tbuckley/cabot-search huggingface dataset:
Bone Lead Levels and Risk of Incident Primary Open-Angle Glaucoma: The VA Normative Aging Study
Authors: Weiye Wang, Sayoko Moroi, Kelly Bakulski, Bhramar Mukherjee, Marc G. Weisskopf, Debra Schaumberg, David Sparrow, Pantel S. Vokonas, Howard Hu, Sung Kyun Park
Journal: Environmental Health Perspectives (2018)

Oxidative stress may play an important role in the etiology of primary open-angle glaucoma (POAG). The association between risk of POAG and lead exposure, which is an environmental source of oxidative stress, has not been fully investigated yet. Our objective was to determine the association between bone lead—a biomarker of cumulative lead dose (tibia lead) or an endogenous source of stored lead (patella lead)—and incident POAG. We examined a prospective cohort of 634 POAG-free men [mean baseline age=66.8 y of age (SD=6.7)] from the Normative Aging Study (NAS) who had tibia and patella K X-ray fluorescence lead measurements between 1 January 1991 and 31 December 1999. They also had standard ocular evaluations by NAS optometrists until 31 December 2014. POAG cases were identified by consistent reports of enlarged or asymmetric cup-to-disc ratio together with visual field defect or existence of disc hemorrhage. We used Cox proportional hazards regressions to estimate hazard ratios (HRs) of incident POAG and adjusted survival curves to examine changes in the risk of POAG during follow-up according to bone lead quartiles. We identified 44 incident cases of POAG by the end of follow-up (incidence rate=74 per 10,000 person-years; median follow-up=10.6 y). In fully adjusted models, 10-fold increases in patella lead and tibia lead were associated with HRs of 5.06 (95% CI: 1.61, 15.88, p=0.005) and 3.07 (95% CI: 0.94, 10.0, p=0.06), respectively. The HRs comparing participants in the third and fourth quartiles with the lowest quartile were 3.41 (95% CI: 1.34, 8.66) and 3.24 (95% CI: 1.22, 8.62) for patella lead (p-for-trend=0.01), and 3.84 (95% CI: 1.54, 9.55) and 2.61 (95% CI: 0.95, 7.21) for tibia lead (p-for-trend=0.02). Our study provides longitudinal evidence that bone lead may be an important risk factor for POAG in the U.S. population. https://doi.org/10.1289/EHP3442.
Effects of Candesartan on Cough and Bronchial Hyperresponsiveness in Mildly to Moderately Hypertensive Patients With Symptomatic Asthma
Authors: HiroshiTanaka, ShinTeramoto, KensukeOashi, ToyohiroSaikai, ShintaroTanaka, KazuhikoSuzuki, MidoriHashimoto, ShosakuAbe
Journal: Circulation (2001)

Background Candesartan, an AT1 receptor antagonist, has been reported to have no association with persistent cough in subjects with hypertension, but there has been no study on the safety of its administration to hypertensive patients with symptomatic asthma. The aim of this study was to compare the adverse effects of candesartan and calcium antagonists on cough, pulmonary function, and bronchial hyperresponsiveness in these patients. Methods and Results Sixty mildly to moderately hypertensive patients with bronchial asthma received either candesartan (n=30) or the calcium antagonists nifedipine or manidipine (n=30) for 6 months. The candesartan group included 5 subjects with a history of ACE inhibitor–induced cough. There were no differences between the 2 groups in patient characteristics, ACE gene polymorphism, pulmonary function, or bronchial hyperresponsiveness to methacholine. Control of hypertension was the primary end point; new cough detected by self-administrated questionnaire and an increase in ...
Abstract 276: The Role of Diacylglycerol Acetyltransferase 1 and 2 in Cardiac Metabolism and Function
Authors: Nathan D Roe, Michal K Handzlik, Tao Li, Rong Tian
Journal: Circulation Research (2017)

