A Population-based Study of DNA Repair Gene Variants in Relation to Non-melanoma Skin Cancer as a Marker of a Cancer-prone Phenotype

For unknown reasons, non-melanoma skin cancer (NMSC) is associated with increased risk of other malignancies. Focusing solely on DNA repair or DNA repair-related genes, this study tested the hypothesis that DNA repair gene variants contribute to the increased cancer risk associated with a personal history of NMSC. From the parent CLUE II cohort study, established in 1989 in Washington County, MD, the study consisted of a cancer-free control group (n 5 2296) compared with three mutually exclusive groups of cancer cases ascertained through 2007: (i) Other (non-NMSC) cancer only (n 5 2349); (ii) NMSC only (n 5 694) and (iii) NMSC plus other cancer (n 5 577). The frequency of minor alleles in 759 DNA repair gene single nucleotide polymorphisms (SNPs) was compared in these four groups. Comparing those with both NMSC and other cancer versus those with no cancer, 10 SNPs had allelic trend P-values <0.01. The two top-ranked SNPs were both within the thymine DNA glycosylase gene (TDG). One was a non-synonymous coding SNP (rs2888805) [per allele odds ratio (OR) 1.40, 95% confidence interval (CI) 1.16-1.70; P-value 5 0.0006] and the other was an intronic SNP in high linkage disequilibrium with rs2888805 (rs4135150). None of the associations had a P-value <6.6310(-5), the threshold for statistical significance after correcting for multiple comparisons. The results pinpoint DNA repair genes most likely to contribute to the NMSC cancer-prone phenotype. A promising lead is genetic variants in TDG, important not only in base excision repair but also in regulating the epigenome and gene expression, which may contribute to the NMSC-associated increase in overall cancer risk.     

American Ginseng Improves Glycemia in Individuals with Normal Glucose Tolerance: Effect of Dose and Time Escalation

Objective: We studied the effect of escalating the dose and administration time of American ginseng (AG, Panax quinquefolius L.) in nondiabetic individuals to achieve further improvements in glucose tolerance seen previously when 3g of AG was taken 40 minutes before a 25g glucose challenge.

Methods: Ten nondiabetic individuals (6M:4F; mean ± STD: age = 41 ± 13 years, BMI = 24.8 ± 3.5 kg/m², FBG = 4.5 ± 0.1mmolL^?1) on 12 separate occasions, randomly received 0 (placebo), 3, 6 or 9g of ground AG root at 40, 80, or 120 minutes before a 25g oral glucose challenge. Capillary blood glucose was measured prior to ingestion of AG or placebo capsules and at 0, 15, 30, 45, 60 and 90 minutes from start of challenge.

Results: Compared with the placebo, 3, 6 and 9g of AG reduced (p<0.05) postprandial incremental glucose at 30, 45 and 60 minutes; also, 3 and 9g of AG did so at 90 minutes. At 60 minutes, 9g of AG reduced incremental postprandial glucose relative to 3g of AG (p<0.05). All AG doses reduced (p<0.05) area under the incremental glucose curve (3g, 26.6%; 6g, 29.3%; 9g, 38.5%). AG taken at different times did not have an additional influence on postprandial glycemia.

Conclusions: In nondiabetic individuals, 3, 6 or 9g of AG taken 40, 80 or 120 minutes before a glucose challenge similarly improved glucose tolerance.     

Common genetic variations of the cytochrome P450 1A1 gene and risk of hepatocellular carcinoma in a Chinese population

Cytochrome P450 1A1 is a major enzyme in the bioactivation of exogenous procarcinogens of hepatocellular carcinoma (HCC). However, the contribution of common genetic variants in CYP1A1 to the HCC risk in Chinese populations has not been thoroughly investigated. In this study, we examined the association between HCC and four selected tagging single nucleotide polymorphisms (SNPs) of CYP1A1, and the risk of CYP1A1 haplotypes/diplotypes in 1006 pathologically confirmed HCC patients and 1015 cancer-free controls, from a Han Chinese population. Haplotypes/diplotypes were constructed from observed genotypes using the Haplo.Stats program. Relative risk was estimated by using multivariable logistic regression method. To summarise, we detected an increased HCC risk in rs4646421 variant carriers (OR 1.30, 95% CI 1.05–1.61) and rs2198843 variant carriers (OR 1.33, 95% CI 1.05-1.69), and a reduced risk of HCC (OR 0.70. 95% CI 0.52–0.94) associated with homozygote carriers of rs4886605 variant. These association signals were also observed in non-smokers with rs4646421 (OR 1.56, 95% CI 1.16–2.08) and rs4886605 (OR 0.61, 95% CI 0.40–0.91). Compared to the most common CYP1A1 haplotype CCAG, the haplotype TTGC conferred an increased risk of HCC (OR 1.26, 95% CI 1.04–1.52). Similarly, the TTGC/TTGC diplotype conferred an increased risk of HCC compared with diplotype CCAG/CCAG (OR 2.06, 95% CI 1.23–3.45, P = 0.006). Interestingly, the diplotype TTAC/CCAG also conferred an increased risk of HCC (OR 1.76, 95% CI 1.22–2.54, P = 0.003). Our results suggested that common genetic variants in CYP1A1 may modulate the risk of developing HCC in the study population, particularly in non-smokers. However, our findings need to be validated in at least one independent study of Han Chinese population.     

