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1.  Personal Use of Hair Dye and the Risk of Certain Subtypes of Non-Hodgkin Lymphoma 
American journal of epidemiology  2008;167(11):1321-1331.
Personal use of hair dye has been inconsistently linked to risk of non-Hodgkin lymphoma (NHL), perhaps because of small samples or a lack of detailed information on personal hair-dye use in previous studies. This study included 4,461 NHL cases and 5,799 controls from the International Lymphoma Epidemiology Consortium 1988–2003. Increased risk of NHL (odds ratio (OR) = 1.3, 95% confidence interval (CI): 1.1, 1.4) associated with hair-dye use was observed among women who began using hair dye before 1980. Analyses by NHL subtype showed increased risk for follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) but not for other NHL subtypes. The increased risks of FL (OR = 1.4, 95% CI: 1.1, 1.9) and CLL/SLL (OR = 1.5, 95% CI: 1.1, 2.0) were mainly observed among women who started using hair dyes before 1980. For women who began using hair dye in 1980 or afterward, increased FL risk was limited to users of dark-colored dyes (OR = 1.5, 95% CI: 1.1, 2.0). These results indicate that personal hair-dye use may play a role in risks of FL and CLL/SLL in women who started use before 1980 and that increased risk of FL among women who started use during or after 1980 cannot be excluded.
PMCID: PMC4025953  PMID: 18408225
case-control studies; hair dyes; lymphoma; non-Hodgkin
2.  Hepatitis C and Non-Hodgkin Lymphoma Among 4784 Cases and 6269 Controls From the International Lymphoma Epidemiology Consortium 
Background & Aims
Increasing evidence points towards a role of hepatitis C virus (HCV) infection in causing malignant lymphomas. We pooled case-control study data to provide robust estimates of the risk of non-Hodgkin’s lymphoma (NHL) subtypes after HCV infection.
The analysis included 7 member studies from the International Lymphoma Epidemiology Consortium (InterLymph) based in Europe, North America, and Australia. Adult cases of NHL (n = 4784) were diagnosed between 1988 and 2004 and controls (n = 6269) were matched by age, sex, and study center. All studies used third-generation enzyme-linked immunosorbent assays to test for antibodies against HCV in serum samples. Participants who were human immunodeficiency virus positive or were organ-transplant recipients were excluded.
HCV infection was detected in 172 NHL cases (3.60%) and in 169 (2.70%) controls (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40–2.25). In subtype-specific analyses, HCV prevalence was associated with marginal zone lymphoma (OR, 2.47; 95% CI, 1.44–4.23), diffuse large B-cell lymphoma (OR, 2.24; 95% CI, 1.68–2.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14–5.79). Notably, risk estimates were not increased for follicular lymphoma (OR, 1.02; 95% CI, 0.65–1.60).
These results confirm the association between HCV infection and NHL and specific B-NHL subtypes (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma).
PMCID: PMC3962672  PMID: 18387498
3.  Non-Hodgkin lymphoma and Obesity: a pooled analysis from the InterLymph consortium 
Nutritional status is known to alter immune function, a suspected risk factor for non-Hodgkin lymphoma (NHL). To investigate whether long-term over, or under, nutrition is associated with NHL self-reported anthropometric data on weight and height from over 10000 cases of NHL and 16000 controls were pooled across 18 case-control studies identified through the International Lymphoma Epidemiology Consortium. Study-specific odds ratios (OR) were estimated using logistic regression and combined using a random-effects model. Severe obesity, defined as BMI of 40 kg m−2 or more, was not associated with NHL overall (pooled OR=1.00, 95% confidence interval (CI) 0.70–1.41) or the majority of NHL subtypes. An excess was however observed for diffuse large B-cell lymphoma (pooled OR=1.80, 95% CI 1.24–2.62), although not all study-specific ORs were raised. Among the overweight (BMI 25–29.9 kg m−2) and obese (BMI 30–39.9 kg m−2), associations were elevated in some studies and decreased in others, while no association was observed among the underweight (BMI<18.5 kg m−2). There was little suggestion of increasing ORs for NHL or its subtypes with every 5 kg m−2 rise in BMI above 18.5 kg m−2. BMI components height and weight were also examined, and the tallest men, but not women, were at marginally increased risk (pooled OR=1.19, 95% CI 1.06–1.34). In summary, whilst we conclude that there is no evidence to support the hypothesis that obesity is a determinant of all types of NHL combined, the association between severe obesity and diffuse large B-cell lymphoma may warrant further investigation.
