tbuckley/cabot-search huggingface dataset:
Abstract 901: Antibody-mediated blockade of annexin A3 (ANXA3) synergistically enhances the efficacy of sorafenib and regorafenib for hepatocellular carcinoma
Authors: Man Tong, Noelia Che, Lei Zhou, Phillis W. Kau, Steve T. Luk, Xin Chen, Jin Ding, Terence K. Lee, Stephanie Ma
Journal: Cancer Research (2018)

Abstract Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only FDA approved first-line targeted drug for advanced HCC, but its effect on patients' survival gain is limited and patients ultimately present disease progression. Molecular mechanism underlying acquired resistance are still far from being well understood. A better understanding of causes of sorafenib resistance, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCC. In this study, we uncovered a role of annexin A3 (ANXA3) in conferring ability of HCC cells to resist sorafenib. ANXA3 was found highly enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Mechanistically, we found overexpression of ANXA3 in sorafenib-resistant HCC cells to suppress PKCδ/p38 associated apoptosis and activate autophagy for cell survival. ANXA3 expression correlated positively with LC3B, an indicator of autophagy induction, in HCC specimens and was associated with a worst overall survival in HCC patients who went on to receive sorafenib treatment. Anti-ANXA3 therapy, alone or combined with sorafenib and regorafenib, the standard of care for advanced HCC, impaired tumor growth in vivo and significantly increased survival. In sum, we found anti-ANXA3 therapy to exhibit abilities to reduce tumor growth and sensitize HCC cells to sorafenib and regorafenib treatment via suppressing autophagy and activating apoptosis. Inhibition of ANXA3 would benefit a subset of patients after sorafenib progression. ANXA3 can also serve as a useful predictive biomarker for patient response to sorafenib treatment. Citation Format: Man Tong, Noelia Che, Lei Zhou, Phillis W. Kau, Steve T. Luk, Xin Chen, Jin Ding, Terence K. Lee, Stephanie Ma. Antibody-mediated blockade of annexin A3 (ANXA3) synergistically enhances the efficacy of sorafenib and regorafenib for hepatocellular carcinoma [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 901.
Kinetics of the Inhibitory Effect of Pepstatin on the Reaction of Hog Renin with Rat Plasma Substrate
Authors: Helmutorth, Eberhardhackenthal, Jeffreylazar, Ulrikemiksche, Franzgross
Journal: Circulation Research (1974)

The reaction between hog renin and rat angiotensinogen followed Michaelis-Menten kinetics. A Km value of 1,109 ng angiotensin/ml was determined for the rate of angiotensin formation at pH 7.4 and 37°C. The pH optimum for the reaction of hog renin with rat angiotensinogen was between 6.8 and 7.0. Pepstatin inhibited the reaction in a noncompetitive way. The maximum inhibitory effect occurred at approximately pH 6; at values above pH 8.0, pepstatin had no inhibitory effect. The effect of pepstatin was reversible, since renin activity could be restored by 24 hours of dialysis against distilled water. A 50% inhibition of the enzymatic activity of 0.01 dog units of hog renin was obtained with 0.45 µg pepstatin/ml.
Characterization of Right Ventricular Diastolic Performance After Complete Repair of Tetralogy of Fallot
Authors: SeamusCullen, DarrylShore, AndrewRedington
Journal: Circulation (1995)

Background Prolonged postoperative recovery caused by a low cardiac output state occurs in some patients after complete repair of tetralogy of Fallot. Biventricular systolic function is usually well preserved in these patients. The contribution of impaired diastolic function, particularly of the right ventricle, has not been studied in detail; therefore, we performed a prospective study of right ventricular diastolic function in this patient group. Methods and Results We studied biventricular systolic and diastolic function using Doppler echocardiographic examination. Tricuspid valve, superior vena caval, pulmonary arterial, and mitral valve Doppler spectrals were obtained during the first postoperative day in 35 patients aged 6 months to 45 years who underwent complete repair of tetralogy of Fallot. Biventricular systolic function was grossly normal in all patients. Isolated restrictive right ventricular physiology characterized by pulmonary arterial antegrade flow coincident with atrial systole and asso...
Abstract 566: High dimensional single cell analysis predicts response to anti-PD-1 immunotherapy
Authors: Carsten Krieg, Malgorzata Nowicka, Silvia Guglietta, Sabrina Schindler, Felix J. Hartmann, Lukas M. Weber, Reinhard Dummer, Mark D. Robinson, Mitchell P. Levesque, Burkhard Becher
Journal: Cancer Research (2018)

