Plausible Biological Pathways Research Articles

Increase in major osteoporotic fractures after therapy with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) can cause severe and sometimes long-standing immune-related adverse events (irAEs). Enhanced immune activation from ICI can theoretically result in osteoclast activation, bone loss and fracture. The...

A State-of-the-Science Review of the Effect of Damp- and Mold-Affected Housing on Mental Health.

While it is well-established that exposure to dampness or mold in homes negatively affects physical health, the association with mental health remains less well evidenced. As plausible psychosocial and biological pathways exist between dampness and mold exposure and poor mental health, a review of evidence is required. This State-of-the-Science review sought to assess what is known about the mental health effects of dampness or mold exposure and identify gaps in the literature and priorities for further research. A comprehensive search of electronic databases (MEDLINE, Embase, PsycInfo, Global Health, Web of Science, and Scopus) was conducted to identify relevant studies published from 2003 to 2023. Eligible studies included observational study designs such as cohort and cross-sectional studies. Target studies for review assessed the effect of dampness and/or mold on mental health outcomes. Of the 1,169 records retrieved, 19 studies met the inclusion criteria. The available evidence described positive associations between residential dampness/mold exposure and poor mental health. In adults, associations were observed for outcomes such as depression, stress, and anxiety, while for children, associations were observed for emotional symptoms and emotional dysregulation. Identified studies generally reported associations between exposure to dampness/mold in the home and poorer mental and emotional health. Given the methodological limitations present in the current evidence base, it is recommended that more research be conducted. https://doi.org/10.1289/EHP14341.

Mixture effects of prenatal exposure to polybrominated diphenyl ethers on urinary oxidative stress biomarkers in the Chemicals in Our Bodies Cohort.

Polybrominated diphenyl ethers (PBDEs) exposure is associated with preterm birth. Laboratory studies suggest that PBDEs lead to elevated oxidative stress, a known contributor to preterm birth in epidemiologic studies. We hypothesized that elevated levels of PBDEs would be associated with increased oxidative stress during human pregnancy. Participants in this analysis were enrolled in the Chemicals in Our Bodies cohort and resided in the San Francisco Bay Area (N=201). Four PBDEs (BDE-47, -99, -100, -153) were measured in second trimester serum. Urinary oxidative stress biomarkers were measured at two timepoints (second and third trimester) and included 8-isoprostane-prostaglandin-F2α [8-iso-PGF2α], 2,3-dinor-5,6-dihydro-8-iso-PGF2α, 2,3-dinor-8-iso-PGF2α, and prostaglandin-F2α [PGF2α]. Associations between individual PBDEs and oxidative stress biomarkers (averaged and trimester specific) were examined using linear regression. Quantile g-computation and Bayesian kernel machine regression (BKMR) were used to assess cumulative effects of PBDEs. Quantile g-computation showed that higher concentrations of PBDEs were associated with increasing 8-iso-PGF2α, 2,3-dinor-8-iso-PGF2α, and PGF2α. Associations were greatest in magnitude for second trimester levels of 2,3-dinor-8-iso-PGF2α (mean change per quartile increase=0.25, 95% confidence interval=0.09, 0.41). Associations were similar using BKMR and linear regression. Our findings suggest that oxidative stress may be a plausible biological pathway by which PBDE exposure might lead to preterm birth.

Screen time, brain network development and socio-emotional competence in childhood: moderation of associations by parent-child reading.

Screen time in infancy is linked to changes in social-emotional development but the pathway underlying this association remains unknown. We aim to provide mechanistic insights into this association using brain network topology and to examine the potential role of parent-child reading in mitigating the effects of screen time. We examined the association of screen time on brain network topology using linear regression analysis and tested if the network topology mediated the association between screen time and later socio-emotional competence. Lastly, we tested if parent-child reading time was a moderator of the link between screen time and brain network topology. Infant screen time was significantly associated with the emotion processing-cognitive control network integration (p = 0.005). This network integration also significantly mediated the association between screen time and both measures of socio-emotional competence (BRIEF-2 Emotion Regulation Index, p = 0.04; SEARS total score, p = 0.04). Parent-child reading time significantly moderated the association between screen time and emotion processing-cognitive control network integration (β = -0.640, p = 0.005). Our study identified emotion processing-cognitive control network integration as a plausible biological pathway linking screen time in infancy and later socio-emotional competence. We also provided novel evidence for the role of parent-child reading in moderating the association between screen time and topological brain restructuring in early childhood.

