tbuckley/cabot-search huggingface dataset:
Inhibition of Granulation Tissue Cell Apoptosis During the Subacute Stage of Myocardial Infarction Improves Cardiac Remodeling and Dysfunction at the Chronic Stage
Authors: KenjiHayakawa, GenzouTakemura, MotooKanoh, YiwenLi, MasahikoKoda, YukinoriKawase, RumiMaruyama, HideshiOkada, ShinyaMinatoguchi, TakakoFujiwara, HisayoshiFujiwara
Journal: Circulation (2003)

Background— Granulation tissue cells at the subacute stage of myocardial infarction (MI) are eliminated by apoptosis to finally make a scar at the chronic stage. We hypothesized that postinfarct inhibition of apoptosis might preserve myofibroblasts and endothelial cells in granulation and modulate chronic left ventricular (LV) remodeling and heart failure. Methods and Results— A pancaspase inhibitor, Boc-Asp-fmk (BAF, 10 μmol/kg per day), or vehicle (control) was given to rats with experimental large MI. The treatment was started on the third day after MI and continued until 4-week-old MI. Two weeks later, the apoptosis of granulation tissue cells was significantly reduced and conversely, the cell population was greater in BAF. Twelve weeks later, BAF showed significantly greater survival rates (84% versus 42%) with significantly smaller LV cavity, lower LV end-diastolic pressure and central venous pressure, and higher LV dP/dt, which indicated improvement of LV remodeling and dysfunction. A scar was esta...
Extracellular Matrix Components HAPLN1, Lumican, and Collagen I Cause Hyaluronic Acid-Dependent Folding of the Developing Human Neocortex
Authors: Katherine R. Long, Ben Newland, Marta Florio, Nereo Kalebic, Barbara Langen, Anna Kolterer, Pauline Wimberger, Wieland B. Huttner
Journal: Neuron (2018)
Abstract 17547: Syncope and Inferior ST Elevations: A Diagnosis Within the Heart
Authors: Neal A Chatterjee, Johannes K Steiner, James R Stone, Gregory D Lewis, Stephanie A Moore, James L Jannuzzi
Journal: Circulation (2015)

A 53 year old woman with a history of diabetes and hypertension presented with syncope, hypotension, and electrocardiography demonstrating inferior ST elevations. The week prior to admission she treated an episode of left knee pain with an admixture of Chinese herbs. Two days prior to presentation she noted the onset of fevers, myalgias and dizziness culminating in syncope the day of admission. Initial electrocardiogram demonstrated complete heart block and junctional escape with inferior ST elevations. Cardiac catheterization demonstrated no epicardial coronary disease. Laboratory studies revealed acute kidney injury, elevated cardiac biomarkers, and a normal white blood cell count with normal differential. Upon transfer to our hospital, the patient was hypotensive requiring temporary ventricular pacing and vasopressor support. Echocardiogram demonstrated severe systolic dysfunction with LVEF of 31%. On arrival, she was noted to have episodes of monomorphic ventricular tachycardia. Etiologies of fulminant myocarditis considered included viral (lymphocytic), giant cell myocarditis, and sarcoid a well as acute eosinophilic myocarditis given recent ingestion of novel herbal mixture. Given the potential for steroid-responsive etiologies, endomyocardial biopsy was performed with institution of mechanical support ( intra-aortic balloon pump) and administration of parenteral steroids. Inotropic and mechanical support were weaned within 72 hours of administration of steroids and she demonstrated normalization of electrical conduction. Biopsy demonstrated acute necrotizing eosinophilic myocarditis (ANEM). Cardiac MRI demonstrated acute myocarditis, subacute inferior infarct, and no LV thrombus. ANEM represents an often fatal, fulminant form of eosinophilic heart disease and can present without systemic eosinophilia. Triggers can include antecedent viral illness and drug hypersensitivity (including herbal mixtures). Eosinophilic proteins can stimulate platelet aggregation and coronary vasoconstriction. Considered mechanisms of inferior infarct included LV thrombus with coronary embolism. The patient was treated with steroids and anticoagulation with recovery of baseline cardiopulmonary function.
Abstract 5209: Overexpression of TGF-β in Smad4 deficient head and neck squamous cell carcinomas promotes myeloid cell infiltration associated with metastatic progression
Authors: Jingjing Yu, Ariel Hernandez, David Raben, Xiao-Jing Wang
Journal: Cancer Research (2018)

