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1.  Circulating Soluble Cytokine Receptors and Colorectal Cancer Risk 
Background
Soluble cytokine receptors and receptor antagonist of proinflammatory cytokines can modify cytokine signaling and may affect cancer risk.
Methods
In a case-cohort study nested within the Women’s Health Initiative cohort of postmenopausal women, we assessed the associations of plasma levels of IL-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-1 (sIL-1R2), IL-6 (sIL-6R and sgp130), and TNF (sTNFR1 and sTNFR2) with risk of colorectal cancer in 433 cases and 821 subcohort subjects. Baseline levels of estradiol, insulin, leptin, IL-6, and TNF-α measured previously were also available for data analysis.
Results
After adjusting for significant covariates – including age, race, smoking, colonoscopy history, waist circumference, and levels of estrogen, insulin, and leptin – relatively high levels of sIL-6R and sIL-1R2 were associated with reduced colorectal cancer risk [hazard ratios comparing extreme quartiles (HRQ4-Q1) for sIL-6R = 0.56, 95% CI = 0.38–0.83; HRQ4-Q1 for sIL-1R2 = 0.44, 95% CI = 0.29–0.67]. The associations with IL-1Ra, sgp130, sTNFR1, and sTNFR2 were null. The inverse association of sIL-1R2 with colorectal cancer risk persisted in cases diagnosed ≤5 and >5 years from baseline blood draw; the association with sIL-6R, however, was not evident in the latter group, possibly indicating that relatively low levels of sIL-6R in cases might be due to undiagnosed cancer at the time of blood draw.
Conclusions
High circulating levels of sIL-1R2 may be protective against colorectal carcinogenesis and/or be a marker of reduced risk for the disease.
Impact
sIL-1R2 has potential to be a chemopreventive and/or immunotherapeutic agent in inflammation-related diseases.
doi:10.1158/1055-9965.EPI-13-0545
PMCID: PMC3947182  PMID: 24192010
soluble cytokine receptor; receptor antagonist; colorectal cancer; IL-1; IL-6; TNF
2.  Resistin, but not Adiponectin and Leptin, is Associated with the Risk of Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Background
Adipose tissue is considered an endocrine organ that secretes adipokines which possibly mediate the effects of obesity on risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and risk of ischemic stroke. We aimed to examine the associations of three adipokines (adiponectin, leptin and resistin) with risk of ischemic stroke.
Methods and Results
We conducted a prospective nested case-control study (972 stroke cases and 972 matched controls) within the Women’s Health Initiative Observational Study cohort. The controls were matched to cases on age, race/ethnicity, date of study enrollment and follow-up time. Adipokine levels were associated with established stroke risk factors, such as obesity and systolic blood pressure. Adjusted for body mass index, the odds ratios (OR) for incident ischemic stroke comparing the highest (Q4) to the lowest quartile (Q1) were 0.81 (95% confidence intervals [CI]: 0.61–1.08; p-trend: 0.068) for adiponectin, 1.15 (95% CI: 0.83–1.59; p-trend: 0.523) for leptin, and 1.57 (95% CI: 1.18–2.08; p-trend: 0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR: 1.39; 95% CI: 1.01–1.90; p-trend: 0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results.
Conclusions
Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other CVD risk factors.
doi:10.1161/STROKEAHA.110.607853
PMCID: PMC4059356  PMID: 21546486
stroke; adipokines; women
3.  Pharmacologic treatment of anxiety disorders in Parkinson's disease 
Objective
Neither best practices nor an evidence-base for the pharmacologic treatment of anxiety in Parkinson's disease has been established. This study investigated pharmacologic treatment of anxiety disorders in idiopathic Parkinson's disease and the associated clinical features.
Design
Cross-sectional.
Setting
Three community-based movement disorder neurology practices
Participants
250 subjects with Parkinson's disease.
Measurements
Anxiety disorder diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Current medications were provided by the treating neurologists at the time of interview.
Results
Amongst subjects with anxiety disorders only, 53% were untreated with medications. However, when anxious subjects with comorbid depressive disorders were included, 70.8% were on medications effective for treatment of anxiety. Subjects with anxiety and comorbid depressive disorders were more likely to be treated for their psychiatric disturbances than subjects with anxiety disorders alone (Odds Ratio 8.33) as were subjects with comorbid motor fluctuations (Odds Ratio, 3.65). There were no differences in the types of anti-anxiety medications used in regard to the presence of depression or motor fluctuations.
