Blood Pressure Effect of Traffic-Related Air Pollution : A Crossover Trial of In-Vehicle Filtration.

BACKGROUND: Ambient air pollution, including traffic-related air pollution (TRAP), increases cardiovascular disease risk, possibly through vascular alterations. Limited information exists about in-vehicle TRAP exposure and vascular changes. OBJECTIVE: To determine via particle filtration the effect of on-roadway TRAP exposure on blood pressure and retinal vasculature. DESIGN: Randomized crossover trial. (ClinicalTrials.gov: NCT05454930). SETTING: In-vehicle scripted commutes driven through traffic in Seattle, Washington, during 2014 to 2016. PARTICIPANTS: Normotensive persons aged 22 to 45 years (n = 16). INTERVENTION: On 2 days, on-road air was entrained into the vehicle. On another day, the vehicle was equipped with high-efficiency particulate air (HEPA) filtration. Participants were blinded to the exposure and were randomly assigned to the sequence. MEASUREMENTS: Fourteen 3-minute periods of blood pressure were recorded before, during, and up to 24 hours after a drive. Image-based central retinal arteriolar equivalents (CRAEs) were measured before and after. Brachial artery diameter and gene expression were also measured and will be reported separately. RESULTS: Mean age was 29.7 years, predrive systolic blood pressure was 122.7 mm Hg, predrive diastolic blood pressure was 70.8 mm Hg, and drive duration was 122.3 minutes (IQR, 4 minutes). Filtration reduced particle count by 86%. Among persons with complete data (n = 13), at 1 hour, mean diastolic blood pressure, adjusted for predrive levels, order, and carryover, was 4.7 mm Hg higher (95% CI, 0.9 to 8.4 mm Hg) for unfiltered drives compared with filtered drives, and mean adjusted systolic blood pressure was 4.5 mm Hg higher (CI, -1.2 to 10.2 mm Hg). At 24 hours, adjusted mean diastolic blood pressure (unfiltered) was 3.8 mm Hg higher (CI, 0.02 to 7.5 mm Hg) and adjusted mean systolic blood pressure was 1.1 mm Hg higher (CI, -4.6 to 6.8 mm Hg). Adjusted mean CRAE (unfiltered) was 2.7 µm wider (CI, -1.5 to 6.8 µm). LIMITATIONS: Imprecise estimates due to small sample size; seasonal imbalance by exposure order. CONCLUSION: Filtration of TRAP may mitigate its adverse effects on blood pressure rapidly and at 24 hours. Validation is required in larger samples and different settings. PRIMARY FUNDING SOURCE: U.S. Environmental Protection Agency and National Institutes of Health.

Paracrine Signals in Calcified Conditioned Media Elicited Differential Responses in Primary Aortic Vascular Smooth Muscle Cells and in Adventitial Fibroblasts.

Our goal was to determine if paracrine signals from different aortic layers can impact other cell types in the diabetic microenvironment, specifically medial vascular smooth muscle cells (VSMCs) and adventitial fibroblasts (AFBs). The diabetic hyperglycemic aorta undergoes mineral dysregulation, causing cells to be more responsive to chemical messengers eliciting vascular calcification. Advanced glycation end-products (AGEs)/AGE receptors (RAGEs) signaling has been implicated in diabetes-mediated vascular calcification. To elucidate responses shared between cell types, pre-conditioned calcified media from diabetic and non-diabetic VSMCs and AFBs were collected to treat cultured murine diabetic, non-diabetic, diabetic RAGE knockout (RKO), and non-diabetic RKO VSMCs and AFBs. Calcium assays, western blots, and semi-quantitative cytokine/chemokine profile kits were used to determine signaling responses. VSMCs responded to non-diabetic more than diabetic AFB calcified pre-conditioned media. AFB calcification was not significantly altered when VSMC pre-conditioned media was used. No significant changes in VSMCs signaling markers due to treatments were reported; however, genotypic differences existed. Losses in AFB α-smooth muscle actin were observed with diabetic pre-conditioned VSMC media treatment. Superoxide dismutase-2 (SOD-2) increased with non-diabetic calcified + AGE pre-conditioned VSMC media, while same treatment decreased diabetic AFBs levels. Overall, non-diabetic and diabetic pre-conditioned media elicited different responses from VSMCs and AFBs.

