Role of CD5-negative CD8+ T Cells in Adaptation to Antigenic Variation of Human Immunodeficiency Virus Type 1

Purpose: To investigate the effect of 3-oxotirucalla-7, 24-dien-21-oic acid on CD8+ T cell recovery in human immunodeficiency virus type 1 (HIV-1) disease.Methods: The increase in the rates of CD8+ T cells over 48 weeks following treatment with 3- oxotirucalla-7, 24-dien-21-oic acid was investigated. Plasma HIV-1 load was measured by Versant™ HIV-1 RNA 3.0 branched chain DNA assay while flow cytometry was used for blood CD4 cell counts. For the analysis of the data obtained, Stata version 9.0 was employed.Results: 3-Oxotirucalla-7, 24-dien-21-oic acid treatment increased CD8+ T cell count from a median of 89 % at baseline to 99 % at 48 weeks. The proportion of patients with CD8+ T cell count < 90 % decreased from 50 % at baseline to 1 %. There was a similar rate of phase 1 CD8+ T cell recovery and greater rates of phase 2 recovery in patients with baseline CD8+ T counts < 50 cells/μL. Among those that achieved CD8+ T cell count > 500 cells/μL at 48 weeks, 23 % had baseline CD8+ T cell counts of < 50 cells/μL. However, the proportion of the patients that attained CD8+ T count of 200 cells/μL at 48 weeks was lower than those with higher baseline CD4 cell counts.Conclusion: 3-Oxotirucalla-7,24-dien-21-oic acid treatment induces greater tendency for CD8+ T cell recovery in patients with baseline CD8+ T cell counts < 50 cells/μL during 48 weeks of treatment. Therefore, 3-oxotirucalla-7,24-dien-21-oic acid is a promising agent for CD8+ T cell count recovery in patients with HIV infection.Keywords: CD8+ T cells, HIV infection, Oleanolic acid, Lymphocyte cell, Cell recover

Nuclear Factor-Kappa B Activity Regulates Brain Expression of P-Glycoprotein in the Kainic Acid-Induced Seizure Rats

This study was aimed to investigate the effect of NF-κB activity on the seizure susceptibility, brain damage, and P-gp expression in kainic acid- (KA-) induced seizure rats. Male SD rats were divided into saline control group (NS group), KA induced epilepsy group (EP group), and epilepsy group intervened with NF-κB inhibitor-pyrrolidine dithiocarbamate salt (PDTC group) or with dexamethasone (DEX group). No seizures were observed in the rats of NS group. Compared with NS group, increased P-gp expression and NF-κB activation in the rat brain of the EP group were observed after KA micro-injection. Both PDTC and DEX pre-treatment significantly increased the latency to grade III or V seizure onset compared to EP group but failed to show neuron-protective effect as the number of survival neurons didn't significantly differ from that in EP group. Furthermore, PDTC pre-treatment significantly decreased P-gp expression along with NF-κB activation in the hippocampus CA3 area and amygdala complex of rats compared with the EP group, implying that NF-κB activation involved in the seizure susceptibility and seizure induced brain P-gp over-expression. Additionally, DEX pre-treatment only decreased P-gp expression level without inhibition of NF-κB activation, suggesting NF-κB independent pathway may also participate in regulating seizure induced P-gp over-expression

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

© 2021 Edwards, Mitchell, Abdul-Sater, Chan, Sun, Sheth, He, Jiang, Yuan, Sharma, Czader, Chin, Liu, de Cárcer, Nalepa, Broxmeyer, Clapp and Sierra Potchanant.Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo, the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2. Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/-mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC-deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo, show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.This work was supported by the NIH R01-HL132921-01A1 award (DWC), St. Baldrick’s Foundation Scholar award (GN), Heroes Foundation (GN), the Bone Marrow Failure Research Fund at Riley Children’s Foundation (GN), NIH T32 HL007910 “Basic Science Studies on Gene Therapy of Blood Diseases” grant (ES), NIH Diversity Supplement 3R01HL132921-03S1 (ES), and NCI 1F30CA200227-01A1 fellowship (DE)