-functional-heterogeneity-of-hematopoietic-stem-progenitor-cells-in-non-del-5q-myelodysplastic-syndromes
#17
Virginie Chesnais, Marie-Laure Arcangeli, Caroline Delette, Alice Rousseau, Hélène Guermouche, Carine Lefevre, Sabrina Bondu, M'boyba Diop, Meyling Cheok, Nicolas Chapuis, Laurence Legros, Sophie Raynaud, Lise Willems, Didier Bouscary, Evelyne Lauret, Olivier A Bernard, Olivier Kosmider, Françoise Pflumio, Michaela Fontenay
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders in which recurrent mutations define clonal hematopoiesis. The origin of the phenotypic diversity of non del(5q) MDS remains unclear. Here, we investigated the clonal architecture of the CD34+CD38- hematopoietic stem/progenitor cell (HSPC) compartment and interrogated dominant clones for MDS-initiating cells. We found that clones mainly accumulate mutations in a linear succession with retention of a dominant subclone. The clone detected in the long-term culture-initiating cell (LTC-IC) compartment and that reconstitutes short-term human hematopoiesis in xenotransplantation models is usually the dominant clone, which gives rise to the myeloid and to a lesser extent to the lymphoid lineage...
November 16, 2016: Blood
https://www.readbyqxmd.com/read/27856426/cytotoxic-t-cells-in-pd-l1-positive-malignant-pleural-mesotheliomas-are-counterbalanced-by-distinct-immunosuppressive-factors
#18
Mark M Awad, Robert E Jones, Hongye Liu, Patrick H Lizotte, Elena V Ivanova, Meghana Kulkarni, Grit S Herter-Sprie, Xiaoyun Liao, Abigail A Santos, Mark A Bittinger, Lauren Keogh, Shohei Koyama, Christina Almonte, Jessie M English, Julianne Barlow, William G Richards, David A Barbie, Adam J Bass, Scott J Rodig, F Stephen Hodi, Kai W Wucherpfennig, Pasi A Jänne, Lynette M Sholl, Peter S Hammerman, Kwok-Kin Wong, Raphael Bueno
PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1-positive and PD-L1-negative malignant pleural mesothelioma samples. We developed a method for immune cell phenotyping using flow cytometry on solid tumors that have been dissociated into single-cell suspensions and applied this technique to analyze 43 resected malignant pleural mesothelioma specimens...
December 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27837410/effect-of-cd40-cd40l-signaling-on-il-10-producing-regulatory-b-cells-in-chinese-children-with-henoch-sch%C3%A3-nlein-purpura-nephritis
#19
Baohui Yang, Xiongjun Tan, Xiao Xiong, Daoqi Wu, Gaofu Zhang, Mo Wang, Shifang Dong, Wei Liu, Haiping Yang, Qiu Li
The aim of the present study was to examine the role and mechanism of interleukin-10 (IL-10)-producing regulatory B cells (B10 cells) in the pathogenesis of Henoch-Schönlein purpura nephritis (HSPN). We examined the percentage of B10 cells, CD19(+)CD24(hi)CD38(hi) B cells, CD19(+)CD24(hi)CD27(+) B cells, Th17 cells, and T regulatory (Treg) cells within the peripheral blood mononuclear cell (PBMC) population in healthy subjects and HSP/HSPN patients. The percentage of B10 cells and CD19(+)CD24(hi)CD38(hi) B cells was reduced in HSPN patients and that of CD19(+)CD24(hi)CD27(+) B cells was decreased only in HSPN patients with hematuria and proteinuria or massive proteinuria...
November 11, 2016: Immunologic Research
https://www.readbyqxmd.com/read/27835618/increased-glucose-transporter-1-expression-on-intermediate-monocytes-from-hiv-infected-women-with-subclinical-cardiovascular-disease
#20
Tiffany R Butterfield, David B Hanna, Robert C Kaplan, Jorge R Kizer, Helen G Durkin, Mary A Young, Marek J Nowicki, Phyllis C Tien, Elizabeth T Golub, Michelle A Floris-Moore, Kehmia Titanji, Margaret A Fischl, Sonya L Heath, Jefferey Martinson, Suzanne M Crowe, Clovis S Palmer, Alan L Landay, Joshua J Anzinger
OBJECTIVE: People living with HIV (PLWH) have chronic immune activation and increased cardiovascular disease (CVD) risk. Activation of monocytes and T lymphocytes causes up-regulation of glucose transporter-1 (GLUT1) for efficient function. PLWH have an increased percentage of GLUT1-expressing monocytes and T lymphocytes, but it is unclear if these cells are associated with CVD. We evaluated expression of GLUT1 and CD38 on monocyte and T lymphocyte populations from HIV-infected women with subclinical CVD...
November 9, 2016: AIDS
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