tbuckley/cabot-search huggingface dataset:
Therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severe<i>E. coli</i>pneumonia
Authors: Jeonghyun Park, Seonguk Kim, Hyungsun Lim, Airan Liu, Shuling Hu, JaeHoon Lee, Hanjing Zhuo, Qi Hao, Michael A Matthay, Jae-W Lee
Journal: Thorax (2018)

Background We previously reported that microvesicles (MVs) released by human mesenchymal stem cells (MSC) were as effective as the cells themselves in both Escherichia coli lipopolysaccharide and live bacteria-induced acute lung injury (ALI) mice models. However, it remained unclear whether the biological effect of MSC MV can be applied to human ALI. Methods In the current study, we tested the therapeutic effects of MSC MVs in a well-established ex vivo perfused human model of bacterial pneumonia. Using human donor lungs not used for transplantation, we instilled E. coli bacteria intrabronchially and, 1 hour later, administered MSC MVs into the perfusate as therapy. Results After 6 hours, instillation of E. coli bacteria caused influx of inflammatory cells, which resulted in significant inflammation, lung protein permeability and pulmonary oedema formation. Administration of MSC MV significantly increased alveolar fluid clearance and reduced protein permeability and numerically lowered the bacterial load in the injured alveolus. The beneficial effect on bacterial killing was more pronounced with pretreatment of MSCs with a Toll-like receptor 3 agonist, polyinosinic:polycytidylic acid (Poly (I:C)), prior to the isolation of MVs. Isolated human alveolar macrophages had increased antimicrobial activity with MSC MV treatment in vitro as well. Although oxygenation and lung compliance levels were similar between injury and treatment groups, administration of MSC MVs numerically decreased median pulmonary artery pressure at 6 hours. Conclusions In summary, MSC MVs increased alveolar fluid clearance and reduced lung protein permeability, and pretreatment with Poly (I:C) enhanced the antimicrobial activity of MVs in an ex vivo perfused human lung with severe bacteria pneumonia.
Abstract 2418: PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis
Authors: Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M. Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu
Journal: Cancer Research (2018)

Abstract Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions Citation Format: Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M. Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu. PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis [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 2418.
Abstract 11322: Detection of Subclinical Left Ventricular Systolic Dysfunction by Real-Time 3D Speckle Tracking Echocardiography in Patients With Myocardial Bridge of Left Anterior Descending Coronary Artery
Authors: Jing PingSun, DianWang, Xing ShengYang, Alex Pui-WaiLee, GengshanMa, Nai FengLiu, Cheuk-ManYu
Journal: Circulation (2014)

Background: To understand the impact of myocardial bridge (MB) on left ventricle (LV) function, we evaluate the myocardial function in patients with MB of the left anterior descending coronary artery (LAD), using real-time 3-dimensional speckle tracking echocardiography (RT3D-STE). Methods: The LAD MB was diagnosed by coronary angiography in 82 patients. According to the percentage of systolic compression (SC), patients were divided into 3 groups: SC  75% as Group III (n=30). Thirty age and gender matched normal subjects were studied as controls. The traditional echocardiography was performed, and LV deformation was estimated by RT3D-STE. Results: The LV ejection fraction was normal in patients with LAD MB. However, the peak longitudinal (LS) and area strain (AS) of the LAD territory were significantly reduced in Group II and III when compared with controls and Group I (p<0.05). The peak circumferential (CS) and radial strain (RS) were ...
Abstract 3913: Selective targeting of circulating tumor cells with agonistic EphA2 ligand
Authors: Ahmed F. Salem, Si Wang, Sandrine Billet, Jie-Fu Chen, Parima Udompholkul, Luca Gambini, Carlo Baggio, Edwin M. Posadas, Neil A. Bhowmick, Maurizio Pellecchia
Journal: Cancer Research (2018)

