tbuckley/cabot-search huggingface dataset:
Abstract 2674: Novel tubulin polymerization inhibitors repress tumor xenografts in nude mice and leukemia in zebrafish
Authors: Yanqi Xie, Liliia Kril, Wen Zhang, Mykhaylo Frasinyuk, Svitlana Bondarenko, Elizabeth Hausman, Zachary Martin, Przemyslaw Wyrebek, Tianxin Yu, Changguo Zhan, Vitaliy Sviripa, Jessica Blackburn, David Watt, Chunming Liu
Journal: Cancer Research (2018)

Abstract In an effort to screen natural compounds and their derivatives as novel agents for cancer treatment, we developed two semisynthetic nature compounds, A14 and A52, which have potencies in an in vitro cell proliferation studies against LS174T and PC-3 cells in the mid-nanomolar range. A14 inhibited more than 90% of in vitro cancer cell proliferation around 300 nM and also inhibited in vivo PC-3 prostate cancer xenografts in nude mice. Cell morphology studies and comparisons with known antineoplastic agents suggested that A14 disrupted microtubule organization. In vitro tubulin polymerization assay suggested that A14 inhibited this process. Based on molecular docking, A14 fits very well in the colchicine-binding site at the interface between the alpha-tubulin and beta-tubulin. Further analyses suggest that A14 sensitivity may correlate with CDK/cyclin activity. A14 inhibited PC-3 prostate cancer xenografts in nude mice. In addition to solid tumors, A14 and its analog A52 strongly inhibited a panel of human leukemia cancer cell lines. Furthermore, these compounds inhibited Myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model. Although many tubulin inhibitors were available, there is no compound that targeting the colchicine-binding site has been approved by FDA for cancer treatment. This new family of tubulin polymerization inhibitors could be further developed for the treatment of both solid and liquid tumors. Citation Format: Yanqi Xie, Liliia Kril, Wen Zhang, Mykhaylo Frasinyuk, Svitlana Bondarenko, Elizabeth Hausman, Zachary Martin, Przemyslaw Wyrebek, Tianxin Yu, Changguo Zhan, Vitaliy Sviripa, Jessica Blackburn, David Watt, Chunming Liu. Novel tubulin polymerization inhibitors repress tumor xenografts in nude mice and leukemia in zebrafish [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 2674.
Abstract 1653: Design and synthesis of basic amino selective estrogen receptor degraders (BA-SERDs) for treatment-resistant breast cancer
Authors: Yunlong Lu, Gregory R. Thatcher
Journal: Cancer Research (2018)

Abstract About 1 in 8 United States women (about 12%) will develop invasive breast cancer during their lifespan. Approximately 40,000 women are expected to die from breast cancer each year. The largest single breast cancer subtype is defined as estrogen receptor alpha (ERα; ESR1) positive breast cancer (75%), wherein ERα played a critical role in cancer cell survival, proliferation and metastasis. The dysregulation of ER signaling formed the most important molecular event in the ER positive (ER+) breast cancer. Endocrine therapy (ET) had been successfully employed on such breast cancer patients and most of them had substantial reduced risks of breast cancer recurrence and mortality in the initial 5-10 years. However, the development of resistance to ET has the greatest impact on clinical use. The emergence of resistance is inevitable over time and will eventually become metastatic disease after long term of ET. Recent studies confirmed treatment failure of SERMs and AIs in ER+ metastatic settings, whereas ERα remains engaged in the advanced disease and contributes to disease pathogenesis. Fortunately, the treatment resistant breast cancer patients remain responsive to fulvestrant (ICI182,780) which has been described as a “pure antagonist” and caused ERα degradation as a SERD. Nonetheless, the pharmaceutical liabilities of fulvestrant including poor solubility and pharmacokinetics (PK) resulted in poor compliance. The clinical development of orally bioavailable SERDs i.e. GDC-0810, AZD9496, RAD1901 is needed to overcome these shortcomings. Herein, our lab identified a novel class of BA-SERDs to circumvent drug resistance. Citation Format: Yunlong Lu, Gregory R. Thatcher. Design and synthesis of basic amino selective estrogen receptor degraders (BA-SERDs) for treatment-resistant breast 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 1653.
Electrocardiographic Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy According to Disease Severity
Authors: KhurramNasir, ChandraBomma, HarikrishnaTandri, ArielRoguin, DarshanDalal, KalpanaPrakasa, CrystalTichnell, CynthiaJames, PhillipJspevak, FrankMarcus, HughCalkins
Journal: Circulation (2004)

