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Introduction: The female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy.Methods: We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (PACT).Results: The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (PACT= 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene PACT= 0.002; overall PACT= 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women.Conclusions: We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT. © 2011 Lee et al.; licensee BioMed Central Ltd.

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 > or =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 (> or =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. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides (AMPs) are naturally occurring components of the immune system that act against bacteria in a variety of organisms throughout the evolutionary hierarchy. There have been many studies focused on the activity of AMPs using biophysical and microbiological techniques; however, a clear and predictive mechanism toward determining if a peptide will exhibit antimicrobial activity is still elusive, in addition to the fact that the mechanism of action of AMPs has been shown to vary between peptides, targets, and experimental conditions. Nonetheless, the majority of AMPs contain hydrophobic amino acids to facilitate partitioning into bacterial membranes and a net cationic charge to promote selective binding to the anionic surfaces of bacteria over the zwitterionic host cell surfaces. This study explores the role of hydrophobic amino acids using the peptide C18G as a model system. These changes were evaluated for the effects on antimicrobial activity, peptide-lipid interactions using Trp fluorescence spectroscopy, peptide secondary structure formation, and bacterial membrane permeabilization. The results show that while secondary structure formation was not significantly impacted by the substitutions, antibacterial activity and binding to model lipid membranes were well correlated. The variants containing Leu or Phe as the sole hydrophobic groups bound bilayers with highest affinity and were most effective at inhibiting bacterial growth. Peptides with Ile exhibited intermediate behavior while those with Val or α-aminoisobutyric acid (Aib) showed poor binding and activity. The Leu, Phe, and Ile peptides demonstrated a clear preference for anionic bilayers, exhibiting significant emission spectrum shifts upon binding. Similarly, the Leu, Phe, and Ile peptides demonstrated greater ability to disrupt lipid vesicles and bacterial membranes. In total, the data indicate that hydrophobic moieties in the AMP sequence play a significant role in the binding and ability of the peptide to exhibit antibacterial activity.

Previous results from research on menopausal hormone therapy (MHT) and lung cancer survival have been mixed and most have not studied women who used estrogen therapy (ET) exclusively. We examined the associations between MHT use reported at baseline and lung cancer-specific mortality in the prospective California Teachers Study cohort. Among 727 postmenopausal women diagnosed with lung cancer from 1995 through 2007, 441 women died before January 1, 2008. Hazard Ratios (HR) and 95% Confidence Intervals (CI) for lung-cancer-specific mortality were obtained by fitting multivariable Cox proportional hazards regression models using age in days as the timescale. Among women who used ET exclusively, decreases in lung cancer mortality were observed (HR, 0.69; 95% CI, 0.52-0.93). No association was observed for estrogen plus progestin therapy use. Among former users, shorter duration (<5 years) of exclusive ET use was associated with a decreased risk of lung cancer mortality (HR, 0.56; 95% CI, 0.35-0.89), whereas among recent users, longer duration (>15 years) was associated with a decreased risk (HR, 0.60; 95% CI, 0.38-0.95). Smoking status modified the associations with deceases in lung cancer mortality observed only among current smokers. Exclusive ET use was associated with decreased lung cancer mortality.

Female steroid hormones are hypothesized to play a protective role in pancreatic cancer risk. However, results from epidemiologic studies that examined hormone-related exposures have been inconsistent. The California Teachers Study is a cohort study of female public school professionals that was established in 1995-1996. Of the 118,164 eligible study participants, 323 women were diagnosed with incident invasive pancreatic cancer through December 31, 2009. Multivariable Cox proportional hazards regression methods were used to estimate hazard ratios and 95% confidence intervals for the association of pancreatic cancer risk with reproductive factors and exogenous hormone use. Current users of estrogen-only therapy at baseline (1995-1996) had a lower risk of pancreatic cancer than did participants who had never used hormone therapy (hazard ratio = 0.59, 95% confidence interval: 0.42, 0.84). Use of estrogen-plus-progestin therapy was not associated with the risk of pancreatic cancer. A longer duration of oral contraceptive use (≥10 years of use compared with never use) was associated with an increased risk of cancer (hazard ratio = 1.72, 95% confidence interval: 1.19, 2.49). Reproductive factors, including age at menarche, parity, breastfeeding, and age at menopause, were not associated with pancreatic cancer risk. Our results suggest that increased estrogen exposure through estrogen-only therapy may reduce pancreatic cancer risk in women.

