tbuckley/cabot-search huggingface dataset:
Abstract 5458: Antiproliferative activity of a novel 8-hydroxyquinoline ruthenium II complex against human breast cancer cell lines
Authors: Amr M. Khalifa, Ahmed S. Sultan
Journal: Cancer Research (2018)

Abstract Ruthenium (Ru) complexes are recognized as the most perspective chemotherapeutic agents available, because of their low general toxicity and variety of modes of action. Ru(II)-based complexes show a higher tendency for ligand exchange reactions and therefore interact with target molecules more rapidly and there cytotoxicity often correlates with the DNA binding ability. The present study was aimed to test the anti-tumor effect of a new formulated ruthenium (II) complex Bis(quinolin-8-olato)bis(triphenylphosphine)ruthenium(II) complex (Ru(quin)2) that was prepared by reaction of the precursor RuCl2(PPh3)3 with Quinolin-8-ol on two human breast cancer cell lines, estrogen receptor-positive (ER+), T-47D, and MDA-MB-231, triple negative breast cancer cell line that display different phenotypic and differentiation patterns ranging from poor to high differentiation. The two tested breast cancer cells showed a significant growth inhibition after 24 h of treatment, but the response of T47D cells to treatment was much higher than that of MDA-MB231 cells. In contrast, the near-normal mammary cell lines, MCF-10A, showed no response to Ru(quin)2 at higher doses. In tested cells, Ru(quin)2 significantly inhibited cells proliferation after 24 h treatment as evaluated by MTT assay, cell morphology alteration, and clonogenic assay. In addition, treated cells showed significant morphological and biochemical signs of apoptosis induction through releasing of histone protein, caspase-3 activation, and G2/M phase cell cycle arrest in a dose-dependent manner compared to control. In T47D cells, Ru(quin)2 significantly downregulated protein expression of STAT3, and S6 kinase1 (S6K1) and significantly upregulated LC3B expression protein, a hallmark of autophagosomes formation, after 24 h of treatment as detected by western blot analysis and immunocytochemistry. Furthermore, in established xenograft tumor model of MDA-MB231 cells in nude mice, the growth of MDA-MB231 tumors that treated with Ru(quin)2 was inhibited by 46.88% compared to the mock group (t=2.821, P&amp;lt;0.05) after three weeks of treatment. Besides, there was no cytotoxicity on both liver and kidney function tests. Collectively, our observations support the anticancer role of the novel Ru(II)- macrocyclic complex that might be through apoptosis and autophagy induction in human breast cancer cell lines. Citation Format: Amr M. Khalifa, Ahmed S. Sultan. Antiproliferative activity of a novel 8-hydroxyquinoline ruthenium II complex against human breast 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 5458.
Intracoronary Flecainide Induces ST Alternans and Reentrant Arrhythmia on Intact Canine Heart
Authors: HidetadaTachibana, MichiyasuYamaki, IsaoKubota, TetsuWatanabe, SouYamauchi, HitonobuTomoike
Journal: Circulation (1999)

Background—The electrical alternans shown on an ST segment, ST alternans, is known as one of the most important predictors of ventricular fibrillation (VF). It has also been reported that sodium channel inhibition changes action potential configuration, especially on the repolarization phase. Thus, the sodium channel blocker may produce ST alternans and trigger reentrant arrhythmia. Methods and Results—A sodium channel blocker (disopyramide, lidocaine, or flecainide) was infused selectively into the left anterior descending coronary artery in anesthetized, open-chest dogs. Sixty unipolar electrograms were simultaneously recorded from the entire cardiac surface of the heart. The amplitude of ST alternans (STa) was determined as the difference in the ST-segment magnitude between 2 consecutive electrograms. We accepted the greatest STa among 60 leads for evaluation. High-dose flecainide (100 μg · kg−1 · min−1) increased STa and evoked a spontaneous VF. The STa in high-dose flecainide loading (8.7±3.4 mV; mea...
Abstract 3148: p140Cap affects breast cancer features through the regulation of the tumor microenvironment composition
Authors: Vincenzo Salemme
Journal: Cancer Research (2018)