Conclusions
These findings suggest that over half of non-depressed Parkinson's disease patients with clinically significant anxiety are untreated with medication. A better understanding of the role of clinical features associated with anxiety in PD, such as depression and motor fluctuations, may improve the recognition and treatment of anxiety disorders in this population.
doi:10.1016/j.jagp.2012.10.023
PMCID: PMC3655116  PMID: 23567419
Parkinson’s disease; Non-motor symptoms; Anxiety; Anxiety disorders; Psychiatric disorders; Treatment
4.  Benzofuran-, benzothiophene-, indazole- and benzisoxazole- quinones: excellent substrates for NAD(P)H:quinone oxidoreductase 1 
Bioorganic & medicinal chemistry  2013;21(11):2999-3009.
A series of heterocyclic quinones based on benzofuran, benzothiophene, indazole and benzisoxazole has been synthesized, and evaluated for their ability to function as substrates for recombinant human NAD(P)H:quinone oxidoreductase (NQO1), a two-electron reductase upregulated in tumor cells. Overall, the quinones are excellent substrates for NQO1, approaching the reduction rates observed for menadione
doi:10.1016/j.bmc.2013.03.071
PMCID: PMC3697102  PMID: 23635904
Quinone; Benzofuran; Benzothiophene; Indazole; Quinone reductase; NQO1
5.  Synthesis of New Quinolinequinone Derivatives and Preliminary Exploration of their Cytotoxic Properties 
Journal of medicinal chemistry  2013;56(10):3806-3819.
A series of 7-amino- and 7-acetamidoquinoline-5,8-diones with aryl substituents at the 2-position were synthesized, characterized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The synthesis of lavendamycin analogs is illustrated. Metabolism studies demonstrated that 7-amino-analogues were generally better substrates for NQO1 than 7-amido-analogues as were compounds with smaller heteroaromatic substituents at the C-2 position. Surprisingly, only two compounds, 7-acetamido-2-(8’-quinolinyl)quinoline-5,8-dione (11) and 7-amino-2-(2-pyridinyl)quinoline-5,8-dione (23) showed selective cytotoxicity toward the NQO1-expressing MDA468-NQ16 breast cancer cells versus the NQO1-null MDA468-WT cells. For all other compounds, NQO1 protected against quinoline-5,8-dione cytotoxicity. Compound 22 showed a potent activity against human breast cancer cells expressing or not expressing NQO1 with IC50 values of respectively 190 nM and 140 nM and a low NQO1 mediated reduction rate, which suggests that the mode of action of 22 differs from lavendamycin and involves an unidentified target(s).
doi:10.1021/jm301689x
PMCID: PMC3752426  PMID: 23574193
Lavendamycin; Suzuki coupling; microwave irradiation; palladium (0) catalysis; quinolinequinones; NQO1; antitumor; cytotoxicity
6.  Coupling of Two Non-processive Myosin 5c Dimers Enables Processive Stepping along Actin Filaments 
Scientific Reports  2014;4:4907.
Myosin 5c (Myo5c) is a low duty ratio, non-processive motor unable to move continuously along actin filaments though it is believed to participate in secretory vesicle trafficking in vertebrate cells. Here, we measured the ATPase kinetics of Myo5c dimers and tested the possibility that the coupling of two Myo5c molecules enables processive movement. Steady-state ATPase activity and ADP dissociation kinetics demonstrated that a dimer of Myo5c-HMM (double-headed heavy meromyosin 5c) has a 6-fold lower Km for actin filaments than Myo5c-S1 (single-headed myosin 5c subfragment-1), indicating that the two heads of Myo5c-HMM increase F-actin-binding affinity. Nanometer-precision tracking analyses showed that two Myo5c-HMM dimers linked with each other via a DNA scaffold and moved processively along actin filaments. Moreover, the distance between the Myo5c molecules on the DNA scaffold is an important factor for the processive movement. Individual Myo5c molecules in two-dimer complexes move stochastically in 30–36 nm steps. These results demonstrate that two dimers of Myo5c molecules on a DNA scaffold increased the probability of rebinding to F-actin and enabled processive steps along actin filaments, which could be used for collective cargo transport in cells.
