tbuckley/cabot-search huggingface dataset:
Long-Term Management of Patients After Venous Thromboembolism
Authors: CliveKearon
Journal: Circulation (2004)

Long-term treatment of venous thromboembolism (VTE) focuses mainly on the duration of anticoagulant therapy, usually with vitamin K (VK) antagonists. The duration of therapy should be individualized based on the risk of recurrent VTE if treatment were stopped and the risk of bleeding if treatment were continued. The risk of recurrence is low if thrombosis was provoked by a major reversible risk factor such as surgery; 3 months of treatment is usually adequate for such patients. The risk of recurrence is high if thrombosis was unprovoked (“idiopathic”) or associated with an irreversible risk factor such as cancer; anticoagulant treatment for at least 6 months, and often indefinitely, is indicated for such patients. Risk of recurrence is intermediate if thrombosis was associated with a minor transient risk factor; such patients can be treated for 3 to 6 months. Within each of these categories, presentation as pulmonary embolism, >1 previous VTE, an underlying malignancy, an antiphospholipid antibody, or sel...
Effects of Blood Flow and Left Atrial Pressure on Pulmonary Venous Resistance
Authors: KizukuKuramoto, SimonRodbard
Journal: Circulation Research (1962)

Pulmonary venular pressure was measured in 11 thoracotomized dogs and in 8 isolated lung lobes by introducing a small catheter (O.D. 0.6 or 0.9 mm.) as far as possible retrograde into the pulmonary veins. In thoracotomized dogs, insufflated with a maximal air pressure of 6 mm. Hg, the mean pulmonary arterial, venular, and left atrial pressures averaged 18.4, 9.1, and 4.2 mm. Hg, respectively. An almost linear relationship was found between venular pressure and pulmonary blood flow, except in the low flow ranges; venular pressures exceeded left atrial pressure by one-fourth to one-half of the gradient from pulmonary artery to left atrium. The calculated pulmonary venous resistance decreased with increased blood flow. The fall in pulmonary vascular resistance resulting from elevation of the left atrial pressure was shown to reside primarily in the venous system, especially when left atrial pressure was low; arterial and capillary resistance also fell, but to a lesser extent. Pulmonary venular pressure is hi...
Abstract 872: IDH1-mutated cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity
Authors: Mohammed Khurshed, Remco J. Molenaar, Johanna W. Wilmink, Hanneke W. van Laarhoven, Cornelis J. van Noorden
Journal: Cancer Research (2018)

Abstract Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer and predicts improved response to treatment with irradiation or chemotherapy. Mutated IDH1 enzymes catalyze neomorphic conversion of α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2HG) with concomitant consumption of NADPH, resulting in decreased reducing power needed for detoxification of e.g. reactive oxygen species (ROS). We report that a small-molecule inhibitor of IDH1-mutation (IDH1MUT) that is being investigated for cancer therapy may limit efficacy of treatment when co-administered with cisplatin. In the present study, we investigated whether the efficacy of treatment with cisplatin, which is a widely-used chemotherapeutic agent, induces DNA strand breaks and oxidative damage in IDH1MUT cancer cells. We found that exposure to cisplatin induced higher levels of ROS, DNA double-strand breaks, and cell death in IDH1MUT cancer cells as compared to IDH1 wild-type (IDH1WT) cancer cells. Besides these cytotoxic effects, mechanistic investigations revealed that cisplatin treatment causes dose-dependent reduction of oxygen consumption and thus the oxidative respiration in lDH1MUT cells and not in lDH1WT cells, which was accompanied by disturbed mitochondrial proteostasis and impaired mitochondrial activity. These effects were abolished by the IDH1MUT inhibitor AGI-5198 and were recapitulated by treatment with D-2HG. Thus, our study shows that altered oxidative stress responses due to a vulnerable oxidative metabolism underlie the sensitivity of IDH1MUT cancer cells to cisplatin. Furthermore, our data offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and imply that administration of IDH1MUT inhibitors in these patients limit efficacy of cisplatin treatment. Citation Format: Mohammed Khurshed, Remco J. Molenaar, Johanna W. Wilmink, Hanneke W. van Laarhoven, Cornelis J. van Noorden. IDH1-mutated cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity [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 872.
Abstract 4065: Suppression of myeloid cell arginase activity leads to therapeutic response in Kras mutant lung cancer by activating anti-tumor immunity
Authors: Juan J. Miret, Paul Kirschmeier, Min Wu, Wei Huang, William Walker, Sangeetha Palakurti, Nick Saccomano, Peter S. Hammerman, Kwok-kin Wong, Esra Akbay
Journal: Cancer Research (2018)