Abstract EphA2 is a tyrosine kinase receptor that is overexpressed in many cancer types like pancreatic, colon and breast cancers. Targeting cancer cells with an EphA2-targeting molecule conjugated with cytotoxic agents can spare normal cells from chemotherapy side effects. Here, we developed (123B9)2, a novel, potent ligand for the EphA2 receptor that binds to EphA2 ligand-binding domain and causes receptor activation at a sub micromolar concentration as evident in biochemical and cell-based assays. Furthermore, our molecule showed enhanced resistance to degradation, making it suitable for in vivo studies. Subsequently, we conjugated (123B9)2 with paclitaxel, a mitotic spindle inhibitor, and administered it in nude mice bearing breast cancer cells MDA-MD-231 in mammary glands. Remarkably, (123B9)2 paclitaxel-conjugate showed significant inhibition of breast cancer circulating tumor cells (CTC)s in orthotropic mice compared to paclitaxel alone. Finally, we are planning to use our molecule as a single agent to target cancer cells. Citation Format: Ahmed F. Salem, Si Wang, Sandrine Billet, Jie-Fu Chen, Parima Udompholkul, Luca Gambini, Carlo Baggio, Edwin M. Posadas, Neil A. Bhowmick, Maurizio Pellecchia. Selective targeting of circulating tumor cells with agonistic EphA2 ligand [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 3913.
Abstract 4180: Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis
Authors: Nicolás Anselmino, Paula Chiarella, Emiliano G. Ortiz, Daiana B. Leonardi, Felipe M. Jaworski, Sofia Lage Vikers, Jimena Giudice, Anna Woloszynska-Read, Roberto P. Meiss, Raul Rugiero, Geraldine Gueron, Elba S. Vazquez
Journal: Cancer Research (2018)

Abstract An abrupt increase in metastatic growth as a consequence of the removal of primary tumors suggests that the concomitant resistance (CR) phenomenon might occur in human cancer. CR occurs in murine tumors and ROS-damaged phenylalanine, meta-tyrosine (m-Tyr), was proposed as the serum anti-tumor factor primarily responsible for CR. Herein, we demonstrate for the first time that CR happens in different experimental human solid tumors (prostate, lung anaplastic, and nasopharyngeal carcinoma). Moreover, m-Tyr was detected in the serum of mice bearing prostate cancer (PCa) xenografts. Primary tumor growth was inhibited in animals injected with m-Tyr. Further, the CR phenomenon was reversed when secondary implants were injected into mice with phenylalanine (Phe), a protective amino acid highly present in primary tumors. PCa cells exposed to m-Tyr in vitro showed reduced cell viability, downregulated NFκB/STAT3/Notch axis, and induced autophagy; effects reversed by Phe. Strikingly, m-Tyr administration also impaired both, spontaneous metastasis derived from murine mammary carcinomas (4T1, C7HI, and LMM3) and PCa experimental metastases. Altogether, our findings propose m-Tyr delivery as a novel approach to boost the therapeutic efficacy of the current treatment for metastasis preventing the escape from tumor dormancy. Citation Format: Nicolás Anselmino, Paula Chiarella, Emiliano G. Ortiz, Daiana B. Leonardi, Felipe M. Jaworski, Sofia Lage Vikers, Jimena Giudice, Anna Woloszynska-Read, Roberto P. Meiss, Raul Rugiero, Geraldine Gueron, Elba S. Vazquez. Game-changing restraint of Ros-damaged phenylalanine, upon tumor metastasis [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 4180.
Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction
Authors: OrianneHenri, ChrisPouehe, MahmoudHoussari, LudovicGalas, LionelNicol, FlorenceEdwards-Lévy, Jean-PaulHenry, AnaisDumesnil, InèsBoukhalfa, SébastienBanquet, DamienSchapman, ChristianThuillez, VincentRichard, PaulMulder, EbbaBrakenhielm
Journal: Circulation (2016)

Background—The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. Methods and Results—We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, le...
Localization of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Human Coronary Arteries
Authors: AtsuyukiNakata, Jun-ichiroMiyagawa, ShizuyaYamashita, MakotoNishida, RitsuTamura, KatsumiYamamori, TadashiNakamura, ShuichiNozaki, KaoruKameda-Takemura, SumioKawata, NaoyukiTaniguchi, ShigekiHigashiyama, YujiMatsuzawa
Journal: Circulation (1996)

Background Heparin-binding epidermal growth factor (EGF)–like growth factor (HB-EGF) is a newly identified member of the EGF family. Our previous in vitro studies showed that HB-EGF is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs), suggesting the role of HB-EGF in the pathogenesis of atherosclerosis. The purposes of the present study were to investigate the localization of HB-EGF in both normal and atherosclerotic human coronary arteries and to elucidate the possible roles of this growth factor in the formation of atherosclerotic lesions. Methods and Results The immunohistochemical localization of HB-EGF, SMCs, macrophages, and EGF receptors (EGFRs) was examined in human coronary arteries obtained at autopsy. The medial SMCs of coronary arteries in neonates, infants, and children consistently synthesized HB-EGF protein. In normal adults, however, the relative number of HB-EGF–positive medial SMCs decreased gradually with age after about 30 years of age. In nonatherosclerotic...
Ca2+ as a Mediator of Ischemic Preconditioning
Authors: HiroshiMiyawaki, MuhammadAshraf
Journal: Circulation Research (1997)