Genetic Inhibition of Mitochondrial Permeability Transition Pore Exacerbates Ryanodine Receptor 2 Dysfunction in Arrhythmic Disease.

The brief opening mode of the mitochondrial permeability transition pore (mPTP) serves as a calcium (Ca2+) release valve to prevent mitochondrial Ca2+ (mCa2+) overload. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to mutations in the Ca2+ release channel complex of ryanodine receptor 2 (RyR2). We hypothesize that inhibiting the mPTP opening in CPVT exacerbates the disease phenotype. By crossbreeding a CPVT model of CASQ2 knockout (KO) with a mouse missing CypD, an activator of mPTP, a double KO model (DKO) was generated. Echocardiography, cardiac histology, and live-cell imaging were employed to assess the severity of cardiac pathology. Western blot and RNAseq were performed to evaluate the contribution of various signaling pathways. Although exacerbated arrhythmias were reported, the DKO model did not exhibit pathological remodeling. Myocyte Ca2+ handling was similar to that of the CASQ2 KO mouse at a low pacing frequency. However, increased ROS production, activation of the CaMKII pathway, and hyperphosphorylation of RyR2 were detected in DKO. Transcriptome analysis identified altered gene expression profiles associated with electrical instability in DKO. Our study provides evidence that genetic inhibition of mPTP exacerbates RyR2 dysfunction in CPVT by increasing activation of the CaMKII pathway and subsequent hyperphosphorylation of RyR2.

HIV-1 Tat Upregulates the Receptor for Advanced Glycation End Products and Superoxide Dismutase-2 in the Heart of Transgenic Mice.

Cardiovascular disorder (CVD) is a common comorbidity in people living with HIV (PLWH). Although the underlying mechanisms are unknown, virotoxic HIV proteins, such as the trans-activator of transcription (Tat), likely contribute to CVD pathogenesis. Tat expression in mouse myocardium has been found to induce cardiac dysfunction and increase markers of endothelial toxicity. However, the role that Tat may play in the development of CVD pathogenesis is unclear. The capacity for Tat to impact cardiac function was assessed using AC16 human cardiomyocyte cells and adult male and female transgenic mice that conditionally expressed Tat [Tat(+)], or did not [Tat(-)]. In AC16 cardiomyocytes, Tat increased intracellular calcium. In Tat(+) mice, Tat expression was detected in both atrial and ventricular heart tissue. Tat(+) mice demonstrated an increased expression of the receptor for advanced glycation end products and superoxide dismutase-2 (SOD-2) in ventricular tissues compared to Tat(-) controls. No changes in SOD-1 or α-smooth muscle actin were observed. Despite Tat-mediated changes at the cellular level, no changes in echocardiographic measures were detected. Tat(+) mice had a greater proportion of ventricular mast cells and collagen; however, doxycycline exposure offset the latter effect. These data suggest that Tat exposure promotes cellular changes that can precede progression to CVD.

Rap1a Activity Elevated the Impact of Endogenous AGEs in Diabetic Collagen to Stimulate Increased Myofibroblast Transition and Oxidative Stress.

Diabetics have an increased risk for heart failure due to cardiac fibroblast functional changes occurring as a result of AGE/RAGE signaling. Advanced glycation end products (AGEs) levels are higher in diabetics and stimulate elevated RAGE (receptor for AGE) signaling. AGE/RAGE signaling can alter the expression of proteins linked to extracellular matrix (ECM) remodeling and oxidative stressors. Our lab has identified a small GTPase, Rap1a, that may overlap the AGE/RAGE signaling pathway. We sought to determine the role Rap1a plays in mediating AGE/RAGE changes and to assess the impact of isolated collagen on further altering these changes. Primary cardiac fibroblasts from non-diabetic and diabetic mice with and without RAGE expression and from mice lacking Rap1a were cultured on tail collagen extracted from non-diabetic or diabetic mice, and in addition, cells were treated with Rap1a activator, EPAC. Protein analyses were performed for changes in RAGE-associated signaling proteins (RAGE, PKC-ζ, ERK1/2) and downstream RAGE signaling outcomes (α-SMA, NF-κB, SOD-2). Increased levels of endogenous AGEs within the diabetic collagen and increased Rap1a activity promoted myofibroblast transition and oxidative stress, suggesting Rap1a activity elevated the impact of AGEs in the diabetic ECM to stimulate myofibroblast transition and oxidative stress.

