Citations

Declines in heart disease and stroke mortality rates are conventionally attributed to reductions in cigarette smoking, recognition and treatment of hypertension and diabetes, effective medications to improve serum lipid levels and to reduce clot formation, and general lifestyle improvements. Recent evidence implicates these and other cerebrovascular factors in the development of a substantial proportion of dementia cases. Analyses were undertaken to determine whether corresponding declines in age‐specific prevalence and incidence rates for dementia and cognitive impairment have occurred in recent years. Data spanning 1 or 2 decades were examined from community‐based epidemiological studies in Minnesota, Illinois, and Indiana, and from the Health and Retirement Study, which is a national survey. Although some decline was observed in the Minnesota cohort, no statistically significant trends were apparent in the community studies. A significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey. Cautious optimism appears justified.

Background— Studies report a protective effect of higher attained educational level (AEL) on cardiovascular outcomes. However, most of these studies have been conducted in high-income countries (HICs) and lack representation from low- and middle-income countries (LMICs), which bear >80% of the global burden of cardiovascular disease. Methods and Results— The Reduction of Atherothrombosis for Continued Health (REACH) Registry is a prospective study of 67 888 subjects with either established atherothrombotic (coronary, cerebrovascular, and/or peripheral arterial) disease or multiple atherothrombotic risk factors enrolled from 5587 physician practices in 44 countries. At baseline, AEL (0 to 8 years, 9 to 12 years, trade or technical school, and university) was self-reported for 61 332 subjects. Outcomes included the baseline prevalence of atherothrombotic risk factors and the rate of incident cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) through 23 months across AEL groups, stratified by sex and world region (LMICs or HICs). Educational attainment was inversely associated with age and diabetes mellitus and directly associated with hypercholesterolemia in all subjects. However, for other risk factors such as obesity, smoking, hypertension, and baseline burden of vascular disease, AEL was protective (inversely associated) in HICs but not protective in LMICs. The protective effect of greater AEL on incident cardiovascular events was strongest in men from HICs ( P <0.0001), more modest in women from HICs ( P =0.0026) and in men from LMICs ( P =0.082), and essentially absent in women from LMICs ( P =0.32). Conclusion— In contrast to HICs, higher AEL may not be protective against cardiovascular events in LMICs, particularly in women.

The spindle assembly checkpoint (SAC) is essential for proper sister chromatid segregation. Defects in this checkpoint can lead to chromosome missegregation and aneuploidy. An increasing body of evidence suggests that aneuploidy can play a causal role in tumorigenesis. However, mutant mice that are prone to aneuploidy have only mild tumor phenotypes, suggesting that there are limiting factors in the aneuploidy-induced tumorigenesis. Here we provide evidence that p53 is such a limiting factor. We show that aneuploidy activates p53 and that loss of p53 drastically accelerates tumor development in two independent aneuploidy models. The p53 activation depends on the ataxia-telangiectasia mutated (ATM) gene product and increased levels of reactive oxygen species. Thus, the ATM-p53 pathway safeguards not only DNA damage but also aneuploidy.

AbstractGenome-wide association and candidate gene studies implicate different genetic variants within the 6p21 chromosomal region with different non-Hodgkin lymphoma (NHL) subtypes. Complementing these efforts, we conducted human leukocyte antigen (HLA) class I and class II genotyping among 610 NHL cases and 555 controls of non-Hispanic white descent from a US multicenter study. Allele-disease associations were assessed by logistic regression for NHL and its subtypes. Statistically significant associations between HLA and NHL subtypes include HLA-DRB1*0101 for follicular lymphoma (odds ratio [OR] = 2.14, P < .001), HLA-DRB1*0401 for diffuse large B-cell lymphoma (DLBCL; OR = 0.45, P = .006), and HLA-DRB1*13 and follicular lymphoma (OR = 0.48, P = .008). We further observed significant heterozygote advantage for HLA class I alleles and NHL, and particularly DLBCL (P trend = .01 for elevated risk with increasing number of homozygous alleles). Our results support a role for HLA in the etiology of NHL and its subtypes.

Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein–Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.

Abstract Purpose: We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP). Experimental Design: Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Results: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels. Conclusion: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.