Reported Influenza in Pregnancy and Subsequent Cancer in the Child

A longitudinal study of 1,959 infants born in the first week of March 1958 to mothers who were reported to have had influenza during pregnancy revealed an incidence of cancer of 4·1 per 1,000 compared with only 0·8 per 1,000 among the 14,791 infants of mothers who had not had influenza.This increase was caused by cases of leukaemia and other neoplasms of lymphatic and haematopoietic tissue (I.C.D. 200-209) (P <0·0001).Data from the reports of the Registrar General for England and Wales were used to estimate the number of infants born in each year from 1955 to 1964 who subsequently died of cancer before 5 years of age. The rates for each year were compared with an estimate of the prevalence of influenza during the preceding winter. After allowing for the overall trend in the cancer death rate, a highly significant correlation was shown with deaths attributed to causes classified as I.C.D. 200-209 (P <0·005), but not with deaths attributed to other cancers. The increase in the risk of developing these neoplasms among children whose mothers had influenza is estimated to be not less than fourfold. Even so the risk remains small (3 to 4 per 1,000).     

Independent Association of Hip Circumference with Metabolic Profile in Different Ethnic Groups

Objective: In whites, a larger hip circumference has been shown to be associated with a better metabolic profile, after adjustment for BMI and waist circumference. Our aim was to investigate this association in a variety of ethnic groups, some highly susceptible to type 2 diabetes. Research Methods and Procedures: We measured weight, height, waist and hip circumferences, systolic and diastolic blood pressure, fasting and 2‐hour postload glucose, triglycerides, and high‐density lipoprotein‐cholesterol in 1020 Melanesians, 767 Micronesians, 3697 Indians, and 2710 Creoles from Pacific and Indian Ocean islands. Leptin and body fat percentage were determined in Indian and Creole Mauritians only. Results: In all ethnic groups, larger hip circumference was associated with lower glucose and triglyceride levels in both sexes and higher high‐density lipoprotein levels in women only, after adjustment for waist circumference, BMI, and age. Adjustment for height or leptin did not materially change the results. Discussion: In conclusion, we confirmed the protective association of relatively larger hips in four nonwhite ethnic groups. Leptin does not seem to play a mediating role in this association.     

Hippo通路与肿瘤相关性研究进展

Hippo通路对控制组织器官大小以及细胞增殖、凋亡有着重要的调节作用。研究表明,Yes相关蛋白作为Hippo通路转录共激活因子,参与了肿瘤的发生发展过程,其过表达可促进细胞的恶性转化。研究Hippo通路在癌症发生发展中的作用及机制将为肿瘤的预防和治疗提供新的思路。     

SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk

Introduction

MicroRNAs (miRNAs) regulate messenger RNAs (mRNAs) and as such have been implicated in a variety of diseases, including cancer. MiRNAs regulate mRNAs through binding of the miRNA 5’ seed sequence (~7–8 nucleotides) to the mRNA 3’ UTRs; polymorphisms in these regions have the potential to alter miRNA-mRNA target associations. SNPs in miRNA genes as well as miRNA-target genes have been proposed to influence cancer risk through altered miRNA expression levels.

Methods

MiRNA-SNPs and miRNA-target gene-SNPs were identified through the literature. We used SNPs from Genome-Wide Association Study (GWAS) data that were matched to individuals with miRNA expression data generated from an Agilent platform for colon tumor and non-tumor paired tissues. These samples were used to evaluate 327 miRNA-SNP pairs for associations between SNPs and miRNA expression levels as well as for SNP associations with colon cancer.

Results

Twenty-two miRNAs expressed in non-tumor tissue were significantly different by genotype and 21 SNPs were associated with altered tumor/non-tumor differential miRNA expression across genotypes. Two miRNAs were associated with SNP genotype for both non-tumor and tumor/non-tumor differential expression. Of the 41 miRNAs significantly associated with SNPs all but seven were significantly differentially expressed in colon tumor tissue. Two of the 41 SNPs significantly associated with miRNA expression levels were associated with colon cancer risk: rs8176318 (BRCA1), OR_AA 1.31 95% CI 1.01, 1.78, and rs8905 (PRKAR1A), OR_GG 2.31 95% CI 1.11, 4.77.

Conclusion

Of the 327 SNPs identified in the literature as being important because of their potential regulation of miRNA expression levels, 12.5% had statistically significantly associations with miRNA expression. However, only two of these SNPs were significantly associated with colon cancer.     

Clustering of GPI-Anchored Folate Receptor Independent of Both Cross-Linking and Association with Caveolin

The distribution of the glycosyl-phosphatidylinositol (GPI)-anchored folate receptor (FR) in a diffuse pattern vs. functional clusters associated with caveolae has been debated. The equivocal nature of direct localization studies is due to possible experimental artifacts such as cross-linking of the protein by the antibody probes prior to fixation and alternatively the use of a disruptive fixation method. Such studies have also been complicated by the use of cells that vastly overexpress FR. In this study a monovalent probe, i.e., a biotinylated folate affinity analogue was used to covalently label FR. Cells expressing moderate levels of FR, i.e., JAR epithelial cells expressing FR-α and recombinant CHO fibroblasts expressing FR-β, were used. The affinity label and either caveolin or antigenic sites on FR were localized by electron microscopy using colloidal gold conjugated antibody probes post-embedding in the relatively permeable LR White resin. The method avoided both receptor cross-linking and early fixation steps and also enabled the use of transport permissive conditions while labeling FR at the cell surface. The results indicate that in steady-state FR is not significantly colocalized with caveolin. However, the receptor molecules occur predominantly in clusters, independent of cross-linking, providing a physical basis for the observed kinetics of receptor internalization and recycling during folate transport. Evidence is also presented to suggest that early mild fixation will disrupt the clustering of FR. Received: 26 September 1996/Revised: 7 May 1997     

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy

There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.     

Association of GWAS-Identified Lung Cancer Susceptibility Loci with Survival Length in Patients with Small-Cell Lung Cancer Treated with Platinum-Based Chemotherapy

Genetic variants have been shown to affect length of survival in cancer patients. This study explored the association between lung cancer susceptibility loci tagged by single-nucleotide polymorphisms (SNPs) identified in the genome-wide association studies and length of survival in small-cell lung cancer (SCLC). Eighteen SNPs were genotyped among 874 SCLC patients and Cox proportional hazards regression was used to examine the effects of genotype on survival length under an additive model with age, sex, smoking status and clinical stage as covariates. We identified 3 loci, 20q13.2 (rs4809957G >A), 22q12.2 (rs36600C >T) and 5p15.33 (rs401681C >T), significantly associated with the survival time of SCLC patients. The adjusted hazard ratio (HR) for patients with the rs4809957 GA or AA genotype was 0.80 (95% CI, 0.66–0.96; P = 0.0187) and 0.73 (95% CI, 0.55–0.96; P = 0.0263) compared with the GG genotype. Using the dominant model, the adjusted HR for patients carrying at least one T allele at rs36600 or rs401681 was 0.78 (95% CI, 0.63–0.96; P = 0.0199) and 1.29 (95% CI, 1.08–1.55; P = 0.0047), respectively, compared with the CC genotype. Stratification analyses showed that the significant associations of these 3 loci were only seen in smokers and male patients. The rs4809957 SNP was only significantly associated with length of survival of patients with extensive-stage but not limited-stage tumor. These results suggest that some of the lung cancer susceptibility loci might also affect the prognosis of SCLC.