Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “FATS”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 613 records · Page 34
All sourcesNASA NTRSDOE OSTI
DOE OSTI2013

Prospective Study of Functional Bone Marrow-Sparing Intensity Modulated Radiation Therapy With Concurrent Chemotherapy for Pelvic Malignancies

Purpose: To test the hypothesis that intensity modulated radiation therapy (IMRT) can reduce radiation dose to functional bone marrow (BM) in patients with pelvic malignancies (phase IA) and estimate the clinical feasibility and acute toxicity associated with this technique (phase IB). Methods and Materials: We enrolled 31 subjects (19 with gynecologic cancer and 12 with anal cancer) in an institutional review board-approved prospective trial (6 in the pilot study, 10 in phase IA, and 15 in phase IB). The mean age was 52 years; 8 of 31 patients (26%) were men. Twenty-one subjects completed {sup 18}F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) simulation and magnetic resonance imaging by use of quantitative IDEAL (IDEAL IQ; GE Healthcare, Waukesha, WI). The PET/CT and IDEAL IQ were registered, and BM subvolumes were segmented above the mean standardized uptake value and below the mean fat fraction within the pelvis and lumbar spine; their intersection was designated as functional BM for IMRT planning. Functional BM-sparing vs total BM-sparing IMRT plans were compared in 12 subjects; 10 were treated with functional BM-sparing pelvic IMRT per protocol. Results: In gynecologic cancer patients, the mean functional BM V{sub 10} (volume receiving {>=}10 Gy) and V{sub 20} (volume receiving {>=}20 Gy) were 85% vs 94% (P<.0001) and 70% vs 82% (P<.0001), respectively, for functional BM-sparing IMRT vs total BM-sparing IMRT. In anal cancer patients, the corresponding values were 75% vs 77% (P=.06) and 62% vs 67% (P=.002), respectively. Of 10 subjects treated with functional BM-sparing pelvic IMRT, 3 (30%) had acute grade 3 hematologic toxicity or greater. Conclusions: IMRT can reduce dose to BM subregions identified by {sup 18}F-fluorodeoxyglucose-PET/CT and IDEAL IQ. The efficacy of BM-sparing IMRT is being tested in a phase II trial.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

Benefit of Adjuvant Brachytherapy Versus External Beam Radiation for Early Breast Cancer: Impact of Patient Stratification on Breast Preservation

Purpose: Brachytherapy after lumpectomy is an increasingly popular breast cancer treatment, but data concerning its effectiveness are conflicting. Recently proposed “suitability” criteria guiding patient selection for brachytherapy have never been empirically validated. Methods: Using the Surveillance, Epidemiology, and End Results–Medicare linked database, we compared women aged 66 years or older with invasive breast cancer (n=28,718) or ductal carcinoma in situ (n=7229) diagnosed from 2002 to 2007, treated with lumpectomy alone, brachytherapy, or external beam radiation therapy (EBRT). The likelihood of breast preservation, measured by subsequent mastectomy risk, was compared by use of multivariate proportional hazards, further stratified by American Society for Radiation Oncology (ASTRO) brachytherapy suitability groups. We compared 1-year postoperative complications using the χ{sup 2} test and 5-year local toxicities using the log-rank test. Results: For patients with invasive cancer, the 5-year subsequent mastectomy risk was 4.7% after lumpectomy alone (95% confidence interval [CI], 4.1%-5.4%), 2.8% after brachytherapy (95% CI, 1.8%-4.3%), and 1.3% after EBRT (95% CI, 1.1%-1.5%) (P<.001). Compared with lumpectomy alone, brachytherapy achieved a more modest reduction in adjusted risk (hazard ratio [HR], 0.61; 95% CI, 0.40-0.94) than achieved with EBRT (HR, 0.22; 95% CI, 0.18-0.28). Relative risks did not differ when stratified by ASTRO suitability group (P=.84 for interaction), although ASTRO “suitable” patients did show a low absolute subsequent mastectomy risk, with a minimal absolute difference in risk after brachytherapy (1.6%; 95% CI, 0.7%-3.5%) versus EBRT (0.8%; 95% CI, 0.6%-1.1%). For patients with ductal carcinoma in situ, EBRT maintained a reduced risk of subsequent mastectomy (HR, 0.40; 95% CI, 0.28-0.55; P<.001), whereas the small number of patients treated with brachytherapy (n=179) precluded definitive comparison with lumpectomy alone. In all patients, brachytherapy showed a higher postoperative infection risk (16.5% vs 9.9% after lumpectomy alone vs 11.4% after EBRT, P<.001); higher incidence of breast pain (22.9% vs 11.2% vs 16.7%, P<.001); and higher incidence of fat necrosis (15.3% vs 5.3% vs 7.7%, P<.001). Conclusions: In this study era, brachytherapy showed lesser breast preservation benefit compared with EBRT. Suitability criteria predicted differential absolute, but not relative, benefit in patients with invasive cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

