Although recent cancer genomics studies have identified a large number of genes that were mutated in human cancers, p53 remains as the most frequently mutated gene. To further elucidate the p53-signalling network, we performed transcriptome analysis on 24 tissues in p53+/+ or p53−/− mice after whole-body X-ray irradiation. Here we found transactivation of a total of 3551 genes in one or more of the 24 tissues only in p53+/+ mice, while 2576 genes were downregulated. p53 mRNA expression level in each tissue was significantly associated with the number of genes upregulated by irradiation. Annotation using TCGA (The Cancer Genome Atlas) database revealed that p53 negatively regulated mRNA expression of several cancer therapeutic targets or pathways such as BTK, SYK, and CTLA4 in breast cancer tissues. In addition, stomach exhibited the induction of Krt6, Krt16, and Krt17 as well as loricrin, an epidermal differentiation marker, after the X-ray irradiation only in p53+/+ mice, implying a mechanism to protect damaged tissues by rapid induction of differentiation. Our comprehensive transcriptome analysis elucidated tissue specific roles of p53 and its signalling networks in DNA-damage response that will enhance our understanding of cancer biology.
SNP rs2294008 in Prostate Stem Cell Antigen (PSCA) and decreased PSCA expression are associated with gastric cancer. The objective of this study is to investigate the role of rs2294008 and PSCA expression in the gastritis-gastric cancer carcinogenic pathway. We conducted a case-control association study of H. pylori-infected gastritis and gastric cancer. rs2294008 was associated with the progression to chronic active gastritis (P = 9.4 × 10–5; odds ratio = 3.88, TT + TC vs CC genotype), but not with H. pylori infection per se nor with the progression from active gastritis to gastric cancer. We also assessed the association of rs2294008 with PSCA mRNA expression in the gastric mucosa at various disease stages and found that rs2294008 was associated with PSCA expression (P = 1.3 × 10–12). H. pylori infection (P = 5.1 × 10–8) and eradication therapy (P < 1 × 10–11) resulted in the reduced and increased PSCA expression, respectively, indicating negative regulation of PSCA expression by H. pylori infection. PSCA expression was decreased in severe gastritis compared with mild gastritis only among T allele carriers. Our findings revealed the regulation of PSCA expression by host genetic variation and bacterial infection might contribute to gastritis progression after H. pylori infection.
SummaryThe distributions of phylloquinone (PK) and menaqui none-4 (MK-4) in various tissues were assessed after the oral administra tion of phylloquinone. Wistar rats were fed a vitamin-K-deficient diet for nine days, fasted for 24h and then given phylloquinone orally at 4mg/kg body weight. Rats were sacrificed 0, 6, 12 and 24h after the administra tion, and an analysis was made of the vitamin K analogues in the plasma, liver, brain, testis, kidney and spleen. The phylloquinone concentration in plasma and the tissues reached a peak 6h after the oral administration of phylloquinone. By contrast, the concentration of MK-4 peaked in the liver, plasma, kidney and spleen at 12h, and in brain and testis at 24h. This data suggests that the ingested phylloquinone was probably con verted into MK-4 within the tissues themselves, rather than via hepatic metabolism. The evidence for this is that, after phylloquinone administra tion, (i) in each of the tissues, the MK-4 concentration increased much more slowly than that of phylloquinone, and (ii) the MK-4 concentration in the plasma and liver reached only much lower levels than those seen in other tissues.
Thoroughbred horses are seasonal mating animals, raised in northern regions or countries. Foals born yearly in spring generally show a typical seasonal compensatory growth pattern, in which their growth rate declines in the first winter and increases in the next spring. In this study, a new empirical adjustment approach is proposed to adjust for this compensatory growth when growth curve equations are estimated, by using 1,633 male body weights of Thoroughbreds as an illustrating example. Based on general Richards growth curve equation, a new growth curve equation was developed and fit to the weight-age data. The new growth curve equation had a sigmoid sub-function that can adjust the compensatory growth, combined with the Richards biological parameter responsible for the maturity of animals. The unknown parameters included in the equations were estimated by SAS NLMIXED procedure. The goodness of fit was examined by using Akaike’s Information Criterion (AIC). The AIC values decreased from 13,053 (general Richards equation) to 12,794 (the newly developed equation), indicating the better fit of the new equation to the weight-age data. The shape of the growth curve was improved during the period of compensatory growth. The proposed method is one of the useful approaches for adjusting seasonal compensatory growth in growth curve estimations for Thoroughbreds, and for their management during the compensatory period. Based on this approach, the optimal growth curve equations can be estimated also for female body weight of Thoroughbreds or other growth traits affected by seasonal compensatory growth.
Thoroughbred horses are seasonal mating animals, and their foals are born yearly in spring seasons. In northern regions or countries, the foals generally show a typical seasonal compensatory growth pattern, where their growth rate declines in winter and increases in the next spring. In this study, a new empirical approach is proposed to adjust for this compensatory growth when growth curve equations are estimated, by using BW of Japanese Thoroughbred colts and fillies raised in Hidaka, Hokkaido. Based on the traditional Richards growth curve equation, new growth curve equations were developed and fit to the weight-age data. The foals generally experience 2 major winter seasons before their debut in horseracing. The new equations had sigmoid subfunctions that can empirically adjust the first and second year compensatory growths, combined with the Richards biological parameter responsible for the maturity of animals. The unknown parameters included in the equations were estimated by SAS NLMIXED procedure. The goodness-of-fit was examined by using several indices of goodness-of-fit (i.e., Akaike's information criterion, Bayesian information criterion, -2 log likelihood, and residual sum of squares) for the multiple applications of the subfunctions. The indices indicated the best fit of the new equations including both subfunctions for the first and second compensatory growths to the weight-age data. The shapes of the growth curves were improved during the periods of compensatory growth. The proposed method is one of the useful approaches for adjusting multiple seasonal compensatory growths in growth curve estimations of Thoroughbreds and for the management of young horses during the compensatory periods.
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