doi:10.1038/srep04907
PMCID: PMC4014986  PMID: 24809456
7.  Monitoring of Internet Forums to Evaluate Reactions to the Introduction of Reformulated OxyContin to Deter Abuse 
Background
Reformulating opioid analgesics to deter abuse is one approach toward improving their benefit-risk balance. To assess sentiment and attempts to defeat these products among difficult-to-reach populations of prescription drug abusers, evaluation of posts on Internet forums regarding reformulated products may be useful. A reformulated version of OxyContin (extended-release oxycodone) with physicochemical properties to deter abuse presented an opportunity to evaluate posts about the reformulation in online discussions.
Objective
The objective of this study was to use messages on Internet forums to evaluate reactions to the introduction of reformulated OxyContin and to identify methods aimed to defeat the abuse-deterrent properties of the product.
Methods
Posts collected from 7 forums between January 1, 2008 and September 30, 2013 were evaluated before and after the introduction of reformulated OxyContin on August 9, 2010. A quantitative evaluation of discussion levels across the study period and a qualitative coding of post content for OxyContin and 2 comparators for the 26 month period before and after OxyContin reformulation were conducted. Product endorsement was estimated for each product before and after reformulation as the ratio of endorsing-to-discouraging posts (ERo). Post-to-preintroduction period changes in ERos (ie, ratio of ERos) for each product were also calculated. Additionally, post content related to recipes for defeating reformulated OxyContin were evaluated from August 9, 2010 through September 2013.
Results
Over the study period, 45,936 posts related to OxyContin, 18,685 to Vicodin (hydrocodone), and 23,863 to Dilaudid (hydromorphone) were identified. The proportion of OxyContin-related posts fluctuated between 6.35 and 8.25 posts per 1000 posts before the reformulation, increased to 10.76 in Q3 2010 when reformulated OxyContin was introduced, and decreased from 9.14 in Q4 2010 to 3.46 in Q3 2013 in the period following the reformulation. The sentiment profile for OxyContin changed following reformulation; the post-to-preintroduction change in the ERo indicated reformulated OxyContin was discouraged significantly more than the original formulation (ratio of ERos=0.43, P<.001). A total of 37 recipes for circumventing the abuse-deterrent characteristics of reformulated OxyContin were observed; 32 were deemed feasible (ie, able to abuse). The frequency of posts reporting abuse of reformulated OxyContin via these recipes was low and decreased over time. Among the 5677 posts mentioning reformulated OxyContin, 825 posts discussed recipes and 498 reported abuse of reformulated OxyContin by such recipes (41 reported injecting and 128 reported snorting).
Conclusions
After introduction of physicochemical properties to deter abuse, changes in discussion of OxyContin on forums occurred reflected by a reduction in discussion levels and endorsing content. Despite discussion of recipes, there is a relatively small proportion of reported abuse of reformulated OxyContin via recipes, particularly by injecting or snorting routes. Analysis of Internet discussion is a valuable tool for monitoring the impact of abuse-deterrent formulations.
doi:10.2196/jmir.3397
PMCID: PMC4026575  PMID: 24800858
Internet; opioid analgesic; drug abuse; prescription drug; OxyContin; epidemiology; surveillance; social media; qualitative research
8.  Selenoprotein P Genetic Variants and mRNA Expression, Circulating Selenium and Prostate Cancer Risk and Survival 
The Prostate  2012;73(7):700-705.
Background
Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions.
Methods
The Physicians’ Health Study (PHS) is a prospective cohort of 22,071 US physicians; we utilized a nested case-control study of 1,352 PCa cases and 1,382 controls. We assessed four SNPs capturing common variation within the SEPP1 locus. In a subset of men (n=80), we evaluated SEPP1 mRNA expression in tumors.
Results
Two SNPs were significantly associated with PCa risk. For rs11959466, each T allele increased risk (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02,1.69; ptrend=0.03). For rs13168440, the rare homozygote genotype decreased risk compared to the common homozygote (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with plasma selenium; increasing selenium levels were associated with decreased PCa risk only among men with the minor allele (pinteraction=0.01). SEPP1 expression was significantly lower in men with lethal PCa than long-term survivors.