Background: Physical activity may be associated with decreasing endometrial cancer risk; it remains unclear whether the association is modified by body size., Methods: Among 93 888 eligible California Teachers Study participants, 976 were diagnosed with incident endometrial cancer between 1995-1996 and 2007. Cox proportional hazards regression methods were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for endometrial cancer associated with long-term (high school through age 54 years) and baseline (3 years prior to joining the cohort) strenuous and moderate recreational physical activity, overall and by body size., Results: Increased baseline strenuous recreational physical activity was associated with decreased endometrial cancer risk (Ptrend=0.006) with approximately 25% lower risk among women exercising >3 h per week per year than among those exercising <1/2 h per week per year (RR, 0.76; 95% CI, 0.63-0.92). This inverse association was observed among overweight/obese women (body mass index ≥25 kg m(-2); Ptrend=0.006), but not among thinner women (Ptrend=0.12). Baseline moderate activity was associated with lower risk among overweight/obese women., Conclusion: Increasing physical activity, particularly strenuous activity, may be a lifestyle change that overweight and obese women can implement to reduce their endometrial cancer risk.

Objective: Although physical activity modulates the hypothalamic-pituitary-ovarian axis, the few studies that have investigated whether physical activity is associated with age at natural menopause have yielded mixed results. We set out to determine whether physical activity is associated with the timing of natural menopause in a large cohort of California women overall and by smoking history., Methods: We investigated the association between long-term physical activity (h/wk/y) and age at natural menopause among 97,945 women in the California Teachers Study. Multivariable Cox proportional hazards regression methods were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). The impact of cigarette smoking (never smoker, former light smoker, former heavy smoker, current light smoker, and current heavy smoker) as an effect modifier was evaluated., Results: In a multivariable model adjusted for body mass index at age 18 years, age at menarche, race/ethnicity, and age at first full-term pregnancy, increased physical activity was statistically significantly associated with older age at natural menopause (P(trend) = 0.005). Higher body mass index at age 18 years (P(trend) = 0.0003) and older age at menarche (P(trend) = 0.0003) were also associated with older age at natural menopause. Hispanic ethnicity (vs non-Hispanic whites; HR, 1.17; 95% CI, 1.09-1.26), current smokers (vs never smokers; HR, 1.68; 95% CI, 1.60-1.75 for current light smokers; HR, 1.38; 95% CI, 1.33-1.44 for current heavy smokers), and older age at first full-term pregnancy (HR(≥29, 2+ full-term pregnancies) vs HR(<29, 2+ full-term pregnancies), 1.10; 95% CI, 1.06-1.14) were associated with earlier age at natural menopause. Upon stratification by smoking history, increased physical activity was statistically significantly associated with older age at natural menopause among heavy smokers only (HR(highest quartile) vs HR(lowest quartile), 0.88; 95% CI, 0.81-0.97; P(trend) = 0.02 for former heavy smokers; HR(highest quartile) vs HR(lowest quartile), 0.89; 95% CI, 0.80-0.99; P(trend) = 0.04 for current heavy smokers)., Conclusions: Age at natural menopause is a complex trait; the determinants of age at natural menopause, including physical activity, may differ by smoking status.

Aim: To investigate LIN28B gene variants in children with idiopathic central precocious puberty (CPP)., Patients and Methods: We studied 178 Brazilian children with CPP (171 girls, 16.8% familial cases). A large multiethnic group (1,599 subjects; Multiethnic Cohort, MEC) was used as control. DNA analysis and biochemical in vitro studies were performed., Results: A heterozygous LIN28B variant, p.H199R, was identified in a girl who developed CPP at 5.2 years. This variant was absent in 310 Brazilian control individuals, but it was found in the same allele frequency in women from the MEC cohort, independent of the age of menarche. Functional studies revealed that when ectopically expressed in cells, the mutant protein was capable of binding pre-let-7 microRNA and inhibiting let-7 expression to the same extent as wild-type Lin28B protein. Other rare LIN28B variants (p.P173P, c.198+ 32&#95;33delCT, g.9575731A>C and c.-11C>T) were identified in CPP patients and controls. Therefore, no functional mutation was identified., Conclusion: In vitro studies revealed that the rare LIN28B p.H199R variant identified in a girl with CPP does not affect the Lin28B function in the regulation of let-7 expression. Although LIN28B SNPs were associated with normal pubertal timing, rare variations in this gene do not seem to be commonly involved in the molecular pathogenesis of CPP., (Copyright © 2012 S. Karger AG, Basel.)

