ARTICLE | doi:10.20944/preprints202112.0217.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: DH、DHF、CD38、ZNF595 and Autophagy
Online: 13 December 2021 (17:07:08 CET)
At present, there are still no specific therapeutic drugs and appropriate vaccines for Dengue. Therefore, it is very important to explore distinct clinical diagnostic indicators. In this study, we combined differentially expressed genes (DEGs) analysis and weighted co-expression network analysis (WGCNA) to screen a stable and robust biomarker which can be used to distinguish three clinical stages of Dengue and severity of Dengue. CD38 can distinguish excellently Early Acute, Late Acute, Convalescent stages for Dengue patients, and ZNF595 can discriminate DHF from DF in whole acute stages. We also found that three clinical stages can be discriminated based on the fractions of Plasma cells, activated memory CD4+ T cells, and Monocytes. In different clinical stages different immune cells function positively. Negative inhibition of viral replication based on Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene set enrichment analysis (GSEA), up-regulated autophagy genes and impairing immune system are potential reasons resulting in dengue hemorrhagic fever (DHF).
REVIEW | doi:10.20944/preprints202004.0045.v1
Subject: Medicine And Pharmacology, Pulmonary And Respiratory Medicine Keywords: SARS-CoV-2; lymphopenia; NAD+ depletion; CD38
Online: 6 April 2020 (09:28:00 CEST)
The emerging of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is associated with high morbidity and mortality rates globally. One of the most prominent characteristics of coronavirus disease-19 (COVID-19) is lymphopenia which is in contrast to other viral infections. This controversy might be explained by the evaluation of impaired innate and adaptive immune responses during the SARS-CoV-2 infection. During the innate immune response, poly-ADP-ribose polymerase (PARP) hyperactivated due to virus entry and extensive DNA damage sequentially leading to NAD+ depletion, ATP depletion and finally cell death. In contrast to the immune response against viral infections, cytotoxic T lymphocytes decline sharply in SARS-CoV-2 infection which might be due to infiltration and trapping in the lower respiratory tract. In addition, there are more factors proposed to involve in lymphopenia in COVID-19 infection like the role of CD38 which functions as NADase and intensifies NAD depletion which in turn affects NAD+ dependent Sirtuin proteins, as the regulators of cell death and viability. Lung tissue sequestration following cytokine storm supposed to be another reason for lymphopenia in COVID-19 patients. Protein 7a as one of the virus-encoded proteins induces apoptosis in various organ-derived cell lines. These mechanisms proposed to induce lymphopenia, although there are still more studies needed to clarify the underlying mechanisms for lymphopenia in COVID-19 patients.
ARTICLE | doi:10.20944/preprints201901.0114.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: multiple myeloma; STAT3; S3I-1757; nanoparticle; CD38
Online: 11 January 2019 (15:40:51 CET)
STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previously packaged STAT3 inhibitors using a novel formulation of nanoparticles (NP) and found encouraging results. In this study, we aimed to further improve the pharmacologic properties of these NP by decorating them with monoclonal anti-CD38 antibodies. NP loaded with S3I-1757 (a STAT3 inhibitor), labeled as S3I-NP, were generated. S3I-NP decorated with anti-CD38 (labeled as CD38-S3I-NP) were found to have a similar nanoparticular size, drug encapsulation and loading as S3I-NP. The release of S3I-1757 at 24 hours was also similar between the two formulations. Using Cy5.5 labeling of the NP, we found that the decoration of anti-CD38 on these NP significantly increased the cellular uptake by two MM cell lines (p<0.001). Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (p<0.001). In a xenograft mouse model, CD38-S3I-NP significantly reduced the tumor size by 4 folds compared to S3I-NP on day 12 after drug administration (p=0.006). The efficacy of CD38-S3I-NP in suppressing STAT3 phosphorylation in the xenografts was confirmed by using immunocytochemistry and western blot analysis. In conclusion, our study suggests that the decoration of anti-CD38 on NP loaded with STAT3 inhibitors can further improve their therapeutic effects against MM.
REVIEW | doi:10.20944/preprints201712.0008.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: mitochondria; mitophagy; transmitophgy; PGC1; mitofusin; DRP1; MIRO1; CD38
Online: 1 December 2017 (13:55:15 CET)
Mitochondria function to generate ATP and also play important roles in cellular homeostasis, signaling, apoptosis, autophagy, and metabolism. The loss of mitochondrial function results in cell death and various types of diseases. Therefore, quality control of mitochondria via intra- and intercellular pathways is crucial. Intracellular quality control consists of biogenesis, fusion and fission, and degradation of mitochondria in the cell, whereas intercellular quality control involves tunneling nanotubes and extracellular vesicles. In this review, we outline the current knowledge on the intra- and intercellular quality control mechanisms of mitochondria.
