tbuckley/cabot-search huggingface dataset:
Adrenomedullin Augments Inducible Nitric Oxide Synthase Expression in Cytokine-Stimulated Cardiac Myocytes
Authors: UichiIkeda, ToshikoKanbe, YasuhiroKawahara, MitsuhiroYokoyama, KazuyukiShimada
Journal: Circulation (1996)

Background Plasma levels of adrenomedullin are increased in patients with congestive heart failure, but there has been no report concerning the effects of adrenomedullin on the heart. We investigated the effects of adrenomedullin on NO synthase activity in cardiac myocytes. Methods and Results We measured the production of nitrite, a stable metabolite of NO, in cultured neonatal rat cardiac myocytes with the Griess reagent. Inducible NO synthase mRNA and protein expression were assayed by Northern and Western blotting, respectively. Incubation of the cultures with interleukin-1β (10 ng/mL) for 24 hours caused a significant increase in nitrite accumulation. Adrenomedullin significantly augmented nitrite production by interleukin-1β–stimulated but not by unstimulated cardiac myocytes in a dose-dependent manner (10−10 to 10−6 mol/L). The adrenomedullin-induced nitrite production by interleukin-1β–stimulated cells was accompanied by increased inducible NO synthase mRNA and protein expression. In the presence ...
A New Treatment for Severe Pulmonary Embolism
Authors: RenéKoning, AlainCribier, LowellGerber, HélèneEltchaninoff, ChristopheTron, VivekGupta, RobertSoyer, BriceLetac
Journal: Circulation (1997)

Background The rheolytic thrombectomy catheter has been specially designed to remove intravascular thrombus from coronary and peripheral arteries. It demonstrates a practical application of Bernoulli’s principle relating to a low-pressure zone in the region of a high-velocity jet. In this device, this effect is created by direct high-pressure saline jets located at the tip. Thrombus is drawn into this region and, because of the large pressure difference, undergoes mechanical thrombolysis due to the powerful mixing forces. The resulting microparticles are aspirated through the same catheter and removed from the body. Methods and Results We report the use of this device in two patients presenting with severe pulmonary embolism and contraindications to thrombolytic therapy. The two procedures were successfully performed with an excellent immediate angiographic result at the site of the rheolytic thrombectomy. In both cases, the clinical improvement was maintained at follow-up with the same good angiographic ...
Paraoxonase-2 Reduces Oxidative Stress in Vascular Cells and Decreases Endoplasmic Reticulum Stress–Induced Caspase Activation
Authors: SvenHorke, InesWitte, PetraWilgenbus, MaximilianKrüger, DennisStrand, UlrichFörstermann
Journal: Circulation (2007)

Background— In the vascular system, elevated levels of reactive oxygen species (ROS) produce oxidative stress and predispose to the development of atherosclerosis. Therefore, it is important to understand the systems producing and those scavenging vascular ROS. Here, we analyzed the ROS-reducing capability of paraoxonase-2 (PON2) in different vascular cells and its involvement in the endoplasmic reticulum stress pathway known as the unfolded protein response. Methods and Results— Quantitative real-time polymerase chain reaction and Western blotting revealed that PON2 is equally expressed in vascular cells and appears in 2 distinct glycosylated isoforms. By determining intracellular ROS, we show that overexpression of PON2 markedly reduced ROS, whereas its knockdown increased ROS levels significantly. Using microscopic and biochemical methods, we found PON2 mainly in the nuclear membrane and endoplasmic reticulum. Furthermore, PON2 expression was induced at both the promoter and protein levels by endoplasm...
Prediction of Head-Up Tilt Test Result by Analysis of Early Heart Rate Variations
Authors: ZiadMallat, EricVicaut, AdamaSangaré, JordankaVerschueren, GuyFontaine, RobertFrank
Journal: Circulation (1997)

