Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.     

Some characteristics of apurinic sites in single- and double-stranded biologically active phi X174 DNA

With biologically active DNA of the bacteriophage phi X174, both single and double-stranded, some physico-chemical and biological parameters of the depurination reaction are studied. It is shown that in single-stranded DNA each apurinic site is lethal, while in double-stranded RFI-DNA only about 5% of these sites are lethal. Furthermore it is concluded that the apurinic sites are formed at different rates in single- and double-stranded DNA and also the conversion into breaks of the apurinic sites is different for both forms of DNA.     

Biochemical and Structural Characterization of Mycobacterial Aspartyl-tRNA Synthetase AspS,a Promising TB Drug Target

The human pathogen Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis (TB), a disease with high worldwide mortality rates. Current treatment programs are under significant threat from multi-drug and extensively-drug resistant strains of M. tuberculosis, and it is essential to identify new inhibitors and their targets. We generated spontaneous resistant mutants in Mycobacterium bovis BCG in the presence of 10× the minimum inhibitory concentration (MIC) of compound 1, a previously identified potent inhibitor of mycobacterial growth in culture. Whole genome sequencing of two resistant mutants revealed in one case a single nucleotide polymorphism in the gene aspS at ⁵³⁵GAC>⁵³⁵AAC (D179N), while in the second mutant a single nucleotide polymorphism was identified upstream of the aspS promoter region. We probed whole cell target engagement by overexpressing either M. bovis BCG aspS or Mycobacterium smegmatis aspS, which resulted in a ten-fold and greater than ten-fold increase, respectively, of the MIC against compound 1. To analyse the impact of inhibitor 1 on M. tuberculosis AspS (Mt-AspS) activity we over-expressed, purified and characterised the kinetics of this enzyme using a robust tRNA-independent assay adapted to a high-throughput screening format. Finally, to aid hit-to-lead optimization, the crystal structure of apo M. smegmatis AspS was determined to a resolution of 2.4 Å.     

Effects of tadpole grazing on periphytic algae in ponds

Tadpole impact on periphytic algae was estimated with an exclosure experiment in the field. Algae growth on control (exposed) and experimental (netted-in) Perspex plates was measured in 12 ponds in 1991 and 8 in 1993.An index of snail (Lymnea and Planorbis)presence in the ponds was used to correct their effect. Grazing pressure (difference in amount of algae between control and experimental plates)differed between ponds. The difference was correlated to amount of Rana tadpoles present in the pond. At the higher densities of tadpoles observed in the study ponds, the algae standing crop on exposed plates was about 50–75% of that on netted-in plates. These result demonstrate that there is potential for effects of exploitation competition in ponds with a high tadpole density. This revised version was published online in July 2006 with corrections to the Cover Date.     

Fast protonation of adenosine and of its radical anion formed by hydrated electron attack; a nanosecond optical and dc-conductivity pulse radiolysis study

The study of the reaction of the hydrated electron with adenosine by optical and dc-conductivity pulse radiolysis on nano- and microsecond timescales has been carried out in an attempt to answer the question whether the electron adduct radical becomes protonated or not. The following conclusions have been reached: (1) the reaction of the hydrated electron with adenosine is followed by a water-mediated protonation, which must be complete with 5 ns; (2) no spectral indication of a further protonation of the protonated electron adduct of adenosine of 2'-deoxyadenosine has been found between 40 and 5000 ns; (3) the equilibrium reaction between radiation produced H3O+ and adenosine with a pKa of 3.5 plays an important role in the kinetics of the conductivity transients.     

Heat-sensitive radiation damage in single-stranded DNA irradiated in a bacterial extract

The effect of heat treatment (45 degrees C) on gamma-irradiated biologically active single-stranded phi X174 DNA, dissolved in a bacterial extract, was studied. The results show that under these circumstances heat-sensitive damage is found, which is absent after irradiation in pure buffer. The damage is non-lethal and probably becomes an apurinic/apyrimidinic site, which is lethal, upon the post-irradiation heat treatment. Prolonged heating converts it into a break. The amount of the initial damage depends on the conditions of irradiation.     

Inactivation and repair of double-stranded DNA damaged by the aziridinyl nitroimidazole RSU 1069.

Incubation of RSU 1069 in the presence of biologically active double-stranded phi X174 DNA resulted in, depending on pH, ionic strength and concentration of drug, inactivation of the DNA. A variety of lesions are induced including a high number of single-strand breaks and alkali-labile lesions, which are at most partly lethal. The main inactivating damage consists probably of base damage, induced by alkylation. A considerable part of the damage induced by RSU 1069 can be repaired by the various repair enzymes of the bacterial host of the phi X174 DNA. Finally the damage (pattern) depends considerably on the ionic composition of the reaction solution, which can be explained by an equilibrium model presented in this paper.