Conclusions
SEPP1 genetic variation was associated with PCa incidence; replication of these results in an independent dataset is necessary. These findings further support a causal link between selenium and PCa, and suggest that the effect of selenium may differ by genetics.
doi:10.1002/pros.22611
PMCID: PMC3640488  PMID: 23129481
genetic variation; selenium; prostate cancer
9.  Inflammatory Plasma Markers and Pancreatic Cancer Risk: a Prospective Study of 5 U.S. Cohorts 
Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α-receptor II (TNF-αR2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1094 controls from Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL6, and TNF-αR2 and risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 (95% CI, 0.74-1.63; Ptrend= 0.81) for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-αR2. In conclusion, pre-diagnostic levels of circulating CRP, IL6, and TNF-αR2 were not associated with risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.
doi:10.1158/1055-9965.EPI-12-1458
PMCID: PMC3650127  PMID: 23462920
10.  THE 2011-2016 TRANSDISCIPLINARY RESEARCH IN ENERGETICS AND CANCER (TREC) INITIATIVE: RATIONALE AND DESIGN 
Cancer causes & control : CCC  2013;24(4):695-704.
Purpose
Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms.
Methods
The National Cancer Institute developed an innovative concept to establish a centers grant mechanism in nutrition, energetics, and physical activity; referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the Centers.
Results
Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes 3 animal studies, 3 cohort studies, 4 randomized clinical trials, 1 cross-sectional study, and 2 modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality.
Conclusion
The NIH Science of Team Science group will evaluate the value-added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk for cancer as well as cancer survivors.
doi:10.1007/s10552-013-0150-z
PMCID: PMC3602225  PMID: 23378138
energetics; obesity; diet; physical activity; cancer; transdisciplinary
11.  Invasive cervical cancer risk among HIV-infected women: A North American multi-cohort collaboration prospective study 
Objective
HIV infection and low CD4+ T-cell count are associated with an increased risk of persistent oncogenic HPV infection – the major risk factor for cervical cancer. Few reported prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women.
Methods
Data were obtained from HIV-infected and -uninfected female participants in the NA-ACCORD with no history of ICC at enrollment. Participants were followed from study entry or January, 1996 through ICC, loss-to follow-up or December, 2010. The relationship of HIV infection and CD4+ T-cell count with risk of ICC was assessed using age-adjusted Poisson regression models and standardized incidence ratios (SIR). All cases were confirmed by cancer registry records and/or pathology reports. Cervical cytology screening history was assessed through medical record abstraction.
Results
A total of 13,690 HIV-infected and 12,021 HIV-uninfected women contributed 66,249 and 70,815 person-years (pys) of observation, respectively. Incident ICC was diagnosed in 17 HIV-infected and 4 HIV-uninfected women (incidence rate of 26 and 6 per 100,000 pys, respectively). HIV-infected women with baseline CD4+ T-cells of ≥ 350, 200–349 and <200 cells/uL had a 2.3-times, 3.0-times and 7.7-times increase in ICC incidence, respectively, compared with HIV-uninfected women (Ptrend =0.001). Of the 17 HIV-infected cases, medical records for the 5 years prior to diagnosis showed that 6 had no documented screening, 5 had screening with low grade or normal results, and 6 had high-grade results.
Conclusions
This study found elevated incidence of ICC in HIV-infected compared to -uninfected women, and these rates increased with immunosuppression.
doi:10.1097/QAI.0b013e31828177d7
PMCID: PMC3633634  PMID: 23254153
Human papilloma virus; HIV-infection; Invasive Cervical Cancer; Immunosuppression
12.  Consistent Group Identification and Variable Selection in Regression with Correlated Predictors 
Statistical procedures for variable selection have become integral elements in any analysis. Successful procedures are characterized by high predictive accuracy, yielding interpretable models while retaining computational efficiency. Penalized methods that perform coefficient shrinkage have been shown to be successful in many cases. Models with correlated predictors are particularly challenging to tackle. We propose a penalization procedure that performs variable selection while clustering groups of predictors automatically. The oracle properties of this procedure including consistency in group identification are also studied. The proposed method compares favorably with existing selection approaches in both prediction accuracy and model discovery, while retaining its computational efficiency. Supplemental material are available online.
doi:10.1080/15533174.2012.707849
PMCID: PMC3678393  PMID: 23772171
Coefficient shrinkage; Correlation; Group identification; Oracle properties; Penalization; Supervised clustering; Variable selection
13.  Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach 
AIDS (London, England)  2013;27(9):1473-1481.