A Prospective Longitudinal Clinical Trial Evaluating Quality of Life After Breast-Conserving Surgery and High-Dose-Rate Interstitial Brachytherapy for Early-Stage Breast Cancer

Purpose: To prospectively examine quality of life (QOL) of patients with early stage breast cancer treated with accelerated partial breast irradiation (APBI) using high-dose-rate (HDR) interstitial brachytherapy. Methods and Materials: Between March 2004 and December 2008, 151 patients with early stage breast cancer were enrolled in a phase 2 prospective clinical trial. Eligible patients included those with Tis-T2 tumors measuring ≤3 cm excised with negative surgical margins and with no nodal involvement. Patients received 3.4 Gy twice daily to a total dose of 34 Gy. QOL was measured using European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, version 3.0, and QLQ-BR23 questionnaires. The QLQ-C30 and QLQ-BR23 questionnaires were evaluated during pretreatment and then at 6 to 8 weeks, 3 to 4 months, 6 to 8 months, and 1 and 2 years after treatment. Results: The median follow-up was 55 months. Breast symptom scores remained stable in the months after treatment, and they significantly improved 6 to 8 months after treatment. Scores for emotional functioning, social functioning, and future perspective showed significant improvement 2 years after treatment. Symptomatic fat necrosis was associated with several changes in QOL, including increased pain, breast symptoms, systemic treatment side effects, dyspnea, and fatigue, as well as decreased role functioning, emotional functioning, and social functioning. Conclusions: HDR multicatheter interstitial brachytherapy was well tolerated, with no significant detrimental effect on measured QOL scales/items through 2 years of follow-up. Compared to pretreatment scores, there was improvement in breast symptoms, emotional functioning, social functioning, and future perspective 2 years after treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Contemporary Toxicity Profile of Breast Brachytherapy Versus External Beam Radiation After Lumpectomy for Breast Cancer

Purpose: We compared toxicities after brachytherapy versus external beam radiation therapy (EBRT) in contemporary breast cancer patients. Methods and Materials: Using MarketScan healthcare claims, we identified 64,112 women treated from 2003 to 2012 with lumpectomy followed by radiation (brachytherapy vs EBRT). Brachytherapy was further classified by multichannel versus single-channel applicator approach. We identified the risks and predictors of 1-year infectious and noninfectious postoperative adverse events using logistic regression and temporal trends using Cochran-Armitage tests. We estimated the 5-year Kaplan-Meier cumulative incidence of radiation-associated adverse events. Results: A total of 4522 (7.1%) patients received brachytherapy (50.2% multichannel vs 48.7% single-channel applicator). The overall risk of infectious adverse events was higher after brachytherapy than after EBRT (odds ratio [OR] = 1.21; 95% confidence interval [CI] 1.09-1.34, P<.001). However, over time, the frequency of infectious adverse events after brachytherapy decreased, from 17.3% in 2003 to 11.6% in 2012, and was stable after EBRT at 9.7%. Beyond 2007, there were no longer excess infections with brachytherapy (P=.97). The overall risk of noninfectious adverse events was higher after brachytherapy than after EBRT (OR=2.27; 95% CI 2.09-2.47, P<.0001). Over time, the frequency of noninfectious adverse events detected increased: after multichannel brachytherapy, from 9.1% in 2004 to 18.9% in 2012 (Ptrend = .64); single-channel brachytherapy, from 12.8% to 29.8% (Ptrend<.001); and EBRT, from 6.1% to 10.3% (Ptrend<.0001). The risk was significantly higher with single-channel than with multichannel brachytherapy (hazard ratio = 1.32; 95% CI 1.03-1.69, P=.03). Of noninfectious adverse events, 70.9% were seroma. Seroma significantly increased breast pain risk (P<.0001). Patients with underlying diabetes, cardiovascular disease, and treatment with chemotherapy had increased infectious and noninfectious adverse events. The 5-year incidences of fat necrosis, breast pain, and rib fracture were slightly higher after brachytherapy than after EBRT (13.7% vs 8.1%, 19.4% vs 16.0%, and 1.6% vs 1.3%, respectively), but the risks were not significantly different for multichannel versus single-channel applicators. Conclusion: Toxicities after breast brachytherapy were distinct from those after EBRT. Temporal toxicity trends may reflect changing technology and evolving practitioner experience with brachytherapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Preliminary Results of a Phase 1 Dose-Escalation Trial for Early-Stage Breast Cancer Using 5-Fraction Stereotactic Body Radiation Therapy for Partial-Breast Irradiation