PMCID: PMC3928289  PMID: 18167059
non-Hodgkin lymphoma; lymphoma; body mass index; weight; height; epidemiology
4.  Blunted accumbal dopamine response to cocaine following chronic social stress in female rats: exploring a link between depression and drug abuse 
Psychopharmacology  2011;218(1):271-279.
Women have twice the risk as men to develop depression. Approximately, 24% of major depression disorder cases have comorbid disorders with substance abuse. Several central systems, including dopaminergic and serotonergic pathways, are thought to be involved in such comorbidity.
The present study established a chronic social stress model in female rats, which produces some cardinal features of depressive-like symptoms. Further, we examined the effects of acute cocaine on dopamine (DA) and serotonin (5-HT) in the nucleus accumbens (NAc) using this model.
Female Long-Evans rats confronted a nursing dam in its home cage for 30 min twice daily for 21 days. The non-stressed control group was handled daily throughout the experiment. During the 21 days of stress, behaviors during confrontations, weight, preference for saccharin, and estrous cycles were measured. Ten days after the last confrontation, the experimental rat was challenged with 10 mg/kg of cocaine, and levels of DA and 5-HT in the NAc were measured using in vivo microdialysis.
During the course of daily confrontations for 21 days, the experimental females significantly increased the duration of immobility, reduced weight gain and the preference for saccharin, and disrupted estrous cycles during the stress. Chronic social stress significantly attenuated cocaine-induced DA levels, and to some extent, attenuated a percent change of 5-HT compared to the non-stressed control group.
Chronic social defeat stress for 21 days induced physiological and behavioral depression-relevant deficits and blunted response of dopaminergic and to some extent, serotonergic neurons to cocaine challenge in females.
PMCID: PMC3901580  PMID: 21638221
Cocaine; Chronic social stress; Depression; Dopamine; Estrous cycles; Females; Nucleus accumbens; Serotonin
5.  Smoking, variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma: a pooled analysis within the InterLymph consortium 
Cancer causes & control : CCC  2012;24(1):125-134.
Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2.
We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case–control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models.
Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07–1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95–1.69) acetylators (pinteraction = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes.
The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes.
PMCID: PMC3529854  PMID: 23160945
Non-Hodgkin lymphoma; Gene environment interaction; Cigarette smoking; N-acetyltransferase; Follicular lymphoma
6.  A functional TNFRSF5 polymorphism and risk of non-Hodgkin lymphoma, a pooled analysis 
Interaction between CD40 and its ligand, CD154, has a key function in immune regulation. Recent experimental data support a role of deregulated CD40 signalling in lymphomagenesis. Data from earlier studies that are part of this pooling study implicate a functional polymorphism (−1C>T, rs1883832) in the TNFRSF5 gene encoding CD40 in the etiology of follicular lymphoma. Here, the association of this variant with non-Hodgkin lymphoma (NHL) risk was replicated in a European multicenter study of 855 NHL cases and 1,206 controls. In the combined analysis of 2,617 cases and 3,605 controls, carrying the TT genotype was associated with an increased risk for all NHL (OR = 1.4; p for linear trend = 0.00009), diffuse large B-cell lymphoma (OR = 1.6; p for linear trend = 0.002) and follicular lymphoma (OR = 1.6; p for linear trend = 0.001). These data suggest a possible role of this functional polymorphism in lymphomas originating within the germinal center.
PMCID: PMC3876741  PMID: 20473910
lymphoma; TNFRSF5; CD40; polymorphism; epidemiology
7.  Obesity and survival in population-based patients with pancreatic cancer in the San Francisco Bay Area 
Cancer causes & control : CCC  2012;23(12):1929-1937.
Obesity has been consistently associated with increased risk of pancreatic cancer incidence and mortality. However, studies of obesity and overall survival in patients with pancreatic cancer are notably lacking, especially in population-based studies.
Active and passive follow-up were used to determine vital status and survival for 510 pancreatic cancer patients diagnosed from 1995–1999 in a large population-based case-control study in the San Francisco Bay Area. Survival rates were computed using Kaplan-Meier methods. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated in multivariable Cox proportional hazards models as measures of the association between pre-diagnostic obesity and pancreatic cancer survival.
