Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk

O6-Alkylguanine DNA alkyltransferase (AGT) plays an important role in the repair of alkylating agent-induced DNA damage and protection from the carcinogenic effects of environmental agents. To examine the importance of the AGT codon 143 and codon 160 polymorphisms in risk for lung cancer and to assess the prevalence of these polymorphisms in different racial groups, we performed genotype analysis of lung cancer patients and matched controls. The prevalence of the AGT143Val allele in controls was 0.07 in Caucasians and 0.03 in African Americans. The AGT143Val allele was not detected in an unmatched Asian control cohort. The prevalence of the AGT160Arg variant allele was 0.01 in Caucasians, 0.02 in African Americans, and 0.03 in Asians. A marginally significant association was observed between the AGT codon 143 (isoleucine/valine) genotype and risk for lung cancer (odds ratio = 2.1; 95% confidence interval = 1.01– 4.7). The prevalence of the AGT160Arg variant allele was similar in lung cancer cases versus matched controls. These results suggest that the AGT codon 143 polymorphism may play an important role in risk for lung cancer

Time to First Cigarette after Waking Predicts Cotinine Levels

There is wide variability in cotinine levels per cigarette smoked. We hypothesized that in addition to smoking frequency, other behavioral measures of nicotine dependence, such as the time to first cigarette after waking, are associated with cotinine levels. To test this hypothesis, we measured plasma and urinary cotinine in a community-based study of 252 black and white daily cigarette smokers. Among one pack per day smokers, plasma cotinine levels varied from 16 to 1,180 ng/mL, a 74-fold difference. Two nicotine dependence phenotypes were discerned by time after waking. Subjects in the “low” dependent phenotype smoked > 30 minutes after waking and nearly all smoked ≤20 cigarettes per day. Cotinine levels increased linearly with cigarette consumption in this group. Subjects in the “high” dependent phenotype smoked ≤30 minutes after waking but had a wide range in the frequency of daily cigarettes (6-70). Compared with the low dependent phenotype, there were relatively small differences in cotinine by cigarette frequency with evidence of a plateau effect in heavy smokers (∼30). After adjusting for cigarette frequency, the levels of cotinine by time to first cigarette were as follows: ≤5 minutes, 437 [95% confidence limits (CL), 380-494]; 6 to 30 minutes, 352 (95% CL, 291-413), 31 to 60 minutes, 229 (95% CL, 140-317), and > 60 minutes, 215 (95% CL, 110-321). Similar findings were observed for urinary cotinine. These findings suggest that the time to first cigarette is a strong predictor of nicotine uptake and should be considered in the design of smoking interventions. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3415–20

Menthol Smoking in relation to Time to First Cigarette and Cotinine: Results from a Community-based Study

Smokers who have their first cigarette shortly after waking, an indicator of nicotine dependence, have substantially higher cotinine levels. There is controversy regarding the role of menthol in nicotine dependence. We hypothesized that menthol smokers have a shorter time to first cigarette (TTFC), and tested whether any statistical association actually reflects increased dependence by measuring nicotine uptake (e.g. cotinine) in the same group of smokers. A cross-sectional community-based study was conducted that included 495 black and white daily cigarette smokers. Results showed a trend between menthol smoking and a shorter TTFC (P less than 0.04 in blacks). Menthol was not an independent predictor of cotinine or an effect modifier with TTFC on cotinine levels in blacks and whites. These results show that while menthol in tobacco is associated with an indicator of nicotine dependence in blacks, menthol was not associated with biological uptake of nicotine in black and white smokers

Risk of Lung Carcinoma Among Users of Nonsteroidal Antiinflammatory Drugs

BACKGROUND; Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the development of lung tumors in experimental animals. To the authors' knowledge there are little data regarding whether regular use of NSAIDs reduces the risk of developing lung carcinoma in humans. METHOD; The association between lung carcinoma risk and regular use of NSAIDs, including aspirin, was evaluated in a hospital-based case–control study of 1038 patients and 1002 controls. RESULTS; The relative risk estimate of lung carcinoma associated with using NSAIDs 3 times a week or more for 1 or more years demonstrated an odds ratio (OR) of 0.68 (95% confidence interval [95% CI], 0.53–0.89). Results were similar when separated by lung histologic type. The association varied by smoking status. The OR was1.28 (95% CI, 0.73–2.25) in never-smokers and 0.60 (95% CI 0.45–0.80) in ever-smokers. The smoking-specific risk estimates for aspirin were similar to those for all NSAIDs. CONCLUSIONS; The results of the current study suggest a possible chemoprotective benefit with the use of NSAIDs among individuals who are former or current smokers

The Nicotine Dependence Phenotype, Time to First Cigarette, and Larynx Cancer Risk

Purpose Cigarette smoking is the major cause of laryngeal cancer. The time to first cigarette after waking in the morning is a behavior associated with several dimensions of nicotine dependence including the dose of smoke uptake. We hypothesized that a short TTFC increases the risk of laryngeal cancer. Methods The analysis was based on data from a hospital-based case–control study of laryngeal cancer. The current analysis included only subjects who were ever cigarette smokers, including 570 cases and 343 controls (832 whites and 81 blacks). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression adjusting for smoking history and other potential confounders. Incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute from 1975 to 2006 were analyzed for trends in laryngeal cancer. Results There was a dose–response relationship between TTFC and supraglottic cancer. Compared to subjects who smoked more than 60 min after waking, the adjusted odds ratio was 1.51 (95% CI, 0.63–3.61) for 30–60 min and 3.13 (95% CI, 1.56–6.30) for 0–30 min. No association was observed between TTFC and cancer of the glottis. In blacks, the TTFC was not associated with the risk of laryngeal cancer. Trends in SEER rates were similar for cancer of the glottis and supraglottis, indicating that the site-specific differences were not affected by unknown confounders. Conclusion A nicotine dependence behavior that is associated with cigarette smoke uptake increases the risk of cancer of the supraglottis larynx, but not glottis larynx

Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings

Considerable interest has been shown in the ability of caloric restriction (CR) to improve multiple parameters of health and to extend lifespan. CR is the reduction of caloric intake - typically by 20 - 40% of ad libitum consumption - while maintaining adequate nutrient intake. Several alternatives to CR exist. CR combined with exercise (CE) consists of both decreased caloric intake and increased caloric expenditure. Alternate-day fasting (ADF) consists of two interchanging days; one day, subjects may consume food ad libitum (sometimes equaling twice the normal intake); on the other day, food is reduced or withheld altogether. Dietary restriction (DR) - restriction of one or more components of intake (typically macronutrients) with minimal to no reduction in total caloric intake - is another alternative to CR. Many religions incorporate one or more forms of food restriction. The following religious fasting periods are featured in this review: 1) Islamic Ramadan; 2) the three principal fasting periods of Greek Orthodox Christianity (Nativity, Lent, and the Assumption); and 3) the Biblical-based Daniel Fast. This review provides a summary of the current state of knowledge related to CR and DR. A specific section is provided that illustrates related work pertaining to religious forms of food restriction. Where available, studies involving both humans and animals are presented. The review includes suggestions for future research pertaining to the topics of discussion

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Lung cancer risk and workplace exposures in black men and women

There are little data on workplace exposures and lung cancer risk in blacks. An ongoing case–control study of lung cancer that included 550 black men and women with lung cancer and 386 age-matched controls was examined by reported occupational exposures and job titles. In men, significant associations were observed with reported exposure to asbestos [odds ratio (OR), 1.8; 95%confidence intervals (CI) 1.03–3.1] and coal dust (OR, 2.8; 95% CI 1.1–7.0). Elevated but nonsignificant risks of 1.4 or more were detected for the following occupations: police/security guards, farmers/farm workers, laborers, and motor-vehicle drivers. In women, nonsignificant increased risks were found with reported exposure to paint (OR, 1.8) and gas fumes (OR, 4.9). Women employed as farmers/farm workers and building maintenance workers had elevated but nonsignificant risks

Cigarette Management System: An operating procedures guide to obtaining and managing investigational tobacco products for regulatory science research

Investigational tobacco products, specifically variable nicotine content research cigarettes (SPECTRUM), are available through the National Institute of Drug Abuse Drug Supply Program. Randomized controlled trials using research cigarettes are intended to support tobacco regulatory science research. The current paper provides an in-depth look into managing research cigarettes for two multi-site clinical trials and the design of a computer-based Cigarette Management System (CMS). The paper provides guidance intended for any investigator using similar products on the operating procedures under Good Clinical Practice standards and describes features of the CMS. The CMS and procedures described have been field tested for the past three years and have dispensed over 160,000 cigarette packs to participants. The CMS can accommodate a range of practical issues with real-world study implementation making it a robust application that is scalable to any study

Clinical trial in healthy malaria-naïve adults to evaluate the safety, tolerability, immunogenicity and efficacy of MuStDO5, a five-gene, sporozoite/hepatic stage Plasmodium falciparum DNA vaccine combined with escalating dose human GM-CSF DNA

When introduced in the 1990s, immunization with DNA plasmids was considered potentially revolutionary for vaccine development, particularly for vaccines intended to induce protective CD8 T cell responses against multiple antigens. We conducted, in 1997−1998, the first clinical trial in healthy humans of a DNA vaccine, a single plasmid encoding Plasmodium falciparum circumsporozoite protein (PfCSP), as an initial step toward developing a multi-antigen malaria vaccine targeting the liver stages of the parasite. As the next step, we conducted in 2000–2001 a clinical trial of a five-plasmid mixture called MuStDO5 encoding pre-erythrocytic antigens PfCSP, PfSSP2/TRAP, PfEXP1, PfLSA1 and PfLSA3. Thirty-two, malaria-naïve, adult volunteers were enrolled sequentially into four cohorts receiving a mixture of 500 μg of each plasmid plus escalating doses (0, 20, 100 or 500 μg) of a sixth plasmid encoding human granulocyte macrophage-colony stimulating factor (hGM-CSF). Three doses of each formulation were administered intramuscularly by needle-less jet injection at 0, 4 and 8 weeks, and each cohort had controlled human malaria infection administered by five mosquito bites 18 d later. The vaccine was safe and well-tolerated, inducing moderate antigen-specific, MHC-restricted T cell interferon-γ responses but no antibodies. Although no volunteers were protected, T cell responses were boosted post malaria challenge. This trial demonstrated the MuStDO5 DNA and hGM-CSF plasmids to be safe and modestly immunogenic for T cell responses. It also laid the foundation for priming with DNA plasmids and boosting with recombinant viruses, an approach known for nearly 15 y to enhance the immunogenicity and protective efficacy of DNA vaccines