Purpose: To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early-stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. Methods and Materials: Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size <3 cm. Patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Starting dose was 30 Gy in 5 fractions and was escalated by 2.5 Gy total for each cohort to 40 Gy. Results: In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. Conclusion: Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose-escalated S-PBI treatment for early-stage breast cancer in the adjuvant setting.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Holocene cold storage practices on the eastern Snake River Plain: A risk-mitigation strategy for lean times

Previous archaeological research in southern Idaho has suggested that climate change over the past 8000 years was not dramatic enough to alter long-term subsistence practices in the region. However, recent isotopic analyses of bison remains from cold storage caves on the Snake River Plain contest this hypothesis. Our results, when examined against an archaeoclimate model, suggest that cold storage episodes coincided with drier, warmer phases that likely reduced forage and water, and thus limited the availability of bison on the open steppe. Within this context we build a risk model to illustrate how environment might have motivated cold storage behaviors. Caching bison in cold lava tubes would have mitigated both intra-annual and inter-annual food shortages under these conditions. This analysis also suggests that skeletal fat, more than meat, may have influenced the selection, transport and storage of bison carcass parts. We deciphered when and how cold storage caves which was used to provide a more comprehensive understanding of foraging behaviors in a broad range of hunting-gathering economies.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Life Cycle Analysis of Renewable Natural Gas and Lactic Acid Production from Waste Feedstocks

Producing fuels and chemicals from waste is considered economically favorable, due to low feedstock cost, and environmentally favorable, due to avoided emissions from conventional waste management practices. In this study, we evaluate the life cycle greenhouse gas (GHG) emission reduction benefits of renewable natural gas (RNG) and lactic acid (LA) production from four types of wet waste feedstocks (wastewater sludge, food waste, swine manure, and fats, oil, and grease [FOG]) via anaerobic digestion (AD) and LA fermentation, respectively. RNG can be used as an alternative to fossil natural gas, while LA from waste feedstocks can displace conventional LA production pathways (mainly from corn via fermentation). Providing comprehensive life cycle GHG emissions of the combinations of waste feedstocks and products through different routes helps identify the GHG hotspots and show where emissions savings come from. The results show that the carbon intensities (CIs) of waste-derived RNG and LA are much lower than those of their counterparts. We estimated the life cycle GHG emissions for RNG to be between -146 and 27 g carbon dioxide equivalent (CO2e)/MJ, much lower than the CI of fossil fuels. Waste-derived LA pathways also show substantially lower CIs, ranging from -4.2 to -1.4 kgCO2e/kg LA, compared to the CIs of LA from corn and corn stover (1.2 and 0.3 kgCO2e/kg LA, respectively). We will also discuss that the low CIs of waste-derived products can come from low yields leading to high emission credits. Thus, life cycle analysis results presented per weight of treated waste can be used to support decisions about which waste feedstocks and products are to be used for sustainable waste valorization. In addition, we found that monetary emission reduction credits can play an important role in driving waste valorization.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗
DOE OSTI2011