Background Head-up tilt testing is a useful test for investigating vasovagal syncope. The determination of early, accurate, predictive criteria for a negative result would permit a reduction in the duration of the tilt test. Methods and Results Patients with no drug use and no illnesses other than recurrent unexplained syncope were recruited. In an initial study (110 consecutive patients), we aimed to determine a predictive criterion based on heart rate variations during the first minutes of upright tilting that could distinguish between patients with positive and negative tilt tests (patients with an early continual decrease in heart rate or blood pressure were excluded). Then we tested the predictive value of the established criterion in a second independent sample of patients with unexplained syncope (109 consecutive patients). An early sustained increase in heart rate ≤18 bpm during the first 6 minutes of upright tilting at a 60° angle allowed us to predict negative tilt tests with 100% specificity, 1...
Role of the JAK/STAT Pathway in Rat Carotid Artery Remodeling After Vascular Injury
Authors: YukihikoSeki, HisashiKai, ReiShibata, TsuyoshiNagata, HideoYasukawa, AkihikoYoshimura, TsutomuImaizumi
Journal: Circulation Research (2000)

Abstract—In cultured vascular smooth muscle cells (VSMCs), Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are expressed constitutively and play a role in angiotensin II (Ang II)–induced intracellular signaling and proliferation. However, little is known regarding the relevance of these proteins to the process of vascular remodeling. The role of JAK and STAT proteins in vascular remodeling and their functional coupling with Ang II were examined in balloon-injured rat carotid artery. Immunoreactive Jak2, Tyk2, Stat1, and Stat3 were not detected in the intact artery. Immunohistostaining showed transient expressions of these JAKs and STATs in medial and neointimal VSMCs at days 2 and 5, respectively, with a peak at day 7 in both layers. The expressions declined to insignificant levels by day 14. Ang II type 1 receptors (AT1s) were coexpressed in the medial and neointimal VSMCs expressing Jak2 and Stat3. The Jak2 and Stat3 inductions in the injured artery were accompanied b...
Abstract 2985: Radiotherapy and αCD40 non-redundantly augment immunity to checkpoint blockade in refractory pancreatic ductal adenocarcinoma
Authors: Hannah Dada, Andrew J. Rech, Christina Twyman-Saint Victor, Andy J. Minn, Robert H. Vonderheide
Journal: Cancer Research (2018)

Abstract Despite the success of cancer immunotherapy in many disease types, pancreatic ductal adenocarcinoma (PDA) is notably unresponsive to immune checkpoint blockade (ICB) with αPD1 and/or αCTLA4. The mechanism of resistance is poorly understood, but tumor epitopes and the microenvironment, which is immunosuppressive and excludes T cells, are thought to be contributory. To improve response to ICB, we used subcutaneous and orthotopic murine models of PDA to investigate the effect of combination therapy with ICB (CTLA-4 and PD-1 antagonist antibodies), CD40 agonist antibody and radiation therapy (RT). Combination therapy with CD40 agonist antibody, ICB and RT resulted in decrease tumor burden, increase overall survival, and generation of long-term immunity. Response is dependent on T and short-lived myeloid cells, while it is independent of innate activation pathways. Together, these results suggest a dual role for both the innate and adaptive immune response in treating PDA. Citation Format: Hannah Dada, Andrew J. Rech, Christina Twyman-Saint Victor, Andy J. Minn, Robert H. Vonderheide. Radiotherapy and αCD40 non-redundantly augment immunity to checkpoint blockade in refractory pancreatic ductal adenocarcinoma [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 2985.
Abstract 5759: Discovery of a novel claudin 6 (CLDN6) specific monoclonal antibody
Authors: Lewis J. Stafford, Brad Screnci, Chidananda Sulli, Erin Rosenberg, Nicholas Molino, David Tucker, Jonathan Sullivan, Trevor Barnes, Jennifer Pfaff, Tanmayee Hazarika, Thomas Charpentier, Samantha Gilman, Rebecca Rimkunas, Rona Wilf, Sharon Willis, Benjamin Doranz, Joseph Rucker, Ross Chambers
Journal: Cancer Research (2018)

