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.
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