Abstract Purpose of study: Transforming growth factor-β (TGF-β) has been shown to promote tumor progression when overexpressed and could be an important biomarker for head and neck squamous cell carcinomas (HNSCC) prognosis and treatment. Overexpression of TGF-β in tumor epithelia and stroma is observed in Smad4 deficient HNSCCs and is known to upregulate inflammation and angiogenesis. Our preliminary studies in Smad4 deficient HNSCC mice have revealed that inhibition of the TGF-β receptor (TGF-βR), specifically of the intracellular kinase domain, did not affect tumor growth in an immune compromised background but significantly decreased the number of metastatic lesions. We aim to elucidate the specific mechanisms by which TGF-β signaling promotes this metastatic phenotype in Smad4 deficient HNSCCs. We hypothesized that Smad4 deficient SCCs overexpress TGF-β to create an inflammatory microenvironment and promote angiogenesis to drive tumor progression in vivo. Methods: Nude mice were injected subcutaneously in the flank with SCC cells derived from keratinocyte-specific Smad4 knockout mice and treated with either a TGF-βR inhibitor (n=5) or a vehicle control (n=6) once primary tumors reached 1mm3. Using immunofluorescence (IF) or immunohistochemistry (IHC), sections of the primary tumor were probed for leukocyte marker CD45, macrophage markers F4/80, iNOS and Arg1, myeloid cell markers CD11b and Ly6G and endothelial cell marker CD31. Results: Smad4 deficient SCCs treated with the TGF-βR inhibitor showed a significant decrease in CD45+ leukocytes, with a specific decrease in CD11b+Ly6G+ cells compared to the vehicle control group. However, there was no difference in the total number of F4/80+ macrophages between TGF-βR inhibitor treated and vehicle control groups. There was also no significant difference in angiogenesis between these two groups as measured by the number of blood vessels/mm2 and the percentage area of the tumor covered by blood vessels. Conclusions: Smad4 deficient SCC tumors treated with the TGF-βR inhibitor showed a significant decrease in myeloid cell populations, suggesting that overexpressed TGF-β plays a role in mediating inflammation in the tumor stromal environment. Treatment of SCC tumors with the TGF-βR inhibitor, however, did not show an affect on angiogenesis compared to the vehicle control. Citation Format: Jingjing Yu, Ariel Hernandez, David Raben, Xiao-Jing Wang. Overexpression of TGF-β in Smad4 deficient head and neck squamous cell carcinomas promotes myeloid cell infiltration associated with metastatic progression [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 5209.
Abstract 19973: Decellularized Extracellular Matrix Exhibits Reduced Stiffness and Immature Collagen Deposition in a Mouse Model of Left Heart Failure
Authors: Kevin Morine, Kyle Quinn, Lauren Baugh, Mark Aronovitz, Irene Georgakoudi, Richard H Karas, Lauren Black, Navin Kapur
Journal: Circulation (2015)

The extracellular matrix (ECM) is a major determinant of myocardial mechanics in heart failure. Existing methods to evaluate ECM composition are limited. Our objective was to perform a non-destructive microstructural and mechanical analysis of de-cellularized ECM in a mouse model of left ventricular (LV) failure.Methods and Results: Wild-type mice were subjected to 8 weeks of trans-aortic constriction (TAC; n=6) and compared to sham operated controls (Sham; n=5). Compared to sham, TAC mice had increased LV and lung weights, increased LV end-diastolic pressure (4±2 vs 25±5 mmHg, p&lt;0.01) and reduced dP/dT (8249±596 vs 4786±984 mmHg/sec, p&lt;0.01). LV collagen abundance by picrosirius red staining was higher in TAC mice (1±0.1 vs 35±12%, p&lt;0.05) and Type I collagen mRNA and protein levels were increased by 80-fold and 2-fold, respectively (p&lt;0.05 for both). Using non-linear optical microscopy, collagen fiber organization, content and cross-linking were quantified from decellularized sections of the LV free wall. Using cumulative second harmonic generation (SHG), a trend to higher total collagen content per tissue volume was observed in TAC mice (0.02±0.01 vs 0.05±0.3, p=0.09). Two photon excited fluorescence within SHG positive voxels was used to measure cross-linking per collagen fiber. Compared to sham, reduced cross-linking was observed in TAC mice (0.2 ±0.1 vs. 0.11±0.04, p=0.02). Next, using tensile mechanical testing no difference in average ECM stiffness (elastic modulus) was observed between groups (31±15 vs 24±7, sham vs TAC, p=0.19). Conclusions: This is the first mechanical analysis of decellularized ECM in a murine model of LV failure. Despite increased Type I collagen mRNA, protein and histologic fibrosis after TAC, the ECM composition analysis showed reduced collagen cross-linking suggestive of functionally immature collagen deposition. Functional maturation of the ECM may be an important target of therapy for heart failure.
Abstract 2401: Effects of carcinoma-associated fibroblasts on cancer metabolism
Authors: Tu Nguyen, Jimmy Kirsch, Karim Nabi, Christos Sazeides, Addison Quinones, Jessica Tan, Marjorie Antonio, Felipe Camelo, Jin Jung, Anne Le
Journal: Cancer Research (2018)