Background— The purpose of this study was to systematically study diagnostic and prognostic electrocardiographic (ECG) characteristics of arrhythmogenic right ventricle dysplasia/cardiomyopathy (ARVD/C). Methods and Results— The patient population included 50 patients with ARVD/C (27 males, 23 females; mean age 38±15 years). We also analyzed the ECG of 50 age- and gender-matched normal control subject and 28 consecutive patients who presented with right ventricular outflow tract (RVOT) tachycardia. Right bundle-branch block (RBBB) was present in 11 patients (22%). T-wave inversions in V1 through V3 were observed in 85% of ARVD/C patients in the absence of RBBB compared with none in RVOT and normal controls, respectively (P<0.0001); epsilon waves were seen in 33%, and a QRS duration ≥110 ms in V1 through V3 was present in 64% of patients. Among those without RBBB, our newly proposed criterion of “prolonged S-wave upstroke in V1 through V3” ≥55 ms was the most prevalent ECG feature (95%) and correlated with...
Solid Pseudo-Papillary Tumor Mimicking as Complicated Pseudocyst
Authors: Sophie Turpin, Marjorie Perron, Stéphanie Vairy, Sébastien Bénali, Amélie Damphousse
Journal: Clinical Nuclear Medicine (2018)

Abstract Pancreatic neoplasm is very rare in the pediatric population. Malignant tumors represent less than 0.2% of pediatric cancer-related mortality. Pancreas lesions can be from exocrine or endocrine origin or present themselves as cystic masses. Clinical, biological, and radiological findings usually are sufficient to establish diagnosis, but in some cases, they may be misleading. We present the case of a young patient presenting a pancreatic mass where anatomical and metabolic characteristics of the lesion were discordant to the final diagnosis.
Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: CristinaBasso, GaetanoThiene, DomenicoCorrado, AnnalisaAngelini, AndreaNava, MarialuisaValente
Journal: Circulation (1996)

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a frequent cause of sudden death in young individuals and athletes. Although familial occurrence has been documented and a gene defect was recently localized on chromosome 14q23-q24 the etiopathogenesis of the disease is still obscure. Methods and Results A pathological study was conducted in 30 hearts with ARVC (age range, 15 to 65 years; mean, 28 years). In the 27 autopsy cases, the mode of death was sudden in 24 and congestive heart failure in 3. ECG, available in 19 cases, showed inverted T waves in the right precordial leads in 15 cases (79%) and ventricular arrhythmias in 15 (79%). Right ventricular aneurysms were present in 15 hearts (50%) and located in the inferior wall in 12. Left ventricle and ventricular septum were involved in 14 (47%) and 6 (20%) cases, respectively. Scattered foci of lymphocytes with myocardial death were observed in 20 cases (67%). Electron microscopy studies, although confirming the myocardial death and ...
Abstract 20882: Implantable Loop Recorder in Inherited Arrhythmogenic Diseases: A Critical Tool for Symptom Diagnosis and Advanced Risk Stratification
Authors: Aeshita Dwivedi, Jacqueline Joza, Marina Cerrone, Steven Fowler, Larry Chinitz
Journal: Circulation (2016)

Introduction: A significant challenge in the management of patients (pts) with inherited arrhythmias (IADs) is the retrospective assessment of events suspected to be clinically relevant. Long term monitoring is critical for the adjudication of syncope and/or palpitations to guide the appropriate use of the ICD for primary prevention. Hypothesis: Implantable loop recorders (ILR) are safe and essential for adjudication of high-risk events in pts with IADs. Methods: We retrospectively reviewed data of all pts referred to the NYU Cardiovascular Genetics Program who underwent insertion of an ILR between 2009-2016. Results: Thirty subjects underwent insertion of an ILR and were followed for a median time of 17 months (IQR 7, 37). There were no complications related to the procedure. In the study group, 53% pts had an established diagnosis (mean age 35 ± 4 years): 5 Brugada 5 Long QT syndromes, 2 CPVT, 2 Hypertrophic and 1 Arrhythmogenic cardiomyopathies. The median time to recurrence was 4 months (IQR 1.2, 23) ...
Prevalence and Clinical Significance of Papillary Muscle Infarction Detected by Late Gadolinium-Enhanced Magnetic Resonance Imaging in Patients With ST-Segment Elevation Myocardial Infarction
Authors: TakashiTanimoto, ToshioImanishi, HironoriKitabata, NobuoNakamura, KeizoKimura, TakashiYamano, KoheiIshibashi, KenichiKomukai, YasushiIno, ShigehoTakarada, TakashiKubo, KumikoHirata, MasatoMizukoshi, AtsushiTanaka, TakashiAkasaka
Journal: Circulation (2010)