Filtering a statistically exactly solvable test model for turbulent tracers from partial observations

A statistically exactly solvable model for passive tracers is introduced as a test model for the authors' Nonlinear Extended Kalman Filter (NEKF) as well as other filtering algorithms. The model involves a Gaussian velocity field and a passive tracer governed by the advection-diffusion equation with an imposed mean gradient. The model has direct relevance to engineering problems such as the spread of pollutants in the air or contaminants in the water as well as climate change problems concerning the transport of greenhouse gases such as carbon dioxide with strongly intermittent probability distributions consistent with the actual observations of the atmosphere. One of the attractive properties of the model is the existence of the exact statistical solution. In particular, this unique feature of the model provides an opportunity to design and test fast and efficient algorithms for real-time data assimilation based on rigorous mathematical theory for a turbulence model problem with many active spatiotemporal scales. Here, we extensively study the performance of the NEKF which uses the exact first and second order nonlinear statistics without any approximations due to linearization. The role of partial and sparse observations, the frequency of observations and the observation noise strength in recovering the true signal, its spectrum, and fat tail probability distribution are the central issues discussed here. The results of our study provide useful guidelines for filtering realistic turbulent systems with passive tracers through partial observations.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Multi-GPU immersed boundary method hemodynamics simulations

Large-scale simulations of blood flow that resolve the 3D deformation of each comprising cell are increasingly popular owing to algorithmic developments in conjunction with advances in compute capability. Among different approaches for modeling cell-resolved hemodynamics, fluid structure interaction (FSI) algorithms based on the immersed boundary method are frequently employed for coupling separate solvers for the background fluid and the cells within one framework. GPUs can accelerate these simulations; however, both current pre-exascale and future exascale CPU-GPU heterogeneous systems face communication challenges critical to performance and scalability. In this paper, we describe, to our knowledge, the largest distributed GPU-accelerated FSI simulations of high hematocrit cell-resolved flows with over 17 million red blood cells. We compare scaling on a fat node system with six GPUs per node and on a system with a single GPU per node. Through comparison between the CPU- and GPU-based implementations, we identify the costs of data movement in multiscale multi-grid FSI simulations on heterogeneous systems and show it to be the greatest performance bottleneck on the GPU.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2020

Cooling and dietary crude protein affected milk production on heat-stressed dairy cows

Environmental factors, such as temperature and humidity, exert dramatic effects on the production, health, and well-being of lactating dairy cows. Heat-stressed cows undergo a series of homeorhetic adaptations that alters cellular homeostasis and nutrient utilization. As such, the objective of this study was to determine the effects of cooling and dietary crude protein (CP) content on fermentability of rumen inoculum, milk production, and health of heat-stressed cows. It was hypothesized that cooled but not heat-stressed cows would support productivity in response to an increase in dietary CP content. Thirty-six multiparous Holstein cows were randomly assigned to 1 of 4 treatments in a 2 × 2 factorial arrangement (9 cows/treatment). Treatments consisted of cooling (CO) or moderate long-term heat stress (HS) and diets containing low CP content (LCP; 12.5% CP) or moderate CP content (MCP; 16.1% CP) of dry matter. The CO treatment provided heat abatement with sprinklers and fans that came on at > 20.0°C, whereas the HS treatment did not provide sprinklers and fans. Cows were housed in pens in a freestall barn, and treatments were imposed for 21 d during July and August. Compared with the HS treatment, CO decreased afternoon rectal and vaginal temperatures (0.60 and 0.70°C) and afternoon respiration rate (27.6 breaths/min). Treatment interactions showed that compared with the LCP treatment, MCP increased milk fat yield (23%) in CO but not in HS cows. Compared with the LCP treatment, MCP decreased milk protein percent (0.14 units) in CO but increased milk protein percent (0.09 units) in HS cows. Rumen inoculum collected on d 21 showed a ~3-fold increase in total gas production in vitro in CO compared with the HS treatment. Relative to the LCP treatment, MCP increased plasma glucose and insulin and decreased total free fatty acids concentrations. In summary, under the conditions of this study CO but not HS cows responded to a CP stimulus by increasing productivity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Impact of galactic cosmic ray simulation on nutritional content of foods