Abstract Checkpoint inhibition of programmed cell death protein 1 (PD-1) has revolutionized cancer therapy. As more and more patients with metastatic melanoma but also other cancers show a dramatic increase in progression-free survival, still a large proportion of patients do not show durable response. As options for monotherapies, as well as combination immunotherapies, increase in the clinics, predictive biomarkers of clinical response are urgently needed. We employed high-dimensional single cell mass cytometry and a machine-learning bioinformatics pipeline for the in-depth characterization of all immune cells in the peripheral blood of stage IV melanoma patients before and at 12 weeks of anti-PD-1 immunotherapy. We observed a clear treatment response of patients under immunotherapy. However, a strong predictor of progression free and overall survival in response to anti-PD-1 immunotherapy before therapy was the frequency of CD14+CD16-HLA-DRhi monocytes. We could confirm this by conventional flow cytometry in an independent, blinded validation cohort and propose this as a novel predictive biomarker for therapy decisions in the clinic. We further present a high dimensional analysis workflow to analyze predictive and prognostic immune biomarkers during future clinical trials. Citation Format: Carsten Krieg, Malgorzata Nowicka, Silvia Guglietta, Sabrina Schindler, Felix J. Hartmann, Lukas M. Weber, Reinhard Dummer, Mark D. Robinson, Mitchell P. Levesque, Burkhard Becher. High dimensional single cell analysis predicts response to anti-PD-1 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 566.
The Pharmacologic Action of Thevetoidin, a Cardioactive Substance Obtained from a Mexican Species of Thevetia
Authors: Rafaelméndez, Ernestosodi-Pallares, Armandonava
Journal: Circulation (1951)

Thevetoidin is a digitalis-like substance isolated from a Mexican species of thevetia. Study of its action on the isolated frog heart, on the anesthetized dog, and on the failing heart of the heart-lung preparation reveals therapeutic and toxic effects of unmistakable digitalis-like character which are quickly established and wear off rapidly. The dose for the treatment of cardiac disorders was deduced from experiments on the failing heart of the heart-lung preparation on the basis of a comparison with ouabain.
Abstract LB-115: Tumor intrinsic PD-1/PD-L1 signalling induces mesenchymal to epithelial transition in canine osteosarcoma cells
Authors: Maciej Parys, Marta Nekulová, Bořivoj Vojtěšek, Jakub Faktor, Ana Lima, Theodore Hupp
Journal: Cancer Research (2018)

Abstract Osteosarcoma (OS) is the most common primary tumor of the bone in both humans and dogs. The dog, with its spontaneously occurring OS, shared pathogenic pathways and active immune system is one of the best models for studying novel immunotherapeutic approaches to human OS. Checkpoint blockade using antibodies against PD-1 has revolutionized the current approach to treatment of melanoma and other cancers. Recent reports have also shown that tumor intrinsic signalling plays a potential role in the success of PD-1 blockade in melanoma although studies in OS have not been published to date. PD-1/PD-L1 signalling has been reported to have role in epithelial to mesenchymal transition. In this study, we wanted to characterize intrinsic PD-1 signalling in canine osteosarcoma. We have created a canine specific PD-1 monoclonal antibody and we identified that PD-1 is intrinsically expressed in the cell line tested- OSA31. To further characterize the effects of PD-1 expression in this cell line we cloned canine PD-1 into a pcDNA 3.1 expression vector and transfected the cell line. Transfection of the cell line with PD-1 resulted in phenotypic changes characteristic for mesenchymal to epithelial transition. Interestingly overexpression of PD-1 as well as blockade of this receptor using the created antibody, resulted in decrease in cellular proliferation. To our knowledge this is the first report to identify role of PD-1 in mesenchymal to epithelial transition. These findings also suggest that PD-1 may be a promising therapeutic target in canine OS and warrant future clinical trials. Citation Format: Maciej Parys, Marta Nekulová, Bořivoj Vojtěšek, Jakub Faktor, Ana Lima, Theodore Hupp. Tumor intrinsic PD-1/PD-L1 signalling induces mesenchymal to epithelial transition in canine osteosarcoma cells [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 LB-115.
Abstract 13951: Circulating Inactive Matrix Gla-protein, Warfarin Use and Large Artery Stiffness in Heart Failure With Reduced Ejection Fraction
Authors: Julio A Chirinos, Izzah Vassim, Swapna Varakantam, Timothy S Phan, Amer Ahmed Syed, Priyanka Bhattacharya, Melissa Beraun, Haideliza Soto-Calderon, Scott R Akers
Journal: Circulation (2016)

