Less than a century ago, gastric cancer (GC) was the most common cancer in the United States and perhaps throughout the world. Despite its worldwide decline in incidence over the past century, GC remains a major killer across the globe. This article reviews the epidemiology, screening, and prevention of gastric cancer. We first discuss the descriptive epidemiology of GC, including its incidence, survival, and mortality, including trends over time. Next, we characterize the risk factors for gastric cancer, both environmental and genetic. Serological markers and histological precursor lesions of GC and early detection of GC of using these markers is reviewed. Finally, we discuss prevention strategies and provide suggestions for further research.

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Context Previous studies indicate that the population attributable risk of bladder cancer for tobacco smoking is 50–65% in men and 20–30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking. Over the last 30 years, incidence rates have remained stable in the United States (men: 123.8/100,000 person-years to 142.2/100,000 person-years; women: 32.5/100,000 person-years to 33.2/100,000 person-years), yet changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer in more recent data. Objective To evaluate the association between tobacco smoking and bladder cancer. Design, Setting, and Participants Men (n=281,394) and women (n=186,134) of the NIH-AARP cohort completed a lifestyle questionnaire and were followed from 1995 through Dec 31, 2006. Previous prospective cohort studies of smoking and incident bladder cancer were identified by systematic review and pooled using fixed effects models with heterogeneity assessed by I2. Main outcome measures Hazard ratios (HR), population attributable risks, and number needed to harm (NNH). Results During 4,518,938 years of follow-up, incident bladder cancer occurred in 3,896 men (144.0/100,000 person-years) and 627 women (34.5/100,000 person-years). Former smokers (119.8/100,000 person-years, HR: 2.22, 95%CI: 2.03–2.44, NNH: 1,250) and current smokers (177.3/100,000 person-years, HR: 4.06, 95%CI: 3.66–4.50; NNH: 727) had higher risks of bladder cancer than never smokers (39.8/100,000 person-years). In contrast, the summary risk estimate for current smoking in seven previous studies (initiated from 1963–1987) was 2.94 (95%CI: 2.45–3.54; I2=0.0%). The population attributable risk for ever smoking in our study was 0.50 (95%CI: 0.45–0.54) in men and 0.52 (95%CI: 0.45–0.59) in women. Conclusions Compared to a pooled estimate of US data from cohorts initiated between 1963 and 1987, relative risks for smoking in the more recent NIH-AARP cohort were higher, with population attributable risks for women comparable to those for men.

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.

Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).

BACKGROUND The disease risks from cigarette smoking increased in the United States over most of the 20th century, first among male smokers and later among female smokers. Whether these risks have continued to increase during the past 20 years is unclear. METHODS We measured temporal trends in mortality across three time periods (1959–1965, 1982–1988, and 2000–2010), comparing absolute and relative risks according to sex and self-reported smoking status in two historical cohort studies and in five pooled contemporary cohort studies, among participants who became 55 years of age or older during follow-up. RESULTS For women who were current smokers, as compared with women who had never smoked, the relative risks of death from lung cancer were 2.73, 12.65, and 25.66 in the 1960s, 1980s, and contemporary cohorts, respectively; corresponding relative risks for male current smokers, as compared with men who had never smoked, were 12.22, 23.81, and 24.97. In the contemporary cohorts, male and female current smokers also had similar relative risks for death from chronic obstructive pulmonary disease (COPD) (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women). Mortality from COPD among male smokers continued to increase in the contemporary cohorts in nearly all the age groups represented in the study and within each stratum of duration and intensity of smoking. Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked. Smoking cessation at any age dramatically reduced death rates. CONCLUSIONS The risk of death from cigarette smoking continues to increase among women and the increased risks are now nearly identical for men and women, as compared with persons who have never smoked. Among men, the risks associated with smoking have plateaued at the high levels seen in the 1980s, except for a continuing, unexplained increase in mortality from COPD.

