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#29054515   2017/10/21 Save this To Up

Blood Transfusion Management and Transfusion-Related Outcomes in Daratumumab-Treated Patients With Relapsed or Refractory Multiple Myeloma.

Daratumumab, a human CD38 monoclonal antibody approved for multiple myeloma (MM) treatment, binds red blood cells (RBCs), resulting in panagglutination in compatibility tests. Published mitigation methods avoid additional testing, ensuring timely release of blood products. Blood transfusion management and transfusion-related outcomes of daratumumab-treated patients in the SIRIUS study are reported, with emphasis on 2 clinical sites.

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#29046481   2017/10/19 Save this To Up

Reevaluation of immune activation in the era of cART and an aging HIV-infected population.

Biological aging is associated with immune activation (IA) and declining immunity due to systemic inflammation. It is widely accepted that HIV infection causes persistent IA and premature immune senescence despite effective antiretroviral therapy and virologic suppression; however, the effects of combined HIV infection and aging are not well defined. Here, we assessed the relationship between markers of IA and inflammation during biological aging in HIV-infected and -uninfected populations. Antibody response to seasonal influenza vaccination was implemented as a measure of immune competence and relationships between IA, inflammation, and antibody responses were explored using statistical modeling appropriate for integrating high-dimensional data sets. Our results show that markers of IA, such as coexpression of HLA antigen D related (HLA-DR) and CD38 on CD4+ T cells, exhibit strong associations with HIV infection but not with biological age. Certain variables that showed a strong relationship with aging, such as declining naive and CD38+ CD4 and CD8+ T cells, did so regardless of HIV infection. Interestingly, the variable of biological age was not identified in a predictive model as significantly impacting vaccine responses in either group, while distinct IA and inflammatory variables were closely associated with vaccine response in HIV-infected and -uninfected populations. These findings shed light on the most relevant and persistent immune defects during virological suppression with antiretroviral therapy.

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#29042997   2017/10/18 Save this To Up

CD19(+)CD24(hi)CD38(hi) regulatory B cells are associated with insulin resistance in type I Hashimoto's thyroiditis in Chinese females.

Hashimoto's thyroiditis (HT) is typically associated with insulin resistance. The aim of the present study was to investigate the role of regulatory B cells (Bregs) in insulin resistance in patients with HT. A total of 52 female patients with type I HT and 35 matched healthy volunteers were enrolled. Demographic and laboratorial data were collected. A 75 g oral glucose tolerance test was performed on each subject. Flow cytometry was performed to evaluate the levels of CD19(+)CD24(hi)CD38(hi) Bregs in peripheral blood. Patients with HT exhibited significantly higher postprandial insulin levels (P<0.01), but normal glucose levels. The level of CD19(+)CD24(hi)CD38(hi) Bregs in patients with HT decreased significantly (P=0.0002) compared with the controls. Pearson's linear correlation model revealed a significant, negative association between anti-thyroid peroxidase antibodies (TPOAb) and homeostasis model assessment of β cell (r=-0.313, P=0.014). The same correlation model revealed a significant, negative association between TPOAb and the disposition index (DI; r=-0.305, P=0.017), and between anti-thyroglobulin antibodies and DI (r=-0.321, P=0.013). Patients with a decreased ratio of CD19(+)CD24(hi)CD38(hi) Bregs to CD19(+) lymphocytes exhibited higher levels of total cholesterol and low-density lipoprotein cholesterol. A decrease in the ratio of CD19(+)CD24(hi)CD38(hi) Bregs to lymphocytes was a significant independent risk factor for hyperinsulinemia (odds ratio=1.372, P=0.035). A decrease in peripheral blood CD19(+)CD24(hi)CD38(hi) Bregs is associated with insulin resistance in HT patients, and was an independent risk factor for postprandial hyperinsulinemia. The present study provided a novel insight into the development of effective therapeutic strategies targeting immune mechanisms associated with HT.

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#29040164   2017/10/17 Save this To Up

CD52 expression on CD4+ T cells in HIV-positive individuals on cART.

Human immune defect virus (HIV) persists in a latent state in quiescent CD4+ T cells preventing eradication of HIV. CD52 is a surface molecule modulated by HIV. We aimed at examining factors related to CD52 expression on CD4+ T cells in HIV-positive individuals and the impact of initiation of combination antiretroviral therapy (cART).

