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At least 937 records · Page 52
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

A novel cantharidin analog N-Benzylcantharidinamide reduces the expression of MMP-9 and invasive potentials of Hep3B via inhibiting cytosolic translocation of HuR

Highlights: • We examined the inhibition of N-Benzylcantharidinamide on MMP-9-mediated invasion. • Unlike cantharidin, N-Benzylcantharidinamide has very low toxicity on Hep3B cells. • The reduced MMP-9 expression was due to HuR-mediated decrease of mRNA stability. • We suggest N-Benzylcantharidinamide as a novel inhibitor of MMP-9-related invasion. - Abstract: Invasion and metastasis are major causes of malignant tumor-associated mortality. The present study aimed to investigate the molecular events underlying inhibitory effect of N-Benzylcantharidinamide, a novel synthetic analog of cantharidin, on matrix metalloproteinase-9 (MMP-9)-mediated invasion in highly metastatic hepatocellular carcinoma Hep3B cells. In this investigation, among six analogs of cantharidin, only N-Benzylcantharidinamide has the inhibitory action on MMP-9 expression at non-toxic dose. The MMP-9 expression and invasion of Hep3B cells were significantly suppressed by treatment of N-Benzylcantharidinamide in a dose-dependent manner. On the other hand, the transcriptional activity of MMP-9 promoter and nuclear levels of NF-κB and AP-1 as the main transcriptional factors inducing MMP-9 expression were not affected by it although the level of MMP-9 mRNA was reduced by treatment of N-Benzylcantharidinamide. Interestingly, the stability of MMP-9 mRNA was significantly reduced by N-Benzylcantharidinamide-treatment. In addition, the cytosolic translocation of human antigen R (HuR), which results in the increase of MMP-9 mRNA stability through interaction of HuR with 3′-untranslated region of MMP-9 mRNA, was suppressed by treatment of N-Benzylcantharidinamide, in a dose-dependent manner. Taken together, it was demonstrated, for the first time, that N-Benzylcantharidinamide suppresses MMP-9 expression by reducing HuR-mediated MMP-9 mRNA stability for the inhibition of invasive potential in highly metastatic Hep3B cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Role of ICAM-1 polymorphisms (G241R, K469E) in mediating its single-molecule binding ability: Atomic force microscopy measurements on living cells

Highlights: • We evaluated both single molecule binding ability and expression level of 4 ICAM-1 mutations. • AFM was used to measure single-molecule binding ability on living cells. • The SNP of ICAM-1 may induce changes in expressions rather than single-molecule binding ability. - Abstract: Atherosclerosis (As) is characterized by chronic inflammation and is a major cause of human mortality. ICAM-1-mediated adhesion of leukocytes in vessel walls plays an important role in the pathogenesis of atherosclerosis. Two single nucleotide polymorphisms (SNPs) of human intercellular adhesion molecule-1 (ICAM-1), G241R and K469E, are associated with a number of inflammatory diseases. SNP induced changes in ICAM-1 function rely not only on the expression level but also on the single-molecule binding ability which may be affected by single molecule conformation variations such as protein splicing and folding. Previous studies have shown associations between G241R/K469E polymorphisms and ICAM-1 gene expression. Nevertheless, few studies have been done that focus on the single-molecule forces of the above SNPs and their ligands. In the current study, we evaluated both single molecule binding ability and expression level of 4 ICAM-1 mutations – GK (G241/K469), GE (G241/E469), RK (R241/K469) and RE (R241/E469). No difference in adhesion ability was observed via cell adhesion assay or atomic force microscopy (AFM) measurement when comparing the GK, GE, RK, or RE genotypes of ICAM-1 to each other. On the other hand, flow cytometry suggested that there was significantly higher expression of GE genotype of ICAM-1 on transfected CHO cells. Thus, we concluded that genetic susceptibility to diseases related to ICAM-1 polymorphisms, G241R or K469E, might be due to the different expressions of ICAM-1 variants rather than to the single-molecule binding ability of ICAM-1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Metformin inhibits epithelial–mesenchymal transition in prostate cancer cells: Involvement of the tumor suppressor miR30a and its target gene SOX4

