Tp53-dependent repression of cell cycle target genes: Global and mechanistic analysis

Most studies of p53 function have focused on genes transactivated by p53. It is less widely appreciated that p53 can repress target genes to affect a particular cellular response. There is evidence that repression is important for p53-induced apoptosis and cell cycle arrest. It is less clear if repression is important for other p53 functions. A comprehensive knowledge of the genes repressed by p53 and the cellular processes they affect is currently lacking. We used an expression profiling strategy to identify p53-responsive genes following adenoviral p53 gene transfer (Ad-p53) in PC3 prostate cancer cells. A total of 111 genes represented on the Affymetrix U133A microarray were repressed more than two fold (p ≤ 0.05) by p53. An objective assessment of array data quality was carried out using RT-PCR of 20 randomly selected genes. We estimate a confirmation rate of >95.5% for the complete data set. Functional over-representation analysis was used to identify cellular processes potentially affected by p53-mediated repression. Cell cycle regulatory genes exhibited significant enrichment (p ≤ 5E-28) within the repressed targets. Several of these genes are repressed in a p53-dependent manner following DNA damage, but preceding cell cycle arrest. These findings identify novel p53-repressed targets and indicate that p53-induced cell cycle arrest is a function of not only the transactivation of cell cycle inhibitors (e.g., p21), but also the repression of targets that act at each phase of the cell cycle. The mechanism of repression of this set of p53 targets was investigated. Most of the repressed genes identified here do not harbor consensus p53 DNA binding sites but do contain binding sites for E2F transcription factors. We demonstrate a role for E2F/RB repressor complexes in our system. Importantly, p53 is found at the promoter of CDC25A. CDC25A protein is rapidly degraded in response to DNA damage. Our group has demonstrated for the first time that CDC25A is also repressed at the transcript level by p53. This work has important implications for understanding the DNA damage cell cycle checkpoint response and the link between E2F/RB complexes and p53 in the repression of target genes. ^

Environmental, health and safety cost benefit analysis in the United States chemical industry

The purpose of this research project is to determine whether there is a cost/benefit to allocating financial and other company-related resources to improve environmental, health and safety performance beyond that which is required by law. The issue of whether a company benefits from spending dollars to achieve environmental, health and safety performance beyond legal compliance is an important issue to the chemical manufacturing industry in the United States because of the voluminous and complex legal requirements impacting environmental, health and safety expenditures. The cost/benefit issue has practical significance because many U.S. chemical manufacturing companies base their environmental, health and safety management strategies on just achieving and maintaining compliance with legal requirements when in reality this strategy may actually be a higher cost way of managing environmental, health and safety practices. This difference in environmental, health and safety management strategy is being investigated to determine if managing environmental, health and safety to achieve performance beyond that which is required by law results in a greater benefit to companies in the U.S. chemical manufacturing sector.

Analysis of clonality and antibiotic resistance among early clinical isolates of Enterococcus faecium in the United States.

BACKGROUND: The Enterococcus faecium genogroup, referred to as clonal complex 17 (CC17), seems to possess multiple determinants that increase its ability to survive and cause disease in nosocomial environments. METHODS: Using 53 clinical and geographically diverse US E. faecium isolates dating from 1971 to 1994, we determined the multilocus sequence type; the presence of 16 putative virulence genes (hyl(Efm), esp(Efm), and fms genes); resistance to ampicillin (AMP) and vancomycin (VAN); and high-level resistance to gentamicin and streptomycin. RESULTS: Overall, 16 different sequence types (STs), mostly CC17 isolates, were identified in 9 different regions of the United States. The earliest CC17 isolates were part of an outbreak that occurred in 1982 in Richmond, Virginia. The characteristics of CC17 isolates included increases in resistance to AMP, the presence of hyl(Efm) and esp(Efm), emergence of resistance to VAN, and the presence of at least 13 of 14 fms genes. Eight of 41 of the early isolates with resistance to AMP, however, were not in CC17. CONCLUSIONS: Although not all early US AMP isolates were clonally related, E. faecium CC17 isolates have been circulating in the United States since at least 1982 and appear to have progressively acquired additional virulence and antibiotic resistance determinants, perhaps explaining the recent success of this species in the hospital environment.