An elevated hazard ratio of 1.3 (95% CI, 0.91–1.81) was observed for obese (body mass index [BMI] ≥30) compared with normal range BMI (<25) patients. Associations between overall survival and known pancreatic cancer prognostic and risk factors did not significantly vary by BMI (all P-interaction ≥0.18), yet elevated HRs consistently were observed for obese compared with normal BMI patients [localized disease at diagnosis (HR, 3.1), surgical resection (HR, 1.6), ever smokers (HR, 1.6), diabetics (HR, 3.3)]. Poor survival was observed among men, older patients, more recent and current smokers, whereas improved survival was observed for Asian/Pacific Islanders.
Our results in general provide limited support for an association between prediagnostic obesity and decreased survival in patients with pancreatic cancer. Patterns of reduced survival associated with obesity in some patient subgroups could be due to chance and require assessment in larger pooled studies.
PMCID: PMC3506392  PMID: 23015286
Pancreatic cancer; obesity; survival; population-based cohort
8.  Parental Smoking and Risk of Childhood Brain Tumors by Functional Polymorphisms in Polycyclic Aromatic Hydrocarbon Metabolism Genes 
PLoS ONE  2013;8(11):e79110.
A recent meta-analysis suggested an association between exposure to paternal smoking during pregnancy and childhood brain tumor risk, but no studies have evaluated whether this association differs by polymorphisms in genes that metabolize tobacco-smoke chemicals.
We assessed 9 functional polymorphisms in 6 genes that affect the metabolism of polycyclic aromatic hydrocarbons (PAH) to evaluate potential interactions with parental smoking during pregnancy in a population-based case-control study of childhood brain tumors. Cases (N = 202) were ≤10 years old, diagnosed from 1984–1991 and identified in three Surveillance, Epidemiology, and End Results (SEER) registries in the western U.S. Controls in the same regions (N = 286) were frequency matched by age, sex, and study center. DNA for genotyping was obtained from archived newborn dried blood spots.
We found positive interaction odds ratios (ORs) for both maternal and paternal smoking during pregnancy, EPHX1 H139R, and childhood brain tumors (Pinteraction = 0.02; 0.10), such that children with the high-risk (greater PAH activation) genotype were at a higher risk of brain tumors relative to children with the low-risk genotype when exposed to tobacco smoke during pregnancy. A dose-response pattern for paternal smoking was observed among children with the EPHX1 H139R high-risk genotype only (ORno exposure = 1.0; OR≤3 hours/day = 1.32, 95% CI: 0.52–3.34; OR>3hours/day = 3.18, 95% CI: 0.92–11.0; Ptrend = 0.07).
Parental smoking during pregnancy may be a risk factor for childhood brain tumors among genetically susceptible children who more rapidly activate PAH in tobacco smoke.
PMCID: PMC3832498  PMID: 24260161
9.  Self-reported history of infections and the risk of non-Hodgkin lymphoma: an InterLymph pooled analysis 
We performed a pooled analysis of data on self-reported history of infections in relation to the risk of non-Hodgkin lymphoma (NHL) from 17 case-control studies that included 12,585 cases and 15,416 controls aged 16–96 years at recruitment. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in two-stage random-effect or joint fixed-effect models, adjusting for age, sex and study centre. Data from the two years prior to diagnosis (or date of interview for controls) were excluded. A self-reported history of infectious mononucleosis (IM) was associated with an excess risk of NHL (OR=1.26, 95% CI=1.01–1.57 based on data from 16 studies); study-specific results indicate significant (I2=51%, p=0.01) heterogeneity. A self-reported history of measles or whooping cough was associated with an approximate 15% reduction in risk. History of other infection was not associated with NHL. We find little clear evidence of an association between NHL risk and infection although the limitations of data based on self-reported medical history (particularly of childhood illness reported by older people) are well recognised.
PMCID: PMC3406230  PMID: 22266776
10.  Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats 
Psychopharmacology  2012;224(1):179-188.
Episodic social defeat stress results in cross-sensitization to cocaine, characterized by augmentation of locomotor activation, dopamine (DA) levels in the nucleus accumbens (NAc), and cocaine self-administration during a 24-hour “binge” in male rats. However, females are more vulnerable than males at each phase of cocaine addiction, and while these sex differences have been replicated in rats, the role of social stress in females remains largely neglected.