Compositionally-Driven Formation Mechanism of Hierarchical Morphologies in Co-Deposited Immiscible Alloy Thin Films.

Co-deposited, immiscible alloy systems form hierarchical microstructures under specific deposition conditions that accentuate the difference in constituent element mobility. The mechanism leading to the formation of these unique hierarchical morphologies during the deposition process is difficult to identify, since the characterization of these microstructures is typically carried out post-deposition. We employ phase-field modeling to study the evolution of microstructures during deposition combined with microscopy characterization of experimentally deposited thin films to reveal the origin of the formation mechanism of hierarchical morphologies in co-deposited, immiscible alloy thin films. Our results trace this back to the significant influence of a local compositional driving force that occurs near the surface of the growing thin film. We show that local variations in the concentration of the vapor phase near the surface, resulting in nuclei (i.e., a cluster of atoms) on the film's surface with an inhomogeneous composition, can trigger the simultaneous evolution of multiple concentration modulations across multiple length scales, leading to hierarchical morphologies. We show that locally, the concentration must be above a certain threshold value in order to generate distinct hierarchical morphologies in a single domain.

Rap1a Regulates Cardiac Fibroblast Contraction of 3D Diabetic Collagen Matrices by Increased Activation of the AGE/RAGE Cascade.

Cardiovascular disease is a common diabetic complication that can arise when cardiac fibroblasts transition into myofibroblasts. Myofibroblast transition can be induced by advanced glycated end products (AGEs) present in the extracellular matrix (ECM) activating RAGE (receptor for advanced glycated end products) to elicit intracellular signaling. The levels of AGEs are higher under diabetic conditions due to the hyperglycemic conditions present in diabetics. AGE/RAGE signaling has been shown to alter protein expression and ROS production in cardiac fibroblasts, resulting in changes in cellular function, such as migration and contraction. Recently, a small GTPase, Rap1a, has been identified to overlap the AGE/RAGE signaling cascade and mediate changes in protein expression. While Rap1a has been shown to impact AGE/RAGE-induced protein expression, there are currently no data examining the impact Rap1a has on AGE/RAGE-induced cardiac fibroblast function. Therefore, we aimed to determine the impact of Rap1a on AGE/RAGE-mediated cardiac fibroblast contraction, as well as the influence isolated diabetic ECM has on facilitating these effects. In order to address this idea, genetically different cardiac fibroblasts were embedded in 3D collagen matrices consisting of collagen isolated from either non-diabetic of diabetic mice. Fibroblasts were treated with EPAC and/or exogenous AGEs, which was followed by assessment of matrix contraction, protein expression (α-SMA, SOD-1, and SOD-2), and hydrogen peroxide production. The results showed Rap1a overlaps the AGE/RAGE cascade to increase the myofibroblast population and generation of ROS production. The increase in myofibroblasts and oxidative stress appeared to contribute to increased matrix contraction, which was further exacerbated by diabetic conditions. Based off these results, we determined that Rap1a was essential in mediating the response of cardiac fibroblasts to AGEs within diabetic collagen.

RAGE Differentially Altered in vitro Responses in Vascular Smooth Muscle Cells and Adventitial Fibroblasts in Diabetes-Induced Vascular Calcification.

The Advanced Glycation End-Products (AGE)/Receptor for AGEs (RAGE) signaling pathway exacerbates diabetes-mediated vascular calcification (VC) in vascular smooth muscle cells (VSMCs). Other cell types are involved in VC, such as adventitial fibroblasts (AFBs). We hope to elucidate some of the mechanisms responsible for differential signaling in diabetes-mediated VC with this work. This work utilizes RAGE knockout animals and in vitro calcification to measure calcification and protein responses. Our calcification data revealed that VSMCs calcification was AGE/RAGE dependent, yet AFBs calcification was not an AGE-mediated RAGE response. Protein expression data showed VSMCs lost their phenotype marker, α-smooth muscle actin, and had a higher RAGE expression over non-diabetics. RAGE knockout (RKO) VSMCs did not show changes in phenotype markers. P38 MAPK, a downstream RAGE-associated signaling molecule, had significantly increased activation with calcification in both diabetic and diabetic RKO VSMCs. AFBs showed a loss in myofibroblast marker, α-SMA, due to calcification treatment. RAGE expression decreased in calcified diabetic AFBs, and P38 MAPK activation significantly increased in diabetic and diabetic RKO AFBs. These findings point to potentially an alternate receptor mediating the calcification response in the absence of RAGE. Overall, VSMCs and AFBs respond differently to calcification and the application of AGEs.

