tbuckley/cabot-search huggingface dataset:
Induction of Early Atherosclerosis in LDL-Receptor–Deficient Mice Immunized With β2-Glycoprotein I
Authors: JacobGeorge, ArnonAfek, BorisGilburd, MiriBlank, YairLevy, AnabelAron-Maor, HanaLevkovitz, AvivShaish, IrisGoldberg, JuriKopolovic, DrorHarats, YehudaShoenfeld
Journal: Circulation (1998)

Background—Immunization with β2-glycoprotein I (β2GPI), the probable target of autoimmune anticardiolipin antibodies, results in experimental antiphospholipid syndrome in different mouse strains. The present study was undertaken to evaluate the effect of β2GPI immunization on the progression of atherosclerosis. Methods and Results—In the first experiment, 3 groups of LDL receptor–deficient (LDL-RD) mice (n=15 per group) were immunized with either β2GPI or ovalbumin or were not immunized and were fed a chow diet for 12 weeks. In a second experiment, 3 groups of LDL-RD mice (n=10 per group) were immunized similarly and fed an atherogenic diet for 6 weeks. All β2GPI-immunized mice developed high titers of anti-β2GPI antibodies as well as a specific lymph node proliferation to β2GPI. The average cholesterol levels did not differ between the mice fed similar diets, regardless of the immunization protocol. Atherosclerosis was enhanced in the β2GPI-immunized mice (mean aortic lesion, 26 000±5700 μm2) in comparis...
Second Internal Thoracic Artery Versus Radial Artery in Coronary Artery Bypass Grafting
Authors: ElfriedeRuttmann, NikolausFischler, AdelSakic, OrestChevtchik, HannesAlber, RolandSchistek, HannoUlmer, MichaelGrimm
Journal: Circulation (2011)

Background—The best second arterial conduit for multiple arterial revascularization (MAR) is still a matter of debate. Previous studies on the benefit of either using the radial artery (RA) or the right internal thoracic artery (RITA) in coronary artery bypass grafting are not conclusive. The aim of our study was to compare the perioperative and long-term outcome of either RA or RITA grafts as second conduits for MAR. Methods and Results—A consecutive series of 1001 patients undergoing first nonemergent coronary artery bypass grafting receiving either RA or RITA as second graft for MAR between 2001 and 2010 were studied. There were 277 patients receiving a RITA and 724 patients receiving a RA in addition to a left internal thoracic artery (LITA). Concomitant saphenous vein grafts (SVG) were grafted in addition as necessary. Propensity score–matched analysis was performed to compare the 2 groups, bilateral ITA±SVG (BITA±SVG group) and the LITA+RA±SVG group relative to overall survival and major adverse car...
Abstract 4191: Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells
Authors: Nobuyuki Kuribayashi, Daisuke Uchida, Makoto Kinouchi, Kyoko Kuribayashi, Tomonori Hasegawa, Shuma Yagisawa, Hitoshi Kawamata
Journal: Cancer Research (2018)

Abstract We have previously demonstrated that the stromal cell-derived factor (SDF)-1/CXCR4 system is involved in the metastasis of head and neck cancer. Additionally, it has been shown that the blockade of CXCR4 by subcutaneous daily injection with AMD3100, a CXCR4 antagonist, may be effective in preventing metastasis in CXCR4-related head and neck cancer. Recent investigations have suggested that AMD070, a novel orally bioavailable inhibitor of CXCR4, may be minimally invasive compared with AMD3100. In the present study, we examined the effect of AMD070 on metastasis induced by the SDF-1/CXCR4 axis in B88-SDF-1 oral cancer cells, which express high levels of SDF-1 and CXCR4. Although treatment with AMD070 did not affect the anchorage-dependent growth of B88-SDF-1 cells, it significantly suppressed the anchorage-independent growth. Moreover, the SDF-1/CXCR4-dependent migration and invasion of B88-SDF-1 cells was significantly inhibited following treatment with AMD070. Subsequently, we performed an experimental therapy using AMD070 to prevent the distant metastasis of B88-SDF-1 cells in vivo. Daily oral administration of AMD070 significantly inhibited the lung metastasis of B88-SDF-1 cells in nude mice. Furthermore, AMD070 treatment did not induce body weight loss despite the tumor bearing-condition of the mice. In addition, we could not detect the apparent macroscopic organ abnormalities associated with the daily oral administration of AMD070. These results indicated that AMD070 could be useful as a novel orally bioavailable inhibitor of oral cancer metastasis. Citation Format: Nobuyuki Kuribayashi, Daisuke Uchida, Makoto Kinouchi, Kyoko Kuribayashi, Tomonori Hasegawa, Shuma Yagisawa, Hitoshi Kawamata. Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer 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 4191.
Characteristics of the Delayed Rectifier Current (IKr and IKs) in Canine Ventricular Epicardial, Midmyocardial, and Endocardial Myocytes
Authors: Da-WeiLiu, CharlesAntzelevitch
Journal: Circulation Research (1995)