Individual and joint association of phenols, parabens, and phthalates with childhood lung function: Exploring the mediating role of peripheral immune responses

The functioning of the respiratory system can be interfered with by exposure to mixtures of environmental chemicals, however, the evidence is still ambiguous. We evaluated the association of exposure to mixtures of 14 chemicals, including 2 phenols, 2 parabens, and 10 phthalates, with four major lung function metrics. Based on data from the National Health and Nutrition Examination Survey 2007–2012, this analysis was conducted among 1462 children aged 6–19 years. Linear regression, Bayesian kernel machine regression, quantile-based g-computation regression, and a generalized additive model were performed to estimate the associations. Mediation analyses were performed to investigate plausible biological pathways mediated by immune cells. Our results indicated that the phenols, parabens, and phthalates mixture was negatively related to lung function parameters. And BPA and PP were identified as important contributors to negative associations with FEV1, FVC, and PEF, with non-linear relationships observed between BPA and those outcomes. The most influential factor for a probable FEF25–75 % decline was MCNP. BPA, and MCNP had an interaction effect on FEF25–75 %. The association of PP with FVC and FEV1 has been postulated to be mediated by neutrophils and monocytes. The findings offer insights into the associations of chemical mixtures with respiratory health and the possible driving mechanism, which would be of significance in adding novel evidence of the role of peripheral immune responses, as well as calling for remediation actions to be prioritized during childhood.

Cytokines as mediators of the associations of prenatal exposure to phenols, parabens, and phthalates with internalizing behaviours at age 3 in boys: A mixture exposure and mediation approach

Childhood internalizing disorders refer to inwardly focused negative behaviours such as anxiety, depression, and somatic complains. Interactions between psychosocial, genetic, and environmental risk factors adversely impact neurodevelopment and can contribute to internalizing disorders. While prenatal exposure to single endocrine disruptors (EDs) is associated with internalizing behaviours in infants, the associations with prenatal exposure to EDs in mixture remain poorly addressed. In addition, the biological mediators of EDs in mixture effects on internalizing behaviours remain unexplored. EDs do not only interfere with endocrine function, but also with immune function and inflammatory processes. Based on this body of evidence, we hypothetised that inflammation at birth is a plausible biological pathway through which prenatal exposure to EDs in mixture could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether exposure to a mixture of EDs increased the odds of internalizing disorders in 459 boy infants at age 3, and whether the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α measured at birth were mediators of this effect. To determine both the joint and individual associations of prenatal exposure to EDs with infant internalizing behaviours and the possible mediating role of cytokines, we used the counterfactual hierarchical Bayesian Kernel Machine Regression (BKMR) regression-causal mediation analysis. We show that prenatal exposure to a complex mixture of EDs has limited effects on internalizing behaviours in boys at age 3. We also show that IL-1β, IL-6, and TNF-α are unlikely mediators or suppressors of ED mixture effects on internalizing behaviours in boys at age 3. Further studies on larger cohorts are warranted to refine the deleterious effects of EDs in mixtures on internalizing behaviours and identify possible mediating pathways.

Sources of Lead Exposure in West Africa

This commentary is an investigation of sources of lead (Pb) exposure in West Africa. Pb is generally acknowledged as one of the most widespread environmental health hazards in West Africa, and there is heightened concern over adverse health effects at various levels of exposure (at doses once considered safe) in the West African region. A literature review for the possible health implications of Pb exposure on human health showed nervous system dysfunction, anemia, and potential cognitive diseases as the major health issues among children, while adults were found to suffer more from cardiovascular dysfunction, neurological decline, and reproductive diseases. Despite a decline in blood lead levels (BLLs), lead exposure continues to be a major public health concern as no level of Pb exposure can be considered safe. Moreover, lowering BLLs entails identifying various lead sources such as gasoline emissions, leaded paint, canned foods, and beverages, as well as plausible biological pathways of lead exposure and response. However, only countries such as Nigeria and Ghana have extensive research available regarding the different sources of Pb exposure. Further, it is not apparent which country is affected the most by Pb exposure. Therefore, this commentary was aimed to explore different literature sources to describe and list the different sources of Pb exposure in 15 West African countries. The findings indicated water, food, and occupational exposure as the major sources of Pb exposure in the region. People with occupations such as e-waste and Pb acid battery recycling, auto mechanics, fuel attending, welding, electronic repairing, farming/spraying, and mining were found to be at immediate risk. Tobacco, spices and paints constituted additional potential sources of exposure. For residents living near landfills or urban area, the major sources of Pb exposure were soil, air, and dust particles. The review revealed a vast research gap on the sources and implications of Pb exposure. Exposure to Pb could further increase due to uncontrolled traffic, urban growth, inadequate urban planning, and the inadequate enforcement of regulations. Therefore, more extensive research on the changing trends of Pb exposure among West African populations is needed.

