Identification of nuclear factor 1 (NF1) as a transcriptional modulator of rat A(2A) adenosine receptor

By a combination of PCR and DNA walking technique, we isolated a 4.8-kb DNA fragment containing a 4.3 kb 5'-flanking region and a 0.5-kb 5'-untranslated region of the rat A(2A) adenosine receptor (A(2A)-R) gene. Various lengths of the 5'-flanking region of the A(2A)-R gene were inserted into an expression vector and transfected into several different cell lines for promoter analysis. Our results reveal that a consensus NF1 element (designated as A(2A)-R/NF1), located between bases -2846 and -2827 of the A(2A)-R gene, functions as a repressor for A(2A)-R promoters in the rat brain-derived type-2 astrocyte cell line (RBA2), which expresses no A(2A)-R. Electrophoretic gel mobility shift assay (EMSA) revealed that two A(2A)-R/NF1-protein complexes of RBA2 nuclear extract were formed. Supershift experiments using an anti-NF1 antibody suggest that NF1 proteins exist in both A(2A)-R/NF1-protein complexes. Furthermore, mutations in the conserved NF1 binding site of this A(2A)-R/NF1 element disturbed DNA-protein formation. Thus, NF1 proteins appear to mediate this cell line-specific suppression of A(2A)-R promoters in RBA2 cells. The importance of NF1 proteins in regulating A(2A)-R promoters was further confirmed in another cell line (Siha) which expresses no endogenous A(2A)-R. Moreover, addition of the A(2A)-R/NF1element upstream of an irrelevant thymidine kinase (TK) promoter suppressed its promoter activity in Siha cells, but not in RBA2 cells. Thus, the NF1-mediated inhibition of the A(2A)-R promoter was promoter- and cell line-specific. In summary, we have defined a distal negative element (A(2A)-R/NF1) that plays a functional role in modulating the expression of A(2A)-R.     

胆囊癌与妊娠关系的全人群病例对照研究

目的探讨胆囊癌与妊娠的关系.方法采用全人群病例对照研究,研究对象为1997年6月1日～2001年5月31日期间确诊、年龄在35～74岁的上海市区女性胆囊癌269例以及按年龄(5岁一组)频数配对的538名人群对照,采用非条件lo-gistic回归模型分析妊娠与胆囊癌的关系.结果胆囊癌合并胆石症者中,与妊娠次数≤2次者比较,妊娠次数(3次,4次,5次及≥6次)的各组调整OR分别为1.33(95%CI:0.59-2.99),1.34(95%CI:0.58-3.11),1.39(95%CI:0.57-3.43)和2.67(95%CI:1.12-6.41),趋势检验P=0.03.结论多次妊娠可能通过胆石症影响胆囊癌的发生,生育因素导致的女性体内雌、孕激素水平的升高可能在胆囊癌病因学中起一定的作用.     

吸烟、饮酒与胆道癌关系的全人群病例对照研究

 目的　探讨吸烟、饮酒与胆道癌的关系。方法　采用全人群病例对照研究 ,研究对象为 1997年6月 1日～ 2 0 0 1年 5月 31日期间确诊的、年龄在 35～ 74岁的上海市区 6 2 7例胆道癌新发病例以及按性别、年龄 (5岁一组 )频数配对的 95 9例人群对照。采用非条件logistic回归模型分析吸烟、饮酒与胆道癌的关系。结果　男性中 ,吸烟对肝外胆管癌和壶腹癌各组的调整OR均大于 1,现仍吸烟者的调整OR分别为 1.5 1(95 %CI:0 .86～ 2 .6 6 ) ,1.5 8(95 %CI:0 .6 9～ 3.5 8) ;OR随吸烟年限增加和开始吸烟年龄提早有所升高 ,但均未达显著水平。饮酒对胆道癌各组OR均无统计学意义。结论　吸烟也许与肝外胆管癌、壶腹癌有联系 ,未发现吸烟与胆囊癌的显著性关联 ;未发现饮酒与胆道癌的显著性关联。     