Abstract Increasing data indicate the key role of the tumor microenvironment in cancer progression, metastasis formation and treatment sensitivity, where the tumor stroma and the immune infiltrate strongly influence tumor features. Our recent studies indicate that the adaptor protein p140Cap is highly expressed in about 50% of ERBB2-amplified breast cancer patients. Its expression correlates with increased patient survival and decreased probability to develop metastasis. Causally, p140Cap negatively regulates breast tumor properties both in vitro and in the NeuT preclinical mouse model. In this study, we observed an indirect influence of p140Cap-expression on tumor immune infiltrate composition of a syngeneic ERBB2+ breast cancer model. p140Cap tumor cells and tumors show reduced level of G-CSF mRNA and protein. Accordingly, we observed a reduced mobilization of G-CSF-dependent myeloid-derived suppressor cells (MDSCs- CD11b+Ly6G+Ly6Clo) from bone marrow and a decreased level of MDSCs in tumor, blood and spleen of mice orthotopically injected with p140Cap tumor cells, compared to controls. This “less” immune suppressive microenvironment associated to p140Cap-expression, was also confirmed by an increase in CD8+, M1 macrophages and Natural Killer lymphocytes concomitant with a decrease in M2 macrophages and FoxP3 regulatory T cells. Interestingly, the expression of p140Cap in cells and tumors significantly reduce the fraction of cancer stem cells and their sphere and tumor initiation frequency, by modulating their proliferative potential. Since that the tumor initiating cell exhibit an enhanced G-CSF production, these data suggest that p140Cap, by regulating the cancer stem cell compartment, limits ERBB2 tumor aggressiveness by creating a tumor microenvironment less favorable to tumor progression. Citation Format: Vincenzo Salemme. p140Cap affects breast cancer features through the regulation of the tumor microenvironment composition [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 3148.
Abstract 5503: Loss of MED12 induces tumor dormancy in human ovarian cancer
Authors: Xiao-Lin Luo, Cheng-Cheng Deng, Ji-Hong Liu, Li-Wu Fu
Journal: Cancer Research (2018)

Abstract Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological malignancies due to high rate of disease relapse. Disease relapse in cancer patients after clinical remission are often referred to tumor dormancy. Here we identify MED12 as an important molecular regulator of tumor dormancy. We found that MED12 knock-out could induce dormancy of EOC cells in vitro and in vivo. Mechanistically, microarray analysis showed that MED12 knock-out decreased the expression of EGFR. Restoration of EGFR expression in MED12 knock-out cells restored the proliferation ability. Additionally, we found that MED12 could bind to the promoter of EGFR, and correlation studies showed that MED12 expression positively correlated with the level of EGFR. Clinical data demonstrated that chemotherapy-resistant patients showed a lower expression of MED12. In conclusion, MED12 plays an important role in regulating dormancy of EOC through regulation of EGFR. Citation Format: Xiao-Lin Luo, Cheng-Cheng Deng, Ji-Hong Liu, Li-Wu Fu. Loss of MED12 induces tumor dormancy in human ovarian cancer [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 5503.
Lactate Improves Prediction of Short‐Term Mortality in Critically Ill Patients With Cirrhosis: A Multinational Study
Authors: Andreas Drolz, Thomas Horvatits, Karoline Rutter, Felix Landahl, Kevin Roedl, Philippe Meersseman, Alexander Wilmer, Johannes Kluwe, Ansgar W. Lohse, Stefan Kluge, Michael Trauner, Valentin Fuhrmann
Journal: Hepatology (2018)