Abstract We tested the hypothesis that elevation of [Ca2+]i during ischemic preconditioning (IPC) stimulates protein kinase C (PKC), which confers the protection against the ischemic injury. Langendorff-perfused rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion (I/R). In preconditioned groups, hearts were subjected to either IPC, consisting of 5-minute global ischemia and 10-minute reperfusion, or high-Ca2+ preconditioning (HCPC), ie, the 5-minute perfusion of higher Ca2+ perfusate (2.3 mmol/L Ca2+) followed by 10-minute perfusion of normal perfusate (1.8 mmol/L Ca2+), and then were subjected to I/R. A significant functional recovery and decreased lactate dehydrogenase release were observed in HCPC and IPC hearts compared with ischemic control hearts. ATP contents of preconditioned hearts were significantly higher than those of the ischemic control hearts. The cell structure in preconditioned hearts was preserved better than that in the ischemic control hearts. Furth...
Abstract 1922: Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma
Authors: Etsuko Yokota, Tomoki Yamatsuji, Munenori Takaoka, Minoru Haisa, Nagio Takigawa, Noriko Miyake, Tomoko Ikeda, Tomoaki Mori, Ohno Serika, Takashi Sera, Takuya Fukazawa, Yoshio Naomoto
Journal: Cancer Research (2018)

Abstract S0X2 is a transcription factor essential for early mammalian development and for the maintenance of stem cells. Recently, SOX2 was identified as a lineage specific oncogene, recurrently amplified and activated in lung and esophageal squamous cell carcinoma (SCC). In this study, we have developed a zinc finger-based artificial transcription factor (ATF) to selectively suppress SOX2 expression in cancer cells and termed the system ATF/SOX2. We engineered the ATF using six zinc finger arrays designed to target a 19 bp site in the SOX2 distal promoter and a KOX transcriptional repressor domain. A recombinant adenoviral vector Ad- ATF/SOX2 that expresses ATF/SOX2 suppressed SOX2 at the mRNA and protein levels in lung and esophageal SCC cells expressing SOX2. In these kinds of cells, Ad-ATF/SOX2 decreased cell proliferation and colony formation more effectively than the recombinant adenoviral vector Ad-shSOX2, which expresses SOX2 short hairpin RNA (shSOX2). Ad-ATF/SOX2 induced the cell cycle inhibitor CDKN1A more strongly than Ad-shSOX2. Importantly, the ATF did not suppress the cell viability of normal human cells. Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model. These results indicate that ATF/SOX2 would lead to the development of an effective molecular-targeted therapy for lung and esophageal SCC. Citation Format: Etsuko Yokota, Tomoki Yamatsuji, Munenori Takaoka, Minoru Haisa, Nagio Takigawa, Noriko Miyake, Tomoko Ikeda, Tomoaki Mori, Ohno Serika, Takashi Sera, Takuya Fukazawa, Yoshio Naomoto. Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell 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 1922.
Congenital Aneurysm of the Right Sinus of Valsalva, Diagnosed by Aortography
Authors: Waltherfalholt, Gregersthomsen
Journal: Circulation (1953)

This paper contains a brief review of the cases, published earlier, of aneurysms of the sinuses of Valsalva, and a case is reported in which the diagnosis was made before rupture of the aneurysm by means of thoracic aortography. No reports are to be found in the literature of the diagnosis of unruptured aortic sinus aneurysms and of the associated clinical findings. Roentgenograms, aortograms and catheterization findings are included.
Abstract 215: Reconstructing the Barrett's-dysplasia-adenocarcinoma sequence from patient-matched stem cells
Authors: Wa Xian, Yanting Zhang, Marcin Duleba, Shan Wang, Frank McKeon
Journal: Cancer Research (2018)