Abstract Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine, feline, rat, guinea pig, and human hearts. In this study, we use standard microelectrode and whole-cell patch-clamp techniques to examine the characteristics of the action potential and the delayed rectifier K+ current (IK) in epicardial, M region (deep subepicardial to midmyocardial), and endocardial cells isolated from the canine left ventricle. Cells from the M region displayed much longer action potential durations (APDs) at slow rates. At a basic cycle length of 4 s, APD measured at 90% repolarization was 358±16 (mean±SEM), 262±12, and 287±11 ms in cells from the M region, epicardium, and endocardium, respectively. Steady state APD-rate relations were steeper in cells from the M region. In complete Tyrode’s solution, IK was smaller in myocytes from the M region when compared with those isolated from the epicardium or endocardium. Further characterization of IK was...
Abstract 19501: Ulk1 Induces Mitochondrial Autophagy by Regulating Mitochondrial Fission and Alternative Autophagy in the Heart
Authors: Toshiro Saito, Junichi Sadoshima
Journal: Circulation (2016)

Degradation of damaged mitochondria by mitochondrial autophagy (MA) is essential for maintaining the healthy function of mitochondria. Although Pink1-Parkin-mediated MA has been extensively investi...
Abstract 5815: Aldose reductase inhibition prevents doxorubicin-induced inflammatory response in endothelial cells and macrophages
Authors: Himangshu Sonowal, Ashish Saxena, Kota V. Ramana, Satish K. Srivastava
Journal: Cancer Research (2018)

Abstract Anthracycline class of chemotherapeutic drugs such as doxorubicin and daunorubicin has been known to be effective in the therapy of various types of cancer. However, in certain cancers such as colon cancer, the use of anthracyclines is restricted due to acquired drug resistance, which requires high amounts of drugs that cause severe toxic side effects. We have recently demonstrated that aldose reductase (AR) inhibitor, fidarestat, increases the sensitivity of doxorubicin towards colon cancer cells death in vitro and in vivo and decreases cardiotoxicity. However, the mechanisms through which AR inhibitor prevents doxorubicin-induced toxicity is not understood. We have examined how AR inhibition prevents doxorubicin-induced endothelial and cardiac toxicity along with inflammatory response in in vitro and in vivo models. Our results demonstrate that fidarestat prevents doxorubicin-induced oxidative stress, endothelial cell death, and monocyte adhesion. Further, fidarestat prevents the activation of NF-κB-dependent expression of endothelial cell markers ICAM-1 and VCAM-1 and expression of various inflammatory cytokines and chemokines in human vascular endothelial cells. In addition, fidarestat prevented the doxorubicin-induced decrease in eNOS and increase in iNOS expression. Similarly, AR inhibition prevented doxorubicin-induced endothelial dysfunction, cardiac hypertrophy, and cardiomyocyte injury in mice. Fidarestat also prevented doxorubicin-induced activation of monocytes and macrophages to proinflammatory phenotype in culture as well as in mouse models. Thus, our results suggest that by preventing doxorubicin-induced inflammatory as well as oxidative stress signals, fidarestat decreases cardiotoxic effects of doxorubicin. This is a novel adjuvant therapy of cancer using aldose reductase inhibitors with anthracyclines that would increase cancer therapeutic efficacy and decrease cardiotoxic side effects. Citation Format: Himangshu Sonowal, Ashish Saxena, Kota V. Ramana, Satish K. Srivastava. Aldose reductase inhibition prevents doxorubicin-induced inflammatory response in endothelial cells and macrophages [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 5815.
Abstract 05: Assessing Population Impact of Statin Treatment for Primary Prevention of Atherosclerotic Cardiovascular Diseases in US
Authors: QuanheYang, YunaZhong, CatheenGillespie, RobertMerritt, BarbaraBowman, MaryGeorge, DanaFlanders
Journal: Circulation (2015)

