Cigarette smoking and disproportionate changes of thoracic skeletal muscles in low-dose chest computed tomography.

Association between smoking intensity and the quantity and quality of thoracic skeletal muscles (TSMs) remains unexplored. Skeletal muscle index (SMI; skeletal muscle area/height2) and percentage of normal attenuation muscle area (NAMA%) were measured to represent the quantity and quality of the skeletal muscles, respectively, and quantification was performed in pectoralis muscle at aortic arch (AA-PM), TSM at carina (C-TSM), erector spinae muscle at T12 (T12-ESM), and skeletal muscle at L1 (L1-SM). Among the 258 men (median age, 62 years [IQR: 58-69]), 183 were current smokers (median smoking intensity, 40 pack-years [IQR: 30-46]). SMI and NAMA% of AA-PM significantly decreased with pack-year (ß = - 0.028 and - 0.076; P < 0.001 and P = 0.021, respectively). Smoking intensity was inversely associated with NAMA% of C-TSM (ß = - 0.063; P = 0.001), whereas smoking intensity showed a borderline association with SMI of C-TSM (ß = - 0.023; P = 0.057). Smoking intensity was associated with the change in NAMA% of L1-SM (ß = - 0.040; P = 0.027), but was not associated with SMI of L1-SM (P > 0.05). Neither NAMA% nor SMI of T12-ESM was affected by smoking intensity (P > 0.05). In conclusion, smoking intensity was associated with the change of TSMs. Its association varied according to the location of TSMs, with the most associated parts being the upper (AA-PM) and middle TSMs (C-TSM).

Yeast-based assays for characterization of the functional effects of single nucleotide polymorphisms in human DNA repair genes.

DNA repair mechanisms maintain genomic integrity upon exposure to various types of DNA damage, which cause either single- or double-strand breaks in the DNA. Here, we propose a strategy for the functional study of single nucleotide polymorphisms (SNPs) in the human DNA repair genes XPD/ERCC2, RAD18, and KU70/XRCC6 and the checkpoint activation gene ATR that are essentially involved in the cell cycle and DNA damage repair. We analyzed the mutational effects of the DNA repair genes under DNA-damaging conditions, including ultraviolet irradiation and treatment with genotoxic reagents, using a Saccharomyces cerevisiae system to overcome the limitations of the human cell-based assay. We identified causal variants from selected SNPs in the present analyses. (i) R594C SNP in RAD3 (human XPD/ERCC2) caused severe reductions in the growth rate of mutant cells upon short-wavelength UV irradiation or chemical reagent treatment. (ii) The growth rates of the selected variants in RAD18, YKU70, and MEC1 were similar to those of wild-type cells on methyl methanesulfonate and hydroxyurea treated media. (iii) We also assessed the structural impact of the SNPs by analyzing differences in the structural conformation and calculating the root mean square deviation, which is a measure of the discordance of the Cα atoms between protein structures. Based on the above results, we propose that these analytical approaches serve as efficient methods for the identification of causal variants of human disease-causing genes and elucidation of yeast-cell based molecular mechanisms.