Rap1a Overlaps the AGE/RAGE Signaling Cascade to Alter Expression of α-SMA, p-NF-κB, and p-PKC-ζ in Cardiac Fibroblasts Isolated from Type 2 Diabetic Mice.

Cardiovascular disease, specifically heart failure, is a common complication for individuals with type 2 diabetes mellitus. Heart failure can arise with stiffening of the left ventricle, which can be caused by "active" cardiac fibroblasts (i.e., myofibroblasts) remodeling the extracellular matrix (ECM). Differentiation of fibroblasts to myofibroblasts has been demonstrated to be an outcome of AGE/RAGE signaling. Hyperglycemia causes advanced glycated end products (AGEs) to accumulate within the body, and this process is greatly accelerated under chronic diabetic conditions. AGEs can bind and activate their receptor (RAGE) to trigger multiple downstream outcomes, such as altering ECM remodeling, inflammation, and oxidative stress. Previously, our lab has identified a small GTPase, Rap1a, that possibly overlaps the AGE/RAGE signaling cascade to affect the downstream outcomes. Rap1a acts as a molecular switch connecting extracellular signals to intracellular responses. Therefore, we hypothesized that Rap1a crosses the AGE/RAGE cascade to alter the expression of AGE/RAGE associated signaling proteins in cardiac fibroblasts in type 2 diabetic mice. To delineate this cascade, we used genetically different cardiac fibroblasts from non-diabetic, diabetic, non-diabetic RAGE knockout, diabetic RAGE knockout, and Rap1a knockout mice and treated them with pharmacological modifiers (exogenous AGEs, EPAC, Rap1a siRNA, and pseudosubstrate PKC-ζ). We examined changes in expression of proteins implicated as markers for myofibroblasts (α-SMA) and inflammation/oxidative stress (NF-κB and SOD-1). In addition, oxidative stress was also assessed by measuring hydrogen peroxide concentration. Our results indicated that Rap1a connects to the AGE/RAGE cascade to promote and maintain α-SMA expression in cardiac fibroblasts. Moreover, Rap1a, in conjunction with activation of the AGE/RAGE cascade, increased NF-κB expression as well as hydrogen peroxide concentration, indicating a possible oxidative stress response. Additionally, knocking down Rap1a expression resulted in an increase in SOD-1 expression suggesting that Rap1a can affect oxidative stress markers independently of the AGE/RAGE signaling cascade. These results demonstrated that Rap1a contributes to the myofibroblast population within the heart via AGE/RAGE signaling as well as promotes possible oxidative stress. This study offers a new potential therapeutic target that could possibly reduce the risk for developing diabetic cardiovascular complications attributed to AGE/RAGE signaling.

Visual teaching aids improve patient understanding and reduce anxiety prior to a colectomy.

BACKGROUND: Informed consent forms consist of large blocks of written information that may be difficult for patients to understand. Visual teaching aids are promising, however, they have not been studied as a pre-operative educational tool for common surgical procedures. We pilot tested the use of a visual teaching aid during the informed consent process for a colectomy. METHODS: A randomized pilot study was performed. Participants were randomized into the visual teaching aid group or standard care. Following the consent process, participants were questioned about potential surgical complications, anxiety, satisfaction, and understanding. RESULTS: 30 participants were enrolled. Potential complication recall and patient-reported understanding were improved in the visual group (p = 0.01, p = 0.03). Anxiety levels were reduced in the visual group (p = 0.02). No statistically significant data were found for satisfaction (p = 0.75). CONCLUSIONS: Utilizing a visual teaching aid during the consent process for colectomy increases patient recall of risks, reduces anxiety, and improves understanding.

Physical Activity Before, During, and After Chemotherapy for High-Risk Breast Cancer: Relationships With Survival.