Background—The frequency of papillary muscle infarction (PapMI) without rupture has not been fully investigated in vivo. Furthermore, the relationship between papillary muscle dysfunction and mitral regurgitation (MR) has been controversial in patients with ST-segment elevation myocardial infarction. Therefore, the aim of this study was to assess the frequency and clinical characteristics of PapMI without rupture using late gadolinium-enhanced magnetic resonance imaging (MRI) in patients with ST-segment elevation myocardial infarction. Methods and Results—One hundred eighteen ST-segment elevation myocardial infarction patients with primary percutaneous coronary intervention underwent cardiac MRI twice 9±4 days and 8±1 months (n=104) after myocardial infarction. MR was categorized by echocardiography. Of these patients, 40% were found to have late gadolinium enhancement of papillary muscle, in which the posterior papillary muscle was involved more frequently than the anterior papillary muscle (77% versus 2...
Abstract 15460: Successful Implantation of an Allogenic In-Body Tissue-Engineered Vascular Graft (Biotube) for Hemodialysis Access in a Beagle Model
Authors: Yasuhide Nakayama, Maya Furukoshi
Journal: Circulation (2016)

Background and Objective: In patients receiving hemodialysis, vascular access via an autologous arteriovenous (AV) shunt is preferred because of its lower rates of all-cause mortality and infection. However, a substantial number of shunt will fail because of stenosis or obstruction at anastomotic site or venous outflow. On the other hand, we developed in-body tissue-engineered vascular grafts (Biotubes), exhibited rapid tissue regeneration and withstand systemic pressure over 5 years. In this study, allogeneic Biotubes were stored for over 1 month and firstly implanted as canine AV hemodialysis shunts. Methods and Results: Biotube vascular grafts (n=9) with 4 mm in diameter and 5 cm in length were prepared as connective tubular tissues with wall thickness of ca. 1 mm by embedding of the molds, assembled with a silicone center rod and a stainless steel tube, into canine abdominal subcutaneous pouches for 2 months. After anti-thrombogenic coating, they were allogeneic implanted between the carotid artery an...
Exercise Training Stimulates Ischemia-Induced Neovascularization via Phosphatidylinositol 3-Kinase/Akt-Dependent Hypoxia-Induced Factor-1α Reactivation in Mice of Advanced Age
Authors: Xian WuCheng, MasafumiKuzuya, WeonKim, HaizhenSong, LinaHu, AikoInoue, KaeNakamura, QunDi, TakeshiSasaki, MichitakaTsuzuki, Guo-PingShi, KenjiOkumura, ToyoakiMurohara
Journal: Circulation (2010)

Background— Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1α–mediated response to hypoxia associated with aging are poorly understood. Here, we report that swimming training (ST) modulates the vascular response to ischemia in aged (24-month-old) mice. Methods and Results— Aged wild-type mice (MMP-2+/+) that maintained ST (swimming 1 h/d) from day 1 after surgery were randomly assigned to 4 groups that were treated with either vehicle, LY294002, or deferoxamine for 14 days. Mice that were maintained in a sedentary condition served as controls. ST increased blood flow, capillary density, and levels of p-Akt, HIF-1α, vascular endothelial growth factor, Fit-1, and matrix metalloproteinase-2 (MMP-2) in MMP-2+/+ mice. ST also increased the numbers of circulating endothelial progenitor cells and their function associated with activation of HIF-1α. All of these effects...
Abstract 11567: A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing
Authors: Hayato Tada, Masa-aki Kawashiri, Atsushi Nohara, Akihiro Inazu, Hiroshi Mabuchi, Masakazu Yamagishi
Journal: Circulation (2015)