Abstract Metabolic changes in the tumor microenvironment impair the generation of an efficient anti-tumor immune response. Reduction of specific amino acids like arginine and tryptophan limit anti-tumor immune responses, contributing to a tumor generated immune suppressive environment. Arginine levels are critical for lymphocyte proliferation and function, and they are regulated by arginase 1 &amp; 2 and nitric oxide synthase. Arginase 1 activity has been associated with most of the immunosuppressive effects resulting from arginine depletion and the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant established tumor models. RNA sequencing of sorted cell populations from immunocompetent genetically engineered KRAS G12D mutant mouse lung tumors, showed that arginase 1 expression is elevated in the myeloid cell population in the tumor microenvironment. Ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSCs) from mouse tumors hindered T cell function by depleting arginine. These MDSCs expressed elevated levels of arginase 1, and inhibition of its activity by an Arg1/2 inhibitor, compound 9, restored effector T cell function. Treatment of a genetically engineered KRAS mutant mouse model with compound 9 increased arginine levels in blood and tumor and led to an increased number of tumor T cells and a significant reduction in tumor volume after 1 week of treatment. Compound 9 had no growth inhibitory activity across several murine and human KRAS mutant lung cancer cell lines in vitro. We also determined by immunohistochemistry that elevated levels of arginase 1 were expressed in granulocytic myeloid cells from KRAS mutant lung cancer patient samples. Given the data reported here and by others, an arginase inhibitor with excellent potency and in vivo target engagement could represent an important new immunotherapeutic agent. We have recently discovered and are fully characterizing molecules that demonstrate excellent potency and selectivity along with oral bioavailability in rodents that provide good arginase target coverage at modest doses. Citation Format: Juan J. Miret, Paul Kirschmeier, Min Wu, Wei Huang, William Walker, Sangeetha Palakurti, Nick Saccomano, Peter S. Hammerman, Kwok-kin Wong, Esra Akbay. Suppression of myeloid cell arginase activity leads to therapeutic response in Kras mutant lung cancer by activating anti-tumor immunity [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 4065.
ADAR1 Is Involved in the Development of Microvascular Lung Injury
Authors: ReuvenRabinovici, KoroushKabir, MeihongChen, YingjunSu, DexinZhang, XiaoxingLuo, Jing-HuaYang
Journal: Circulation Research (2001)

Abstract—Deamination of adenosine on pre-mRNA to inosine is a recently discovered process of posttranscription modification of pre-mRNA, termed A-to-I RNA editing, which results in the production of proteins not inherent in the genome. The present study aimed to identify a role for A-to-I RNA editing in the development of microvascular lung injury. To that end, the pulmonary expression and activity of the RNA editase ADAR1 were evaluated in a mouse model of endotoxin (15 mg/kg IP)–induced microvascular lung injury (n=5) as well as in cultured alveolar macrophages stimulated with endotoxin, live bacteria, or interferon. ADAR1 expression and activity were identified in sham lungs that were upregulated in lungs from endotoxin-treated mice (at 2 hours). Expression was localized to polymorphonuclear and monocytic cells. These events preceded the development of pulmonary edema and leukocyte accumulation in lung tissue and followed the local production of interferon-γ, a known inducer of ADAR1 in other cell syst...
Abstract 5643: TCRβ repertoire analysis from a prophylactic MUC1 cancer vaccine trial
Authors: Michelle L. Miller, Jason Lohmueller, John R. McKolanis, Robert Schoen, Olivera J. Finn
Journal: Cancer Research (2018)