The Impact of Harsh Parenting on the Development of Obesity in Adulthood: An Examination of Epigenetic/Gene Expression Mediators Among African American Youth.

Objective: We examined the association of prospectively assessed harsh parenting during adolescence with body mass index (BMI) in young adulthood among African American youth. We also assessed the role of methylation of obesity-related genes and gene expression markers of obesity as mediators of this association, providing a pathway for the biological embedding of early harsh parenting and its long-term impact on young adult health.Methods: Hypotheses were tested with a sample of 362 African American youth for whom harsh parenting was assessed at ages 10–15, BMI was assessed at age 10 and 29, and both DNA methylation (DNAm) and gene expression of obesity genes were assessed at age 29. Mediational analyses were conducted using bootstrap methods to generate confidence intervals.Results: Controlling for genetic risk for obesity and health-related covariates, harsh parenting across childhood and adolescence was associated with change in BMI (Δ BMI) from ages 10–29. In addition, we found that the indirect effect of harsh parenting on Δ BMI was mediated through obesity-related DNAm and accounted for 45.3% of the total effect. Further, obesity-related DNAm mediated the effect of harsh parenting on gene expression of obesity-related genes (GEOG), and GEOG, in turn, mediated the impact of obesity-related DNAm on ΔBMI. This pathway accounted for 3.4% of the total effect. There were no gender differences in the magnitude of this indirect effect.Conclusions: The results suggest that alterations in methylation and gene expression mediate the impact of harsh parenting on change in obesity from childhood to young adulthood, illustrating plausible biological pathways from harsh parenting to obesity and bolstering the hypothesis that harsh parenting in childhood and adolescence can become biologically embedded and contribute to obesity.

The effect of short-term fine particulate matter exposure on glucose homeostasis: A panel study in healthy adults

As an emerging risk factor, long-term exposure to fine particulate matter (PM2.5) has been linked to glucose homeostasis in numerous epidemiological researches. However, the acute adverse effects of PM2.5 exposure on glucose homeostasis among healthy population are not well described. The study aims to investigate the short-term association between PM2.5 exposure and glucose homeostasis among the healthy populations. We scheduled 8 repeated physical examinations with venous blood collection every 1–2 weeks from 9 September 2019 to 7 January 2020 in a panel of 70 healthy adults (aged 18–26) in Wuhan, China. We measured the individual hourly PM2.5 concentrations, fasting blood glucose (FBG), insulin (FINS) along HOMA-B and HOMA-IR. The linear mixed-effect model was conducted to evaluate the acute effect of PM2.5 on glucose homeostasis. PM2.5 concentrations range varied from 7.38 to 115.38 μg/m3, with an average level of 38.34 μg/m3. Each 10 μg/m3 increment in 3-days PM2.5 moving average was associated with a 4.19% increase in FINS (95% CI: 2.35, 6.05), 5.95% increase in HOMA-B (95% CI: 3.66, 8.26), and 3.77% increase in HOMA-IR (95% CI: 1.41, 4.64), respectively. We found the adverse effect on HOMA-IR was greater in the overweight (%Change = 7.98; 95% CI: 3.54, 12.61) than in the normal-weight (%Change = 3.35; 95% CI: 1.34, 5.38). And the lifestyle factors, such as exercise also showed a modification effect on the short-term association between PM2.5 and glucose homeostasis. Conclusively, exposure to PM2.5 for short-term, even within hours, was positively associated with elevated IR status and impaired glucose homeostasis in the healthy population. The result may suggest a plausible biological pathway underlying PM2.5 and metabolic events.

