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Alumina–tantalum carbide (Al2O3–TaC and Al2O3–Ta2C) composites were synthesized by incorporating aluminothermic reduction into a self-propagating combustion process. The test specimens adopted were composed of Ta2O5, Al, Al4C3, and carbon powders. Experimental evidence showed that the use of Al4C3 to provide Al and carbon decreased combustion exothermicity and hindered Ta2O5 from being fully reduced. In contrast, for the formation of Al2O3–TaC and Al2O3–Ta2C composites, Al4C3-free samples with molar ratios of Ta2O5:Al:C = 3:10:6 and 3:10:3, respectively, exhibited the highest combustion temperature and reaction rate in the self-propagating high-temperature synthesis process and yielded products with very few minor phases.

A numerical investigation is performed into the heat transfer and entropy generation within a fully-developed mixed convection flow of Al 2 O 3 –water nanofluid in a vertical channel. The simulations focus specifically on the effects of the Brinkman number, mixed convection dimensionless parameter, and nanoparticle concentration on the velocity distribution, temperature distribution, Nusselt number and entropy generation within the channel. In performing the simulations, the velocity and temperature fields within the channel are computed using the differential transformation method (DTM) given the assumption of asymmetric heated walls. It is shown that the results obtained by the DTM method for the Nusselt numbers on the hot and cold walls, respectively, are in good agreement with the analytical results presented in the literature. In addition, it is shown that for a lower Brinkman number, the local Nusselt number of the nanofluid on the hot wall is greater than that of pure water and increases with an increasing nanoparticle concentration. However, given a higher value of the Brinkman number, the local Nusselt number of the nanofluid on the cold wall is less than that of pure water. Finally, it is shown that the average entropy generation number of the nanofluid is less than that of pure water. In general, the results presented in this study confirm the accuracy and feasibility of the DTM method in solving fluidic heat transfer problems and provide a useful insight into the effects of viscous dissipation on the entropy generation within vertical asymmetrically-heated channels containing mixed convection flow.

Homocysteine (HCY) and high sensitivity C reactive protein (hs-CRP) were suggested to be involved in post-stroke depression (PSD), which is a frequent mood disorder after stroke. However, the combined effect of HCY and hs-CRP on PSD remains unclear.A total of 598 acute ischemic stroke patients from 7 of 26 centers participating in the China Antihypertensive Trial in Acute Ischemic Stroke with HCY or hs-CRP measurements were included in this analysis. PSD status was evaluated by 24-item Hamilton Depression Rating Scale at 3 months after stroke.Two hundred and forty-one (40.30%) participants were considered as PSD. HCY and hs-CRP levels were not significantly different between PSD and non-PSD patients. Interesting, in a maximally adjusted model, the odds ratio (95% confidence interval) of PSD was 1.90 (1.18-3.06) for coexistence of HCY ≥ 14.65 μmol/l and hs-CRP ≥ 1.90 mg/l compared with the other levels (HCY 14.65 μmol/l and/or hs-CRP 1.90 mg/l). Adding combination of HCY and hs-CRP to a model containing conventional risk factors could significantly improve risk reclassification for PSD.Coexistence of both higher HCY and higher hs-CRP in the acute phase of ischemic stroke were associated with subsequent PSD, independently of established conventional risk factors.

Background and aims Serum cystatin C (CysC) is associated with the risk of ischemic stroke and may predict cardiovascular events and death after ischemic stroke onset. However, the association between serum CysC and functional outcome in ischemic stroke patients remains unclear, and whether lipid component level influences the relationship between them has not been studied. Methods A total of 3348 ischemic patients from China Antihypertensive Trial in Acute Ischemic Stroke were included in the study. Serum CysC was used to calculate estimated glomerular filtration rate (eGFRCysC) at baseline. The primary outcome was poor functional outcome (modified Rankin Scale score ≥3) at one year after ischemic stroke. Secondary outcomes were death, stroke recurrence, vascular events and combination of the aforementioned outcomes. Results The association between eGFRCysC and primary outcome was appreciably modified by low-density lipoprotein cholesterol (LDL-C) (pinteraction = 0.048). Low eGFRCysC was associated with primary outcome only in ischemic stroke patients with LDL-C ≥4.14 mmol/l rather than all patients. The multivariable adjusted odds ratio (95% confidence interval) of poor functional outcome associated with low eGFRCysC was 3.94 (1.04–14.98) and a positive linear dose-response relationship between them was observed among patients with LDL-C ≥4.14 mmol/l (p for linearity = 0.021). Subgroup analyses further confirmed these associations. There was no association between eGFR based on serum creatinine and poor functional outcome of stroke. Conclusions Low eGFRCysC may be an independent predictor for 1-year poor functional outcome in ischemic stroke patients with LDL-C ≥4.14 mmol/l. Further studies are needed to replicate our findings and to clarify the potential mechanisms.

Importance Despite extensive knowledge of hypertension treatment, the prevalence of uncontrolled hypertension is high and increasing in low- and middle-income countries. Objective To test whether a community health worker–led multicomponent intervention would improve blood pressure (BP) control among low-income patients with hypertension. Design, Setting, and Participants A cluster randomized trial was conducted in 18 centers for primary health care within a national public system providing free medications and health care to uninsured patients in Argentina. A total of 1432 low-income adult patients with uncontrolled hypertension were recruited between June 2013 and April 2015 and followed up to October 2016. Interventions Nine centers (743 patients) were randomized to the multicomponent intervention, which included a community health worker–led home intervention (health coaching, home BP monitoring, and BP audit and feedback), a physician intervention, and a text-messaging intervention over 18 months. Nine centers (689 patients) were randomized to usual care. Main Outcomes and Measures The coprimary outcomes were the differences in systolic and diastolic BP changes from baseline to the end of follow-up of patients with hypertension. Secondary outcomes included the proportion of patients with controlled hypertension (BP