This study examined sex and estrous cycle differences in behavioral and dopaminergic cross-sensitization to cocaine, as well as cocaine taking in an unlimited access self-administration “binge.”
Long-Evans rats underwent episodic social defeat and were assessed ten days later for either (1)behavioral sensitization, as determined by locomotor activity in response to acute cocaine (10 mg/kg, ip), (2)neural sensitization, as determined by in vivo microdialysis of DA in the NAc shell in response to acute cocaine, or (3)intravenous self-administration of cocaine (0.3 mg/kg/infusion) in an unlimited access “binge.”
Social defeat stress resulted in behavioral and dopaminergic cross-sensitization in both sexes, but the effect was larger and longer lasting in stressed females. Furthermore, while stress engendered a longer “binge” in both sexes, females had a significantly longer “binge” duration than males.
These data suggest that socially stressed females exhibit a larger and longer lasting behavioral and neural cross-sensitization, as well as more dysregulated cocaine taking, than males possibly due to different alterations in the dopaminergic response in the NAc. Furthermore, estrogens appear to play a facilitatory role in both behavioral and dopaminergic sensitization.
PMCID: PMC3684960  PMID: 22926005
social stress; sex differences; cocaine; dopamine; behavioral sensitization; neural sensitization; self-administration; microdialysis
11.  An Absolute Risk Model to Identify Individuals at Elevated Risk for Pancreatic Cancer in the General Population 
PLoS ONE  2013;8(9):e72311.
We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.
Patients and Methods
Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.
Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84–2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19–1.76]), obesity (body mass index >30 kg/m2) (OR: 1.26 [1.09–1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13–2.18], case-control OR: 1.80 [1.40–2.32]), family history of pancreatic cancer (OR: 1.60 [1.20–2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10–1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97–2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19–1.40]), rs401681(5p15.33) (OR: 1.18 [1.10–1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18–1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.
Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.
PMCID: PMC3772857  PMID: 24058443
12.  Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer 
Carcinogenesis  2012;33(7):1384-1390.
Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case–control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10−6, 1.6 × 10−5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10−5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
PMCID: PMC3405651  PMID: 22523087
13.  Mitochondrial DNA sequence variation and risk of pancreatic cancer 
Cancer Research  2011;72(3):686-695.
Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases=286, controls=283) in a San Francisco Bay Area pancreatic cancer case-control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (p<0.05) with the strongest finding for mt5460g in the ND2 gene (odds ratio (OR)=3.9, 95% confidence interval (CI)=1.5–10; p=0.004) which encodes an A331T substitution. Haplogroup K was nominally associated with reduced pancreatic cancer risk (OR = 0.32, CI=0.13–0.76; p=0.01) when compared with the most common haplogroup, H. A total of 19 haplogroup-specific rare variants yielded nominal statistically significant associations (p<0.05) with pancreatic cancer risk, with the majority observed in genes involved in oxidative phosphorylation. Weighted-sum statistics were used to identify an aggregate effect of variants in the 22 mitochondrial tRNAs on pancreatic cancer risk (p=0.02). While the burden of singleton variants in the HV2 and 12S RNA regions was three times higher among European haplogroup N cases than controls, the prevalence of singleton variants in ND4 and ND5 was two to three times higher among African haplogroup L cases than in controls. Together, the results of this study provide evidence that aggregated common and rare variants and the accumulation of singleton variants are important contributors to pancreatic cancer risk.
PMCID: PMC3271167  PMID: 22174369
Pancreatic cancer; mitochondrial DNA; oxidative phosphorylation; DNA sequencing; epidemiology
14.  Survival in Population-based Pancreatic Cancer Patients: San Francisco Bay Area, 1995–1999 
American Journal of Epidemiology  2011;174(12):1373-1381.
