AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Police-initiated diversion for youth to prevent future delinquent behavior: a systematic review

BackgroundOverly punitive responses to youth misconduct may have the unintended consequence ofincreasing the likelihood of future delinquency; yet, overly lenient responses may fail to serveas a corrective for the misbehavior. Police diversion schemes are a collection of strategiespolice can apply as an alternative to court processing of youth. Police-initiated diversionschemes aim to reduce reoffending by steering youth away from deeper penetration into thecriminal justice system and by providing an alternative intervention that can help youthaddress psychosocial development or other needs that contribute to their problem behavior.ObjectivesThe objective of this review was to synthesize the evidence on the effectiveness of pre-courtinterventions involving police warning or counseling and release, and cautioning schemes inreducing delinquent behavior.Search methodsA combination of 26 databases and websites were searched. References of relevant reviewswere also scanned to identify studies. We also consulted with experts in the field. Searcheswere executed by two reviewers and conducted between August 2016 and January 2017.Selection criteriaOnly experimental and quasi-experimental designs were eligible for this review. All quasiexperimentaldesigns must have had a comparison group similar to the police diversionintervention group with respect to demographic characteristics and prior involvement indelinquent behavior (i.e., at similar risk for future delinquent behavior). Additionally, studiesmust have included youth participants between 12 and 17 years of age who either underwenttraditional system processing or were diverted from court processing through a police-leddiversion program. Studies were also eligible if delinquency-related outcomes, includingofficial and non-official (self-report or third-party reporting) measures of delinquency werereported.Data collection and analysisThis study used meta-analysis to synthesize results across studies. This method involvedsystematic coding of study features and conversion of study findings into effect sizesreflecting the direction and magnitude of any police-led diversion effect. There were 19independent evaluations across the 14 primary documents coded for this review. From this,we coded 67 effect sizes of delinquent behavior post diversion across 31 diversion-traditionalprocessing comparisons. We analyzed these comparisons using two approaches. The firstapproach selected a single effect size per comparison based on a decision rule and the secondused all 67 effect sizes, nesting these within comparison condition and evaluation design.ResultsThe general pattern of evidence is positive, suggesting that police-led diversion modestlyreduces future delinquent behavior of low-risk youth relative to traditional processing.Authors’ conclusionsThe findings from this systematic review support the use of police-led diversion for low-riskyouth with limited or no prior involvement with the juvenile justice system. Thus, policedepartments and policy-makers should consider diversionary programs as part of the mix ofsolutions for addressing youth crime

Telomeric sequence diversity within the genus Saccharomyces

Conservation of telomeric DNA repeat sequences has been found across evolutionarily diverse eukaryotes. Here we report on a marked telomeric sequence diversity within the budding yeast genus Saccharomyces. Cloning and sequencing of telomeric repeat units from S. castellii, S. dairensis, S. exiguus and S. kluyveri showed a length variation between 8 and 26 bp, as well as a distinct variation in the degree of homogeneity, among the species. In S. castellii and S. dairensis, TCTGGGTG constituted a majority of the telomeric repeat units. However, the character of the variant repeats differed: in S. castellii the major class of variant repeats contained additional TG dinucleotides per repeat unit, [TCTGGGTG(TG)(1-3)], whereas in S. dairensis the major variant repeat is the shorter, uniform sequence TCTGGG. This result suggests mechanistic differences in the action of the telomerases of these closely related yeasts. Despite their length and homogeneity differences, all the Saccharomyces telomeric sequences show a conserved core which is also shared by the Candida glabrata telomeric sequence. This evolutionary similarity may be partly explained by the preservation of a binding site for the RAP1 protein

A Trypanosoma Brucei Protein Complex That Binds G-overhangs And Co-purifies With Telomerase Activity