The estrogen-related receptor α (ERRα) is an orphan nuclear receptor (NR) that plays a role in energy homeostasis and controls mitochondrial oxidative respiration. Increased expression of ERRα in certain ovarian, breast, and colon cancers has a negative prognosis, indicating an important role for ERRα in cancer progression. An interaction between ERRα and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has also recently been shown to regulate an enzyme in the β-oxidation of free fatty acids, thereby suggesting that ERRα plays an important role in obesity and type 2 diabetes. Therefore, it would be prudent to identify compounds that can act as activators of ERRα. In this study, we screened ∼10,000 (8311 unique) compounds, known as the Tox21 10K collection, to identify agonists of ERRα. We performed this screen using two stably transfected HEK 293 cell lines, one with the ERRα-reporter alone and the other with both ERRα-reporter and PGC-1α expression vectors. After the primary screening, we identified more than five agonist clusters based on compound structural similarity analysis (e.g., statins). By examining the activities of the confirmed ERRα modulators in other Tox21 NR assays, eliminating those with promiscuous NR activity, and performing follow-up assays (e.g., small interfering RNA knockdown), we identified compounds that might act as endocrine disrupters through effects on ERRα signaling. To our knowledge, this study is the first comprehensive analysis in discovering potential endocrine disrupters that affect the ERRα signaling pathway.

PURPOSE: Therapeutic strategies against hormonal receptor-positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized. EXPERIMENTAL DESIGN: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. RESULTS: Estrogen acted as a growth-driver of trastuzumab-resistant COH-SC31 tumors, but an accelerator in trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied with increasing ER-positive cell population in vivo. Instead, MLN0128 in combination with anti-estrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. CONCLUSION: Compared to the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupling with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future “co-clinical” trials to tailor personalized medicine in clinical practice.

Background To examine the effect of abnormal glucose regulation on prognosis and whether hypoglycemic treatment during hospitalization improves prognosis in acute ischemic stroke patients. Methods A total of 3882 acute ischemic stroke patients with an elevated systolic blood pressure between 140 mm Hg and 220 mm Hg were included in the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a combination of death and major disability (modified Rankin Scale score ≥ 3) at 3 months after stroke. Secondary outcomes included death, major disability, and vascular events. Results Compared with normal fasting plasma glucose, odds ratios (95% confidence interval) associated with impaired fasting glucose (IFG) and diabetes mellitus (DM) were 1.25 (0.92–1.68) and 1.38 (1.13–1.67) for composite outcome of death or major disability, respectively, and there was a significant trend for death or major disability ( P trend = 0.001). A linear association between fasting plasma glucose and the risk of combined outcome of death and major disability was observed among the patients without hypoglycemic treatment during hospitalization ( P for linearity = 0.005). We found protective effect of hypoglycemic treatment for risk of death (odds ratio, 0.47; 95% confidence interval, 0.24–0.92) among ischemic stroke patients with DM. Conclusions Abnormal glucose regulation, especially DM, increased risks of 3-month poor outcomes after an acute ischemic stroke and hypoglycemic treatment during hospitalization might improve prognosis in ischemic stroke patients with DM.

Heterocyclic amines (HCAs) produced during high-temperature cooking have been studied extensively in terms of their genotoxic/genetic effects, but recent work has implicated epigenetic mechanisms involving non-coding RNAs. Colon tumors induced in the rat by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) have altered microRNA (miRNA) signatures linked to dysregulated pluripotency factors, such as c-Myc and Kruppel-like factor 4 (KLF4). We tested the hypothesis that dysregulated miRNAs from PhIP-induced colon tumors would provide a "PhIP signature" for use in other target organs obtained from a 1-year carcinogenicity bioassay in the rat. Downstream targets that were corroborated in the rat were then investigated in human cancer datasets. The results confirmed that multiple let-7 family members were downregulated in PhIP-induced skin, colon, lung, small intestine, and Zymbal's gland tumors, and were associated with c-myc and Hmga2 upregulation. PhIP signature miRNAs with the profile mir-21high/mir-126low/mir-29clow/mir-215low/mir-145low were linked to reduced Klf4 levels in rat tumors, and in human pan-cancer and colorectal cancer. It remains to be determined whether this PhIP signature has predictive value, given that more than 20 different genotoxic HCAs are present in the human diet, plus other agents that likely induce or repress many of the same miRNAs. Future studies should define more precisely the miRNA signatures of other HCAs, and their possible value for human risk assessment.

Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer.

Age-standardized Prevalence (95% Confidence Intervals) of Chronic Obstructive Pulmonary Disease in Current Smokers according to intensity and duration exposure. (DOCX 14 kb)

Ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) versus age in adult women. (DOCX 213 kb)

Ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) versus age in adult men. (DOCX 167 kb)

Age-standardized Prevalence (95% Confidence Intervals) of Chronic Obstructive Pulmonary Disease According to Demographic and Other Risk Factors. (DOCX 19 kb)

Performance of the Fixed-Ratio method versus the Lower-Limit-of-Normal method. (DOCX 15 kb)

Percentage of non-respondents or excluded participants by location, sex, age, education and smoking status. (DOCX 15 kb)

The purpose of this study is to validate an analytical method in assessing demanded mental workloads for physical therapists, and to discuss its possible ergonomics implications on the design of healthcare working systems in which physical therapists are considered as the users. A task analysis was first used to understand the operation steps of three identified physical therapies. Then, the McCracken–Aldrich technique was applied to assign ratings of mental workload demanded for performing each step of the therapies. Finally, the assigned ratings were validated by the analysis of correlation with the answers of the NASA-TLX questionnaire collected from seventeen physical therapists in the rehabilitation center of a university-affiliated hospital. Results showed that the proposed McCracken–Aldrich technique was suitable as an analysis tool for predicting metal workloads of physical therapists. Some possible implications about the information provision and user interface design for reducing therapists' mental workloads on current therapy operations were discussed. Relevance to industry Results of this paper are expected to contribute the research and development in healthcare industry on its system design and workflow analysis.

