tbuckley/cabot-search huggingface dataset:
ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration
Authors: Takuo Hirose, Alfredo Cabrera-Socorro, David Chitayat, Thomas Lemonnier, Olivier Féraud, Carmen Cifuentes-Diaz, Nicolas Gervasi, Cedric Mombereau, Tanay Ghosh, Loredana Stoica, Jeanne d’Arc Al Bacha, Hiroshi Yamada, Marcel A. Lauterbach, Marc Guillon, Kiriko Kaneko, Joy W. Norris, Komudi Siriwardena, Susan Blasér, Jérémie Teillon, Roberto Mendoza-Londono, Marion Russeau, Julien Hadoux, Sadayoshi Ito, Pierre Corvol, Maria G. Matheus, Kenton R. Holden, Kohji Takei, Valentina Emiliani, Annelise Bennaceur-Griscelli, Charles E. Schwartz, Genevieve Nguyen, Matthias Groszer
Journal: Journal of Clinical Investigation (2019)

Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.
Abstract 16203: Deletion of Foxp Repressors Induces Rapid-Onset Cardiomyopathy in Adult Mice
Authors: Yan Li, Ann Chokas, Jeffrey Brandimarto, Shanru Li, Xi Liu, Edward E Morrisey, Thomas P Cappola
Journal: Circulation (2011)

Transcriptomic studies in the human and murine heart have demonstrated that forkhead (FOX) binding motifs are enriched within the promoters of regulated heart failure genes, but a functional link between FOX repressors and adult heart failure has not been established. Here we demonstrate that disruption of Foxp signaling in the adult heart is sufficient to cause heart failure. Quantitative RT-PCR studies in isolated myocytes demonstrate that Foxp1 and Foxp4 are among the most highly expressed FOX transcription factors (TFs) in myocytes. As these TFs are known to repress transcription via formation of homo- and hetero-dimers, we used the MerCreMer system to delete both factors in the adult mouse heart. We created tamoxifen- inducible cardiac-specific knockout (KO) mice (alphaMHC-MerCreMer het /Foxp1 flox/flox /Foxp4 flox/flox ) and, to account for potential nonspecific Cre-mediated cardiotoxicity, we compared them to alphaMHC-MerCreMer het  controls. After treatment with intraperitoneal tamoxifen at ∼3 months of age, controls remained normal, but KO animals developed signs of heart failure and a profound cardiomyopathy characterized by a drop in ejection fraction (KO 27 % vs. control 55%; p
Inflamed phenotype of splenic marginal zone B-cell lymphomas with expression of PD-L1 by intratumoral monocytes/macrophages and dendritic cells
Authors: Christelle Vincent-Fabert, Isabelle Soubeyran, Valérie Velasco, Marie Parrens, Robin Jeannet, Emilie Lereclus, Nathalie Gachard, Jean Feuillard, Nathalie Faumont
Journal: Cellular and Molecular Immunology (2019)
LBP-08-The World’s Largest Hepatitis C Screening Program in Egypt
Authors: Wael Abdel-Razek, Mohamed Hassany, Dr Khaled Kabil, Islam Ammar, Hany Dabous, Wahed Doss, Manal Hamdy El-Sayed, yehia elshazly, Gamal Esmat, Imam WAKED, Magdi El-Serafy
Journal: Journal of Hepatology (2019)
Abstract 15853: Identification of Novel Sites Required for PCSK9 Autocatalytic Cleavage
Authors: Yongcheng Huang, Oksana Palyha, Jose Castro-Perez, Anita Lee, Xi Ai, Sookhee Ha, Michael Kavana, Anthony Ogawa, Yusheng Xiong, Haihong Zhou, Shirly Pinto
Journal: Circulation (2015)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that promotes degradation of cell surface LDL receptors (LDLRs). Decrease in circulating PCSK9 levels by monoclonal antibodies is correlated with improved lipid profiles in humans. In contrast to therapeutic antibodies, strategies to inhibit PCSK9 with a small molecule have proven to be challenging. Here we explored a potential strategy to decrease PCSK9 level by inhibiting its autocatalytic cleavage and subsequent secretion. We discovered a tool compound, which represents a highly reactive lactone series irreversible inhibitors, that can non-specifically bind to multiple sites on PCSK9 and prevent its autocatalytic cleavage and secretion. Mass spectrometry studies confirmed that serine residues 326 (S326) and 329 (S329) are the main binding sites. Structurally, S326 and S329 are far away from the PCSK9 autocatalytic cleavage site serine 386 (S386). Mutagenesis of S326/S329 reduced PCSK9 autocatalytic cleavage intracellularly. Through structural modeling, we identified additional residues serine 294 (S294) and asparagine 298 (N298) that interact with S326 and S329. Mutagenesis of S294 and N298 also reduced PCSK9 autocatalytic cleavage and secretion. In addition, by using the in-trans expression system of PCSK9, we determined that the effect of S326/S329 on PCSK9 secretion is not through their direct impact on PCSK9 autocatalytic cleavage. In conclusion, we have discovered a novel mechanism that regulates PCSK9 secretion, and we have determined the critical residues that are involved in this regulatory mechanism.