Background: Sitosterolemia is an extremely rare inherited disease characterized by increased levels of plant sterols such as sitosterol, the cause of which is ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene mutations. Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent self-limiting fever and serositis caused by mutations in FEMV gene. Molecular diagnosis for such cases through candidate-gene approaches have required a huge effort for a long time. Whole exome sequencing (WES) technologies have already accelerated genetic studies of Mendelian disorders, yielding approximately ~30 % of success for diagnosing, and there is great interest in extending this approach to this rare phenotype. Methods and Results: WES was performed for the proband (14 yr Japanese female, initial LDL cholesterol = 535 mg/dl) with histories of recurrent self-limiting episodes of fever and serositis. Among 206,430 variants found in the individual, we found 18,220 nonsense, missense, or splice site variants, of which 3,087 were rare (minor allele frequency ≤0.01 or not reported) in 1000 Genome (Asian population). Filtering assuming recessive pattern of inheritance successfully narrowed down the candidate to the compound heterozygous mutations in ABCG5 gene (c.1256C&gt;T or p.Arg419His / c.1763-1T&gt;G [splice acceptor site]) and MEFV gene (c.329 A&gt;G or p.Leu110Pro / c.442G&gt;C or p.Glu148Val). She was genetically diagnosed as a coincidence of sitosterolemia and FMF for the first time. Conclusion: We report the first case exhibiting rare coincidence of sitosterolemia and FMF identified using WES. Such comprehensive approach is useful to identify causative mutations for multiple unrelated inherited diseases.
Flufenamic acid inhibits secondary hemorrhage and BSCB disruption after spinal cord injury
Authors: Yingtao Yao, Jianyi Xu, Tingting Yu, Zhilong Chen, Zhiyong Xiao, Jiedong Wang, Yiqiang Hu, Yongchao Wu, Dan Zhu
Journal: Theranostics (2018)

Acute spinal cord injury (SCI) induces secondary hemorrhage and initial blood-spinal cord barrier (BSCB) disruption.The transient receptor potential melastatin 4 (Trpm4) together with sulfonylurea receptor 1 (Sur1) forms the Sur1-Trpm4 channel complex.The up-regulation of Sur1-Trpm4 after injury plays a crucial role in secondary hemorrhage, which is the most destructive mechanism in secondary injuries of the central nervous system (CNS).The matrix metalloprotease (MMP)-mediated disruption of the BSCB leads to an inflammatory response, neurotoxin production and neuronal cell apoptosis.Thus, preventing secondary hemorrhage and BSCB disruption should be an important goal of therapeutic interventions in SCI.Methods: Using a moderate contusion injury model at T10 of the spinal cord, flufenamic acid (FFA) was injected intraperitoneally 1 h after SCI and then continuously once per day for one week.Results: Trpm4 expression is highly up-regulated in capillaries 1 d after SCI.Treatment with flufenamic acid (FFA) inhibited Trpm4 expression, secondary hemorrhage, and capillary fragmentation and promoted angiogenesis.In addition, FFA significantly inhibited the expression of MMP-2 and MMP-9 at 1 d after SCI and significantly attenuated BSCB disruption at 1 d and 3 d after injury.Furthermore, we found that FFA decreased the hemorrhage-and BSCB disruption-induced activation of microglia/macrophages and was associated with smaller lesions, decreased cavity formation, better myelin preservation and less reactive gliosis.Finally, FFA protected motor neurons and improved locomotor functions after SCI. Conclusion:This study indicates that FFA improves functional recovery, in part, due to the following reasons:(1) it inhibits the expression of Trpm4 to reduce the secondary hemorrhage; and (2) it inhibits the expression of MMP-2 and MMP-9 to block BSCB disruption.Thus, the results of our study suggest that FFA may represent a potential therapeutic agent for promoting functional recovery.
Should We Emergently Revascularize Occluded Coronaries for Cardiac Arrest
Authors: EisukeKagawa, KeigoDote, MasayaKato, ShotaSasaki, YoshinoriNakano, MasatoKajikawa, AkifumiHigashi, KihoItakura, AkihikoSera, IchiroInoue, TakujiKawagoe, MasaharuIshihara, YujiShimatani, SatoshiKurisu
Journal: Circulation (2012)