双(2,6-哌嗪二酮)类抗肿瘤药物的研究:2,3-二乙酰氧基-1,4-二(3′,5′-二酮-N4′-取代哌嗪甲基)苯的合成

Seventeen compounds having the structure of 2,3-diacetoxy-1,4-bis(3′,5′- dioxo-N⁴′-substituted piperazinyl methyl)benzene were designed and synthesized based on chelation hypothesis. Their antitumor activities on P388 cells,Hep cells and SGC 7901 cells in vitro were tested. Preliminary results showed that compound 4e has potent antitumor effect against P388 cells and.Hep cells in vitro.     

Pathology of stranded beluga whales (Delphinapterus leucas) from the St. Lawrence Estuary, Québec, Canada

From June 1983 to May 1986, thirteen carcasses of stranded beluga whales from a polluted area of the St. Lawrence River, Canada were necropsied. High performance liquid chromatography was performed on the brains of three other animals to determine concentrations of benzo a pyrene (BaP). Two juvenile animals had severe multisystemic lesions one of which, a severe necrotizing dermatitis, was associated with a Herpesvirus-like particle. Four adults had five varieties of tumours. An adult had a systemic nocardiosis and a juvenile was affected ty a non 0:1 Vibrio cholerae septicemia. High concentrations of BaP adducts were found in the brains which were analyzed. Occurrence of BaP adducts in the brain of three whales of this population coincides with the high incidence of tumours. This and the previous finding of high concentrations of organochlorine in the tissues of these animals suggest an important role of industrial contaminants in the recent decrease of this population.     

Segregation analysis of autosomal dominant polycystic kidney disease

The results of classical segregation analysis on 159 families with polycystic kidney disease (PKD) are presented. It had been previously estimated that about 95 % of autosomal dominant PDK (ADPKD) families have PKD 1, the gene localized to chromosome 16p. The main purpose of the study was to determine if PKD shows any segregation distortion and to obtain new estimates of the age-dependent penetrance. Penetrance at the early ages of onset has increased during the last decade, presumably because of improvements in renal imaging and consequent earlier age of diagnosis. In the current study, the mean age of diagnosis was estimated to be 20 years, with a standard deviation (SD) of 15.94. Under the best fitting model (autosomal dominant), over 70 % penetrance was estimated by age 30 years, over 95 % by 50 years, and 99 % by 55 years. Thus, diagnosis of this disease at an early age is possible without total reliance on DNA typing. The segregation ratio defined through the transmission probability in our model was not significantly different from 0.50, but its confidence limits were broad: 0.36 to 0.64. Neither transmission probability nor penetrance was significantly influenced by gender. The mutation rate was estimated to be 6.9 × 10^?5, in accordance with the previously observed high mutation rate for PKD. However, the mutation rate in our study may be overestimated because it neglects low penetrance alleles and phenocopies. © 1993 Wiley-Liss, Inc.     

Molecular evidence that in situ-transduced fetal liver hematopoietic stem/progenitor cells give rise to medullary hematopoiesis in adult rats

We exploited the ability to transduce fetal liver hematopoietic stem/progenitor cells in situ with recombinant retrovirus, together with the ability to analyze proviral integration patterns into chromosomal DNA, to detect the cellular and organ fate of hematopoietic stem and progenitor-derived progeny in tissues and in the circulation of neonatal and adult rats. Two hundred seventeen fetuses were injected with retrovirus supernatant on day 16 of gestation, before the development of the bone marrow cavity. The progeny of 41 stem and progenitor cells from 97 liveborn rats were clonally identified. Pluripotent and lineage-restricted stem/progenitor clones derived from the fetal liver consistently gave rise to progeny in the marrow of newborn and adult rats. Patterns of differentiation of transduced stem and progenitor cells fell into distinct subsets. Blood cells derived from in situ transduced cells that originated in the fetal liver circulated throughout the life span of the adult animals. These data provide molecular evidence of the origin of medullary cavity hematopoiesis by cells derived from the fetal liver that were transduced in vivo, homed to the developing medullary cavity and proliferated in a normal medullary hematopoietic microenvironment.     

大环内酯类抗生素麦迪霉素的电化学特性

在K₂HPO₄,NH₄Cl+NH₃和NaOH的10%(v/v)乙醇水溶液中,除0.01mol·L^-1以上NaOH液作为支持电解质外,麦迪霉素的伏安波皆为两个峰。峰A相当于它的甲醛基还原波,峰B为催化吸附氢波。溶液pH对两峰有强烈的影响。实验表明伏安波有吸附特性,且不可逆。两峰的ip与麦迪霉素的浓度成正比,线性范围分别为3×10^-6～3×10^-5mol·L^-1和1×10^-7～4×10^-5mol·L^-1,检测限为:1×10-6mol·L^-1和5×10^-8mol·L^-1。可应用于麦迪霉素的定量测定。研究了两峰的特性和电极机理,测定了有关的物理常数。