In this paper, a series-connected battery charging/discharging analyzer is developed to automatically test the batteries with a complete charging and discharging cycle. A micro-controller unit (MCU) is integrated to sample the battery voltage and current and calculate the charging efficiency. The charging and discharging processes are also controlled by the MCU according to the battery voltage and current. The charger provided by the battery manufacturer is used to charge the series-connected batteries. The voltage and current during testing procedure would be displayed on a LCD by the MCU. After the whole charging/discharging testing, the calculated charging efficiency would also be displayed on the LCD. From the experimental results, it is seen that the maximum voltage and current errors are about 0.23V and 0.1A respectively..

Both androgen and phosphatidylinositol 3-kinase (PI3K) signaling are critical for cell proliferation of androgen receptor (AR)–positive prostate cancer cells, but the underlying mechanisms are still not fully understood. Here we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a Ser/Thr kinase functioning downstream of PI3K, is an AR transcriptional target and promotes prostate cancer cell proliferation. SGK3 expression is up-regulated by androgen DHT via AR. We identified an AR-binding region at the sgk3 locus, which confers androgen responsiveness of sgk3 promoters. Interestingly, we found that androgen/AR-dependent SGK3 expression requires estrogen receptor (ER) (including both isoforms, ERα and ERβ). Depletion of ER blocked DHT-induced SGK3 expression. Functionally, knockdown of SGK3 expression significantly decreased LNCaP prostate cancer cell proliferation by inhibiting G1 to S phase cell cycle progression. We further provided evidence that SGK3 promotes p70 S6 kinase (p70S6K) activation and increases cyclin D1 levels. In summary, our study identifies SGK3 as an AR target and provides a novel androgen-induced cell proliferation mechanism mediated by the AR-SGK3-p70S6K-cyclin D1 pathway in prostate cancer cells.

Endocrine disrupting chemicals (EDCs) interfere with the biosynthesis, metabolism, and functions of steroid hormones, including estrogens and androgens. Aromatase enzyme converts androgen to estrogen. Thus, EDCs against aromatase significantly impact estrogen- and/or androgen-dependent functions, including the development of breast cancer. The current study aimed to develop a biologically relevant cell-based high-throughput screening assay to identify EDCs that act as aromatase inhibitors (AIs), estrogen receptor (ER) agonists, and/or ER antagonists. The AroER tri-screen assay was developed by stable transfection of ER-positive, aromatase-expressing MCF-7 breast cancer cells with an estrogen responsive element (ERE) driven luciferase reporter plasmid. The AroER tri-screen can identify: estrogenic EDCs, which increase luciferase signal without 17β-estradiol (E2); anti-estrogenic EDCs, which inhibit the E2-induced luciferase signal; and AI-like EDCs, which suppress a testosterone-induced luciferase signal. The assay was first optimized in a 96-well plate format and then miniaturized into a 1536-well plate format. The AroER tri-screen was demonstrated to be suitable for high-throughput screening in the 1536-well plate format, with a 6.9-fold signal-to-background ratio, a 5.4% coefficient of variation, and a screening window coefficient (Z-factor) of 0.78. The assay suggested that bisphenol A (BPA) functions mainly as an ER agonist. Results from screening the 446 drugs in the National Institutes of Health Clinical Collection revealed 106 compounds that modulated ER and/or aromatase activities. Among these, two AIs (bifonazole and oxiconazole) and one ER agonist (paroxetine) were confirmed through alternative aromatase and ER activity assays. These findings indicate that AroER tri-screen is a useful high-throughput screening system for identifying ER ligands and aromatase-inhibiting chemicals.

Mobile ad hoc networks (MANETs) are ideal for situations where a fixed infrastructure is unavailable or infeasible. Today's MANETs, however, may suffer from network partitioning. This limitation makes MANETs unsuitable for applications such as crisis management and battlefield communications, in which team members might need to work in groups scattered in the application terrain. In such applications, intergroup communication is crucial to the team collaboration. To address this weakness, we introduce in this paper a new class of ad-hoc network called Autonomous Mobile Mesh Network (AMMNET). Unlike conventional mesh networks, the mobile mesh nodes of an AMMNET are capable of following the mesh clients in the application terrain, and organizing themselves into a suitable network topology to ensure good connectivity for both intra- and intergroup communications. We propose a distributed client tracking solution to deal with the dynamic nature of client mobility, and present techniques for dynamic topology adaptation in accordance with the mobility pattern of the clients. Our simulation results indicate that AMMNET is robust against network partitioning and capable of providing high relay throughput for the mobile clients.

Viral replication depends on host proteins to supply energy and replication accessories for the sufficient production of viral progeny. In this study, we identified fructose-bisphosphate aldolase A as a binding partner of Japanese encephalitis virus (JEV) untranslated regions (UTRs) on the antigenome via RNA affinity capture and mass spectrometry. Direct interaction of aldolase A with JEV RNAs was confirmed by gel mobility shift assay and colocalization with active replication of double-stranded RNA in JEV-infected cells. Infection of JEV caused an increase in aldolase A expression of up to 33%. Knocking down aldolase A reduced viral translation, genome replication, and viral production significantly. Furthermore, JEV infection consumed 50% of cellular ATP, and the ATP level decreased by 70% in the aldolase A-knockdown cells. Overexpression of aldolase A in aldolase A-knockdown cells increased ATP levels significantly. Taken together, these results indicate that JEV replication requires aldolase A and consumes ATP. This is the first report of direct involvement of a host metabolic enzyme, aldolase A protein, in JEV replication.