BACKGROUND: Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based on data collected at one occasion. We examined how pre- and postdiagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. METHODS: Included were 1340 patients enrolled in the Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at 1- and 2-year intervals after enrollment was collected. Patients were categorized according to the Physical Activity Guidelines for Americans as meeting the minimum guidelines (yes/no) and incrementally as inactive, low active, moderately active (meeting the guidelines), or high active. RESULTS: In joint-exposure analyses, patients meeting the guidelines before and 1 year after diagnosis experienced statistically significant reductions in hazards of recurrence (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.42 to 0.82) and mortality (HR = 0.51, 95% CI = 0.34-0.77); associations were stronger at 2-year follow-up for recurrence (HR = 0.45, 95% CI = 0.31 to 0.65) and mortality (HR = 0.32, 95% CI = 0.19 to 0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI = 0.24 to 0.68), moderate- (HR = 0.42, 95% CI = 0.23 to 0.76), and high-active patients (HR = 0.31, 95% CI = 0.18 to 0.53). CONCLUSIONS: Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the guidelines.

A Cost Effective and Adaptable Scratch Migration Assay.

Cell migration is a key component in both physiological and pathological events. Normal cell migration is required for essential functions such as development and mounting an immune response. When a defect or alteration occurs with the cell migration process, it can have detrimental outcomes (i.e., cancer metastasis, wound healing, and scar formation). Due to the importance of cell migration, it is necessary to have access to a cell migration assay that is affordable, adaptable, and repeatable. Utilizing the common scratch migration assay, we have developed a new approach to analyzing cell migration that uses general laboratory equipment. The method described uses visual markers that allow for recapturing specific areas of interest without the use of time-lapse microscopy. In addition, it provides flexibility in the experimental design, ranging from altering the migration matrix substrate to the addition of pharmacological modifiers. Furthermore, this protocol outlines a way to account for the area of cell migration, which is not considered by several methods when examining cell migration. This new approach offers a scratch migration assay to a larger audience and will provide greater opportunity for researchers to examine the physiological and pathophysiological impact of cell migration.

Extracellular matrix components isolated from diabetic mice alter cardiac fibroblast function through the AGE/RAGE signaling cascade.

Individuals suffering from diabetes have an increased risk of developing cardiovascular complications such as heart failure. Heart failure can be a result of the stiffening of the left ventricle, which occurs when cardiac fibroblasts become "active" and begin to remodel the extracellular matrix (ECM). Fibroblast "activation" can be triggered by the AGE/RAGE signaling cascade. Advanced Glycation End products (AGEs) are produced and accumulate in the ECM over time in a healthy individual, but under hyperglycemic conditions, this process is accelerated. In this study, we investigated how the presence of AGEs in either non-diabetic or diabetic ECM affected fibroblast-mediated matrix remodeling. In order to address this question, diabetic and non-diabetic fibroblasts were embedded in 3D matrices composed of collagen isolated from either non-diabetic or diabetic mice. Fibroblast function was assessed using gel contraction, migration, and protein expression. Non-diabetic fibroblasts displayed similar gel contraction to diabetic cells when embedded in diabetic collagen. Thus, suggesting the diabetic ECM can alter fibroblast function from an "inactive" to "active" state. Addition of AGEs increase the AGE/RAGE cascade leading to increased gel contraction, whereas inhibiting the cascade resulted in little or no gel contraction. These results indicated 1) the ECM from diabetic and non-diabetic mice differ from one another, 2) diabetic ECM can impact fibroblast function and shift them toward an "active" state, and 3) that fibroblasts can modify the ECM through activation of the AGE/RAGE signaling cascade. These results suggested the importance of understanding the impact diabetes has on the ECM and fibroblast function.

Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221).

PURPOSE: Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS: Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS: There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION: Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

Persistent organic pollutants (POPs) increase rage signaling to promote downstream cardiovascular remodeling.

