tbuckley/cabot-search huggingface dataset:
Toward the Best Treatment for Uncomplicated Patients With Type B Acute Aortic Dissection
Authors: Akira Marui, Takaaki Mochizuki, Norimasa Mitsui, Tadaaki Koyama, Fumiko Kimura, Mayumi Horibe
Journal: Circulation (1999)

Background —In the treatment of type B acute aortic dissection without complications, better results are obtained if surgery is performed before enlargement of the aorta in patients who are predicted to show aortic enlargement and if drug-based treatment is continued for patients who are predicted to show no enlargement. The purpose of this study was to predict the acute-phase factors that may affect chronic-phase aortic enlargement by studying chronic-phase enlargement of dissections in patients without complications during the acute phase. Methods and Results —In 101 patients with type B acute dissection who had no complications, univariate and multivariate factor analyses were performed to determine the predictors for chronic-phase enlargement (≥60 mm) of the dissected aorta. The independent predominant predictors for aortic enlargement in the chronic phase were a maximum aortic diameter of ≥40 mm and a patent false lumen during the acute phase. The values of actuarial freedom from aortic enlargement for the patients with a maximum aortic diameter of 40 mm and a patent false lumen at 1, 5, and 10 years were 43%, 33%, and 22%, respectively, whereas in patients with a maximum aortic diameter of &lt;40 mm and a closed false lumen, the values were 97%, 94%, and 84%, respectively. Conclusions —These results suggest that patients with type B acute aortic dissection who show a maximum aortic diameter of ≥40 mm and a patent false lumen should undergo surgery earlier during the chronic phase before enlargement of aorta, whereas patients with a maximum aortic diameter of &lt;40 mm and a closed false lumen should continue to receive hypotensive therapy.
Blockade of Vascular Endothelial Growth Factor Suppresses Experimental Restenosis After Intraluminal Injury by Inhibiting Recruitment of Monocyte Lineage Cells
Authors: KishoOhtani, KensukeEgashira, Ken-ichiHiasa, QingweiZhao, ShiroKitamoto, MinakoIshibashi, MakotoUsui, ShujiroInoue, YoshikazuYonemitsu, KatsuoSueishi, MasatakaSata, MasabumiShibuya, KenjiSunagawa
Journal: Circulation (2004)

Background— Therapeutic angiogenesis by delivery of vascular endothelial growth factor (VEGF) has attracted attention. However, the role and function of VEGF in experimental restenosis (neointimal formation) after vascular intraluminal injury have not been addressed. Methods and Results— We report herein that blockade of VEGF by soluble VEGF receptor 1 (sFlt-1) gene transfer attenuated neointimal formation after intraluminal injury in rabbits, rats, and mice. sFlt-1 gene transfer markedly attenuated the early vascular inflammation and proliferation and later neointimal formation. sFlt-1 gene transfer also inhibited increased expression of inflammatory factors such as monocyte chemoattractant protein-1 and VEGF. Intravascular VEGF gene transfer enhanced angiogenesis in the adventitia but did not reduce neointimal formation. Conclusions— Increased expression and activity of VEGF are essential in the development of experimental restenosis after intraluminal injury by recruiting monocyte-lineage cells.
Androgen Receptor Promotes Sex-Independent Angiogenesis in Response to Ischemia and Is Required for Activation of Vascular Endothelial Growth Factor Receptor Signaling
Authors: SumikoYoshida, Ken-ichiAihara, YasumasaIkeda, YukaSumitomo-Ueda, RyokoUemoto, KazueIshikawa, TakayukiIse, ShusukeYagi, TakashiIwase, YasuhiroMouri, MatomoSakari, TakahiroMatsumoto, Ken-ichiTakeyama, MasashiAkaike, MitsuruMatsumoto, MasatakaSata, KennethWalsh, ShigeakiKato, ToshioMatsumoto
Journal: Circulation (2013)