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#29037136   2017/10/17 Save this To Up

Effect of Priming of Multipotent Mesenchymal Stromal Cells with Interferon γ on Their Immunomodulating Properties.

Multipotent mesenchymal stromal cells (MSCs) are widely used for cell therapy, in particular for prophylaxis and treatment of graft-versus-host disease. Due to their immunomodulatory properties, MSCs affect the composition of lymphocyte subpopulations, which depends on the immunological state of the organism and can change in different diseases and during treatment. Administration of MSCs is not always effective. Treatment of MSCs with different cytokines (in particular IFN-γ) leads to enhancement of their immunomodulatory properties. The aim of this study was to investigate subpopulational alterations and activation markers in lymphocytes (activated and non-activated) after interaction with MSCs and MSCs pretreated with IFN-γ (γMSCs) in vitro. Lymphocytes were co-cultured with MSCs or γMSCs for 4 days. The proportion of CD4+ and CD8(+) expressing CD25, CD38, CD69, HLA-DR, and PD-1 and distribution of memory and effector subsets were measured by flow cytometry after co-cultivation of lymphocytes with MSCs or γMSCs. The distribution of lymphocyte subpopulations changes during culturing. In non-activated lymphocytes cultured without MSCs, decrease in the proportion of naïve cells and increase in the number of effector cells was observed. That could be explained as activation of lymphocytes in the presence of serum in culturing medium. Co-culturing of lymphocytes with MSCs and γMSCs leads to retention of their non-activated state. Activation of lymphocytes with phytohemagglutinin increases the number of central memory cells and activates marker expression. Interaction with MSCs and γMSCs prevents activation of lymphocytes and keeps their naïve state. Priming with IFN-γ did not induce MSCs inhibitory effect on activation of lymphocytes.

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#29035673   2017/10/16 Save this To Up

Extracellular Pyridine Nucleotides as Immune Elicitors in Arabidopsis.

The pyridine nucleotides nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP) are coenzymes that function in both metabolic reactions and intracellular signaling. Emerging evidence from animal research indicates that NAD(P) also acts in the extracellular space (ECS). We have shown in the model plant Arabidopsis that (1) exogenous NAD(P) induces immune responses, (2) pathogen infection causes leakage of intracellular NAD(P) into the extracellular fluid at concentrations sufficient to induce immune responses, and (3) removal of extracellular NAD(P) [eNAD(P)] by expressing the human NAD(P)-metabolizing ectoenzyme CD38 partially compromises systemic acquired resistance. Based on these results, we hypothesize that eNAD(P) is a novel damage-associated molecular pattern (DAMP) in plants; during plant-microbe interaction, intracellular NAD(P) is released from dead or dying cells into the ECS where it interacts with the adjacent healthy cells' surface receptors/targets, which in turn activate downstream specific immune signaling pathways. Our recent identification of LecRK-I.8, a lectin receptor kinase, as the first cell surface NAD(+)-binding receptor has provided compelling evidence for this hypothesis. Further identification of cell surface eNAD(P) receptors/targets and their downstream signaling components in Arabidopsis as well as determination of the generality of eNAD(P) signaling in crops will help establish eNAD(P) as a conserved DAMP in plants.

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#29035453   2017/10/16 Save this To Up

Immunophenotyping of Chronic Lymphocytic Leukemia.

Chronic Lymphocytic Leukemia (CLL) is one of the most common diagnoses made by flow cytometry laboratories. There is no consensus on which markers need to be used in flow cytometry for accurate immunophenotyping. Herein, we investigated the role of markers used in flow cytometry in the distinction between CLL and MCL.

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#29035307   2017/10/16 Save this To Up

Effects of Three Lipidated Oxytocin Analogs on Behavioral Deficits in CD38 Knockout Mice.

