tbuckley/cabot-search huggingface dataset:
Abstract 4063: Target immunosuppressive myeloid cells to enhance cancer immunotherapy
Authors: Xin Lu
Journal: Cancer Research (2018)

Abstract A significant fraction of advanced prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade (ICB) using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/ programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to ICB, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumor immune evasion. Circulating MDSC abundance correlates with PSA levels and metastasis in PCa patients. Mouse models of PCa show that MDSCs (CD11b+ Gr1+) promote tumor initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of ICB agents together with targeted agents that neutralize MDSCs yet preserve T cell function. Here we developed a novel chimeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and dactolisib, also showed minimal anti-tumor activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when ICB was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of IL-1ra and suppression of MDSC-promoting cytokines secreted by PCa cells. These observations illuminate a clinical path hypothesis for combining ICB with MDSC-targeted therapies in the treatment of mCRPC. More recently, through mass spectrometry we uncovered a new mechanism by which MDSCs employ potent reactive nitrogen species (RNS) to inactivate key molecules in the T cell activation signaling pathway. Agents that neutralize RNS generate significant anti-tumor effect when combined with ICB in prostate cancer. Citation Format: Xin Lu. Target immunosuppressive myeloid cells to enhance cancer immunotherapy [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 4063.
Abstract 323: Dronedarone Impairs Cardiac Mitochondrial Oxidative Phosphorylation in Dose-Dependent Manner
Authors: LarisaEmelyanova, SirishaGudlawar, FarhanRizvi, EkhsonHolmuhamedov, MonikaThakur, MahekMirza, ArshadJahangir
Journal: Circulation Research (2014)

Introduction: Dronedarone (DR), a new antiarrhythmic drug, was recently shown to worsen heart failure (HF) and mortality in patients with atrial fibrillation and left ventricular dysfunction. However, the mechanism underlying the adverse effect is not known. Since, myocardium depends on mitochondrial oxidative phosphorylation (OXPHOS), we hypothesized that DR impairs mitochondrial function, which could further compropmise energetic reserves predisposing to worsening of HF and death in patients with HF. Methods: Mitochondria isolated from rat heart (2 month old, SD) were treated with DR (1, 5, 10, 20, 50 μM), and the effect on oxygen consumption rate (OCR) in State 3 (St 3, ADP stimulated), State 4 (St 4o, oligomycin) and following FCCP addition were determined using Seahorse XF24 Analyzer in the presence of glutamate/malate (complex I substrates) and succinate/rotenone (complex II substrate). Results: DR dose dependently reduced St 3 respiration both in the presence of complex I (Fig). In the presence of ...
Endothelin-Converting Enzyme Expression in the Rat Vascular Injury Model and Human Coronary Atherosclerosis
Authors: TohruMinamino, HirokiKurihara, MasaakiTakahashi, KoheiShimada, KojiMaemura, HideakiOda, TakatoshiIshikawa, TakashiUchiyama, KazuhikoTanzawa, YoshioYazaki
Journal: Circulation (1997)

Background Endothelin 1 has been implicated in various human diseases, including atherosclerosis. In this study, we examined the expression and localization of endothelin-converting enzyme-1 (ECE-1), the final key enzyme of endothelin 1 processing, in rat carotid arteries after balloon injury and in human coronary atherosclerotic lesions. Methods and Results ECE-1 mRNA levels and ECE activity in rat balloon-injured arteries started to increase between 2 and 5 days after injury. The endothelin 1 content of tissue in injured arteries was concomitantly increased. Immunohistochemical staining located ECE-1 signals in endothelial cells in uninjured arteries, whereas ECE-1 immunoreactivity was detected in neointimal smooth muscle cells in injured arteries 5 to 14 days after balloon denudation. The size of the neointima was effectively reduced by phosphoramidon, an inhibitor of neutral metalloproteases, including ECE-1. In human coronary atherosclerotic lesions, intense ECE-1 immunoreactivity was detected in sub...
Abstract 43: Association of Severe Hypoglycemia With Cardiovascular Disease and All-cause Mortality in Older Adults With Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Alexandra K Lee, Bethany Warren, Clare J Lee, Elbert S Huang, A. Richey Sharrett, Josef Coresh, Elizabeth Selvin
Journal: Circulation (2017)