Background—Hypoandrogenemia is associated with an increased risk of ischemic diseases. Because actions of androgens are exerted through androgen receptor (AR) activation, we studied hind-limb ischemia in AR knockout mice to elucidate the role of AR in response to ischemia. Methods and Results—Both male and female AR knockout mice exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of AR knockout mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor (VEGF) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and endothelial nitric oxide synthase. ...
Abstract 12326: Optimal Targeted Temperature in Comatose Survivors After Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation
Authors: EisukeKagawa, KeigoDote, MasayaKato, ShotaSasaki, NoboruOda, YoshinoriNakano, YasukiKihara
Journal: Circulation (2014)

Introduction: Even after the report of the Targeted Temperature Management trial, optimal targeted temperature (TT) in targeted temperature management for comatose survivors after cardiac arrest is still controversial. Hypothesis: We assessed the hypothesis that lower TT provides improved outcomes in patients after cardiac arrest. Methods: Adult comatose survivors of cardiac arrest without obvious extra-cardiac causes and treated with targeted temperature management were enrolled in this study. We assessed the association between TTs, and favorable outcomes. We divided the study patients into 2 groups according to TT < 34°C (33°C group) or not (34°C group). Favorable outcomes were defined as 90-day cerebral performance category of 1 or 2. P < 0.05 was defined as statistically significant. Results: Among all the study patients (N = 221), there were no significant differences in age, sex, rate of initial shockable rhythms, bystander initiated cardiopulmonary resuscitation (CPR), time interval from collapse ...
Taussig-Bing Heart with Mitral Valve Straddling
Authors: Nobuokitamura, Atsuyoshitakao, Masahikoando, Yasuharuimai, Sojikonno
Journal: Circulation (1974)

Seven autopsied cases of the Taussig-Bing Heart diagnosed at the Heart Institute of Japan were reexamined for this report. Three cases had been correctly classified according to the original description of the Taussig-Bing Heart. The remaining four cases provided examples of a rare variation of this malformation. Characteristic features included the following: the mitral valve straddled the ventricular septum in all cases; the chordae of the anterior leaflet crossed over the septum into the right ventricle through a large subpulmonary ventricular septal defect; and an abnormal muscle ridge, extending from the caudal part of the parietal band, covered the right ventricular side of the ventricular septal defect. Although these four cases differ anatomically from the original Taussig-Bing Heart, their hemodynamics are similar. We have called this anomaly the Taussig-Bing Heart with mitral valve straddling.
Abstract 5207: HIF-1α regulates the Tie2 receptor on Tie2-expressing monocytes in PyMT breast tumors and augments angiogenic function and metastatic potential
Authors: Kayla J. Steinberger, Mary Forget, Xiaokui Mo, Randall Evans, Amy Gross, Leni Moldovan, Andrey Bobko, Valery Khramstov, Clay B. Marsh, Timothy D. Eubank
Journal: Cancer Research (2018)

Abstract Tissue oxygenation in the tumor microenvironment serves as a significant parameter in tumor pathophysiology. In fact, normalization of tumor oxygen is associated with inhibition of tumor growth and metastatic capacity. Irregular tumor vessels produced during tumor angiogenesis have low blood perfusion; thus, oxygen transport is decreased in tumors. Tie2-expressing monocytes (TEMs) are a distinct subset of proangiogenic monocytes selectively recruited to tumors in breast cancer patients. Due to the hypoxic nature of the tumor microenvironment, we investigated if oxygen regulates the trafficking of these cells into tumors or if oxygen regulates monocyte differentiation into TEMs once inside the tumor proper. To understand the differentiation of F4/80+/Tie2- cells to Tie2-positivity, we orthotopically implanted PyMT breast tumor cells containing particulate lithium octa-n-butoxy-naphthalocyanine (LiNcBuO) into the mammary fat pads of LysM-Cre control and HIF-1αfl/fl/LysM-Cre mice and evaluated tissue oxygenation by electron paramagnetic resonance (EPR), TEM infiltration, tumor angiogenesis, and metastatic potential. Longitudinal monitoring of physiologic oxygen in tumors using EPR demonstrates the significant role of oxygen-driven TEM regulation in tumor angiogenesis and progression. Citation Format: Kayla J. Steinberger, Mary Forget, Xiaokui Mo, Randall Evans, Amy Gross, Leni Moldovan, Andrey Bobko, Valery Khramstov, Clay B. Marsh, Timothy D. Eubank. HIF-1α regulates the Tie2 receptor on Tie2-expressing monocytes in PyMT breast tumors and augments angiogenic function and metastatic potential [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 5207.
Abstract 3926: Discovering a novel microtubule inhibitor overcoming tumor multidrug resistance
Authors: Nannan Ning, Chengyong Wu, Min Wu, Yamei Yu, Changjun Zhu, Cyril Benes, Jianming Zhang, Xianming Deng, Qiang Chen, Ruibao Ren
Journal: Cancer Research (2018)