Mapping pleiotropic loci using a fast-sequential testing algorithm

Pleiotropy (i.e., genes with effects on multiple traits) leads to genetic correlations between traits and contributes to the development of many syndromes. Identifying variants with pleiotropic effects on multiple health-related traits can improve the biological understanding of gene action and disease etiology, and can help to advance disease-risk prediction. Sequential testing is a powerful approach for mapping genes with pleiotropic effects. However, the existing methods and the available software do not scale to analyses involving millions of SNPs and large datasets. This has limited the adoption of sequential testing for pleiotropy mapping at large scale. In this study, we present a sequential test and software that can be used to test pleiotropy in large systems of traits with biobank-sized data. Using simulations, we show that the methods implemented in the software are powerful and have adequate type-I error rate control. To demonstrate the use of the methods and software, we present a whole-genome scan in search of loci with pleiotropic effects on seven traits related to metabolic syndrome (MetS) using UK-Biobank data (n~300 K distantly related white European participants). We found abundant pleiotropy and report 170, 44, and 18 genomic regions harboring SNPs with pleiotropic effects in at least two, three, and four of the seven traits, respectively. We validate our results using previous studies documented in the GWAS-catalog and using data from GTEx. Our results confirm previously reported loci and lead to several novel discoveries that link MetS-related traits through plausible biological pathways.

Serum Anti-Müllerian Hormone Levels Were Negatively Associated With Body Fat Percentage in PCOS Patients.

BackgroundObesity is a state of excess body fat accumulation, and appears to be closely associated with polycystic ovary syndrome (PCOS). Notably, plausible biological pathways through which obesity can regulate anti-Müllerian hormone (AMH) production have been proposed, and women with PCOS characteristically have an increased AMH level. Body fat accumulation can be described by body fat percentage (BFP). However, the relationship between BFP and AMH still remains unclear.Materials and MethodsA total of 87 controls and 156 PCOS patients were divided into lean and overweight/obese groups, and the PCOS patients were further divided into hyper-AMH and normal-AMH subgroups. Univariate regression was used to assess the unadjusted relationship between AMH and outcome variables, multivariable regression analysis was performed to test whether and how serum AMH levels were associated with BFP after adjusting for other co-variables. Receiver-operating characteristic (ROC) curve analyses were used to test the utility of BFP for the diagnosis of PCOS.ResultsBFP was higher in PCOS patients compared with controls, regardless of obesity. Serum AMH levels were negatively associated with BFP in the PCOS group (r = -0.371; P < 0.001) but not in the control group (r = -0.095; P = 0.385). Multivariable logistic regression analysis showed that elevated BFP was associated with a high risk of PCOS (odds ratio, 1.290; 95% confidence interval, 1.084–1.534, P = 0.004). Furthermore, the combination of BFP and serum AMH into a multivariate model gave an improved area under the curve (AUC) of 88.5%, with a sensitivity of 72.4% and specificity of 87.4%; the positive and negative predictive values were 91.2% and 63.9%, respectively. One limitation of this study is all the conclusion reported was based on small sample size.ConclusionsHerein, we described the negative correlation between BFP and serum AMH levels for the first time, and the present results highlight the importance of further investigation into the role of BFP, especially in body fat-related AMH change as it relates to the underlying pathogenesis of PCOS.

Characterizing prenatal maternal distress with unique prenatal cortisol trajectories.

It is widely assumed that glucocorticoids represent a primary mechanism through which exposure to adversity and maternal psychological distress shape prenatal developmental trajectories of both mother and fetus. However, despite repeated investigations and the fact that prenatal cortisol has been reliably linked to developmental outcomes, the empirical evidence supporting an association between prenatal cortisol and maternal distress is scarce. In this study, a novel approach to assessing links between maternal prenatal psychological distress and gestational cortisol profiles, general growth mixture modeling (GGMM), was applied. Measures of pregnancy anxiety, perceived stress, and state anxiety and depressive symptoms as well as plasma samples (for determination of cortisol) were collected from 250 women 4 times during pregnancy. Using GGMM, 3 cortisol trajectory groups were identified, including a typical group (n = 199) that exhibited the expected steady increase in cortisol throughout gestation, a steep group (n = 31) displaying an accelerated increase in cortisol over the course of pregnancy relative to the typical group, and a flat group (n = 20) with relatively higher cortisol levels early in pregnancy that plateaued in midgestation. Women reporting the highest distress scores exhibited trajectories expected to be associated with the least optimal developmental outcomes (flatter trajectories characterized by relatively higher levels early in gestation and lower levels late in gestation). These findings suggest that psychological distress during pregnancy is associated with unique prenatal cortisol profiles and support further examination of this link, to enable continued evaluation of a plausible biological pathway by which maternal psychological distress programs fetal development. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Prospective Study of Eating Habits as a Predictor of Incident Coronary Heart Disease Hospitalization and Mortality: The 2004 Canadian Community Health Survey