Objective
CD4 and CD8 T-cell activation are independent predictors of AIDS. The complete activation profile of both T-cell subtypes and their predictive value for AIDS risk is largely unknown.
Design
A total of 564 AIDS-free women in the Women's Interagency HIV Study were followed over 6.1 years (median) after T-cell activation assessment. A cluster analysis approach was used to evaluate the concurrent activation patterns of CD4 and CD8 T cells at the beginning of follow-up in relation to AIDS progression.
Methods
Percentages of CD4 and CD8 T cells with HLA-DR± and CD38± were assessed by flowcytometry. Eight immunologic variables (four on each CD4+ and CD8+: DR± and CD38±) were assessed to yield a 4-cluster solution on samples obtained before clinical endpoints. Proportional hazards survival regression estimated relative risks for AIDS progression by cluster membership.
Results
Compared with the other three clusters, outstanding activation features of each distinct cluster of women were: Cluster 1: higher CD8+CD38– DR– (average = 41% of total CD8 T-cell pool), CD4+CD38– DR– (average = 53% of total CD4 T-cell pool), and CD8+CD38– DR+ (28%); Cluster 2: higher CD8+CD38+DR– (44%) and CD4+CD38+DR– (58%); Cluster 3: higher CD8+CD38+DR+ (49%) and CD4+ CD38+DR– (48%); Cluster 4: higher CD8+CD38+DR+ (49%), CD4+CD38+DR+ (36%) and CD4+CD38– DR+ (19%). Compared with cluster 1, women in cluster 4 had two-fold increased risk of AIDS progression (Hazard ratio = 2.13; 95% confidence interval = 1.30–3.50) adjusted for CD4 cell count, HIV RNA, and other confounders.
Conclusion
A profile including CD4 and CD8 T-cell activation provided insight into HIV pathogenesis indicating concurrent hyperactivation of CD4 and CD8 T cells is associated with AIDS progression.
doi:10.1097/QAD.0b013e3283601bad
PMCID: PMC3949252  PMID: 23945505
AIDS; cluster analysis; immune activation
14.  Factor Selection and Structural Identification in the Interaction ANOVA Model 
Biometrics  2013;69(1):70-79.
Summary
When faced with categorical predictors and a continuous response, the objective of analysis often consists of two tasks: finding which factors are important and determining which levels of the factors differ significantly from one another. Often times these tasks are done separately using Analysis of Variance (ANOVA) followed by a post-hoc hypothesis testing procedure such as Tukey’s Honestly Significant Difference test. When interactions between factors are included in the model the collapsing of levels of a factor becomes a more difficult problem. When testing for differences between two levels of a factor, claiming no difference would refer not only to equality of main effects, but also equality of each interaction involving those levels. This structure between the main effects and interactions in a model is similar to the idea of heredity used in regression models. This paper introduces a new method for accomplishing both of the common analysis tasks simultaneously in an interaction model while also adhering to the heredity-type constraint on the model. An appropriate penalization is constructed that encourages levels of factors to collapse and entire factors to be set to zero. It is shown that the procedure has the oracle property implying that asymptotically it performs as well as if the exact structure were known beforehand. We also discuss the application to estimating interactions in the unreplicated case. Simulation studies show the procedure outperforms post hoc hypothesis testing procedures as well as similar methods that do not include a structural constraint. The method is also illustrated using a real data example.
doi:10.1111/j.1541-0420.2012.01810.x
PMCID: PMC3772552  PMID: 23323643
Interaction ANOVA model; Grouping; Multiple comparisons; Oracle propery; Shrinkage; Variable selection
15.  Remating and Sperm Competition in Replicate Populations of Drosophila melanogaster Adapted to Alternative Environments 
PLoS ONE  2014;9(2):e90207.