Highlights: • Metformin inhibits TGF-β-induced EMT in prostate cancer (PCa) cells. • Metformin upregulates tumor suppressor miR30a and downregulates SOX4 in PCa cells. • SOX4 is a target gene of miR30a. - Abstract: Tumor metastasis is the leading cause of mortality and morbidity of prostate cancer (PCa) patients. Epithelial–mesenchymal transition (EMT) plays a critical role in cancer progression and metastasis. Recent evidence suggested that diabetic patients treated with metformin have lower PCa risk and better prognosis. This study was aimed to investigate the effects of metformin on EMT in PCa cells and the possible microRNA (miRNA)-based mechanisms. MiRNAs have been shown to regulate various processes of cancer metastasis. We herein showed that metformin significantly inhibits proliferation of Vcap and PC-3 cells, induces G0/G1 cell cycle arrest and inhibits invasiveness and motility capacity of Vcap cells. Metformin could inhibit TGF-β-induced EMT in Vcap cells, as manifested by inhibition of the increase of N-cadherin (p = 0.013), Vimentin (p = 0.002) and the decrease of E-cadherin (p = 0.0023) and β-catenin (p = 0.034) at mRNA and protein levels. Notably, we demonstrated significant upregulation of miR30a levels by metformin (P < 0.05) and further experiments indicated that miR30a significantly inhibits proliferation and EMT process of Vcap cells. Interestingly, we identified that SOX4, a previously reported oncogenic transcriptional factor and modulator of EMT, is a direct target gene of miR30a. Finally, we screened the expression of miR30a and SOX4 in 84 PCa cases with radical prostatectomy. Of note, SOX4 overexpression is significantly associated with decreased levels of miR30a in PCa cases. In all, our study suggested that inhibition of EMT by metformin in PCa cells may involve upregulation of miR30a and downregulation of SOX4.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Blockage of mitochondrial calcium uniporter prevents iron accumulation in a model of experimental subarachnoid hemorrhage

Highlights: • Iron accumulation was involved in the acute phase following SAH. • Blockage of MCU could attenuate cellular iron accumulation following SAH. • Blockage of MCU could decrease ROS generation and improve cell energy supply following SAH. • Blockage of MCU could alleviate apoptosis and brain injury following SAH. - Abstract: Previous studies have shown that iron accumulation is involved in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH) and chelation of iron reduced mortality and oxidative DNA damage. We previously reported that blockage of mitochondrial calcium uniporter (MCU) provided benefit in the early brain injury after experimental SAH. This study was undertaken to identify whether blockage of MCU could ameliorate iron accumulation-associated brain injury following SAH. Therefore, we used two reagents ruthenium red (RR) and spermine (Sper) to inhibit MCU. Sprague–Dawley (SD) rats were randomly divided into four groups including sham, SAH, SAH + RR, and SAH + Sper. Biochemical analysis and histological assays were performed. The results confirmed the iron accumulation in temporal lobe after SAH. Interestingly, blockage of MCU dramatically reduced the iron accumulation in this area. The mechanism was revealed that inhibition of MCU reversed the down-regulation of iron regulatory protein (IRP) 1/2 and increase of ferritin. Iron–sulfur cluster dependent-aconitase activity was partially conserved when MCU was blocked. In consistence with this and previous report, ROS levels were notably reduced and ATP supply was rescued; levels of cleaved caspase-3 dropped; and integrity of neurons in temporal lobe was protected. Taken together, our results indicated that blockage of MCU could alleviate iron accumulation and the associated injury following SAH. These findings suggest that the alteration of calcium and iron homeostasis be coupled and MCU be considered to be a therapeutic target for patients suffering from SAH.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

NMR ({sup 1}H and {sup 13}C) based signatures of abnormal choline metabolism in oral squamous cell carcinoma with no prominent Warburg effect

At functional levels, besides genes and proteins, changes in metabolome profiles are instructive for a biological system in health and disease including malignancy. It is understood that metabolomic alterations in association with proteomic and transcriptomic aberrations are very fundamental to unravel malignant micro-ambient criticality and oral cancer is no exception. Hence deciphering intricate dimensions of oral cancer metabolism may be contributory both for integrated appreciation of its pathogenesis and to identify any critical but yet unexplored dimension of this malignancy with high mortality rate. Although several methods do exist, NMR provides higher analytical precision in identification of cancer metabolomic signature. Present study explored abnormal signatures in choline metabolism in oral squamous cell carcinoma (OSCC) using {sup 1}H and {sup 13}C NMR analysis of serum. It has demonstrated down-regulation of choline with concomitant up-regulation of its break-down product in the form of trimethylamine N-oxide in OSCC compared to normal counterpart. Further, no significant change in lactate profile in OSCC possibly indicated that well-known Warburg effect was not a prominent phenomenon in such malignancy. Amongst other important metabolites, malonate has shown up-regulation but D-glucose, saturated fatty acids, acetate and threonine did not show any significant change. Analyzing these metabolomic findings present study proposed trimethyl amine N-oxide and malonate as important metabolic signature for oral cancer with no prominent Warburg effect. - Highlights: • NMR ({sup 1}H and {sup 13}C) study of Oral Squamous cell Carcinoma Serum. • Abnormal Choline metabolomic signatures. • Up-regulation of Trimethylamine N-oxide. • Unchanged lactate profile indicates no prominent Warburg effect. • Proposed alternative glucose metabolism path through up-regulation of malonate.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Elevated β-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells

Ovarian cancer is the fifth leading cause of cancer-related mortalities in women. Epithelial ovarian cancer (EOC) represents approximately 90% of all ovarian malignancies. Most EOC patients are diagnosed at advanced stages and current chemotherapy regimens are ineffective against advanced EOC due to the development of chemoresistance. It is important to better understand the molecular mechanisms underlying acquired resistance to effectively manage this disease. In this study, we examined the expression of the Wnt/β-catenin signaling components in the paired cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) EOC cell lines. Our results showed that several negative regulators of Wnt signaling are downregulated, whereas a few Wnt ligands and known Wnt/β-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/β-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of β-catenin and higher β-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of β-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for β-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/β-catenin signaling activity contributes to carboplatin resistance in A2780cp cells. - Highlights: • Wnt ligands and target genes are upregulated in cisplatin resistant A2780cp cells. • Negative regulators of Wnt signaling are down-regulated in A2780cp cells. • β-catenin transcriptional activity is higher in A2780cp cells compared to A2780s cells. • Inhibition of β-catenin activity increases carboplatin cytotoxicity in A2780cp cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

miR-625 suppresses cell proliferation and migration by targeting HMGA1 in breast cancer

Dysregulation of microRNA contributes to the high incidence and mortality of breast cancer. Here, we show that miR-625 was frequently down-regulated in breast cancer. Decrease of miR-625 was closely associated with estrogen receptor (P = 0.004), human epidermal growth factor receptor 2 (P = 0.003) and clinical stage (P = 0.001). Kaplan–Meier and multivariate analyses indicated miR-625 as an independent factor for unfavorable prognosis (hazard ratio = 2.654, 95% confident interval: 1.300–5.382, P = 0.007). Re-expression of miR-625 impeded, whereas knockdown of miR-625 enhanced cell viabilities and migration abilities in breast cancer cells. HMGA1 was confirmed as a direct target of miR-625. The expressions of HMGA1 mRNA and protein were induced by miR-625 mimics, but reduced by miR-625 inhibitor. Re-introduction of HMGA1 in cells expressing miR-625 distinctly abrogated miR-625-mediated inhibition of cell growth. Taken together, our data demonstrate that miR-625 suppresses cell proliferation and migration by targeting HMGA1 and suggest miR-625 as a promising prognostic biomarker and a potential therapeutic target for breast cancer. - Highlights: • miR-625 expression was significantly decreased in breast cancer. • Decrease of miR-625 was associated with poor clinical outcomes and unfavorable overall survival. • miR-625 overexpression inhibits cell proliferation and migration in vitro. • miR-625 directly targets and suppresses the expression of HMGA1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibition of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Suppressive effects of lysozyme on polyphosphate-mediated vascular inflammatory responses

Lysozyme, found in relatively high concentration in blood, saliva, tears, and milk, protects us from the ever-present danger of bacterial infection. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate(PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of lysozyme and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Lysozyme suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/or production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, lysozyme demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of lysozyme on various systemic inflammatory diseases, such as sepsis or septic shock. -- Highlights: •PolyP is shown to be an important mediator of vascular inflammation. •Lysozyme inhibited PolyP-mediated hyperpermeability. •Lysozyme inhibited PolyP-mediated septic response. •Lysozyme reduced PolyP-induced septic mortality.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

RIP2 deficiency attenuates cardiac hypertrophy, inflammation and fibrosis in pressure overload induced mice

