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Biomedical subjects

Richard G Stevens

Publications and source records attributed to Richard G Stevens.

At least 19 recordsLinked to original sources
PubMed2007

Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin's lymphoma.

Circadian disruption is theorized to cause immune dysregulation, which is the only established risk factor for non-Hodgkin's lymphoma (NHL). Genes responsible for circadian rhythm are also involved in cancer-related biological pathways as potential tumor suppressors. However, no previous studies have examined associations between circadian genes and NHL risk. In this population-based case control study (n = 455 cases; 527 controls), we examined the only identified nonsynonymous polymorphism (Ala394Thr; rs2305160) in the largest circadian gene, neuronal PAS domain protein 2 (NPAS2), in order to examine its impact on NHL risk. Our results demonstrate a robust association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with reduced risk of NHL (OR = 0.66, 95% CI: 0.51-0.85, p = 0.001), especially B-cell lymphoma (OR = 0.61, 95% CI: 0.47-0.80, p <or= 0.0001). These findings provide the first molecular epidemiologic evidence supporting a role of circadian genes in lymphomagenesis, which suggests that genetic variations in circadian genes might be a novel panel of promising biomarkers for NHL and warrants further investigation.

Aged↗
PubMed2006

Epidemiology of colonic aberrant crypt foci: review and analysis of existing studies.

Since first described in a rodent model in 1987, aberrant crypt foci (ACF) in the colon have been shown to exhibit many of the molecular features of the more advanced colonic neoplasms including cancer. Therefore, they may be early lesions with potential for progression, and be valuable biomarkers for reduction of risk of colorectal cancer (CRC). For this review, we searched PubMed, and reference lists of recent publications, for studies which reported on associations of features of ACF in humans, such as number or size, with subject characteristics, such as age or family history of CRC. Over 150 papers have reported on ACF in humans. However, the vast majority of these publications are concerned with molecular and morphological features of biopsied lesions, and not their epidemiology. None of the epidemiological studies were of optimum design, primarily due to their absence of a well-defined subject sampling frame or method. Given their 'first-generation' nature, consistent findings were of increased ACF number with age and with synchronous advanced colonic neoplasia. One study reported a higher mean number of ACF in subjects with a family history of CRC than in those without. The strongest evidence on the ability of ACF to predict a diagnosis of CRC will be from prospective studies with baseline ACF assessment in a large sample of disease-free persons (many thousands) who are followed carefully for many years. In the interim, because ACF are asymptomatic, well-designed cross-sectional studies are feasible and will yield valuable information on the relation of ACF to the known risk factors for CRC. This information can then be used to improve the design of prospective studies, and of clinical intervention trials that use ACF as an intermediate endpoint.

Colonic Neoplasms↗
PubMed2006

Aberrant crypt foci in patients with a positive family history of sporadic colorectal cancer.

Early detection is crucial in the prevention of colorectal cancer (CRC) deaths. The earliest detectable neoplastic lesion in the colon is the aberrant crypt foci (ACF). A major question is whether ACF are precursors of CRC, and thus, early biomarkers for CRC risk. If so, we hypothesized that the number of ACF would be higher in patients who had a family history of CRC compared to patients without. We counted ACF in the distal 20cm of colon/rectum during 103 colonoscopic examinations using a prototype Close Focus Colonoscope (Olympus Corp.) with methylene blue chromendoscopy. Each patient was asked whether they had a family history of CRC in a first degree relative, or a personal history of CRC or adenoma. Patients answering 'no' to these questions (n=17) had a mean number of ACF of 4.4; the mean was significantly higher in the patients with a positive family history of CRC (9.0, p<0.01; n=43) or a personal history of advanced adenoma (7.5, p<0.05; n=34).

Adenocarcinoma↗
PubMed2006

Shift work, light at night, and breast cancer on Long Island, New York.

The hypothesized association between breast cancer and circadian disruption was evaluated in the Electromagnetic Fields and Breast Cancer on Long Island Study. Participants included 576 women with breast cancer diagnosed from August 1996 to June 1997 and 585 population-based controls (87% and 83% participation rates, respectively) aged < 75 years and living in the same Long Island, New York, home for > or = 15 years. An in-person interview ascertained light-at-night exposure histories through shift work (previous 15 years) and at home (previous 5 years). Odds ratios and 95% confidence intervals were estimated by unconditional multivariate logistic regression. Breast cancer was not associated with overall shift work (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.79, 1.38) or evening shift work (OR = 1.08, 95% CI: 0.81, 1.44). However, overnight shift workers were at lower risk than women never working shifts (OR = 0.55, 95% CI: 0.32, 0.94). Women who frequently turned on lights at home during sleep hours (> or = twice/week and > or = twice/night) had increased risks (OR = 1.65, 95% CI: 1.02, 2.69). The latter results suggest positive associations with residential light-at-night exposure, or they could reflect response biases. Furthermore, overall and evening shift work were not significant factors, and analyses of overnight shift workers yielded reduced risk estimates. The study thus provides mixed evidence for the light-at-night hypothesis.