The effects of NOS1 gene on asthma and total IgE levels in Taiwanese children,and the interactions with environmental factors

Wang T‐N, Tseng H‐I, Kao C‐C, Chu Y‐T, Chen W‐Y, Wu P‐F, Lee C‐H, Ko Y‐C. The effects of NOS1 gene on asthma and total IgE levels in Taiwanese children, and the interactions with environmental factors.
Pediatr Allergy Immunol 2010: 21: 1064–1071.
© 2010 John Wiley & Sons A/S Asthma is a complex disorder, which is known to be affected by interactions between genetic and environmental factors. The aim of this study was to investigate the three microsatellite polymorphisms of GT repeats in intron 2, AAT repeats in intron 20, and CA repeats in exon 29 of the NOS1 gene in 155 asthmatic children and 301 control children, and the interaction with environmental factors in southern Taiwan. Total serum IgE, phadiatop test and genetic polymorphisms were measured. The genotype frequency of 14/14‐AAT repeats of the NOS1 gene was significantly higher in the asthmatic group (p = 0.01). Total IgE concentrations were higher in asthmatic children (p = 0.015) carrying the NOS1 14/14‐AAT genotype than in subjects with other polymorphisms. The gene and environmental interaction effects were 3.83‐fold, 6.86‐fold, and 8.04‐fold (all corrected p‐values <0.001) between subjects carrying at least one NOS1 14‐AAT allele and exposure to cockroaches, high levels of total IgE, and positive response against the phadiatop test in asthmatic children. The findings of this study provide strong evidence that NOS1 gene with 14‐AAT tandem repeats has a significant effect in asthmatic children. Environmental factors and atopic status will enhance the asthmatic risk for children who carry NOS1 susceptible allele.     

Correlations of dietary intake and blood nutrient levels with esophageal cancer mortality in China

Using dietary, blood nutrient, and esophageal cancer mortality data from 65 Chinese counties, we examined several correlations to help provide clues to the influence of diet and nutrition on the geographic variation of esophageal cancer in China. Esophageal cancer mortality was significantly inversely related to reported fruit consumption and to plasma ascorbic acid concentration. The age-adjusted mortality rates were more than three times higher for counties in the lowest compared with the highest quartile of fruit intake or plasma vitamin C. Positive correlations with intake of moldy vegetables were observed but not with tobacco and alcohol consumption. There were suggestive inverse associations with blood selenium and riboflavin but little effect of fat-soluble vitamins. Limitations of ecological data preclude causal inferences, but the relationships provide leads to dietary factors that may contribute to the exceptionally high rates of esophageal cancer in several areas of China.     

Trichomonosis and subsequent risk of prostate cancer in the Prostate Cancer Prevention Trial

We previously observed a positive association between a history of trichomonosis, a sexually transmitted infection caused by the protozoan, Trichomonas vaginalis, and prostate cancer risk in the Health Professionals Follow‐up Study. To determine the reproducibility of this finding, we conducted a second, prospective investigation of trichomonosis and prostate cancer in the Prostate Cancer Prevention Trial. Participants were men (≥55 years of age) with no evidence of prostate cancer at enrollment (n = 18,882). Men were screened annually for prostate cancer, and if not diagnosed during the trial, were offered an end‐of‐study prostate biopsy. Cases were a sample of men diagnosed with prostate cancer on any biopsy after visit 2 or on their end‐of‐study biopsy (n = 616). Controls were men not diagnosed with prostate cancer during the trial or on their end‐of‐study biopsy (n = 616). Controls were frequency‐matched to cases by age, treatment arm, and family history of prostate cancer. Serum from visit 2 was tested for anti‐T. vaginalis IgG antibodies. No association was observed between T. vaginalis serostatus and prostate cancer. 21.5% of cases and 24.8% of controls had low seropositivity, and 15.2% and 15.0% had high seropositivity. Compared to seronegative men, the odds ratio of prostate cancer for men with low seropositivity was 0.83 [95% confidence interval (CI): 0.63–1.09), and that for men with high seropositivity was 0.97 (95% CI: 0.70–1.34). Given the original strong biologic rationale and potential for prevention, additional studies are warranted to help resolve discrepancies between study findings and to further investigate this hypothesis from a variety of different approaches. © 2008 Wiley‐Liss, Inc.     