Introduction: There is concern that the strong association of severe hypoglycemia with cardiovascular disease (CVD) and all-cause mortality is confounded by diabetes severity or may not be causal and simply reflects general vulnerability. Our objective was to determine if the association of hypoglycemia with CVD and death withstood rigorous adjustment for likely confounders that prior studies have not adequately accounted for. Methods: We included ARIC participants aged 65+ at Visit 4 (1996-1998) with diagnosed diabetes and CMS Part B insurance. Severe hypoglycemia was identified through 2013 with ICD-9 codes from hospitalizations, emergency department visits, and ambulance services. CVD events (coronary heart disease, stroke, or heart failure) and death were assessed through 2013. Hypoglycemia was a time-varying exposure in progressively adjusted Cox models that included demographics, clinical characteristics, comorbidities, cognitive function, and activities of daily living and instrumental activities of daily living. Results: Of the 464 eligible participants, hypoglycemic events occurred in 65 participants prior to CVD or censoring and in 94 participants prior to death or censoring. The crude incidence rates of CVD and death were higher in persons with hypoglycemia compared to those without (CVD: 10.6 vs. 5.08 per 100 person-years (PY), p&lt;0.001; death: 14.3 vs. 4.5 per 100 PY, p&lt;0.001). After adjustment for age, sex, and race-center, hypoglycemia was strongly associated with both CVD and death ( Figure ). After additional adjustment for confounders, the hazard ratios (HR) for hypoglycemia were substantially attenuated but remained significant (CVD HR: 1.61 (95%CI 1.06-2.46); death HR: 1.83 (95%CI 1.35-2.84)). Conclusion: After adjustment for rigorously measured shared risk factors, hypoglycemia was associated with both CVD and death. These results suggest that severe hypoglycemia may influence CVD risk and death independently of diabetes severity and general vulnerability.
Abscopal effect of radiotherapy combined with immune checkpoint inhibitors
Authors: Yang Liu, Yinping Dong, Li Kong, Fang Shi, Hui Zhu, Jinming Yu
Journal: Journal of Hematology & Oncology (2018)

Radiotherapy (RT) is used routinely as a standard treatment for more than 50% of patients with malignant tumors. The abscopal effect induced by local RT, which is considered as a systemic anti-tumor immune response, reflects the regression of non-irradiated metastatic lesions at a distance from the primary site of irradiation. Since the application of immunotherapy, especially with immune checkpoint inhibitors, can enhance the systemic anti-tumor response of RT, the combination of RT and immunotherapy has drawn extensive attention by oncologists and cancer researchers. Nevertheless, the exact underlying mechanism of the abscopal effect remains unclear. In general, we speculate that the immune mechanism of RT is responsible for, or at least associated with, this effect. In this review, we discuss the anti-tumor effect of RT and immune checkpoint blockade and discuss some published studies on the abscopal effect for this type of combination therapy. In addition, we also evaluate the most appropriate time window for the combination of RT and immune checkpoint blockade, as well as the optimal dose and fractionation of RT in the context of the combined treatment. Finally, the most significant purpose of this review is to identify the potential predictors of the abscopal effect to help identify the most appropriate patients who would most likely benefit from the combination treatment modality.
Personalized cancer neoantigen vaccines come of age
Authors: Yanhong Chu, Qin Liu, Jia Wei, Baorui Liu
Journal: Theranostics (2018)

