Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

The interplay between structure and agency in shaping the mental health consequences of job loss

Main themes that emerged from the qualitative exploration of the psychological distress of job loss included stress, changes to perceived control, loss of self-esteem, shame and loss of status, experiencing a grieving process, and financial strain. Drawing on two models of agency we identified the different ways workers employed their agency, and how their agency was enabled, but mainly constrained, when dealing with job loss consequences. Respondents’ accounts support the literature on the moderating effects of economic resources such as redundancy packages. The results suggest the need for policies to put more focus on social, emotional and financial investment to mediate the structural constraints of job loss. Our study also suggests that human agency must be understood within an individual’s whole of life circumstances, including structural and material constraints, and the personal or interior factors that shape these circumstances.The authors acknowledge support from the National Health and Medical Research Council Capacity Building Grant (324724). The research was supported by the SA Department of Health and the SA Department of Families and Communities through the Human Services Research and Innovation Program (HSRIP), and the Australian Research Council Linkage Program (LP0562288), with the Department of Health (DOH) serving as Industry Partner. Professor Fran Baum was supported by an ARC Federation Fellowship and Drs Newman and Ziersch by the SA Premier’s Science and Research Fund

Stores healthy options project in remote indigenous communities (SHOP@RIC): a protocol of a randomised trial promoting healthy food and beverage purchases through price discounts and in-store nutrition education

BackgroundIndigenous Australians suffer a disproportionate burden of preventable chronic disease compared to their non-Indigenous counterparts – much of it diet-related. Increasing fruit and vegetable intakes and reducing sugar-sweetened soft-drink consumption can reduce the risk of preventable chronic disease. There is evidence from some general population studies that subsidising healthier foods can modify dietary behaviour. There is little such evidence relating specifically to socio-economically disadvantaged populations, even though dietary behaviour in such populations is arguably more likely to be susceptible to such interventions.This study aims to assess the impact and cost-effectiveness of a price discount intervention with or without an in-store nutrition education intervention on purchases of fruit, vegetables, water and diet soft-drinks among remote Indigenous communities.Methods/DesignWe will utilise a randomised multiple baseline (stepped wedge) design involving 20 communities in remote Indigenous Australia. The study will be conducted in partnership with two store associations and twenty Indigenous store boards. Communities will be randomised to either i) a 20% price discount on fruit, vegetables, water and diet soft-drinks; or ii) a combined price discount and in-store nutrition education strategy. These interventions will be initiated, at one of five possible time-points, spaced two-months apart. Weekly point-of-sale data will be collected from each community store before, during, and for six months after the six-month intervention period to measure impact on purchasing of discounted food and drinks. Data on physical, social and economic factors influencing weekly store sales will be collected in order to identify important covariates. Intervention fidelity and mediators of behaviour change will also be assessed.DiscussionThis study will provide original evidence on the effectiveness and cost-effectiveness of price discounts with or without an in-store nutrition education intervention on food and drink purchasing among a socio-economically disadvantaged population in a real-life setting

5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, is responsible for complete Freund's adjuvant-induced thermal hyperalgesia in mice