Background—Extracorporeal membrane oxygenation (ECMO) and percutaneous coronary intervention (PCI) may be useful in cardiopulmonary resuscitation. However, little is known about the combination of ECMO and intra-arrest PCI. This study investigated the efficacy of rapid-response ECMO and intra-arrest PCI in patients with cardiac arrest complicated by acute coronary syndrome who were unresponsive to conventional cardiopulmonary resuscitation. Methods and Results—This multicenter cohort study was conducted with the use of the database of ECMO in Hiroshima City, Japan. Between January 2004 and May 2011, rapid-response ECMO was performed in 86 patients with acute coronary syndrome who were unresponsive to conventional CPR. The median age of the study patients was 63 years, and 81% were male. Emergency coronary angiography was performed in 81 patients (94%), and intra-arrest PCI was performed in 61 patients (71%). The rates of return of spontaneous heartbeat, 30-day survival, and favorable neurological outcomes...
Response to Letter Regarding Article, “Implementation of the Fifth Link of the Chain of Survival Concept for Out-of-Hospital Cardiac Arrest”
Authors: TakashiTagami, HiroyukiYokota, KazuhikoHirata, ToshiyukiTakeshige, MasatakaSatake, JunichirohMatsui, MakotoTakinami, ShuichiSatake, TokuoYui, KunihiroItabashi, ToshioSakata, RyoichiTosa, ShigekiKushimoto, HisaoHirama
Journal: Circulation (2013)
Abstract 2069: Therapeutic targeting of ependymoma as informed by oncogenic enhancers
Authors: Stephen C. Mack, Global Ependymoma Network of Excellence
Journal: Cancer Research (2018)

Abstract Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas commonly resist chemotherapy and lack available targeted agents for clinical trial development. In the case of genomically balanced ependymomas, and those driven by fusion oncoproteins, we hypothesized that the chromatin landscapes could uncover oncogenes that would inform actionable targets for therapy and reveal specific transcriptional circuitries to identify molecular origins of the disease. We therefore interrogated the oncogenic drivers of ependymoma by characterizing the active regulatory landscapes of 42 primary tumors through an integrative analysis of H3K27ac ChIP-seq, RNA-seq, whole-exome sequencing (WES), whole genome sequencing (WGS), copy number profiling, and DNA methylation profiling. Across the landscape of ependymal tumors, enhancer mapping revealed putative oncogenes, including NFIX, MIRLET7BHG, FGFR1, WEE1, and MTSS1L, and delineated subgroup specific enhancer lesions. Reconstruction of enhancer networks permitted the identification of core transcription factors (TFs) that establish ependymoma cell state, and lineage-specifying TFs that dictate molecular subgroup identity. Lineage-associated TFs point to distinct spatio-temporal origins of ependymoma subgroups such as FOXJ1 TF activity and expression observed preferentially in subsets of hindbrain ependymomas. To translate our results into a potential clinical paradigm, we demonstrate cancer dependencies on super enhancer associated genes and lineage TFs, and establish the utility of chromatin landscape analysis to predict novel targets for cancer therapy. Citation Format: Stephen C. Mack, Global Ependymoma Network of Excellence. Therapeutic targeting of ependymoma as informed by oncogenic enhancers [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 2069.
Drug-Eluting Balloon in Peripheral Intervention for Below the Knee Angioplasty Evaluation (DEBATE-BTK)
Authors: FrancescoLiistro, ItaloPorto, PaoloAngioli, SimoneGrotti, LuciaRicci, KennethDucci, GiovanniFalsini, GiorgioVentoruzzo, FilippoTurini, GuidoBellandi, LeonardoBolognese
Journal: Circulation (2013)

Background—The 1-year restenosis rate after balloon angioplasty of long lesions in below-the-knee arteries may be as high as 70%. Our aim was to investigate the efficacy of a paclitaxel drug-eluting balloons versus conventional percutaneous transluminal angioplasty (PTA) for the reduction of restenosis in diabetic patients with critical limb ischemia undergoing endovascular intervention of below-the-knee arteries. Methods and Results—The Drug-Eluting Balloon in Peripheral Intervention for Below the Knee Angioplasty Evaluation (DEBATE-BTK) is a randomized, open-label, single-center study comparing drug-eluting balloons and PTA. Inclusion criteria were diabetes mellitus, critical limb ischemia (Rutherford class 4 or higher), significant stenosis or occlusion >40 mm of at least 1 below-the-knee vessel with distal runoff, and life expectancy >1 year. Binary in-segment restenosis at a 1-year angiographic or ultrasonographic follow-up was the primary end point. Clinically driven target lesion revascularization,...