Lactate levels and lactate clearance are known predictors of outcome in critically ill patients in the intensive care unit (ICU). The prognostic value of lactate is not well established in liver cirrhosis and acute-on-chronic liver failure (ACLF). The aim of this study was to assess the prognostic value of lactate levels and clearance in critically ill patients with cirrhosis. Patients with cirrhosis admitted to the ICU were studied at the University Medical Center Hamburg-Eppendorf (n = 566, derivation cohort) and the Medical University of Vienna and the University Hospitals Leuven (n = 250, validation cohort). Arterial lactate was measured on admission and during the first 24 hours. Patients were followed for 1 year and outcome was assessed. Admission lactate was directly related to the number of organs failing and to 28-day mortality (area under receiver operating characteristic [AUROC] 0.72; P < 0.001). This also applied to lactate follow-up measurements after 6, 12, and 24 hours (P < 0.001 for all, AUROC > 0.70 for all). Lactate clearance had significant predictive ability for 28-day mortality in patients with elevated serum lactate ≥5 mmol/L. Admission lactate and 12-hour lactate clearance (in patients with admission lactate ≥5 mmol/L), respectively, were identified as significant predictors of 1-year mortality, independent of Chronic Liver Failure Consortium acute-on-chronic liver failure score (CLIF-C ACLFs). A lactate-adjusted CLIF-C ACLFs was developed (CLIF-C ACLFsLact ), which performed significantly better than the original CLIF-C ACLFs in prediction of 28-day mortality in the derivation and validation cohort. Conclusion: Lactate levels appropriately reflect severity of disease and organ failure and were independently associated with short-term mortality in critically ill patients with liver cirrhosis. Lactate is a simple but accurate prognostic marker, and its incorporation improved performance of CLIF-C ACLFs significantly.
Chest Compression–Only Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest With Public-Access Defibrillation
Authors: TakuIwami, TetsuhisaKitamura, TakashiKawamura, HideoMitamura, KenNagao, MorimasaTakayama, YoshihikoSeino, HideharuTanaka, HiroshiNonogi, NaohiroYonemoto, TakeshiKimura
Journal: Circulation (2012)

Background—It remains unclear which is more effective to increase survival after out-of-hospital cardiac arrest in those with public-access defibrillation, bystander-initiated chest compression–only cardiopulmonary resuscitation (CPR) or conventional CPR with rescue breathing. Methods and Results—A nationwide, prospective, population-based observational study covering the whole population of Japan and involving consecutive out-of-hospital cardiac arrest patients with resuscitation attempts has been conducted since 2005. We enrolled all out-of-hospital cardiac arrests of presumed cardiac origin that were witnessed and received shocks with public-access automated external defibrillation (AEDs) by bystanders from January 1, 2005, to December 31, 2009. The main outcome measure was neurologically favorable 1-month survival. We compared outcomes by type of bystander-initiated CPR (chest compression–only CPR and conventional CPR with compressions and rescue breathing). Multivariable logistic regression was used ...
Abstract 2256: Efficient large-scale cell classification and analysis for MultiOmyxTMassays: A deep learning approach
Authors: Mate L. Nagy, Arezoo Hanifi, Ahalya Tirupsur, Geoffrey Wong, Jun Fang, Nicholas Hoe, Qingyan Au, Raghav K. Padmanabhan
Journal: Cancer Research (2018)

