Thu T. Nguyen

Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling

Targeting protein kinase C (PKC) isoforms by the small molecule inhibitor enzastaurin has shown promising preclinical activity in a wide range of tumor cells. We further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of beta-catenin in regulating growth and survival of tumor cells. Specifically, inhibition of PKC leads to rapid accumulation of beta-catenin by preventing the phosphorylation required for its proteasomal degradation. Microarray analysis and small-interfering RNA (siRNA)-mediated gene silencing in MM cells revealed that accumulated beta-catenin activates early endoplasmic reticulum stress signaling via eIF2alpha, C/EBP-homologous protein (CHOP), and p21, leading to immediate growth inhibition. Furthermore, accumulated beta-catenin contributes to enzastaurin-induced cell death. Sequential knockdown of beta-catenin, c-Jun, and p73, as well as overexpression of beta-catenin or p73 confirmed that accumulated beta-catenin triggers c-Jun-dependent induction of p73, thereby conferring MM cell apoptosis. Our data reveal a novel role of beta-catenin in endoplasmic reticulum (ER) stress-mediated growth inhibition and a new proapoptotic mechanism triggered by beta-catenin on inhibition of PKC isoforms. Moreover, we identify p73 as a potential novel therapeutic target in MM. Based on these and previous data, enzastaurin is currently under clinical investigation in a variety of hematologic malignancies, including MM.

Current state of US breastfeeding laws

This study systematically examined state-level laws protecting breastfeeding, including their current status and historical development, as well as identified gaps across US states and regions. The National Conference of State Legislatures summarised breastfeeding laws for 50 states and DC as of September 2010, which we updated through May 2011. We then searched LexisNexis and Westlaw to find the full text of laws, recording enactment dates and definitions. Laws were coded into five categories: (1) employers are encouraged or required to provide break time and private space for breastfeeding employees; (2) employers are prohibited from discriminating against breastfeeding employees; (3) breastfeeding is permitted in any public or private location; (4) breastfeeding is exempt from public indecency laws; and (5) breastfeeding women are exempt from jury duty. By May 2011, 1 state had enacted zero breastfeeding laws, 10 had one, 22 had two, 12 had three, 5 had four and 1 state had laws across all five categories. While 92% of states allowed mothers to breastfeed in any location and 57% exempted breastfeeding from indecency laws, 37% of states encouraged or required employers to provide break time and accommodations, 24% offered breastfeeding women exemption from jury duty and 16% prohibited employment discrimination. The Northeast had the highest proportion of states with breastfeeding laws and the Midwest had the lowest. Breastfeeding outside the home is protected to varying degrees depending on where women live; this suggests that many women are not covered by comprehensive laws that promote breastfeeding.

Instrumental variable approaches to identifying the causal effect of educational attainment on dementia risk

PURPOSE Education is an established correlate of cognitive status in older adulthood, but whether expanding educational opportunities would improve cognitive functioning remains unclear given limitations of prior studies for causal inference. Therefore, we conducted instrumental variable (IV) analyses of the association between education and dementia risk, using for the first time in this area, genetic variants as instruments as well as state-level school policies. METHODS IV analyses in the Health and Retirement Study cohort (1998-2010) used two sets of instruments: (1) a genetic risk score constructed from three single-nucleotide polymorphisms (SNPs; n = 7981); and (2) compulsory schooling laws (CSLs) and state school characteristics (term length, student teacher ratios, and expenditures; n = 10,955). RESULTS Using the genetic risk score as an IV, there was a 1.1% reduction in dementia risk per year of schooling (95% confidence interval, -2.4 to 0.02). Leveraging compulsory schooling laws and state school characteristics as IVs, there was a substantially larger protective effect (-9.5%; 95% confidence interval, -14.8 to -4.2). Analyses evaluating the plausibility of the IV assumptions indicated estimates derived from analyses relying on CSLs provide the best estimates of the causal effect of education. CONCLUSIONS IV analyses suggest education is protective against risk of dementia in older adulthood.

Racial differences in blood pressure response to calcium channel blocker monotherapy: A meta-analysis

BACKGROUND A systematic literature review was conducted to determine whether US blacks and whites have differential blood pressure (BP) response to calcium channel blocker (CCB) monotherapy. METHODS Six published studies made up the final cohort of eligible articles. Multiple treatment groups within some studies led to a total of eight sets of estimates for BP reduction with a total of 6,851 white or nonblack participants and 3,371 black participants. RESULTS The pooled difference in systolic blood pressure (SBP) change between blacks and whites was -2.7 mm Hg (95% confidence interval (CI): -4.0, -1.3) with blacks having greater response. The difference in diastolic blood pressure (DBP) between blacks and whites was -0.4 mm Hg (95% CI: -1.0, 0.3) with blacks having greater response. Using a dichotomous outcome measure, whites were found to be just as likely as blacks to attain the DBP goal of <90 mm Hg or a 10 mm Hg or greater change (relative risk: 1.00 95% CI: 0.91, 1.11). In addition, examination of the continuous distribution of BP responses of whites and blacks showed over 90% overlap in treatment response. CONCLUSION Assessment of differential response to CCB monotherapy by race in published data depends on choice of outcome metric. Nonetheless, the results of this systematic review indicate that BP response is qualitatively similar in US blacks and whites, suggesting that patient race is not likely to offer any clinical utility for decisions about the likely effect of this antihypertensive therapy.