The prevalence of sexual conflict in nature, as well as the supposedly arbitrary direction of the resulting coevolutionary trajectories, suggests that it may be an important driver of phenotypic divergence even in a constant environment. However, natural selection has long been central to the operation of sexual conflict within populations and may therefore constrain or otherwise direct divergence among populations. Ecological context may therefore matter with respect to the diversification of traits involved in sexual conflict, and if natural selection is sufficiently strong, such traits may evolve in correlation with environment, generating a pattern of ecologically-dependent parallel evolution. In this study we assess among-population divergence both within and between environments for several traits involved in sexual conflict. Using eight replicate populations of Drosophila melanogaster from a long-term evolution experiment, we measured remating rates and subsequent offspring production of females when housed with two separate males in sequence. We found no evidence of any variation in male reproductive traits (offense or defense). However, the propensity of females to remate diverged significantly among the eight populations with no evidence of any environmental effect, consistent with sexual conflict promoting diversification even in the absence of ecological differences. On the other hand, females adapted to one environment (ethanol) tended to produce a higher proportion of offspring sired by their first mate as compared to those adapted to the other (cadmium) environment, suggesting ecologically-based divergence of this conflict phenotype. Because we find evidence for both stochastic population divergence operating outside of an ecological context and environment-dependent divergence of traits under sexual conflict, the interaction of these two processes is an important topic for future work.
doi:10.1371/journal.pone.0090207
PMCID: PMC3934985  PMID: 24587283
16.  A compendium of RNA-binding motifs for decoding gene regulation 
Nature  2013;499(7457):172-177.
RNA-binding proteins are key regulators of gene expression, yet only a small fraction have been functionally characterized. Here we report a systematic analysis of the RNA motifs recognized by RNA-binding proteins, encompassing 205 distinct genes from 24 diverse eukaryotes. The sequence specificities of RNA-binding proteins display deep evolutionary conservation, and the recognition preferences for a large fraction of metazoan RNA-binding proteins can thus be inferred from their RNA-binding domain sequence. The motifs that we identify in vitro correlate well with in vivo RNA-binding data. Moreover, we can associate them with distinct functional roles in diverse types of post-transcriptional regulation, enabling new insights into the functions of RNA-binding proteins both in normal physiology and in human disease. These data provide an unprecedented overview of RNA-binding proteins and their targets, and constitute an invaluable resource for determining post-transcriptional regulatory mechanisms in eukaryotes.
doi:10.1038/nature12311
PMCID: PMC3929597  PMID: 23846655
17.  Ethyl 3-(9-chloro-10-oxo-9,10-di­hydro­anthracen-9-yl)-5-methyl­isoxazole-4-carboxyl­ate 
The asymmetric unit of the title compound, C21H16ClNO4, contains two independent mol­ecules (A and B), each adopting a conformation wherein the isoxazole ring is roughly orthogonal to the anthrone ring. The dihedral angle between the mean plane of the isoxazole (all atoms) and the mean plane of the anthrone (all atoms) is 88.48 (3)° in one mol­ecule and 89.92 (4)° in the other. The ester is almost coplanar with the isoxazole ring, with mean-plane dihedral angles of 2.48 (15) and 8.62 (5)°. In both mol­ecules, the distance between the ester carbonyl O atom and the anthrone ketone C atom is about 3.3 Å. The anthrone ring is virtually planar (r.m.s. deviations of 0.070 and 0.065 Å) and adopts a shallow boat conformation in each mol­ecule, as evidenced by the sum of the six intra-B-ring torsion angles [41.43 (15) and 34.38 (15)° for molecules A and B, respectively]. The closest separation between the benzene moieties of anthrones A and B is 5.1162 (7) Å, with an angle of 57.98 (5)°, consistent with an edge-to-face π-stacking inter­action. In the crystal, weak C—H⋯O and C—H⋯N inter­actions link the mol­ecules, forming a three-dimensional network.
doi:10.1107/S1600536814003080
PMCID: PMC3998422  PMID: 24765016
19.  Hepatocyte Growth Factor and the Risk of Developing Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Background
Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke.