Cardiac triglyceride (TG) plays an important role in myocardial metabolism. TG synthesis is catalyzed by diacylglycerol:acetyltransferase (DGAT). Enhancing cardiac TG synthesis and turnover, by means of overexpression DGAT1, has protected hearts against stresses while blocking the TG turnover causes cardiomyopathy. In the meantime DGAT inhibitors are being developed for lipid lowering therapy, raising concerns whether DGAT inhibition affects cardiac function. Here we determined the role of the two cardiac DGAT isoforms in TG synthesis and turnover in the heart and their contribution to cardiac fatty acid metabolism. Using an inducible cardiac specific DGAT1 deletion mouse (iKO) together with DGAT2-specific inhibitor, we were able to achieve graded inhibition of TG synthesis and turnover as determined by 13 C-NMR spectroscopy of isolated perfused mouse heart. The iKO heart has normal TG level (CON 5.7±1.2 vs. 6.9±0.7 μg/mg wwt) and perfusing hearts with glucose (5.5mM), fatty acids (0.4mM) and lactate (1.2mM) for 1hr did not change the TG content in control (CON, pre-perfusion 3.9 ± 0.6 vs. post-perfusion 4.5 ± 0.7 μg/mg wwt), iKO (3.8±0.6 vs. 4.2±0.5 μg/mg wwt) or iKO+DGAT2 inhibitor (3.8±0.6 vs. 5.0±0.8 μg/mg wwt). Relative to CON, the rate of 13 C labeled fatty acids incorporation into the TG pool decreased by 32% in iKO (AUC 5.170 of 7.547, p&lt;0.05) which was accompanied by an increase the oxidation of exogenous fatty acids (relative FAO: 48.5±5.3 for CON vs. 67.0±4.1% for iKO, p&lt;0.05). Cardiac function, assessed by echocardiography (FS: CON 47.5±1.3 vs. iKO 45.8±3.0%, p&gt;0.05) or by rate pressure product of the isolated perfused heart (CON 39149±1047 vs. iKO 40836±3424 bpm*mmHg, p&gt;0.05) is normal in iKO hearts and remained unchanged after treatment with the DGAT2 inhibitor (37083±8507 bpm*mmHg). Coinhibition of DGAT1 and 2 abrogated 13 C labeled fatty acids incorporation into the TG pool by 58% (AUC 5.042 of 11.82, p&lt;0.05) and suppressed expression of PPARα target genes relative to non-treated control hearts (p&lt;0.05). Taken together, our data show that both DGAT1 and 2 contribute TG synthesis in the heart. Inhibition of both isoforms abrogated TG synthesis and reduced PPARα activity in the heart but did not affect cardiac function in isolated perfused heart.
Allopurinol Attenuates Left Ventricular Remodeling and Dysfunction After Experimental Myocardial Infarction
Authors: NielsEngberding, StephanSpiekermann, ArndSchaefer, AndréHeineke, AntjeWiencke, MajaMüller, MartinFuchs, DeniseHilfiker-Kleiner, BurkhardHornig, HelmutDrexler, UlfLandmesser
Journal: Circulation (2004)

Background— Accumulating evidence suggests a critical role for increased reactive oxygen species (ROS) production in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). Increased expression of xanthine oxidase (XO), a major source of ROS, has recently been demonstrated in experimental and clinical heart failure; however, a potential role for LV remodeling processes remains unclear. We therefore studied the effect of long-term treatment with allopurinol, a potent XO inhibitor, on myocardial ROS production and LV remodeling and dysfunction after MI. Methods and Results— Mice with extensive anterior MI (n=105) were randomized to treatment with either vehicle or allopurinol (20 mg · kg−1 · d−1 by gavage) for 4 weeks starting on day 1 after surgery. Infarct size was similar among the groups. XO expression and activity were markedly increased in the remote myocardium of mice after MI, as determined by electron spin resonance spectroscopy. Myocardial ROS production was increased af...
MicroRNA-Mediated Epigenetic Silencing of Sirtuin1 Contributes to Impaired Angiogenic Responses
Authors: IngoVolkmann, RegallaKumarswamy, NilsPfaff, JanFiedler, SeemaDangwal, AngelikaHolzmann, SandorBatkai, RobertGeffers, AchimLother, LutzHein, ThomasThum
Journal: Circulation Research (2013)