Abstract Objectives Eating habits such as skipping breakfast and snacking are increasingly common practices among North American adults; however, their long-term effects on incident coronary heart disease (CHD) outcomes remain unknown. Previous studies of breakfast skipping and/or eating frequency and cardiometabolic risk have suggested plausible biological pathways for either a protective or harmful relationship to exist, especially when other cardiometabolic risk factors such as diabetes, hypertension, and obesity are present. The objectives of this study were to assess whether long-term associations exist between eating habits (skipping breakfast and eating frequency) and incident CHD (hospitalization and mortality risk), and whether these are intensified by the presence of cardiometabolic risk factors. Methods Skipping breakfast (yes/no) and eating frequency (times per day) were assessed via a 24-hour dietary recall in a nationally representative sample of 13,587 adults (aged ≥18 years) in the 2004 Canadian Community Health Survey (CCHS), who were free of CHD and cancer. Data from the CCHS 2.2 were linked to the population-based Discharge Abstract Database and Canadian Mortality Database to determine the incidence of CHD hospitalization and mortality in the subsequent 9 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results During follow-up, 762 cases of CHD hospitalization and mortality were documented. Skipping breakfast was not associated with risk of CHD hospitalization and mortality in all participants together (multivariable-adjusted HR = 1.02, 95% CI: 0.74–1.39) or within baseline risk factor subgroups (hypertension: n = 2472; 0.95, 0.55–1.64; diabetes: n = 826; 1.38, 0.65–2.93; BMI ≥ 30 kg/m2: n = 2942; 1.43, 0.84–2.43). Similarly, no associations were observed between eating frequency and risk of CHD hospitalization and mortality. Conclusions Skipping breakfast and eating frequency were not associated with either increased or decreased risk of CHD hospitalization and mortality in this cohort of Canadian adults. Funding Sources Nova Scotia Health Research Foundation Development and Innovative Grant and a Nova Scotia Health Authority Research Foundation New Investigator Grant to LEC.

Abstract P518: Prospective Study of Skipping Meals to Lose Weight as a Predictor of Incident Type 2 Diabetes and Coronary Heart Disease: The Canadian 1995 Nova Scotia Health Survey

Introduction: Skipping meals is an increasingly common practice to lose weight among North American adults of all bodyweights. However, due to a lack of long-term studies, the long-term effect of skipping meals to lose weight on cardiometabolic health outcomes such as a diagnosis of type 2 diabetes mellitus (T2DM) or incident coronary heart disease (CHD) remains unknown, although previous short-term studies of skipping meals and risk factors for T2DM and CHD have suggested plausible biological pathways for a relationship to exist in either direction, protective or harmful. Hypothesis: We assessed the hypotheses that skipping meals to lose weight was associated with long-term risk of incident T2DM and CHD in the Canadian 1995 Nova Scotia Health Survey (NSHS95), and that these associations were influenced by cardiometabolic risk factors. Methods: Skipping meals to lose weight was assessed via questionnaire in a cohort of 2,898 adults in the NSHS95 and was linked to population-based health care administrative databases to determine incidence of T2DM and/or CHD in the following 23 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for T2DM and CHD. Results: During 23 years of follow-up, 430 incident cases of T2DM and 632 incident cases of CHD were diagnosed. Compared to participants who did not skip meals to lose weight, those who did skip meals to lose weight (2.7%) had an 87% higher risk of T2DM (multivariable-adjusted HR=1.87, 95% CI: 1.11-3.17). This association was no longer present after adjustment for baseline body mass index (BMI) (HR=1.42, 0.83-2.42). After stratification by BMI, skipping meals was associated with T2DM among participants who had BMI &lt;25 kg/m 2 (n=1,030; HR=4.42, 1.01-19.30) but not among participants with BMIs of 25-29.9 kg/m 2 (n=1,123; HR=1.07, 0.39-2.96) or 30+ kg/m 2 (n=586; HR=1.21, 0.61-2.39). The multivariable-adjusted (including BMI) association was also present within participants with elevated cholesterol (n=1,450; HR=1.88, 1.00-3.53) and high blood pressure (n=1,363; HR=2.07, 1.11-3.85), but not among those without. No significant association was observed between skipping meals to lose weight and CHD risk before (HR=1.14, 0.67-1.96) or after adjustment for BMI (HR=1.05, 0.61-1.81), or within subgroups. Conclusion: These findings suggest that skipping meals to lose weight may be a predictive modifiable risk factor for developing T2DM over time, especially among people with a BMI &lt;25 kg/m 2 , potentially working in connection or iteration with other T2DM risk factors. With the growing number of popular diets that include skipping meals, future studies are warranted to understand perturbations of potential metabolic consequences.