Introduction: American College of Cardiology/American Heart Association (ACC/AHA) new cholesterol treatment guidelines recommend consideration of statin treatment for a larger proportion of population for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). It is important to assess the population impact of statin treatment under these new guidelines. Hypothesis: We assessed the hypothesis that increased statin use for the primary prevention of ASCVD might be accompanied by adverse effects among population. Methods: We used 2010 US Census, Multiple Cause Mortality, Third National Health and Nutrition Examination Survey Linked Mortality File (NHANES III 1988-2006, n=7095) and NHANES 2005-2010 (n=3178) participants 40-75 years of age to estimate prevalence of statin use, annual ASCVD deaths prevented and excess adverse effects by age, sex, and race/ethnicity if everyone followed updated guidelines. Results: Among 33.0 million adults aged 40-75 years meeting new guidelines for primary pr...
Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1‐Dependent Manner in Mice
Authors: Ling Yang, Weijun Wang, Xiaozhan Wang, Jinfang Zhao, Li Xiao, Wenfang Gui, Huiqian Fan, Jing Xia, Zhonglin Li, Jingjing Yan, Afnan Alasbahi, Qingjing Zhu, Xiaohua Hou
Journal: Hepatology (2018)

Hepatic ischemia/reperfusion (I/R) is a major challenge for liver surgery and specific severe conditions of chronic liver disease. Current surgical and pharmacological strategies are limited to improve liver function after hepatic I/R injury. Thus, an in-depth understanding of the liver I/R mechanism is pivotal to develop new therapeutic methods. The cellular repressor of E1A-stimulated genes (Creg), a key regulator of cellular proliferation, exerts protective roles in cardiovascular diseases and participates in lipid accumulation and inflammatory response in the liver. However, the role of Creg in hepatic I/R remains largely unknown. A genetic engineering technique was used to explore the function of Creg in hepatic I/R injury. Hepatocyte-specific Creg knockout (CregΔHep ) and transgenic mice were generated and subjected to hepatic I/R injury, as were the controls. Creg in hepatocytes prevented against liver I/R injury by suppressing cell death and inflammation. In vitro studies were performed using primary hepatocytes isolated from CregΔHep that were challenged by hypoxia/reoxygenation insult. These cells exhibited more cell death and inflammatory cytokines production similar to observations in vivo. Moreover, further molecular experiments showed that Creg suppressed mitogen-activated protein kinase (MAPK) signaling by inhibiting TAK1 (TGF-β-activated kinase 1) phosphorylation. Inhibiting TAK1 by 5Z-7-ox or mutating the TAK1-binding domain of Creg abolished the protective role of Creg indicating that Creg binding to TAK1 was required for prevention against hepatic I/R injury. Conclusion: These data demonstrate that Creg prevents hepatocytes from liver I/R injury. The Creg-TAK1 interaction inhibited the phosphorylation of TAK1 and the activation of MAPK signaling, which protected against cell death and inflammation during hepatic I/R injury.
Multifunctional melanin-like nanoparticles for bone-targeted chemo-photothermal therapy of malignant bone tumors and osteolysis
Authors: Yitong Wang, Quan Huang, Xiao He, Hui Chen, Yuan Zou, Yiwen Li, Kaili Lin, Xiaopan Cai, Jianru Xiao, Qiang Zhang, Yiyun Cheng
Journal: Biomaterials (2018)
MCI-154 Increases Ca2+ Sensitivity of Reconstituted Thin Filament
Authors: MasatakaSata, SeiryoSugiura, HiroshiYamashita, HideoFujita, Shin-ichiMomomura, TakashiSerizawa
Journal: Circulation Research (1995)

Abstract MCI-154 (6-[4-(4′-pyridylamino)phenyl]-4,5-dihydro-3(2H)pyridazinone hydrochloride trihydrate) is a potent novel cardiotonic agent whose positive inotropism is shown to be mainly based on an increase in Ca2+ sensitivity of the contractile apparatus. To elucidate the exact mechanism through which this drug acts, we investigated the movement of the reconstituted thin filament on a myosin layer in vitro. Cardiac thin filaments were reconstituted from actin and tropomyosin-troponin complex purified from rat cardiac acetone powder separately. Double staining of the filament showed that tropomyosin-troponin complex was integrated along actin filament homogeneously. Thin filaments thus prepared were fluorescently labeled and made to slide on rat cardiac myosin fixed on a glass coverslip while varying the [Ca2+] of the medium (control, pH 7.2 at 25°C). When [Ca2+] was low, the filaments showed only brownian motion. However, above a certain level of [Ca2+] (the threshold [Ca2+]), the filaments started to ...
Abstract 1459: A mechanism counteracting micronucleation for maintenance of genomic integrity
Authors: Matthias Samwer, Maximilian W. Schneider, Rudolf Hoefler, Philipp Schmalhorst, Julian Jude, Johannes Zuber, Daniel W. Gerlich
Journal: Cancer Research (2018)