ARTICLE | doi:10.20944/preprints202008.0439.v1
Subject: Social Sciences, Behavior Sciences Keywords: oxytocin; CD38; OXTR; rs3796863; rs53576; polymorphism; adolescents; psychosocial characteristics; Strengths and Difficulties Questionnaire
Online: 20 August 2020 (07:30:29 CEST)
Oxytocin (OT) is regarded as an extremely important prosocial neuropeptide that dramatically affects the establishment of social connections from infancy to adulthood. OT effects on the psychoemotional state are pretty individual and may be dependent on age, gender, ethnocultural factors, social environment, the presence of stress factors, and features of personality. The Strengths and Difficulties Questionnaire (SDQ) is a brief psychopathological screening tool and is recommended for the detection and classification of psychosocial problems in adolescents. The current field school-based study, conducted among urban Siberian adolescents (n = 298 aged 12–18) explored the relation of SDQ scales in relation to genotypes of CD38 gene that controls oxytocin release, rs3796863, and oxytocin receptor gene (OXTR), rs53576. The results of our study show that during the adolescence period, OT pathway high activity can cause some negative effects, such as emotional instability in young (aged 12–14) adolescent girls in the case of carriage of the rs3796863 A allele and emotional disturbances in older (aged 15–18) adolescent boys who are carriers of a GG variant of rs53576. Our results support the hypothesis of OT-mediated excessive social sensitivity which can lead to some age-sex depending psychosocial problems during adolescence.
ARTICLE | doi:10.20944/preprints202108.0536.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: interferon gamma; cancer immunotherapy; viral vectors; alphavirus; bone marrow-derived macrophages; spheroids; CD38; Pam3CSK4
Online: 30 August 2021 (10:18:08 CEST)
Interferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogramme the tumour microenvironment. However, the antitumour immunomodulatory properties of IFNg still need to be validated due to variable therapeutic outcomes in preclinical and clinical studies. We developed a replication-deficient Semliki Forest virus vector expressing IFNg (SFV/IFNg) and evaluated its immunomodulatory antitumour potential in vitro in a model of 3D spheroids and in vivo in immunocompetent 4T1 mouse breast cancer model. We demonstrated that SFV-derived IFN-g stimulated bone marrow macrophages to acquire the tumoricidal M1 phenotype in 3D nonattached conditions. Coculturing SFV/IFNg-infected 4T1 spheroids with BMDMs inhibited spheroid growth. In the orthotopic 4T1 mouse model, intratumoural administration of SFV/IFNg virus particles alone or in combination with the Pam3CSK4 TLR2/1 ligand led to significant inhibition of tumour growth compared to the administration of the control SFV/Luc virus particles. Analysis of the composition of intra-tumoural lymphoid cells isolated from tumours after SFV/IFNg treatment revealed an increase in CD4+ and CD8+ and a decrease in T-reg (CD4+/CD25+/FoxP3+) cell populations. Furthermore, a significant decrease in the populations of cells bearing myeloid cell markers CD11b, CD38 and CD206 was observed. In conclusion, the SFV/IFNg vector induces a therapeutic antitumour T-cell response and inhibits myeloid cell infiltration in treated tumours.
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Acute Lymphoblastic Leukaemia; Flow Cytometry Data; Fisher’s Ratio; CD38; mathematical oncology; response biomarkers; personalized medicine
Online: 27 October 2020 (15:20:10 CET)
Artificial intelligence methods may help in unveliling information hidden in high-dimensional oncological data. Flow cytometry studies of haematological malignancies provide quantitative data with the potential to be used for the construction of response biomarkers. Many computational methods from the bioinformatics toolbox can be applied to these data but have not been exploited in their full potential in leukaemias, specifically for the case of childhood B-cell acute lymphoblastic leukemia. In this paper we analysed flow cytometry data obtained on diagnosis from 54 paediatric B-cell acute lymphoblastic leukemia patients from two local institutions. We constructed classifiers based on the Fisher’s Ratio to quantify differences in expression levels of immunophenotypical markers between patients with relapsing and non-relapsing disease. The distribution of the marker CD38 was found and validated to have a strong discriminating power between both patient cohorts, thus providing a classifier.
REVIEW | doi:10.20944/preprints201810.0577.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: myeloma; daratumumab; elotuzumab; isatuximab; CD38; JNJ- 63723283; denosumab; checkpoint inhibitors; BCMA; bispecific T-cell engager; antibody-drug conjugates
Online: 24 October 2018 (12:11:23 CEST)
The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 FDA approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development.