The chromosomal ends of Trypanosoma brucei, like those of most eukaryotes, contain conserved 5′-TTAGGG-3′ repeated sequences and are maintained by the action of telomerase. Fractionated T. brucei cell extracts with telomerase activity were used as a source of potential regulatory factors or telomerase-associated components that might interact with T. brucei telomeres. Electrophoretic mobility shift assays and UV cross-linking were used to detect possible single-stranded telomeric protein-DNA complexes and to estimate the approximate size of the protein constituents. Three single-stranded telomeric protein-DNA complexes were observed. Complex C3 was highly specific for the G-strand telomeric repeat sequence and shares biochemical characteristics with G-rich, single-stranded telomeric binding proteins and with components of the telomerase holoenzyme described in yeast, ciliates, and humans. Susceptibility to RNase A or chemical nuclease (hydroxyl radical) pre-treatment showed that complex C3 was tightly associated with an RNA component. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry was used to estimate the molecular mass of the peptides obtained by in-gel Lys-C digestion of low abundance C3-associated proteins. The molecular masses of the peptides showed no homologies with other proteins from trypanosomes or with any protein in the data bases screened.2772896906Greider, C., (1996) Annu. Rev. Biochem., 65, pp. 337-365Van Der Ploeg, L.H.T., Lin, A.Y.C., Borst, P., (1984) Cell, 36, pp. 459-468Blackburn, E.H., Challoner, P.B., (1984) Cell, 36, pp. 447-457Mufioz-Jordan, J., Cross, G., De Lange, T., Griffith, J., (2001) Nature, 20, pp. 579-588Cano, M.I.N., (2001) Trends Parasitol., 17, pp. 9425-9429Slijepcevic, P., (1998) Exp. Cell Res., 244, pp. 268-274Henderson, E., Blackburn, E., (1989) Mol. Cell. Biol., 9, pp. 345-348Wellinger, R., Wolf, A., Zakian, V., (1993) Cell, 72, pp. 51-60Mcelligott, R., Wellinger, R.J., (1997) EMBO J., 16, pp. 3705-3714Virta-Pearlman, V., Morris, D., Lundblad, V., (1996) Genes Dev., 10, pp. 3094-3104Nugent, C., Hughes, T., Lue, N., Lundblad, V., (1996) Science, 274, pp. 249-252Gandhi, L., Collins, K., (1998) Genes Dev., 12, pp. 721-733Krauskopf, A., Blackburn, E.H., (1996) Nature, 383, pp. 354-357Shore, D., (1995) Telomeres, pp. 139-191. , (Blackburn, E. and Greider, C., eds), Cold Spring Harbor Laboratory, Cold Spring Harbor, NYKrauskopf, A., Blackburn, E.H., (1998) Proc. Natl. Acad. Sci. U. S. A., 95, pp. 12486-12491Kirion, G., Liu, K., Liu, C., Lustig, A.J., (1993) Genes Dev., 7, pp. 1146-1159Shore, D., (1997) J. Biol. Chem., 378, pp. 591-597Brocolli, D., Smogorzewska, A., Chong, L., De Lange, T., (1997) Nat. Genet., 17, pp. 231-235Li, B., Oestreich, S., De Lange, T., (2000) Cell, 101, pp. 471-483Zhou, J., Hidaka, K., Futcher, B., (2000) Mol. Cell. Biol., 20, pp. 1947-1955Lin, J.-J., Zakian, V., (1994) Nucleic Acids Res., 22, pp. 4906-4913Gray, J., Celander, D., Price, C., Cech, T., (1991) Cell, 67, pp. 807-814O'Reilly, M., Teichmann, S., Rhodes, D., (1999) Curr. Opin. Struct. Biol., 9, pp. 56-65Lu, Q., Schierer, T., Kang, S., Henderson, E., (1998) Nucleic Acids Res., 26, pp. 1613-1620Froelich-Ammon, S., Dickinson, B., Bevilacqua, J., Schultz, S., Cech, T., (1998) Genes Dev., 12, pp. 1504-1514Smith, C., Blackburn, E.H., (1999) J. Cell Biol., 145, pp. 203-214Van Steensel, B., Smogorzewska, A., De Lange, T., (1998) Cell, 92, pp. 401-413Blackburn, E.H., (2000) Nature, 408, pp. 53-56Chong, L., Van Steensel, B., Broccoli, D., Erdjument-Bromage, H., Hanish, J., Tempst, P., De Lange, T., (1995) Science, 270, pp. 1663-1667Cooper, J.P., Watanabe, Y., Nurse, P., (1998) Nature, 392, pp. 828-831Bourns, B., Alexander, M., Smith, A., Zakian, V., (1998) Mol. Cell. Biol., 18, pp. 5600-5608Kass-Eiler, A., Greider, C., (2000) Trends Biochem. Sci., 25, pp. 200-204Lanzer, M., Fischer, K., Le Blancq, S., (1995) Mol. Biochem. Parasitol., 70, pp. 1-8Cross, G., (1996) Bioessays, 18, pp. 283-291Borst, P., Rudenko, G., Taylor, M., Blundell, P., Van Leeuwen, F., Bitter, W., Cross, M., McCulloch, R., (1996) Arch. Med. Res., 27, pp. 379-388Van Der Ploeg, L., Gottesdiener, K., Tse, D., Chung, H., Weiden, M., (1992) Mechanisms of Eukaryotic DNA Recombination, pp. 179-187. , (Gottesman, M. E., and Vogel, H. J., eds), Academic Press, New YorkMyler, P., Sisk, E., McDonagh, P., Martinez-Calvillo, S., Schnaufer, A., Sunkin, S., Yan, S., Stuart, K., (2000) Biochem. Soc. Trans., 28, pp. 527-531Chiurrillo, M.A., Cano, M.I., Franco, J.S., Ramirez, J.L., (1999) Mol. Biochem. Parasitol., 100, pp. 173-183Eid, J., Sollner-Webb, B., (1995) Mol. Cell. Biol., 15, pp. 389-397Eid, J., Sollner-Webb, B., (1997) J. Biol. Chem., 272, pp. 14927-14936Field, H., Field, M., (1996) Exp. Parasitol., 83, pp. 155-158Cano, M.I., Dungan, J., Agabian, N., Blackburn, E.H., (1999) Proc. Natl. Acad. Sci. U. S. A., 96, pp. 3616-3621Bienen, E.J., Hammadi, E., Hill, G.C., (1981) Exp. Parasitol., 51, pp. 408-417Sambrook, J., Fritsch, E., Maniatis, T., (1989) Molecular Cloning: a Laboratory Manual, 2nd Ed., , Cold Spring Harbor Laboratory, Cold Spring Harbor, NYAusubel, F.M., Brent, R., Kingston, R.E., Moore, D.D., Seidman, J.G., Smith, J.A., Struhl, K., (1997) Current Protocols in Molecular Biology, 2. , John Wiley & Sons, Inc., New YorkHarrington, L., Hull, C., Crittenden, J., Greider, C., (1995) J. Biol. Chem., 270, pp. 8893-8901Savery, N., Belyaeva, T., Busby, S., (1996) Gene Transcription: DNA-binding Proteins. Essential Techniques Series, pp. 1-5. , (Dockerty, K., ed), John Wiley & Sons, Inc., Chichester, United KingdomJohnston, S., Lew, J., Berman, J., (1999) Mol. Cell. Biol., 19, pp. 923-933Blasco, M., Gasser, S., Lingner, J., (1999) Genes Dev., 13, pp. 2353-2359Evans, S., Lundblad, V., (1999) Science, 286, pp. 117-120Nakayama, J., Saito, H., Nakamura, H., Matsuura, A., Ishikawa, F., (1997) Cell, 88, pp. 875-884Le, S., Sternglanz, R., Greider, C., (2000) Mol. Biol. Cell, 11, pp. 999-1010Lundblad, V., Blackburn, E.H., (1993) Cell, 73, pp. 347-360Gottschling, D., Zakian, V., (1986) Cell, 47, pp. 195-205Harrington, L., Mcphail, T., Mar, V., Zhou, W., Oulton, R., Bass, M., Arruda, I., Robinson, M., (1997) Science, 275, pp. 973-977Morris, D., Lundblad, V., (1997) Curr. Biol., 7, pp. 969-97