Patient vital status generally is passively obtained by cancer registries, and no previous population-based studies have used extensive active follow-up to compute a more accurate overall survival rate for pancreatic cancer. Therefore, the authors used multiple active and passive follow-up methods to determine vital status and date of death for 1,954 pancreatic cancer patients diagnosed from 1995 to 1999 in a large population-based study in the San Francisco Bay Area, California. Survival rates were estimated by using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals were estimated by using multivariable Cox proportional-hazards models. Vital status was confirmed for >99% of 1,954 patients. The overall 5-year survival rate was 1.3% and was greater in patients who were younger and who had localized disease, well-differentiated tumors, and surgical resection. Shorter survival was associated with older age at diagnosis, male sex, distant/metastatic disease, and poorly differentiated tumors. Longer survival was observed for Asian/Pacific Islanders compared with non-Hispanic whites and for any active treatment regardless of tumor stage. With an almost complete follow-up, the authors observed a low overall 5-year survival rate. Although the results provide further evidence of poor survival among patients with pancreatic cancer, the data also suggest that within-stage-of-disease patients survived somewhat longer with therapy.
PMCID: PMC3276299  PMID: 22047824
cohort studies; pancreatic neoplasms; survival
15.  Childhood Brain Tumors and Maternal Cured Meat Consumption in Pregnancy: Differential Effect by Glutathione S-Transferases 
Some epidemiologic studies suggest that maternal consumption of cured meat during pregnancy may increase risk of brain tumors in offspring. We explored whether this possible association was modified by fetal genetic polymorphisms in genes coding for glutathione S-transferases (GSTs) that may inactivate nitroso compounds.
We assessed six GST variants: GSTM1 null, GSTT1 null, GSTP1I105V (rs1695), GSTP1A114V (rs1138272), GSTM3*B (3 bp deletion), and GSTM3A-63C (rs1332018) within a population-based case-control study with data on maternal prenatal cured meat consumption (202 cases and 286 controls born in California or Washington, 1978-1990).
Risk of childhood brain tumor increased with increasing cured meat intake by the mother during pregnancy among children without GSTT1 (odds ratio [OR]=1.29, 95% confidence interval [CI] 1.07-1.57 for each increase in the frequency of consumption per week) or with potentially reduced GSTM3 (any -63C allele, OR=1.14, 95% CI 1.03-1.26), whereas no increased risk was observed among those with GSTT1 or presumably normal GSTM3 levels (interaction p=0.01 for each).
Fetal ability to deactivate nitrosoureas may modify the association between childhood brain tumors and maternal prenatal consumption of cured meats.
These results support the hypothesis that maternal avoidance during pregnancy of sources of some nitroso compounds or their precursors may reduce risk of brain tumors in some children.
PMCID: PMC3397426  PMID: 21914837
brain neoplasms; child; glutathione transferase; meat; nitro compounds
16.  Biologic markers of sun exposure and melanoma risk in women: pooled case-control analysis 
A model has been proposed whereby melanomas arise through two distinct pathways dependent upon the relative influence of host susceptibility and sun exposure. Such pathways may explain site-specific patterns of melanoma occurrence. To explore this model, we investigated the relationship between melanoma risk and general markers of acute (recalled sunburns) and chronic (prevalent solar keratoses) sun exposure, stratified by anatomic site and host phenotype. Our working hypothesis was that head and neck melanomas have stronger associations with solar keratoses and weaker associations with sunburn than trunk melanomas. We conducted a collaborative analysis using original data from women subjects of 11 case–control studies of melanoma (2575 cases, 3241 controls). We adjusted for potential confounding effects of sunlamp use and sunbathing. The magnitude of sunburn associations did not differ significantly by melanoma site, nevus count or histologic sub-type of melanoma. Across all sites, relative risk of melanoma increased with an increasing number of reported lifetime ‘painful’ sunburns, lifetime ‘severe’ sunburns and ‘severe’ sunburns in youth (ptrend<0.001), with pooled odds ratios for the highest category of sunburns vs no sunburns of 3.22 (95%CI 2.04–5.09) for lifetime ‘painful’ sunburns, 2.10 (95%CI 1.30–3.38) for lifetime ‘severe’ sunburns, and 2.43 (95%CI 1.61–3.65) for ‘severe’ sunburns in youth. Solar keratoses strongly increased the risk of head and neck melanoma (pOR 4.91, 95% CI 2.10–11.46), but data were insufficient to assess risk for other sites. Reported sunburn is strongly associated with melanoma on all major body sites.