Foods packaged for future deep-space exploration missions may be prepositioned ahead of astronaut arrival, and will be exposed to galactic cosmic rays (GCRs) and solar radiation in deep space at higher levels and different spectrums than those found in low-Earth orbit (LEO). In this study, we have evaluated the impact of a GCR simulation (approximately 0.5 and 5 Gy doses) at the NASA Space Radiation Laboratory (NSRL) on two retort thermostabilized food products that are good sources of radiation labile nutrients (thiamin, vitamin E, or unsaturated fats). No trends or nutritional differences were found between the radiation-treated samples and the control immediately after treatment or one-year after treatment. Small changes in a few nutrients were measured following one-year of storage. Further studies are needed to confirm these results, as the foods in this study were heterogeneous, and this may have masked meaningful changes due to pouch-to-pouch variations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2010

Obesity-resistant S5B rats showed great cocaine conditioned place preference than the obesity-prone OM rats

Dopamine (DA) and the DA D2 receptor (D2R) are involved in the rewarding and conditioned responses to food and drug rewards. Osborne-Mendel (OM) rats are genetically prone and S5B/P rats are genetically resistant to obesity when fed a high-fat diet. We hypothesized that the differential sensitivity of these two rat strains to natural rewards may also be reflected in sensitivity to drugs of abuse. Therefore, we tested whether OM and S5B/P rats showed a differential preference to cocaine using conditioned place preference (CPP). To also evaluate whether there is specific involvement of the D2R in this differential conditioning sensitivity, we then tested whether the D2R agonist bromocriptine (BC) would differentially affect the effects of cocaine in the two strains. OM and S5B/P rats were conditioned with cocaine (5 or 10 mg/kg) in one chamber and saline in another for 8 days. Rats were then tested for cocaine preference. The effects of BC (0.5, 1, 5, 10, 20 mg/kg) on cocaine preference were then assessed in subsequent test sessions. OM rats did not show a significant preference for the cocaine-paired chamber on test day. Only the S5B/P rats showed cocaine CPP. Later treatment with only the highest dose of BC resulted in reduced cocaine CPP in S5B/P rats when treated with 5 mg/kg cocaine and in OM rats treated with 10 mg/kg cocaine. Our results indicated that obesity-resistant S5B rats showed greater cocaine CPP than the obesity-prone OM rats. These findings do not support a theory of common vulnerability for reinforcer preferences (food and cocaine). However, they show that BC reduced cocaine conditioning effects supporting at least a partial regulatory role of D2R in conditioned responses to drugs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2010

Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats

The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long-Evans rats were treated by gavage with 0.09, 0.87, or 8.73 mg AMM/kg body weight (BW), vehicle, or 100 mg ATR/kg BW positive control, on gestation days 15 19. Preputial separation was significantly delayed in 0.87 mg and 8.73 mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2011

Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated as byproducts of natural and anthropogenic combustion processes. Despite significant public health concern, physiologically based pharmacokinetic (PBPK) modeling efforts for PAHs have so far been limited to naphthalene, plus simpler PK models for pyrene, nitropyrene, and benzo[a]pyrene (B[a]P). The dearth of published models is due in part to the high lipophilicity, low volatility, and myriad metabolic pathways for PAHs, all of which present analytical and experimental challenges. Our research efforts have focused upon experimental approaches and initial development of PBPK models for the prototypic PAH, B[a]P, and the more potent, albeit less studied transplacental carcinogen, dibenzo[def,p]chrysene (DBC). For both compounds, model compartments included arterial and venous blood, flow limited lung, liver, richly perfused and poorly perfused tissues, diffusion limited fat, and a two compartment theoretical gut (for oral exposures). Hepatic and pulmonary metabolism was described for both compounds, as were fractional binding in blood and fecal clearance. Partition coefficients for parent PAH along with their diol and tetraol metabolites were estimated using published algorithms and verified experimentally for the hydroxylated metabolites. The preliminary PBPK models were able to describe many, but not all, of the available data sets, comprising multiple routes of exposure (oral, intravenous) and nominal doses spanning several orders of magnitude. Supported by Award Number P42 ES016465 from the National Institute of Environmental Health Sciences. -- Highlights: Black-Right-Pointing-Pointer We present PBPK models for benzo[a]pyrene (B[a]P) and dibenzo[def,p]chrysene (DBC). Black-Right-Pointing-Pointer B[a]P model accurately predicts data from multiple sources over a wide dose range. Black-Right-Pointing-Pointer DBC model was based on the B[a]P model as less chemical specific data is available. Black-Right-Pointing-Pointer DBC model accurately predicted preliminary pharmacokinetic data. Black-Right-Pointing-Pointer DBC model underscored data gaps on metabolism, binding and pharmacokinetics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice

Epidemiology studies indicate that exposure to endocrine disruptors during developmental “window” contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) γ as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARγ activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. -- Highlights: ► DES induced adipocyte differentiation in a dose-dependent manner in 3T3-L1 cells. ► DES activated adipogenic critical regulators and markers in vitro and in vivo. ► Perinatal exposure to DES led to the obese phenotype in female offspring. ► DES might be a potential chemical stressor for obesity and obesity-related disorders.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Hepatic lipid profiling of deer mice fed ethanol using {sup 1}H and {sup 31}P NMR spectroscopy: A dose-dependent subchronic study

Chronic alcohol abuse is a 2nd major cause of liver disease resulting in significant morbidity and mortality. Alcoholic liver disease (ALD) is characterized by a wide spectrum of pathologies starting from fat accumulation (steatosis) in early reversible stage to inflammation with or without fibrosis and cirrhosis in later irreversible stages. Previously, we reported significant steatosis in the livers of hepatic alcohol dehydrogenase (ADH)-deficient (ADH{sup −}) vs. hepatic ADH-normal (ADH{sup +}) deer mice fed 4% ethanol daily for 2 months [Bhopale et al., 2006, Alcohol 39, 179–188]. However, ADH{sup −} deer mice fed 4% ethanol also showed a significant mortality. Therefore, a dose-dependent study was conducted to understand the mechanism and identify lipid(s) involved in the development of ethanol-induced fatty liver. ADH{sup −} and ADH{sup +} deer mice fed 1, 2 or 3.5% ethanol daily for 2 months and fatty infiltration in the livers were evaluated by histology and by measuring dry weights of extracted lipids. Lipid metabolomic changes in extracted lipids were determined by proton ({sup 1}H) and {sup 31}phosphorus ({sup 31}P) nuclear magnetic resonance (NMR) spectroscopy. The NMR data was analyzed by hierarchical clustering (HC) and principle component analysis (PCA) for pattern recognition. Extensive vacuolization by histology and significantly increased dry weights of total lipids found only in the livers of ADH{sup −} deer mice fed 3.5% ethanol vs. pair-fed controls suggest a dose-dependent formation of fatty liver in ADH{sup −} deer mouse model. Analysis of NMR data of ADH{sup −} deer mice fed 3.5% ethanol vs. pair-fed controls shows increases for total cholesterol, esterified cholesterol, fatty acid methyl esters (FAMEs), triacylglycerides and unsaturation, and decreases for free cholesterol, phospholipids and allylic and diallylic protons. Certain classes of neutral lipids (cholesterol esters, fatty acyl chain (-COCH{sub 2}-) and FAMEs) were also mildly increased in ADH{sup −} deer mice fed 1 or 2% ethanol. Only small increases were observed for allylic and diallylic protons, FAMEs and unsaturations in ADH{sup +} deer mice fed 3.5% ethanol vs. pair-fed controls. PCA of NMR data showed increased clustering by gradual separation of ethanol-fed ADH{sup −} deer mice groups from their respective pair-fed control groups and corresponding ethanol-fed ADH{sup +} deer mice groups. Our data indicate that dose of ethanol and hepatic ADH deficiency are two key factors involved in initiation and progression of alcoholic fatty liver disease. Further studies on characterization of individual lipid entities and associated metabolic pathways altered in our deer mouse model after different durations of ethanol feeding could be important to delineate mechanism(s) and identify potential biomarker candidate(s) of early stage ALD. -- Highlights: ► Dose-dependent ethanol-induced fatty liver was studied in deer mouse model. ► A NMR-based lipidomic approach with histology and dry lipid weights was used. ► We used principal component analysis (PCA) to analyze the NMR lipidomic data. ► Dose-dependent clustering patterns by PCA were compared among the groups.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM{sub 10})

Exposure to ambient air particulate matter (particles less than 10 μm or PM{sub 10}) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM{sub 10}. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM{sub 10}/saline exposure for 4 weeks ± lovastatin (5 mg/kg/day) treatment. PM{sub 10} exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM{sub 10} impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM{sub 10} increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM{sub 10}. Taken together, statins protect against PM{sub 10}-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties. - Highlights: • Coarse particulate matter (PM{sub 10}) accelerated balloon injury-induced plaque formation. • Lovastatin decreased intimal macrophages, lipid accumulation, and intimal area. • Lovastatin promoted smooth muscle cell recruitment into plaques. • Lovastatin reduced the expression of vasoactive mediators (iNOS, COX-2, and ET-1). • Lovastatin did not reduce blood lipid levels in PM{sub 10}-exposed rabbits.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

The contribution of heavy metals in cigarette smoke condensate to malignant transformation of breast epithelial cells and in vivo initiation of neoplasia through induction of a PI3K–AKT–NFκB cascade

Cigarette smoking is a crucial factor in the development and progression of multiple cancers including breast. Here, we report that repeated exposure to a fixed, low dose of cigarette smoke condensate (CSC) prepared from Indian cigarettes is capable of transforming normal breast epithelial cells, MCF-10A, and delineate the biochemical basis for cellular transformation. CSC transformed cells (MCF-10A-Tr) were capable of anchorage-independent growth, and their anchorage dependent growth and colony forming ability were higher compared to the non-transformed MCF-10A cells. Increased expression of biomarkers representative of oncogenic transformation (NRP-1, Nectin-4), and anti-apoptotic markers (PI3K, AKT, NFκB) were also noted in the MCF-10A-Tr cells. Short tandem repeat (STR) profiling of MCF-10A and MCF-10A-Tr cells revealed that transformed cells acquired allelic variation during transformation, and had become genetically distinct. MCF-10A-Tr cells formed solid tumors when implanted into the mammary fat pads of Balb/c mice. Data revealed that CSC contained approximately 1.011 μg Cd per cigarette equivalent, and Cd (0.0003 μg Cd/1 × 10{sup 7} cells) was also detected in the lysates from MCF-10A cells treated with 25 μg/mL CSC. In similar manner to CSC, CdCl{sub 2} treatment in MCF-10A cells caused anchorage independent colony growth, higher expression of oncogenic proteins and increased PI3K–AKT–NFκB protein expression. An increase in the expression of PI3K–AKT–NFκB was also noted in the mice xenografts. Interestingly, it was noted that CSC and CdCl{sub 2} treatment in MCF-10A cells increased ROS. Collectively, results suggest that heavy metals present in cigarettes of Indian origin may substantially contribute to tumorigenesis by inducing intercellular ROS accumulation and increased expression of PI3K, AKT and NFκB proteins. - Highlights: • Repeated exposure of CSC causes malignant transformation in MCF-10A. • MCF-10A-Tr cells showed a distinct STR profile and tumor inducing characteristics. • Increased expression of PI3K, AKT, and NFκB protein in MCF-10A-Tr and solid tumor. • Increased ROS and PI3K-AKT-NFκB proteins in smoke carcinogen exposed MCF-10A cells. • Cadmium may be a strong contributor to the transformation of MCF-10A cells.

60 APPLIED LIFE SCIENCES↗