Abstract Microtubule inhibitors, as chemotherapeutic drugs, are widely used for cancer treatment in clinic. However, the development of multidrug resistance (MDR) in cancer is a major challenge for microtubule inhibitors in its clinical implementation. From a high throughput drug screening using cells transformed by oncogenic RAS, we identified a small molecule AR8-1006 that blocks cell proliferation. The analysis of structure-activity relationship indicated that this serial of scaffold represents a potent inhibitor of tumor cell growth. AR8-1006 shows activities against a larger panel of more than 1000 human cancer cell lines with a wide variety of tissue origins. Further analysis showed that this compound depolymerizes microtubules and affects formation of the spindle. Interestingly, it induces the spike-like conformation of microtubules in vitro and in vivo, which is different from typical microtubule modulators. Structural analysis revealed that this serial of compounds binds to the colchicine pocket at the intra-dimer interface, though mostly not overlapping with colchicine binding. More importantly, AR8-1006 displays favorable pharmacological properties on overcoming tumor MDR both in vitro and in vivo. Taken together, our data reveal a novel scaffold represented by AR8-1006 that could be developed as cancer therapeutics, especially for tumor multidrug resistance. Citation Format: Nannan Ning, Chengyong Wu, Min Wu, Yamei Yu, Changjun Zhu, Cyril Benes, Jianming Zhang, Xianming Deng, Qiang Chen, Ruibao Ren. Discovering a novel microtubule inhibitor overcoming tumor multidrug resistance [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 3926.
Abstract 1494: SOX18: A novel master regulator of high-grade serous ovarian tumorigenesis
Authors: Annie Y. Liu, Kevin C. Vavra, Rosario I. Corona, Forough Abassi, Marcos Fonseca, Felipe Segato, Matthew L. Freedman, Simon A. Gayther, Houtan Noushmehr, Kate Lawrenson
Journal: Cancer Research (2018)