PMCID: PMC3035752  PMID: 20857492
17.  The neurotensin-1 receptor agonist PD149163 inhibits conditioned avoidance responding without producing catalepsy in rats 
Agonists for neurotensin (NT)-1 receptors have produced antipsychotic-like effects in many animals, including reversal of prepulse inhibition deficits and psychostimulant-induced increases in spontaneous activity. The present study sought to provide a basic assessment of the putative antipsychotic effects of PD149163 in rats using a two way conditioned avoidance response task, which is highly validated for screening antipsychotic drugs, and an inclined grid assessment, which is used to assess extrapyramidal side effect liability. PD149163 (0.0625-8.0 mg/kg) significantly suppressed conditioned avoidance responding (CAR) following administration of a 1.0 or 8.0 mg/kg dose. PD149163 failed to significantly increase catalepsy scores. The typical antipsychotic drug haloperidol (0.01 – 1.0 mg/kg) significantly suppressed CAR at a 0.1, 0.3, and 1.0 mg/kg dose, and a significant increase in catalepsy scores was found at the 1.0 mg/kg dose. The atypical antipsychotic drug clozapine (2.5-10.0 mg/kg) also produced a significant inhibition of CAR, which occurred following administration of a 10.0 mg/kg dose. Clozapine failed to significantly increase catalepsy scores. Finally, d-amphetamine (1.0 mg/kg), serving as a negative control, failed to suppress CAR or increase catalepsy scores. These data further suggest that PD149163 may have atypical antipsychotic-like properties.
PMCID: PMC3110992  PMID: 21277173
PD149163; neurotensin; haloperidol; clozapine; conditioned avoidance response; catalepsy
18.  Sunbeds and sunlamps: who used them and their risk for melanoma 
Pigment cell & melanoma research  2011;24(3):574-581.
Sunbed/sunlamp use was recently classified as carcinogenic. This report considers characteristics of those who use sunbeds/sunlamps and the effect of sunbed/sunlamp use on their risk for melanoma within a large case-control study carried out in 1991–2. Females were more likely than males to have used sunbeds/sunlamps. Use by females increased strongly and significantly with younger ages and with the perceived ability to tan. For females the individual risk for melanoma increased with typical session time and frequency of sessions. Use before age 20, current use and years of use were not significant. The use patterns of occasional and frequent users were very different. We estimate that typical 5 minute sessions would increase the risk for melanoma by 19% for frequent users (10+ sessions) and by 3% for occasional users (1–9 sessions). Body sites that are not generally exposed to sunlight were more common sites of primary melanomas for frequent sunbed/sunlamp users. For males, measures of sunbed/sunlamp use were not significantly associated with melanoma risk.
PMCID: PMC3107003  PMID: 21362155
sunbeds/sunlamps; risk factor; melanoma; UVR; dysplastic nevi
19.  Intake of folate, vitamins B6, B12 and methionine and risk of pancreatic cancer in a large population-based case-control study 
Cancer causes & control : CCC  2009;20(8):1317-1325.
Folate and other methyl-group nutrients may play a key role in pancreatic carcinogenesis through their effects on DNA integrity. We examined the association between pancreatic cancer and intake of folate, vitamins B6, B12 and methionine in a large population-based case-control study.
Risk factor data were collected during in-person interviews with 532 pancreatic cancer cases diagnosed in 1995-1999 and 1701 frequency-matched controls in the San Francisco Bay Area. Dietary history and supplement use were obtained using a semi-quantitative food frequency questionnaire developed at Harvard University. Adjusted unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) as estimates of the relative risk.
Total folate intake was inversely associated with pancreatic cancer (5th vs. 1st quintile: OR=0.67, 95% CI=0.48-0.93, Ptrend=0.04). Increased vitamin B12 from food was positively associated with pancreatic cancer although risk estimates for quintiles 3 to 5 were similar (5th vs. 1st quintile: OR=1.9, 95% CI=1.3-2.6, Ptrend=0.001). Intake of vitamin B6 or methionine was not associated with pancreatic cancer risk.
Our study provided some support for an inverse association between folate intake and pancreatic cancer risk. The increased pancreatic cancer risk with vitamin B12 intake from food warrants further investigation.
