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author:("Ma, huiyang")
1.  Anthropometric, behavioral, and female reproductive factors and risk of multiple myeloma: a pooled analysis 
Cancer causes & control : CCC  2013;24(7):1279-1289.
Background
Risk of developing multiple myeloma (MM) rises with age and is greater among men and blacks than among women and whites, respectively, and possibly increased among obese persons. Other risk factors remain poorly understood. By pooling data from two complementary epidemiologic studies, we assessed whether obesity, smoking, or alcohol consumption alters MM risk and whether female reproductive history might explain the lower occurrence of MM in females than males.
Methods
The Los Angeles County MM Case-Control Study (1985-92) included 278 incident cases and 278 controls, matched on age, sex, race, and neighborhood of residence at case’s diagnosis. We estimated MM risk using conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). In the prospective California Teachers Study (CTS), 152 women were diagnosed with incident MM between 1995-2009; we calculated hazard ratios using Cox proportional hazards analysis. Data from the two studies were pooled using a stratified, nested case-control sampling scheme (10:1 match) for the CTS; conditional logistic regression among 430 cases and 1,798 matched controls was conducted.
Results
Obesity and smoking were not associated with MM risk in the individual or combined studies. Alcohol consumption was associated with decreased MM risk among whites only (pooled OR=0.66, 95% CI=0.49-0.90) for ever vs. never drinking). Higher gravidity and parity were associated with increased MM risk, with pooled ORs of 1.38 (95% CI=1.01-1.90) for ≥3 versus 1-2 pregnancies and 1.50 (95% CI=1.09-2.06) for ≥3 versus 1-2 live births.
Conclusions
Female reproductive history may modestly alter MM risk, but appears unlikely to explain the sex disparity in incidence. Further investigation in consortial efforts is warranted.
doi:10.1007/s10552-013-0206-0
PMCID: PMC3684420  PMID: 23568533
multiple myeloma; women; reproductive; modifiable; risk factors; association; pooling; case-control; cohort; epidemiology
2.  Recreational physical activity and risk of papillary thyroid cancer among women in the California Teachers Study 
Cancer epidemiology  2012;37(1):46-53.
Purpose
Little is known about the relationship between physical activity and thyroid cancer risk, and few cohort data on this association exist. Thus, the present study aimed to prospectively examine long-term activity and risk of papillary thyroid cancer among women.
Methods
116,939 women in the California Teachers Study, aged 22 to 79 years with no history of thyroid cancer at cohort entry, were followed from 1995-1996 through 2009; 275 were diagnosed with invasive papillary thyroid cancer. Cox proportional-hazards regression provided relative risk (RR) estimates and 95% confidence intervals (CI) for associations between thyroid cancer and combined strenuous and moderate recreational physical activity both in the long-term (high school through age 54 years or current age if younger than 54 years) and recently (during the three years prior to joining the cohort).
Results
Overall, women whose long-term recreational physical activity averaged at least 5.5 MET-hours/week (i.e. were active) had a non-significant 23% lower risk of papillary thyroid cancer than inactive women (RR=0.77, 95% CI: 0.57, 1.04). RR estimates were stronger among normal weight or underweight women (body mass index, BMI<25.0 kg/m2, trend p=0.03) than among overweight or obese women (trend p=0.35; homogeneity-of-trends p=0.03). A similar pattern of risk was observed for recent activity (BMI<25 kg/m2, trend p=0.11; BMI≥25 kg/m2, trend p=0.16; homogeneity-of-trends p=0.04). Associations for long-term activity did not appear to be driven by activity in any particular life period (e.g. youth, adulthood).
Conclusions
Long-term physical activity may reduce papillary thyroid cancer risk among normal weight and underweight women.
doi:10.1016/j.canep.2012.09.003
PMCID: PMC3543486  PMID: 23116823
Physical activity; thyroid cancer; cancer prevention; women; overweight/obesity; Body Mass Index
3.  Quantitative measures of estrogen receptor expression in relation to breast cancer-specific mortality risk among white women and black women 
Introduction
The association of breast cancer patients’ mortality with estrogen receptor (ER) status (ER + versus ER-) has been well studied. However, little attention has been paid to the relationship between the quantitative measures of ER expression and mortality.
Methods
We evaluated the association between semi-quantitative, immunohistochemical staining of ER in formalin-fixed paraffin-embedded breast carcinomas and breast cancer-specific mortality risk in an observational cohort of invasive breast cancer in 681 white women and 523 black women ages 35-64 years at first diagnosis of invasive breast cancer, who were followed for a median of 10 years. The quantitative measures of ER examined here included the percentage of tumor cell nuclei positively stained for ER, ER Histo (H)-score, and a score based on an adaptation of an equation presented by Cuzick and colleagues, which combines weighted values of ER H-score, percentage of tumor cell nuclei positively stained for the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) results. This is referred to as the ER/PR/HER2 score.