Patterns of alcohol and illicit substance use in the United States and Mexico. Substantive and methodologic issues in the cross-national analysis of alcohol and drug use data

This research examines prevalence of alcohol and illicit substance use in the United States and Mexico and associated socio-demographic characteristics. The sources of data for this study are public domain data from the U.S. National Household Survey of Drug Abuse, 1988 (n = 8814), and the Mexican National Survey of Addictions, 1988 (n = 12,579). In addition, this study discusses methodologic issues in cross-cultural and cross-national comparison of behavioral and epidemiologic data from population-based samples. The extent to which patterns of substance abuse vary among subgroups of the U.S. and Mexican populations is assessed, as well as the comparability and equivalence of measures of alcohol and drug use in these national samples.^ The prevalence of alcohol use was somewhat similar in the two countries for all three measures of use: lifetime, past year and past year heavy use, (85.0%, 68.1%, 39.6% and 72.6%, 47.7% and 45.8% for the U.S. and Mexico respectively). The use of illegal substances varied widely between countries, with U.S. respondents reporting significantly higher levels of use than their Mexican counterparts. For example, reported use of any illicit substance in lifetime and past year was 34.2%, 11.6 for the U.S., and 3.3% and 0.6% for Mexico. Despite these differences in prevalence, two demographic characteristics, gender and age, were important correlates of use in both countries. Men in both countries were more likely to report use of alcohol and illicit substances than women. Generally speaking, a greater proportion of respondents in both countries 18 years of age or older reported use of alcohol for all three measures than younger respondents; and a greater proportion of respondents between the ages of 18 and 34 years reported use of illicit substances during lifetime and past year than any other age group.^ Additional substantive research investigating population-based samples and at-risk subgroups is needed to understand the underlying mechanisms of these associations. Further development of cross-culturally meaningful survey methods is warranted to validate comparisons of substance use across countries and societies. ^

Colorectal cancer screening: Racial/ethnic and gender disparities in a population-based cross-sectional analysis of the United States

Gender and racial/ethnic disparities in colorectal cancer screening (CRC) has been observed and associated with income status, education level, treatment and late diagnosis. According to the American Cancer Society, among both males and females, CRC is the third most frequently diagnosed type of cancer and accounts for 10% of cancer deaths in the United States. Differences in CRC test use have been documented and limited to access to health care, demographics and health behaviors, but few studies have examined the correlates of CRC screening test use by gender. This present study examined the prevalence of CRC screening test use and assessed whether disparities are explained by gender and racial/ethnic differences. To assess these associations, the study utilized a cross-sectional design and examined the distribution of the covariates for gender and racial/ethnic group differences using the chi square statistic. Logistic regression was used to estimate the prevalence odds ratio and to adjust for the confounding effects of the covariates. ^ Results indicated there are disparities in the use of CRC screening test use and there were statistically significant difference in the prevalence for both FOBT and endoscopy screening between gender, χ2, p≤0.003. Females had a lower prevalence of endoscopy colorectal cancer screening than males when adjusting for age and education (OR 0.88, 95% CI 0.82–0.95). However, no statistically significant difference was reported between racial/ethnic groups, χ 2 p≤0.179 after adjusting for age, education and gender. For both FOBT and endoscopy screening Non-Hispanic Blacks and Hispanics had a lower prevalence of screening compared with Non-Hispanic Whites. In the multivariable regression model, the gender disparities could largely be explained by age, income status, education level, and marital status. Overall, individuals between the age "70–79" years old, were married, with some college education and income greater than $20,000 were associated with a higher prevalence of colorectal cancer screening test use within gender and racial/ethnic groups. ^

The medical malpractice insurance "crises" and federal medical malpractice tort reform: Collection and analysis of bills passed by the United States House of Representatives from 1995--2005