Androgen and prostate cancer: is the hypothesis dead?

Data from animal, clinical, and prevention studies support the role of androgen in prostate cancer growth, proliferation, and progression. However, results serum-based epidemiologic studies in humans have been inconclusive. Part of the inconsistency in these findings stems from differences in study population, assay accuracy, intraperson variation, and limited sample size. Recently, data from a large pooled analysis of 18 prospective studies (3,886 cases and 6,438 healthy controls) showed no association between serum androgen and prostate cancer risk. It is not surprising that the pooled analysis did not find a positive link between circulating levels of total testosterone and prostate cancer risk because, individually, few of the 18 studies included in the pooled analysis reported a substantial positive association. The null result, however, does not pronounce a death sentence for the androgen hypothesis; rather, it underscores the importance of a better understanding of androgen action within the prostate, including the relationship between tissue and serum levels of androgen. In this commentary, we explain why circulating levels of testosterone may not reflect androgen action in the prostate and why tissue levels of androgen, in particular dihydrotestosterone, and the androgen receptor and its coregulators are critical to androgen action in the prostate and should be incorporated in future studies. It is timely to integrate system thinking into our research and use an interdisciplinary approach that involves different disciplines, including epidemiology, endocrinology, pathology, and molecular biology, to help dissect the complex interplay between sex steroids and genetic and lifestyle factors in prostate cancer etiology.     

Should adequacy criteria in cervicovaginal cytology be modified after radiotherapy,chemotherapy, or hysterectomy?

BACKGROUND.

The general criterion of an unsatisfactory Papanicolaou (Pap) test in the 2001 version of the Bethesda system is not applicable to patients after treatment with radiotherapy, chemotherapy, or hysterectomy. The current study was performed to determine whether specimen adequacy criteria for Pap tests should be modified for these conditions.

METHODS.

Consecutive patients who underwent conventional Pap tests between March and August 2006 were reviewed. The original reports were done according to the 2001 Bethesda system, with cellularity criteria modified in patients with a history of radiotherapy, chemotherapy, or hysterectomy. The slides of these patients were reviewed again. The degrees of cellularity, obscuring red blood cells, and inflammation were recorded.

RESULTS.

The final analyses included 7033 patients for which there were complete data. The original interpretation was unsatisfactory in 4.4% of all samples. When the 1337 slides obtained from patients with a history of radiotherapy, chemotherapy, and/or hysterectomy were reviewed using the general satisfactory threshold of >8000 squamous cells/slide and <75% of the epithelium obscured, the incidence of unsatisfactory Pap tests increased from 4.3% to 13.2% (176 of 1337 slides). The odds ratios for unsatisfactory Pap tests for a history of radiotherapy, chemotherapy, and age >50 years were 2.70, 2.51, and 1.39, respectively. The majority of unsatisfactory Pap tests were because of low cellularity. The lower limits of adequate cellularity after radiotherapy or chemotherapy can be set at 2000 cells/slide, which can lower the unsatisfactory rate while at the same time resulting in no increase in the false‐negative rate. Hysterectomy alone was not found to be associated with unsatisfactory Pap tests.

CONCLUSIONS.

In patients who received pelvic radiotherapy or chemotherapy, the incidence of low‐cellularity Pap tests was unacceptably high. A lower cellularity (estimated 2000 cell/slide) could be used as a satisfactory threshold. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.