Background: large artery stiffness increases pulsatile afterload to the LV and is strongly predictive of adverse outcomes in heart failure and reduced ejection fraction (HFrEF). The identification of pathways related to arterial stiffness may provide novel therapeutic targets. Matrix Gla-protein (MGP) is a vitamin K-dependent protein that inhibits arterial calcification. Vitamin K deficiency leads to production of inactive non-phosphorylated and uncarboxylated MGP (dp-ucMGP). We hypothesized that greater levels of dp-ucMGP, indicating impaired MGP activation, are related to arterial stiffness in human HFrEF. Methods: We studied 50 subjects with HFrEF and 279 control subjects without HF. dp-ucMGP MGP was measured with ELISA (VitaK; The Netherlands). In a subgroup of subjects (34 with HFrEF and 146 with no HF), carotid-femoral PWV (a measure of large artery stiffness) was measured with arterial tonometry (Sphygmocor Device). Carotid-radial PWV, a measure of medium-sized muscular artery stiffness, was also measured. Results: Subjects with HFrEF demonstrated markedly increased levels of dp-ucMGP (654.7 vs. 426.8; P=0.004). Among subjects with HFrEF, warfarin use (standardized Beta 0.66; P&lt;0.0001) was the main predictor of dp-ucMGP. In turn, dp-ucMGP predicted carotid-femoral PWV (Beta=0.43; P=0.01) in HFrEF, even after adjustment for age, gender, mean arterial pressure and heart rate (Beta=0.43; P =0.007). In contrast, dp-ucMGP was not associated with carotid-radial PWV, a measure of muscular artery stiffness. Conclusions: HFrEF is associated with reduced levels of inactive dp-ucMGP, particularly in the setting of warfarin use. Circulating dp-ucMGP is independently associated with large artery stiffness in HFrEF, likely due to its role in vascular calcification. This suggests that deficient vitamin-K dependent activation of MGP may contribute to arterial stiffness in HFrEF and could be targeted with vitamin K supplementation and/or the use of anticoagulants other than warfarin. This hypothesis needs to be tested in future trials.
The Rate of Disappearance of Lanatoside C. and Digitoxin from the Blood of Rats
Authors: Renébine, Meyerfriedman, Catherinebland
Journal: Circulation (1950)

By means of the embryonic duck heart preparation, both lanatoside C. and digitoxin could be detected and quantitatively measured in the sera of rats after parenteral administration of both drugs. A study of the behavior of the two glycosides in blood indicated that a striking difference existed in the respective rates of disappearance of both drugs from the bloodstream.
Integrin-Targeted MicroSPECT-CT Imaging of Inflamed Atherosclerotic Plaques in Mice
Authors: David Vancraeynest, Véronique Roelants, François-Xavier Hanin, Stephan Walrand, Matthew Morrison, Agnes Pasquet, Bernhard Gerber, Vanesa Bol, Anne Bol, Caroline Bouzin, François Jamar, Jean-Louis Vanoverschelde
Journal: Circulation (2012)