Oxytocin (OT) is a nonapeptide that plays an important role in social behavior. Nasal administration of OT has been shown to improve trust in healthy humans and social interaction in autistic subjects. As is consistent with the nature of a peptide, OT has some unfavorable characteristics: it has a short half-life in plasma and shows poor permeability across the blood-brain barrier. Analogs with long-lasting effects may overcome these drawbacks. To this end, we have synthesized three analogs: lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated to the cysteine and tyrosine residues, lipo-oxytocin-2 (LOT-2) and lipo-oxytocin-3 (LOT-3), which include one palmitoyl group conjugated at the cysteine or tyrosine residue, respectively. The following behavioral deficits were observed in CD38 knockout (CD38(-/-)) mice: a lack of paternal nurturing in CD38(-/-) sires, decreased ability for social recognition, and decreased sucrose consumption. OT demonstrated the ability to recover these disturbances to the level of wild-type mice for 30 min after injection. LOT-2 and LOT-3 partially recovered the behaviors for a short period. Conversely, LOT-1 restored the behavioral parameters, not for 30 min, but for 24 h. These data suggest that the lipidation of OT has some therapeutic benefits, and LOT-1 would be most useful because of its long-last activity.

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#29030054   2017/10/14 Save this To Up

Inhibiting the CD38/cADPR pathway protected rats against sepsis associated brain injury.

The CD38/cADPR pathway has been found to play roles in various inflammatory conditions. However, whether CD38 plays a protective or detrimental effect in the central nervous system (CNS) is controversial. The aim of this study was to determine the effect of CD38/cADPR pathway in sepsis associated brain injury.

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#29025987   2017/10/13 Save this To Up

Preclinical development of CD38-targeted [(89)Zr]Zr-DFO-daratumumab for imaging multiple myeloma.

Multiple myeloma (MM) is a plasma B-cell hematologic cancer that causes significant skeletal morbidity. Despite improvements in survival, heterogeneity in response remains a major challenge in MM. Cluster of differentiation 38 (CD38) is a type II transmembrane glycoprotein over-expressed in myeloma cells and is implicated in MM cell signaling. Daratumumab is US Food and Drug Administration approved high-affinity monoclonal antibody targeting CD38 that is clinically benefiting refractory MM patients. Here, we evaluated [(89)Zr]Zr-DFO-daratumumab positron emission tomography/computed tomography (PET/CT) imaging in MM tumor models. Methods: Daratumumab was conjugated to desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) for radiolabeling with Zr-89. Chelator conjugation was confirmed by electrospray ionization-mass spectrometry (ESI-MS), and radiolabeling was monitored by instant thin-layer chromatography. Daratumumab was additionally conjugated to Cyanine5 (Cy5) dye for cell microscopy. In vitro and in vivo evaluation of [(89)Zr]Zr-DFO-daratumumab was performed using CD38+ human myeloma MM1.S-luciferase (MM1.S) cells. Cellular studies determined the affinity, immunoreactivity, and specificity of [(89)Zr]Zr-DFO-daratumumab. CD38(low) 5TGM1-luciferase (5TGM1) murine MM cells served as negative controls. [(89)Zr]Zr-DFO-daratumumab PET/CT small animal imaging was performed in severe combined immunodeficient (SCID) mice bearing solid and disseminated MM tumors. Tissue biodistribution (7 days after tracer administration, 1.11 MBq/animal, n = 4-6/group) was performed in wild-type and MM1.S tumor-bearing SCID mice. Results: Specific activity of 55.5 MBq/nmol (0.37 MBq/µg) was reproducibly obtained with [(89)Zr]Zr-DFO-daratumumab. Flow cytometry confirmed CD38 expression (>99%) on the surface of MM1.S cells. Confocal microscopy with daratumumab-Cy5 demonstrated specific cell binding. A dissociation constant, Kd: 3.3 nM (± 0.58) and receptor density, Bmax: 10.1 fmol/mg (±0.64) was obtained with saturation binding assay. [(89)Zr]Zr-DFO-daratumumab/PET demonstrated specificity and sensitivity for detecting CD38(+) myeloma tumors of variable sizes (8.5 to 128 mm(3) ) with standardized uptake values ranging from 2.1 to 9.3. Discrete medullar lesions, confirmed by bioluminescence images, were efficiently imaged with [(89)Zr]Zr-DFO-daratumumab/PET. Biodistribution at seven days post administration of [(89)Zr]Zr-DFO-daratumumab showed prominent tumor uptake (27.7 ± 7.6 %ID/g). In vivo blocking was achieved with a 200-fold excess of unlabeled daratumumab. Conclusion: [(89)Zr]Zr-DFO- and Cy5-daratumumab demonstrated superb binding to CD38(+) human MM cells and significantly low binding to CD38(low) MM cells. Daratumumab bio-conjugates are being evaluated for image guided delivery of therapeutic radionuclides.

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