Abstract A hallmark of eukaryotic cells is that they store all their chromosomes in a single nucleus. This is important for the maintenance of genomic integrity, as individual chromosomes packaged into separate micronuclei are prone to massive DNA damage. Micronuclei are characteristic for cancer cells and thought to drive the evolution of cancer genomes. However, the mechanisms normally promoting the packaging of all chromosomes into a single nucleus have remained largely elusive. Animal cells undergo an open mitosis, in which the cell disassembles its nucleus to release a set of individualized chromosomes. At the end of mitosis, cells reassemble a single nucleus around a complete set of chromosomes, utilizing endoplasmic reticulum-derived membranes. How cells restrict nuclear envelope assembly to the surface around the set of anaphase chromosomes is unclear. It has been proposed that the mitotic spindle may help anaphase chromosomes form a continuous surface by bringing them into proximity. Using live cell imaging, we found that the mitotic spindle is not required to form a single nucleus in human cells. We then performed an RNAi screen for spindle-independent factors that are required to shape a single nucleus and identified the protein barrier-to-autointegration factor (BAF). BAF has been previously suggested to contribute to nuclear assembly by linking chromatin to nuclear envelope membranes containing “LEM” domain (Lap2/Emerin/Man1) proteins. However, by RNAi and mutational analysis, we unexpectedly discovered that BAF's LEM-binding activity was dispensable for nuclear assembly in human cells. Instead, we found that BAF's ability to dimerize and cross-bridge distant DNA segments was essential to shape a single nucleus. By probing purified chromatin and recombinant BAF proteins with atomic force microscopy, we found that BAF forms a rigid shell at the chromatin surface, depending on its DNA-DNA cross-bridging activity. In cells, BAF restricted membranes to the surface formed by the set of anaphase chromosomes, thereby preventing the formation of micronuclei. Thus, BAF regulates chromosome mechanics to shape a single nucleus during mitotic exit. Citation Format: Matthias Samwer, Maximilian W. Schneider, Rudolf Hoefler, Philipp Schmalhorst, Julian Jude, Johannes Zuber, Daniel W. Gerlich. A mechanism counteracting micronucleation for maintenance of genomic integrity [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 1459.
Abstract LB-005: Anti-tumoral effects of novel lymphatic delivery of anti-CTLA-4 in a metastatic murine breast cancer model
Authors: Sunkuk Kwon, Fred Christian Velasquez, Russel F. Ross, Wen-Jen Hwu, Eva M. Sevick-Muraca
Journal: Cancer Research (2018)

Abstract The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is an immune checkpoint receptor expressed by the activated T-cells and plays a key role in modulating T-cell function. Blockade of CTLA-4 after systemic administration can induce an antitumor immune response by promoting the activation and proliferation of tumor-specific T cells. Despite important clinical benefits, systemic intravenous administration of anti-CTLA-4 antibody often results in off-target toxicities (i.e., severe immune-related adverse events) by inappropriately activating naïve-T cells in distant lymph nodes (LNs) and other lymphoid tissues where non-tumor, self-antigens rather than tumor antigens are presented. Thus, efficient direct delivery of checkpoint inhibitors into the regional lymphatics could provide maximal drug exposure to targets within tumor-draining LN basins and their efferent lymphatic vessels before emptying into the blood vasculature for systemic delivery to the tumor. In this study, we used a novel, infusion device, SOFUSATM, consisting of a 66 mm2 microneedle array with a 6 micron polyether ketone nanotopographical film heat-formed over each microneedle to infuse therapeutic doses into the lymphatics in mice. 4T1 mouse mammary tumor cells transfected with luciferase (4T1-luc) were injected into the mammary fat pad of BALB/C mice. Anti-(cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody (10mg/kg) was administered on days 11, 15, 19, and 23 via SOFUSATM. SOFUSATM infusion occurred on the right dorsal back. While further studies are underway, our preliminary data demonstrated that when the repeated dose of anti-mCTLA-4 was successfully delivered via SOFUSATM, significant tumor shrinkage occurred when compared to the untreated group and the group of mice treated with conventional intraperitoneal (i.p.) administrations. Our bioluminescence imaging data showed no lymph node and distant organ metastases in mice dosed with SOFUSATM as compared to the untreated mice and mice with i.p. treatment, both of which showed LNs, lung, or liver metastases. Our study may revolutionize immunotherapies by moving from advanced, systemic to “first-line” loco-regional, cancer treatment. Citation Format: Sunkuk Kwon, Fred Christian Velasquez, Russel F. Ross, Wen-Jen Hwu, Eva M. Sevick-Muraca. Anti-tumoral effects of novel lymphatic delivery of anti-CTLA-4 in a metastatic murine breast cancer model [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 LB-005.
Beneficial Effects of Pentoxifylline in Patients With Idiopathic Dilated Cardiomyopathy Treated With Angiotensin-Converting Enzyme Inhibitors and Carvedilol
Authors: DanielSkudicky, AnnetteBergemann, KarenSliwa, GeoffreyCandy, PinhasSareli
Journal: Circulation (2001)