Breast Neoplasms↗
PubMed2006

Artificial lighting in the industrialized world: circadian disruption and breast cancer.

Breast cancer risk is high in industrialized societies, and increases as developing countries become more Westernized. The reasons are poorly understood. One possibility is circadian disruption from aspects of modern life, in particular the increasing use of electric power to light the night, and provide a sun-free environment during the day inside buildings. Circadian disruption could lead to alterations in melatonin production and in changing the molecular time of the circadian clock in the suprachiasmatic nuclei (SCN). There is evidence in humans that the endogenous melatonin rhythm is stronger for persons in a bright-day environment than in a dim-day environment; and the light intensity necessary to suppress melatonin at night continues to decline as new experiments are done. Melatonin suppression can increase breast tumorigenesis in experimental animals, and altering the endogenous clock mechanism may have downstream effects on cell cycle regulatory genes pertinent to breast tissue development and susceptibility. Therefore, maintenance of a solar day-aligned circadian rhythm in endogenous melatonin and in clock gene expression by exposure to a bright day and a dark night, may be a worthy goal. However, exogenous administration of melatonin in an attempt to achieve this goal may have an untoward effect given that pharmacologic dosing with melatonin has been shown to phase shift humans depending on the time of day it's given. Exogenous melatonin may therefore contribute to circadian disruption rather than alleviate it.

Alcohol Drinking↗
PubMed2006

Does incidence of breast cancer and prostate cancer decrease with increasing degree of visual impairment.

OBJECTIVE: The issue of light at night and cancer continuously attracts discussion. The major hypotheses are that melatonin may decrease risk of hormone-related cancers, particularly breast cancer, or even act as a potent antioxidant and thus have a protective effect against cancer development in general. METHODS: We tested the hypothesis that blind persons are at lower risk of cancer in a follow-up study linking a cohort of 17,557 persons with visual impairment identified from the Finnish Register of Visual Impairment with cancer incidence data of the Finnish Cancer Registry for years 1983-2003. RESULTS: Breast cancer risk in females decreased by degree of visual impairment, and a similar but less consistent trend was observed for prostate cancer in males. The incidence for the remaining cancers among nearly to totally blind persons was significantly higher than in average Finnish population. CONCLUSIONS: Our findings add to the suggestive epidemiological evidence for a decreased risk of hormone-related cancers in people with visual impairment and, consequently, a relationship between visible light at night and breast cancer risk. The result is strongly against the hypothesis of a systemic protective effect related lack of visible light.

Blindness↗
PubMed2006

Does "clock" matter in prostate cancer?

The ancient adaptation of a 24-hour circadian clock has profound effect on our daily biochemical, physiologic, and behavioral processes, including the monitoring of sex hormone levels. Although the disruption of the circadian cycle has been implicated in the etiology of hormone-related female breast cancer, few studies have been undertaken to determine if a link exists in the development of the most common cancer type among men whose etiology remains largely unknown: hormone-related prostate cancer. Here, we hypothesize that both altered-lighted environments and genetic variations in genes responsible for maintaining circadian rhythms may result in deregulation of clock-associated biological processes, such as androgen expression, and consequently influence an individual's risk of prostate cancer. There is also a potential for the interaction of genetic variants and exposures, such as evening shift work. Confirmation of this hypothesis will add to our understanding of the role of the circadian clock in prostate tumorigenesis and further facilitate the development of novel risk and prognostic biomarkers for prostate cancer.

Androgens↗
PubMed2005

Sleep duration and breast cancer: a prospective cohort study.

Breast cancer incidence has increased during recent decades for reasons that are only partly understood. Prevalence of sleeping difficulties and sleepiness has increased, whereas sleeping duration per night has decreased. We hypothesized that there is an inverse association between sleep duration and breast cancer risk, possibly due to greater overall melatonin production in longer sleepers. This population-based study includes information from women born in Finland before 1958. Sleep duration, other sleep variables, and breast cancer risk factors were assessed by self-administered questionnaires given in 1975 and in 1981. Breast cancer incidence data for 1976 to 1996 was obtained from the Finnish Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox proportional hazards models adjusting for potential confounders. Altogether, 242 cases of breast cancer occurred over the study period among the 12,222 women with sleep duration data in 1975. For these women, the HRs for breast cancer in the short (< or =6 hours), average (7-8 hours), and long sleep (> or =9 hours) duration groups were 0.85 (CI, 0.54-1.34), 1.0 (referent), and 0.69 (CI, 0.45-1.06), respectively. Analysis restricted to the 7,396 women (146 cases) whose sleep duration in 1975 and 1981 were in the same duration group (stable sleepers) yielded HRs of 1.10 (CI, 0.59-2.05), 1.0, and 0.28 (CI, 0.09-0.88), with a decreasing trend (P = 0.03). This study provides some support for a decreased risk of breast cancer in long sleepers.