Abstract Traditional immunohistochemistry (IHC) techniques utilize one slide per biomarker. When clinical samples are precious and the number of serial sections is limited, comprehensive biomarker profiling becomes difficult with IHC. MultiOmyx is a proprietary, multiplexing methodology capable of staining up to 60 biomarkers on the same slide. The output of the assay enables quantitative profiling of tissues at a single cell level. The assay generates data for millions of cells with billions of queryable data points. To detect and classify cells efficiently at this large scale, we developed an image analysis framework using Deep Learning. Our framework consists of seven major steps: (1) manual annotation of a small subset of the nuclear staining channel (DAPI); (2) training of a fully convolutional neural network [1] on this annotation-set to generate a feature map identifying cell centers; (3) application of the trained network in (2) on the nuclear stain (DAPI) of the entire dataset to delineate individual cells; (4) manual annotation of a small subset of each of the other biomarker channels; (5) training of a convolutional neural network on these annotation-sets for binary classification of each of the biomarkers; (6) application of these classifiers to the entire dataset; (7) combination of the binary classification results to identify phenotypes of interest. For our output, we provide both visual label maps and classification summary tables for individual and co-localized biomarkers at the region of interest level and the entire slide level. In addition, combining the phenotype and location information allows us to visualize complex spatial relationships in the tissue. The benefits of using this Deep Learning framework are greatly felt through increased time efficiency without a loss in accuracy, when compared to more traditional computer vision methods requiring high levels of parameter fine-tuning. For future work, we plan on fully automating the approach as more manual annotation-sets are generated. Citation Format: Mate L. Nagy, Arezoo Hanifi, Ahalya Tirupsur, Geoffrey Wong, Jun Fang, Nicholas Hoe, Qingyan Au, Raghav K. Padmanabhan. Efficient large-scale cell classification and analysis for MultiOmyxTMassays: A deep learning approach [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 2256.
β-catenin oncogenic activation rewires fatty acid catabolism to fuel hepatocellular carcinoma
Authors: Alexandra Montagner, Laurent Le Cam, Hervé Guillou
Journal: Gut (2018)

Liver cancer is a major public health issue and generally considered an inflammation-related cancer developing in response to genotoxic exposure or in patients with viral, alcoholic or non-alcoholic hepatitis. It is a leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) representing 90% of primary liver cancer cases. Various pathways are dysregulated in HCC, including p53 and other cell cycle regulators, chromatin modifiers, oxidative stress, insulin and growth factor signalling, and Wnt/β-catenin signalling. In this issue, Senni and colleagues1 demonstrate the role of fatty acid oxidation as a source of energy in the metabolic adaptation triggered by β-catenin oncogenic activation in hepatocytes. This work describes an atypical cancer cell addiction to fatty acids and represents an important discovery that may pave the way for novel therapeutics.

The Wnt/β-catenin pathway2 plays a key role in many aspects of hepatic homeostasis, including the regulation of unique liver features, such as metabolic zonation.3 In the absence of Wnt stimulation, the cytosolic concentration of β-catenin remains low because a multiprotein complex that includes the tumour suppressor adenomatous polyposis coli ( APC ) promotes the phosphorylation of β-catenin, and thereby its proteasomal degradation. In response to Wnt stimulation, the degradation complex is recruited to the plasma membrane, which leads to β-catenin stabilisation, …
How do we stop people smoking at the front doors of our hospitals?
Authors: Scott McGlynn, Paul McClymont, Chris Isles
Journal: BMJ (2018)

Over a million smokers are treated in UK hospitals each year and a small proportion of them feel compelled to smoke when they are admitted or visit. The image of smokers—in wheelchairs, with dripstands and catheter bags—congregating in front of our hospitals is all too familiar for those of us who walk past them as we come to work. 

We recognise that smoking in the open air isn’t a threat to anyone else’s health, but it nevertheless gives the wrong impression of hospitals as promoters of a healthy lifestyle. When our new hospital in Dumfries opened last year we were worried that smokers would soon congregate around the front entrance.

A British Thoracic Society (BTS) audit in 2016 of 14 750 patients across 146 hospitals in the …
Widening of the Excitable Gap and Enlargement of the Core of Reentry During Atrial Fibrillation With a Pure Sodium Channel Blocker in Canine Atria
Authors: AyakaKawase, TakanoriIkeda, KazuoNakazawa, TakashiAshihara, TsunetoyoNamba, TetsuyaKubota, KaoruSugi, HironoriHirai
Journal: Circulation (2003)