Objective: To investigate the effect of surgical menopause due to bilateral oophorectomy on mortality, in light of evidence that bilateral oophorectomy among premenopausal women rapidly reduces endogenous hormone levels, thereby modifying risks of cardiovascular disease and breast cancer., Design: The California Teachers Study (CTS) is a prospective cohort study of 133,479 women initiated in 1995-1996 through a mailed, self-administered questionnaire. Relative risks and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression., Setting: None., Patient(s): California Teachers Study participants who, at baseline, reported having surgical menopause due to bilateral oophorectomy (n = 9,785), were compared with participants with natural menopause (n = 32,219)., Intervention(s): None., Main Outcome Measure(s): We investigated whether bilateral oophorectomy was associated with all-cause, cardiovascular, or cancer mortality, overall and by menopausal hormone therapy use status., Result(s): Among participants aged <45 years at menopause, multivariable relative risks were 0.86 (95% CI, 0.74-1.00), 0.85 (95% CI, 0.66-1.11), and 0.91 (95% CI, 0.67-1.23) for all-cause mortality, cardiovascular mortality, and cancer mortality, respectively. Among participants with an age at menopause of ≥45 years, multivariable relative risks were 0.87 (95% CI, 0.80-0.94), 0.83 (95% CI, 0.71-0.96), and 0.84 (95% CI, 0.72-0.98) for all-cause, cardiovascular, and cancer mortality, respectively. The association between bilateral oophorectomy and mortality did not differ by baseline status of hormone therapy use., Conclusion(s): Surgical menopause due to bilateral oophorectomy vs. natural menopause does not increase all-cause, cardiovascular, or cancer mortality., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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 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 RR = 1.33, 95% 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 HT 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., (Copyright © 2011 UICC.)

Genome-wide genotyping of a cohort using pools rather than individual samples has long been proposed as a cost-saving alternative for performing genome-wide association (GWA) studies. However, successful disease gene mapping using pooled genotyping has thus far been limited to detecting common variants with large effect sizes, which tend not to exist for many complex common diseases or traits. Therefore, for DNA pooling to be a viable strategy for conducting GWA studies, it is important to determine whether commonly used genome-wide SNP array platforms such as the Affymetrix 6.0 array can reliably detect common variants of small effect sizes using pooled DNA. Taking obesity and age at menarche as examples of human complex traits, we assessed the feasibility of genome-wide genotyping of pooled DNA as a single-stage design for phenotype association. By individually genotyping the top associations identified by pooling, we obtained a 14- to 16-fold enrichment of SNPs nominally associated with the phenotype, but we likely missed the top true associations. In addition, we assessed whether genotyping pooled DNA can serve as an inexpensive screen as the second stage of a multi-stage design with a large number of samples by comparing the most cost-effective 3-stage designs with 80% power to detect common variants with genotypic relative risk of 1.1, with and without pooling. Given the current state of the specific technology we employed and the associated genotyping costs, we showed through simulation that a design involving pooling would be 1.07 times more expensive than a design without pooling. Thus, while a significant amount of information exists within the data from pooled DNA, our analysis does not support genotyping pooled DNA as a means to efficiently identify common variants contributing small effects to phenotypes of interest. While our conclusions were based on the specific technology and study design we employed, the approach presented here will be useful for evaluating the utility of other or future genome-wide genotyping platforms in pooled DNA studies.

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. A total of 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 age stratified Cox proportional hazards models were fit to estimate relative risks (RRs) 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., (Copyright © 2010 UICC.)

Background: Oral contraceptives (OC) are widely used in the United States. 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. A total of 1,064 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 [(relative risk, RR)] 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 2 independent studies demonstrated no overall association between OC use and survival among women with breast cancer., (©2011 AACR)

Background: Urinary bladder cancer is two to four times more common among men than among 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 developing 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 (summary RR = 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., (©2011 AACR.)

Previous research suggests that cardiac vagal regulation (indexed by respiratory sinus arrhythmia, or RSA) provides a physiological substrate for affect regulation, which presumably underlies adaptive interpersonal functioning.The authors tested these associations in the context of daily interactions between 68 cohabiting couples. Participants underwent a laboratory assessment of RSA during rest and also during a series of psychological stressors. Subsequently, they kept daily measures of affect and interaction quality for 21 days. Individual differences in baseline and stress levels of RSA moderated within-person associations between daily affect and the quality of couple interactions. The pattern of results differed for women versus men. Men with lower vagal tone or higher vagal reactivity had stronger associations between daily negative affect and daily negative interactions, and men with higher vagal tone had more positive daily interactions overall. Women with higher vagal tone had stronger associations between daily positive affect and daily positive interactions.

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, a total of 727 women had a diagnosis of 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(trend) values ≥0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT [estrogen (E)-alone, E + progestin (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., (©2011 AACR.)

Purpose: Overweight or obese breast cancer patients have a worse prognosis compared with normal-weight patients. This may be attributed to hyperinsulinemia and dysregulation of adipokine levels associated with overweight and obesity. Here, we evaluate whether low levels of adiponectin and a greater level of insulin resistance are associated with breast cancer mortality and all-cause mortality., Patients and Methods: We measured glucose, insulin, and adiponectin levels in fasting serum samples from 527 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between adiponectin and insulin and glucose levels (expressed as the Homeostatic Model Assessment [HOMA] score) represented as continuous measures and median split categories, along with breast cancer mortality and all-cause mortality, using Cox proportional hazards models., Results: Increasing HOMA scores were associated with reduced breast cancer survival (hazard ratio [HR], 1.12; 95% CI, 1.05 to 1.20) and reduced all-cause survival (HR, 1.09; 95% CI, 1.02 to 1.15) after adjustment for possible confounders. Higher levels of adiponectin (above the median: 15.5 μg/mL) were associated with longer breast cancer survival (HR, 0.39; 95% CI, 0.15 to 0.95) after adjustment for covariates. A continuous measure of adiponectin was not associated with either breast cancer-specific or all-cause mortality., Conclusion: Elevated HOMA scores and low levels of adiponectin, both associated with obesity, were associated with increased breast cancer mortality. To the best of our knowledge, this is the first demonstration of the association between low levels of adiponectin and increased breast cancer mortality in breast cancer survivors.