Abstract Claudin 6 (CLDN6) is a tight junction molecule that is involved in cell to cell adhesion of epithelial and endothelial cell sheets. CLDN6 is considered an oncofetal protein which is not expressed in normal human tissue but is expressed in some cancers such as endometrial, ovarian and testis cancer. Expression of CLDN6 in endometrial and urothelial cancer leads to a poor prognosis. The problem of developing antibodies against CLDN6 is that the family member claudin 9 (CLDN9) is highly homologous, only varying by 2 amino acids in the extracellular domain. To address this need, Integral Molecular has developed the MPS Discovery Engine® to enable the isolation, characterization, and engineering of monoclonal antibodies for tight junction proteins, GPCRs, ion channels, and transporters. MPS utilizes a collection of technologies to address each of the barriers to monoclonal antibody development against the native extracellular epitopes of multispan membrane proteins. These include, antigen engineering to attain high levels of surface expression, DNA and Lipoparticle immunization to present native epitopes to the immune system, diverse immunization host species to deal with highly conserved proteins, Lipoparticles (high concentration native membrane proteins) to enable phage display, microfludic B-cell isolation to isolate rare MAbs, and shotgun mutagenesis (comprehensive alanine scanning) for epitope mapping. Using the MPS Discovery Engine® we were able to successfully screen a large panel of clones for claudin 6 specificity. From these clones there were 72 potential antibodies that reacted with either claudin 6 or 6/9. A subset of these antibodies reacted only to claudin 6 and not to claudin 9 which has led to our lead drug candidate. With our MPS Discovery Engine® platform, we have the ability to target intact, conformationally specific, and functional antibodies to multipass membrane proteins. Citation Format: Lewis J. Stafford, Brad Screnci, Chidananda Sulli, Erin Rosenberg, Nicholas Molino, David Tucker, Jonathan Sullivan, Trevor Barnes, Jennifer Pfaff, Tanmayee Hazarika, Thomas Charpentier, Samantha Gilman, Rebecca Rimkunas, Rona Wilf, Sharon Willis, Benjamin Doranz, Joseph Rucker, Ross Chambers. Discovery of a novel claudin 6 (CLDN6) specific monoclonal antibody [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 5759.
Protease-Activated Receptor 2–Mediated Vasodilatation in Humans In Vivo
Authors: JonathanRobin, RajeshKharbanda, PeterMclean, RichardCampbell, PatrickVallance
Journal: Circulation (2003)

Background— Systemic hypotension as a consequence of vascular dysfunction is a well-recognized and important feature of critical illness. Although serine protease activation has been implicated as a cause of vascular dysfunction in systemic inflammation, the mechanism is unknown. Recently, a class of receptors with an entirely novel mechanism of action, protease-activated receptors (PARs), has been identified that would explain the link between protease activation and systemic hypotension. Our aim was to test the hypothesis that in vivo activation of protease-activated receptor 2 (PAR-2) in humans would mediate vasodilatation. Methods and Results— For these first-in-human studies, an activating peptide for the human PAR-2 receptor was synthesized and administered to healthy volunteers. Using both the dorsal hand vein technique and forearm plethysmography, we studied the effects of PAR-2 activation in human blood vessels and investigated the mechanism of vasodilation. Activation of PAR-2 receptors in vivo ...
Noninvasive Diagnosis of Dual AV Node Physiology in Patients With AV Nodal Reentrant Tachycardia by Administration of Adenosine-5′-Triphosphate During Sinus Rhythm
Authors: BernardBelhassen, RomanFish, MichaelGlikson, AharonGlick, MichaelEldar, ShlomoLaniado, SamiViskin
Journal: Circulation (1998)

Background—Atrioventricular nodal reentry tachycardia (AVNRT) represents the most commonly encountered type of regular paroxysmal supraventricular tachycardia. This study determined whether administration of adenosine-5′-triphosphate (ATP) during sinus rhythm may be useful in the noninvasive diagnosis of dual AV nodal pathways. Methods and Results—During electrophysiological study, we intravenously administered incremental doses of ATP (from 10 to 50 mg) during sinus rhythm to patients with spontaneous and inducible sustained AVNRT (study group, n=42) and to patients with no evidence of dual AV nodal physiology or inducible AVNRT (control group, n=21). Signs suggestive of dual AV node physiology after ATP administration during sinus rhythm (“jump” of AH ≥50 ms between 2 consecutive beats, ≥1 AV nodal echo beat, or initiation of AVNRT) were observed in 32 (76%) of 42 study patients but in only 1 (5%) of the 21 control patients (P<0.001). Similar results were observed when only surface lead recordings (with...
Abstract LB-008: Intracellular delivery of SOCS3 suppresses hepatocelluar carcinoma progression
Authors: Seulmee Shin, Kuysook Lee, Yunseo Hwang, Youngsil Choi, Daewoong Jo
Journal: Cancer Research (2018)