Genetic Underpinnings of Musculoskeletal Pain During Treatment With Aromatase Inhibitors for Breast Cancer: A Biological Pathway Analysis.

Musculoskeletal pain (MSKP) is the most reported symptom during treatment with aromatase inhibitors (AIs) for breast cancer. The mechanisms underlying MSKP are multidimensional and not well understood. The goals of this biological pathway analysis were to (1) gain an understanding of the genetic variation and biological mechanisms underlying MSKP with AI therapy and (2) identify plausible biological pathways and candidate genes for future investigation. Genes associated with MSKP during AI therapy or genes involved in drug metabolism of and response to AIs were identified from the literature. Studies published through February 2019 were queried in PubMed®. The genes identified from the literature were entered into QIAGEN's Ingenuity® Pathway Analysis (IPA) software to generate canonical pathways, upstream regulators, and networks through a core analysis. The 17 genes identified were ABCB1, ABCG1, CYP17A1, CYP19A1, CYP27B1, CYP2A6, CYP3A4, CYP3A5, ESR1, OATP1B1, OPG, RANKL, SLCO3A1, TCL1A, UGT2A1, UGT2B17, and VDR. These genes are involved in encoding bone-remodeling regulators, drug-metabolizing enzymes (cytochrome P450 family, UDP-glucuronosyltransferases family), or drug transporters (ATP-binding cassette transporters, organic anion transporters). Multiple plausible biological pathways (e.g., nicotine degradation, melatonin degradation) and candidate genes (e.g., NFKB, HSP90, AKT, ERK1/2, FOXA2) are proposed for future investigation based on the IPA results. Multiple genes and molecular-level etiologies may contribute to MSKP with AI therapy in women with breast cancer. Our innovative combination of gene identification from the literature plus biological pathway analysis allowed for the emergence of novel candidate genes and biological pathways for future investigations.

Association between Marijuana Use and Serum Gamma-Glutamyltransferase in US Adults

TPS 771: Diet and lifestyle, Exhibition Hall, Ground floor, August 26, 2019, 3:00 PM - 4:30 PM Background/Aim: Several epidemiological studies have reported positive associations between marijuana use and adverse cardiovascular effects, yet there is insufficient evidence to draw definitive conclusions. Few studies have been performed to examine the possible biological mechanisms responsible for this observation. In this study, we examined whether current marijuana use is associated with elevated serum levels of gamma glutamyl transferase (GGT), a biomarker of oxidative stress that is linked to cardiovascular disease risk. Methods: We combined questionnaire data with laboratory measurements (GGT and cotinine) in serum samples available for adults aged ≥ 18 years participating in the US National Health and Nutrition Examination Survey during 2005 to 2014. We categorized the participants into 496 exclusive current cigarette smokers (self-reported cigarette smoking within the five days prior to examination, but neither used marijuana nor any other tobacco products), 105 recent exclusive marijuana users (self-reported use of marijuana within the five days prior to examination but never used any tobacco products) and 2524 nonusers (neither used any tobacco nor marijuana products in life). We performed comparative analyses of the adjusted geometric means (aGMs) of GGT among those groups using multiple regression models, adjusted for age, gender, race/ethnicity, body mass index, education, poverty-income ratio, fasting length, serum cotinine and average alcohol drinks/day. Results: Recent exclusive marijuana users had a small but significantly higher aGM of GGT (23.4 u/L, 95% confidence interval, CI: 20.3, 27.0 u/L) compared to nonusers (20.0 u/L, CI: 19.0, 21.1 u/L) (p=0.046). Cigarette smokers had the highest aGM of GGT (30.2 u/L, CI: 24.3, 37.6 u/L) among these groups. Conclusions: The findings suggest a plausible biological pathway for effects of exclusive marijuana use on cardiovascular disease risk. Future studies are needed to confirm these findings and to better examine the health effects of marijuana in the environment of liberalized use.