There continues to be interest in targeting epigenetic ‘readers, writers and erasers’ for the treatment of cancer and other pathologies. A mechanistic understanding is frequently lacking, however, for the synergy observed when combining deacetylase and bromodomain inhibitors. We identified cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane (SFN). N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 (HDAC3) and β-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl ‘reader’ proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. The BET inhibitor JQ1 synergized with SFN in colon cancer cells, and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with SFN+JQ1 in combination implicated a BET/BRD9 acetyl switch, and a shift in the pool of acetyl ‘reader’ proteins in favor of BRD9 regulated target genes. These results highlight the competition that exists among the ‘readers’ of acetylated histone and non-histone proteins, and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments. Citation Format: Gavin S. Johnson, Praveen Rajendran, Li Li, Ying-Shiuan Chen, W. Mohaiza Dashwood, Nhung Nguyen, Ahmet M. Ulusan, Furkan Ertem, Mutian Zhang, Deqiang Sun, Yun Huang, Shan Wang, Hon-Chiu E. Leung, David Lieberman, Laura M. Beaver, Emily Ho, Mark T. Bedford, Kyle Chang, Eduardo Vilar, Roderick H. Dashwood. CCAR2 acetylation establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2614.

Background. Aromatase inhibitors (AIs), letrozole (Femarâ / Femaraâ) and exemestane (Aromasinâ), are widely used anti-hormonal drugs for breast cancer. Both compounds strongly reduce circulating estradiol levels in postmenopausal women. In the setting of metastatic breast cancer, these drugs may be used after another, causing new responses in selected patients by switching to the alternative drug after progressing on the first choice. This well-known ”lack of cross resistance” has been recognized for some time and is documented by several clinical trials. However, the precise explanation for this clinical observation is still unknown. The availability of mechanistic information may lead to an improved strategy against hormone-sensitive breast cancer. Patients and methods. NEO-LET-EXE was a neoadjuvant, randomized, open-label, intra-patient cross-over trial. Postmenopausal patients with estrogen receptor (ER) positive (>50%), HER-2 negative, locally advanced breast cancer were enrolled. Sequential blood samples (obtained at baseline, after 2 months and 4 months of treatment) were available from 29 patients. All patients were randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d) for 2 months followed by another 2 months on the alternative compound. The total estrogenic activities in the collected blood samples were determined using AroER tri-screen assay developed by the Chen laboratory. The assay utilizes MCF-7aro ERE cells which contain both aromatase and ER. The samples were assayed in the presence as well as the absence of letrozole, to estimate relative contributions of estrogen and estrogen+androgen to the activities, respectively. Results. Using the highly sensitive AroER tri-screen assay, estrogenic activity were detected at three time points in all blood samples. Importantly, a significantly higher total estrogenic activity was found during therapy with exemestane compared to letrozole in 23 out of 26 patients. Only in three patients, the activity was higher during therapy with letrozole compared to exemestane. When letrozole was included in the assay, the estrogenic activities in most samples collected during exemestane treatment were further reduced, suggesting that low levels of androgen were present in samples from exemestane treatment. Four samples collected after exemestane treatment and three after letrozole treatment had higher activities than baseline samples when assay was carried out with letrozole. Discussion. Our results suggest the AroER tri-screen to be a very sensitive method to estimate the overall estrogen-mediated activity in human samples. Significant higher levels of estrogenic activity in human serum were observed during exemestane than those during letrozole treatment. Our observations, that additional letrozole could reduce further the estrogen activity in the exemestane-treated samples, demonstrate probably residual aromatase activity during therapy with exemestane alone.In addition to distinguish the effects of exemestane and letrozole, our results also demonstrate that the assay can also potentially detect the effects of estrogenic mimics. Citation Format: Bahrami N, Chang G, Kanaya N, Sauer T, Gravdehaug B, Chen S, Geisler J. Total estrogenic activity during neoadjuvant therapy with letrozole and exemestane – An intra-patient cross-over comparison using the AroER tri-screen [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-16.

Triple negative breast cancer (TNBC) comprises approximately 15% of breast cancers and is associated with a poor prognosis. Many patients with TNBC relapse quickly and commonly develop metastases. There are no individualized targeted adjuvant or induction treatments for TNBC, and the current treatments are highly toxic. Development of chemoprevention methods using natural products would be beneficial to patients at risk of TNBC. To investigate the inhibitory effect of blueberries on inflammation-induced TNBC and identify the mechanism underlying modulation of inflammatory proteins by blueberries, we induced a proinflammatory microenvironment by feeding female MDA-MB-231 tumor-bearing mice a high fat western diet (W) with 5% whole blueberry powder (BB) and studied the effect on tumor formation and metastasis. We showed that mice fed a BB diet had significantly smaller tumors, less ulceration, and significantly less metastasis to the inguinal lymph nodes than mice fed a W diet. In BB-fed mice, serum levels of specific antiinflammatory cytokines were increased and specific cytokine expression was also altered. Together, these results suggest that blueberries may inhibit TNBC and TNBC-related metastasis by reducing inflammation via specific cytokine-driven pathways and thus reduce tumor growth and metastasis.