Abstract Rationale: In previous studies, it has been found that cancer-associated fibroblasts (CAFs) interaction with carcinoma cells and helped cancer cell grow which contributed to cancer progression and aggressiveness. However, how CAFs helped cancer cells grow, specifically what nutrition CAFs provides to tumors has not yet been fully understood. Objectives: We are studying cancer metabolism to identify pathways to target for cancer therapy. Therefore, in this study, we sought to determine which key metabolites in glucose metabolism, specifically glycolysis and the tricarboxylic acid (TCA) cycle metabolites that CAFs feed cancer cells in order for pancreatic cancer cells (P198), to grow better. Measurement Methods and Main Results: We first assessed pancreatic cancer cell proliferation (P198 cells) with and without the presence of CAFs through the co-culture technique. We assessed P198 cell number after the co-culture. We found that P198 cells grew better when co-cultured with CAFs as compared to P198 that was grown alone. We next investigated which metabolites produced from the CAFs cells are feeding P198 cells. In order to determine which metabolites from glucose were provided from CAFs to P198 cells, we first grew CAFs in 13C6-labeled glucose, removed the labeling medium, then co-cultured P198 with CAFs. The collected metabolites were assessed using Agilent 6520 Quadrupole-Time-of-Flight (Q-TOF) mass spectrometer with Agilent 1260 HPLC and a 6490 triple-quadrupole (QQQ) mass spectrometer. Metabolites were identified by retention time using in-house compound standard databases. In parallel, metabolites were identified using MS/MS fragmentation data under identical conditions. Metabolic pathways were reconstructed and analyzed in three categories: bioenergetics, biosynthesis and redox homeostasis of glucose metabolism to study these metabolic pathways exchanged between CAF and P198. Metabolite peak intensities were normalized to the protein concentration and cell number. We observed an increase in intensities of metabolites in the TCA cycle and glycolysis in P198 after co-culture with CAFs. Conclusion: These data supports growth benefits of pancreatic cancer in the presence of CAFs. We also found evidence of the metabolic exchange between CAFs and pancreatic cancer cells, which potentially explains the growth benefit. Citation Format: Tu Nguyen, Jimmy Kirsch, Karim Nabi, Christos Sazeides, Addison Quinones, Jessica Tan, Marjorie Antonio, Felipe Camelo, Jin Jung, Anne Le. Effects of carcinoma-associated fibroblasts on cancer metabolism [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 2401.
Abstract 18173: Medical Management of Papillary Fibroelastoma is Associated With Low Risk of Embolization in Selected Cases
Authors: Terry Bauch, WahWah Htun
Journal: Circulation (2015)

Introduction: Papillary fibroelastoma (PFE) is a rare primary cardiac tumor with a variable clinical spectrum. Surgical excision is recommended in symptomatic patients, but the optimal management of asymptomatic patients is quite controversial. Hypothesis and Method: We hypothesized that non-surgical cases would have excess embolic events, and performed a retrospective and prospective observational study to evaluate the course of patients diagnosed with PFE at our institution. We queried our echo database from 2006 to 2014 for patients age 18 years or older with a mass suggestive of PFE on a cardiac valve by TTE or TEE; significant valvular calcifications, endocarditis, or serial echos with contradictory interpretations were excluded. Electronic health records were reviewed, and those with available outcomes data comprised the final study cohort. Outcomes were collected prospectively from time of identification through May 1st, 2015. Results: We identified 60 cohort patients aged 29 to 89 years (mean 67 +-12); 60% were women, and 85% of PFE were on the aortic valve, with the largest reported dimension 0.2 cm to 1.4 cm. Follow-up data were available for 3 to 126 months (median 40). Surgical excision was performed on 22 patients (38%), mean age 66 +-11 years. Among the remaining 38 patients who did not undergo initial excision, mean age 67 +- 12 years, frailty was cited as the justification in 50%. In the initial non-surgical cohort, 12 received coumadin for unrelated indications such as atrial fibrillation, and 22 received daily Aspirin. In the initial non-surgical cohort, 15 underwent surgical valve repair with resection of the PFE and 7 underwent valve replacement. No post-surgical recurrences were found by TTE. None of the patients in the entire cohort had clinically evident embolic events during follow-up. Conclusion: This is the first reported study to include prospective outcomes data for PFE. Our data suggest that watchful waiting may be a reasonable strategy in selected patients. The optimal medical therapy remains unknown, and larger randomized trials are needed to establish practice guidelines.
Abstract 5256: A prospective study of inflammatory diet potential and risk of hepatocellular carcinoma (HCC)
Authors: Yanan Ma, Tracey G. Simon, Fred K Tabung, Lindsay Y. King, Dawn Q. Chong, Long Nguyen, Trang VoPham, Charles S. Fuchs, Jeffrey A. Meyerhardt, Kathleen E. Corey, Hamed Khalili, Stephanie Smith-Warner, Raymond T. Chung, Edward L. Giovannucci, Andrew T. Chan, Xuehong Zhang
Journal: Cancer Research (2018)