Are self-reported neighbourhood characteristics associated with onset of functional limitations in older adults with or without memory impairment?

Background Neighbourhood resources may preserve functional independence in older adults, but little is known about whether benefits differ for individuals with normal and impaired memory. We evaluated the extent to which neighbourhood context was related to onset of instrumental and basic activities of daily living (I/ADL) limitations and whether relationships were modified by memory impairment. Methods Health and Retirement Study participants 50+ years of age without baseline I/ADL limitations (n=8726 for IADL and n=8345 for ADL models) were interviewed biennially for up to 8 years. Self-reported neighbourhood characteristics were scaled from 0 (worst) to 1 (best). Memory, assessed by direct and proxy cognitive assessments, was dichotomised at the 20th centile. We used pooled logistic regression models, adjusted for demographics and individual characteristics. Results Low neighbourhood physical disorder (OR=0.51 (95% CI: 0.37 to 0.69)), high social cohesion (OR=0.46 (0.34 to 0.62)), and high safety (OR=0.59 (0.46 to 0.76)) were associated with reduced incidence of IADL limitations. These neighbourhood characteristics were also associated with lower incidence of ADL limitations (disorder OR=0.59 (0.43 to 0.81)); social cohesion OR=0.60 (0.45 to 0.81)); safety OR=0.74 (0.58 to 0.93)). High social ties were not related to ADLs (OR=1.01(0.80 to 1.28)) or IADLs (OR=0.93(0.74 to 1.17)). The benefits of these neighbourhood characteristics for ADLs were similar among those with and without memory impairment but primarily observed among those without memory impairment for IADLs. Conclusions Older adults living in neighbourhoods with low physical disorder, high social cohesion and high safety experience lower incidence of IADL and ADL limitations. Memory status modified the estimated effects of neighbourhood characteristics on IADL but not ADL limitations.

Modifiable risk factors for nursing home admission among individuals with high and low dementia risk

BACKGROUND Strategies to prevent or delay nursing home admission in individuals with cognitive impairment are urgently needed. We hypothesized that physical inactivity, not consuming alcohol (as opposed to moderate alcohol use), and having a history of smoking predict nursing home admission among individuals with normal cognitive function, but these behavioral factors would have attenuated associations with nursing home admission among individuals with impaired cognition. METHODS We performed a prospective cohort study among 7631 Health and Retirement Study participants aged 65+ at baseline. Baseline dementia risk (high versus low, based on brief psychometric assessments and proxy reports) and modifiable risk factors (physical inactivity, ever smoking, and not consuming alcohol) were used to predict nursing home admission in pooled logistic regression models. We evaluated whether estimated effects of modifiable factors varied by dementia risk, comparing both relative and absolute effects using interaction terms between dementia risk and each modifiable risk factor. RESULTS Low dementia probability was associated with lower nursing home admission risk (RR=0.49; 95% CI: 0.41, 0.59). Physical inactivity (RR=1.27; 95% CI: 1.15, 1.41), ever smoking (RR=1.12; 95% CI: 1.01, 1.25), and not consuming alcohol (RR=1.28; 95% CI: 1.13, 1.45) predicted increased relative risk of nursing home admission regardless of cognitive status. The relative effects of modifiable risk factors were similar for those with low and high dementia risk. CONCLUSION Although cognitive impairment associated with incipient dementia strongly predicts nursing home admission, this risk can be partially ameliorated with modifiable risk factors such as physical activity.

Self-Reported Daily Stress, Squelching of Anger and the Management of Daily Stress and the Prevalence of Uterine Leiomyomata: The Ultrasound Screening Study.

Self-reported daily stress, ways of managing stress and squelching anger were examined in association with uterine leiomyomata (aka fibroids). These stress factors were obtained from 560 Black and 375 White women enrolled in the National Institute of Environmental Health Sciences Uterine Fibroid Study. Race-specific prevalence differences (PD) and 95% confidence intervals (95% CI) were calculated. Black women with severe stress had a prevalence of fibroids that was 11% higher (95% CI: 0%, 21%) than those in the no or mild stress group (referent). White women with severe stress, compared to the referent, had a non-significantly (NS) higher prevalence of fibroids [PD = 7%; 95% CI: (-103, 213)]. For both groups, moderate daily stress was associated with a weak elevation (NS) in fibroid prevalence. Black women who reported squelching their anger had an elevated prevalence of fibroids (8%) compared to non-squelchers [95% CI: (-03, 153)] while there was no association for White women. Women with symptomatic fibroids had higher stress than those without, but exclusion of symptomatic women only slightly attenuated the associations. Consistent with a previous report, symptomatic fibroids may cause stress. However, further research is warranted to prospectively investigate a possible aetiologic role for stress in the development of fibroids.

