Integrating these new approaches will require the rigor of data and sample collection and validation inherent in epidemiological research, and mandates linking of tissue repositories with wellcharacterized epidemiological, clinical, and followup data.In summary, the approaches of molecular epidemiology with the ability to obtain and validate patient data and samples can provide a major integrative force for these disciplines.Biochemistry. Carcinogenesis. Cell. Biotechniques. Hereditas. Cancer. OS Scientific Publishers. Mutagenesis. Carcinogenesis. Carcinogenesis. Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans.Carcinogenesis. Carcinogenesis. Carcinogenesis. Carcinogenesis. Carcinogenesis. Carcinogenesis. Click on Request Permissions which will take you to the Copyright Clearance Centers Quantitative spectrofluorophotometry demonstrated that these treatments promoted time and concentrationdependent degradation of DNA, resulting in the formation of and eventual release of small DNA fragments. Corresponding damage to bulk DNA was demonstrated by enhancedfluorescence alkaline unwinding analysis.DNA fragmentation was not induced by phospholipase C or synthetic diglyceride; in fact, the effects of sphingomyelinase and ceramide were substantially reduced by coexposure to these agents, suggesting opposing roles for diglyceride and ceramidemediated signals in the regulation of apoptosis.Phospholipase A and arachidonic acid failed to promote DNA fragmentation, as did phospholipase D.Characterization of DNA strand breaks by alkaline and neutral elution analyses confirmed that ceramide action was restricted to breakage of mature, doublestranded DNA but not of nascent DNA.The induction of DNA damage was associated with appearance of apoptotic morphology and decreased clonogenicity.These results demonstrate that the ceramidedependent signaling system selectively induces apoptosis and raise the possibility that ceramideactivated enzymes represent important components in a signaling cascade involved in the regulation of programmed cell death.Programmed cell death, or apoptosis, is an active, energydependent process through which living cells participate in their own destruction and is initiated by a variety of physiological and pharmacological stimuli. A fundamental component of this response is the stereotypical degradation of genomic DNA to oligonucleosomal fragments has been shown to initiate apoptotic cell death and DNA fragmentation in several mammalian cell lines, including the human leukemia cell lines HL. This response is mediated through positive coupling of the type B receptor to a neutral sphingomyelinase. The present studies were undertaken to assess the potential involvement of ceramidedependent signaling processes in the induction of DNA damage in a variety of mammalian cell lines.Our findings indicate that pharmacological manipulations that increase the availability of intracellular free ceramide induce apoptotic DNA fragmentation and cell death.All cultures were passed twice weekly and maintained under a humidified atmosphere of air CO at C.Pelleted cells were resuspended in saline and subjected to timed alkaline denaturation in. To characterize DNA strand breaks, cells were either or and exposed to test agents for appropriate intervals.Bacto agar; cultures were maintained for days, and formation of colonies. The occurrence and mode of cell death in each treatment group were determined based on the expression of cytoarchitectural characteristics of either apoptosis or necrosis; cells were scored for each treatment.TNF has also been demonstrated to promote sphingomyelin catabolism, as reflected by decreased sphingomyelin content and reciprocally increased availability of intracellular ceramide, in HL and U cells.