Background: A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain., Methods: We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58)., Results: The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up., Conclusions: In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.

Objective: To investigate whether obesity and hormone therapy (HT) are associated with ovarian cancer risk among women in the California Teachers Study cohort., Methods: Of 56,091 women age ≥ 45 years, 277 developed epithelial ovarian cancer between 1995 and 2007. Multivariate Cox regression was performed., Results: Among women who never used HT, greater adult weight gain, waist circumference and waist-to-height ratio, but not adult BMI, increased risk of ovarian cancer. Compared to women who never used HT and had a stable adult weight, risk of ovarian cancer was increased in women who gained ≥ 40 lb (relative risk (RR) 1.8, 95% confidence interval (CI): 1.0-3.0) or used HT for >5 years (RR 2.3 95% CI: 1.3-4.1). Having both exposures (RR 1.9, 95% CI: 0.99-3.5), however, did not increase risk more than having either alone. Results were similar for waist circumference and weight-to-height ratio; however, differences across HT groups were not statistically significant., Conclusions: This study suggests that abdominal adiposity and weight gain, but not overall obesity, increase ovarian cancer risk and that there may be a threshold level beyond which additional hormones, whether exogenous or endogenous, do not result in additional elevation in risk. However, large pooled analyses are needed to confirm these findings.

Background: Although it is well established that combined estrogen-progestin therapy (EPT) increases breast cancer risk, questions remain regarding the effect of different formulations of hormones, whether certain women are at particularly high risk, and whether risk varies by tumor subtype., Methods: We investigated hormone therapy (HT) use in relation to breast cancer risk in the California Teachers Study cohort; after a mean follow-up of 9.8 years, 2,857 invasive breast cancers were diagnosed., Results: Compared with women who had never used HT, women who reported 15 or more years of estrogen therapy (ET) use had a 19% greater risk of breast cancer (95% confidence interval, 1.03-1.37), whereas women using EPT for 15 or more years had an 83% greater risk (95% confidence interval, 1.48-2.26). Breast cancer risk was highest among women using continuous combined EPT regimens. Risks associated with EPT and ET use were increased with duration of HT use for women with a body mass index (BMI) of <29.9 kg/m(2) but not for women with BMI of >or=30 kg/m(2). Elevated risks associated with EPT and ET use were confined to tumors that were positive for both estrogen and progesterone receptors and those that were HER2+ but were slightly diminished for HER2- tumors., Conclusions: Breast cancer risks increased with longer duration of ET and EPT use, and risks were highest for continuous-combined EPT use. Furthermore, risks varied by BMI and tumor subtype., Impact: These findings underscore the need for personalized risk-benefit discussions with women contemplating HT use., ((c)2010 AACR.)

Puberty is an important developmental stage during which reproductive capacity is attained. The timing of puberty varies greatly among healthy individuals in the general population and is influenced by both genetic and environmental factors. Although genetic variation is known to influence the normal spectrum of pubertal timing, the specific genes involved remain largely unknown. Genetic analyses have identified a number of genes responsible for rare disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. Recently, the first loci with common variation reproducibly associated with population variation in the timing of puberty were identified at 6q21 in or near LIN28B and at 9q31.2. However, these two loci explain only a small fraction of the genetic contribution to population variation in pubertal timing, suggesting the need to continue to consider other loci and other types of variants. Here we provide an update of the genes implicated in disorders of puberty, discuss genes and pathways that may be involved in the timing of normal puberty, and suggest additional avenues of investigation to identify genetic regulators of puberty in the general population., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

As we move forward from the current generation of genome-wide association (GWA) studies, additional cohorts of different ancestries will be studied to increase power, fine map association signals, and generalize association results to additional populations. Knowledge of genetic ancestry as well as population substructure will become increasingly important for GWA studies in populations of unknown ancestry. Here we propose genotyping pooled DNA samples using genome-wide SNP arrays as a viable option to efficiently and inexpensively estimate admixture proportion and identify ancestry informative markers (AIMs) in populations of unknown origin. We constructed DNA pools from African American, Native Hawaiian, Latina, and Jamaican samples and genotyped them using the Affymetrix 6.0 array. Aided by individual genotype data from the African American cohort, we established quality control filters to remove poorly performing SNPs and estimated allele frequencies for the remaining SNPs in each panel. We then applied a regression-based method to estimate the proportion of admixture in each cohort using the allele frequencies estimated from pooling and populations from the International HapMap Consortium as reference panels, and identified AIMs unique to each population. In this study, we demonstrated that genotyping pooled DNA samples yields estimates of admixture proportion that are both consistent with our knowledge of population history and similar to those obtained by genotyping known AIMs. Furthermore, through validation by individual genotyping, we demonstrated that pooling is quite effective for identifying SNPs with large allele frequency differences (i.e., AIMs) and that these AIMs are able to differentiate two closely related populations (HapMap JPT and CHB)., Competing Interests: The authors have declared that no competing interests exist.