Rationale:Transforming growth factor (TGF)-β was linked to abnormal vessel function and can mediate impairment of endothelial angiogenic responses. Its effect on microRNAs and downstream targets in this context is not known. Objective:To study the role of microRNAs in TGF-β–mediated angiogenic activity. Methods and Results:MicroRNA profiling after TGF-β treatment of endothelial cells identified miR-30a-3p, along with other members of the miR-30 family, to be strongly silenced. Supplementation of miR-30a-3p restored function in TGF-β–treated endothelial cells. We identified the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) to be a direct and functional target of miR-30a-3p. Viral overexpression of MeCP2 mimicked the effects of TGF-β, suggesting that derepression of MeCP2 after TGF-β treatment may be responsible for impaired angiogenic responses. Silencing of MeCP2 rescued detrimental TGF-β effects on endothelial cells. Microarray transcriptome analysis of MeCP2-overexpressing endothelial cells ide...
Circulating and intrahepatic antiviral B cells are defective in hepatitis B
Authors: Alice R. Burton, Laura J. Pallett, Laura E. McCoy, Kornelija Suveizdyte, Oliver E. Amin, Leo Swadling, Elena Alberts, Brian R. Davidson, Patrick T.F. Kennedy, Upkar S. Gill, Claudia Mauri, Paul A. Blair, Nadege Pelletier, Mala K. Maini
Journal: Journal of Clinical Investigation (2018)

B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21–CD27– atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1hiatMBC and impairing B cell immunity.
Hyperinsulinemia and Autonomic Nervous System Dysfunction in Obesity
Authors: MicheleEmdin, AmaliaGastaldelli, ElzaMuscelli, AlbertoMacerata, AndreaNatali, StefaniaCamastra, EleFerrannini
Journal: Circulation (2001)

Background—Because hyperinsulinemia acutely stimulates adrenergic activity, it has been postulated that chronic hyperinsulinemia may lead to enhanced sympathetic tone and cardiovascular risk. Methods and Results—In 21 obese (body mass index, 35±1 kg/m2) and 17 lean subjects, we measured resting cardiac output (by 2-dimensional echocardiography), plasma concentrations and timed (diurnal versus nocturnal) urinary excretion of catecholamines, and 24-hour heart rate variability (by spectral analysis of ECG). In the obese versus lean subjects, cardiac output was increased by 22% (P<0.03), and the nocturnal drop in urinary norepinephrine output was blunted (P=0.01). Spectral power in the low-frequency range was depressed throughout 24 hours (P<0.04). During the afternoon and early night, ie, the postprandial phase, high-frequency power was lower, heart rate was higher; and the ratio of low to high frequency, an index of sympathovagal balance, was increased in direct proportion to the degree of hyperinsulinemia ...
Inflammasome Activation of Cardiac Fibroblasts Is Essential for Myocardial Ischemia/Reperfusion Injury
Authors: MasanoriKawaguchi, MasafumiTakahashi, TakekiHata, YuichiroKashima, FumitakeUsui, HajimeMorimoto, AtsushiIzawa, YasukoTakahashi, JunyaMasumoto, JunKoyama, MinoruHongo, TetsuoNoda, JunNakayama, JunjiSagara, Shun'ichiroTaniguchi, UichiIkeda
Journal: Circulation (2011)

Background—Inflammation plays a key role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury; however, the mechanism by which myocardial I/R induces inflammation remains unclear. Recent evidence indicates that a sterile inflammatory response triggered by tissue damage is mediated through a multiple-protein complex called the inflammasome. Therefore, we hypothesized that the inflammasome is an initial sensor for danger signal(s) in myocardial I/R injury. Methods and Results—We demonstrate that inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, is crucially involved in the initial inflammatory response after myocardial I/R injury. We found that inflammasomes are formed by I/R and that its subsequent activation of inflammasomes leads to interleukin-1β production, resulting in inflammatory responses such as inflammatory cell infiltration and cytokine expression in the heart. In mice deficient for apoptosis-associated speck-like adaptor protein and caspase-1, these in...
Abstract 3634: PET/CT imaging prediction of response to checkpoint blockade in advanced non-small cell lung cancer patients
Authors: Wei Mu, Jin Qi, Hong Lu, Mathew Schabath, Yoganand Balagurunathan, Ilke Tunali, Shari Pilon-Thomas, Robert J. Gillies
Journal: Cancer Research (2018)