Although the pathological cardiac hypertrophy presents a leading cause of morbidity and mortality worldwide, our knowledge of the molecular mechanisms underlying the disease is still poor. Here, we reported that receptor-interacting serine/threonine-protein kinase 2 (RIP2), promoting pro-inflammatory gene expression, enhanced the pathological cardiac hypertrophy in animals. The effects of RIP2 on the cardiac hypertrophy triggered by pathological stimuli have not been fully investigated. In our study, mice were subjected to aortic banding (AB) surgery to explore the pathological, echocardiographic and molecular mechanisms. RIP2 expressed highly in cardiomyocytes after AB operation in wild type (WT) mice. RIP2-knockout (KO) attenuated cardiac hypertrophy, inflammation and fibrosis in mice 4 weeks after AB-surgery. First, RIP2 knockout down-regulated hypertrophic markers of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) in the heart of AB-operated mice.in addition, RIP2-deficiency reduced toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) activation, mitogen-activated protein kinases (MAPKs) phosphorylation and transforming growth factor-β1 (TGF-β1)/SMADs expressions, contributing to the suppression of inflammatory response and fibrosis, as further evidenced by down-regulated pro-inflammatory cytokines, including Tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-18, as well as fibrosis markers of Collagen I, Collagen III and α-smooth muscle actin (α-SMA). Taken together, our data indicated that RIP2-deficience ameliorated cardiac hypertrophy, inflammation and fibrosis through modulating multiple signaling pathways. - Highlights: • Overexpression of RIP2 contributed to development of hypertrophic heart. • RIP2-knockout attenuates cardiac injury and dysfunction in hypertrophic heart. • RIP2-deficience alleviates inflammation in heart of hypertrophic mice. • RIP2-deletion inhibits fibrosis in the heart of hypertrophic mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

shRNA interference of NLRP3 inflammasome alleviate ischemia reperfusion-induced myocardial damage through autophagy activation

Myocardial ischemia-reperfusion (I/R) injury always occur during the recovery of myocardial blood supply with high morbidity and mortality. Although, various therapeutic schedules were applied in clinic, there are real problems that have to be resolved on curative effect. Nod-like receptor protein 3 (NLRP3) inflammasome has moderation effects on cellular damage and inflammatory reaction after I/R injury. Our research aims to investigate a more effective approach to restrain the activation of NLRP3 inflammasome in treating myocardial I/R injury. Results indicated that cell viability, Bax/Bcl-2 expression were affected hardly by sh-NLRP3 transfection in normal cells. However, the decreased cell viability and increased Bax/Bcl-2 expression level caused by I/R were remarkably suppressed through sh-NLRP3 transfection. Besides that, the reduced levels of pro-autophagy proteins (Beclin1, Agt7, LC3II/LC3I) while enhanced level of anti-autophagy protein (p62) and apoptosis-related proteins (Bax/Bcl-2) were significantly repressed via sh-NLRP3 transfection. Nevertheless, the autophagy inhibitor 3 MA could reverse the results. Moreover, in vivo experiment suggested that NLRP3 was up-regulated in wild type (WT) rats with I/R injury. The expansion of infarct size induced by ischemia was tremendously constricted in NLRP3 knockout (KO) rats. NLRP3 silence had nearly no impact on myocardial enzymes (AST, LDH and CK) expressions, inflammatory factors (TNF-α and IL-1β) expressions and cell apoptosis in rats without I/R injury. Nonetheless, the elevated levels of myocardial enzymes, inflammatory factors and cell apoptosis caused by I/R injury were vastly inhibited in NLRP3 KO rats. Furthermore, NLRP3 KO itself would lead to higher level of pro-autophagy proteins (Beclin1, Agt7, LC3II/LC3I) while lower level of anti-autophagy protein (p62) in vivo. The decreased expressions of pro-autophagy proteins while increased expressions of anti-autophagy protein induced by I/R injury were remarkably suppressed by NLRP3 KO. Taken together, our study indicated that shRNA interference of NLRP3 inflammasome attenuated myocardial I/R injury via autophagy activation. These findings demonstrated that NLRP3 KO may a promising therapy in myocardial I/R injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Cashew nut roasting: Chemical characterization of particulate matter and genotocixity analysis