There have been three medical malpractice insurance "crises" in the United States over a time spanning roughly the past three decades (Poisson, 2004, p. 759-760). Each crisis is characterized by a number of common features, including rapidly increasing medical malpractice insurance premiums, cancellation of existing insurance policies, and a decreased willingness of insurers to offer or renew medical malpractice insurance policies (Poisson, 2004, p. 759-760). Given the recurrent "crises," many sources argue that medical malpractice insurance coverage has become too expensive a commodity—one that many physicians simply cannot afford (U.S. Department of Health and Human Services [HHS], 2002, p. 1-2; Physician Insurers Association of America [PIAA], 2003, p. 1; Jackiw, 2004, p. 506; Glassman, 2004, p. 417; Padget, 2003, p. 216). ^ The prohibitively high cost of medical liability insurance is said to limit the geographical areas and medical specializations in which physicians are willing to practice. As a result, the high costs of medical liability insurance are ultimately said to affect whether or not people have access to health care services. ^ In an effort to control the medical liability insurance crises—and to preserve or restore peoples' access to health care—every state in the United States has passed "at least some laws designed to reduce medical malpractice premium rates" (GAO, 2003, p.5-6). More recently, however, the United States has witnessed a push to implement federal reform of the medical malpractice tort system. Accordingly, this project focuses on federal medical malpractice tort reform. This project was designed to investigate the following specific question: Do the federal medical malpractice tort reform bills which passed in the House of Representatives between 1995 and 2005 differ in respect to their principle features? To answer this question, the text of the bills, law review articles, and reports from government and private agencies were analyzed. Further, a matrix was compiled to concisely summarize the principle features of the proposed federal medical malpractice tort reform bills. Insight gleaned from this investigation and matrix compilation informs discussion about the potential ramifications of enacting federal medical malpractice tort reform legislation. ^

A meta-analysis: Obesity and colorectal cancer screening

Of cancer death, colorectal cancer death ranks second in the United States. Obesity is an important risk factor for colorectal cancer (1). Early detection of colorectal cancer when it is localized can effectively reduce mortality of colorectal cancer and increase survival time of patients if they are treated. Also, previous studies showed that obese women were more likely to delay breast cancer screening and cervical cancer screening than normal weight women (2-5). However, results from prior studies demonstrating the relationship between obesity and colorectal cancer screening are not consistent. This research was done to conduct a meta-analysis of previous cross-sectional studies selected from the Medline database and to evaluate the association between obesity and colorectal cancer screening. While the odds ratio was not statistically different from one, the results from this meta-analysis under the random effects model showed that obese people are slightly less likely to have colorectal cancer screening compared to normal weight individuals (OR,0.93;95% CI 0.75-1.15). This meta-analysis was particularly sensitive to one individual study (6) and the effect of obesity on colorectal cancer screening was statistically significant (OR, 0.87; 95% CI, 0.81-0.92) after removing Heo's study. Further systematic studies focused on whether the effect of obesity on colorectal cancer screening is limited to women only are suggested. ^

ECONOMIC ANALYSIS OF THE DEMAND FOR PRESCRIPTION MEDICINE IN THE UNITED STATES

The purpose of this study was to understand the role of principle economic, sociodemographic and health status factors in determining the likelihood and volume of prescription drug use. Econometric demand regression models were developed for this purpose. Ten explanatory variables were examined: family income, coinsurance rate, age, sex, race, household head education level, size of family, health status, number of medical visits, and type of provider seen during medical visits. The economic factors (family income and coinsurance) were given special emphasis in this study.^ The National Medical Care Utilization and Expenditure Survey (NMCUES) was the data source. The sample represented the civilian, noninstitutionalized residents of the United States in 1980. The sample method used in the survey was a stratified four-stage, area probability design. The sample was comprised of 6,600 households (17,123 individuals). The weighted sample provided the population estimates used in the analysis. Five repeated interviews were conducted with each household. The household survey provided detailed information on the United States health status, pattern of health care utilization, charges for services received, and methods of payments for 1980.^ The study provided evidence that economic factors influenced the use of prescription drugs, but the use was not highly responsive to family income and coinsurance for the levels examined. The elasticities for family income ranged from -.0002 to -.013 and coinsurance ranged from -.174 to -.108. Income has a greater influence on the likelihood of prescription drug use, and coinsurance rates had an impact on the amount spent on prescription drugs. The coinsurance effect was not examined for the likelihood of drug use due to limitations in the measurement of coinsurance. Health status appeared to overwhelm any effects which may be attributed to family income or coinsurance. The likelihood of prescription drug use was highly dependent on visits to medical providers. The volume of prescription drug use was highly dependent on the health status, age, and whether or not the individual saw a general practitioner. ^