Methods and Results
We conducted a nested case-control study (972 incident stroke cases and 1:1 age- and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women’s Health Initiative Observational Study, a cohort of postmenopausal women aged 50–79 years. Baseline HGF levels were correlated positively with body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P-values <0.05). Baseline HGF levels were higher among cases than controls (geometric means 601.8 vs. 523.2 pg/mL, p = 0.003). Furthermore, the risk of incident ischemic stroke was significantly greater amongst women in the highest versus lowest quartile of plasma HGF levels (odds ratio [OR] = 1.46; 95% confidence interval [CI]: 1.12–1.91; Ptrend = 0.003), in a conditional logistic regression model that adjusted for BMI. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR=1.39; 95% CI=1.04–1.85, Ptrend=0.023).
Conclusions
Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease among postmenopausal women aged 50–79 years.
doi:10.1161/STROKEAHA.109.567719
PMCID: PMC3903044  PMID: 20203323
Hepatocyte growth factor; ischemic stroke; women
20.  A Prospective Study of Plasma Adiponectin and Pancreatic Cancer Risk in Five US Cohorts 
Background
The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and chronic inflammation, the mechanistic basis of the associations is poorly understood.
Methods
To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case–control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided.
Results
Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P heterogeneity = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios ([ORs] 95% confidence intervals [CIs]) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P trend = .04). Restricted cubic spline regression confirmed a nonlinear association (P nonlinearity < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P interaction > .10).
Conclusions
In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.
doi:10.1093/jnci/djs474
PMCID: PMC3545904  PMID: 23243202
21.  Expression of Human NAD(P)H:Quinone Oxidoreductase (DT-Diaphorase) in Chinese Hamster Ovary Cells: Effect on the Toxicity of Antitumor Quinones 
Molecular pharmacology  1996;50(4):728-735.
SUMMARY
Previous studies have indicated that NAD(P)H:quinone oxidoreductase [DT-diaphorase (NQO1)] plays an important role in the bioreductive activation of quinone-containing antitumor agents. Although these studies demonstrated that purified NQO1 can reduce these compounds in vitro, the importance NQO1 in the intracellular activation of quinone-containing antitumor agents remains controversial. In our study, we transfected human NQO1 into Chinese hamster ovary cells that do not normally express NQO1 activity and obtained stable clones that expressed NQO1 activity of 19–3527 nmol of 2,6-dichlorophenolindophenol reduced/min/mg of protein. The level of NQO1 expression correlated with an increased killing by streptonigrin, EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)-propenol), and 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone, but mitomycin C sensitivity was independent of this activity. NQO1 expression also led to a slight decrease in the sensitivity of cells to menadione. Our data demonstrate that compounds that are efficient substrates for NQO1 in vitro are also bioactivated in cultured mammalian cells when they are transfected with human NQO1. These results are consistent with the relative abilities of mitomycin C, streptonigrin, EO9, and 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone to serve as substrates for bioreduction by human NQO1, and show that NQO1 levels are not necessarily predictive in terms of sensitivity to mitomycin C.
PMCID: PMC3883621  PMID: 8863816
22.  Global regulation of mRNA translation and stability in the early Drosophila embryo by the Smaug RNA-binding protein 
Genome Biology  2014;15(1):R4.
Background
Smaug is an RNA-binding protein that induces the degradation and represses the translation of mRNAs in the early Drosophila embryo. Smaug has two identified direct target mRNAs that it differentially regulates: nanos and Hsp83. Smaug represses the translation of nanos mRNA but has only a modest effect on its stability, whereas it destabilizes Hsp83 mRNA but has no detectable effect on Hsp83 translation. Smaug is required to destabilize more than one thousand mRNAs in the early embryo, but whether these transcripts represent direct targets of Smaug is unclear and the extent of Smaug-mediated translational repression is unknown.
Results
To gain a panoramic view of Smaug function in the early embryo, we identified mRNAs that are bound to Smaug using RNA co-immunoprecipitation followed by hybridization to DNA microarrays. We also identified mRNAs that are translationally repressed by Smaug using polysome gradients and microarrays. Comparison of the bound mRNAs to those that are translationally repressed by Smaug and those that require Smaug for their degradation suggests that a large fraction of Smaug’s target mRNAs are both translationally repressed and degraded by Smaug. Smaug directly regulates components of the TRiC/CCT chaperonin, the proteasome regulatory particle and lipid droplets, as well as many metabolic enzymes, including several glycolytic enzymes.