Exposure to environmental contaminants and consumption of a high, saturated fatty diet has been demonstrated to promote precursors for metabolic syndrome (hyperglycemia, hyperinsulinemia, and hypertriglyceridemia). The purpose of this study was to determine if exposure to the most prevalent environmental persistent organic pollutants (POPs) would act as causative agents to promote metabolic syndrome independent of dietary intake. We hypothesized that POPs will activate the advanced glycated end-product (AGE)-and receptor for AGE (RAGE) signaling cascade to promote downstream signaling modulators of cardiovascular remodeling and oxidative stress in the heart. At 5-weeks of age nondiabetic (WT) and diabetic (ob/ob) mice were exposed POPs mixtures by oral gavage twice a week for 6-weeks. At the end of 6-weeks, animals were sacrificed and the hearts were taken for biochemical analysis. Increased activation of the AGE-RAGE signaling cascade via POPs exposure resulted in elevated levels of fibroblast differentiation (α-smooth muscle actin) and RAGE expression indicated maladaptive cardiac remodeling. Conversely, the observed decreased superoxide dismutase-1 and -2 (SOD-1 and SOD-2) expression may exacerbate the adverse changes occurring as a result of POPs treatment to reduce innate cardioprotective mechanisms. In comparison, ventricular collagen levels were decreased in mice exposed to POPs. In conclusion, exposure to organic environmental pollutants may intensify oxidative and inflammatory stressors to overwhelm protective mechanisms allowing for adverse cardiac remodeling.

Diesel Exhaust Induces Mitochondrial Dysfunction, Hyperlipidemia, and Liver Steatosis.

OBJECTIVE: Air pollution is associated with increased cardiovascular morbidity and mortality, as well as dyslipidemia and metabolic syndrome. Our goal was to dissect the mechanisms involved. Approach and Results: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE (9-hydroxyoctadecadienoic) and 13-HODE (13-hydroxyoctadecadienoic), lipid, and carbohydrate metabolism. Findings were corroborated, and mechanisms were further assessed in HepG2 hepatocytes in culture. ApoE knockout mice exposed to inhaled diesel exhaust (DE, 6 h/d, 5 days/wk for 16 weeks) exhibited elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and higher hepatic levels of 9-HODE and 13-HODE, as compared to control mice exposed to filtered air. A direct effect of DE exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo, this led to increased triglyceride content and significant downregulation of ACAD9 mRNA expression. Treatment of HepG2 cells with DE particles and oleic acid did not alter de novo lipogenesis but inhibited total, mitochondrial, and ATP-linked oxygen consumption rate, indicative of mitochondrial dysfunction. Treatment of isolated mitochondria, prepared from mouse liver, with DE particles and oleic acid also inhibited mitochondrial complex activity and ß-oxidation. CONCLUSIONS: DE exposure leads to dyslipidemia and liver steatosis in ApoE knockout mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.

Associations between self-reported diet during treatment and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221).

BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment. METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900). RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05). CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.

Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci.

OBJECTIVE: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. PATIENTS AND METHODS: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus

Exposure to an environmentally relevant mixture of organochlorine compounds and polychlorinated biphenyls Promotes hepatic steatosis in male Ob/Ob mice.

Hepatic steatosis is recognized as an independent risk factor for the development of cardiovascular disease. While obesity and type 2 diabetes are well-established risk factors in the development of hepatic steatosis, recent studies have revealed exposure to mixtures of persistent organic pollutants (POPs), which are environmental contaminants in various fatty foods, can promote steatosis. Thus, the present study was designed to determine if exposure to a defined mixture of prevalent polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides or their metabolites promote hepatic steatosis in a genetically induced model of type 2 diabetes, the leptin-deficient ob/ob mouse. Male C57BL/6J wild type (WT) or ob/ob mice were administered an environmentally relevant mixture of PCBs and OCs for 7 weeks via oral gavage. Exposure to POPs did not significantly alter fasting serum glucose or insulin levels. However, POPs exposure significantly increased hepatic triglyceride content in ob/ob animals, while decreasing serum triglyceride levels. This POPs-mediated increase in hepatic triglyceride content did not appear to be associated with significantly increased inflammation in either the liver or adipose. Exposure to POPs significantly induced the expression of cytochrome P450 3a11 in WT animals, yet the expression of this cytochrome was significantly downregulated in ob/ob animals regardless of POPs exposure. Taken together, the present data indicate exposure to an environmentally relevant mixture of both PCBs and OC pesticides in ob/ob mice promotes hepatic steatosis while decreasing hypertriglyceridemia, which demonstrates exposure to a defined mixture of POPs alters systemic lipid metabolism in a genetically induced model of obesity and type 2 diabetes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1399-1411, 2017.