Abstract Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the second-leading cause of cancer-related death worldwide. In the U.S., the incidence rate of HCC has tripled since 1975. Although preliminary evidence suggesting a biological impact of diet on multiple inflammatory pathways implicated in hepatocarcinogenesis, the most comprehensive review by the WCRF/AICR concluded that the relationship between diet and HCC remains largely unknown. HCC is an inflammation-related cancer but few studies have investigated diet quality based on its inflammatory potential in relation to HCC risk. The empirical dietary inflammatory pattern scores (EDIP) score were calculated from validated food frequency questionnaires. It characterized dietary inflammatory potential based on circulating levels of inflammatory bio-markers. We prospectively followed 49,674 men in the Health Professionals Follow-up Study (1986-2012), and 74,139 women in the Nurses' Health Study (1984-2012). Cox regression analyses were used to calculate hazards ratios (HR) for HCC risk adjusting for body mass index, smoking, history of diabetes, race, physical activity, and regular aspirin use. We documented a total of 89 incident HCC cases (44 in women and 45 in men) over 28 years, encompassing 1,522,972 person-years of follow-up. Compared to the lowest tertile, the highest tertile of the EDIP score was associated with a multivariable HR for HCC of 2.86 (95%CI, 1.20-6.81) among women (P-trend=0.01) and of 0.68 (95%CI, 0.31-1.50) among men (P-trend=0.35). Future study is warranted to confirm this finding and elucidate the potential biological basis. Key words: inflammation, dietary patterns, HCC A. T. C. and X. Z contributed equally to this work. Citation Format: Yanan Ma, Tracey G. Simon, Fred K Tabung, Lindsay Y. King, Dawn Q. Chong, Long Nguyen, Trang VoPham, Charles S. Fuchs, Jeffrey A. Meyerhardt, Kathleen E. Corey, Hamed Khalili, Stephanie Smith-Warner, Raymond T. Chung, Edward L. Giovannucci, Andrew T. Chan, Xuehong Zhang. A prospective study of inflammatory diet potential and risk of hepatocellular carcinoma (HCC) [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 5256.
Abstract IA12: The role of malignant RNA editing in leukemia stem cell generation
Authors: Catriona H. M. Jamieson
Journal: Clinical Cancer Research (2017)

Abstract Deregulation of RNA processing contributes to cancer progression and drug resistance. As a major driver of coding and noncoding transcriptomic diversity, adenosine deaminase associated with RNA1 (ADAR1) induces hydrolytic deamination of adenosines (A) to inosines (I) in response to proinflammatory cytokines elicited by viral infection or malignant microenvironments. Recently, we and other groups demonstrated that enhanced A-to-I RNA editing promotes therapeutic resistance of many cancers, including myeloproliferative neoplasms (MPN). As a paradigm for dissecting the molecular evolution of cancer, MPNs are initiated in hematopoietic stem cells (HSCs) by BCR-ABL1, JAK2 V617F or CALR mutation expression and transform to acute myeloid leukemia (AML) as a result of malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs). With regard to the role of noncoding RNA editing in LSC evolution, ADAR1 enhances self-renewal of preleukemic progenitors in CML by impairing let-7 microRNA (miRNA) biogenesis. Moreover, ADAR1 editase activity suppresses the expression of miRNAs that regulate cell cycle, cancer progression, p53 stabilization, and WNT signaling. In addition to noncoding transcript deregulation, A-to-I editing is also observed in coding regions of stem cell regulatory transcripts, such as the sonic hedgehog transcriptional activator GLI1, and induces mis-splicing of GSK3β, thereby enhancing β-catenin activation. In summary, RNA editing research will inform the development of clinically tractable strategies for predicting and preventing LSC generation. Citation Format: Catriona H. M. Jamieson. The role of malignant RNA editing in leukemia stem cell generation [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA12.
Ventricular Arrhythmias Following Ibrutinib Initiation for Lymphoid Malignancies
Authors: Avirup Guha, Mohamed H. Derbala, Qiuhong Zhao, Tracy E. Wiczer, Jennifer A. Woyach, John C. Byrd, Farrukh T. Awan, Daniel Addison
Journal: Journal of the American College of Cardiology (2018)
Reestablishment of the Endothelial Lining by Endothelial Cell Therapy Stabilizes Experimental Abdominal Aortic Aneurysms
Authors: GrégoryFranck, JianpingDai, AlexandreFifre, SaravuthNgo, ClaireJustine, StéphanieMichineau, EricAllaire, MarianneGervais
Journal: Circulation (2013)