Background: Several studies have reported associations between long-term exposure to ambient fine particulate matter (PM) and cardiovascular mortality. However, the health impacts of long-term exposure to specific constituents of PM(2.5) (PM with aerodynamic diameter < or = 2.5 microm) have not been explored., Methods: We used data from the California Teachers Study, a prospective cohort of active and former female public school professionals. We developed estimates of long-term exposures to PM(2.5) and several of its constituents, including elemental carbon, organic carbon (OC), sulfates, nitrates, iron, potassium, silicon, and zinc. Monthly averages of exposure were created using pollution data from June 2002 through July 2007. We included participants whose residential addresses were within 8 and 30 km of a monitor collecting PM(2.5) constituent data. Hazard ratios (HRs) were estimated for long-term exposure for mortality from all nontraumatic causes, cardiopulmonary disease, ischemic heart disease (IHD), and pulmonary disease., Results: Approximately 45,000 women with 2,600 deaths lived within 30 km of a monitor. We observed associations of all-cause, cardiopulmonary, and IHD mortality with PM(2.5) mass and each of its measured constituents, and between pulmonary mortality and several constituents. For example, for cardiopulmonary mortality, HRs for interquartile ranges of PM(2.5), OC, and sulfates were 1.55 [95% confidence interval (CI), 1.431.69], 1.80 (95% CI, 1.681.93), and 1.79 (95% CI, 1.582.03), respectively. Subsequent analyses indicated that, of the constituents analyzed, OC and sulfates had the strongest associations with all four outcomes., Conclusions: Long-term exposures to PM(2.5) and several of its constituents were associated with increased risks of all-cause and cardiopulmonary mortality in this cohort. Constituents derived from combustion of fossil fuel (including diesel), as well as those of crustal origin, were associated with some of the greatest risks. These results provide additional evidence that reduction of ambient PM(2.5) may provide significant public health benefits.

Introduction: Although pregnancy-related factors such as nulliparity and late age at first full-term pregnancy are well-established risk factors for invasive breast cancer, the roles of these factors in the natural history of breast cancer development remain unclear., Methods: Among 52,464 postmenopausal women participating in the California Teachers Study (CTS), 624 were diagnosed with breast carcinoma in situ (CIS) and 2,828 with invasive breast cancer between 1995 and 2007. Multivariable Cox proportional hazards regression methods were used to estimate relative risks associated with parity, age at first full-term pregnancy, breastfeeding, nausea or vomiting during pregnancy, and preeclampsia., Results: Compared with never-pregnant women, an increasing number of full-term pregnancies was associated with greater risk reduction for both breast CIS and invasive breast cancer (both P trend < 0.01). Women having four or more full-term pregnancies had a 31% lower breast CIS risk (RR = 0.69, 95% CI = 0.51 to 0.93) and 18% lower invasive breast cancer risk (RR = 0.82, 95% CI = 0.72 to 0.94). Parous women whose first full-term pregnancy occurred at age 35 years or later had a 118% greater risk for breast CIS (RR = 2.18, 95% CI = 1.36 to 3.49) and 27% greater risk for invasive breast cancer (RR = 1.27, 95% CI = 0.99 to 1.65) than those whose first full-term pregnancy occurred before age 21 years. Furthermore, parity was negatively associated with the risk of estrogen receptor-positive (ER+) or ER+/progesterone receptor-positive (PR+) while age at first full-term pregnancy was positively associated with the risk of ER+ or ER+/PR+ invasive breast cancer. Neither of these factors was statistically significantly associated with the risk of ER-negative (ER-) or ER-/PR- invasive breast cancer, tests for heterogeneity between subtypes did not reach statistical significance. No clear associations were detected for other pregnancy-related factors., Conclusions: These results provide some epidemiologic evidence that parity and age at first full-term pregnancy are involved in the development of breast cancer among postmenopausal women. The role of these factors in risk of in situ versus invasive, and hormone receptor-positive versus -negative breast cancer merits further exploration.