Cancer vaccines have encountered their ideal personalized partner along with evidence for great breakthroughs in the identification and synthesis of neoantigens.Individual cancer neoantigen vaccines are capable of eliciting robust T-cell responses and have been demonstrated to achieve striking clinical efficacy due to their high immunogenicity and central thymic tolerance escape of neoantigens.Two recent phase I clinical trials have provided support for the hypothesis and have heralded a nascent era of personalized vaccines in the field of immunotherapy.This review aims to address the identification of neoepitopes and describes advances made in personalized vaccines.In addition, this review discusses the challenges related to the exploitation of vaccine therapy, and provides potential thoughts for the improvement of vaccine design and applications.
Effects of Barium Chloride on Resting and Action Potentials of Ventricular Fibers of the Frog
Authors: Morriskleinfeld, Edwardstein, Stanleymeyers
Journal: Circulation Research (1954)

By means of an intracellular capillary electrode the effects of barium chloride on the resting and action potentials of ventricular fibers of the frog were recorded in hearts with circulation intact and hearts isolated and perfused. The changes were essentially similar in both preparations. The major change observed was a statistically significant (p <0.01) increase in duration of the action potential. Changes were also observed in the magnitude of the resting and action potential, in the rate of depolarization, and in rhythm, but these did not occur invariably. By a series of exclusion experiments it was demonstrated that barium has a direct effect on the ventricular fibers of the frog's heart.
SP0067 To taper or not to taper biological dmard
Authors: B. Fautrel
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Remission is more and more achievable in the course of rheumatoid arthritis (RA) or spondyloarthritis (SpA). Tapering strategies have been proposed to reduce the risk of overtreatment of patients with inactive disease. They have been tested in several observational or randomised controled trials. On this basis, EULAR guidelines recommend to consider careful DMARD tapering in people with sustained remission. The lecture will develop the potential benefits and risks of a tapering strategy for people affected by RA or SpA, in remission thanks to biologic agents. It will also highlight the residual unmet needs for the care of RA or SpA patients in remission. <h3>Disclosure of Interest</h3> None declared
Abstract 2587: Imbalances in the disposition of estrogen and naphthalene in Taiwanese breast cancer patients
Authors: Po-Hsiung Lin, Dar-Ren Chen, Wei-Chung Hsieh, Mao-Huei Ko, Yi-Lun Liao
Journal: Cancer Research (2018)

Abstract The aims of this study were to measure the background level of quinone metabolites of 17β-estradiol (E2), including E2-2,3-Q and E2-3,4-Q, and naphthalene quinone (1,2-NPQ and 1,4-NPQ)-derived protein adducts in human albumin (Alb) derived from breast cancer patients (n=143) and healthy controls (n=122) in Taiwanese women and to explore the relationships between these adducts with risk factors of breast cancer. Results from the analysis indicated that Alb adducts of estrogen quinones, including E2-2,3-Q-4-S-Alb and E2-3,4-Q-2-S-Alb were detected in all subjects with mean levels at 400 and 676 pmole/g in cancer patients and 204 and 67 pmole/g in controls, respectively. In addition, the mean levels of Alb adducts of 1,2-NPQ and 1,4-NPQ on human serum albumin were estimated to be 209 and 73.6 pmole/g in cancer patients and 113 and 174 pmole/g in controls, respectively. Levels of E2-2,3-Q-4-S-Alb correlated significantly with those of E2-3,4-Q-2-S-Alb. Similarly, levels of 1,4-NPQ-Alb correlated significantly with those of 1,2-NPQ-Alb. Additionally, we noticed that E2-2,3-Q-4-S-Alb and E2-3,4-Q-2-S-Alb positively correlated with 1,4-NPQ-Alb (p&amp;lt;0.001) whereas levels of E2-2,3-Q-4-S-Alb associated with 1,2-NPQ-Alb (p&amp;lt;0.01). Furthermore, we observed that ratio of E2-3,4-Q-2-S-Alb to E2-2,3-Q-4-S-Alb in breast cancer patients were ~5 fold greater than those of healthy controls whereas ratio of 1,2-NPQ-Alb to 1,4-NPQ-Alb in cancer patients were ~4 fold greater than those of healthy controls. This evidence suggests that the cumulative body burden of estrogen quinones is a significant indicator of the risk of developing breast cancer and that breast cancer risk is associated with the imbalances in the disposition of estrogen and naphthalene in Taiwanese women. Citation Format: Po-Hsiung Lin, Dar-Ren Chen, Wei-Chung Hsieh, Mao-Huei Ko, Yi-Lun Liao. Imbalances in the disposition of estrogen and naphthalene in Taiwanese breast 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 2587.
Life cycle environmental emissions and health damages from the Canadian healthcare system: An economic-environmental-epidemiological analysis
Authors: Matthew J. Eckelman, Jodi D. Sherman, Andrea J. MacNeill
Journal: PLoS Medicine (2018)

