ABSTRACT
Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.
Subject(s)
Chromosomes, Human, Pair 10 , Chromosomes, Human, Pair 12 , Genetic Loci , Genetic Predisposition to Disease , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Case-Control Studies , Child , Child, Preschool , Chromatin Assembly and Disassembly , Chromosome Deletion , Computational Biology/methods , Female , Gene Expression Profiling , Genome-Wide Association Study , Genotype , High-Throughput Nucleotide Sequencing , Humans , Infant , Male , Molecular Sequence Annotation , Polymorphism, Single Nucleotide , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Quantitative Trait Loci , Sequence Analysis, DNAABSTRACT
BACKGROUND: Polymorphic variation at the 5p15.33 (TERT-CLPTM1L) locus is associated with the risk of many cancers but a relationship with colorectal cancer (CRC) risk has yet to be defined. METHODS: We used data from six genome-wide association studies (GWAS) of CRC, linkage disequilibrium mapping and imputation, to examine the relationship between 73 single-nucleotide polymorphisms at 5p15.33 and CRC risk in detail. RESULTS: rs2736100, which localises to intron 2 of TERT, provided the strongest evidence of an association with CRC (P=2.28 × 10â»4). The association was also shown in an independent series of 10 047 CRC cases and 6918 controls (P=0.02). A meta-analysis of all seven studies (totalling 16 039 cases, 16 430 controls) provided increased evidence of association (P=2.49 × 10â»5; per allele odds ratio=1.07). The association of rs2736100 on CRC risk was shown to be independent of 15 low-penetrance variants previously identified. CONCLUSION: The rs2736100 association demonstrates an influence of variation at 5p15.33 on CRC risk and further evidence that the 5p15.33 (TERT-CLPTM1L) locus has pleiotropic effects (reflecting generic or lineage-specific effects) on cancer risk.
Subject(s)
Chromosomes, Human, Pair 5 , Colorectal Neoplasms/genetics , Linkage Disequilibrium , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , Telomerase/genetics , Adult , Aged , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Middle Aged , Odds Ratio , Risk Assessment , Risk FactorsABSTRACT
A method is described for the determination of pipothiazine in human plasma, based on reversed-phase HPLC. The method has been applied in a pharmacokinetic study of pipothiazine in six psychiatric patients receiving repeated depot intramuscular injections for six months. A number of compounds likely to be taken concurrently by patients were tested for potential to interfere with the assay. There was no evidence of "dose-dumping" in the period following injection. Comparison of the pharmacokinetic profiles after the first and sixth injections showed no evidence of drug accumulation.
Subject(s)
Phenothiazines/blood , Adult , Chromatography, High Pressure Liquid , Female , Humans , Male , Middle AgedABSTRACT
Two hundred and sixty college students completed a questionnaire that provided information regarding their sexual experience, knowledge, and attitudes; their self-evaluations on dimensions related to sexuality; and their level of heterosocial anxiety (anxiety experienced in social interactions with members of the other sex). Compared with subjects low in heterosocial anxiety, highly anxious respondents were less sexually experienced, engaged in sexual activity less frequently, had fewer sexual partners, were less likely to have engaged in oral sex, expressed a higher degree of apprehension about sex, and had a somewhat higher incidence of sexual dysfunctions. In addition, low socially anxious women tended to use the pill, whereas highly anxious women preferred the condom. High and low heterosocially anxious respondents also differed on self-ratings related to their sexuality but did not differ in their attitudes or knowledge regarding sex. The results are discussed in terms of the cognitive, behavioral, and affective concomitants of social anxiety.
PIP: 260 college students (170 women and 90 men) at Denison University in Ohio completed a questionnaire that provided information regarding their sexual experience, knowledge, and attitudes; their self-evaluations on dimensions related to sexuality; and their level of heterosocial anxiety (anxiety experienced in social interactions with members of the opposite sex). Students ranged in age from 17 to 22 years, with a mean of 19.1 years. Compared with subjects low in heterosocial anxiety, highly anxious respondents were less sexually experienced, engaged in sexual activity less frequently, had fewer sexual partners, were less likely to have engaged in oral sex, expressed a higher degree of apprehension about sex, and had a somewhat higher incidence of sexual dysfunctions. In addition, low socially anxious women tended to use the pill, whereas highly anxious women prefered the condom. High and low heterosocially anxious respondents also differed on self-ratings related to their sexuality but did not differ in their attitudes or knowledge regarding sex. Consistent with expectations, the sexual behavior of individuals who scored high versus low in heterosocial anxiety differed on nearly every dimension examined, and these differences were generally obtained for both female and male respondents. The only surprising finding involved differences in contraceptive use by high and low socially anxious women. It had been expected that sexually active women who are high in heterosocial anxiety would choose birth control pills as a contraceptive method. They clearly demonstrated a preference for the condom.
Subject(s)
Anxiety/psychology , Contraception Behavior , Sexual Behavior , Social Environment , Adolescent , Adult , Female , Health Knowledge, Attitudes, Practice , Humans , Interpersonal Relations , MaleABSTRACT
The anthelmintic activities of nitroxynil, closantel and rafoxanide were tested in cattle against six- and eight-week-old infections of Fasciola hepatica. Administered by subcutaneous injection, nitroxynil and rafoxanide at dose rates of 10 and 3 mg/kg bodyweight respectively were 88.5 and 36.1 per cent effective in eliminating a six-week-old infection of F hepatica and 85.8 and 60.4 per cent effective against an eight-week-old infection. Closantel administered by intramuscular injection at a dose rate of 2.5 mg/kg bodyweight was 60.0 per cent effective against an eight-week-old F hepatica infection.