Results
After controlling for age at diagnosis, race, study site, tumor stage, and histologic grade in multivariable Cox proportional hazards regression models, both percentage of tumor cell nuclei positively stained for ER (Ptrend = 0.0003) and the ER H-score (Ptrend = 0.0004) were inversely associated with breast cancer-specific mortality risk. The ER/PR/HER2 score was positively associated with breast cancer-specific mortality risk in women with ER + tumor (Ptrend = 0.001). Analyses by race revealed that ER positivity was associated with reduced risk of breast cancer-specific mortality in white women and black women. The two quantitative measures for ER alone provided additional discrimination in breast cancer-specific mortality risk only among white women with ER + tumors (both Ptrend ≤ 0.01) while the ER/PR/HER2 score provided additional discrimination for both white women (Ptrend = 0.01) and black women (Ptrend = 0.03) with ER + tumors.
Conclusions
Our data support quantitative immunohistochemical measures of ER, especially the ER/PR/HER2 score, as a more precise predictor for breast cancer-specific mortality risk than a simple determination of ER positivity.
doi:10.1186/bcr3486
PMCID: PMC3978823  PMID: 24070170
4.  Breast Cancer Receptor Status: Do Results from a Centralized Pathology Laboratory Agree with SEER Registry Reports? 
We investigated the extent to which estrogen receptor (ER) and progesterone receptor (PR) status results from a centralized pathology laboratory agree with ER and PR results from community pathology laboratories reported to two Surveillance, Epidemiology and End Results (SEER) registries (Los Angeles County and Detroit) and whether statistical estimates for the association between reproductive factors and breast cancer receptor subtypes differ by the source of data. The agreement between the centralized laboratory and SEER registry classifications was substantial for ER (κ = 0.70) and nearly so for PR status (κ = 0.60). Among the four subtypes defined by joint ER and PR status, the agreement between the two sources was substantial for the two major breast cancer subtypes (ER−/PR−, κ = 0.69; ER+/PR+, κ = 0.62) and poor for the two rarer subtypes (ER+/PR−, κ = 0.30; ER−/PR+, κ = 0.05). Estimates for the association between reproductive factors (number of full-term pregnancies, age at first full-term pregnancy, and duration of breastfeeding) and the two major subtypes (ER+/PR+ and ER−/PR−) differed minimally between the two sources of data. For example, parous women with at least four full-term pregnancies had 40% lower risk for ER+/PR+ breast cancer than women who had never been pregnant [centralized laboratory, odds ratio, 0.60 (95% confidence interval, 0.39–0.92); SEER, odds ratio, 0.57 (95% confidence interval, 0.38–0.85)]; no association was observed for ER−/PR− breast cancer (both Ptrend > 0.30). Our results suggest that conclusions based on SEER registry data are reasonably reliable for ER+/PR+ and ER−/PR− subtypes.
doi:10.1158/1055-9965.EPI-09-0301
PMCID: PMC3782852  PMID: 19661080
6.  Body Size and the Risk of Postmenopausal Breast Cancer Subtypes in the California Teachers Study Cohort 
Cancer causes & control : CCC  2012;10.1007/s10552-012-9897-x.
Purpose
To evaluate how the association between body size and breast cancer risk varies by tumor receptor subtype, host factors and other exposures among women in the California Teacher Study cohort.
Methods
Among 52,642 postmenopausal women, 2,321 developed invasive breast cancer with known estrogen- and progesterone-receptor status (1,652 ER+PR+, 338 ER+PR−, 312 ER−PR−) between 1995 and 2007. In a subset of 35,529 with waist circumference data, 1,377 developed invasive breast cancer with known ERPR status (991 ER+PR+, 208 ER+PR−, 169 ER−PR−) between 1997 and 2007. Multivariate Cox regression was performed to estimate relative risks (RR) and 95% confidence intervals (CI).
Results
Obesity, adult weight gain of ≥40 pounds, greater abdominal adiposity and greater height increased risk of ER+PR+ breast cancer. The increased risk associated with postmenopausal obesity was limited to those who did not use hormone therapy (HT) at cohort entry (RR=1.37, 95% CI: 1.05–1.78 for BMI ≥30 vs. <25 kg/m2; P-interaction=0.14) and those who were not overweight or obese at age 18 (P-interaction=0.06). The increased risk associated with greater abdominal adiposity was limited to those who were not also overweight or obese (P-interaction=0.01). Neither obesity, abdominal adiposity nor height were associated with the risk of ER−PR− tumors.
Conclusions
The effects of body size on postmenopausal breast cancer risk differed by hormone receptor subtype, and among women with ER+PR+ tumors, by HT use and early adult body size.
doi:10.1007/s10552-012-9897-x
PMCID: PMC3366039  PMID: 22286371
breast cancer; obesity; hormone receptor status; abdominal adiposity; hormone therapy
7.  Characteristics of Triple-Negative Breast Cancer in Patients With a BRCA1 Mutation: Results From a Population-Based Study of Young Women 
Journal of Clinical Oncology  2011;29(33):4373-4380.
Purpose
Triple-negative breast cancers (TNBCs) are tumors with low or no expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. These tumors have a poor prognosis, remain a clinical challenge, and are more common among women with BRCA1 mutations. We tested whether there are distinguishing features of TNBC after BRCA1 mutation status has been taken into account.
Patients and Methods
We sequenced BRCA1 and BRCA2 genes in a population-based sample of 1,469 patients with incident breast cancer age 20 to 49 years from Los Angeles County (California). Information on tumor receptor status was available for 1,167 women. Clinical, pathologic, and hormone-related lifestyle characteristics were compared across patient subgroups defined by BRCA1 mutation status and triple-negative receptor status.
