Monoclonal antibody (MoAb) 2C5, a nucleosome-specific antinuclear autoantibody (ANA) from the repertoire of aged mice, was recently reported to recognize the surface of various tumor cells but not normal cells. Surface-bound nucleosomes (NSs) were previously proven to be MoAb 2C5's target on the outer membrane of tumor cells. Furthermore, MoAb 2C5 was found to have a strong antitumor effect during the early stages of tumor development. In an attempt to further increase antitumor effect of nucleosome-specific tumorocidal monoclonal antibody against established tumors, we investigated a possible way to enhance antibody association with tumor cells. Evidence is presented here demonstrating that the in vitro treatment of tumor cells (S49 T lymphoma) resulting in a partial cell death and massive liberation of intact NSs from dead tumor cells into the culture medium was accompanied by a 50-fold increase of MoAb 2C5 binding to the surface of surviving tumor cells. Massive NS release was observed in the case of S49 T-cell treatment with dexamethasone and vincristine. However, a partial cell killing that was not accompanied with NS release (EL4 lymphoma treatment with doxorubicin) did not result in the enhanced binding of MoAb 2C5 to the surface of surviving tumor cells. The use of NS-specific tumorocidal antibodies, such as MoAb 2C5, in combination with another NS release-inducing tumor therapy, should provide an enhanced antibody-tumor binding.
BackgroundAging is a biological process strongly determined by genetics. However, only a few single nucleotide polymorphisms (SNPs) have been reported to be consistently associated with aging. While investigating whether copy number variations (CNVs) could fill this gap, we focused on CNVs that have not been studied in previous SNP-based searches via tagging SNPs.MethodsTaqMan qPCR assays were developed to quantify 20 common CNVs in 222 senior American Caucasians in order to reveal possible association with longevity. The replication study was comprised of 1283 community-dwelling senior European Caucasians. Replicated CNVs were further investigated for association with healthy aging and aging-related diseases, while association with longevity was additionally tested in Caenorhabditis elegans.ResultsIn the discovery study of ≥80 vs.<80 years old seniors, a homozygous intronic CNV deletion in the CNTNAP4 gene was inversely associated with survival to the age of 80 (OR=0.51, 95%CI 0.29-0.87, p=0.015 before correction for multiple testing). After stratification by sex, association remained significant in females (OR=0.41, 95%CI 0.21-0.77, p=0.007), but not in males (OR=0.97, 95%CI 0.33-2.79, p=1). The finding was validated in a replication study (OR=0.66, 95%CI 0.48-0.90, p=0.011 for females). CNTNAP4 association with longevity was supported by a marked 25% lifespan change in C. elegans after knocking down the ortholog gene. An inverse association of the CNV del/del variant with female healthy aging was observed (OR=0.39, 95%CI 0.19-0.76, p=0.006). A corresponding positive association with aging-related diseases was revealed for cognitive impairment (OR=2.17, 95%CI 1.11-4.22, p=0.024) and, in independent studies, for Alzheimer’s (OR=4.07, 95%CI 1.17-14.14, p=0.036) and Parkinson’s (OR=1.59, 95%CI 1.03-2.42, p=0.041) diseases.ConclusionThis is the first demonstration for association of the CNTNAP4 gene and one of its intronic CNV polymorphisms with aging. Association with particular aging-related diseases awaits replication and independent validation.
A population of CD4+ cells has been identified in the murine female genital tract (FGT). Phenotypic studies of FGT CD4+ cells demonstrate that they express CD3 and that the majority of these cells are alpha beta TCR+Thy-1+. Most of the Thy-1+CD4+alpha beta TCR+ cells resemble memory T cells based on their expression of CD44, L-selectin and CD45RB antigens. The vast majority of Thy-1+CD4+alpha beta TCR+ FGT cells are CD5+ and all of them are B220-. Systemic stimuli including infection with Trypanosoma brucei brucei, injection with anti-CD3 epsilon, or bacterial superantigens staphylococcal enterotoxin A or B cause a rapid accumulation of CD4+ cells in the FGT exceeding that observed for CD4+ cells in spleen and lymph nodes (LN). Expansion of the FGT CD4+ cells, which are phenotypically distinct from the splenic and LN CD4+ T cells, is due to local proliferation rather than an influx of cells from the circulation. The CD4+ population in the FGT of adult nu/nu mice is dramatically reduced, indicating its thymic dependency. In lpr/lpr mice, FGT CD4 cells do not display changes characteristic of splenic or LN CD4 cells in the same animals. These findings demonstrate that the CD4+ cells of the murine FGT are thymic dependent, but that they constitute a T cell lineage that phenotypically and, probably functionally, is distinct from other peripheral CD4+ T cell populations.