Background—Loss of the endothelium and its replacement by a thick thrombus are structural features of human abdominal aortic aneurysms (AAAs). In AAAs, the relationship between aortic diameter expansion, the presence of thrombus, and the lack of endothelial cells (ECs) remains unexplored. We hypothesized that reendothelialization by cell therapy would modulate aortic wall destruction and ultimately stabilize AAAs. We evaluated the impact of local seeding of rat aortic ECs or peripheral blood–derived outgrowth ECs on AAA evolution. Methods and Results—Rat aortic ECs (n=30) or serum-free medium (controls; n=29) were seeded endovascularly immediately (day 0) or 14 days after surgery in the rat xenograft model. Rat aortic EC seeding prevented AAA formation and stabilized formed AAAs at 28 days (diameter increase at day 0+28, 51±6% versus 83±6%; day 14+28, −1±4% versus 22±6% in rat aortic ECs and controls, respectively; P<0.01). This stabilizing effect was associated with the reestablishment of the endothelial...
Tamibarotene maintenance improved relapse-free survival of acute promyelocytic leukemia: a final result of prospective, randomized, JALSG-APL204 study
Authors: Akihiro Takeshita, Norio Asou, Yoshiko Atsuta, Toru Sakura, Yasunori Ueda, Masashi Sawa, Nobuaki Dobashi, Yasuhiro Taniguchi, Rikio Suzuki, Masaru Nakagawa, Shigehisa Tamaki, Maki Hagihara, Katsumichi Fujimaki, Hiroaki Furumaki, Yukako Obata, Hiroyuki Fujita, Masamitsu Yanada, Yoshinobu Maeda, Noriko Usui, Yukio Kobayashi, Hitoshi Kiyoi, Shigeki Ohtake, Itaru Matsumura, Tomoki Naoe, Yasushi Miyazaki
Journal: Leukemia (2018)
Abstract 4789: Clinical candidate DBPR112: A novel epidermal growth factor receptor inhibitor as a promising treatment for non-small cell lung cancer
Authors: Hsing-Pang Hsieh, Jang-Yang Chang, Ching-Chuan Kuo, John Hsu
Journal: Cancer Research (2018)

Abstract Lung cancer is one of the chief causes of cancer death in the world; in addition, non-small cell lung cancer (NSCLC) accounts for 85% of the lung cancer deaths. The development of tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have shown remarkable effects in patients but some acquired resistance after treatment. Therefore, the discovery of efficacious EGFR-TKIs poses an utmost priority. Our team at IBPR has designed and synthesized a series of compounds by high throughput parallel synthesis platform. In the subsequent structure-activity relationship study (SAR) and lead optimization, approximate 150 compounds were synthesized, which concluded that the presence of an N,N-dimethyl functional group on the Michael acceptor and the S-chirality of the phenylaminoethanol side chain were both essential. Consequently, DBPR112 was identified as a potent EGFR-TKI clinical candidate showing excellent inhibitory ability on EGFRL858R/T790M and EGFR exon 20 insertion. DBPR112 was orally effective against the growth of human lung H1975 tumors subcutaneously xenografted in nude mice. A dramatic reduction in tumor size was noted with DBPR112 treatment, while displaying negligible body weight loss in all dosing groups. Furthermore, DBPR112 was more tolerable than afatinib in mice. To date, all pre-clinical studies were completed, and the IND application of DBPR112 was approved by US FDA in 2016 and the Phase I clinical trial has been initiated since July 2017 in Taiwan. Citation Format: Hsing-Pang Hsieh, Jang-Yang Chang, Ching-Chuan Kuo, John Hsu. Clinical candidate DBPR112: A novel epidermal growth factor receptor inhibitor as a promising treatment for non-small cell lung 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 4789.