Integrational analysis of miRNAs data sets as a plausible missing linker between Epstein-Barr virus and vitamin D in relapsing remitting MS patients

Given the multifactorial state of autoimmune complex diseases such as multiple sclerosis (MS), it is not clear if different risk factors act jointly or independently. Despite intensive studies investigating multi aspects of MS risk factors, findings with regards to potential biomarkers that may link these risk factors remained largely inconclusive.System biology or data integration utilizes different validated datasets to extract meaningful information and map the plausible biological pathways and networks. As such, we integrated eight transcriptome datasets to find the differentially expressed miRNAs in peripheral blood (PB) between relapsing remitting MS patients (RRMS) and normal group. After identification the targeted genes of miRNAs, the hub genes were used to construct the underlying protein–protein interaction network and signaling pathways.As results, 9 miRNAs were best exemplified by significant dysregulation including hsa-mir-15a, hsa-mir-484, hsa-mir-30d, hsa-mir-145, hsa-mir-363, has-let-7e, hsa-mir-30a, hsa-let-7b, and hsa-mir-146a. System biology analysis of miRNAs in PB of RRMS patients clearly indicates the involvement of miRNAs in many vital pathways and highlighted the possibility of an association between miRNAs with EBV and vitamin D in MS pathogenesis.Described novel pathways and genes related to miRNAs such as Transient receptor potential channels and Acid sphingomyelinase may provide a potential target for therapeutic approaches although further functional studies are warranted to test these candidates.

Positive Affect and Health: What Do We Know and Where Next Should We Go?

Positive affect (PA) is associated with better health across a wide range of physical health outcomes. This review reflects on why the study of PA is an essential component of our understanding of physical health and expands on pathways that connect these two variables. To encourage forward movement in this burgeoning research area, measurement and design issues in the study of PA and health are discussed, as are the connections between PA and a range of different health outcomes. Plausible biological, social, and behavioral pathways that allow for positive feelings to get under the skin and influence physical wellness are detailed and framed in the context of several theoretical models. Finally, new directions for the field and important methodological and interpretative considerations that are essential to moving this important research area forward are explored.

Prometastatic Molecular Profiles in Breast Tumors From Socially Isolated Women.

BackgroundSocial isolation is associated with accelerated breast cancer progression and increased disease recurrence and mortality, but the underlying biological mechanisms remain poorly understood. In preclinical models, beta-adrenergic signaling from fight-or-flight stress responses can stimulate prometastatic processes in the tumor microenvironment including upregulation of M2 macrophages, epithelial–mesenchymal transition (EMT), and lymphovascular invasion. This study examines whether the same pathways are upregulated in breast tumors from socially isolated cancer patients.MethodsEMT and M1/M2 macrophage gene expression programs were analyzed by genome-wide transcriptional profiling, and lymphatic and vascular density were assessed by immunohistochemistry in primary tumors from 56 early-stage breast cancer patients who were part of the UCLA RISE study. Social isolation was quantified by the Social Provisions Scale, and disease characteristics were assessed by medical record review. General linear models were used to quantify differential gene expression across risk factor groups. Linear regression models were used to examine associations between social isolation and lymphovascular invasion.ResultsTumors from socially isolated patients showed upregulated expression of genes involved in EMT (average score difference = +0.080 log2 mRNA abundance ± 0.034 standard error) and M2 macrophage polarization (+0.033 ± 0.014) as well as increased density of lymphatic vessels (β= –.29) but no difference in blood vessel density. TELiS promoter–based bioinformatics analyses indicated activation of CREB family transcription factors that mediate the gene-regulatory effects of β-adrenergic signaling (log2 fold-difference in promoter binding site prevalence: mean ± standard error = +0.49 ± 0.19). ConclusionsPrimary breast tumors from socially isolated patients show multiple prometastatic molecular alterations, providing a plausible biological pathway through which poor social support may accelerate breast cancer progression and defining new targets for intervention.

Depressive symptoms predict head and neck cancer survival: Examining plausible behavioral and biological pathways.

Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined. Patients (n = 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up. Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P < .001), higher rates of chemoradiation interruption (odds ratio, 0.865; 95% CI, 0.774-0.966; P = .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P = .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results. Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine disruption and inflammation. Cancer 2018;124:1053-60. © 2018 American Cancer Society.