High dietary sodium and low potassium intake have been related to increased blood pressure (BP) in animal experiments, observational epidemiologic studies, and randomized controlled clinical trials.1–3 However, BP responses to dietary sodium and potassium intake vary considerably among individuals.2,4–6 The increased BP response to sodium, also known as salt sensitivity, has been associated with an increased risk of hypertension, cardiovascular disease, and premature death.7,8 The cold pressor test (CPT), which measures BP response to the stimulus of external cold, has been used for the evaluation of cardiovascular reactivity to stress in normotensive and hypertensive subjects. Cardiovascular hyper-reactivity to stress has been related to the development of hypertension and cardiovascular disease.9–11 In addition, increased BP response to the CPT has been associated with greater BP responses to changes in dietary sodium and potassium intake.12 Previous studies have indicated that both genetic and environmental factors may contribute to BP responses to dietary sodium and potassium intake and to the CPT.13–17 The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study aimed to investigate genetic factors related to BP responses to dietary sodium and potassium interventions, as well as the CPT.18 The study participant recruitment, dietary intervention, and data collection were conducted between October 2003 and July 2005. The study used a family-based feeding study design, and each family was ascertained through a proband with untreated prehypertension or stage 1 hypertension. Families of those with hypertension are most likely enriched in genetic variants for hypertension and tend to be more sensitive to dietary sodium and potassium interventions and the CPT. This design should potentially maximize the study power for identifying genetic variants for BP responses to dietary sodium and potassium intake and the CPT. A total of 1,906 study participants from 633 families took part in a 21-day dietary intervention including a 7-day low-sodium feeding, a 7-day high-sodium feeding, and a 7-day high-sodium feeding with potassium supplementation. The GenSalt study observed that BP responses to dietary sodium and potassium interventions and the CPT varied greatly among individuals.19 The GenSalt study also indicated that the heritabilities for BP responses to dietary sodium and potassium interventions and to the CPT were moderate, ranging 0.24–0.42.14 Novel genetic variants have been identified that are associated with BP responses among the GenSalt study population.20–28 To replicate and validate significant findings of the GenSalt study, we recruited an independent sample from rural north China and conducted the same measurements and interventions as the GenSalt study. Here we present the detailed design and methods of the GenSalt replication study, as well as the baseline characteristics and blood pressure responses to the dietary sodium and potassium interventions and the CPT.

Aromatase is a key enzyme in estrogen synthesis, and aromatase inhibitors (AIs) have been developed for treating estrogen-responsive breast cancer. Because of its nondiscriminatory inhibition of estrogen synthesis, patients treated with AIs also contract diseases typically associated with estrogen deficiency, such as bone deterioration. Our laboratory found that the citrus flavonone hesperetin could inhibit aromatase, and the selective estrogen receptor modulator nature of flavonoid might counteract the undesirable effect of AIs. In the present study, we employed an established postmenopausal model for breast carcinogenesis to examine the drug interaction between hesperetin and letrozole, one of the AIs. Athymic mice were ovariectomized and transplanted with aromatase-overexpressing MCF-7 cells (MCF-7aro). Hesperetin was administered in the diet at 5000 ppm, and letrozole was injected sc at different doses. Results showed that either hesperetin or letrozole could reduce plasma estrogen level and inhibit tumor growth. Most importantly, the letrozole-induced bone loss measured as bone volume fraction was reversed by hesperetin without compromising on the deterrence of MCF-7aro tumor growth. Taken together, the present study suggested that hesperetin could be a potential cotherapeutic agent to AI.

Background: While aromatase inhibitors are effective for ER/PR positive breast cancer, resistance frequently develops. EXE is a steroidal AI and has a weak hormone-like activity. Long-term EXE treatment up-regulated amphiregulin-mediated EGFR activation and EXE resistance could result from ER-EGFR cross-talk. In cell culture and animal studies, acquired resistance to EXE was significantly delayed with intermittent use, associated with decreased production of amphiregulin. For first line therapy in MBC, EXE had a median progression free survival (PFS) of 10 mos. As second and third line therapies, PFS decreased to 4.7 mos and 2 mos, respectively. After ≥ 2 of prior endocrine therapy, PFS to EXE ranged between 3.4 mos to 3.7 mos. The rationale for this study was that after long-term estrogen deprivation clinically equivalent to long-term exposure to AI, estrogen may induce apoptosis. With intermittent EXE use, we hope to delay the acquired AI resistance. Methods: Aims were to: 1) assess the PFS and 2) compete response (CR), partial response (PR) and clinical benefit rate [CBR=CR +PR + Stable disease (SD)≥ 6 mos], assessment of toxicity, compliance with medication adherence, and quality of life with assessment of bone health. The study included: 1) ER/PR positive MBC in first, second line/third line hormonal therapy, and one prior chemotherapy for MBC with no prior EXE allowed. EXE was given 25 mg daily × 14 days then 7 days off treatment, each 21-day cycle, imaging was done after every three cycles. Correlatives with estradiol level were drawn at day 1 and day 15 in each cycle. Results: From June 2008 to 2012 we enrolled 33 MBC patients ER/PR positive MBC with a median age of 60 yrs (42–79). At this cut off data date, 2 were inevaluable due to incidental colon cancer and change in treatment choice. 17 patients received treatment as first line (52%), 10 as second or third line hormonal therapy (30%), and 6 who received chemotherapy for MBC (18%). Median PFS and (95% CI) was 6.2 mos (1.9–12.2), 4.2 mos (2.1–10.1), and 3.2 mos (2.1-NR), respectively. For first line patients, there were 3 PRs and 4 with SD>6 mos for a CBR of 7/14 (50%). For second/third line, there were 3 with SD>6 mos for a CBR of 3/9(33%), no response seen in the prior chemotherapy group. The major metastatic sites included bone, liver, lung. 4 patients were Her2+ (13%). Adverse effects including hot flashes (62%), insomnia (31%), nausea (24%), bone pain (17%), fatigue (41%), joint pain (31%) were observed. Median number of cycles delivered is 6 (2–24) for first line, 5.5 (1–15) for second/third line, and 5 (2–9) for prior chemotherapy. Correlatives and QOL assessments are ongoing. Conclusions: Compared to the standard continuous EXE, PFS and CBR is inferior in the intermittent EXE as first line therapy, as second and third line therapy, the median PFS was 4.2 comparable to reported 3.7 mos with the CBR was 33% to 31.5% observed in the EFFECT trial. Interestingly, hot-flash rate was much higher at 62% compared to 11.2% in the EFFECT trial. Arthralgia is comparable at 31%. Patients who already received chemotherapy do not appear to respond favorably to intermittent hormonal therapy. Full response data with correlatives regarding the estradiol levels will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-08.