SAT-065-Shear wave elastography for skeletal muscle: A novel approach to insulin resistance in cirrhosis
Authors: Kazufumi Kobayashi, Hitoshi Maruyama, Soichiro Kiyono, Kengo Kanayama, Susumu Maruta, Takahiro Maeda, Hiroaki Kanzaki, Yuko Kusakabe, Tomoko Saito, Sadahisa Ogasawara, Eiichiro Suzuki, Yoshihiko Ooka, Akinobu Tawada, Tetsuhiro Chiba, Masato Nakamura, Shingo Nakamoto, Shin Yasui, Naoya Kato
Journal: Journal of Hepatology (2019)
Nexilin Is a New Component of Junctional Membrane Complexes Required for Cardiac T-Tubule Formation
Authors: Canzhao Liu, Simone Spinozzi, Jia-Yu Chen, Xi Fang, Wei Feng, Guy Perkins, Paola Cattaneo, Nuno Guimarães-Camboa, Nancy D. Dalton, Kirk L. Peterson, Tongbin Wu, Kunfu Ouyang, Xiang-Dong Fu, Sylvia M. Evans, Ju Chen
Journal: Circulation (2019)

Membrane contact sites are fundamental for transmission and translation of signals in multicellular organisms. The junctional membrane complexes in the cardiac dyads, where transverse (T) tubules are juxtaposed to the sarcoplasmic reticulum, are a prime example. T-tubule uncoupling and remodeling are well-known features of cardiac disease and heart failure. Even subtle alterations in the association between T-tubules and the junctional sarcoplasmic reticulum can cause serious cardiac disorders. NEXN (nexilin) has been identified as an actin-binding protein, and multiple mutations in the NEXN gene are associated with cardiac diseases, but the precise role of NEXN in heart function and disease is still unknown.
Cardio-Oncology Rehabilitation to Manage Cardiovascular Outcomes in Cancer Patients and Survivors: A Scientific Statement From the American Heart Association
Authors: Susan C. Gilchrist, Ana Barac, Philip A. Ades, Catherine M. Alfano, Barry A. Franklin, Lee W. Jones, Andre La Gerche, Jennifer A. Ligibel, Gabriel Lopez, Kushal Madan, Kevin C. Oeffinger, Jeannine Salamone, Jessica M. Scott, Ray W. Squires, Randal J. Thomas, Diane J. Treat-Jacobson, Janet S. Wright
Journal: Circulation (2019)

Cardiovascular disease is a competing cause of death in patients with cancer with early-stage disease. This elevated cardiovascular disease risk is thought to derive from both the direct effects of cancer therapies and the accumulation of risk factors such as hypertension, weight gain, cigarette smoking, and loss of cardiorespiratory fitness. Effective and viable strategies are needed to mitigate cardiovascular disease risk in this population; a multimodal model such as cardiac rehabilitation may be a potential solution. This statement from the American Heart Association provides an overview of the existing knowledge and rationale for the use of cardiac rehabilitation to provide structured exercise and ancillary services to cancer patients and survivors. This document introduces the concept of cardio-oncology rehabilitation, which includes identification of patients with cancer at high risk for cardiac dysfunction and a description of the cardiac rehabilitation infrastructure needed to address the unique exposures and complications related to cancer care. In this statement, we also discuss the need for future research to fully implement a multimodal model of cardiac rehabilitation for patients with cancer and to determine whether reimbursement of these services is clinically warranted.