Adult↗
PubMed2005

Exploring lag and duration effect of sunshine in triggering suicide.

BACKGROUND: Sunshine is considered to have a beneficial impact on mood. Interestingly, it has been consistently found that the incidence of suicide reaches a peak during early summer. METHODS: In order to explore the pattern of sunshine and suicide risk in a time frame of up to nine days and investigate possible lag and duration parameters of sunshine in the triggering of suicide, Greek daily suicide and solar radiance data were analyzed for a 10-year period using logistic regression models. RESULTS: The solar radiance during the day before the suicide event was significantly associated with an increased suicide risk (OR=1.020 per MW/m2). The average solar radiance during the four previous days was also significantly associated with an increased suicide risk (OR=1.031 per MW/m2). Differences among genders include the longer sunshine exposure needed in males to trigger suicide, compared to females and a lag period of three to four days that was found to lapse in females till the suicide. The increase in suicide risk in June compared to December, attributable to the daily sunshine effect, varies from 52% to 88%, thus explaining the already known suicide monthly seasonality. LIMITATIONS: No individual data on solar radiance exposure, mental disorders, alcohol consumption or suicide method were available. CONCLUSION: The effect of sunshine in the triggering of suicide may be mediated through a mechanism with a specific lag and duration effect, during the nine days preceding suicide. We hypothesize that sunshine acts as a natural antidepressant which first improves motivation, then only later improves mood, thereby creating a potential short-term increased risk of suicide initially upon its application.

Affect↗
PubMed2005

Alcohol consumption and serum hormone levels during pregnancy.

Factors that change sex hormone levels during pregnancy may have long-term health consequences for the offspring, including changes in breast cancer risk. A cross-sectional analysis of alcohol consumption and hormone levels in 339 pregnant women sampled from the Child Health and Development Study cohort was undertaken. Alcohol intake was queried from 1959 to 1966, long before any hazards of drinking during pregnancy were publicized. Third trimester serum hormone levels including estradiol and testosterone were analyzed. Among 339 pregnant women, 196 reported some alcohol consumption during pregnancy. The drinkers were divided into three groups with intake levels of 0.2-0.5, 0.6-2.0, and 2.1-12.5 ounces of ethanol per week. The second group corresponds to a median intake of approximately 2 drinks per week, and the last group corresponds to a median intake of approximately 1 drink per day, which is considered "light" to "moderate" drinking. Maternal estradiol levels were not associated with alcohol intake during pregnancy. However, serum testosterone was significantly lower, by 12.2%, in the latter two groups of drinking pregnant women, [confidence interval (CI)=-3.0 to 25.2] and 25.6% (CI=9.2-39.5), respectively. The alcohol intakes reported are far below those shown to cause fetal alcohol syndrome, or any of the fetal alcohol effects so far studied. Light alcohol intake during pregnancy is associated with lower maternal testosterone. The health implications are uncertain, but may include an increased breast density in the daughters of drinking mothers.

Alcohol Drinking↗
PubMed2005

Circadian disruption and breast cancer: from melatonin to clock genes.

The global impact of breast cancer is large and growing. It seems clear that something about modern life is the culprit, yet there is thus far a lack of satisfactory explanations for most of the increases in risk as societies industrialize. Support has developed for a possible role of "circadian disruption," particularly from an altered-lighted environment (such as light at night). Lighting during the night of sufficient intensity can disrupt circadian rhythms, including reduction of circulating melatonin levels and resetting of the circadian pacemaker of the suprachiasmatic nuclei. Reduced melatonin may increase breast cancer risk through several mechanisms, including increased estrogen production and altered estrogen receptor function. The genes that drive the circadian rhythm are emerging as central players in gene regulation throughout the organism, particularly for cell-cycle regulatory genes and the genes of apoptosis. Aspects of modern life that can disrupt circadian rhythms during the key developmental periods (eg, in utero and during adolescence) may be particularly harmful. Epidemiologic studies should consider gene and environment interactions such as circadian gene variants and shift work requirements on the job.

Breast Neoplasms↗
PubMed2005

Period3 structural variation: a circadian biomarker associated with breast cancer in young women.

Circadian disruption has been indicated as a risk factor for breast cancer in recent epidemiologic studies. A novel finding in circadian biology is that genes responsible for circadian rhythm also regulate many other biological pathways, including cell proliferation, cell cycle regulation, and apoptosis. Therefore, mutations in circadian genes could conceivably result in deregulation of these processes and contribute to tumor development, and be markers for susceptibility to human cancer. In this study, we investigated the association between an exonic length variation in a circadian gene, Period3 (Per3), and breast cancer risk using blood samples collected from a recently completed breast cancer case-control study in Connecticut. There were 389 Caucasian cases and 432 Caucasian controls included in our analysis. We found that the variant Per3 genotype (heterozygous + homozygous 5-repeat alleles) was associated with an increased risk of breast cancer among premenopausal women (odds ratio, 1.7; 95% confidence interval, 1.0-3.0). Our finding suggests that the circadian genes might be a novel panel of potential biomarkers for breast cancer and worth further investigation.

Adult↗
PubMed2004

Dietary iron promotes azoxymethane-induced colon tumors in mice.

There is accumulating evidence that high levels of dietary iron may play a role in colon carcinogenesis. We used a mouse model to investigate the impact of elevated dietary iron on incidence of aberrant crypt foci (ACF; a preneoplastic lesion) on tumor formation and on induction of oxidative stress. A/J mice were injected intraperitoneally, once a week for 6 weeks, with the colonotropic carcinogen, azoxymethane (AOM) or saline (vehicle controls). Following AOM or saline treatments, mice were placed on diets of high (3,000 ppm) and low (30 ppm) iron. Mice in each treatment group were sacrificed at 6 and 10 weeks following the final injection with AOM or saline. Colons were removed for subsequent histopathological analysis, which revealed average increases of 4.6 +- 1.3 vs. 10.4 +- 2.5 total tumors at 6 weeks and 30.75 +- 2.7 vs. 41.5 +- 4.4 total tumors at 10 weeks per AOM-treated mouse on low- and high-iron diets, respectively. There were no significant differences in incidence of ACF attributable to iron, although there was a trend toward greater crypt multiplicity per focus in mice on high-iron diets. Notably, no tumors were observed in mice receiving vehicle control injections in place of carcinogen, regardless of the level of dietary iron. These data suggest that iron exerts its effect at the stage of tumor promotion, but is not sufficient to initiate tumor formation. To learn more about mechanisms by which iron promotes tumor growth, colons were assayed for several biomarkers of oxidative stress [BOS; total F2-isoprostanes (F2-IsoPs), 15-F2t-isoprostanes (8-IsoPGF2s), Isofurans (IsoFs), and 8-hydroxyguanosines (8-OH[d]Gs)], as well as iron absorption, programmed cell death, and cellular proliferation. Elevated PCNA and TUNEL staining of the colon epithelium revealed hyperproliferative and apoptotic responses to iron, while no significant differences between iron groups were observed in each of the BOS that were assayed. Our results suggest that, following carcinogen exposure, elevated dietary iron promotes the growth of tumors with altered cellular homeostasis through a mechanism that is independent of oxidative stress.

Animals↗
PubMed2003

HFE mutation and dietary iron content interact to increase ischemia/reperfusion injury of the heart in mice.

Hereditary hemochromatosis is an inherited pathological condition characterized by iron overload in several vital organs including heart. To increase our understanding of the underlying pathogenic mechanisms of hereditary hemochromatosis, we used a HFE gene knockout mouse model that replicates hereditary hemochromatosis. A group of mice with no copies of HFE gene and corresponding wild-type mice were maintained either on low-iron (30 ppm) or high-iron (300 ppm) diet since birth. The results of our study revealed that HFE gene knockout mouse hearts were susceptible to ischemia-reperfusion injury as evidenced by increased postischemic ventricular dysfunction, increased myocardial infarct size and cardiomyocyte apoptosis compared with wild-type control hearts. The degree of injury increased in the hearts of the mice fed high-iron diet. The hearts of the HFE knockout mice showed increased iron deposition, increased content of reactive oxygen species (ROS) as evidenced by the increased formation of malondialdehyde, and reduced antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase. The results suggest that increased amount of ROS and reduced antioxidant reserve secondary to iron overloading may be instrumental for the susceptibility of the HFE gene knockout mice to cardiac injury.

Administration, Oral↗
PubMed2003

Oxidative damage in colon and mammary tissue of the HFE-knockout mouse.

The HFE mutation is common and, when homozygous, can lead to a morbid accumulation of body iron and the disease hereditary hemochromatosis. Heterozygotes compose 10-15% of the European-American population, and have evidence of elevated body iron compared to homozygous normal people. Dietary iron content was hypothesized to interact with the HFE genotype to influence oxidative damage in mammary and colon tissue. Two groups of HFE-knockout mice were fed a standard iron diet (300 ppm) or a low iron diet (30 ppm). There was a significantly elevated concentration of malondialdehyde (by HPLC) in mammary (305 pmol/g vs. 166, p =.04) and colon (349 pmol/g vs. 226, p =.02) tissue among those mice on the standard iron diet compared to those on the low iron diet. These results suggest that dietary modification may affect the course of iron overload from HFE mutations.

Animals↗