Background: Non-Hodgkin lymphoma (NHL) is a malignancy etiologically linked to immunomodulatory exposures and disorders. Endogenous female sex hormones may modify immune function and influence NHL risk. Few studies have examined associations between reproductive factors, which can serve as surrogates for such hormonal exposures, and NHL risk by subtype., Methodology/principal Findings: Women in the California Teachers Study cohort provided detailed data in 1995-1996 on reproductive history. Follow-up through 2007 identified 574 women with incident B-cell NHL. Hazard rate ratios (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models to assess associations between reproductive factors and all B-cell NHL combined, diffuse large B-cell lymphomas, follicular lymphomas, and B-cell chronic lymphocytic leukemias/small lymphocytic lymphomas. Pregnancy was marginally associated with lower risk of B-cell NHL (RR = 0.84, 95% CI = 0.68-1.04). Much of the reduction in risk was observed after one full-term pregnancy relative to nulligravid women (RR = 0.75, 95% CI = 0.54-1.06; P for trend <0.01), particularly for diffuse large B-cell lymphomas (P for trend = 0.13), but not among women who had only incomplete pregnancies. Age at first full-term pregnancy was marginally inversely associated with B-cell NHL risk overall (P for trend = 0.08) and for diffuse large B-cell lymphomas (P for trend = 0.056). Breast feeding was not associated with B-cell NHL risk overall or by subtype., Conclusions: Full-term pregnancy and early age at first full-term pregnancy account for most of the observed reduction in B-cell NHL risk associated with gravidity. Pregnancy-related hormonal exposures, including prolonged and high-level exposure to progesterone during a full-term pregnancy may inhibit development of B-cell NHL.

Background: Although recent reviews have suggested active smoking to be a risk factor for breast cancer, the association with passive smoke exposure remains controversial. This risk association was explored in a large prospective study of women, the California Teachers Study., Methods: Detailed lifetime information on passive smoke exposure by setting (home, work, or social) and by age of exposure was collected in 1997 from 57,523 women who were lifetime nonsmokers and had no history of breast cancer. In the ensuing decade, a total of 1,754 women were diagnosed with invasive breast cancer. Cox proportional hazards models were fit to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) associated with several lifetime passive smoke exposure metrics., Results: For all breast cancer, measures of higher lifetime passive smoking intensity and duration were associated with nonstatistically significant HRs of 1.11 to 1.14. For postmenopausal women, HRs for lifetime low, medium, and high cumulative exposure were 1.17 (95% CI, 0.91-1.49), 1.19 (95% CI, 0.93-1.53), and 1.26 (95% CI, 0.99-1.60). For women exposed in adulthood (age > or =20 years), risk was elevated at the highest level of cumulative exposure (HR, 1.18; 95% CI, 1.00-1.40), primarily among postmenopausal women (HR, 1.25; 95% CI, 1.01-1.56). A statistically significant dose response was detected when analysis was restricted to women with moderate to high levels of passive smoke exposure., Conclusion: These results suggest that cumulative exposures to high levels of sidestream smoke may increase breast cancer risk among postmenopausal women who themselves have never smoked tobacco products.

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.

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 (3.0 h/wk/y), or high activity (>3.0 h/wk/y of either activity type). Multivariable relative risks (RR) and 95% confidence intervals (95% 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 were 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.

Background: Gonadotropin releasing hormone (GNRH1) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3)., Methods: We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition (EPIC), Multiethnic Cohort (MEC), Nurses' Health Study (NHS), and Women's Health Study (WHS). Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects., Results: Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels., Conclusion: Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.

Context: Although the timing of puberty is a highly heritable trait, little is known about the genes that regulate pubertal timing in the general population. Several genes have been identified that, when mutated, cause disorders of delayed or absent puberty such as hypogonadotropic hypogonadism (HH)., Objective: Because severe variants in HH-related genes cause a severe puberty phenotype, we hypothesized that common subtle variation in these genes could contribute to the population variation in pubertal timing., Design: We assessed common genetic variation in 10 HH-related genes in 1801 women from the Hawaii and Los Angeles Multiethnic Cohort with either early (age<11 yr) or late (age>14 yr) menarche and in other replication samples. In addition to these common variants, we also studied the most frequently reported HH mutations to assess their role in the population variation in pubertal timing. SETTING AND PATIENTS/OTHER PARTICIPANTS: Within the general community, 1801 women from the Hawaii and Los Angeles Multiethnic Cohort participated., Main Outcome Measures: We assessed the association of genetic variation with age at menarche., Results: We found no significant association between any of the variants tested and age at menarche, although we cannot rule out modest effects of these variants or of other variants at long distances from the coding region. In several self-reported racial/ethnic groups represented in our study, we observed an association between estimated genetic ancestry and age at menarche., Conclusions: Our results suggest that common variants near 10 HH-related loci do not play a substantial role in the regulation of age at menarche in the general population.