FRI-180-JNJ-64530440, a novel capsid assembly modulator: single- and multiple-ascending dose safety, tolerability and pharmacokinetics in healthy volunteers
Authors: Thomas Kakuda, Jeysen Yogaratnam, Christopher Westland, Edward Gane, Christian Schwabe, Megha Patel, Willem Talloen, Oliver Lenz, Pieter van Remoortere
Journal: Journal of Hepatology (2019)
Abstract 21405: Dynamic Enhancement Pattern is Different Between Unstable and Stable Coronary Plaque: Analysis With 320-Row Area Detector Computed Tomography
Authors: Tomoki Kameyama, Hiroyuki Ihori, Kazumasa Ohara, Makoto Nonomura, Hiroshi Inoue
Journal: Circulation (2017)

Introduction: Intraplaque neovascularization is a marker of unstable coronary plaque. We investigated a difference in dynamic enhancement pattern of coronary plaque between stable and unstable angina pectoris, using 320-row area detector computed tomography (CT), which enables whole-heart volumetric acquisition in a single gantry rotation. Hypothesis &amp; Methods: We analyzed 106 coronary plaque segments in 38 patients (mean age 69.8±8.3 years, 32 male) with angina pectoris (13 stable, 25 unstable) who underwent coronary CT and percutaneous coronary intervention (PCI). Coronary plaques were evaluated using 320-row area detector CT with and without contrast enhancement. Culprit plaques (PCI target) of unstable patients were defined as unstable plaque(n=35), whereas culprit plaques of stable patients and non-culprit plaque were defined as stable plaque(n=71). Coronary plaque without contrast enhancement, corresponding to the plaque detected by contrast enhanced CT, was identified using unique calcification as a landmark. The mean Hounsfield unit (HU) in the coronary plaque was measured, and the presence of positive vascular remodeling was evaluated. Coronary artery stenosis was quantified by coronary angiography. Results: Unstable patients were younger than stable patients (66.6±7.2 vs 76.1±6.7 years, p&lt;0.01). Positive vascular remodeling and spotty calcification was more frequently observed in unstable than stable patients (68.4% vs 15.4%, p&lt; 0.01 and 45.5% vs 86.4%, p&lt;0.05 respectively). Coronary artery stenosis was not different between the 2 groups. In CT without contrast enhancement, plaque HU was not different between the 2 groups (unstable: 25.0±32.4 vs stable: 24.9±33.1). With contrast enhancement, plaque HU was significantly elevated in both groups from those without contrast enhancement to 53.9±24.1 (unstable: p&lt;0.01) and to 42.6±33.5 (stable: p&lt;0.01). Unstable plaque showed higher enhancement (delta HU) than stable plaque (28.9±23.5 vs 17.7±25.5, p=0.024). Conclusions: Dynamic enhancement pattern is different between unstable and stable coronary plaque. Compared to stable plaque, unstable plaque shows higher contrast enhancement, suggesting the increased neovascularization in the plaque.
Isolated Thoracic Perfusion with Chemofiltration (ITP-F) for progressive and pre-treated malignant pleural mesothelioma.