Abstract Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors PD-1 and PD-L1 has emerged as a one of the most successful treatment approaches in advanced Non-small Cell Lung Cancer (NSCLC) patients. However, given its adverse effects, high cost and only approximately 20% response rate, accurate response predication is import to identify patients most likely to respond. In previous work, we and others have shown that tumor acidosis, generated from high rates of glucose metabolism, was a potent inhibitor of anti-tumor immunity and that neutralization of acid improved response to checkpoint blockade. In this study, we investigated the value of pre-therapy PET/CT images on response prediction to test the hypothesis that the most metabolically active tumors would have the poorest response to checkpoint blockade. 64 patients were retrospectively curated with pathology verified NSCLC and who did not receive intervening treatments between the PET/CT imaging and initiation of anti-PD1 therapy. Responders (long-term and ongoing responders, n=22) and non-responders (non-responders and transient responders, n=42) were classified according to RECIST criteria. These patients were randomly divided into two groups (n=32 each) for training and testing, respectively. From their images, we constructed 5 different fusion images comprised of PET and CT data. We then extracted 455 quantitative features from these fusion images, as well as the original PET/CT images. We then generated an additional 975 fusion features calculated from the above 455 features, as well as some clinical features (location, age, sex, and histologic type). From these, the most informative features were selected with Receiver Operating Characteristic Curve (ROC) analysis, and these were analyzed with a combined 2-layer cascade support vector machine (cSVM) classification model to relate the features to prediction of objective response. From this we determined that the most informative features were fusion features. With the cSVM, the training set achieved accuracy and area under the ROC curve (AUROC) for classifying response of 100% and 1.00, respectively. Using this model on the test set achieved accuracy and AUROC of 89.66% and 0.86, respectively. We conclude from that PET/CT fusion images may be useful prior to initiation of therapy to predict response to checkpoint blockade in advanced non-small cell lung cancer patients. Citation Format: Wei Mu, Jin Qi, Hong Lu, Mathew Schabath, Yoganand Balagurunathan, Ilke Tunali, Shari Pilon-Thomas, Robert J. Gillies. PET/CT imaging prediction of response to checkpoint blockade in advanced non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3634.
Abstract 4951: Inhibiting guanylate binding protein 1 (GBP1) impedes ovarian cancer progression
Authors: Dhanir Tailor, Vineet Kumar, Mallesh Pandrala, Angel Resendez, Sanjay V. Malhotra
Journal: Cancer Research (2018)

Abstract Ovarian cancer, the most common gynecologic malignancy, is a leading cause of cancer deaths in women. Seventy percent of patients at diagnosis present with stage III or IV disease, in which the tumor has disseminated beyond the ovaries and pelvic organs to distant sites. Despite resection and and chemotherapy, 80% of patients diagnosed with advanced epithelial ovarian cancer develop recurrent disease and overall prognosis is poor. Resistance to chemotherapeutic agents such as carboplatin and paclitaxel (taxane-based drugs) accounts for the lack of effectiveness of current therapy. Characterization of taxane-resistant tumors has shown that Class III β-tubulin (βTUB3) is significantly overexpressed in ovarian cancer as well as other cancers. Also, molecular characterization of the causes of treatment resistance revealed that βTUB3 plays a prominent role in the incorporation of guanylate binding protein 1, a conditionally expressed GTPase normally involved in the inflammatory response, as one of the critical effectors of taxane and radiotherapy resistance in ovarian cancer. Once in the cytoskeleton, GBP1 binds to pro-survival kinases such as serine/threonine-protein kinase pim-1 (PIM1) and initiates a signaling cascade that induces treatment resistance. We hypothesize that inhibiting the activity of GBP1 will restore sensitivity to taxane therapy. This is now well supported by our preliminary proof-of-concept studies. We have demonstrated that natural product-derived small molecule SU093 stabilizes GBP1 in a nonbinding conformation, resulting in the inhibition of GBP1:PIM1 interaction. The mechanistic studies using confocal microscopy showed that SU093 inhibits GBP1 by blocking its nuclear translocation and disrupts the tubulin dynamics. Cell cycle analysis showed that SU093 leads to G1 phase arrest followed by apoptotic cell death. SU093 treatment also induced pro-apoptotic protein Bax and reduced anti-apoptotic protein Bcl2. Overall, our in vitro and in vivo investigations provide a compelling foundation to develop a novel therapy to treat ovarian cancer by inhibition of GBP1. Citation Format: Dhanir Tailor, Vineet Kumar, Mallesh Pandrala, Angel Resendez, Sanjay V. Malhotra. Inhibiting guanylate binding protein 1 (GBP1) impedes ovarian cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4951.
Weight loss as a predictor of mortality in patients with interstitial lung disease
Authors: Janelle Pugashetti, Julia Graham, Noelle Boctor, Cesar Mendez, Elena Foster, Maya Juarez, Richart Harper, Brian Morrissey, Michael Kadoch, Justin M. Oldham
Journal: European Respiratory Journal (2018)