We studied the relationship of blood pressure (BP) trajectories during the first seven days after symptom onset with short- and long-term major clinical outcomes among patients with acute ischemic stroke. A total of 4,036 patients with acute ischemic stroke and elevated systolic BP from the CATIS trial were included in this analysis. Three BPs were measured every 2 hours for the first 24 hours, every 4 hours during the second and third days, and every 8 hours thereafter for the remainder of the seven days. Latent class models were used to identify subgroups that share a similar underlying trajectory in BP in the acute phase. Five systolic BP trajectories of high, high-to-moderate low, moderate high, moderate low, and low were identified. Compared to the high trajectory, multiple-adjusted odds ratios (95% CI) of death and major disability at 3 months for high-to-moderate low, moderate high, moderate low, and low trajectories were 0.61 (0.44 to 0.86), 0.63 (0.48 to 0.84), 0.49 (0.37 to 0.65), and 0.42 (0.30 to 0.59), respectively (overall p

It is well known that blood pressure (BP) responses to dietary sodium intake vary among individuals (salt-sensitivity and salt-resistance). However, it is unknown whether salt-sensitivity and salt-resistance predict the risk of hypertension. We conducted a dietary sodium intervention study among 1,906 Han Chinese in 2003-05 and followed the study participants in 2008-09 and 2011-12. The dietary intervention included a 7-day low-sodium feeding (51.3 mmol/day) and a 7-day high-sodium feeding (307.8 mmol/day). Three BP measurements were obtained during each of the 3 days of baseline observation and on days 5, 6, and 7 of each intervention period. We used latent class models to identify subgroups that share a similar underlying trajectory in BP responses to sodium intervention. Over an average of 7.4 years of follow-up, we identified 514 incident hypertension cases. The mean (standard deviation) change in systolic BP during low-sodium and high-sodium interventions according to salt-sensitive and -resistant groups are shown in the following table. In addition, age, sex, and baseline BP-adjusted and multiple-adjusted odds ratios (95% CI) of incident hypertension are shown in the following table. These data indicate that high responses or non-responses to dietary sodium intervention are related to the risk of hypertension. Furthermore, this is the first prospective cohort study to indicate that individuals with either salt-sensitivity or salt-resistance are at an increased risk for hypertension and should be targeted for dietary intervention.

BACKGROUND Hypertension is the leading global preventable risk factor for premature death. While hypertension prevalence has been declining in high-income countries, it has increased continuously in low- and middle- income countries. METHODS We conducted a cross-sectional survey in 7,524 women and men aged 35-74 years from randomly selected samples in 4 cities (Bariloche and Marcos Paz, Argentina; Temuco, Chile; and Pando-Barros Blancos, Uruguay) in 2010-2011. Three blood pressure (BP) measurements were obtained by trained observers using a standard mercury sphygmomanometer. Hypertension was defined as a mean systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg and/or use of antihypertensive medications. RESULTS An estimated 42.5% of the study population (46.6% of men and 38.7% of women) had hypertension and an estimated 32.5% (36.0% of men and 29.4% of women) had prehypertension. Approximately 63.0% of adults with hypertension (52.5% of men and 74.3% of women) were aware of their disease condition, 48.7% (36.1% of men and 62.1% of women) were taking prescribed medications to lower their BP, and only 21.1% of all hypertensive patients (13.8% of men and 28.9% of women) and 43.3% of treated hypertensive patients (38.1% of men and 46.5% of women) achieved BP control. CONCLUSIONS This study indicates that the prevalence of hypertension is high while awareness, treatment, and control are low in the general population in the Southern Cone of Latin America. These data call for bold actions at regional and national levels to implement effective, practical, and sustainable intervention programs aimed to improve hypertension prevention, detection, and control. Fil: Rubinstein, Adolfo Luis. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Irazola, Vilma. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Calandrelli, Matias. Sanatorio San Carlos, San Carlos de Bariloche; Argentina Fil: Chung-Shiuan, Chen. Tulane University School of Public Health and Tropical Medicine. Department of Epidemiology; Estados Unidos Fil: Gutierrez, Laura. Instituto de Efectividad Clínica y Sanitaria; Argentina Fil: Lanas, Fernando. Universidad de La Frontera; Chile Fil: Manfredi, Jose A.. Universidad de la República; Uruguay Fil: Mores, Nora. Municipalidad de Marcos Paz, Provincia de Buenos Aires; Argentina Fil: Poggio, Rosana. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ponzo, Jacqueline. Universidad de la República; Uruguay Fil: Seron, Pamela. Universidad de La Frontera; Chile Fil: Bazzano, Lydia A.. Tulane University School of Public Health and Tropical Medicine. Department of Epidemiology; Estados Unidos Fil: He, Jiang. Tulane University School of Public Health and Tropical Medicine. Department of Epidemiology; Estados Unidos