Results
Forty-eight percent of BRCA1 mutation carriers had TNBC compared with only 12% of noncarriers. Within BRCA1 mutation carriers, as well as within noncarriers, triple-negative receptor status was associated with younger age at diagnosis and higher tumor grade. Among women without a BRCA1 mutation, we observed that women with TNBC had higher premenopausal body mass index and earlier age at first full-term pregnancy than those with non-TNBC. Age at menarche and other reproductive factors were not associated with triple-negative status regardless of BRCA1 mutation status. Within BRCA1 mutation carriers, Ashkenazi Jewish women were about five times more likely to have TNBC than non–Ashkenazi Jewish women.
Conclusion
Our results suggest that among BRCA1 mutation carriers, as among noncarriers, there are unique characteristics associated with the triple-negative subtype. The findings in Ashkenazi Jewish BRCA1 mutation carriers should be confirmed.
doi:10.1200/JCO.2010.33.6446
PMCID: PMC3221522  PMID: 22010008
8.  The association of body mass index with mortality in the California Teachers Study 
Although underweight and obesity have been associated with increased risk of mortality, it remains unclear whether the associations differ by hormone therapy (HT) use and smoking. The authors examined the relationship between body mass index (BMI) and mortality within the California Teachers Study (CTS), specifically considering the impact of hormone therapy (HT) and smoking. The authors examined the associations of underweight and obesity with risks of all-cause and cause-specific mortality, among 115,433 women participating in the CTS, and specifically examined whether HT use or smoking modifies the effects of obesity. Multivariable Cox proportional hazards regression provided estimates of relative risks (RRs) and 95% confidence intervals (CIs). During follow up, 10,574 deaths occurred. All-cause mortality was increased for underweight (BMI < 18.5; adjusted relative risk [RR] = 1.33, 95% confidence interval [CI] =1.20–1.47) and obese participants (BMI ≥ 30: RR = 1.27, 95% CI = 1.19–1.37) relative to BMI of 18.5 – 24.9). Respiratory disease mortality was increased for underweight and obese participants. Death from any cancer, and breast cancer specifically, and cardiovascular disease was observed only for obese participants. The obesity and mortality association remained after stratification on HT and smoking. Obese participants remained at greater risk for mortality after stratification on menopausal hormone therapy and smoking. Obesity was associated with increased all-cause mortality, as well as death from any cancer (including breast), and cardiovascular and respiratory diseases. These findings help to identify groups at risk for BMI-related poor health outcomes.
doi:10.1002/ijc.25905
PMCID: PMC3246901  PMID: 21207419
9.  Obesity and Survival Among Black Women and White Women 35 to 64 Years of Age at Diagnosis With Invasive Breast Cancer 
Journal of Clinical Oncology  2011;29(25):3358-3365.
Purpose
To evaluate the effect of obesity on survival among black women and white women with invasive breast cancer and to determine whether obesity explains the poorer survival of black women relative to white women.
Patients and Methods
We observed 4,538 (1,604 black, 2,934 white) women who were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. Multivariate Cox regression models were used to examine the effect of body mass index (BMI, in kilograms per square meter) 5 years before diagnosis on risk of death from any cause and from breast cancer.
Results
During a median of 8.6 years of follow-up, 1,053 women died (519 black, 534 white), 828 as a result of breast cancer (412 black, 416 white). Black women were more likely to die than white women (multivariate-adjusted relative risk [RR], 1.33; 95% CI, 1.16 to 1.53). Compared with women with BMI of 20 to 24.9 kg/m2, those who were obese (BMI ≥ 30 kg/m2) had a greater risk of all-cause mortality (RR, 1.23; 95% CI, 1.04 to 1.47) and breast cancer–specific mortality (RR, 1.20; 95% CI, 0.99 to 1.46). These associations were observed among white women (all-cause RR, 1.54; 95% CI, 1.21 to 1.96; breast cancer RR, 1.46; 95% CI, 1.11 to 1.92), but not among black women (all-cause RR, 1.03; 95% CI, 0.81 to 1.29; breast cancer RR, 1.02; 95% CI, 0.79 to 1.33).
Conclusion
Obesity may play an important role in mortality among white but not black patients with breast cancer. It is unlikely that differences in obesity distributions between black women and white women account for the poorer survival of black women.
doi:10.1200/JCO.2010.34.2048
PMCID: PMC3164241  PMID: 21788570
10.  Cigarette Smoking, Passive Smoking, and Non-Hodgkin Lymphoma Risk: Evidence From the California Teachers Study 
American Journal of Epidemiology  2011;174(5):563-573.