This study investigated changes in day-to-day affect, behavior, and physiology (hypothalamic-pituitary-adrenocortical axis activity) associated with temporary physical separations from romantic partners (such as those brought about by work-related travel). Daily diaries and measures of salivary cortisol were collected from 42 couples over a 21-day period that was timed to coincide with a naturally occurring 4- to 7-day separation. There were significant changes from preseparation to separation and from separation to reunion in the quality of partners' interactions, their positive and negative affect, sleeping problems, subjective stress, physical symptoms, and cortisol levels. Separation and reunion effects were generally more pronounced in homebound partners, partners with high attachment anxiety, and partners who had less contact with each other during the separation. Separation and reunion effects were not moderated by relationship length, relationship satisfaction, how often couples underwent separations, or the presence of children in the home. The results are discussed with respect to the role of daily proximity and contact between partners for day-to-day affective and physiological regulation., ((c) 2008 APA, all rights reserved)

Background: Early studies of incomplete pregnancy and development of breast cancer suggested that induced abortion might increase risk. Several large prospective studies, which eliminate recall bias, did not detect associations, but this relationship continues to be debated., Study Design: To further inform this important question, we examined invasive breast cancer as it relates to incomplete pregnancy, including total number of induced abortions, age at first induced abortion and total number of miscarriages among women participating in the ongoing California Teachers Study (CTS) cohort. Incomplete pregnancy was self-reported on the CTS baseline questionnaire in 1995-1996. Incident breast cancers were ascertained in 3324 women through 2004 via linkage with the California Cancer Registry., Results: Using Cox multivariable regression, we found no statistically significant association between any measure of incomplete pregnancy and breast cancer risk among nulliparous or parous women., Conclusion: These results provide strong evidence that there is no relationship between incomplete pregnancy and breast cancer risk.

Previous studies on the relationship between obesity and circulating insulin-like growth factor (IGF) hormones show inconsistent findings and have not considered the possibility of racial/ethnic-specific differences that may exist. We therefore examined the relationship between obesity status [as measured by body mass index (BMI)] and plasma levels of the IGF proteins, IGF-I, IGF-binding protein 3 (IGFBP-3), and the molar ratio of IGF-I/IGFBP-3 in Whites, African Americans, Latinos, Japanese Americans, and Native Hawaiians from the ongoing Hawaii and Los Angeles Multiethnic Cohort Study. We measured plasma IGF-I and IGFBP-3 by ELISA in a random sample of 811 Multiethnic Cohort participants (53% male, age range = 47-82 at blood draw). In a multivariate regression of IGF-I levels, we found a statistically significant interaction between race/ethnicity and obesity status (P = 0.005). Plasma IGF-I levels declined with increasing BMI most dramatically in Latinos and Japanese. This decline was attenuated in Whites and absent in African-American and Native Hawaiian subjects. In Japanese, the quadratic term (BMI(2)) was statistically significant in a multivariate model (P = 0.002). In Latinos, the adjusted least-squares mean IGF-I levels in ng/mL for BMI < 25, 25 to 29.99, and >or=30 were 184.6, 147.7, and 132.7, respectively. No interaction between race/ethnicity and BMI explained the plasma IGFBP-3 levels in these data. These results may help to resolve the uncertainty in the relationship between circulating IGF levels and obesity and highlight the potential importance of racial/ethnic-specific effects among these factors in explaining ethnic disparities in obesity-related cancers.

Background: Auricular elastic cartilage is a potential source of autologous cells for lining the luminal surfaces of cardiovascular prostheses. We tested this potential in vitro and in vivo using a left ventricular assist device (LVAD) and a calf model., Methods: In vitro, auricular cartilage was harvested from the anesthetized ear of a calf, isolated, and cultured on tissue culture dishes. Primary chondrocytes were typed by immunocytochemistry, transferred into culture media, passaged twice, and seeded onto the blood-contacting luminal surfaces of four LVADs (HeartMate; Thoratec Corporation, Woburn, MA). Seeded cell linings were preconditioned under simulated flow conditions to promote cell adhesion to luminal surfaces. Seeding efficiency and cumulative cell loss under flow conditions were quantitated. In vivo, one of the four autologous chondrocyte-lined and preconditioned LVADs was implanted into the tissue-donor calf; run for 7 days; explanted; and evaluated grossly, by scanning electron microscopy, and by transmission electron microscopy., Results: The efficiency of seeding chondrocytes onto the luminal surfaces of the four LVADs was 95.11% +/- 4.23% (n = 4). Cumulative cell loss during preconditioning under flow conditions in vitro did not exceed 12% (n = 4). After 7 days of in vivo implantation, the luminal surfaces of the implanted LVAD demonstrated an intact, strongly adherent cellular lining., Conclusions: Auricular elastic cartilage is a ready and easily accessible source of chondrocytes whose ability to produce collagen II and other important extracellular matrix constituents allows them to adhere strongly to the luminal surfaces of LVADs. The simple method of isolating and expanding auricular chondrocytes presented here could be used to provide strongly adherent autologous cell linings for LVADs and other cardiovascular devices. If and when chondrocytes can be genetically engineered to produce antithrombogenic factors and then used to line the luminal surfaces of LVADs or other cardiovascular prostheses, they may be able to improve the hemocompatibility of the blood-biomaterial interface in such devices. Our successful feasibility study in a calf model warrants further studies of this concept in vivo.

