Inherited susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes

Background: Susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes may reflect the way a person deals with carcinogenic challenges. This susceptibility (also referred to as mutagen sensitivity) has been found to be increased in patients with environmentally related cancers, including cancers of the head and neck, lung, and colon, and, in combination with carcinogenic exposure, this susceptibility can greatly influence cancer risk. The purpose of this study was to assess the heritability of mutagen sensitivity. Methods: Heritability was determined by use of a maximum likelihood method that employed the FISHER package of pedigree analysis. Bleomycin-induced breaks per cell values for 135 healthy volunteers without cancer were determined. These individuals were from 53 different pedigrees and included 25 monozygotic twin pairs (n = 50), 14 pairs of dizygotes (twin pairs and siblings, n = 28), and 14 families selected on the basis of a first-degree relative who was successfully treated for head and neck cancer and who had no sign of recurrence for at least 1 year. All data were analyzed simultaneously, and different models of familial resemblance were fitted to the data. All P values are two-sided. Results: Our results showed no evidence for the influence of a shared family environment on bleomycin-induced chromatid breaks. Genetic influences, however, were statistically significant (P = .036) and accounted for 75% of the total variance. Conclusions: The high heritability estimate of the susceptibility to bleomycin-induced chromatid breaks indicates a clear genetic basis. The findings of this study support the notion that a common genetic susceptibility to DNA damage - and thereby a susceptibility to cancer - may exist in the general population

Tadpole renormalization and relativistic corrections in lattice NRQCD

We make a comparison of two tadpole renormalization schemes in the context of the quarkonium hyperfine splittings in lattice NRQCD. Improved gauge-field and NRQCD actions are analyzed using the mean-link $u_{0,L}$ in Landau gauge, and using the fourth root of the average plaquette $u_{0,P}$. Simulations are done for $c\bar c$, $b\bar c$, and $b\bar b$ systems. The hyperfine splittings are computed both at leading and at next-to-leading order in the relativistic expansion. Results are obtained at lattice spacings in the range of about 0.14~fm to 0.38~fm. A number of features emerge, all of which favor tadpole renormalization using $u_{0,L}$. This includes much better scaling behavior of the hyperfine splittings in the three quarkonium systems when $u_{0,L}$ is used. We also find that relativistic corrections to the spin splittings are smaller when $u_{0,L}$ is used, particularly for the $c\bar c$ and $b\bar c$ systems. We also see signs of a breakdown in the NRQCD expansion when the bare quark mass falls below about one in lattice units. Simulations with $u_{0,L}$ also appear to be better behaved in this context: the bare quark masses turn out to be larger when $u_{0,L}$ is used, compared to when $u_{0,P}$ is used on lattices with comparable spacings. These results also demonstrate the need to go beyond tree-level tadpole improvement for precision simulations.Comment: 14 pages, 7 figures (minor changes to some phraseology and references

Control of oocyte release by progesterone receptor-regulated gene expression

The progesterone receptor (PGR) is a nuclear receptor transcription factor that is essential for female fertility, in part due to its control of oocyte release from the ovary, or ovulation. In all mammals studied to date, ovarian expression of PGR is restricted primarily to granulosa cells of follicles destined to ovulate. Granulosa cell expression of PGR is induced by the pituitary Luteinizing Hormone (LH) surge via mechanisms that are not entirely understood, but which involve activation of Protein Kinase A and modification of Sp1/Sp3 transcription factors on the PGR promoter. Null mutations for PGR or treatment with PGR antagonists block ovulation in all species analyzed, including humans. The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture. Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR. Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes