Nobel laureates' letter to President Bush.
Explore the source record for details and available documents.
Embryo Disposition↗
Biomedical subjects
R Laughlin
Publications and source records attributed to R Laughlin.
Surgical stress shifts the intestinal Escherichia coli population to that of a more adherent phenotype: role in barrier regulation.
BACKGROUND: We have shown that the combination of surgical stress and starvation in mice is associated with a defect in epithelial permeability and increased numbers of mucosa-associated Escherichia coli in the cecum. The aim of this study was to determine the specific role of mucosa-associated E coli on epithelial barrier dysfunction in this model. METHODS: Cecal E coli were harvested from mice 48 hours after a sham operation (control mice) or after a 30% surgical hepatectomy with only water provided ad libitum (short-term starvation) after the surgical procedure. Strains were tested for their ability to adhere to and alter the transepithelial electrical resistance (TEER) of cultured young adult mouse colon epithelial cells. TEER changes were further characterized by mannitol fluxes to confirm a defect in paracellular permeability. RESULTS: Strains of cecal E coli harvested from hepatectomy-starved mice adhered to and altered the permeability of young adult mouse colon cells, whereas E coli from the cecum of control mice were less adherent and had no effect on epithelial permeability. The effect of the strains harvested from mice after hepatectomy on the TEER of young adult mouse colon cells was inhibited by mannose and reversed by ciprofloxacin. CONCLUSION: The combination of surgical stress and short-term starvation is associated with a greater abundance of adherent and barrier-altering strains of E coli in the mouse cecum.
Animals↗
Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer.
Oxidative stress, resulting from the imbalance between prooxidant and antioxidant states, damages DNA, proteins, cell membranes, and mitochondria and seems to play a role in human breast carcinogenesis. Dietary sources of antioxidants (chemical) and endogenous antioxidants (enzymatic), including the polymorphic manganese superoxide dismutase (MnSOD), can act to reduce the load of oxidative stress. We hypothesized that the valine-to-alanine substitution that seems to alter transport of the enzyme into the mitochondrion, changing its efficacy in fighting oxidative stress, was associated with breast cancer risk and that a diet rich in sources of antioxidants could ameliorate the effects on risk. Data were collected in a case-control study of diet and breast cancer in western New York from 1986 to 1991. Caucasian women with incident, primary, histologically confirmed breast cancer were frequency-matched on age and county of residence to community controls. Blood specimens were collected and processed from a subset of participants in the study (266 cases and 295 controls). Using a RFLP that distinguishes a valine (V) to alanine (A) change in the -9 position in the signal sequence of the protein for MnSOD, we characterized MnSOD genotypes in relation to breast cancer risk. We also evaluated the effect of the polymorphism on risk among low and high consumers of fruits and vegetables. Premenopausal women who were homozygous for the A allele had a 4-fold increase in breast cancer risk in comparison to those with 1 or 2 V alleles (odds ratio, 4.3; 95% confidence interval, 1.7-10.8). Risk was most pronounced among women below the median consumption of fruits and vegetables and of dietary ascorbic acid and alpha-tocopherol, with little increased risk for those with diets rich in these foods. Relationships were weaker among postmenopausal women, although the MnSOD AA genotype was associated with an almost 2-fold increase in risk (odds ratio, 1.8; confidence interval, 0.9-3.6). No appreciable modification of risk by diet was detected for these older women. These data support the hypothesis that MnSOD and oxidative stress play a significant role in breast cancer risk, particularly in premenopausal women. The finding that risk was greatest among women who consumed lower amounts of dietary antioxidants and was minimal among high consumers indicates that a diet rich in sources of antioxidants may minimize the deleterious effects of the MnSOD polymorphism, thereby supporting public health recommendations for the consumption of diets rich in fruits and vegetables as a preventive measure against cancer.
Aged↗
Alcohol dehydrogenase 3 genotype modification of the association of alcohol consumption with breast cancer risk.
OBJECTIVES: Because alcohol dehydrogenase 3 (ADH3) is rate-limiting in alcohol oxidation and is polymorphic, we examined ADH3 genotype in relation to alcohol intake and breast cancer risk. METHODS: We conducted a case-control study among Caucasian women aged 40-85 with incident, pathologically confirmed breast cancer and controls, frequency-matched on age and county. Queries included alcohol intake in the past 20 years. Genomic DNA was genotyped for the exon VIII ADH polymorphism by PCR followed by restriction enzyme digestion. Computation of odds ratios (OR) and 95% confidence intervals (CI) was by unconditional logistic regression. RESULTS: We found increased risk among pre- (OR 2.3, 95%, CI 1.2-4.3) but not postmenopausal women (OR 1.1, 95% CI 0.7-1.7) associated with ADH3(1-1) compared to ADH3(1-2) and ADH3(2-2) genotypes. Risk was increased for premenopausal women with the ADH3(1-1) genotype and alcohol intake above the median (OR 3.6, 95% CI 1.5-8.8) compared to lighter drinkers with the ADH3(2-2) or ADH3(1-2) genotypes. ORs were close to null for premenopausal women in other drinking and genotype groups and for postmenopausal women categorized by genotype and alcohol consumption. CONCLUSION: Among premenopausal women there may be a group more genetically susceptible to an alcohol consumption effect on breast cancer risk.
Adult↗
Increased type 1 fimbrial expression among commensal Escherichia coli isolates in the murine cecum following catabolic stress.
Although indigenous bacteria intimately colonize the intestinal mucosa, under normal conditions the intestinal epithelial cell is free of adherent bacteria. Nonetheless, commensal bacteria such as Escherichia coli adhere to and translocate across the intestinal epithelium in association with a number of pathologic states including hemorrhagic shock, immunosuppression, traumatic tissue injury, and lack of enteral feedings. The adhesins involved in the adherence of indigenous E. coli to the intestinal epithelium in vivo following catabolic stress are unknown. We have developed a mouse model to study the bacterial adhesins which mediate the increased intestinal adherence of E. coli after partial hepatectomy and short-term starvation. Our studies demonstrated that hepatectomy and starvation in the mouse were associated with a 7,500-fold increase in the numbers of E. coli bacteria adhering to the cecum. In addition, erythrocyte agglutination studies, as well as immunostaining of fimbrial preparations and electron micrographs of the bacteria, revealed that surface type 1 fimbriae were more abundant in the commensal E. coli harvested from the ceca of the stressed mice. These E. coli isolates adhered to a mouse colon cell line and injected cecal loops in a mannose-inhibitable manner, which suggests a role for type 1 fimbriae in the adherence of the E. coli isolates to the cecum in vivo following host catabolic stress.
Adhesins, Escherichia coli↗
Genetic polymorphisms in catechol-O-methyltransferase, menopausal status, and breast cancer risk.
Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of estrogen catechols. In a case-control study, we evaluated the association of the low-activity allele (COMT(Met)) with breast cancer risk. Compared to women with COMT(Val/Val), COMT(Met/Met) was associated with an increased risk among premenopausal women [odds ratio (OR), 2.1; confidence interval (CI), 1.4-4.3] but was inversely associated with postmenopausal risk (OR, 0.4; CI, 0.2-0.7). The association of risk with at least one low-activity COMT(Met) allele was strongest among the heaviest premenopausal women (OR, 5.7; CI, 1.1-30.1) and among the leanest postmenopausal women (OR, 0.3; CI, 0.1-0.7), suggesting that COMT, mediated by body mass index, may be playing differential roles in human breast carcinogenesis, dependent upon menopausal status.
Body Mass Index↗
Breast cancer risk, meat consumption and N-acetyltransferase (NAT2) genetic polymorphisms.
Although inconsistencies exist, some studies have shown that meat consumption is associated with breast cancer risk. Several heterocyclic amines (HAs), formed in the cooking of meats, are mammary carcinogens in laboratory models. HAs are activated by polymorphic N-acetyltransferase (NAT2) and rapid NAT2 activity may increase risk associated with HAs. We investigated whether ingestion of meat, chicken and fish, as well as particular concentrated sources of HAs, was associated with breast cancer risk, and if NAT2 genotype modified risk. Caucasian women with incident breast cancer (n = 740) and community controls (n = 810) were interviewed and administered a food frequency questionnaire. A subset of these women (n = 793) provided a blood sample. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to determine NAT2 genotype. Consumption of red meats, as well as an index of concentrated sources of HAs, was not associated with increased breast cancer risk, nor did risk vary by NAT2 genotype. In post-menopausal women, higher fish consumption was inversely associated with risk (odds ratio = 0.7; 95% confidence interval, 0.4-1.0); among pre-menopausal women, there was the suggestion of inverse associations between risk and pork and chicken intake. Our results suggest that consumption of meats and other concentrated sources of HAs is not associated with increased breast cancer risk. However, due to the strong biologic plausibility for a role of some HAs in mammary carcinogenesis, and the likely measurement error in evaluation of sources of HAs in this study, further studies of these possible relationships are warranted.
Amines↗
Lactation history and breast cancer risk.
Lifetime lactation in relation to breast cancer risk was examined in a case-control study in two counties in western New York. Cases were women age 40 years and over with incident, primary, histologically confirmed breast cancer. Controls were age- and county-frequency matched, selected from New York State driver's license records (for those less than age 65 years) and from Health Care Finance Administration Records (for those age 65 or more). Included were women with at least one livebirth (253 premenopausal and 367 postmenopausal cases and 266 premenopausal and 427 postmenopausal controls). Breast cancer risk was very weakly associated with long duration of lactation among premenopausal women; the odds ratio for at least 20 months lifetime lactation was 0.50 (95% confidence interval 0.21-1.12). Among postmenopausal women, the protective effect of lactation was restricted to women with first lactation before age 25 years (odds ratio = 0.67, 95% confidence interval 0.46-0.95). However, age at first birth was highly correlated with age at first lactation. Neither insufficient milk as a reason for not breastfeeding nor having received medication to stop milk flow was associated with increased risk. These findings are in accordance with accumulating evidence that lactation may have a weak protective effect on breast cancer risk.
Aged↗
Exercise, occupational activity, and risk of endometrial cancer.
We conducted a case-control study in western New York state among 232 women with newly-diagnosed endometrial cancer and 631 controls selected from the community. Physical activity was measured by participation in vigorous exercise and walking at four time periods: at age 16, and at 20, 10, and 2 years before the interview and by occupational activity based on a detailed lifetime history. Women who did a moderate amount of vigorous exercise at age 16 and at 20 years before the interview were at reduced risk as compared with those who reported no activity, with odds ratios (OR) (95% confidence intervals) of 0.51 (0.31-0.83) and 0.50 (0.29-0.89), respectively. However, there was no evidence of declining risk with greater amount of activity. At later times, 10 years and 2 years before the interview, being in the highest group with regard to vigorous activity was associated with a slightly but nor significant lower risk as compared with women who reported no activity; the adjusted OR were 0.72 (0.43-1.19) and 0.67 (0.42-1.09), respectively. Being in the highest category of miles walked at age 16 (i.e., > or = 15 miles per week) was associated with a slightly reduced risk as compared with not walking at all (OR 0.64 (0.26-1.16)), whereas the number of miles walked at other times was not related to reduced risk. Occupational physical activity was not related to the risk of endometrial cancer. Overall, these results indicate that physical activity at levels prevalent in this population has at most a modest relationship to reduced risk of endometrial cancer.
Adolescent↗
Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk.
OBJECTIVE: To determine if N-acetyltransferase 2 (NAT2) polymorphisms result in decreased capacity to detoxify carcinogenic aromatic amines in cigarette smoke, thus making some women who smoke more susceptible to breast cancer. DESIGN: Case-control study with genetic analyses. DNA analyses were performed for 3 polymorphisms accounting for 90% to 95% of the slow acetylation phenotype among whites. SETTING AND PARTICIPANTS: White women with incident primary breast cancer (n=304) and community controls (n=327). RESULTS: Neither smoking nor NAT2 status was independently associated with breast cancer risk. There were no clear patterns of increased risk associated with smoking by NAT2 status among premenopausal women. In postmenopausal women, NAT2 strongly modified the association of smoking with risk. For slow acetylators, current smoking and smoking in the distant past increased breast cancer risk in a dose-dependent manner (odds ratios [95% confidence intervals] for the highest quartile of cigarettes smoked 2 and 20 years previously, 4.4 [1.3-14.8] and 3.9 [1.4-10.8], respectively). Among rapid acetylators, smoking was not associated with increased breast cancer risk. CONCLUSIONS: Our results suggest that smoking may be an important risk factor for breast cancer among postmenopausal women who are slow acetylators, demonstrate heterogeneity in response to carcinogenic exposures, and may explain previous inconsistent findings for cigarette smoking as a breast cancer risk factor.
Adult↗
Merit, quality, and the SBIR.
Explore the source record for details and available documents.
Commerce↗
Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients.
BACKGROUND: Given the international variations in breast cancer incidence rates and the changes in breast cancer incidence among migrant populations, it has been hypothesized that diet is a factor influencing risk of this disease. Many studies indicate that a diet high in vegetables and fruits may protect against breast cancer. PURPOSE: We conducted a case-control study of diet, including the intake of non-food supplements, and premenopausal breast cancer risk. We evaluated in detail usual intake of vegetables and fruits (each measured as the total reported grams consumed for all queried vegetables and fruit), vitamins C and E, folic acid, individual carotenoids, and dietary fiber with its components. METHODS: Case patients (n=297) were identified through pathology records from hospitals in Erie and Niagara counties in western New York. They consisted of premenopausal women 40 years of age or oder who were diagnosed with breast cancer from November 1986 through April 1991. Control subjects (n=311), frequency-matched to case patients on the basis of age and county of residence, were randomly selected from New York State Department of Motor Vehicles records. In-person interviews included detailed reports of usual diet in the period 2 years before the interview. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There was a reduction in risk associated with high intake of several nutrients. With the lowest quartile of intake as the referent, adjusted ORs for the highest quartile of intake for specific nutrients were as follows: vitamin C (OR=0.53; 95% CI=0.33-0.86), alpha-tocopheral (OR=0.55; 95% CI=0.34-0.88), folic acid (OR=0.50; 95% CI=0.31-0.82), alpha-carotene (OR=0.67; 95% CI=0.42-1.08) and beta-carotene (OR=0.46; 95% CI=0.28-0.74), lutein + zeaxanthin (OR=0.47; 95% CI=0.28.0-77), and dietary fiber from vegetables and fruits (OR=0.48; 95% CI=0.30-0.78). No association with risk was found for beta-cryptoxanthin, lycopene, or grain fiber. Fruits were weakly associated with a reduction in risk (fourth quartile OR=0.67; 95% CI=0.42-1.09). No association was found between breast cancer risk and intake of vitamins C and E and folic acid taken as supplements. A strong inverse association between total vegetable intake and risk was observed (fourth quartile OR=0.46; 95% CI=0.28-0.74). This inverse association was found to be independent of vitamin C,alpha-tocopherol, folic acid, dietary fiber, and alpha-carotene. Adjusting for beta-carotene or lutein + zeaxanthin somewhat attenuated the inverse association with vegetable intake. CONCLUSIONS: In this population, intake of vegetables appears to decrease premenopausal breast cancer risk. This effect may be related, in part, to beta-carotene and lutein + zeaxanthin in vegetables. It appears, however, that, of the nutrients and food components examined, no single dietary factor explains the effect. Evaluated components found together in vegetables may have a synergistic effect on breast cancer risk; alternatively, other unmeasured factors in these foods may also influence risk.
Adult↗
A cytochrome P4502E1 genetic polymorphism and tobacco smoking in breast cancer.
Known breast-cancer risk factors account for only part of the variability in breast-cancer incidence. Tobacco smoke is not commonly considered a breast carcinogen, but many of its constituents, such as N-nitrosamines, are carcinogenic in laboratory animal studies. Herein, we assessed a cytochrome P4502E1 (CYP2E1) genetic polymorphism (a Dral restriction enzyme site in intron 6) as a risk factor for breast cancer in both premenopausal and postmenopausal women. Because N-nitrosamines are metabolically activated by CYP2E1, the risk among women smokers was investigated. Caucasian women were enrolled in a case-control study of breast cancer between 1986 and 1991. A subset of the women (219 premenopausal and 387 postmenopausal women) consented to phlebotomy. The allelic frequencies for the premenopausal women (D allele = 0.91 and C allele = 0.09) and postmenopausal women (D allele = 0.93 and C allele = 0.07) were similar to those previously reported. There was no statistically significant association between the CYP2E1 polymorphism and breast-cancer risk for premenopausal or postmenopausal women (adjusted odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.48, 2.24, and OR = 1.01, 95% CI = 0.55, 1.84, respectively). When the women were categorized as nonsmokers versus smokers (those who smoked more than one cigarette per week for more than 1 yr), premenopausal women with one or two C alleles who had a history of smoking were found to be at increased risk (unadjusted OR = 7.00, 95% CI = 0.75, 14.53, and adjusted OR = 11.09, 95% CI = 1.51, 81.41), although the number of study subjects with those genotypes was small. The small number of study subjects with a C allele precluded meaningful classification by level of smoking, but categorizing the smokers into two groups (above and below the median) also suggested an increased risk. Premenopausal women with the DD genotype and postmenopausal women with any genotype were not at increased risk. Breast-cancer risk was not related to the CYP2E1 genotype in either premenopausal nonsmokers or smokers (adjusted OR = 0.66, 95% CI = 0.20, 2.17, and OR = 2.13, 95% CI = 0.60, 7.59, respectively) or postmenopausal nonsmokers or smokers (OR = 0.90, 95% CI = 0.34, 2.35, and OR = 1.02, 95% CI = 0.46, 2.23, respectively), although the difference in the ORs for premenopausal nonsmokers and smokers suggests an increased risk for smokers. While there are limitations to this study, particularly related to the small number of subjects with the DC and CC genotypes, the study suggests that some women may be susceptible to tobacco smoke because of a CYP2E1 polymorphism. However, these results are preliminary and must be replicated.
Adult↗
The association of polymorphic N-acetyltransferase (NAT2) with breast cancer risk.
Explore the source record for details and available documents.
Arylamine N-Acetyltransferase↗
Cytochrome P4501A1 and glutathione S-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk.
Polycyclic aromatic hydrocarbons, possible human breast carcinogens, are metabolized by cytochrome P4501A1 (CYP1A1) and glutathione S-transferase (GSTM1). A CYP1A1 polymorphism (isoleucine to valine substitution in exon 7) or the null allele for GSTM1 may affect the mutagenic potential of polycyclic aromatic hydrocarbons. We examined polymorphisms in GSTM1 and CYP1A1 in relation to breast cancer risk. Included were 216 postmenopausal Caucasian women with incident breast cancer and 282 community controls. DNA analyses suggested no increased breast cancer risk with the null GSTM1 genotype [odds ratio (OR) = 1.10; CI, 0.73-1.64], although there was some indication that the null genotype was associated with risk among the youngest postmenopausal women (OR = 2.44; CI, 0.89-6.64). Slightly elevated risk was associated with the CYP1A1 polymorphism (OR = 1.61; CI, 0.94-2.75) and was highest for those who smoked up to 29 pack-years (OR = 5.22; CI, 1.16-23.56). Statistical power to detect an effect may be limited by small numbers, and larger sample sizes would be required to corroborate these suggestive findings.
Age Factors↗
Interaction of family history of breast cancer and dietary antioxidants with breast cancer risk (New York, United States).
We sought to determine if specific dietary antioxidants may be particularly effective in reducing breast cancer risk for women reporting family history (FH) of breast cancer in a first-degree relative. Interviews regarding usual diet, health, and family histories were conducted with 262 premenopausal and 371 postmenopausal women with incident, primary breast cancer from western New York (United States). These women were frequency-matched by age and county of residence with community controls. Among premenopausal women, there was a significant interaction between FH and alpha-tocopherol; alpha-tocopherol was associated with significantly decreased risk among FH+ women (adjusted fourth-quartile odds ratio [OR] = 0.01, 95 percent confidence interval [CI] = 0.0-0.3). This association was much weaker for FH- women [OR = 0.7, CI = 0.4-1.2]. For FH- women, a significant inverse association was observed between beta-carotene and premenopausal breast-cancer risk (OR = 0.4, CI = 0.3-0.5), but not for FH+ women (OR = 0.5, CI = 0.1-4.0). Similar relationships, although not as strong, were noted among postmenopausal women. Although limited by small numbers, these results suggest that biologic mechanisms of tumorigenesis may differ in FH+ and FH- women, and that alpha-tocopherol may be a potential chemopreventive agent for women with a family history of breast cancer, particularly premenopausal women.
Adult↗
Lifetime alcohol consumption and risk of breast cancer.
The relation of lifetime alcohol intake to risk of breast cancer in pre- and postmenopausal women was examined in a case-control study in western New York. Cases with incident primary histologically confirmed breast cancer diagnosed during the period 1986-1991 (n = 740) and controls, frequency age-matched women drawn from New York state driver's license records (age < 65 yrs) and from records of the Health Care Finance Administration (age > or = 65 yrs, n = 810), were interviewed regarding intake of wine, beer, and hard liquor 2, 10, and 20 years ago and at 16 years of age. Although women in this study had generally low intakes of alcohol, there was little evidence of increased risk of breast cancer with intake of alcohol at any of the time periods or with an index of total lifetime intake. There was a weak indication of an increase in risk with beer for intakes of at least one drink per day. This risk was evident for 2, 10, and 20 years ago but not at 16 years of age. In this group with relatively low intakes of alcohol, evidence was weak for an association of increased risk of breast cancer with intake of alcohol, with the possible exception of a weak association with beer intake.
Adolescent↗
Risk of premenopausal breast cancer and use of electric blankets.
Electric blanket use, estimated to significantly increase background exposure to 60-Hz electromagnetic fields, has been hypothesized to increase breast cancer risk. From 1986 to 1991 in western New York State, the authors investigated the use of electric blankets as a risk factor for breast cancer in a case-control study of premenopausal women. A total of 290 premenopausal breast cancer cases and 289 age-matched randomly selected community controls were queried in regard to their use of electric blankets in the previous 10 years, including frequency of use in season and mode of use. After adjusting for age, education, and other risk factors, the odds ratio for use of an electric blanket at any time in the previous 10 years (40% of cases and 37% of controls) was 1.18 (95% confidence interval (CI) 0.83-1.68). Estimates of risk did not differ in a dose-response fashion for number of years of electric blanket use. The risk associated with daily use in season relative to nonuse was 1.27 (95% CI 0.86-1.88). The risk of breast cancer among those who reported use of the blanket through the night was 1.43 (95% CI 0.94-2.17). However, the risk for those who reported daily use in season, continuously throughout the night for the previous 10 years was 1.10 (95% CI 0.59-2.05). These findings do not support the hypothesis that electric blanket use is associated with an increased risk for breast cancer. Studies with improved measures of more highly exposed individuals with quantification of total electromagnetic field exposure might clarify the uncertainties regarding risk of breast cancer associated with such exposure.
Adult↗