The putative tumor suppressor gene EphA3 fails to demonstrate a crucial role in murine lung tumorigenesis or morphogenesis

Treatment of non-small cell lung cancer (NSCLC) is based on histological analysis and molecular profiling of targetable driver oncogenes. Therapeutic responses are further defined by the landscape of passenger mutations, or loss of tumor suppressor genes. We report here a thorough study to address the physiological role of the putative lung cancer tumor suppressor EPH receptor A3 (EPHA3), a gene that is frequently mutated in human lung adenocarcinomas. Our data shows that homozygous or heterozygous loss of EphA3 does not alter the progression of murine adenocarcinomas that result from Kras mutation or loss of Trp53, and we detected negligible postnatal expression of EphA3 in adult wildtype lungs. Yet, EphA3 was expressed in the distal mesenchyme of developing mouse lungs, neighboring the epithelial expression of its Efna1 ligand; this is consistent with the known roles of EPH receptors in embryonic development. However, the partial loss of EphA3 leads only to subtle changes in epithelial Nkx2-1, endothelial Cd31 and mesenchymal Fgf10 RNA expression levels, and no macroscopic phenotypic effects on lung epithelial branching, mesenchymal cell proliferation, or abundance and localization of CD31-positive endothelia. The lack of a discernible lung phenotype in EphA3-null mice might indicate lack of an overt role for EPHA3 in the murine lung, or imply functional redundancy between EPHA receptors. Our study shows how biological complexity can challenge in vivo functional validation of mutations identified in sequencing efforts, and provides an incentive for the design of knock-in or conditional models to assign the role of EPHA3 mutation during lung tumorigenesis

The putative tumor suppressor gene EphA3 fails to demonstrate a crucial role in murine lung tumorigenesis or morphogenesis

Treatment of non-small cell lung cancer (NSCLC) is based on histological analysis and molecular profiling of targetable driver oncogenes. Therapeutic responses are further defined by the landscape of passenger mutations, or loss of tumor suppressor genes. We report here a thorough study to address the physiological role of the putative lung cancer tumor suppressor EPH receptor A3 (EPHA3), a gene that is frequently mutated in human lung adenocarcinomas. Our data shows that homozygous or heterozygous loss of EphA3 does not alter the progression of murine adenocarcinomas that result from Kras mutation or loss of Trp53, and we detected negligible postnatal expression of EphA3 in adult wildtype lungs. Yet, EphA3 was expressed in the distal mesenchyme of developing mouse lungs, neighboring the epithelial expression of its Efna1 ligand; this is consistent with the known roles of EPH receptors in embryonic development. However, the partial loss of EphA3 leads only to subtle changes in epithelial Nkx2-1, endothelial Cd31 and mesenchymal Fgf10 RNA expression levels, and no macroscopic phenotypic effects on lung epithelial branching, mesenchymal cell proliferation, or abundance and localization of CD31-positive endothelia. The lack of a discernible lung phenotype in EphA3-null mice might indicate lack of an overt role for EPHA3 in the murine lung, or imply functional redundancy between EPHA receptors. Our study shows how biological complexity can challenge in vivo functional validation of mutations identified in sequencing efforts, and provides an incentive for the design of knock-in or conditional models to assign the role of EPHA3 mutation during lung tumorigenesis.Peer reviewe

Sitting Behaviors and Mental Health among Workers and Nonworkers: The Role of Weight Status

Objective. To explore the associations between sitting time in various domains and mental health for workers and nonworkers and the role of weight status. Design. Cross-sectional analyses were performed for 1064 respondents (47% men, mean age 59 years) from the Doetinchem Cohort Study 2008-2009. Sedentary behavior was measured by self-reported time spent sitting during transport, leisure time, and at work. Mental health was assessed by the Mental Health Inventory (MHI-5). BMI was calculated based on measured body height and weight. Results. Neither sitting time during transport nor at work was associated with mental health. In the working population, sitting during leisure time, and particularly TV viewing, was associated with poorer mental health. BMI was an effect modifier in this association with significant positive associations for healthy-weight non-workers and obese workers. Conclusion. Both BMI and working status were effect modifiers in the relation between TV viewing and mental health. More longitudinal research is needed to confirm the results and to gain insight into the causality and the underlying mechanisms for the complex relationships among sedentary behaviors, BMI, working status, and mental health