Authors: Karl R. Aigner, Emir Selak, Andreas Sendler
Journal: Journal of Clinical Oncology (2015)

7556 Background: Treatment of patients (pts.) with progressive malignant pleural mesothelioma (MPM) after multimodal therapy remains a therapeutic challenge. Survival of the pts. is low and the treatment options are sparse. We report on a phase II study on isolated thoracic perfusion with subsequent chemofiltration as a locoregional therapeutic strategy in this situation. Methods: 21 pts. (19 male, 2 female, mean age 65.5 yrs.) with epitheliolid mesothelioma were included in this study after informed consent. 10 pts. had prior surgical resection, all pts. had adjuvant/additive therapy, general including cisplatin and pemetrexed. Following multimodal therapy all pts. demonstrated progress in CT scan. No pt. had abdominal, cerebral or bone metastases. After insertion of a venous and arterial 21 ch. stop flow catheter via a femoral access, the inferior caval vein was blocked distal the right atrium, the arterial catheter was blocked in the aorta at the diaphragm. Chemotherapy consisted of 60 mg/m2 cisplatinum and 15 mg/m2 mitoxantron q 3 weeks till progress. The agents were administered via the arterial access, followed by 15 min of thoracic perfusion followed by chemofiltration for 45 min. The procedure was done under general anesthesia. Endpoint of the study was overall survival. Median follow-up was 48 month. Results: A total of 107 cycles (mean 5) were administered. Toxicity was low with leucopenia and thrombocytopenia CTC grad I in 9 pts. and mucositis grad II in 6 pts.. Surgical complications CTC grad I occurred in 40 % of the pat. (lymphatic fistula). There was no gastrointestinal or neuro- toxicity. One year survival was 50% (Kaplan-Meier), 2 year survival was 37.5% and 3 year survival was 37.5%. Median survival was 12 months. Conclusions: Intraarterial, isolated thoracic perfusion with subsequent chemofiltration (ITP-F) for pretreated patients with MPM, which are progressive after multimodal therapy, is a valuable additional treatment option with low side effects. It offers in a palliative situation a reasonable survival with good quality of life.
FRI-449-Complex ATP7B mutation patterns in Wilson disease and a evaluation of a yeast model for functional analysis of the individual variant
Authors: Xiaojin Li, Wei Zhang, Donghu Zhou, Tingxia Lv, Anjian Xu, Hejing Wang, Xinyan Zhao, Bei Zhang, Yanmeng Li, Siyu Jia, Yu Wang, Xiaoming Wang, Zhen Wu, Weijia Duan, Qianyi Wang, Yuemin Nan, Jia Shang, Wei Jiang, Yongpeng Chen, sujun Zheng, Mei Liu, LiYing Sun, Hong You, Ji-Dong Jia, Xiaojuan Ou, Jian Huang
Journal: Journal of Hepatology (2019)
FRI-479-Hepatocellular carcinoma with extrahepatic metastasis: Are there still candidates for transarterial chemoembolization as an initial treatment?
Authors: Jihye Kim, Dong Hyun Sinn, Moon Seok CHOI, Wonseok Kang, Geum-Yon Gwak, Yong Han Paik, Joon Hyeok Lee, Kwang Cheol Koh, Seung Woon Paik, Byung Chul Yoo
Journal: Journal of Hepatology (2019)
THU-064-Identification of new epigenetic targets in hepatic fibrosis
Authors: Marina Bárcena-Varela, Hannah Paish, Laura Alvarez, Julen Oyarzabal, Felipe Prosper, Giuseppe Mazza, Krista Rombouts, Fiona Oakley, Jelena Mann, Carmen Berasain, Matías A Avila, Maite G Fernandez-Barrena
Journal: Journal of Hepatology (2019)
Anlotinib can overcome acquired resistance to EGFR-TKIs via FGFR1 signaling in non-small cell lung cancer
Authors: Z. Lian, W. Du, J. Zhu, Y. Zeng, Z. Liu, J.-A. Huang
Journal: Annals of Oncology (2019)