Abstract Mucin 1 (MUC1) is a large transmembrane glycoprotein that is overexpressed and hypoglycosylated in many adenocarcinomas, including colon cancer. In the hypoglycosylated state, the peptide core of the 20aa variable number of tandem repeats (VNTR) region is exposed, allowing it to function as an altered-self ligand for antibodies and T cells. VNTR peptides have been previously used as antigens in therapeutic cancer vaccines. A clinical trial was conducted to test immunogenicity and safety of a MUC1 100mer VNTR peptide+polyICLC adjuvant vaccine in a prophylactic setting in patients with premalignant colon adenomas who were at high risk for later developing colon cancer. In this premalignant setting, where patients were expected to have fewer immunosuppressive countermeasures usually present in patients with cancer, nearly half of the individuals generated IgG antibodies with no noted adverse effects. Because the antibody response was isotype-switched, it suggested simultaneous T cell activation. To determine whether changes in T cell clonal abundance following immunization could be detected, we sequenced and analyzed TCRβ repertoires from PBMCs of 21 antibody-responders collected before and after both primary and one-year booster vaccinations. Of the patients analyzed, we identified 8 TCRβ sequences from three patients that were significantly elevated after both priming and boosting immunizations, potentially identifying T cell clones that expanded in response to the vaccine. 16 TCRβ sequences from four individuals were significantly decreased at both time points, potentially identifying T cell clones that left circulation to participate in immune responses in secondary lymphoid organs or tissues. The timing of blood collection at two weeks post immunization may have been too late to allow us to detect all of the vaccine-expanded clones before they left circulation. In summary, we found 24 TCRβ CDR3 sequences from 7/21 vaccine responders that significantly changed in frequency after both primary and booster vaccinations. TCR sequencing studies from patients' T cells expanded in vitro with MUC1 peptide will be performed to determine if they overlap with those sequenced ex vivo. Citation Format: Michelle L. Miller, Jason Lohmueller, John R. McKolanis, Robert Schoen, Olivera J. Finn. TCRβ repertoire analysis from a prophylactic MUC1 cancer vaccine trial [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 5643.
Abstract 4780: A novel, potent and selective FGFR4 inhibitor, HM81422 in hepatocellular carcinoma with FGFR4-driven pathway activation
Authors: JaeHo Lee, Hyunjeong Kang, Kyounghwa Koo, Youngeun Ha, Sun Young Lim, Joo-Yun Byun, Hyunkyung Yu, Taehun Song, Moonsub Lee, Seung Hyun Jung, Taewoo Kim, Hyojeong Bang, Eunyoung Kim, Jahoon Kang, Ho Jeong Lee, YoungHoon Kim, YoungGil Ahn, KweeHyun Suh, Sun-Jin Kim
Journal: Cancer Research (2018)

Abstract Introduction: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the second most frequent cause of cancer-related death, however, treatment options are very limited. In recent studies, aberrant signaling through FGFR4 and its ligand, FGF19 have been identified as the oncogenic driver in a subset of HCCs and reported to be associated with poor prognosis. About 30% of HCC patients have altered FGF19/FGFR4 pathway signaling, therefore, the treatment with FGFR4 inhibitor may produce benefit. Materials and Method: Using the structure-based design, we have generated a novel, potent and selective FGFR4 inhibitor, HM81422 with irreversible-covalent binding mode, and evaluated its anti-tumor activity in a variety of HCC cell lines, HCC cell line xenografts and orthotopic grafts. Results: Biochemical selectivity assays demonstrated that HM81422 is highly selective towards FGFR4 compared to other FGFR isotypes as well as a panel of several kinases. The treatment of HM81422 to FGF19 amplified and overexpressed HCC cell lines led to suppression of FGF19/FGFR4 signaling pathway and concomitant reduction in cell viability in dose-dependent manner. Oral administration of HM81422 to mice bearing FGF19 altered HCC cells showed dose-dependent pharmacokinetics, pharmacodynamic modulation of FGFR4 signaling and antitumor efficacy in xenograft models. And HM81422 demonstrated inhibition of tumor growth in an orthotopic liver xenograft model of FGF19 altered HCC in nude mice. Conclusion: In conclusion, the treatment of HCC patients with a potent and selective FGFR4 inhibitor, HM81422, can be an attractive approach targeting approximately 30% of HCC patients by inhibiting altered FGF19-mediated signaling cascade. Further preclinical studies with HM81422 will be performed and reported soon. Citation Format: JaeHo Lee, Hyunjeong Kang, Kyounghwa Koo, Youngeun Ha, Sun Young Lim, Joo-Yun Byun, Hyunkyung Yu, Taehun Song, Moonsub Lee, Seung Hyun Jung, Taewoo Kim, Hyojeong Bang, Eunyoung Kim, Jahoon Kang, Ho Jeong Lee, YoungHoon Kim, YoungGil Ahn, KweeHyun Suh, Sun-Jin Kim. A novel, potent and selective FGFR4 inhibitor, HM81422 in hepatocellular carcinoma with FGFR4-driven pathway activation [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 4780.
Abstract P295: The Inflammasome Is Involved in Myocardial Ischemia-Reperfusion Injury
Authors: MasafumiTakahashi, MasanoriKawaguchi, FumitakeUsui, HiroakiKimura, Shun'ichiroTaniguchi, UichiIkeda
Journal: Circulation Research (2011)