Oncogenic Ras Disrupts Epithelial Integrity by Activating the Transmembrane Serine Protease Hepsin

Ras proteins play a causal role in human cancer by activating multiple pathways that promote cancer growth and invasion. However, little is known about how Ras induces the first diagnostic features of invasion in solid tumors, including loss of epithelial integrity and breaching of the basement membrane (BM). In this study, we found that oncogenic Ras strongly promotes the activation of hepsin, a member of the hepsin/TMPRSS type II transmembrane serine protease family. Mechanistically, the Ras-dependent hepsin activation was mediated via Raf-MEK-ERK signaling, which controlled hepsin protein stability through the heat shock transcription factor-1 stress pathway. In Ras-transformed three-dimensional mammary epithelial culture, ablation of hepsin restored desmosomal cell-cell junctions, hemidesmosomes, and BM integrity and epithelial cohesion. In tumor xenografts harboring mutant KRas, silencing of hepsin increased local invasion concomitantly with accumulation of collagen IV. These findings suggest that hepsin is a critical protease for Ras-dependent tumorigenesis, executing cell-cell and cell-matrix pathologies important for early tumor dissemination. Significance: These findings identify the cell-surface serine protease hepsin as a potential therapeutic target for its role in oncogenic Ras-mediated deregulation of epithelial cell-cell and cell-matrix interactions and cohesion of epithelial structure.Peer reviewe

The beginning of time? Evidence for catastrophic drought in Baringo in the early nineteenth century

New developments in the collection of palaeo-data over the past two decades have transformed our understanding of climate and environmental history in eastern Africa. This article utilises instrumental and proxy evidence of historical lake-level fluctuations from Baringo and Bogoria, along with other Rift Valley lakes, to document the timing and magnitude of hydroclimate variability at decadal to century time scales since 1750. These data allow us to construct a record of past climate variation not only for the Baringo basin proper, but also across a sizable portion of central and northern Kenya. This record is then set alongside historical evidence, from oral histories gathered amongst the peoples of northern Kenya and the Rift Valley and from contemporary observations recorded by travellers through the region, to offer a reinterpretation of human activity and its relationship to environmental history in the nineteenth century. The results reveal strong evidence of a catastrophic drought in the early nineteenth century, the effects of which radically alters our historical understanding of the character of settlement, mobility and identity within the Baringo–Bogoria basin

Modifiable Risk Factors for Accelerated Decline in Processing Speed: Results from Three Dutch Population Cohorts

Background: Several lifestyle, cardiovascular and psychosocial factors are associated with risk of cognitive decline and dementia. We studied the independent associations of a broad set of modifiable risk factors with decline in processing speed in three large population-based cohorts with up to 23 years of follow-up. Methods: We used data of 9,666 participants from the Doetinchem Cohort Study, the Longitudinal Aging Study Amsterdam, and the Maastricht Aging Study. Decline in processing speed was measured with the letter digit substitution task or the alphabet coding task and modeled using quadratic latent growth curves. Associations of modifiable risk factors with level and rate of decline in processing speed were investigated by estimating associations with level of processing speed at different centering ages. Results: Latent growth curves showed that decline in processing speed accelerated with age. Smoking, not drinking alcohol and depressive symptoms were associated with a lower level of processing speed in all cohorts. In two of the cohorts, more physical activity, drinking more than two glasses of alcohol per day, higher BMI and diabetes were associated with a lower level of processing speed. Depressive symptoms and diabetes were also associated with faster decline in processing speed. Conclusion: Several modifiable risk factors are associated with the level of processing speed in older age, while few are also related to the rate of decline

Western Indian Ocean marine and terrestrial records of climate variability: a review and new concepts on land-ocean interactions since AD 1660