The role of literacy in the association between educational attainment and depressive symptoms

There is a consistent association between education and depressive symptoms, but research on the mechanisms to explain this association remains limited. No study has formally evaluated the extent to which the association between education and depressive symptoms is mediated through a foundational skill such as literacy. Inverse odds ratio weighting (IORW) was used to estimate total, natural direct, and natural indirect effects in examining literacy as a mediator of the association between education and depressive symptoms. Health and Retirement Study participants born in the U.S. between 1900 and 1947 were interviewed biennially for up to 12 years (N = 16,718). Literacy was assessed with a brief vocabulary measure. Depressive symptoms were measured using the 8-item Centers for Epidemiologic Studies-Depression (CES-D) scale. Decomposition estimates were derived using regression analyses of repeated measures of depressive symptoms. Standard errors were obtained using a nonparametric bootstrap with the individual as the independent unit to account for dependence of observations within an individual. In a large cohort of older Americans, a one standard deviation difference in educational attainment (~ 3 years) was associated with a 0.35-point decrement in CES-D score (95% CI: -0.38, -0.32). This decrement represents a 0.22 standard deviation difference in depressive symptoms. Using IORW, the estimated effect of education on depressive symptoms mediated through literacy was -0.10 (95% CI: -0.18, -0.01), which represents 28% of the total effect. Education confers many benefits; as demonstrated by this study for depressive symptoms, one important benefit is literacy.

Validation of a theoretically motivated approach to measuring childhood socioeconomic circumstances in the Health and Retirement Study

Childhood socioeconomic status (cSES) is a powerful predictor of adult health, but its operationalization and measurement varies across studies. Using Health and Retirement Study data (HRS, which is nationally representative of community-residing United States adults aged 50+ years), we specified theoretically-motivated cSES measures, evaluated their reliability and validity, and compared their performance to other cSES indices. HRS respondent data (N = 31,169, interviewed 1992–2010) were used to construct a cSES index reflecting childhood social capital (cSC), childhood financial capital (cFC), and childhood human capital (cHC), using retrospective reports from when the respondent was <16 years (at least 34 years prior). We assessed internal consistency reliability (Cronbach’s alpha) for the scales (cSC and cFC), and construct validity, and predictive validity for all measures. Validity was assessed with hypothesized correlates of cSES (educational attainment, measured adult height, self-reported childhood health, childhood learning problems, childhood drug and alcohol problems). We then compared the performance of our validated measures with other indices used in HRS in predicting self-rated health and number of depressive symptoms, measured in 2010. Internal consistency reliability was acceptable (cSC = 0.63, cFC = 0.61). Most measures were associated with hypothesized correlates (for example, the association between educational attainment and cSC was 0.01, p < 0.0001), with the exception that measured height was not associated with cFC (p = 0.19) and childhood drug and alcohol problems (p = 0.41), and childhood learning problems (p = 0.12) were not associated with cHC. Our measures explained slightly more variability in self-rated health (adjusted R2 = 0.07 vs. <0.06) and number of depressive symptoms (adjusted R2 > 0.05 vs. < 0.04) than alternative indices. Our cSES measures use latent variable models to handle item-missingness, thereby increasing the sample size available for analysis compared to complete case approaches (N = 15,345 vs. 8,248). Adopting this type of theoretically motivated operationalization of cSES may strengthen the quality of research on the effects of cSES on health outcomes.

Neighbourhood looking glass: 360º automated characterisation of the built environment for neighbourhood effects research

Background Neighbourhood quality has been connected with an array of health issues, but neighbourhood research has been limited by the lack of methods to characterise large geographical areas. This study uses innovative computer vision methods and a new big data source of street view images to automatically characterise neighbourhood built environments. Methods A total of 430 000 images were obtained using Google’s Street View Image API for Salt Lake City, Chicago and Charleston. Convolutional neural networks were used to create indicators of street greenness, crosswalks and building type. We implemented log Poisson regression models to estimate associations between built environment features and individual prevalence of obesity and diabetes in Salt Lake City, controlling for individual-level and zip code-level predisposing characteristics. Results Computer vision models had an accuracy of 86%–93% compared with manual annotations. Charleston had the highest percentage of green streets (79%), while Chicago had the highest percentage of crosswalks (23%) and commercial buildings/apartments (59%). Built environment characteristics were categorised into tertiles, with the highest tertile serving as the referent group. Individuals living in zip codes with the most green streets, crosswalks and commercial buildings/apartments had relative obesity prevalences that were 25%–28% lower and relative diabetes prevalences that were 12%–18% lower than individuals living in zip codes with the least abundance of these neighbourhood features. Conclusion Neighbourhood conditions may influence chronic disease outcomes. Google Street View images represent an underused data resource for the construction of built environment features.