Human health is dependent upon environmental health. Air pollution is a leading cause of morbidity and mortality globally, and climate change has been identified as the single greatest public health threat of the 21st century. As a large, resource-intensive sector of the Canadian economy, healthcare itself contributes to pollutant emissions, both directly from facility and vehicle emissions and indirectly through the purchase of emissions-intensive goods and services. Together these are termed life cycle emissions. Here, we estimate the extent of healthcare-associated life cycle emissions as well as the public health damages they cause.We use a linked economic-environmental-epidemiological modeling framework to quantify pollutant emissions and their implications for public health, based on Canadian national healthcare expenditures over the period 2009-2015. Expenditures gathered by the Canadian Institute for Health Information (CIHI) are matched to sectors in a national environmentally extended input-output (EEIO) model to estimate emissions of greenhouse gases (GHGs) and >300 other pollutants. Damages to human health are then calculated using the IMPACT2002+ life cycle impact assessment model, considering uncertainty in the damage factors used. On a life cycle basis, Canada's healthcare system was responsible for 33 million tonnes of carbon dioxide equivalents (CO2e), or 4.6% of the national total, as well as >200,000 tonnes of other pollutants. We link these emissions to a median estimate of 23,000 disability-adjusted life years (DALYs) lost annually from direct exposures to hazardous pollutants and from environmental changes caused by pollution, with an uncertainty range of 4,500-610,000 DALYs lost annually. A limitation of this national-level study is the use of aggregated data and multiple modeling steps to link healthcare expenditures to emissions to health damages. While informative on a national level, the applicability of these findings to guide decision-making at individual institutions is limited. Uncertainties related to national economic and environmental accounts, model representativeness, and classification of healthcare expenditures are discussed.Our results for GHG emissions corroborate similar estimates for the United Kingdom, Australia, and the United States, with emissions from hospitals and pharmaceuticals being the most significant expenditure categories. Non-GHG emissions are responsible for the majority of health damages, predominantly related to particulate matter (PM). This work can guide efforts by Canadian healthcare professionals toward more sustainable practices.
Abstract 5331: Repression of <i>TET</i> genes and enhancement of DNA methyltransferase activity are critical for induction of aberrant DNA methylation
Authors: Hideyuki Takeshima, Tohru Niwa, Harumi Yamada, Satoshi Yamashita, Mika Wakabayashi, Toshikazu Ushijima
Journal: Cancer Research (2018)