We examine the relationship between three tropical and two subtropical western Indian Ocean coral oxygen isotope time series to surface air temperatures (SAT) and rainfall over India, tropical East Africa and southeast Africa. We review established relationships, provide new concepts with regard to distinct rainfall seasons, and mean annual temperatures. Tropical corals are coherent with SAT over western India and East Africa at interannual and multidecadal periodicities. The subtropical corals correlate with Southeast African SAT at periodicities of 16–30 years. The relationship between the coral records and land rainfall is more complex. Running correlations suggest varying strength of interannual teleconnections between the tropical coral oxygen isotope records and rainfall over equatorial East Africa. The relationship with rainfall over India changed in the 1970s. The subtropical oxygen isotope records are coherent with South African rainfall at interdecadal periodicities. Paleoclimatological reconstructions of land rainfall and SAT reveal that the inferred relationships generally hold during the last 350 years. Thus, the Indian Ocean corals prove invaluable for investigating land–ocean interactions during past centuries

Weight change over five-year periods and number of components of the metabolic syndrome in a Dutch cohort

Overweight and obesity are associated with the metabolic syndrome (MetS). We studied the association of weight change over three consecutive 5-year periods with the number of MetS components in people aged 20–59 years. 5735 participants from the Doetinchem Cohort Study were included. Weight was measured in round 1 and at each 5-year interval follow-up (round 2, 3 and 4). Weight change was defined as the absolute weight change between two consecutive measurements. The number of MetS components (assessed in round 2, 3 and 4) was based on the presence of the following components of the MetS: central obesity, raised blood pressure, reduced high density lipoprotein cholesterol and elevated glucose. Associations of weight change and the number of components of the MetS were analyzed with Generalized Estimating Equations for Poisson regression, stratified for 10-year age groups. For each age group, 1 kg weight gain was positively associated with the number of components of the MetS, independent of sex and measurement round. The association was stronger in 30–39 years (adjusted rate ratio: 1.044; 95%CI: 1.040–1.049) and smaller in older age groups. Compared to stable weight (>−2.5 kg and < 2.5 kg), weight loss (≤−2.5 kg) and weight gain (≥2.5 kg) was associated with a lower and higher rate ratio respectively, for the number of components of the MetS. Our results support the independent association of weight change with the number of MetS components with a more pronounced association in younger people

Adherence to the EAT-Lancet Healthy Reference Diet in Relation to Risk of Cardiovascular Events and Environmental Impact: Results From the EPIC-NL Cohort

Background The Healthy Reference Diet (HRD) was created to formulate dietary guidelines that would be healthy and sustainable. We aimed to construct a diet score measuring adherence to the HRD and to explore its association with cardiovascular events and environmental impact. Methods and Results We included 35 496 participants from the population-based EPIC-NL (European Prospective Investigation into Cancer and Nutrition-Netherlands) study. HRD scores were calculated using data from food frequency questionnaires (0-140). Data on morbidity and mortality were retrieved through linkage with national and death registries. Data on environmental impact indicators were obtained from life cycle assessments. Associations between adherence to the HRD and cardiovascular events were estimated with Cox proportional hazard models. Linear regression analysis was conducted for the adherence to the HRD and each environmental indicator. High adherence to the HRD was associated with 14%, 12%, and 11% lower risks of cardiovascular disease (hazard ratio [HR]Q4vsQ1, 0.86 [95% CI, 0.78-0.94]), coronary heart disease (HRQ4vsQ1, 0.88 [95% CI, 0.78-1.00]), and total stroke (HRQ4vsQ1, 0.89 [95% CI, 0.72-1.10]), respectively. High HRD adherence was associated with 2.4% (95% CI, -5.0 to 0.2) lower greenhouse gas emissions, 3.9% (95% CI, -5.2 to -2.6) less land use, 0.5% (95% CI, -2.6 to 1.6), less freshwater eutrophication, 3.3% (95% CI, -5.8 to -0.8), less marine eutrophication, 7.7% (95% CI, -10.8 to -4.6), less terrestrial acidification, and 32.1 % (95% CI, 28.5-35.7) higher blue water use. Conclusions High adherence to the HRD was associated with lower risk of cardiovascular disease, coronary heart disease, and modestly lower levels of most environmental indicators but a higher level of blue water use