Background: Particulate matter (PM) is potentially harmful to health and related to genotoxic events, an increase in the number of hospitalizations and mortality from respiratory and cardiovascular diseases. The present study conducted the first characterization of elemental composition and polycyclic aromatic hydrocarbon (PAH) analysis of PM, as well as the biomonitoring of genotoxic activity associated to artisanal cashew nut roasting, an important economic and social activity worldwide. Methods: The levels of PM{sub 2.5} and black carbon were also measured by gravimetric analysis and light reflectance. The elemental composition was determined using X-ray fluorescence spectrometry and PAH analysis was carried out by gas chromatography–mass spectrometry. Genotoxic activity was measured by the Tradescantia pallida micronucleus bioassay (Trad-MCN). Other biomarkers of DNA damage, such as nucleoplasmic bridges and nuclear fragments, were also quantified. Results: The mean amount of PM{sub 2.5} accumulated in the filters (January 2124.2 µg/m{sup 3}; May 1022.2 µg/m{sup 3}; September 1291.9 µg/m{sup 3}), black carbon (January 363.6 µg/m{sup 3}; May 70 µg/m{sup 3}; September 69.4 µg/m{sup 3}) and concentrations of Al, Si, P, S, Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, Se, Br and Pb were significantly higher than the non-exposed area. Biomass burning tracers K, Cl, and S were the major inorganic compounds found. Benzo[k]fluoranthene, indene[1,2,3-c,d]pyrene, benzo[ghi]perylene, phenanthrene and benzo[b]fluoranthene were the most abundant PAHs. Mean benzo[a]pyrene-equivalent carcinogenic power values showed a significant cancer risk. The Trad-MCN bioassay revealed an increase in micronucleus frequency, 2–7 times higher than the negative control and significantly higher in all the months analyzed, possibly related to the mutagenic PAHs found. Conclusions: This study demonstrated that artisanal cashew nut roasting is a serious occupational problem, with harmful effects on workers' health. Those involved in this activity are exposed to higher PM{sub 2.5} concentrations and to 12 PAHs considered potentially mutagenic and/or carcinogenic. The Trad-MCN with T. pallida was sensitive and efficient in evaluating the genotoxicity of the components and other nuclear alterations may be used as effective biomarkers of DNA damage. - Highlights: • The cashew nut roasting generated high concentrations of particulate matter fine. • The biomass burning tracers K, Cl, S were the major inorganic compounds found. • It was identified 12 PAHs considered to be potentially mutagenic and/or carcinogenic. • The genotoxic potential of this activity was confirmed by the Trad MCN assay. • This activity is a serious occupational problem with harmful effects to health workers.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2014

Summer outdoor temperature and occupational heat-related illnesses in Quebec (Canada)

Background: Predicted rise in global mean temperature and intensification of heat waves associated with climate change present an increasing challenge for occupational health and safety. Although important scientific knowledge has been gathered on the health effects of heat, very few studies have focused on quantifying the association between outdoor heat and mortality or morbidity among workers. Objective: To quantify the association between occupational heat-related illnesses and exposure to summer outdoor temperatures. Methods: We modeled 259 heat-related illnesses compensated by the Workers' Compensation Board of Quebec between May and September, from 1998 to 2010, with maximum daily summer outdoor temperatures in 16 health regions of Quebec (Canada) using generalized linear models with negative binomial distributions, and estimated the pooled effect sizes for all regions combined, by sex and age groups, and for different time lags with random-effect models for meta-analyses. Results: The mean daily compensation count was 0.13 for all regions of Quebec combined. The relationship between daily counts of compensations and maximum daily temperatures was log-linear; the pooled incidence rate ratio (IRR) of daily heat-related compensations per 1 °C increase in daily maximum temperatures was 1.419 (95% CI 1.326 to 1.520). Associations were similar for men and women and by age groups. Increases in daily maximum temperatures at lags 1 and 2 and for two and three-day lag averages were also associated with increases in daily counts of compensations (IRRs of 1.206 to 1.471 for every 1 °C increase in temperature). Conclusion: This study is the first to quantify the association between occupational heat-related illnesses and exposure to summer temperatures in Canada. The model (risk function) developed in this study could be useful to improve the assessment of future impacts of predicted summer outdoor temperatures on workers and vulnerable groups, particularly in colder temperate zones. - Highlights: • 259 heat-related compensated illnesses were modeled with ambient temperature • An overall risk ratio of 1.419 (95% CI 1.326–1.520) for every 1 °C increase was found • Risk estimates were similar for men and women and by large age groups. • There were little lag effects (IRRs of 1.206 to 1.471 for every 1 °C increase)

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Toxicity of Bacillus thuringiensis var. israelensis in aqueous suspension on the South American common frog Leptodactylus latrans (Anura: Leptodactylidae) tadpoles

