Daratumumab is the first CD38 monoclonal antibody drug approved for the treatment of patients with multiple myeloma. It can bind to CD38 expressed by tumor cells, inhibit tumor cell growth and induce myeloma cell apoptosis through a variety of immune-related mechanisms. Meanwhile, CD38 is also expressed in other cells, including regulatory T cells, regulatory B cells and myeloid-derived suppressor cells, which provides a theoretical basis for the treatment of hematological tumor diseases other than non-multiple myeloma diseases. This article reviews the research progress and application of this part.
Humans ; Multiple Myeloma/pathology* ; ADP-ribosyl Cyclase 1 ; Antibodies, Monoclonal/pharmacology* ; Hematologic Neoplasms/drug therapy*

OBJECTIVE: To investigate the predict significance of the high aldehyde dehydrogenase activity (ALDH METHODS: Bone marrow samples of 23 t(8;21) AML patients diagnosis and achieved complete remission in our hospital from April 2015 to June 2016 were collected, then flow cytometry method was used to detect the activity of ALDH, relationship between it and relapse was analyzed. RESULTS: All the patients were followed up for a median of 32 (2-52) months. The median percentage of CD34 CONCLUSION The percentage of CD34
ADP-ribosyl Cyclase 1 ; Antigens, CD34 ; Flow Cytometry ; Humans ; Leukemia, Myeloid, Acute ; Neoplastic Stem Cells ; Prognosis ; Recurrence ; Remission Induction

Multiple myeloma (MM), considered an incurable hematological malignancy, is characterized by its clonal evolution of malignant plasma cells. Although the application of autologous stem cell transplantation (ASCT) and the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have doubled the median overall survival to eight years, relapsed and refractory diseases are still frequent events in the course of MM. To achieve a durable and deep remission, immunotherapy modalities have been developed for relapsed/refractory multiple myeloma (RRMM). Among these approaches, chimeric antigen receptor (CAR) T-cell therapy is the most promising star, based on the results of previous success in B-cell neoplasms. In this immunotherapy, autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure. Tisagenlecleucel and Axicabtagene, targeting the CD19 antigen, are the two pacesetters of CAR T-cell products. They were approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Their development enabled unparalleled efficacy in combating hematopoietic neoplasms. In this review article, we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.
ADP-ribosyl Cyclase 1/immunology* ; B-Cell Maturation Antigen/immunology* ; Humans ; Immunotherapy, Adoptive/methods* ; Multiple Myeloma/therapy* ; Receptors, Chimeric Antigen/immunology* ; Receptors, G-Protein-Coupled/immunology* ; Signaling Lymphocytic Activation Molecule Family/immunology* ; Syndecan-1/immunology* ; T-Lymphocytes/immunology*

BACKGROUND: Serum antinuclear antibodies (ANAs) are positive in some patients with chronic lymphocytic leukemia (CLL), but the prognostic value of ANAs remains unknown. The aim of this study was to evaluate the role of ANAs as a prognostic factor in CLL. METHODS: This study retrospectively analyzed clinical data from 216 newly diagnosed CLL subjects with ANAs test from 2007 to 2017. Multivariate Cox regression analyses were used to screen the independent prognostic factors related to time to first treatment (TTFT), progression free survival (PFS) and overall survival (OS). Receiver operator characteristic curves and area under the curve (AUC) were utilized to assess the predictive accuracy of ANAs together with other independent factors for OS. RESULTS: The incidence of ANAs abnormality at diagnosis was 13.9%. ANAs positivity and TP53 disruption were independent prognostic indicators for OS. The AUC of positive ANAs together with TP53 disruption was 0.766 (95% confidence interval [CI]: 0.697-0.826), which was significantly larger than that of either TP53 disruption (AUC: 0.706, 95% CI: 0.634-0.772, P = 0.034) or positive ANAs (AUC: 0.595, 95% CI: 0.520-0.668, P < 0.001) in OS prediction. Besides, serum positive ANAs as one additional parameter to CLL-international prognostic index (IPI) obtained superior AUCs in predicting CLL OS than CLL-IPI alone. CONCLUSION This study identified ANAs as an independent prognostic factor for CLL, and further investigations are needed to validate this finding.
ADP-ribosyl Cyclase 1 ; blood ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Antinuclear ; blood ; Autoimmunity ; physiology ; Female ; Humans ; Kaplan-Meier Estimate ; Leukemia, Lymphocytic, Chronic, B-Cell ; blood ; mortality ; Male ; Middle Aged ; Multivariate Analysis ; Mutation ; genetics ; Proportional Hazards Models ; Retrospective Studies ; Survival Analysis ; Tumor Suppressor Protein p53 ; blood ; Young Adult ; ZAP-70 Protein-Tyrosine Kinase ; blood