Epidemiologic studies conducted to date have shown evidence of a causal relation between smoking and non-Hodgkin lymphoma (NHL) risk. However, previous studies did not account for passive smoking exposure in the never-smoking reference group. The California Teachers Study collected information about lifetime smoking and household passive smoking exposure in 1995 and about lifetime exposure to passive smoking in 3 settings (household, workplace, and social settings) in 1997–1998. Multivariable-adjusted relative risks and 95% confidence intervals were estimated by fitting Cox proportional hazards models with follow-up through 2007. Compared with never smokers, ever smokers had a 1.11-fold (95% confidence interval (CI): 0.94, 1.30) higher NHL risk that increased to a 1.22-fold (95% CI: 0.95, 1.57) higher risk when women with household passive smoking were excluded from the reference category. Statistically significant dose responses were observed for lifetime cumulative smoking exposure (intensity and pack-years; both P ’s for trend = 0.02) when women with household passive smoking were excluded from the reference category. Among never smokers, NHL risk increased with increasing lifetime exposure to passive smoking (relative risk = 1.51 (95% CI: 1.03, 2.22) for >40 years vs. ≤5 years of passive smoking; P for trend = 0.03), particularly for follicular lymphoma (relative risk = 2.89 (95% CI: 1.23, 6.80); P for trend = 0.01). The present study provides evidence that smoking and passive smoking may influence NHL etiology, particularly for follicular lymphoma.
doi:10.1093/aje/kwr127
PMCID: PMC3202153  PMID: 21768403
cohort studies; lymphoma, non-Hodgkin; smoking; tobacco smoke pollution
11.  Oral contraceptives, menopausal hormone therapy use and risk of B-cell non-Hodgkin lymphoma in the California Teachers Study 
We examined oral contraceptive (OC) and menopausal hormonal therapy (MHT) use in relation to risk of B-cell non-Hodgkin lymphoma (NHL). Women under age 85 years participating in the California Teachers Study with no history of hematopoietic cancer were followed from 1995 through 2007. 516 of 114,131 women eligible for OC use analysis and 402 of 54,758 postmenopausal women eligible for MHT use analysis developed B-cell NHL. Multivariable adjusted and stratified Cox proportional hazards models were fit to estimate relative risks (RR) and 95% confidence intervals (95% CI). Ever versus never OC use was marginally associated with lower B-cell NHL risk, particularly among women first using OCs before age 25 years (RR=0.72, 95%CI=0.51-0.99); yet, no duration-response effect was observed. No association was observed for ever versus never MHT use among postmenopausal women (RR=1.05, 95%CI=0.83-1.33) overall, or by formulation (estrogen alone, ET, or estrogen plus progestin, EPT). Among women with no MHT use, having bilateral oophorectomy plus hysterectomy was associated with greater B-cell NHL risk than having natural menopause (RR=3.15, 95%CI=1.62-6.13). Bilateral oophorectomy plus hysterectomy was not associated with risk among women who used ET or EPT. These results indicate that exogenous hormone use does not strongly influence B-cell NHL risk.
doi:10.1002/ijc.25730
PMCID: PMC3258672  PMID: 20957632
non-Hodgkin lymphoma; oral contraceptives; menopausal hormonal therapy; hysterectomy; bilateral oophorectomy
12.  Hormonal Factors and the Risk of Papillary Thyroid Cancer in the California Teachers Study Cohort 
Background
Despite the increasing incidence of thyroid cancer, there is limited information on its etiology. The strikingly higher rates in young women, compared to men, suggest that sex steroid hormones may be involved in the development of this disease.
Methods
We investigated the effects of menstrual, reproductive, and other hormonal factors on papillary thyroid cancer risk in the prospective California Teachers Study (CTS) cohort. Among 117,646 women, 233 were diagnosed with invasive histologically-confirmed papillary thyroid cancer after cohort enrollment and before January 1, 2008. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression models.
Results
Among younger women (age <45 years at baseline; approximately one-third of the cohort), but not older women, later age at menarche (age ≥14 years) was associated with increased risk (RR=1.88, 95% CI: 1.13–3.13; pinteraction by age=0.06). Risk was also increased among young women who had longer (>30 days) adolescent menstrual cycles (RR=1.78, 95% CI: 1.01–3.14) and whose last pregnancy had ended within five years of cohort enrollment (RR=2.21, 95% CI: 1.13–4.34). Among older women (age ≥45 years at baseline), ever use of estrogen-only therapy was associated with a statistically non-significant increase in risk (RR=1.69, 95% CI: 0.95–2.98).
Conclusions
The findings from this prospective analysis suggest that several factors related to delayed pubertal development and the transient effects of pregnancy may be particularly important in influencing risk in young women.
Impact
These results suggest the importance of future research into the role of progesterone and the estrogen-to-progesterone ratio.
doi:10.1158/1055-9965.EPI-11-0381
PMCID: PMC3288117  PMID: 21791618
papillary thyroid cancer; menstrual factors; reproductive factors; exogenous hormone use; epidemiology
13.  Oral contraceptive use and survival in women with invasive breast cancer 
Background
Oral contraceptives (OCs) are widely used in the U.S. Although the relation between OC use and breast cancer incidence has been widely studied, the few studies examining associations between OC use prior to breast cancer diagnosis and survival are inconsistent.
Methods
Women with invasive breast cancer participating in the Women's Contraceptive and Reproductive Experiences (CARE) Study, a population-based case-control study (4565 women ages 35–64 years), and the California Teachers Study (CTS) cohort (3929 women ages 28–91 years) were followed for vital status. 1064 women died in the CARE Study (median follow-up, 8.6 years) and 523 died in the CTS (median follow-up, 6.1 years). Cox proportional hazards regression provided hazard rate ratio estimates (RRs) with 95% confidence intervals (CIs) for risk of death from any cause and from breast cancer.