The effects of commercial formulations of Bacillus thuringiensisvar.israelensis (Bti) on non-target organisms are still a matter of debate; in amphibians, the risks of Bti are little known. To evaluate the toxicity of a commercial liquid (aqueous suspension, AS) formulation of Bti (Introban{sup ®}) on Leptodactylus latrans tadpoles, including median lethal concentration (LC{sub 50}) and no-and lowest–observed-effect concentrations (NOEC and LOEC, respectively), as well as the possible effects of Bti on oxidative responses, erythrocytes genotoxicity, and histology of the intestines. In the laboratory, tadpoles were exposed to nominal concentrations of 0 (control), 2.5, 5, 10, 20 and 40 mg/L of formulated Bti-AS. Glutathione S-transferase (GST) and catalase (CAT) activities, as well as formation of erythrocyte nuclear abnormalities (ENAs), and histological effect were measured in tadpoles displaying survival rates >85%. L. latrans tadpoles were sensitive to exposure to Bti-AS, reaching 100% mortality after 48 h of exposure at the highest concentration. Bti-AS induced GST and CAT enzymes and genotoxicity (erythrocyte's nuclear abnormalities), and caused intestine's histopathology. Our results demonstrate that toxicity of Bti-AS is dose-dependent for L. latrans tadpoles and that sublethal exposure alters enzymes of oxidative stress, induces genotoxicity, and causes intestine damage. Further research is needed to evaluate the ecotoxicological risk of the massive use of Bti formulations on amphibian populations that commonly used suburban wastewater or urban waterbodies to reproduce and where this biopesticide is frequently applied. - Highlights: • An ecotoxicological evaluation of a Bti formulation on amphibian was conducted. • Toxicity of Bti-AS was dose-dependent for Leptodactylus latrans tadpoles. • Sublethal exposure altered the enzymes of oxidative stress (GST and CAT). • Bti-AS was genotoxic because increased MN frequencies (CO: 0.82–2.74‰). • Bti-AS caused the inflammatory infiltration in the lamina propria of intestine.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Elevated blood pressure and household solid fuel use in premenopausal women: Analysis of 12 Demographic and Health Surveys (DHS) from 10 countries

Highlights: • We obtained data from 12 standard DHS conducted in ten countries. • Data were nationally representative and internationally comparable. • We assessed the link between household cooking fuel and BP in women aged 15-49 years. • Dirty fuel use was linked with raised BP and hypertension, mainly in rural women. • Using cleaner fuels may reduce hypertension related morbidity and mortality in L/MIC. Approximately three billion people are exposed to household air pollution (HAP) from solid fuel cookstoves. Studies from single settings have linked HAP with elevated blood pressure (BP), but no evidence exists from multi-country analyses.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Performance of low-cost monitors to assess household air pollution

Highlights: • We assessed PM{sub 2.5} and CO low-cost monitors in semi-controlled and field studies. • Devices experienced high failure rate and susceptibility to environmental changes. • Low-cost monitors tested may not be ready to replace more established methods. Exposure to household air pollution is a leading cause of morbidity and mortality globally. However, due to the lack of validated low-cost monitors with long-lasting batteries in indoor environments, most epidemiologic studies use self-reported data or short-term household air pollution assessments as proxies of long-term exposure. We evaluated the performance of three low-cost monitors measuring fine particulate matter (PM{sub 2.5}) and carbon monoxide (CO) in a wood-combustion experiment conducted in one household of Spain for 5 days (including the co-location of 2 units of HAPEX and 3 units of TZOA-R for PM{sub 2.5} and 3 units of EL-USB-CO for CO; a total of 40 unit-days). We used Spearman correlation (ρ) and Concordance Correlation Coefficient (CCC) to assess accuracy of low-cost monitors versus equivalent research-grade devices. We also conducted a field study in India for 1 week (including HAPEX in 3 households and EL-USB-CO in 4 households; a total of 49 unit-days). Correlation and agreement at 5-min were moderate-high for one unit of HAPEX (ρ = 0.73 / CCC = 0.59), for one unit of TZOA-R (ρ = 0.89 / CCC = 0.62) and for three units of EL-USB-CO (ρ = 0.82–0.89 / CCC = 0.66–0.91) in Spain, although the failure or malfunction rate among low-cost units was high in both settings (60% of unit-days in Spain and 43% in India). Low-cost monitors tested here are not yet ready to replace more established exposure assessment methods in long-term household air pollution epidemiologic studies. More field validation is needed to assess evolving sensors and monitors with application to health studies.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Diurnal temperature range in relation to death from stroke in China

Highlights: • Stroke mortality was significantly and negatively associated with DTR. • Temperature and individual factors could modify association of DTR and stroke death. • This is the first multicity study to examine stroke death burden from DTR. Stroke is the second leading cause of death in the world. It has multiple risk factors of which some, such as ambient temperature, are less well documented.

54 ENVIRONMENTAL SCIENCES↗