Conclusions
Smaug plays a direct and global role in regulating the translation and stability of a large fraction of the mRNAs in the early Drosophila embryo, and has unanticipated functions in control of protein folding and degradation, lipid droplet function and metabolism.
doi:10.1186/gb-2014-15-1-r4
PMCID: PMC4053848  PMID: 24393533
23.  Do socio-economic gradients in smoking emerge differently across time by gender? Implications for the tobacco epidemic from a pregnancy cohort in California, USA 
Social science & medicine (1982)  2012;76(1):101-106.
Understanding current patterns of population smoking by socioeconomic position (SEP) can be substantially enhanced by research that follows birth cohorts over long periods of time, yet such data in the US are rare. Information from birth cohorts followed during critical time periods when the health consequences of smoking became widely known can inform the ways in which current smoking prevalence has been shaped by the historical processes that preceded it. The present study utilizes data from a substudy of the Child Health and Development Study pregnancy cohort (N = 1612). Women were queried about smoking status in 1959–1962, 1971–1972 and 1977–1980. Women were divided into three cohorts based on date of birth. Offspring represented another birth cohort assessed for smoking in 1977–1980. Results indicated that the overall prevalence of smoking exhibited cohort-specific patterns that persisted across time. Notably, the youngest maternal cohort (born 1937–1946) had high smoking prevalence throughout and showed no appreciable decrease (44.7%, 41.4%, 40.1% for 1959–1962, 1971–1972, and 1977–1980). Results also indicated that the relation of smoking to SEP exhibited cohort-specific patterns over time. Among the oldest birth cohort (born 1914–1930), no inverse relation of SEP to smoking was observed at any time; in contrast, an inverse relation emerged by 1959–1962 among the youngest cohort of mothers. Among the adolescent offspring, there was a strong SEP gradient (OR = 2.0, 95% CI = 1.4–3.0) that was stronger than in any maternal birth cohort at any assessment (β = 0.40, SE = 0.1, p < 0.01). We conclude that SEP gradients in smoking emerge across birth cohorts rather than time alone, with increasingly strong gradients across time especially among younger cohorts.
doi:10.1016/j.socscimed.2012.10.011
PMCID: PMC3612831  PMID: 23186639
U.S.; Gender; Socio-economic position; Smoking; Longitudinal studies; Birth cohort effects
24.  Relation of HLA Class I and II Supertypes with Spontaneous Clearance of Hepatitis C Virus 
Genes and immunity  2013;14(5):330-335.
Human leukocyte antigen (HLA) genotype has been associated with probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; p=0.004) was associated with HCV persistence while DR8 (PR=1.8; p=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became non-significant in analysis that included supertypes while B*57:03 (PR=1.9; p=0.008) and DRB1*07:01 (PR=1.7; p=0.005) retained significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance.
doi:10.1038/gene.2013.25
PMCID: PMC3723800  PMID: 23636221
hepatitis C virus; HLA; human leukocyte antigen; supertype
25.  Efficient Robust Regression via Two-Stage Generalized Empirical Likelihood 
Large- and finite-sample efficiency and resistance to outliers are the key goals of robust statistics. Although often not simultaneously attainable, we develop and study a linear regression estimator that comes close. Efficiency obtains from the estimator’s close connection to generalized empirical likelihood, and its favorable robustness properties are obtained by constraining the associated sum of (weighted) squared residuals. We prove maximum attainable finite-sample replacement breakdown point, and full asymptotic efficiency for normal errors. Simulation evidence shows that compared to existing robust regression estimators, the new estimator has relatively high efficiency for small sample sizes, and comparable outlier resistance. The estimator is further illustrated and compared to existing methods via application to a real data set with purported outliers.
doi:10.1080/01621459.2013.779847
PMCID: PMC3747015  PMID: 23976805
Asymptotic efficiency; Breakdown point; Constrained optimization; Efficient estimation; Empirical likelihood; Exponential tilting; Least trimmed squares; Robust regression; Weighted least squares

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