Hepatocellular carcinoma is among the most common and lethal cancers in humans. Hepatocellular carcinoma is commonly associated with physical or functional inactivation of the p53 tumor suppressor, high levels of chromosomal instability, and disease conditions causing chronic cycles of hepatocyte death and regeneration. Mounting evidence has implicated regeneration-induced telomere erosion as a potential mechanism fueling genome instability. In mouse models of hepatocellular carcinoma, telomere dysfunction has been shown to enhance initiation of hepatic neoplasias yet constrain full malignant progression of these neoplasms possibly due to activation of a p53-dependent checkpoint and/or intolerable levels of genomic instability. Here, in a hepatocellular carcinoma–prone model brought about through toxin-induced hepatocyte injury and regeneration, we sought to determine the cooperative interactions of germ line p53 mutation and telomere dysfunction [produced by telomerase reverse transcriptase (mTERT) gene knockout]. In the setting of intact telomeres, p53 mutation had no effect on hepatocarcinogenesis, whereas in the setting of telomere dysfunction, p53 mutation enabled advanced hepatocellular carcinoma disease. Notably, there was no evidence of deletion or mutation of the wild-type p53 allele in the late generation mTert^−/−p53^+/− mice, suggesting that reduced levels of p53 potently enable hepatocellular carcinoma progression in the setting of telomere dysfunction. Thus, this study supports a model that, in the face of chronic liver damage, attenuated p53 function and telomere-induced chromosomal instability play critical and cooperative roles in the progression of hepatocellular carcinoma. (Cancer Res 2006; 66(9): 4766-73)

Colorectal cancer (CRC) screening rates are lower in rural areas in the USA. To guide the design of interventions to improve CRC screening, a systematic review was conducted to identify CRC screening barriers for rural populations. A search was conducted in four literature databases - Medline, CINAHL, Embase, and Scopus - for articles from 1998 to 2017 that examine CRC screening barriers in rural areas. This review included a total of 27 articles reporting perceived CRC screening barriers by rural residents or providers or examining factors associated with CRC screening of rural populations in the USA. The most frequently reported barriers were high screening cost and lack of insurance coverage, embarrassment or discomfort undergoing screening, lack of knowledge or perceived need on CRC screening, and lack of physician recommendation. These barriers were confirmed in quantitative studies examining their association with CRC screening status. Age, marital status, and race/ethnicity were the most frequently reported factors associated with CRC screening in rural areas. Lack of prevention attitude toward cancer, perceived lack of privacy, shortage of specialists, and distance to test facilities were reported as rural-specific barriers for CRC screening. Main barriers for CRC screening at both the individual and healthcare system level are identified in rural areas and they are in line with those found in urban areas in general. In particular, lack of prevention attitude toward cancer, perceived lack of privacy, shortage of specialists, and distance to test facilities disproportionately hamper CRC screening for rural Americans.

Intrahepatic cholangiocarcinoma (CCA) is a lethal malignancy of the biliary epithelium associated with p53 mutations, bile duct injury, inflammation, and fibrosis. Here, to validate these processes in CCA, we developed a liver cirrhosis model driven by chronic intermittent toxin exposure, which provokes bile duct injury/necrosis and proliferation, fibroblast recruitment, and progressive extracellular matrix (ECM) changes. Fibrotic changes in the matrix microenvironment, typified by increased type I and III collagens and fibroblast recruitment, were shown to stimulate biliary epithelium hyperplasia with subsequent progression to malignant intrahepatic CCA only in mice harboring a p53 mutant allele. These murine CCAs bear histologic and genetic features of human intrahepatic CCA, including dense peritumoral fibrosis, increased inducible nitric oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression, c-Met activation, cErbB2 overexpression, down-regulation of membrane-associated E-cadherin, and p53 codon 248 mutation. Thus, p53 deficiency, chronic bile duct injury/proliferation, and the fibrotic matrix microenvironment cooperate to induce intrahepatic CCA, highlighting the key role of the ECM microenvironment in this common liver cancer. (Cancer Res 2006; 66(13): 6622-7) (Cancer Res 2006; 66(13): 6622-7)

Background: Association between high adiposity and the clinical progression of dementia remains puzzling. Objective: To separately examine the association between body mass index (BMI) and cognitive, functional, and behavioral declines before, at, an

Objectives To examine (1) the association between household socioeconomic status (SES) and whether a household spends money on cigarettes and (2) socioeconomic variations in proportion of total household expenditure spent on cigarettes among smoking households. Methods We pooled data from six consecutive years, 2010–2015, of the Consumer Expenditure Interview Survey. The interviews involved a structured questionnaire about household income, demographics and expenditures including expenditure on cigarettes. Households that reported cigarette expenditure in the previous 3 months were distinguished as smoking households. SES indicators were household poverty status, education and occupation of the head of household. Logistic regression was used to assess the association of household smoking status with SES. Fractional logistic regression was used to assess the association of cigarette expenditure as a proportion of total household expenditure with SES. The analysis sample size was 39 218. Results The probability of spending money on cigarettes was higher among lower SES households. Households in poverty compared with those above 300% of poverty threshold had 1.86 (95% CI 1.61 to 2.16), households headed by a person with less than high school education compared with those headed by a person with at least a bachelor’s degree had 3.37 (95% CI 2.92 to 3.89) and households headed by a blue-collar work compared with those headed by a person in a managerial occupation had 1.45 (95% CI 1.26 to 1.66) higher odds of spending money on cigarettes. Similarly, the proportion of total household expenditure spent on cigarettes was higher among lower SES smoking households. Conclusion Lower SES households are more likely to spend money on cigarettes and spend a larger proportion of their total expenditure on cigarettes. We recommend strategies effective in reducing smoking among low SES smokers.