Background— This study aimed to assess the effects of pilsicainide, a pure sodium channel blocker, on electrophysiological action and wavefront dynamics during atrial fibrillation (AF). Methods and Results— In a newly developed model of isolated, perfused, and superfused canine atria (n=12), the right and left endocardia were mapped simultaneously by use of a computerized mapping system. AF was induced with 1 to 5 μmol/L acetylcholine. The antifibrillatory actions of pilsicainide on AF cycle length (AFCL), refractory period (RP), conduction velocity (CV), excitable gap (EG), and the core of the mother rotor were studied. The RP was defined as the shortest coupling interval that could capture the fibrillating atrium. The EG was estimated as the difference between the AFCL and RP. At baseline, multiple wavefronts were observed. After 2.5 μg/mL infusion of pilsicainide, all preparations showed irregular activity, and AF was terminated in 2 preparations. The AFCL and RP were prolonged, and CV was decreased si...
Abstract 19372: Role of TRP Channels in Mechanical Stimulation Responses of Coronary Pericytes
Authors: Eugene Cilento, Zhiping Cao, Jeffrey Iliff, Nabil Alkayed, Sanjiv Kaul
Journal: Circulation (2016)

Pericytes are contractile cells which have been implicated in control of the microcirculation. It is not clear, however, if pericytes sense mechanical forces, and which mechanisms are involved. We performed global gene expression analysis using RNAseq in primary cultured myocardial pericytes, and found multiple mechanosensor candidates previously demonstrated to mediate mechanotransduction in vascular smooth muscle cells, including transient receptor potential (TRP) channels TRPM4 and TRPM7. In vascular smooth muscle cells, TRP channels have been implicated in the regulation of vascular tone. Therefore, we hypothesized that TRP channels play a role in the pericyte response to mechanical stimulation. Using qPCR and immunoblotting, we further confirmed expression in these cells. Immunocytochemistry of TRPM7 revealed membrane localization, while TRPM4 showed predominantly perinuclear localization. To simulate mechanical stimulation by compressive force, weight (1g/cm2) was placed atop glass coverslip-covered...
Abstract 4803: CXCR6-directed therapeutic approach potentiates efficacy of docetaxel in prostate cancer
Authors: Neeraj Kapur, Hina Mir, Guru Sonpavde, James W. Lillard, Shailesh Singh
Journal: Cancer Research (2018)

Abstract Development of chemo-resistance negatively impacts therapeutic outcome of advanced prostate cancer (PCa). Molecular mechanism used by cancer cells to overcome therapeutic effect is still undefined. Here, we demonstrate the influence of CXCR6/CXCL16 mediated molecular signals on the efficacy of docetaxel (DTX). Out data showed poor DTX efficacy on PCa cells (LNCaP, PC3, and DU145) after stimulating CXCR6 with soluble CXCL16, while significant improvement in cytotoxic effect of DTX was observed after CXCR6 blockade using anti-CXCR6 monoclonal antibody. Interestingly, CXCR6, CXCL16, and ADAM-10, a metalloproteinase involved in CXCL16 cleavage from PCa cell membranes, were significantly elevated in response to DTX treatment. This was further confirmed on xenograft tumor by immunohistochemistry. Further, phospho-proteomic profiling and western blot analysis showed activation of pro-survival molecules: GSK-3β, NFκB, ERK/1/2, and survivin following soluble CXCL16 treatment. Activation of CXCR6-CXCL16 axis also inhibited expression of the epithelial marker (E-cadherin) while increased expression of mesenchymal markers (β-catenin, α-SMA, vimentin, snail), which highlights the role of CXCR6 in promoting mesenchymal phenotype that is known to have a significant impact on cancer progression and therapeutic outcome. Thus, our study shows that CXCR6-CXCL16 signaling instigates chemotherapeutic resistance by increasing pro-survival signaling and promoting mesenchymal phenotype. Hence, combining CXCR6 blockade with DTX would be a better treatment option for advanced, drug-resistant PCa. Citation Format: Neeraj Kapur, Hina Mir, Guru Sonpavde, James W. Lillard, Shailesh Singh. CXCR6-directed therapeutic approach potentiates efficacy of docetaxel in prostate cancer [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 4803.
Heritable Pulmonary Arterial Hypertension With Elevated Pulmonary Wedge Pressure
Authors: FranckDigne, Jean-LouisSablayrolles, DavidMontani, ThierryLaperche, JulietteRousseau, PhilippeGuyon, VictorStratiev, ThierryRoyer, DavidAttias
Journal: Circulation (2012)