Background—We previously reported beneficial effects of pentoxifylline, a xanthine-derived agent known to inhibit the production of tumor necrosis factor-α, in patients with idiopathic dilated cardiomyopathy treated with diuretics, digoxin, and ACE inhibitors. Since then, 3 large clinical trials showed important clinical benefits of β-blockers in this population. Therefore, we designed the present study to establish whether in patients with heart failure already receiving treatment with ACE inhibitors and β-blockers, the addition of pentoxifylline would have an additive beneficial effect. Methods and Results—In a single-center, prospective, double-blind, randomized, placebo-controlled study, 39 patients with idiopathic dilated cardiomyopathy were randomized to pentoxifylline 400 mg TID (n=20) or placebo (n=19) if they had a left ventricular ejection fraction <40% after 3 months of therapy with digoxin, ACE inhibitors, and carvedilol. Primary end points were New York Heart Association functional class, exe...
Abstract 4953: Metabolic targeting of chemoresistance perturbs clonal complexity in pancreatic cancer
Authors: Sara Loponte, Denise Corti, Sahil Seth, Edoardo Del Poggetto, I-Lin Ho, Chieh-Yuan Li, Shan Jiang, Joseph R. Marszalek, Maria Emilia Di Francesco, Giannicola Genovese, Giulio Draetta, Alessandro Carugo, Andrea Viale
Journal: Cancer Research (2018)

Abstract A major barrier to achieving durable remission and definitive cure in oncology patients is the emergence of tumor resistance, a common outcome of different disease types independent from the therapeutic approach undertaken. Patients with pancreatic ductal adenocarcinoma (PDAC) continue to have a poor prognosis despite concerted efforts to advance new drugs to the clinic. One reason for this, in PDAC and other tumors, is that tumors are constantly adapting and evolving in response to external perturbations. To better investigate tumor evolution in response to therapy we developed a new clonal tracking platform that enables the in vivo study of long term self-renewing compartments and the generation of cohorts of patient-derived xenografts in which tumors are virtually identical and maintained by the same clones (clonal replica tumors), representing a unique tool to address fundamental questions about clonal dynamics in response to pharmacological treatment. Using this novel approach we demonstrate that standard of care in pancreatic cancer, despite inducing tumor regression, has minimal effect on the clonal composition of tumors that eventually relapse. Transcriptomic and metabolic characterization of residual tumor cells in patient derived xenograft models as well as in patients after chemoradiation shows that resistant cells that contribute to tumor relapse are metabolically rewired to upregulate mitochondrial respiration (OXPHOS). Combining a novel inhibitor of oxidative phosphorylation (IACS-010759), developed at the MD Anderson Institute for Applied Cancer Science and currently in phase I clinical trial in relapsed/refractory acute myelogenous leukemia and advanced solid tumors, with standard of care drugs drastically reduces tumor clonal complexity, underscoring the promise of inhibiting mitochondrial respiration as a new therapeutic strategy to prolong patient survival by eradicating resistant clones that survive chemoradiation. Citation Format: Sara Loponte, Denise Corti, Sahil Seth, Edoardo Del Poggetto, I-Lin Ho, Chieh-Yuan Li, Shan Jiang, Joseph R. Marszalek, Maria Emilia Di Francesco, Giannicola Genovese, Giulio Draetta, Alessandro Carugo, Andrea Viale. Metabolic targeting of chemoresistance perturbs clonal complexity in pancreatic 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 4953.