Abstract Background Practical methods to deliver proteins systemically in animals have been hampered by poor tissue penetration and inefficient cytoplasmic localization of internalized proteins. Therefore, we have developed novel cell-penetrating peptides (CPPs), named advanced macromolecule transduction domains (aMTDs), to deliver therapeutically active macromolecule including proteins systemically in vivo. The suppressor of cytokine signaling 3 (SOCS3) is negative feedback regulator of JAK/STAT signaling that plays a key role in inflammation, fibrosis and carcinogenesis in the liver. Furthermore, hypermethylation of CpG islands in the SOCS3 promoter is correlated with its transcriptional silencing in some cancers, including hepatocellular carcinoma (HCC). Objective The present study utilized aMTD sequences to develop improved cell-permeable (iCP-) SOCS3 as a protein-based biotherapeutics against HCC. Methods Cell permeable SOCS3 proteins, with and without a 12-amino acid aMTD sequence, were expressed at high yields in E. coli. The proteins also contained a solubilization domain (SD) to enhance the solubility of the recombinant proteins in physiological buffers. Results iCP-SOCS3 fused to aMTD/SD suppressed cancer cell phenotypes (e.g., 84% inhibition of proliferation, arrested cell cycle progression, 86% inhibition of migration/invasion), apoptotic loss of cell viability (40 ~ 80% in HCC cell lines: Hep3B2.1-7, HepG2, Huh7 and SK-Hep1) and changes in apoptosis biomarker expression (e.g., Bcl-2 and cleaved caspase-3). In contrast, iCP-SOCS3 did not affect proliferation and apoptosis of non-cancer cells (Chang). In addition, iCP-SOCS3 also significantly suppressed the tumor growth (70% inhibition in Hep3B2.1-7; 67% inhibition in HepG2, respectively) in human-mouse xenograft models. The anti-tumor activity of iCP-SOCS3 was accompanied by changes in the expression of biomarkers linked to SOCS3 signaling including cyclin E, p21, Bax and VEGF. Furthermore, iCP-SOCS3 suppressed tumor growth equivalently to Cisplatin®, a well-established cytotoxic agent, but without observed toxicity or adverse effects. These results suggest that iCP-SOCS3 inhibits the growth of HCC tumor cells and tumor xenografts. Conclusions These results provide further evidence that SOCS3 can function as a tumor suppressor and intracellular delivery of iCP-SOCS3 may provide a novel protein therapy against HCC. Citation Format: Seulmee Shin, Kuysook Lee, Yunseo Hwang, Youngsil Choi, Daewoong Jo. Intracellular delivery of SOCS3 suppresses hepatocelluar carcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-008.
Prevention of Rat Cerebral Aneurysm Formation by Inhibition of Nitric Oxide Synthase
Authors: ShunichiFukuda, NobuoHashimoto, HiroakiNaritomi, IzumiNagata, KazuhikoNozaki, SoichiroKondo, MichiharuKurino, HaruhikoKikuchi
Journal: Circulation (2000)

Background—Cerebral saccular aneurysm is a major cause of subarachnoid hemorrhage, one of the cerebrovascular diseases with the highest mortality. The mechanisms underlying the development of aneurysms, however, still remain unclear. We have made a series of reports on an animal model of experimentally induced cerebral aneurysms that resemble human cerebral aneurysms in their location and morphology, suggesting that the arterial wall degeneration associated with aneurysm formation develops near the apex of arterial bifurcation as a result of an increase in wall shear stress. Using the animal model and human specimens, we examined the role of nitric oxide (NO) in the degenerative changes and cerebral aneurysm formation. Methods and Results—Inducible NO synthase (iNOS) was immunohistochemically located at the orifice of human and rat aneurysms. Nitrotyrosine distribution was also seen in the human aneurysm. Although no iNOS immunostaining was found in normal arteries, iNOS immunoreactivity was observed in p...
Abstract 3589: Preclinical evaluation of mesothelin-specific T cell receptor (TCR) fusion constructs (TRuC™s) utilizing the signaling power of the complete TCR complex: A new opportunity for solid tumor therapy
Authors: Jian Ding, Ekta Patel, Patrick Tavares, Justin Quinn, Rashmi Choudhary, Bonnie Le, Olga Kiner, Solly Weiler, Daniel R. Getts, Patrick Baeuerle, Robert Hofmeister
Journal: Cancer Research (2018)