Results
No association was observed for any OC use prior to diagnosis and all-cause mortality (CARE Study: RR=1.01 (95% CI=0.86–1.19); CTS: RR=0.84 (95% CI=0.67–1.05)). A decreased risk of all-cause mortality was observed in the CTS among women with more than 10 years of OC use (RR=0.67, 95% CI=0.47–0.96); however, no trend of decreasing risk with increasing OC duration was observed (P-trend=0.22), and no association was observed in the CARE study. No associations were observed for breast cancer-specific mortality.
Conclusions
OC use is not associated with all-cause or breast cancer-specific mortality among women with invasive breast cancer.
Impact
These two independent studies demonstrated no overall association between OC use and survival among women with breast cancer.
doi:10.1158/1055-9965.EPI-11-0022
PMCID: PMC3132273  PMID: 21551244
Oral contraceptives; breast cancer; survival; risk assessment
14.  Lower Risk in Parous Women Suggests Hormonal Factors Important in Bladder Cancer Etiology 
Background
Urinary bladder cancer is two-to-four times more common among men than women, a difference in risk not fully explained by established risk factors. Our objective was to determine whether hormonal and reproductive factors are involved in female bladder cancer.
Methods
We analyzed data from two population-based studies: the Los Angeles-Shanghai Bladder Cancer Study, with 349 female case-control pairs enrolled in Los Angeles and 131 female cases and 138 frequency-matched controls enrolled in Shanghai; and the California Teachers Study (CTS), a cohort of 120,857 women with 196 incident cases of bladder urothelial carcinoma diagnosed between 1995 and 2005. We also conducted a meta-analysis summarizing associations from our primary analyses together with published results.
Results
In primary data analyses, parous women experienced at least 30% reduced risk of bladder cancer compared with nulliparous women (Shanghai: OR=0.38, 95%CI: 0.13–1.10; CTS: RR=0.69, 95%CI: 0.50–0.95) consistent with results of a meta-analysis of nine studies (summary RR=0.73, 95%CI: 0.63–0.85). The CTS, which queried formulation of menopausal hormone therapy (HT), revealed a protective effect for use of combined estrogen and progestin compared with no HT (RR=0.60, 95%CI: 0.37–0.98). Meta-analysis of three studies provided a similar effect estimate (summaryRR=0.65, 95%CI: 0.48–0.88).
Conclusions
A consistent pattern of reduced bladder cancer risk was found among parous women and those who used estrogen and progestin for HT.
Impact
These results suggest that more research is warranted to investigate hormonal and reproductive factors as possible contributors to bladder cancer risk.
doi:10.1158/1055-9965.EPI-11-0017
PMCID: PMC3312020  PMID: 21493870
urothelial carcinoma; parity; pregnancy; progestin; estrogen
15.  MENOPAUSAL HORMONE THERAPY DOES NOT INFLUENCE LUNG CANCER RISK: RESULTS FROM THE CALIFORNIA TEACHERS STUDY 
Background
Results from studies examining the association between hormone therapy (HT) and lung cancer risk disagree.
Methods
We examined the associations between HT use and lung cancer risk among 60,592 postmenopausal women enrolled in the prospective California Teachers Study cohort. Between 1995 and 2007, 727 women were diagnosed with lung cancer. Multivariable Cox proportional hazards regression models were fit using age as the time metric.
Results
No measure of HT use was associated with lung cancer risk (all p-values for trend≥0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT (E-alone, E+P use), type of menopause, or lung cancer histology were observed.
Conclusions
Our findings do not support an association between HT and lung cancer.
Impact
This large-scale, prospective study, which capitalizes on the detailed hormone use, smoking history, and type of menopause information available within this unique cohort, was unable to find any association between intake of HT and lung cancer risk.
doi:10.1158/1055-9965.EPI-10-1182
PMCID: PMC3065239  PMID: 21266521
16.  Hepatic HNF4α Is Essential for Maintaining Triglyceride and Cholesterol Homeostasis 
Objective
Loss-of-function mutations in human hepatocyte nuclear factor 4α (HNF4α) are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. In this report, we determined the effect of acute loss or augmentation of hepatic HNF4α function on lipid homeostasis.
Methods and Results
We generated adenovirus expressing LacZ (Ad-shLacZ) or small hairpin RNA of Hnf4α (Ad-shHnf4α). Tail vain injection of C57BL/6J mice with Ad-shHnf4α reduced hepatic Hnf4α expression and resulted in striking phenotypes including the development of fatty liver and a >80% decrease in plasma levels of triglycerides, total cholesterol and HDL-C. These latter changes were associated with reduced hepatic lipogenesis and impaired VLDL secretion. Deficiency in hepatic Hnf4α did not affect intestinal cholesterol absorption despite decreased expression of genes involved in bile acid synthesis. Consistent with the loss-of-function data, over-expression of Hnf4α induced numerous genes involved in lipid metabolism in isolated primary hepatocytes. Interestingly, many of these HNF4α-regulated genes were not induced in wild-type mice that over-expressed hepatic Hnf4α. Due to selective gene regulation, mice over-expressing hepatic Hnf4α had unchanged plasma triglyceride levels and decreased plasma cholesterol levels.