Abstract Introduction: Both esophageal and gastric adenocarcinoma (EAC; GAC) evolve from intestinal metaplasia (Barrett's and gastric IM, respectively) in a multi-decade and multi-step process involving transitions through low- and high-grade dysplasia often referred to as the “Correa Sequence”. In early stage EAC, each of these lesions can be seen co-existing in the 2-D topology of the distal esophagus. We have adapted methods we originally developed for cloning normal stem cells of the gastrointestinal tract to capturing stem cells of each of these lesions. We anticipate that a clonal analysis of these stem cells will reveal key steps in the evolution of highly lethal EAC. Methods: Libraries of stem cell clones were generated from a series of patient-specific endoscopic biopsies derived from normal, Barrett's, dysplasia, and EAC. Single cell-derived clones were analyzed by in vitro differentiation, whole genome expression analysis, and SNP-based copy number variation. Results: Highly undifferentiated, ground state stem cells were cloned from multiple endoscopic biopsies of patients with early EAC. Based on sampling site and adjacent biopsy histology, tissue corresponding to normal esophagus, gastric epithelia, Barrett's, and EAC were taken in these biopsies dissociated for stem cell cloning. All the clones derived showed unlimited proliferative potential and the ability to differentiate to normal or diseased epithelia in vitro. Thus the normal esophageal and gastric stem cells gave rise to squamous and gastric epithelia, the Barrett's stem cells yielded intestinal metaplasia, and dysplastic and EAC clones yielded highly proliferative and disordered epithelia marked by a loss of cell polarity. In contrast to the germline genotypes of the normal stem cells, those from Barrett's, dysplasia, and EAC sustained increasingly large numbers of copy number variation events, single nucleotide variations, and chromosomal aneuploidies. Significantly, all single cell-derived clones of EAC yielded “intestinal” adenocarcinoma following xenografting to immunodeficient mice. We are presently exploiting the genomic alterations present in hundreds of sample clones from each patient to reconstruct the evolutionary events that accompanied the progression to a highly lethal cancer. Conclusions: Stem cells from all stages of lesions along to the path to epithelial cancers can be cloned and independently propagated to yield insights into the evolution of cancer. In addition, these cloned cells should enable insights into intratumor heterogeneity, therapy resistance, and drug discovery. Citation Format: Wa Xian, Yanting Zhang, Marcin Duleba, Shan Wang, Frank McKeon. Reconstructing the Barrett's-dysplasia-adenocarcinoma sequence from patient-matched stem 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 215.
Abstract 5120: Adipocyte-derived lipids mediate melanoma progression via FATP proteins
Authors: Maomao Zhang
Journal: Cancer Research (2018)

Abstract During melanoma progression, tumor cells come into direct contact with subcutaneous tissues and these advanced lesions portend a poor prognosis. Despite the fact that subcutaneous tissues are largely composed of adipocytes, little is known about the mechanisms by which adipocytes influence melanoma. Using both in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. This is accompanied by direct transfer of fatty acids from adipocytes to melanoma cells, which increases tumor cell metabolism and invasion programs. These adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six related FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAFV600E in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. These data demonstrate that adipocytes in the tumor microenvironment can drive melanoma progression through FATP lipid transporters, and represents a new target aimed at interrupting adipocyte-melanoma crosstalk. Citation Format: Maomao Zhang. Adipocyte-derived lipids mediate melanoma progression via FATP proteins [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 5120.
Abstract 2494: A novel tool for monitoring endogenous progesterone receptor expression by mCherry using CRISPR-Cas9 genome editing technique
Authors: Yiyang Li, Xiangbing Meng, Kuo-kuang Wen, Meng Wu, Adam Dupuy, Kimberly Leslie, Shujie Yang
Journal: Cancer Research (2018)

Abstract Expression of progesterone receptor (PR) is a favorable prognostic marker for multiple solid tumors. However, PR expression is reduced or lost in malignant tumors which hinders response to progesterone therapy. Thus, monitoring and restoring functional PR expression is of utmost importance to sensitize progesterone therapy in endometrial cancer. We developed a stable cell line expressing the endogenous PR gene tagged a reporter gene (Hygromycin and mCherry) with CRISPR/Cas9-mediated genome editing. This allows efficient monitoring of PR expression in its native epigenetic landscape. The reporter gene expression faithfully reflects and amplifies PR expression following treatment with histone deacetylase inhibitor, romidepsin. This reporter gene transfected cells were successfully used to screen the FDA-approved 1018 library by high throughput screening in searching of potential novel drugs that increase PR expression. This strategy provides an efficient drug screening tool that can be used to screen novel PR inducers in multiple cancer cell lines. Citation Format: Yiyang Li, Xiangbing Meng, Kuo-kuang Wen, Meng Wu, Adam Dupuy, Kimberly Leslie, Shujie Yang. A novel tool for monitoring endogenous progesterone receptor expression by mCherry using CRISPR-Cas9 genome editing technique [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 2494.