<p>Abstract</p> <p>Background</p> <p>The role of serotonin (5-hydroxytrptamine, 5-HT) in the modulation of pain has been widely studied. Previous work led to the hypothesis that 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, might by itself influence pain thresholds.</p> <p>Results</p> <p>In the present study, we investigated the role of 5-HIAA in inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) into the hind paw of mice. Wild-type mice were compared to mice deficient of the 5-HT transporter (5-HTT-/- mice) using behavioral tests for hyperalgesia and high-performance liquid chromatography (HPLC) to determine tissue levels of 5-HIAA. Wild-type mice reproducibly developed thermal hyperalgesia and paw edema for 5 days after CFA injection. 5-HTT-/- mice treated with CFA had reduced thermal hyperalgesia on day 1 after CFA injection and normal responses to heat thereafter. The 5-HIAA levels in spinal cord and sciatic nerve as measured with HPLC were lower in 5-HTT-/- mice than in wild-type mice after CFA injection. Pretreatment of wild-type mice with intraperitoneal injection of para-chlorophenylalanine (p-CPA), a serotonin synthesis inhibitor, resulted in depletion of the 5-HIAA content in spinal cord and sciatic nerve and decrease in thermal hyperalgesia in CFA injected mice. The application of exogenous 5-HIAA resulted in potentiation of thermal hyperalgesia induced by CFA in 5-HTT-/- mice and in wild-type mice pretreated with p-CPA, but not in wild-type mice without p-CPA pretreatment. Further, methysergide, a broad-spectrum serotonin receptor antagonist, had no effect on 5-HIAA-induced potentiation of thermal hyperalgesia in CFA-treated wild-type mice.</p> <p>Conclusion</p> <p>Taken together, the present results suggest that 5-HIAA plays an important role in modulating peripheral thermal hyperalgesia in CFA induced inflammation, probably via a non-serotonin receptor mechanism.</p

Adherence to Cancer Prevention Guidelines in 18 African Countries

Background Cancer rates in Africa are projected to double by 2030 due to aging and increased exposure to cancer risk factors, including modifiable risk factors. We assessed adherence to 5 modifiable cancer risk factors across 18 African countries. Methods Data on adults 18 years and older were obtained from the 2002–2004 World Health Survey. Adherence to current World Cancer Research Fund guidelines on smoking, alcohol, body weight, physical activity, and nutrition was assessed. Adherence scores ranged from 0 (no guideline met) to 5 (all guidelines met). Determinants of adherence were assessed using multivariable linear regression adjusted for individual and country level characteristics. Results Across all countries, adherence to the guidelines among adults was high for smoking (72%–99%) and alcohol (85%–100%), but low for body weight (1.8%–78%), physical activity (3.4%–84%) and nutrition (1.4%–61%). Overall adherence score ranged from 2.32 in Mali to 3.72 in Comoros. In multivariable models, residing in low versus high SES households was associated with reduced adherence by 0.24 and 0.21 points for men and women respectively after adjusting for age, gender, education, and marital status (p<0.001). Every % increase in GDP spent on health was associated with increased adherence by 0.03 in men and 0.09 in women (p<0.001). Conclusions The wide variation in adherence to cancer prevention guidelines observed across countries and between population sub-groups suggests the need for targeted public health efforts to improve behaviors related to body weight, physical activity and nutrition

The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer

INTRODUCTION. HJURP (Holliday Junction Recognition Protein) is a newly discovered gene reported to function at centromeres and to interact with CENPA. However its role in tumor development remains largely unknown. The goal of this study was to investigate the clinical significance of HJURP in breast cancer and its correlation with radiotherapeutic outcome. METHODS. We measured HJURP expression level in human breast cancer cell lines and primary breast cancers by Western blot and/or by Affymetrix Microarray; and determined its associations with clinical variables using standard statistical methods. Validation was performed with the use of published microarray data. We assessed cell growth and apoptosis of breast cancer cells after radiation using high-content image analysis. RESULTS. HJURP was expressed at higher level in breast cancer than in normal breast tissue. HJURP mRNA levels were significantly associated with estrogen receptor (ER), progesterone receptor (PR), Scarff-Bloom-Richardson (SBR) grade, age and Ki67 proliferation indices, but not with pathologic stage, ERBB2, tumor size, or lymph node status. Higher HJURP mRNA levels significantly decreased disease-free and overall survival. HJURP mRNA levels predicted the prognosis better than Ki67 proliferation indices. In a multivariate Cox proportional-hazard regression, including clinical variables as covariates, HJURP mRNA levels remained an independent prognostic factor for disease-free and overall survival. In addition HJURP mRNA levels were an independent prognostic factor over molecular subtypes (normal like, luminal, Erbb2 and basal). Poor clinical outcomes among patients with high HJURP expression were validated in five additional breast cancer cohorts. Furthermore, the patients with high HJURP levels were much more sensitive to radiotherapy. In vitro studies in breast cancer cell lines showed that cells with high HJURP levels were more sensitive to radiation treatment and had a higher rate of apoptosis than those with low levels. Knock down of HJURP in human breast cancer cells using shRNA reduced the sensitivity to radiation treatment. HJURP mRNA levels were significantly correlated with CENPA mRNA levels. CONCLUSIONS. HJURP mRNA level is a prognostic factor for disease-free and overall survival in patients with breast cancer and is a predictive biomarker for sensitivity to radiotherapy.National Institutes of Health, National Cancer Institute (R01 CA116481, P50 CA 5820, P30 CA 82103, U54 CA 112970); Office of Science; U.S. Department of Energy Office of Science, Office of Biological & Environmental Research (DE-AC02-05CH11231

Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency

The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreERT2 mice were generated and crossed with Lmx1bflox/flox mice to obtain Pet1-CreERT2; Lmx1bflox/flox mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L-amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2

Geographic and Racial Variation in Premature Mortality in the U.S.: Analyzing the Disparities

Life expectancy at birth, estimated from United States period life tables, has been shown to vary systematically and widely by region and race. We use the same tables to estimate the probability of survival from birth to age 70 (S70), a measure of mortality more sensitive to disparities and more reliably calculated for small populations, to describe the variation and identify its sources in greater detail to assess the patterns of this variation. Examination of the unadjusted probability of S70 for each US county with a sufficient population of whites and blacks reveals large geographic differences for each race-sex group. For example, white males born in the ten percent healthiest counties have a 77 percent probability of survival to age 70, but only a 61 percent chance if born in the ten percent least healthy counties. Similar geographical disparities face white women and blacks of each sex. Moreover, within each county, large differences in S70 prevail between blacks and whites, on average 17 percentage points for men and 12 percentage points for women. In linear regressions for each race-sex group, nearly all of the geographic variation is accounted for by a common set of 22 socio-economic and environmental variables, selected for previously suspected impact on mortality; R2 ranges from 0.86 for white males to 0.72 for black females. Analysis of black-white survival chances within each county reveals that the same variables account for most of the race gap in S70 as well. When actual white male values for each explanatory variable are substituted for black in the black male prediction equation to assess the role explanatory variables play in the black-white survival difference, residual black-white differences at the county level shrink markedly to a mean of −2.4% (+/−2.4); for women the mean difference is −3.7% (+/−2.3)

Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice

Introduction Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome. Methods Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues. Results Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both nulliparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and nulliparous donors

Ancillary human health benefits of improved air quality resulting from climate change mitigation

<p>Abstract</p> <p>Background</p> <p>Greenhouse gas (GHG) mitigation policies can provide ancillary benefits in terms of short-term improvements in air quality and associated health benefits. Several studies have analyzed the ancillary impacts of GHG policies for a variety of locations, pollutants, and policies. In this paper we review the existing evidence on ancillary health benefits relating to air pollution from various GHG strategies and provide a framework for such analysis.</p> <p>Methods</p> <p>We evaluate techniques used in different stages of such research for estimation of: (1) changes in air pollutant concentrations; (2) avoided adverse health endpoints; and (3) economic valuation of health consequences. The limitations and merits of various methods are examined. Finally, we conclude with recommendations for ancillary benefits analysis and related research gaps in the relevant disciplines.</p> <p>Results</p> <p>We found that to date most assessments have focused their analysis more heavily on one aspect of the framework (e.g., economic analysis). While a wide range of methods was applied to various policies and regions, results from multiple studies provide strong evidence that the short-term public health and economic benefits of ancillary benefits related to GHG mitigation strategies are substantial. Further, results of these analyses are likely to be underestimates because there are a number of important unquantified health and economic endpoints.</p> <p>Conclusion</p> <p>Remaining challenges include integrating the understanding of the relative toxicity of particulate matter by components or sources, developing better estimates of public health and environmental impacts on selected sub-populations, and devising new methods for evaluating heretofore unquantified and non-monetized benefits.</p