OBJECTIVE: To investigate the apoptosis of CD34CD38-KG1a leukemia stem cells induced by Qinba selenium-mushroom extract(FA-2-b-β), and its related mechanism. METHODS: CD34CD38--KG1a cells were isolated from KG1a cell line by magnetic activated cell sorting. The proliferation ability of KG1a stem cells treatd by various concentration of FA-2-b-β(1.2-2.4 mg/ml) in vitro for 24 and 48 hours were tested by cell counting Kit-8(CCK8). Flow cytometry was used to detect the apoptosis rate of KG1a stem cells in each group after treated by FA-2-b-β in vitro. Expression of BAX,BCL-2,Casepase-3 and Cyclin D1 protein were detected by Western blot. RESULTS: The proportion of CD34CD38--KG1a stem cells was (95.35±2.63）% after immunomagnetic isolation. The proliferation of KG1a stem cells was inhibited significantly by FA-2-b-β, which shows a time- and dose-dependent manner (24 h,r=0.943; 48 h,r=0.976). Flow cytometry shows that with the increasing of drug concentration, the apoptosis was also increased, when KG1a stem cells was treated by FA-2-b-β for 24 h. Western blot indicated that the expression of apoptosis-related protein BAX and Casepase-3 were up-regulated, the expression of BCL-2 and Cyclin D1 were down-regulated. CONCLUSION FA-2-b-β can regulate proliferation and apoptosis KG1a stem cells, the involved mechanism may be related with the activation of mitochondrial-mediated apoptotic pathway.
ADP-ribosyl Cyclase 1 ; Antigens, CD34 ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Membrane Glycoproteins ; Neoplastic Stem Cells ; Selenium

Objective: To investigate the characteristic and prognostic significance of leukemia stem cells associated antigens expressions including CD34, CD38, CD123, CD96 and TIM-3 in t (8;21) AML. Methods: Bone marrow samples of 47 t (8;21) AML patients were collected at diagnosis from October 2015 to April 2018 in Peking University Peoples' Hospital, then flow cytometry method was performed to detect the expression frequencies of CD34, CD38, CD123, CD96 and TIM-3 to analyze the relationship between leukemia stem cells associated antigens expressions and relapse. Results: Of 47 t (8;21) AML patients tested, the median percentages of CD34(+)CD38(-), CD34(+) CD38(-)CD123(+), CD34(+)CD38(-) CD96(+) and CD34(+) CD38(-) TIM-3(+) cells among nucleated cells were 2.37%, 0.24%, 0.27% and 0.06%, respectively. All the frequencies of CD34(+)CD38(-), CD34(+)CD38(-)CD123(+), CD34(+)CD38(-)CD96(+) and CD34(+) CD38(-)TIM-3(+) cells had no impact on the achievement of CR after the first course of induction. All higher frequencies of CD34(+)CD38(-), CD34(+)CD38(-)CD123(+), CD34(+)CD38(-)CD96(+) cells were related to higher 2-year CIR rate. Whereas, the frequency of CD34(+) CD38(-) TIM-3(+) cells had no impact on CIR rate. Both high frequency of CD34(+) CD38(-) cells and the high level of minimal residual diseases (patients with <3-log reduction in the RUNX1-RUNX1T1 transcript level after the second consolidation therapy) were independent poor prognostic factors of CIR[P=0.025, HR=6.9 (95%CI 1.3-37.4) ; P=0.031, HR=11.1 (95%CI 1.2-99.2) ]. Conclusion: Different leukemia stem cells associated antigens had distinct prognostic significance in t (8;21) AML. High frequencies of CD34(+) CD38(-), CD34(+) CD38(-) CD123(+) and CD34(+)CD38(-)CD96(+) cells at diagnosis predicted relapse in patients with t (8;21) AML.
ADP-ribosyl Cyclase 1 ; Antigens, CD ; Flow Cytometry ; Humans ; Interleukin-3 Receptor alpha Subunit ; Leukemia, Myeloid, Acute ; Neoplastic Stem Cells ; Prognosis ; Stem Cells