Background: As a novel multitarget receptor tyrosine kinase inhibitor, anlotinib has been demonstrated to be effective in inhibition of tumor angiogenesis and growth. Interestingly, a subset of advanced non-small cell lung cancer (NSCLC) patients who are refractory to EGFR-TKIs are sensitive to anlotinib treatment, the underlying molecular mechanism remained unclear. Herein, we mainly focus on elucidating the regulatory mechanism treated with anlotinib in overcoming acquired resistance to EGFR-TKIs in NSCLC and thus may develop novel therapeutic strategies for anlotinib aiming at improving the prognosis of patients resistant to TKIs. Methods: High throughput sequencing analysis, western blot analysis, real-time quantitative reverse transcriptase PCR, RNA interference, CCK-8 and flow cytometry were performed on human NSCLC EGFR-resistant cell lines. Results: Based on high-throughput sequencing analysis, FGFR1 was highly expressed in gefitinib-resistant cell line when compared to HCC827. In line with the data, anlotinib application obviously inhibitied cell viability, proliferation and promoted apoptosis in HCC827GR cell line. Knockdown of FGFR1 can reverse gefitinib resistance. Research into possible mechanisms indicated that anlotinib treatment down-regulated the phosphorylation levels of Erk and Akt. Conclusions: Anlotinib can overcome acquired resistance to EGFR-TKIs via inhibiting FGFR1 signaling pathway, which provide a mechanism evidence for the treatment of NSCLC patients. Legal entity responsible for the study: The First Affiliated Hospital of Soochow University. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Kahalalide F antitumor activity depends on cell membrane levels of Scs7/FA2H-mediated sphingolipid hydroxylation
Authors: Ana Herrero, Enrique Alvarez, Sergio Moreno
Journal: Cancer Research (2007)

4829  Kahalalide F (KF) is a novel antitumor drug of marine origin that is being currently tested in phase II clinical trials in a variety of tumors. In vitro studies in prostate and breast cancer cells revealed that KF induced cell death by oncosis (Suarez et al. Mol Cancer Ther 2: 863-872, 2003), however, the mechanism of action of this small natural peptide remains mostly unknown. To provide some insight into the mode of action of KF in eukaryotic cells we have used the yeast Saccharomyces cerevisiae as a model system. Flow cytometry analysis revealed that KF permeabilizes S. cerevisiae cells to Propidium iodide (PI), indicating that it induces the formation of pores in the yeast cell membrane. KF-induced pore formation was found to be both rapid and concentration dependent. We have screened the complete set of approximately 5,000 viable S. cerevisiae haploid deletion mutants to identify genes that, when deleted, confer sensitivity or resistance to KF. Using this method we have identified scs7 mutants as the most resistant strain to the action of KF. Scs7 mutant cells were completely resistant to PI staining after treatment with KF, revealing that the drug is unable to form pores in this mutant cell membrane. In overexpression studies, high levels of Scs7 turn the cells sensitive to KF. KF-dependent pore formation was more efficient in cells overexpressing Scs7 than in wild-type cells. Scs7 is a sphingolipid alpha-hydroxylase homologue of the human FA2H protein, a fatty acid 2-hydroxylase, located in the ER, and it is involved in the formation of HFA (hydroxy fatty acid sphingolipids). The functional role of shingolipid hydroxylation is largely unknown, but it seems to affect membrane conformation. To test whether levels of FA2H protein also modulates sensitivity to KF in higher eukaryotes we overexpressed the human protein in COS1 monkey cells and analyzed sensitivity to the drug. We found that hFA2H overexpression leads to increased sensitivity to KF, as was also found in yeast. Currently we are evaluating whether hFA2H silencing will also lead to KF resistance in mammalian cells. Taken together our results suggest that the cell membrane, and particularly 2-hydroxy sphingolipids are targets for KF activity. These finding may have important implications in the development of KF as tumor cells with high FA2H expression are expected to be particularly sensitive to KF. Experiments to analyze levels of FA2H expression in tumors versus normal tissues are under way. If a correlation between FA2H levels and sensitivity to KF is established, FA2H could become a marker of KF activity and help guide patient selection.