Background: Accumulating evidence indicates that inflammation is involved in the pathophysiology of myocardial ischemia-reperfusion (I/R) injury. However, the mechanism of I/R-initiated inflammation remains to be determined. The inflammasome is a multiprotein complex consisting of nod-like receptor (NLR), apoptosis-associated speck-like adaptor protein (ASC), and caspase-1, and regulates caspase-1-dependent maturation of IL-1beta and IL-18. In the present study, we investigated the role of inflammasome in myocardial I/R injury. Methods and Results: Wild-type (WT), ASC−/−, and caspase-1−/− mice were subjected to 30 min LAD ligation, followed by reperfusion. ASC and caspase-1 were expressed at the site of myocardial I/R injury. Deficiency of ASC and caspase-1 reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and subsequent injuries such as infarct development, myocardial fibrosis, and dysfunction in myocardial I/R injury. To determine the contribution of inflamm...
Molecular Imaging of Coronary Atherosclerosis and Myocardial Infarction
Authors: FlorianLeuschner, MatthiasNahrendorf
Journal: Circulation Research (2011)

Motivated by the promise to transform preclinical research and clinical care, cardiovascular molecular imaging has made advances toward targeting coronary atherosclerosis and heart failure. Here, we discuss recent progress in the field, highlight how molecular imaging may facilitate preventive patient care, and review specific challenges associated with coronary and heart failure imaging. Practical considerations stress the potential of fluorescence imaging for basic research and discuss hybrid protocols such as FMT-CT and PET-MRI.
Abstract 17429: A Porcine Model of Heart Failure With Preserved Ejection Fraction Induced by Sustained Severe Hypertension
Authors: Zhe Zhen, Ziyi Zhu, Song-Yan Liao, Chika Shuto, Cary Hata, Peter Chen, Hung-Fat Tse
Journal: Circulation (2015)

Background: Currently, the lack of well-established large animal models of heart failure with preserved ejection fraction (HFpEF) is one of the major hurdles for developing effective therapies for HFpEF. Here, we describe a large animal model of HFpEF induced by sustained hypertension (HT) that mimics human diseases. Methods: We induced sustained severe hypertension in 9 adult pigs using a combination of intravenous Angiotensin-II (Ang-II, 0.015mg/hr) delivery with an osmotic infusion pump and subcutaneous implantation of deoxycorticosterone acetate (DOCA) pellets (100mg/kg) for 10 weeks. All animals underwent invasive blood pressure (BP) telemetry monitoring and serial invasive pressure-volume (PV) loop assessment as well as echocardiographic examination at baseline, 10 weeks and 18 weeks. Results: Mean systolic and diastolic BP at baseline was 88/61 mmHg which increased immediately after Ang-II infusion plus DOCA (Week 0,158/105 mmHg) and progressively elevated up to Week 10 (171/126mmHg) that persisted out to Week 18 (183/137mmHg) despite termination of Ang-II infusion. Serial echocardiograms showed the development of left ventricular hypertrophy with significant increase in left ventricular mass with preserved left ventricular ejection fraction (Figure, upper panel). PV loop showed progressive elevation of pulmonary artery capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and end-diastolic pressure volume relationship (EDPVR) without change in end-systolic pressure volume relationship, suggestive of left ventricular diastolic dysfunction (Figure, lower panel). Conclusions: We successfully established a clinically relevant large animal model of HFpEF induced by sustained HT, which can be used for future investigation of new treatments for HFpEF.
Abstract 1897: Determining the role of PRCP/PREP in triple negative breast cancer
Authors: Ricardo E. Perez, Lei Duan, Carl G. Maki
Journal: Cancer Research (2018)