PMCID: PMC3306816  PMID: 19415507
Pancreatic neoplasms; diet; micronutrients; folic acid; case-control studies
20.  Intake of fatty acids and antioxidants and pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area 
There are no well-established modifiable risk factors for pancreatic cancer except smoking. Some dietary factors have been associated with pancreatic cancer risk and require further study. We examined the associations among intake of specific fatty acids and antioxidants and risk of pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area. Unconditional logistic regression models were used to compute odds ratios (OR) and 95% confidence intervals (CI) as estimates of relative risk. Positive associations were observed for high levels of the eight individual saturated fatty acids (4th vs. 1st quartile: ORs ranged from 1.6 to 2.6; all Ptrend<0.001), monounsaturated palmitoleic and oleic fatty acids [OR=1.6 (95%CI: 1.2-2.1) and 1.4 (95%CI: 1.1-1.9); both Ptrend <0.01], and polyunsaturated linolenic acid [OR=1.5 (95%CI: 1.1-2.0); Ptrend=0.02]. Inverse associations were observed for high levels of gadolic acid [4th vs. 1st quartile: OR=0.68 (95%CI: 0.50-0.92); Ptrend=0.007] and omega-3 fatty acids [≥0.85g/day vs. 1st quartile: OR=0.47 (95%CI: 0.25-0.90)]. An inverse association also was observed for high total intake of vitamin C [4th vs. 1st quartile: OR=0.69 (95%CI: 0.51-0.94); Ptrend=0.004] and of vitamin E [OR=0.67 (95%CI: 0.49-0.92); Ptrend=0.01]. Although similar decreased risks also were observed for high supplemental intake of these two vitamins (both Ptrend<0.01), no association was observed for intake from food alone. These results support the hypotheses that a high intake of saturated and certain monounsaturated fatty acids may increase the risk of pancreatic cancer, whereas greater intake of omega-3 fatty acids, vitamins C and E may reduce the risk.
PMCID: PMC2930138  PMID: 20104522
Pancreatic neoplasms; nutrients; fatty acids; antioxidants; case-control studies
21.  Birth Order and Risk of Non-Hodgkin Lymphoma—True Association or Bias? 
American Journal of Epidemiology  2010;172(6):621-630.
There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983–2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.
PMCID: PMC2950815  PMID: 20720098
birth order; case-control studies; lymphoma, non-Hodgkin; selection bias; social class
22.  Cigarette, cigar and pipe smoking, passive smoke exposure, and risk of pancreatic cancer: a population-based study in the San Francisco Bay Area 
BMC Cancer  2011;11:138.
To examine the influence of cigarette, cigar and pipe smoking, cessation of cigarette smoking and passive smoke exposure on the risk of pancreatic cancer.
Exposure data were collected during in-person interviews in a population-based case-control study of pancreatic cancer (N = 532 cases, N = 1701 controls) in the San Francisco Bay Area. Odds ratios (ORs) were adjusted for potential confounders.
The adjusted odds ratio (OR) of pancreatic cancer among current smokers was 1.9 (95% confidence interval (CI), 1.4-2.7). A significant, positive trend in risk with increasing pack-years of smoking was observed (P-trend <0.0001). Compared with participants who continued to smoke, former smokers had no statistically significant elevation in risk of pancreatic cancer 10 years after smoking cessation, with risk reduced to that of never smokers regardless of prior smoking intensity. Both men and women experienced similar increased risk of pancreatic cancer with increasing smoking duration. Cigar and pipe smoking and exposure to passive smoke were not associated with pancreatic cancer.
Cigarette smoking is associated with an increased risk of pancreatic cancer. Smokers who had quit for ≥10 years no longer experienced an increased risk. Future work will help to determine the effect of declining smoking rates on pancreatic cancer incidence.
PMCID: PMC3094325  PMID: 21496267
23.  Tumor Necrosis Factor (TNF) and Lymphotoxin-α (LTA) Polymorphisms and Risk of Non-Hodgkin Lymphoma in the InterLymph Consortium 
American Journal of Epidemiology  2010;171(3):267-276.