FRI-344-Preclinical characterization of FM101, a first-in-class A3 adenosine receptor modulator for the treatment of non-alcoholic steatohepatitis
Authors: Changho Shon, Su-Yeon Choi, Jeong-Su Park, Chong-Woo Park, Jiyoun Lee, Yoon-Seok Roh
Journal: Journal of Hepatology (2019)
Value of post-radiotherapy for limited stage small cell lung cancer on basis of a prognostic scoring model
Authors: J. Yu, W. Ouyang, J. Hu, J. Zhang, C. Xie
Journal: Annals of Oncology (2019)

Background: Small cell lung carcinoma (SCLC) rarely underwent surgical treatment. The aim of the study was to investigate the value of postoperative radiotherapy for limited stage small cell lung cancer based on a prognostic scoring model. Methods: We searched the Surveillance, Epidemiology, and End Results (SEER) database for all cases of limited stage SCLC treated by surgical resection and chemotherapy between 2004-2014. A prognostic scoring model was built to evaluate the prognostic value of postoperative radiotherapy on the basis of a Cox proportional hazards model. Overall survival (OS) and cancer-specific survival (CSS) was compared in the different risk groups. Results:Table61P Multivariable analysis of the association between clinical variables and overall survival (n = 767)OSVariablesHR (95%CI)PAge (>65 vs ≤ 65 y)1.35 (1.17-1.57)<0.001Race (White vs non-white)1.18 (0.90-1.55)0.238Sex (Male vs Female)1.33 (1.15-1.54)<0.001Grade (Poor/ undifferentiated vs Well/Moderately/NOS0.99 (0.86-1.15)0.922Lymph Node Stage (N+ vs N-)1.36 (1.17-1.58)0.001T stage (T3/4 vs T1/2)1.31 (1.08-1.58)0.005Laterality (Left vs Right vs NOS)1.04 (0.91-1.19)0.55Primary lobe (Main bronchus vs Upper vs Middle vs Lower vs Overlapping lesion of lung or NOS)1.01 (0.94-1.09)0.717 Open table in a new tab A total of 767 patients were included in this study. The post-radiotherapy did not show significant benefit on 5-year OS (Surgery + postoperative radiotherapy vs Surgery alone, 20.5% vs. 19.6%; p = 0.298). Multivariate analysis determined that age, sex, T stage, lymph nodes status were independent prognostic factors for OS. A prognostic scoring system was developed by using these factors, with each factor scored as 1 point. The total score ≤ 1 was defined as low-risk group, while the score > 1 was identified as high-risk group. In the high-risk group, patients who received postoperative radiotherapy did not provide the significantly survival benefit, compared with the surgery alone (5-year OS, 14.1% vs. 12.6%, p = 0.085; 5-year CSS, 40.5% vs. 41.7%, p = 0.393). After propensity score matching, postoperative radiotherapy could significantly improve outcomes (5-year OS, Surgery + postoperative radiotherapy vs Surgery alone, 12.4% vs. 9.4%; p = 0.011; 5-year CSS, Surgery + postoperative radiotherapy vs Surgery alone, 38.9% vs. 30.9%; p = 0.03). The corresponding survival benefit that was not showed in the low-risk group. Conclusions: On the basis of the prognostic scoring model, postoperative-radiotherapy in addition to surgery provides better outcomes than surgery alone for limited stage SCLC in high risk group. Prospective studies are needed to validate these results. Legal entity responsible for the study: Jing Yu. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Abstract 12949: Elamipretide (BendaviaTM) Restores 4-Hydroxy-2-Nonenal Protein Adducts and Aldehyde Dehydrogenase-2 Activity and mRNA Expression in Left Ventricular Myocardium of Dogs With Advanced Heart Failure
Authors: Ramesh C Gupta, Vinita Singh-Gupta, Kefei Zhang, Jiang Xu, Hani N Sabbah
Journal: Circulation (2016)

Background: 4-hydroxy-2-nonenal (4HNE), a reactive aldehyde, is generated in the failing heart and contributes to cardiomyocyte injury and death. Aldehyde dehydrogenase-2 (ALDH2) plays a key role i...
TCTAP C-150 Anterior ST-Elevation Myocardial Infarction in Dengue Shock Syndrome and Platelet of 10,000
Authors: Supawat Ratanapo, Viroj Muangsillapsart, Thipakorn Phangmiangdee, Tanyarat Aramsareewong, Nakarin Sansanayudh, Chumpol Piamsomboon
Journal: Journal of the American College of Cardiology (2019)