Abstract Chronic inflammation is deeply involved in the development of human cancers by inducing epigenetic alterations, such as aberrant DNA methylation. Among various inflammatory cytokines, the expression of Il1b, Tnf, and Nos2, is associated with induction of aberrant DNA methylation. However, the molecular mechanisms by which these cytokines induce aberrant DNA methylation remain unclear. Here, we show that the activation of the NF-kB signaling pathway, downstream of IL-1β and TNF-α, caused up-regulation of specific miRNAs, such as miR-20a, miR-26b, and miR-29c, and that these miRNAs caused repression of the Tet methylcytosine dioxygenases (Tet) genes, Tet1, Tet2, and Tet3. TET repression by overexpression of one of these miRNAs in cultured cells appeared to be insufficient for induction of aberrant DNA methylation as detected by an Infinium MethylationEPIC BeadChip array. However, triple knockout of TET genes induced strong DNA methylation at thousands of genomic loci. At the same time, exposure to nitric oxide, produced by Nos2, enhanced enzymatic activity of DNA methyltransferases (DNMTs). Treatment of cultured cells with nitric oxide induced weak DNA methylation at hundreds of genomic loci. These results show that both the repression of TET genes and enhancement of DNMT activity, induced by chronic inflammation, are critical for induction of aberrant DNA methylation. ''Vicious'' combination of such dysregulations might have a synergistic effect on induction of aberrant DNA methylation. Citation Format: Hideyuki Takeshima, Tohru Niwa, Harumi Yamada, Satoshi Yamashita, Mika Wakabayashi, Toshikazu Ushijima. Repression of TET genes and enhancement of DNA methyltransferase activity are critical for induction of aberrant DNA methylation [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 5331.
Abstract 15381: Nanoparticle-mediated Delivery of Pioglitazone Ameliorates Inflammation and Inhibits Atherosclerotic Plaque Rupture in Apolipoprotein-E Deficient Mice
Authors: Soichi Nakashiro, Tetsuya Matoba, Jun-ichiro Koga, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira
Journal: Circulation (2014)

Background: Monocytes/macrophages play major roles in atherosclerotic plaque destabilization and rupture. Although PPARγ agonist including pioglitazone enhances alternative activation of monocytes/...
Abstract 1393: JARID1 family inhibitor recovers sensitivity of drug-tolerant subpopulation in lung cancer cell lines
Authors: Shin Ariga, Ichiro Kinoshita, Junko Kikuchi, Yasushi Shimizu, Hirotoshi Dosaka-Akita
Journal: Cancer Research (2018)

Abstract Epigenetic alteration contributes to tumor initiation, progression and invasion. Epigenetic machinery has become a major focus for the new development of molecular targeted cancer therapeutics. H3K4 trimethylation (H3K4me3) is an epigenetic mark which exist surrounding the transcription start site and have been presumed to be associated with cancer stem like cells. JARID1 family is demethylase of H3K4me2/me3. Especially, JARID1a and JARID1b have been suggested to have oncogenic properties in several cancers, including lung cancer. Here we examined the effects of a JARID1 family inhibitor against human lung cancer cell lines. 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT) was screened from more than 15000 small molecules as a JARID1 family inhibitor by Sayegh et al. First, we confirmed that PBIT increased H3K4me3 levels in time-dependent and dose-dependent manners in non-small cell lung cancer cell lines. PBIT inhibited cell growth in a dose-dependent manner with the IC50 value of about 10 µM to 30 µM. Next, we detected drug-tolerant persisters (DTPs) from each cell line by exposing them to very high concentration of the drug that is effective to each of the cell lines (gefitinib 10µ for PC9, PC3 and HCC827; AZD9291 5µM for H1975; CDDP 100µM for H226; paclitaxel 500nM for H460, A549 and H1299). DTPs detected were less than 1% in each cell line after 9-day exposure. These small subpopulations showed increased expression of JARID1a and/or JARID1b. Likewise, side population cells, which are considered to contain cancer stem like cells, showed increased expression of JARID1a and decreased H3K4me3 levels. PBIT in combination with anticancer drugs reduced colony formation of DTPs from all cell lines whose DTPs formed colonies. The DTPs showed decreased H3K4me3 levels and increased expression of cancer stem cell marker Oct-4, while these changes were abrogated by subsequent PBIT treatment. These results indicate that PBIT, a JARID1 family inhibitor, recovers sensitivity of drug-resistant lung cancer cells. Citation Format: Shin Ariga, Ichiro Kinoshita, Junko Kikuchi, Yasushi Shimizu, Hirotoshi Dosaka-Akita. JARID1 family inhibitor recovers sensitivity of drug-tolerant subpopulation in lung cancer cell lines [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 1393.