The diffusion of DNA in cytoplasm is thought to be an important determinant of the efficacy of gene delivery and antisense therapy. We have measured the translational diffusion of fluorescein-labeled double-stranded DNA fragments (in base pairs (bp): 21, 100, 250, 500, 1000, 2000, 3000, 6000) after microinjection into cytoplasm and nucleus of HeLa cells. Diffusion was measured by spot photobleaching using a focused argon laser spot (488 nm In nucleus, all DNA fragments were nearly immobile, whereas FITC dextrans of molecular size up to 580 kDa were fully mobile. These results suggest that the highly restricted diffusion of DNA fragments in nucleoplasm results from extensive binding to immobile obstacles and that the decreased lateral mobility of DNAs >250 bp in cytoplasm is because of molecular crowding. The diffusion of DNA in cytoplasm may thus be an important rate-limiting barrier in gene delivery utilizing non-viral vectors.The diffusional mobility of DNA fragments in cytoplasm is thought to be an important determinant of the efficacy of DNA delivery in gene therapy and antisense oligonucleotide therapy (1-3). Liposome-mediated gene transfer involves endocytic uptake, release from endosomes, dissociation of DNA from lipid, diffusion through cytoplasm, transport across nuclear pores, and diffusion to nuclear target sites (4 -7). Although considerable attention has been given to the mechanisms of cellular DNA internalization, nuclear uptake, and subsequent molecular events, little is known about the diffusive properties of introduced DNA fragments in cytoplasm and nucleus. It is not known whether the diffusion of DNA fragments is hindered by binding and steric interactions or how the size and physical structure of DNA affect its diffusional properties.Recent studies have provided information about the diffusional mobilities of small and macromolecule-sized solutes in cytoplasm and nucleus. Spot photobleaching measurements indicated that small solutes diffuse freely and rapidly in cytoplasm and nucleus, with diffusion coefficients only 3-4 times lower than that in water (8, 9). Analysis of the individual factors slowing solute diffusion, including fluid-phase viscosity, binding, and collisional interactions, indicated that the principal barrier for diffusion of small solutes was collisional interactions due to macromolecular crowding (8). The "fluid-phase" viscosity of cytoplasm and nucleus, defined as the viscosity sensed by a small probe that does not interact with cellular components, was determined by time-resolved anisotropy (10) and ratio imaging of a viscosity-sensitive fluorescent probe (11) to be only 1.2-1.4 times greater than the viscosity of water. The translational diffusion of larger, macromolecule-sized solutes (FITC 1 -labeled dextrans and Ficolls) in cytoplasm and nucleus was only 3-4-fold slower than in water for solutes Ͻ500 -750 kDa (12) but was markedly slowed for larger solutes (11, 12). The diffusional mobilities of targeted green fluorescent protein chimeras have been measured recently i...

Matrix metalloproteinases (MMPs) regulate ductal morphogenesis, apoptosis, and neoplastic progression in mammary epithelial cells. To elucidate the direct effects of MMPs on mammary epithelium, we generated functionally normal cells expressing an inducible autoactivating stromelysin-1 (SL-1) transgene. Induction of SL-1 expression resulted in cleavage of E-cadherin, and triggered progressive phenotypic conversion characterized by disappearance of E-cadherin and catenins from cell–cell contacts, downregulation of cytokeratins, upregulation of vimentin, induction of keratinocyte growth factor expression and activation, and upregulation of endogenous MMPs. Cells expressing SL-1 were unable to undergo lactogenic differentiation and became invasive. Once initiated, this phenotypic conversion was essentially stable, and progressed even in the absence of continued SL-1 expression. These observations demonstrate that inappropriate expression of SL-1 initiates a cascade of events that may represent a coordinated program leading to loss of the differentiated epithelial phenotype and gain of some characteristics of tumor cells. Our data provide novel insights into how MMPs function in development and neoplastic conversion.