Herein, we report a patient showing panagglutination in the unexpected antibody identification test after the administration of daratumumab. The patient was a 66-year-old woman who had undergone multiple cycles of chemotherapy and autologous peripheral blood stem cell transplantation for treating multiple myeloma; however, despite treatment, she had relapsed. Therefore, daratumumab, on clinical trials in Korea, started to be administered. After administration of daratumumab, the result of antibody screening test was positive, on the contrary to the result prior to the administration. Moreover, all positive reactions were shown in the antibody identification to the panel cells. After destroying CD38 antigens on the surface of RBCs using DTT, negative results were obtained. Daratumumab—a novel therapeutic human CD38 monoclonal antibody that can be used as targeted immunotherapy—is an FDA-approved drug for treating multiple myeloma. Because CD38 is expressed not only on myeloma cells, but also on red blood cells (RBCs), the use of daratumumab might lead to RBC agglutinations, and thereby resulting in false-positive results on the pre-transfusion tests. Therefore, caution is needed in case of a patient receiving daratumumab. Furthermore, additional test using DTT is required, especially when panagglutination was shown in the antibody identification test, as in this case.
Aged ; Antigens, CD38 ; Drug Therapy ; Erythrocytes ; Female ; Humans ; Korea ; Mass Screening ; Multiple Myeloma* ; Peripheral Blood Stem Cell Transplantation

BACKGROUNDAcute lung injury (ALI) is a common complication of sepsis that is associated with high mortality. Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI.

METHODSSeptic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-μ, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured.

RESULTSNAD+, cADPR, CD38, and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-μ and MDA levels (P < 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats.

CONCLUSIONSThe CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI.

ADP-ribosyl Cyclase 1 ; metabolism ; Acute Lung Injury ; chemically induced ; drug therapy ; Animals ; Calcium ; metabolism ; Cyclic ADP-Ribose ; analogs & derivatives ; antagonists & inhibitors ; metabolism ; therapeutic use ; Male ; Malondialdehyde ; metabolism ; Rats ; Rats, Sprague-Dawley ; Sepsis ; complications ; Superoxide Dismutase ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

No abstract available.
Aged ; Antigens, CD38/analysis ; Biomarkers, Tumor/analysis ; Biopsy ; Gastrointestinal Hemorrhage/diagnosis/*etiology/therapy ; Gastroscopy ; Hematemesis/etiology ; Humans ; Immunohistochemistry ; Male ; Melena/etiology ; Membrane Glycoproteins/analysis ; Multiple Myeloma/*complications/immunology/pathology/therapy ; Recurrence ; Stomach Neoplasms/*complications/immunology/pathology/therapy

CD38 is a multifunctional enzyme expressed in a variety of mammalian tissues, its catalytic activity was involved in a wide range of physiological processes. Based on the reported inhibitor of human CD38 NADase, 33 purine derivatives were designed and synthesized. The biological activity assay showed that compounds 20 and 38 exhibited almost the same extent of inhibitory activities on human CD38 NADase as the lead compound H2. The results also revealed that small substituents at C-6 of purine ring gave no obvious effect on inhibitory activity, but phenylpropionyl moiety at N-2 could affect the binding mode of the compound with CD38. This study provides a reliable basis for future rational design of inhibitors for CD38.
ADP-ribosyl Cyclase 1 ; antagonists & inhibitors ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; Humans ; Purines ; chemical synthesis ; chemistry