Evaluating the U.S. Global Health Policy Initiative

In understanding that the efforts made in improving global health affects the health of U.S. citizens, a policy analysis of President Barak Obama's Global Health Initiative was conducted. Using materials gathered from experts in the field of health and their findings and recommendations, paired with the current policies of other G8 countries that pledged to support the efforts of improving global health, the analysis was conducted using four specifically defined criteria. The set criteria determine the appropriateness, responsiveness, effectiveness and equity of Obama's GHI in comparison to other G8 country health policies and overall global health priorities. G8 countries without a specific global health policy, or with a policy that was not in English were excluded from this study and Switzerland, headquarters of the World Health Organization, was added due to its membership in the OECD, and the fact that it has a specific foreign health policy. In evaluating the U.S. Global Health Initiative it is clear that in terms of implementing foreign policy specific to health, the United States is on the forefront alongside the United Kingdom and Switzerland. Other G8 Countries have pledged monies and in order to Millennium Development Health Goals by 2015. The U.S. Global Health Policy does not address issues necessary to meet Millennium Development Goals in Health. Instead the Global Health Initiative is focused narrowly on Fighting and rolling back the HIV/Aids Epidemic based on President Bush's PEPFAR policy. Policy recommendations for a more effective and efficient Global Health Initiative include building upon the PEPFAR policy foundation in order to strengthen health systems worldwide, allowing individuals and communities to combat unnecessary death and disease through research, education, and other preventative methods.^

Mexico: A new heavy weight in a global world

In the last three decades, obesity has been gaining recognition as a serious public health problem in Mexico. This epidemic developed insidiously in a country that was still focused on chronic under-nutrition in the population. During that same period, macro-economic reforms projected Mexico into the global economic arena. Foreign investments, trade in goods and services, and technological transfers were promoted through participation in numerous trade agreements between Mexico and other countries. The North American Trade Agreement (NAFTA), signed in 1994, promised an integrated market between the three North American countries: Canada, the United States, and Mexico. Although these trade policies were likely to have effects on the available food supply in Mexico, this association has not been elucidated. In this case study, we examine how these trade liberalization policies may have influenced the food supply in Mexico.^ Information on the trade of food commodities between the United States and Mexico and the nature of foreign investment in Mexico was compiled using public data available through American, Mexican, and other international published reports for 1986 through 2011. After the implementation of NAFTA, an increase in trade and investments was observed between Mexico and its two North American partners, but most of the trade increase occurred between the US and Mexico. Since the liberalization of trade policies between these counties, exports of fruit and vegetables into the U.S. from Mexico have increased, while exports of cereals, fats, vegetable oils, meat, dairy products and processed foods from the U.S. into Mexico have increased. During this same time period, there has been an increase in the foreign direct investment in the food industry in Mexico, as well as changes in the types and amounts of dietary energy available on a population level. Specifically, between 1990 to 2006, the dietary energy supply per person has increased 6.1% available animal protein has increased 35.8%, and available fat has increased 18.9%.^ Thus, this case study suggests that the recent changes in food-related industries through foreign direct investment and market liberalization may be likely contributors to the obesogenic food environment in Mexico. Although this initial case study provides interesting data, whether trade liberalization policies should be considered hazardous for health as a distal determinant of the obesity epidemic needs to be further examined using a more stringent study design or further follow up of the US Mexico trade data.^