Abstract High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer. Recent data indicate that fallopian tube secretory epithelial cells (FTSECs) represent the cell of origin for HGSOC. While many studies have characterized molecular features associated with HGSOC biology, the master transcription factors (TFs) that drive disease development are not known. To identify master TFs for HGSOC, we first performed an integrative analysis of gene expression profiles from 73 FTSEC samples and 394 HGSOCs from The Cancer Genome Atlas (TCGA) project. We then integrated these data with chromatin immunoprecipitation sequencing (ChIP-seq) analyses performed on primary HGSOC samples to select active chromatin regions marked by H3k27ac and to identify super-enhancer (SE) regions. These analyses identified overexpressed TFs that coincide with tumor-specific SEs, a hallmark of master TFs. We identified multiple putative master TFs including SOX18, which was highly overexpressed in HGSOCs relative to normal FTSECs (log2 fold change in expression = 3.5, p = 2.5x10-19). SOX18 is a TF that regulates development of blood and lymphatic vessels, but its association with HGSOC development has not been reported before. We examined the expression of SOX18 in ~8,000 tumors representing 17 tumor types from TCGA. SOX18 expression was significantly elevated in HGSOC relative to any other tumor types, suggesting it is highly specific to this cancer. We found that SOX18 is highly expressed in the HGSOC cell lines UWB1.289, Kuramochi, and EFO21, and we then performed lentiviral-mediated shRNA knockdown of SOX18 in these cell lines to establish the effects of SOX18 depletion on neoplastic phenotypes. In ongoing experiments, we are performing gene expression profiling and H3k27ac ChIP-seq analysis after SOX18 knockdown to identify SOX18 target genes and characterize the landscape of SOX18 binding sites in HGSOC. These studies will likely identify novel molecular biomarkers that may represent much-needed therapeutic targets for HGSOC. Citation Format: Annie Y. Liu, Kevin C. Vavra, Rosario I. Corona, Forough Abassi, Marcos Fonseca, Felipe Segato, Matthew L. Freedman, Simon A. Gayther, Houtan Noushmehr, Kate Lawrenson. SOX18: A novel master regulator of high-grade serous ovarian 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 1494.
Abstract 3521: Glutamine metabolic inhibition synergizes with L-asparaginase in MYCN-amplified neuroblastoma
Authors: Micah J. Maxwell, Brad Poore, Allison Hanaford, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2018)

Abstract Neuroblastoma is the most common extracranial solid tumor in children. Though it accounts for about 10% of pediatric cancers, it is disproportionately responsible for 15% of pediatric cancer deaths. MYCN is amplified in 20% of neuroblastomas and correlates with adverse outcome. MYCN is involved in the maintenance of cancer stem cells, as well as in driving tumor cell growth, proliferation and tumorigenesis. Attempts to inhibit MYCN directly have been largely unsuccessful. MYCN is known to drive tumor cell reliance on glutamine for cellular metabolism. 6-Diazo-5-oxo-L-norleucine (DON) is a well-characterized glutamine analogue that inhibits glutamine metabolism by irreversibly inactivating multiple glutamine-utilizing enzymes. DON was well tolerated in a previous phase I clinical trial in pediatric patients, but it has never been systematically tested in neuroblastoma patients. We show that MYCN-amplification confers sensitivity to DON therapy in in vitro models of neuroblastoma, and that DON administered by intraperitoneal injection twice weekly significantly reduces flank tumor volume in orthotopic mouse models of MYCN-amplified neuroblastoma (mean tumor volume 1715 mm3 vs. 207 mm3 in control animals, p-value = 0.00017 by t-test). We have also developed an orally bioavailable DON prodrug, JHU083, and we found that this drug administered orally three times weekly was similarly able to suppress neuroblastoma tumor growth in mice (mean tumor volume 1,115 mm3 vs. 217 mm3 in control animals, p-value = 0.0000088 by t-test). In metabolic flux experiments, tracing glutamine and glucose donation of 13C and 15N via liquid chromatography/mass spectrometry, DON prevents asparagine synthesis, depleting intracellular asparagine levels by 40% compared to control treated cells (p-value = 0.006). DON combined with L-asparaginase synergistically inhibits growth of MYCN-amplified neuroblastoma cell lines (CI = 0.25 by the Chou-Talalay method, indicating strong synergy; p-value = 0.00011). We conclude that DON depletes cellular pools of asparagine, and combination therapy with DON and L-asparaginase synergistically inhibits the growth of MYCN-amplified neuroblastoma. These studies provide the preclinical justification for potential clinical trials for the use of DON or DON prodrugs in combination with L-asparaginase as new therapeutic options for patients with MYCN-amplified neuroblastoma. Citation Format: Micah J. Maxwell, Brad Poore, Allison Hanaford, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe. Glutamine metabolic inhibition synergizes with L-asparaginase in MYCN-amplified neuroblastoma [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 3521.
Abstract 1481: Selective protein expression in tumor cells controlled by progression elevated gene-3 promoter
Authors: Ruben Pando, Tej Shrestha, Marla Pyle, Deryl Troyer
Journal: Cancer Research (2018)