The paper presented a sustainable design model for integrated evaluation of the design and supply chain of a product for the sustainable objectives. To design a product, there can be alternative ways to assign the detailed specifications to fulfill the same design objectives. In the design alternative cases, different material and manufacturing processes with various supply chain activities may be required for the production. Therefore, it is required to evaluate the different design cases based on the sustainable objectives. In this research, a closed-loop design model is developed by integrating the forward design model and reverse design model. From the supply chain point of view, the decisions in the forward design model are connected with the forward supply chain. The decisions in the reverse design model are connected with the reverse supply chain considering the sustainable objectives. The purpose of this research is to develop a mathematical model for analyzing the design cases by integrated evaluating the criteria in the closed-loop design and the closed-loop supply chain. The decision variables are built to represent the design cases of the forward design and reverse design. The cost parameters in a forward design include the costs of material and manufacturing processes. The cost parameters in a reverse design include the costs of recycling, disassembly, reusing, remanufacturing, and disposing. The mathematical model is formulated to minimize the total cost under the design constraints. In practical applications, the decisions of the mathematical model can be used for selecting a design case for the purpose of sustainable design of a product. An example product is demonstrated in the paper. The test result shows that the sustainable design model is useful for integrated evaluation of the design and the supply chain to achieve the sustainable objectives., {"references":["Tseng, Yuan-Jye, and Yi-Shiuan Chen, \"A Closed-loop Design Model for Sustainable Manufacturing by Integrating Forward Design and Reverse Design,\" International Journal of Social, Behavioral, Educational, Economic and Management Engineering, Vol. 9, No. 7, 2015, pp. 2217-2213.","Y.-J. Tseng, and Y-J Wang, \"A Product Development for Green Logistics Model by Integrated Evaluation of Design and Manufacturing and Green Supply Chain\", ICIME 2013 International Conference on Industrial and Mechanical Engineering (World Academy of Science, Engineering and Technology), London, UK, July 08-09, 2013, vol. 7, no. 7, pp. 420-425.","C. A. Weber, J. R. Current, and W. C. Benton, \"Vendor Selection Criteria and Methods,\" European Journal of Operational Research, vol. 50, pp. 2-18, 1991.","R. G. Kasilingam, and C. P. 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The research was to appraise the utility of the patient-derived tumor xenografts (PDXs) as models of estrogen receptor positive (ER+HER2- and ER+HER2+) breast cancers. We compared protein expression profiles by Reverse Phase Protein Array (RPPA) in tumors that resulted in PDXs compared to those that did not. Our overall PDX intake rate for ER+ breast cancer was 9% (9/97). The intake rate for ER+HER2+ tumors (3/16, 19%) was higher than for ER+HER2- tumors (6/81, 7%). Heat map analyses of RPPA data showed that ER+HER2- tumors were divided into 2 groups by luminal A/B signature [protein expression of ER, AR, Bcl-2, Bim (BCL2L11), GATA3 and INPP4b], and this expression signature was also associated with the rate of PDX intake. Cell survival pathways such as the PI3K/AKT signaling and RAS/ERK pathways were more activated in the specimens that could be established as PDX in both classes. Expression of the ER protein itself may have a bearing on the potential success of an ER+ PDX model. In addition, HER2 and its downstream protein expressions were up-regulated in the ER+HER2+ patient tumors that were successfully established as PDX models. Moreover, the comparison of RPPA data between original and PDX tumors suggested that the selection/adaptation process required to grow the tumors in mice is unavoidable for generation of ER+ PDX models, and we identified differences between patient tumor samples and paired PDX tumors. A better understanding of the biological characteristics of ER+PDX would be the key to using PDX models in assessing treatment strategies in a preclinical setting.

Few data are available on population level regarding domain-specific correlates of physical activity (PA) in Latin America.The aim of this study was to examine the relationships among PA patterns and their main sociodemographic determinants and cardiovascular risk factors in the Southern Cone of Latin America.CESCAS I is a population-based prospective cohort study with a 4-stage stratified sampling of a general population of 7,524 adults aged 35 to 74 years from 4 midsized cities in Argentina, Chile, and Uruguay. PA was assessed using the transcultural adaptation of the International Physical Activity Questionnaire long form. The questionnaire asked about frequency (days per week) and duration (minutes per day) of moderate and vigorous intensity activities in 3 different domains: work, leisure time, and active transportation (walking and bicycling). PA levels of ≥600 metabolic equivalent tasks (MET) minutes per week was considered sufficiently active. Odds ratios for associations of sufficiently active status with sociodemographic determinants and cardiovascular risk factors were obtained using multivariable-adjusted logistic regression models.Almost 65%) of the participants reported ≥600 MET minutes per week. The lowest prevalence of sufficiently active individuals was seen in Temuco, Chile (58.0%), among women (58.7%), older individuals (55.4%), those with higher educational level (61.6%), and homemakers (53.4%). Approximately 22.8% of the population reported no PA. In multivariable analysis, PA levels were lower among women, individuals who were older, obese, university educated, with clerical work, retired/unemployed or homemakers, and those with physical limitations. Future interventions to increase PA levels in the Southern Cone of Latin America must take into account disparities by gender and socioeconomic status. The promotion of PA during leisure time in women--unemployed and homemakers--and of active transportation for those performing office or clerical work should be a priority in this population.

To identify the unmet supportive care needs and related factors in caregivers of patients with advanced lung cancer. A cross-sectional study of 166 lung cancer patient-caregivers dyads was recruited at a medical center. The supportive care needs, fatigue, and sleep disturbance of caregivers were collected. Patients were assessed for symptom severity, anxiety, and depression. Logistic regression was used to reveal the related factors of unmet supportive care needs. Of the 166 dyads surveyed, the top unmet needs were information needs, health care professional/health care service needs, and daily living needs. Patients’ anxiety was positively correlated to overall caregiving needs, health care professional/health care service needs, interpersonal communication needs, and psychological/emotional needs of caregivers. The information needs and health care professional/health care service needs were related to the caregivers’ fatigue. The sleep disturbance of caregivers was associated with their overall caregiving needs, daily living needs, and psychological/emotional needs. Future interventions to meet the needs of caregivers should include specific needs assessment and continuing education in caregiving.

Background The effect of early blood pressure reduction on cognitive function in patients with acute ischemic stroke remains unknown. Aim We tested whether antihypertensive treatment would reduce cognitive impairment in patients with acute ischemic stroke. Methods In the China Antihypertensive Trial in Acute Ischemic Stroke, patients with elevated blood pressure were randomly assigned to receive antihypertensive treatment or to discontinue all hypertensive medications within 48 h of onset. Cognitive function was measured by the Mini-Mental State Examination and Montreal Cognitive Assessment at 3 months after randomization in a subsample of 638 participants. Results Mean systolic blood pressure was reduced by 21.5 mmHg in the antihypertensive treatment group and 13.9 mmHg in the control group within 24 h after randomization ( P Conclusions These data indicated that early blood pressure reduction with antihypertensive medication in patients with acute ischemic stroke had no effect on cognitive impairment at 3 months.

Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor (HR)-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest, and induced apoptosis. LBH589 treatment also reduce the levels of NF-κB1 which overexpresses when AI-resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-κB1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-κB1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-κB1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 repressed NF-κB1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-κB1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-κB1 pathway.