Abstract Despite success in treating hematological malignancies, T cells expressing chimeric antigen receptors (CARs) have shown poor efficacy in solid tumor indications. The poor utility of CARs is thought to be due to a number of factors including T cell exhaustion and a lack of persistence. Utilizing only the CD3ζ chain of six distinct T cell receptor subunits in combination with a costimulatory domain, the CARs bypass the natural TCR signaling complex. The failure to initiate and harness a complete TCR response is arguably a primary underlying factor preventing CAR-T cell success in solid tumor indications. Here, we present a novel T cell engineering platform: T Cell Receptor Fusion Constructs (TRuC™s), which target tumors in a MHC non-restricted fashion. Unlike CARs, the constructs integrate into the TCR complex, harnessing the full potential of natural T cell activation, effector function and regulation. Here we demonstrate preclinical evidence underscoring the efficacy of TRuC™-T cells re-programmed to target the solid tumor antigen mesothelin (TC-210). TC-210 showed robust anti-tumor activity in vitro and in vivo in mesothelioma, lung and ovarian tumor models. Surprisingly, this activity was associated with less proinflammatory cytokine production compared to CAR-T cells with the same binder and was supported by strong TRuC™-T cell persistence. Taken together, mesothelin targeting TRuC™-T cells have potent anti-tumor activity and present a promising approach for treating mesothelin-expressing solid tumors. Citation Format: Jian Ding, Ekta Patel, Patrick Tavares, Justin Quinn, Rashmi Choudhary, Bonnie Le, Olga Kiner, Solly Weiler, Daniel R. Getts, Patrick Baeuerle, Robert Hofmeister. Preclinical evaluation of mesothelin-specific T cell receptor (TCR) fusion constructs (TRuC™s) utilizing the signaling power of the complete TCR complex: A new opportunity for solid tumor therapy [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 3589.
DETERRED: PD-L1 blockade to evaluate the safety of lung cancer therapy using carboplatin, paclitaxel, and radiation combined with MPDL3280A (atezolizumab).
Authors: Steven H. Lin, Yan Lin, Justina Price, Matthew Parker, Daniel Richard Gomez, James William Welsh, Ritsuko Komaki, Jonathan M. Kurie, George R. Simon, George R. Blumenschein, Jenean A. Young, See-Chun Phan, Alan Sandler, Vassiliki Papadimitrakopoulou, John Heymach, Anne S. Tsao
Journal: Journal of Clinical Oncology (2017)

3064 Background: Immune checkpoint blockade in non-small cell lung cancer (NSCLC) may be enhanced when combined with radiation therapy. Atezolizumab (atezo) is a humanized and Fc receptor modified monoclonal antibody that blocks programmed death-ligand-1 (PD-L1) interacting with PD-1 or B7.1 sparing PD-L2, which may result in less pulmonary toxicity. We report the early safety data of combining atezo added sequentially after standard concomitant chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). Methods: This is a phase II study in LA-NSCLC assessing the safety and feasibility of adding atezo to CRT in two parts: I) sequentially (N = 10) with CP after completing CRT, or II) concurrently (N = 30) with CRT followed by consolidation atezo with CP. We report on the early toxicity results from part I of the trial. Atezo was given at 1200 mg IV Q3 weeks with consolidation CP for 2 cycles after CRT followed by atezo monotherapy for up to one year. Radiation dose at 60-66 Gy in 30-33 fractions was combined with weekly low dose CP, followed by 2 cycles of full dose CP. Dose limiting toxicities were defined as any adverse events (AEs) ≥ grade 3 within 15 weeks of start of therapy or any immune-related AEs during atezo treatment. Results: From January to December 2016, 10 evaluable patients were enrolled. Seven patients have received consolidation atezo ranging from 1 to 14 doses, with 3 yet to receive atezo after completing CRT. Three patients reported potential immune-related AEs. One patient developed grade 3 arthralgia, and another developed grade 2 radiation-induced pneumonitis, which resolved with steroids. A third patient who experienced grade 3 dyspnea due to COPD exacerbation after 1 dose of atezo discontinued additional therapy. Of the 7 patients who have received atezo, 2 patients developed progression of disease after 6 and 8 doses of atezo. Conclusions: Atezo consolidation with 2 cycles of CP after CRT appears to be feasible and well tolerated with manageable toxicities. Additional data from part I will be reported. Conditions for proceeding after part I are met and part II of the study which adds atezo to CRT followed by atezo-CP consolidation is open for accrual. Clinical trial information: NCT02525757.