The Drosophila salivary gland is proving to be an excellent experimental system for understanding how cells commit to specific developmental programs and, once committed, how cells implement such decisions. Through genetic studies, the factors that determine where salivary glands will form, the number of cells committed to a salivary gland fate, and the distinction between the two major cell types (secretory cells and duct cells) have been discovered. Within the next few years, we will learn the molecular details of the interactions among the salivary gland regulators and salivary gland target genes. We will also learn how the early-expressed salivary gland genes coordinate their activities to mediate the morphogenetic movements required to form the salivary gland and the changes in cell physiology required for high secretory activity.

Salivary gland formation in the Drosophila embryo is dependent on the homeotic gene Sex combs reduced (Scr). When Scr function is missing, salivary glands do not form, and when SCR is expressed everywhere in the embryo, salivary glands form in new places. Scr is normally expressed in all the cells that form the salivary gland. However, as the salivary gland invaginates, Scr mRNA and protein disappear. Homeotic genes, such as Scr, specify tissue identity by regulating the expression of downstream target genes. For many homeotic proteins, target gene specificity is achieved by cooperatively binding DNA with cofactors. Therefore, it is likely that SCR also requires a cofactor(s) to specifically bind to DNA and regulate salivary gland target gene expression. Here, we show that two homeodomain-containing proteins encoded by the extradenticle (exd) and homothorax (hth) genes are also required for salivary gland formation. exd and hth function at two levels: (1) exd and hth are required to maintain the expression of Scr in the salivary gland primordia prior to invagination and (2) exd and hth are required in parallel with Scr to regulate the expression of downstream salivary gland genes. We also show that Scr regulates the nuclear localization of EXD in the salivary gland primordia through repression of homothorax (hth) expression, linking the regulation of Scr activity to the disappearance of Scr expression in invaginating salivary glands., (Copyright 2000 Academic Press.)

Salivary gland formation in the Drosophila embryo is linked to the expression of the homeotic gene Sex combs reduced (Scr). When Scr function is missing, salivary glands do not form, and when SCR is expressed everywhere, salivary glands form in new places. However, not every cell that expresses Scr is recruited to a salivary gland fate. Along the anterior-posterior axis, the posteriorly expressed proteins encoded by the teashirt (tsh) and Abdominal-B (Abd-B) genes block SCR activation of salivary gland genes, and along the dorsal-ventral axis, the secreted signaling molecule encoded by decapentaplegic (dpp) prevents activation of salivary gland genes by SCR in dorsal regions of parasegment 2. We have identified five downstream components in the DPP signaling cascade required to block salivary gland gene activation. These components include two known receptors, the type I receptor encoded by the thick veins (tkv) gene and the type II receptor encoded by the punt (put) gene; two of the four known Drosophila members of the Smad family of proteins which transduce signals from the receptors to the nucleus, Mothers against dpp (Mad) and Medea (Med); and, finally, a large zinc-finger transcription factor encoded by the schnurri (shn) gene. These results reveal how anterior-posterior and dorsal-ventral patterning information is integrated at the level of organ-specific gene expression., (Copyright 1999 Academic Press.)

TGF-beta signaling from the cell surface to the nucleus is mediated by the SMAD family of proteins, which have been grouped into three classes based upon sequence identity and function. Receptor-regulated, or pathway-restricted, SMADs (R-SMADs) are phosphorylated by ligand-specific serine/threonine kinase receptors. Phosphorylated R-SMADs oligomerize with the coactivating, or shared, SMAD (Co-SMAD) mediator and translocate to the nucleus where the complex directs transcription of downstream target genes. Inhibitory SMADs (I-SMADs) block receptor-mediated phosphorylation of R-SMADs. In Drosophila, one member of each class of SMAD has been reported: MAD, an R-SMAD, MEDEA, a Co-SMAD, and DAD, an I-SMAD. Here, we report the first identification of a novel Drosophila R-SMAD, which we have named Smox for Smad on X. We have localized the Smox gene to a specific interval on the X chromosome and shown that Smox is transcribed throughout development., (Copyright 1998 Academic Press.)

We report on the characterization of the first loss-of-function mutation in a Drosophila CREB gene, dCREB-A. In the epidermis, dCREB-A is required for patterning cuticular structures on both dorsal and ventral surfaces since dCREB-A mutant larvae have only lateral structures around the entire circumference of each segment. Based on results from epistasis tests with known dorsal/ventral patterning genes, we propose that dCREB-A encodes a transcription factor that functions near the end of both the DPP- and SPI-signaling cascades to translate the corresponding extracellular signals into changes in gene expression. The lateralizing phenotype of dCREB-A mutants reveals a much broader function for CREB proteins than previously thought.