Aromatase inhibitors (AI) are currently the first line therapy for estrogen receptor (ER)-positive postmenopausal women. De novo AI resistance is when a patient intrinsically does not respond to an AI therapy as well as other targeted endocrine therapy. To characterize this type of resistance and to examine potential therapies for treatment, we have generated two cell models for de novo resistance. These models derive from MCF-7 cells that stably overexpress aromatase and Akt (AKT-aro) or HER2 (HER2-aro). Evaluation of these cell lines revealed that the activities of aromatase and ER were inhibited by AI and ICI 187280 (ICI) treatment, respectively; however, cell growth was resistant to therapy. Proliferation in the presence of the pure anti-estrogen ICI, indicates that these cells do not require ER for cell growth and distinguishes these cells from the acquired AI resistant cells. We further determined that the HSP90 inhibitor 17-DMAG suppressed the growth of the AI-resistant cell lines studied. Our analysis revealed 17-DMAG-mediated decreased expression of growth promoting signaling proteins. It was found that de novo AI resistant AKT-aro and HER2-aro cells could not be resensitized to letrozole or ICI by treatment with 17-DMAG. In summary, we have generated two cell lines which display the characteristics of de novo AI resistance. Together, these data indicate the possibility that HSP90 inhibitors may be a viable therapy for endocrine therapy resistance although additional clinical evaluation is needed.

Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective antitumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2(-/-) mice that phenotypically resemble nascent primary tumour cells. Using class I prediction algorithms, we identify mutant spectrin-β2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T-cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-β2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.

Background/Aims: Angiogenesis may play an important role in the renal repair process after injury. We investigated the association between plasma endostatin, an endothelial-specific antiangiogenic factor, and chronic kidney disease (CKD). Methods: We compared plasma endostatin levels in 201 CKD patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) 2 or presence of albuminuria (≥30 mg/24 h). Results: After adjustment for established CKD risk factors, the median (interquartile range) of plasma endostatin was 276.7 ng/dl (199.3–357.5) in patients with CKD and 119.4 ng/dl (103.7–134.6) in controls without CKD (p < 0.0001 for group difference). log-transformed plasma endostatin was significantly and inversely correlated with eGFR (r = –0.83, p < 0.0001) and positively correlated with log-transformed urine albumin (r = 0.66, p < 0.0001) in the study participants. In addition, one standard deviation increase in log-transformed plasma endostatin (0.55 ng/dl) was associated with a decline in eGFR of –26.2 ml/min and an increase in urine albumin of 3.26 mg/ 24 h after adjusting for multiple covariables. Furthermore, the multivariable-adjusted odds ratio for CKD comparing the highest tertile (≥131.4 ng/dl) to the two lower tertiles of plasma endostatin was 21.6 (95% CI: 10.2–45.5; p < 0.0001). Conclusion: These data indicate that elevated plasma endostatin is strongly and independently associated with CKD. Prospective cohort studies and clinical trials are warranted to further examine the causal relationship between endostatin and risk of CKD and to develop novel interventions targeting circulating endostatin aimed at reducing CKD risk.

Backgrounds: In randomized trials for early stage breast cancer, patients who received adjuvant zolendronic acid (ZA) had superior disease-free survival and greater tumor shrinkage. Preclinical data suggest that ZA has anti-cancer properties by modulating angiogenesis and tumor immune environment. This is the pilot study to assess changes in tumor biomarkers and immunological function in response to a single dose of ZA in paired tumor specimens (from core biopsy and definitive surgery). Methods: Postmenopausal women with early stage invasive ductal breast carcinoma who have estrogen receptor and/or progesterone receptor positive tumor for which a lumpectomy or mastectomy was planned prior to systemic therapy were enrolled. A single dose of ZA 4mg IV was given 10-14 days prior to their planned definitive surgery. 14 biomarkers in tumor tissue was assayed; 10 by gene microarray (VEGF, IL1β, IL-6, MMP-1, MMP-2, MMP-9, TGF, Interferon α and STAT3)) and 4 by RT-PCR(P13K, PTEN, IGF-1-R, EGFR. Patient blood samples were drawn at baseline, at 48-72hrs after the single dose of ZA and at the time of surgery and assayed for cytokines and chemokines by using 30-plex Luminex panels. Results: Eight patients were enrolled in the study (median age 65 and range (57-75); 4 caucatians, 2 hispanic and 1 asian; 6 stage I, 1 stage II and 1 stage III). 30-plex luminex assays showed MIG, IP-10 and IL-12 were found to increase in Day 1-3 of ZA therapy from baseline and normalized by Day 10-24. MCP-1, IL2R, MIP-1b and Eotaxin were found to have changes in Day 1-3 from baseline and mix outcome by Day 10-24. EGF, G-CSF, HGF, IFN-alpha and IFN-gamma and RANTES showed no clear pattern among eight patients. Tumor markers and proteomics from pair tumor samples will be presented. Conclusions: Changes in multiple tumor biomarkers and immunological markers, MIG, IP-10, IL-12, MCP-1, IL2R, MIP-1b, Eotaxin, IFN-alpha and IFN-gamma are seen within 2 weeks of a single dose of ZA. Citation Format: Cho M, Gong J, Chen S, Yu H, Wong L, Kruper L, Mortimer J. A pilot study of the impact of a single dose of zolendronic acid on biomarkers in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-18.

BACKGROUND/OBJECTIVE: Previous clinical trials have documented that soy protein reduces low-density lipoprotein cholesterol and increases high-density lipoprotein (HDL) cholesterol compared with milk protein. However, the effect of soy protein on lipids compared with carbohydrate has not been not well studied. We examined the effect of soy and milk protein supplementation on lipids and lipoproteins compared with carbohydrate among adults without hypercholesterolemia. SUBJECTS/METHODS: We conducted a randomized, double-blind, 3-phase crossover trial among 352 US adults with serum total cholesterol level of