The interstitial lung diseases (ILDs) are a diverse group of diffuse parenchymal lung disorders that commonly result in pulmonary fibrosis. ILDs are broadly classified according to known and unknown aetiologies. Connective tissue disease-associated ILD (CTD-ILD) and chronic hypersensitivity pneumonitis (CHP) are among the most common ILDs of known aetiology, while idiopathic pulmonary fibrosis (IPF) and unclassifiable ILD (U-ILD) are among the most common of unknown aetiology [1–4]. Weight loss in patients with ILD was associated with increased mortality risk in those with IPF and U-ILD <http://ow.ly/Nk0D30l2Apm>
Abstract P091: Ethnic Disparities in Social and Psychosocial Factors Modify the Effect of Genes on Body Mass Index
Authors: Erin B Ware, Jennifer A Smith, Jessica Faul, Sharon L Kardia
Journal: Circulation (2016)

Introduction: Obesity/body mass index (BMI) is one of the leading risk factors of cardiovascular disease (CVD) in both African American and non-Hispanic white populations. Identifying the range of factors that lead to the persistent and pronounced differences in the BMI of populations is critical for developing effective strategies for reducing these inequalities and ultimately reducing the incidence of CVD. It is posited that these differences arise from the interplay between both biological (genes) and social factors (environments). Standard approaches to this complex problem of incorporating “bio-social” data remain fractured; examining only biological, or only social determinants of the diseases/risk factors in question. This paradigm is not effective in uncovering the origins of diseases that arise from the relationships between multiple systems. By incorporating both biological and sociological data, we seek to better understand the health disparities underlying obesity. Hypotheses: We hypothesize that there will be gene regions associated with BMI in both African and non-Hispanic whites, but not necessarily the same regions across ethnicity. We expect stronger associations in each ethnicity with gene regions defined from meta-analysis of that ethnicity. We hypothesize that low socioeconomic position, lower levels of social support and higher levels of anger, ongoing stressful life events, and depressive symptoms will modify the effects of genetic predictors on BMI. Methods: We used novel, gene region-based analysis methods (Sequence Kernel Association Testing and Gene-Environment Set Association Test) with gene regions identified from 103 known obesity loci (97 from published GWAS meta-analysis in European ancestry and 6 from African ancestry), to examine the effect of gene regions on BMI in up to 3,000 African Americans and up to 12,000 non-Hispanic whites from the Health and Retirement Study. We also investigated the modification of these gene regions’ effects on BMI by social and psychosocial environment and compared across ethnicity. Results and Conclusions: Preliminary results indicate strong gene-region associations in African Americans with several genes including GPRC5B (p=0.024), SH2B1 (p=0.016) and TNNI3K (p=0.004) as well as statistically significant associations between BMI and social/psychosocial variables (bivariate p&lt;0.01 for anger, social support, socioeconomic position, stressful life events and depression scores in non-Hispanic whites; depression score in African Americans). Gene-region results in the non-Hispanic whites and interaction results are forthcoming. In conclusion, investigating gene-by-psychosocial and gene-by-socioeconomic interactions for one of the most important risk factors for chronic diseases in older adults could help motivate new bridges to be built between biological and social scientists.