Background: New therapeutic targets are needed to fight aging-related diseases and increase life span. A new female-specific association with diseases and limited survival past 80 years was recently reported for a copy number variation (CNV) in the CNTNAP4 gene from the neurexin superfamily. Objective: We asked whether there are CNVs that are associated with aging phenotypes within other genes from the neurexin superfamily and whether this association is sex specific. Methods: Select CNV polymorphisms were genotyped with proprietary TaqMan qPCR assays. Results: A case/control study, in which a group of 81- to 90-year-old community-dwelling Caucasians with no chronic diseases (case) was compared to a similar control group of 65- to 75-year-olds, revealed a negative association with healthy aging for the ins allele of common esv11910 CNV in the CNTNAP2 gene (n = 388; OR = 0.29, 95% CI: 0.14-0.59, p = 0.0004 for males, and OR = 0.82, 95% CI: 0.42-1.57, p = 0.625 for females). This male-specific association was validated in a study of an independent group of 76- to 80-year-olds. To look for a corresponding positive association of the allele with aging-related diseases, two case subgroups of 81- to 90-year-olds, one composed of individuals with cognitive impairment and the other with various diseases not directly related to the nervous system, such as cardiovascular diseases, etc., were compared to a healthy control subgroup of the same age. A positive male-specific association was found for both cases (OR = 2.75, p = 0.008 for association with cognitive impairment, and OR = 3.18, p = 0.002 for other diseases combined). Conclusions: A new male-specific association with aging is reported for a CNV in the CNTNAP2 gene. The polymorphism might be useful for diagnosing individual genetic predispositions to healthy aging versus aging complicated by chronic diseases.
Circulating nucleic acids (CNA) are known to be enriched in repetitive DNA sequences in humans. Here, bovine sera CNA were analyzed to determine if cell stress-related short interspersed nucleotide elements (SINEs) could be detected in sera from cattle associated with bovine spongiform encephalopathy (BSE). Nucleic acids were extracted, amplified, cloned, and sequenced from the sera of protease-resistant prion protein (PrP res )-positive cattle (n ؍ 2) and sera from BSE-cohort cows (n ؍ 6); 150 out of 163 clones revealed the presence of, on average, an 80-bp sequence from the 3 region of Bov-tA SINE. A PCR protocol was developed that differentially identified SINE-associated CNA in BSE-exposed versus normal cattle. CNA were extracted from a serum vesicular fraction after controlled blood collection and processing procedures. Sera from four confirmed cases of BSE, 137 BSE-exposed cohort animals associated with eight confirmed BSE cases, and 845 healthy, PrP res -negative control cows were tested. All four sera from confirmed BSE cases were repeatedly reactive in the assay. BSE-exposed cohorts had a 100-fold higher occurrence of repeatedly reactive individuals per cohort (average ؍ 63%; range ؍ 33% to 91%), compared to healthy controls (average ؍ 0.6%; P < 0.001). This study shows that BSE-confirmed and cohort animals possess a unique profile of SINEassociated serum CNA that can be utilized as a marker that highly correlates to BSE exposure.
BackgroundThe cholesteryl ester transfer protein (CETP) polymorphism I405V has been suggested to be involved in longevity and susceptibility to cardiovascular diseases. An enhanced reverse cholesterol transport due to enhanced HDL levels has been hypothesized to be the underlying mechanism. However, clinical trials with HDL-enhancing drugs failed to show beneficial effects. Consequently, it has been postulated that genetic variations enhancing HDL levels are cardioprotective only if they also decrease LDL levels.MethodsA cross-sectional study was conducted to genotype 1028 healthy blood donors and 1517 clinically well characterized elderly for CETP I405V.ResultsWe could not find any association of this polymorphism with age for both, males or females, in any of these cohorts (P = 0.71 and P = 0.57, respectively, for males and P = 0.55 and P = 0.88, respectively, for females). In addition, no association with cardiovascular diseases could be observed in the elderly cohort (males OR = 1.12 and females OR = 0.88). In the same cohort, the CETP V405V genotype was associated with significantly enhanced HDL levels (P = 0.03), mostly owing to the female sex (P = 0.46 for males, P = 0.02 for females), whereas LDL and triglyceride levels were unchanged (P = 0.62 and P = 0.18, respectively).ConclusionOur data support the recent hypothesis that variations enhancing HDL levels without affecting LDL levels are not associated with the risk for cardiovascular diseases.
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