Conclusions
Loss of hepatic HNF4α results in severe lipid disorder as a result of dysregulation of multiple genes involved in lipid metabolism. In contrast, augmentation of hepatic HNF4α activity lowers plasma cholesterol levels but has no effect on plasma triglyceride levels due to selective gene regulation. Our data indicate that hepatic HNF4α is essential for controlling the basal expression of numerous genes involved in lipid metabolism and is indispensable for maintaining normal lipid homeostasis.
doi:10.1161/ATVBAHA.110.217828
PMCID: PMC3079249  PMID: 21071704
17.  Estrogenic botanical supplements, health-related quality of life, fatigue, and hormone-related symptoms in breast cancer survivors: a HEAL study report 
Background
It remains unclear whether estrogenic botanical supplement (EBS) use influences breast cancer survivors' health-related outcomes.
Methods
We examined the associations of EBS use with health-related quality of life (HRQOL), with fatigue, and with 15 hormone-related symptoms such as hot flashes and night sweats among 767 breast cancer survivors participating in the Health, Eating, Activity, and Lifestyle (HEAL) Study. HRQOL was measured by the Medical Outcomes Study short form-36 physical and mental component scale summary score. Fatigue was measured by the Revised-Piper Fatigue Scale score.
Results
Neither overall EBS use nor the number of EBS types used was associated with HRQOL, fatigue, or hormone-related symptoms. However, comparisons of those using each specific type of EBS with non-EBS users revealed the following associations. Soy supplements users were more likely to have a better physical health summary score (odds ratio [OR] = 1.66, 95% confidence interval [CI] = 1.02-2.70). Flaxseed oil users were more likely to have a better mental health summary score (OR = 1.76, 95% CI = 1.05-2.94). Ginseng users were more likely to report severe fatigue and several hormone-related symptoms (all ORs ≥ 1.7 and all 95% CIs exclude 1). Red clover users were less likely to report weight gain, night sweats, and difficulty concentrating (all OR approximately 0.4 and all 95% CIs exclude 1). Alfalfa users were less likely to experience sleep interruption (OR = 0.28, 95% CI = 0.12-0.68). Dehydroepiandrosterone users were less likely to have hot flashes (OR = 0.33, 95% CI = 0.14-0.82).
Conclusions
Our findings indicate that several specific types of EBS might have important influences on a woman's various aspects of quality of life, but further verification is necessary.
doi:10.1186/1472-6882-11-109
PMCID: PMC3234199  PMID: 22067368
18.  (2,4-Difluoro­phen­yl)[1-(1H-1,2,4-triazol-1-yl)cyclo­prop­yl]methanone 
The asymmetric unit of the title compound, C12H9F2N3O, contains two independent mol­ecules (A and B) in which the benzene and cyclo­propane rings form dihedral angles of 33.0 (1) and 29.7 (1)°, respectively. In the crystal, weak inter­molecular C—H⋯O hydrogen bonds link alternating A and B mol­ecules into chains along [010].
doi:10.1107/S1600536811040037
PMCID: PMC3247327  PMID: 22219945
19.  Parents’ Ages at Birth and Risk of Adult-onset Hematologic Malignancies Among Female Teachers in California 
American Journal of Epidemiology  2010;171(12):1262-1269.
Although advanced parental age at one's birth has been associated with increased risk of breast and prostate cancers, few studies have examined its effect on adult-onset sporadic hematologic malignancies. The authors examined the association of parents’ ages at women's births with risk of hematologic malignancies among 110,999 eligible women aged 22–84 years recruited into the prospective California Teachers Study. Between 1995 and 2007, 819 women without a family history of hematologic malignancies were diagnosed with incident lymphoma, leukemia (primarily acute myeloid leukemia), or multiple myeloma. Multivariable-adjusted Cox proportional hazards models provided estimates of relative risks and 95% confidence intervals. Paternal age was positively associated with non-Hodgkin lymphoma after adjustment for race and birth order (relative risk for age ≥40 vs. <25 years = 1.51, 95% confidence interval: 1.08, 2.13; P-trend = 0.01). Further adjustment for maternal age did not materially alter the association. By contrast, the elevated non-Hodgkin lymphoma risk associated with advanced maternal age (≥40 years) became null when paternal age was included in the statistical model. No association was observed for acute myeloid leukemia or multiple myeloma. Advanced paternal age may play a role in non-Hodgkin lymphoma etiology. Potential etiologic mechanisms include de novo gene mutations, aberrant paternal gene imprinting, or telomere/telomerase biology.
doi:10.1093/aje/kwq090
PMCID: PMC2915497  PMID: 20507900
cohort studies; hematologic neoplasms; leukemia, myeloid, acute; lymphoma, non-Hodgkin; maternal age; paternal age
20.  The roles of herbal remedies in survival and quality of life among long-term breast cancer survivors - results of a prospective study 
BMC Cancer  2011;11:222.
Background
Few data exist on survival or health-related quality of life (QOL) related to herbal remedy use among long-term breast cancer survivors. The objective of this report is to examine whether herbal remedy use is associated with survival or the health-related QOL of these long-term breast cancer survivors.