Cytomegalovirus is associated with reduced telomerase activity in the Whitehall II cohort

Telomere length and telomerase activity have received increased attention as markers of cellular aging, but the determinants of inter-individual variation in these markers are incompletely understood. Cytomegalovirus (CMV) infection may be particularly important for telomere and telomerase dynamics due to its dramatic impact on peripheral blood lymphocyte composition, i.e., increasing the number and proportions of highly differentiated T cells that are characterized by shorter telomere length (TL) and lowered telomerase activity (TA). However, the possible relationship between CMV infection and leukocyte TL and TA has not been well-examined in vivo. This study examined the associations of CMV seropositivity and CMV IgG antibodies with leukocyte (TL) and (TA) in a sample of 434 healthy individuals (ages 53-76) from the Whitehall II cohort. Positive CMV serostatus was significantly associated with lower TA among women, and higher CMV IgG antibody levels were associated with lower TA in the overall sample. However, neither CMV seropositivity nor CMV IgG antibody levels (reflecting subclinical reactivation) among the seropositive were significantly associated with TL. These associations were robust to adjustment for age, employment grade, BMI, and smoking status. The results demonstrate that CMV seropositivity and subclinical reactivation predict lower TA. Future longitudinal studies should test whether the association of CMV with lower TA contributes to accelerated telomere shortening over time