Background and aim. αVβ3 integrin is expressed in endothelial cells and macrophages of atherosclerotic plaques and may represent a valuable marker of plaque vulnerability. To test this, we evaluated whether the integrin specific tracer 99mTc-NC100692 can be used for imaging inflamed atherosclerotic lesions in mice. Methods. Hyperlipidemic ApoE-/- mice on a Western diet (n=7) and normally fed adult C57BL6 control mice (n=4) were injected with NC100692 (51.8 ± 3.7 MBq). A blocking peptide was infused immediately before the tracer injection in 3 additional ApoE-/- mice that served as control. After 90 min, the animals were imaged with a µSPECT system, and immediately thereafter on a MDCT system to obtain contrast-enhanced images of the aorta. Images from both modalities were fused and the signal was quantified in the aortic arch and in the vena cava for blood pool activity substraction. The aorta was carefully dissected after imaging for gamma well counting and histology. Results. A significantly higher tracer uptake (defined as the counts/pixel ratio between the aortic arch and the vena cava) was observed between the ApoE-/- mice and 2 control mice groups (1.56 ± 0.33 vs 0.82 ± 0.24 (C57BL6) vs 0.98 ± 0.11 (blocking peptide) respectively; p<0.05, see graph). Furthermore, a significant tracer activity was observed by gamma counting in the aorta of ApoE-/- mice compared with 2 control mice groups (0.015 ± 0.004 vs 0.007 ± 0.006 µCi/mg of tissue; p<0.05). Finally, immunostaining with antibodies against integrin correlated well with the presence of macrophages into atherosclerotic lesions of ApoE-/- mice. Conclusion. NC100692 allows for the in vivo detection of inflamed atherosclerotic plaques in mice and may thus represent an interesting non invasive approach for identifying vulnerable plaques in patients.
Abstract 3585: T cell receptor-stabilized regenerated CD8ab cytotoxic T lymphocytes for cancer immunotherapy
Authors: Atsutaka Minagawa, Akitsu Hotta, Yohei Kawai, Yutaka Yasui, Yasushi Uemura, Masaki Yasukawa, Tetsuya Nakatsura, Shin Kaneko
Journal: Cancer Research (2018)

Abstract The use of antigen-specific T cell derived induced iPSCs as a cell source for regeneration of cytotoxic T lymphocytes (CTLs) have advantages in rejuvenation profile, and reproducible number of CTLs. However for the safe and efficient regenerated T cell immunotherapy, strict antigen specificity is essential. Here we report CD8αβ T cells differentiated from T cell-derived iPSCs underwent additional rearrangement of the T cell receptor (TCR) α-chain gene at the CD4/CD8 double positive stage during in vitro differentiation and lost antigen specificity. CRISPR knockout of a recombinase gene in the T-iPSCs successfully prevented this additional TCR rearrangement. Moreover, when CD8αβ T cells were differentiated from non-T cell-derived but antigen-specific TCR-transduced iPSCs, they showed monoclonal expression of the transduced TCR. TCR stabilized regenerated CD8αβ T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies. Citation Format: Atsutaka Minagawa, Akitsu Hotta, Yohei Kawai, Yutaka Yasui, Yasushi Uemura, Masaki Yasukawa, Tetsuya Nakatsura, Shin Kaneko. T cell receptor-stabilized regenerated CD8ab cytotoxic T lymphocytes for 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 3585.
Abstract 3626: A genome scale screen to identify regulators of PD-L1 in HNSCC
Authors: Jacqueline Mann, Megan Ludwig, Aditi Kulkarni, Judy Kafelghazal, Julia Eisenberg, Rebecca Hoesli, Alexey Nesvizhskii, Chad Brenner
Journal: Cancer Research (2018)

Abstract The immune checkpoint inhibitor Pembrolizumab was recently approved for the treatment of metastatic and recurrent HNSCC, but only 18% of patients in the initial trial responded to therapy, and it remains difficult to predict patients likely to experience benefit. We expect a broader understanding of checkpoint regulation in HNSCC to lead to improved response rates and identification of potential responders. To this end, we sought to identify targetable genetic factors modulating PD-L1, a molecule that serves to dampen the anti-tumor immune response. We developed a high throughput screen employing a Genome-scale CRISPR Knock-Out (GeCKO) library in HNSCC cell lines to identify targetable genes and pathways that may regulate PD-L1 expression. In UM-SCC-49, stable knockout pools with representation of approximately 300 gRNAs for each of over 20,000 target genes were expanded and serially sorted to create stable sub-populations with enhanced or diminished PD-L1 expression. These sub-populations were sequenced to identify gRNAs that increased or reduced PD-L1 expression, indicating that their genetic targets may function to regulate PD-L1. We observed 70% library coverage (44,900 gRNAs) in the initial population and 15% and 11% coverage in the sub-populations selected for high and low PD-L1 expression, respectively. We prioritized for validation 61 gRNAs that were enriched at least 2 fold in High or Low PDL1 pool over the control pool. Future experiments focus on validation of these targets in UM-SCC-49 and other cell lines. As we expand this screen and validate hits across multiple genetic backgrounds, we expect to reveal signaling networks promoting immune evasion and potential targets for combination immunotherapeutic protocols. Citation Format: Jacqueline Mann, Megan Ludwig, Aditi Kulkarni, Judy Kafelghazal, Julia Eisenberg, Rebecca Hoesli, Alexey Nesvizhskii, Chad Brenner. A genome scale screen to identify regulators of PD-L1 in HNSCC [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 3626.
Abstract 19146: Increasing Donor Age is a Risk Factor for Permanent Pacing After Orthotopic Heart Transplantation
Authors: FerdiAkca, TamasSzili-Torok, RahatMuslem, OlivierManintveld, AlinaConstantinescu, OzcanBirim, KadirCaliskan
Journal: Circulation (2014)