Methods
In 1999-2000, we collected the information of herbal remedy use and QOL during a telephone interview with 371 Los Angeles Non-Hispanic/Hispanic white women who had survived more than 10 years after breast cancer diagnosis. QOL was measured using the Medical Outcomes Study Short Form-36 (SF-36) questionnaire. Patients were followed for mortality from the baseline interview through 2007. 299 surviving patients completed a second telephone interview on QOL in 2002-2004. We used multivariable Cox proportional hazards methods to estimate relative risks (RR) and 95% confidence intervals (CI) for mortality and applied multivariable linear regression models to compare average SF-36 change scores (follow-up - baseline) between herbal remedy users and non-users.
Results
Fifty-nine percent of participants were herbal remedy users at baseline. The most commonly used herbal remedies were echinacea, herbal teas, and ginko biloba. Herbal remedy use was associated with non-statistically significant increases in the risks for all-cause (44 deaths, RR = 1.28, 95% CI = 0.62-2.64) and breast cancer (33 deaths, RR = 1.78, 95% CI = 0.72-4.40) mortality. Both herbal remedy users' and non-users' mental component summary scores on the SF-36 increased similarly from the first survey to the second survey (P = 0.16), but herbal remedy users' physical component summary scores decreased more than those of non-users (-5.7 vs. -3.2, P = 0.02).
Conclusions
Our data provide some evidence that herbal remedy use is associated with poorer survival and a poorer physical component score for health-related QOL among women who have survived breast cancer for at least 10 years. These conclusions are based on exploratory analyses of data from a prospective study using two-sided statistical tests with no correction for multiple testing and are limited by few deaths for mortality analysis and lack of information on when herbal remedy use was initiated or duration of or reasons for use.
doi:10.1186/1471-2407-11-222
PMCID: PMC3126792  PMID: 21645383
herb; breast cancer; survival; mortality; QOL
21.  Menopausal Hormone Therapy Use and Risk of Invasive Colon Cancer 
American Journal of Epidemiology  2010;171(4):415-425.
Results from epidemiologic studies of hormone therapy use and colon cancer risk are inconsistent. This question was investigated in the California Teachers Study (1995–2006) among 56,864 perimenopausal or postmenopausal participants under 80 years of age with no prior colorectal cancer by using Cox proportional hazards regression. Incident invasive colon cancer was diagnosed among 442 participants. Baseline-recent hormone therapy users were at 36% lower risk for colon cancer versus baseline-never users (baseline-recent users: relative risk (RR) = 0.64, 95% confidence interval (CI): 0.51, 0.80). Results did not differ by formulation. Estimated risk was lower among baseline-recent hormone therapy users with increasing duration between 5 and 15 years of use (RR = 0.49, 95% CI: 0.35, 0.68), but the trend did not persist in the longest duration group, more than 15 years of use (RR = 0.69, 95% CI: 0.52, 0.92; Ptrend = 0.60). Long-term recreational physical activity, obesity, regular use of nonsteroidal antiinflammatory medications, and daily alcohol intake did not modify these effects; baseline-recent use was more strongly associated with colon cancer risk among women with a family history of colorectal cancer (Pheterogeneity = 0.04). Baseline-recent hormone therapy use was inversely associated with invasive colon cancer risk among perimenopausal and postmenopausal women in the California Teachers Study.
doi:10.1093/aje/kwp434
PMCID: PMC2842195  PMID: 20067917
colonic neoplasms; hormone replacement therapy; lung neoplasms; parity; prospective studies; reproduction; smoking
22.  Use of Four Biomarkers to Evaluate the Risk of Breast Cancer Subtypes in the Women’s Contraceptive and Reproductive Experiences Study 
Cancer research  2010;70(2):575-587.
Epidemiological studies have suggested that some hormone-related breast cancer risk factors differentially influence risk of breast cancer subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) expression status in tumor tissue. However, it remains unclear whether human epidermal growth factor receptor-2 (HER2) and p53 protein (p53) expression status in tumor tissue further differentiate these exposure-risk-group associations. We evaluated the associations of oral contraceptive (OC) use and reproductive factors with incident invasive breast cancer subtypes among 1197 population-based cases and 2015 controls from the Los Angeles County or Detroit components of the Women’s Contraceptive and Reproductive Experiences Study. We used multivariable polychotomous unconditional logistic regression methods to conduct case-control comparisons by ER/PR/HER2/p53 status. We found that OC use was not associated with any breast cancer subtype defined by ER/PR/HER2/p53, except for a 2.9-fold increased risk for triple negative (ER−/PR−/HER2−) tumors among older women (ages 45–64 years) who started OC use before age 18. Parity was associated with decreased risk of luminal A (ER+ or PR+, HER2−), luminal B (ER+ or PR+, HER2+), and ER−/PR−/HER2+ tumors. Age at first full-term pregnancy was positively associated with luminal A tumors among older women. Neither of these reproductive factors was associated with triple negative tumors. Long duration of breastfeeding lowered risk of triple negative and luminal A tumors. No further differential risk patterns were noted when p53 was also considered. These results provide evidence supporting a difference in some hormone-related risk factor profiles between triple negative and other breast cancer subtypes defined by ER/PR/HER2.
doi:10.1158/0008-5472.CAN-09-3460
PMCID: PMC2807992  PMID: 20068186
ER/PR/HER2/p53; breast cancer; hormone-related factors; oral contraceptive; reproductive factors
23.  Body Size, Recreational Physical Activity, and B-Cell Non-Hodgkin Lymphoma Risk Among Women in the California Teachers Study 
American Journal of Epidemiology  2009;170(10):1231-1240.