In an International Lymphoma Epidemiology Consortium pooled analysis, polymorphisms in 2 immune-system-related genes, tumor necrosis factor (TNF) and interleukin-10 (IL10), were associated with non-Hodgkin lymphoma (NHL) risk. Here, 8,847 participants were added to previous data (patients diagnosed from 1989 to 2005 in 14 case-control studies; 7,999 cases, 8,452 controls) for testing of polymorphisms in the TNF –308G>A (rs1800629), lymphotoxin-α (LTA) 252A>G (rs909253), IL10 –3575T>A (rs1800890, rs1800896), and nucleotide-binding oligomerization domain containing 2 (NOD2) 3020insC (rs2066847) genes. Odds ratios were estimated for non-Hispanic whites and several ethnic subgroups using 2-sided tests. Consistent with previous findings, odds ratios were increased for “new” participant TNF –308A carriers (NHL: per-allele odds ratio (ORallelic) = 1.10, Ptrend = 0.001; diffuse large B-cell lymphoma (DLBCL): ORallelic = 1.23, Ptrend = 0.004). In the combined population, odds ratios were increased for TNF –308A carriers (NHL: ORallelic = 1.13, Ptrend = 0.0001; DLBCL: ORallelic = 1.25, Ptrend = 3.7 × 10−6; marginal zone lymphoma: ORallelic = 1.35, Ptrend = 0.004) and LTA 252G carriers (DLBCL: ORallelic = 1.12, Ptrend = 0.006; mycosis fungoides: ORallelic = 1.44, Ptrend = 0.015). The LTA 252A>G/TNF –308G>A haplotype containing the LTA/TNF variant alleles was strongly associated with DLBCL (P = 2.9 × 10−8). Results suggested associations between IL10 –3575T>A and DLBCL (Ptrend = 0.02) and IL10 –1082A>G and mantle cell lymphoma (Ptrend = 0.04). These findings strengthen previous results for DLBCL and the LTA 252A>G/TNF –308A locus and provide robust evidence that these TNF/LTA gene variants, or others in linkage disequilibrium, are involved in NHL etiology.
PMCID: PMC2842204  PMID: 20047977
lymphoma; lymphoma, non-Hodgkin; lymphotoxin-alpha; meta-analysis; polymorphism, genetic; polymorphism, single nucleotide; tumor necrosis factor-alpha
24.  Vitamin D, calcium, and retinol intake, and pancreatic cancer in a population-based case–control study in the San Francisco Bay area 
Cancer Causes & Control  2010;22(1):91-100.
The aim of this study was to evaluate a complex association among intake of dietary vitamin D, calcium, and retinol, and pancreatic cancer risk.
Pancreatic cancer cases (n = 532) diagnosed in 1995–1999 were identified using rapid case ascertainment methods and were frequency matched to population-based controls (n = 1,701) in the San Francisco Bay Area. Detailed dietary data were collected during in-person interviews using a validated semi-quantitative food-frequency questionnaire. Adjusted unconditional logistic regression was used to estimate odds ratios (ORs) and confidence intervals.
In men, increased pancreatic cancer risk was associated with currently recommended dietary vitamin D intake levels (highest (≥450 IU/day) vs. lowest (<150 IU/day) intake, OR = 2.6, trend-p = 0.009) and total vitamin D intake from diet and supplements (for <800 IU/day). ORs for dietary vitamin D intake remained increased after adjustment for intake of retinol and calcium, although confidence intervals included unity. Stratified analyses showed that ORs were higher among men with lower intake of retinol and lower physical activity but there was no evidence of statistical interaction. No associations with vitamin D intake were observed among women, although ORs typically were elevated. ORs increased with increased dietary calcium intake among men (trend-p = 0.008) and not women.
Our results among men showing an increased risk of pancreatic cancer associated with dietary intake of vitamin D and of calcium require confirmation in further studies. Continued investigation is needed to clarify the complex role of vitamin D and calcium in pancreatic cancer risk and to determine their optimal intake level and preventive effects for pancreatic cancer.
PMCID: PMC3002162  PMID: 21072578
Pancreatic neoplasms; Vitamin D; Vitamin A; Retinol; Calcium
25.  Solvent exposure and non-Hodgkin Lymphoma: no risk in a population-based study in the San Francisco Bay Area 
The literature on environmental exposures and risk of non-Hodgkin Lymphoma(NHL) is inconsistent and no occupational exposures have been conclusively identified as causal factors. We used job exposure matrices to assess the association between occupational exposure to solvents in a population-based case-control study of NHL (N=1591 cases,N=2515 controls) in the San Francisco Bay Area between 1988 and 1995. Occupational histories were collected during in-person interviews and were coded according to the 1980 U.S. Department of Commerce Alphabetic Index of Industries and Occupations. Odds ratios (ORs) and 95% confidence intervals (CI) were adjusted for potential confounders. Our results have provided no support for an association between NHL and occupational exposure to solvents.
PMCID: PMC2782419  PMID: 19900943
lymphoma, non-Hodgkin; case-control; occupational exposure; solvents

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