Abstract The progression elevated gene-3 (PEG-3) promoter is a rodent gene that has shown strong activity in tumor progression. Demonstrating tumor specificity and activity in at least five different human cancers, PEG-3 is considered a novel promoter for tumor-specific gene expression. Understanding how PEG-3 controls expression of reporter proteins is of biomedical significance because of the role it could play in new therapeutic strategies against certain types of cancer. In this study, we aim to use the PEG-3 promoter to observe the expression of firefly luciferase 2 (luc 2), a bioluminescent reporter protein, in the transfection of mammalian cells. Ultimately, we plan to use PEG-3 to express a therapeutic gene, cytosine deaminase, in cancer specific areas of breast, lung, and ovary. Citation Format: Ruben Pando, Tej Shrestha, Marla Pyle, Deryl Troyer. Selective protein expression in tumor cells controlled by progression elevated gene-3 promoter [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 1481.
Abstract 20727: β-agonism Induces Recruitment of Diazoxide-Sensitive Katp Channels Via 14-3-3 in Human Atrial-Like Cardiomyocytes
Authors: Joshua Lader, Lei Bu, Bruce Gelb, Glenn Fishman
Journal: Circulation (2016)

Introduction: KATP channels couple cellular metabolism and electrophysiology. Their molecular composition and sensitivity to potassium channel openers vary in different tissues and species. Rodent atrial KATP channels are activated by diazoxide and have been implicated in arrhythmogenesis in models of hypertension and excess β-adrenergic tone. In contrast, human atrial KATP channels are activated by pinacidil (insensitive to diazoxide) and modulate APD only during extreme metabolic stress. Hypothesis: Changes in the human atrial action potential associated with β-agonism are mediated by recruitment of diazoxide-sensitive KATP channels. Methods: We used human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes where expression of a fluorescent reporter is driven by the atrial-specific gene sarcolipin. Atrial specification was induced with retinoic acid. Di-4-ANBDQBS was used to perform optical action potential measurements on days 65-80 of differentiation. Results: All data are for APD90 wi...
Genetic Analysis of the Interleukin-18 System Highlights the Role of the Interleukin-18 Gene in Cardiovascular Disease
Authors: LaurenceTiret, TiphaineGodefroy, EdithLubos, VivianeNicaud, David-AlexandreTregouet, SandrineBarbaux, RenateSchnabel, ChristophBickel, ChristineEspinola-Klein, OdettePoirier, ClairePerret, ThomasMünzel, Hans-JurgenRupprecht, KarlLackner, FrançoisCambien, StefanBlankenberg
Journal: Circulation (2005)

Background— Interleukin (IL)-18 plays a key role in atherosclerosis and its complications. The present study investigated the genetic variability of 4 genes of the IL-18 system—IL18, IL18R1, IL18RAP, and IL18BP—in relation to circulating IL-18 levels and cardiovascular mortality. Methods and Results— Twenty-two polymorphisms were genotyped in 1288 patients with coronary artery disease prospectively followed up during a median period of 5.9 years. The end point was death from cardiovascular causes (n=142). Baseline IL-18 levels were predictive of cardiovascular deaths occurring during ≤4 years of follow-up (HR=2.96, 95% CI 1.54 to 5.70, P=0.001 for the top compared with the bottom quartile) but not of later deaths. Haplotypes of the IL18 gene were associated with IL-18 levels (P=0.002) and cardiovascular mortality (P=0.006) after adjustment for cardiovascular risk factors. The same haplotype was associated with both a 9% lowering effect on IL-18 levels and a protective effect on risk (HR=0.57, 95% CI 0.36 ...
Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: a nationwide, register-based cohort study
Authors: Araz Rawshani, Naveed Sattar, Stefan Franzén, Aidin Rawshani, Andrew T Hattersley, Ann-Marie Svensson, Björn Eliasson, Soffia Gudbjörnsdottir
Journal: The Lancet (2018)