Introduction: Due to extreme scarcity of donor hearts in The Netherlands, increasingly older and marginal donor hearts are accepted for orthotopic heart transplantation (HTx). We evaluated the relationship between the age of the donor and the need for pacemaker (PM) implantation early or late after HTx. Methods: The demographic and clinical data of all consecutive patients transplanted between 1984 until 2014 at our center were analyzed (n=612, 74% male; median follow up of 97 months [IQR 38-161]). Three groups were created based on donor age: Group I (0-35 y, n=345), Group II (35-50 y, n=190) and Group III (>50 y, n=77). The primary outcome was permanent PM implantation after HTx for either sinus node dysfunction (SND) or AV block (AVD). The need for early (90 days) was evaluated. The following secondary parameters were analyzed: recipient age, ischemic time, and death. Results: The mean recipient age at HTx was 46.4 ± 14.3 years [range 2-72 y] and donor age 32.8 ± 13.7 y. Significant older donor hearts ...
Letter by Keidar and Gamliel-Lazarovich Regarding Article, “Effects of A Novel Aldosterone Synthase Inhibitor for Treatment of Primary Hypertension: Results of a Randomized, Double-Blind, Placebo- and Active-Controlled Phase 2 Trial”
Authors: ShlomoKeidar, AvivaGamliel-Lazarovich
Journal: Circulation (2012)
Abstract P170: Nicorandil Inhibits Gáq-Induced Chronic Heart Failure in Transgenic Mice
Authors: Masamichi Hirose, Yasuchika Takeishi, Hisashi Shimojo, Toshihide Kashihara, Tsutomu Nakada, Ulrike Mende, Mitsuhiko Yamada
Journal: Circulation Research (2011)

Introduction: Beneficial effects of nicorandil on the treatment of hypertensive heart failure (HF) and ischemic heart disease have been suggested. However, whether nicorandil has inhibitory effects on HF and ventricular arrhythmias caused by the activation of G protein alpha q (Gαq) -coupled receptor (GPCR) signaling pathway still remains unknown. We examined effects of chronic and acute administration of nicorandil on the development of HF and ventricular action potential (VAP) in transgenic mice with transient cardiac expression of activated Gαq (Gαq-TG), respectively. Method and Results: Nicorandil (6 mg/kg/day) or vehicle was chronically administered in Gαq-TG mice for 24 weeks from 8 weeks of age, and then ventricular function, and electrical and structural changes were investigated in the hearts. Chronic nicorandil administration improved the reduction of left ventricular fractional shortening (p &lt; 0.001) in Gαq-TG hearts. During 10 min of electrocardiogram recording, premature ventricular contractions (more than 20 beats/min) were observed in 7 of 10 vehicle-treated Gαq-TG but in none of 10 nicorandil-treated Gαq-TG hearts (p &lt; 0.01). QT interval was significantly shorter in nicorandil-treated Gαq-TG than in vehicle-treated Gαq-TG hearts (p &lt; 0.05). Chronic nicorandil administration improved the increased ventricular interstitial fibrosis (p &lt; 0.05) but not cardiac hypertrophy in Gαq-TG left ventricles. Real time RT-PCR revealed that mRNA expression levels of s sulfonylurea receptor 2B (SUR-2B) were decreased in vehicle-treatd Gαq-TG but not in nicorandil-treated Gαq-TG. In addition, chronic nicorandil increased endotherial nitric oxide syntheses gene expression in Gαq-TG hearts (p &lt; 0.05). Acute nicorandil administration (1 microM) significantly shortened the prolonged VAP duration and reduced the number of PVCs in vehicle treated Gαq-TG hearts. Conclusions: These findings suggest that nicorandil inhibits ventricular electrical and structural remodeling and arrhythmias through the shortening of VAP duration and the increased expression of SUR-2B and eNOS in a mouse model of HF.