Abstract Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancer cases. Currently, the only effective treatment for TNBC is chemotherapy agents. A well-established characteristic of TNBC is the ability of these cells to become metastatic following chemotherapy treatment resulting in increased mortality. New forms of treatment which target TNBC are urgently needed. Insulin receptor substrate 1 (IRS1) has been extensively studied in the regulation of the insulin and insulin-like growth factor receptor signaling cascades, specifically in the induction of the intracellular PI3K/AKT/mTORC1 and MAP kinase pathways. The roles of such pathways in cancer are currently being studied and considered for therapeutic targeting. We previously showed that the stability and levels of IRS1 are maintained by prolylcarboxypeptidase proteins PRCP/PREP in pancreatic cancer cells. Our hypothesis is that PRCP/PREP are potential therapeutic targets in TNBC. Specifically, we hypothesize that blocking the expression or reducing the activity of PRCP/PREP will inhibit the PI3K/AKT/mTORC1 pathway in TNBC cells and, in turn, reduce growth and survival in these cells. To test this, we will be treating a number of TNBC cell lines with a PRCP/PREP inhibitor and determining IRS1/2 protein levels, AKT/mTORC1 signaling, and growth and survival. TNBC cells were screened for sensitivity against the PRCP/PREP inhibitor, Y-ox. Sensitive cells treated with Y-ox showed earlier reduction in the IRS1/AKT/mTORC1 signaling, as well as earlier loss of cell viability compared to those cells with relative resistance to Y-ox. Similarly, cells treated with the IRS1/2 inhibitor NT-157 and the AKT inhibitor, MK-2206 showed loss of cell viability similarly seen with the PRCP/PREP inhibitor, Y-ox. In conclusion, the results shown in this study show a possible new therapeutic target against triple negative breast cancer in the inhibition of PRCP/PREP leading to loss of cell proliferation and viability. Citation Format: Ricardo E. Perez, Lei Duan, Carl G. Maki. Determining the role of PRCP/PREP in triple negative 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 1897.
Response to Letter Regarding Article, “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 (2011)
The Fumagillin Analogue TNP-470 Inhibits DNA Synthesis of Vascular Smooth Muscle Cells Stimulated by Platelet-Derived Growth Factor and Insulin-like Growth Factor-I
Authors: HidenoriKoyama, YoshikiNishizawa, MasayukiHosoi, ShinyaFukumoto, KyokoKogawa, AtsushiShioi, HirotoshiMorii
Journal: Circulation Research (1996)

The effect of an angiogenesis inhibitor, TNP-470, on DNA synthesis and its underlying signaling cascades stimulated by platelet-derived growth factor (PDGF)-BB and insulin-like growth factor (IGF)-I were examined in bovine vascular smooth muscle cells (SMCs). PDGF-BB (10 ng/mL)– and IGF-I (100 ng/mL)–stimulated increase in DNA synthesis was completely abolished by simultaneous treatment with TNP-470 (1.0 ng/mL). TNP-470 had no effects on PDGF receptor autophosphorylation or early signal transduction, such as activation of mitogen-activated protein kinase and immediate early gene expression. PDGF-BB induced an increase in mRNA levels of cyclin D1, cyclin-dependent kinase (cdk) 4, and cdk2, as well as the activity of cdk2, which preceded the G1/S boundary, as estimated by the kinetics of DNA synthesis. The PDGF-BB–induced activation of cdk2 was inhibited by TNP-470, which was correlated with decreased cdk2 mRNA levels. In contrast, TNP-470 had no or less marked effect on cyclin D1 and cdk4 mRNA levels induc...