Objective
To investigate passive smoking throughout the life course and the risk of rheumatoid arthritis (RA), while accounting for personal smoking.
Methods
We analyzed the Nurses’ Health Study II ...prospective cohort, using information collected via biennial questionnaires. We assessed the influence of 1) maternal smoking during pregnancy (in utero exposure), 2) childhood parental smoking, and 3) years lived with smokers since age 18. Incident RA and serostatus were determined by medical record review. Using the marginal structural model framework, we estimated the controlled direct effect of each passive smoking exposure on adult incident RA risk by serologic phenotype, controlling for early‐life factors and time‐updated adulthood factors including personal smoking.
Results
Among 90,923 women, we identified 532 incident RA cases (66% seropositive) during a median of 27.7 years of follow‐up. Maternal smoking during pregnancy was associated with RA after adjustment for confounders, with a hazard ratio (HR) of 1.25 (95% confidence interval 95% CI 1.03–1.52), but not after accounting for subsequent smoking exposures. Childhood parental smoking was associated with seropositive RA after adjustment for confounders (HR 1.41 95% CI 1.08–1.83). In the controlled direct effect analyses, childhood parental smoking was associated with seropositive RA (HR 1.75 95% CI 1.03–2.98) after controlling for adulthood personal smoking, and the association was accentuated among ever smokers (HR 2.18 95% CI 1.23–3.88). There was no significant association of adulthood passive smoking with RA (HR 1.30 for ≥20 years of living with a smoker versus none 95% CI 0.97–1.74).
Conclusion
We found a potential direct influence of childhood parental smoking on adult‐onset incident seropositive RA even after controlling for adulthood personal smoking.
Bone metastasis is the major deleterious event in prostate cancer (PCa). TMPRSS2-ERG fusion is one of the most common chromosomic rearrangements in PCa. However, its implication in bone metastasis ...development is still unclear. Since bone metastasis starts with the tropism of cancer cells to bone through specific migratory and invasive processes involving osteomimetic capabilities, it is crucial to better our understanding of the influence of TMPRSS2-ERG expression in the mechanisms underlying the bone tropism properties of PCa cells. We developed bioluminescent cell lines expressing the TMPRSS2-ERG fusion in order to assess its role in tumor growth and bone metastasis appearance in a mouse model. First, we showed that the TMPRSS2-ERG fusion increases cell migration and subcutaneous tumor size. Second, using intracardiac injection experiments in mice, we showed that the expression of TMPRSS2-ERG fusion increases the number of metastases in bone. Moreover, TMPRSS2-ERG affects the pattern of metastatic spread by increasing the incidence of tumors in hind limbs and spine, which are two of the most frequent sites of human PCa metastases. Finally, transcriptome analysis highlighted a series of genes regulated by the fusion and involved in the metastatic process. Altogether, our work indicates that TMPRSS2-ERG increases bone tropism of PCa cells and metastasis development.
•MET amplification enhances proliferation of EGFR mutated NSCLC cells in vitro.•MET amplification also promotes cell migration and EMT phenotype.•In vivo, MET amplification increases tumor growth and ...metastatic spread.
Five to 20% of metastatic EGFR-mutated non-small cell lung cancers (NSCLC) develop acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) through MET amplification. The effects of MET amplification on tumor and patient phenotype remain unknown.
We investigated,in vitro and in vivo, the impact of MET amplification on the biological properties of the HCC827 cell line, derived from an EGFR-mutated NSCLC. We further evaluated the time to new metastases after EGFR-TKI progression in EGFR-mutated NSCLC, exhibiting MET amplification or high MET overexpression.
MET amplification significantly enhanced proliferation, anchorage independent growth, anoikis resistance, migration, and induced an epithelial to mesenchymal transition. In vivo, MET amplification significantly increased the tumor growth and metastatic spread. Treatment with a MET-TKI reversed this aggressive phenotype. We found that EGFR-mutated NSCLC patients exhibiting MET amplification on a re-biopsy, performed after EGFR-TKI progression, displayed a shorter time to new metastases after EGFR-TKI progression than patients with high MET overexpression but no MET amplification.
MET amplification increases metastatic spread even in the context of an already pre-existing strong driver mutation such as EGFR mutation. These results prompt development of therapeutic strategies aiming at preventing emergence of MET amplification.
A key problem in QSAR is the selection of appropriate descriptors to form accurate regression equations for the compounds under study. Inductive logic programming (ILP) algorithms are a class of ...machine-learning algorithms that have been successfully applied to a number of SAR problems. Unlike other QSAR methods, which use attributes to describe chemical structure, ILP uses relations. This gives ILP the advantages of not requiring explicit superimposition of individual compounds in a dataset, of dealing naturally with multiple conformations, and of using a language much closer to that used normally by chemists. We unify ILP and standard regression techniques to give a QSAR method that has the strength of ILP at describing steric structure with the familiarity and power of regression methods. Complex pharmacophores, correlating with activity, were identified and used as new indicator variables, along with the comparative molecular field analysis (CoMFA) prediction, to form predictive regression equations. We compared the formation of 3D-QSARs using standard CoMFA with the use of ILP on the well-studied thermolysin zinc protease inhibitor dataset and a glycogen phosphorylase inhibitor dataset. In each case the addition of ILP variables produced statistically better results (P < 0.01 for thermolysin and P < 0.05 for GP datasets) than the CoMFA analysis. Moreover, the new ILP variables were not found to increase the complexity of the final QSAR equations and gave possible insight into the binding mechanism of the ligand−protein complex under study.
Osteoarthritis (OA) is the most prevalent disease among aging adults, projected to soon affect nearly one billion people worldwide. It bears the hallmarks of structural joint changes leading to ...stiffness, pain, and a decreased ability to perform normal daily functions. Despite the large number of people affected by this debilitating disease, current research on dietary and lifestyle factors that may be related to hip osteoarthritis in women has been limited. Findings have included that intakes of garlic, onions, leeks, and non-citrus fruit were inversely associated with hip OA. Sugar-sweetened beverages and alcohol have been minimally studied in relation to hip OA, although consumption of sugar-sweetened beverages has been associated with knee OA progression in men, and alcohol intake has been associated with an increased risk of hand OA. No association between alcohol consumption and hip OA was found in an earlier study using the Nurses’ Health Study cohort, but at the time fewer cases of hip OA had occurred. Studies of physical activity and hip OA have revealed divergent results, with no association as well as harmful and protective associations having been found. Our aim was to further investigate the relationship between discretionary physical activity and hip OA, and to determine the associations between sugar-sweetened beverages and alcohol with hip OA in women. In Chapter 1 we evaluated the association between sugar-sweetened beverage consumption and hip OA. We found no overall association between sugar-sweetened beverages and hip OA, even when investigating latency periods of up to 20-24 years. In Chapter 2 we evaluated the association between alcohol consumption and hip OA. We found a potentially important, positive dose-response relationship. This relationship was seen for both wine and liquor consumption, remained with latency periods up to 20-24 years, and alcohol consumption earlier in mid-life was also significantly associated with hip OA. In Chapter 3 we evaluated the association between discretionary physical activity and hip OA. While total discretionary physical activity was not associated with hip OA, when we investigated individual forms of physical activity we found that high joint-load activity, such as running and racquet sports, were associate with a higher risk of hip OA.
Abstract The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, ...lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis.
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