Nutritional status and physical activity are known to alter immune function, which may be relevant to lymphomagenesis. The authors examined body size measurements and recreational physical activity in relation to risk of B-cell non-Hodgkin lymphoma (NHL) in the prospective California Teachers Study. Between 1995 and 2007, 574 women were diagnosed with incident B-cell NHL among 121,216 eligible women aged 22–84 years at cohort entry. Multivariable-adjusted relative risks and 95% confidence intervals were estimated by fitting Cox proportional hazards models for all B-cell NHL combined and for the 3 most common subtypes: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Height was positively associated with risk of all B-cell NHLs (for >1.70 vs. 1.61–1.65 m, relative risk = 1.50, 95% confidence interval: 1.16, 1.96) and chronic lymphocytic leukemia/small lymphocytic lymphoma (relative risk = 1.93, 95% confidence interval: 1.09, 3.41). Weight and body mass index at age 18 years were positive predictors of B-cell NHL risk overall. These findings indicate that greater height, which may reflect genetics, early life immune function, infectious exposures, nutrition, or growth hormone levels, may play a role in NHL etiology. Adiposity at age 18 years may be more relevant to NHL etiology than that in later life.
doi:10.1093/aje/kwp268
PMCID: PMC2781760  PMID: 19822569
body mass index; body size; cohort studies; exercise; hip; lymphoma, non-Hodgkin; waist-hip ratio
24.  Long-term and recent recreational physical activity and survival after breast cancer: the California Teachers Study 
Introduction
Long-term physical activity is associated with lower breast cancer risk. Little information exists on its association with subsequent survival.
Methods
California Teachers Study cohort members provided information in 1995–1996 on long-term (high school through age 54 years) and recent (past 3 years) participation in moderate and strenuous recreational physical activities. The 3,539 women diagnosed with invasive breast cancer after cohort entry and through December 31, 2004, were followed through December 31, 2005. Of these, 460 women died, 221 from breast cancer. Moderate and strenuous physical activities were combined into low (≤0.50 hr/wk/yr of any activity), intermediate (0.51–3.0 hr/wk/yr of moderate or strenuous activity but no activity >3.0 hr/wk/yr) or high activity (>3.0 hr/wk/yr of either activity type). Multivariable relative risks (RR) and 95% confidence intervals (CI) for mortality were estimated using Cox proportional hazards methods, adjusting for race/ethnicity, estrogen receptor status, disease stage, and baseline information on comorbidities, body mass index, and caloric intake.
Results
Women with high or intermediate levels of long-term physical activity had lower risk of breast cancer death (RR=0.53, 95% CI=0.35–0.80; and RR=0.65, 95% CI=0.45–0.93, respectively) than women with low activity levels. These associations were consistent across estrogen receptor status and disease stage, but confined to overweight women. Deaths due to causes other than breast cancer were related only to recent activity.
Conclusions
Consistent long-term participation in physical activity before breast cancer diagnosis may lower risk of breast cancer death, providing further justification for public health strategies to increase physical activity throughout the lifespan.
doi:10.1158/1055-9965.EPI-09-0538
PMCID: PMC2783945  PMID: 19843680
25.  Forkhead box transcription factor O1 inhibits cholesterol 7α-hydroxylase in human hepatocytes and in high fat diet-fed mice 
Biochimica et biophysica acta  2009;1791(10):991-996.
The conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism. Bile acids are metabolic regulators of triglycerides and glucose metabolism in the liver. This study investigated the roles of FoxO1 in the regulation of cholesterol 7α-hydroxylase (CYP7A1) gene expression in primary human hepatocytes. Adenovirusmediated expression of a phosphorylation defective and constitutively active form of FoxO1 (FoxO1-ADA) inhibited CYP7A1 mRNA expression and bile acid synthesis, while siRNA knockdown of FoxO1 resulted in a ~ 6-fold induction of CYP7A1 mRNA in human hepatocytes. Insulin caused rapid exclusion of FoxO1 from the nucleus and resulted in induction of CYP7A1 mRNA expression, which was blocked by FoxO1-ADA. In high fat diet-fed mice, CYP7A1 mRNA expression was repressed and inversely correlated to increased hepatic FoxO1 mRNA expression and FoxO1 nuclear retention. In conclusion, our current study provides direct evidence that FoxO1 is strong repressor of CYP7A1 gene expression and bile acid synthesis. Impaired regulation of FoxO1 may cause down-regulation of CYP7A1 gene expression and contribute to dyslipidemia in insulin resistance.
doi:10.1016/j.bbalip.2009.05.004
PMCID: PMC2743791  PMID: 19463968
bile acid synthesis; insulin; gene expression; nuclear receptor; metabolic diseases

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