tbuckley/cabot-search huggingface dataset:
Abstract 3579: RegCAR-TTM: Enabling next-generation CAR-T therapy
Authors: Xu Zhang, Ke Tang, Qingxuan Song, Si Chen, christopher Kasbek, Tianjiao Wang, Jun Huang
Journal: Cancer Research (2018)

Abstract Chimeric Antigen Receptor (CAR) T-Cell Therapy has been emerging as a means of powerful cancer immunotherapy with its exceptional therapeutic efficacy, however, the full potential of CAR-T therapy is hampered by its severe side effects. Thus, CAR-T therapy that is controllable for optimal efficacy and safety is in need developing. To enable controllable CAR-T therapy, we have established a technology platform, RegCAR-TTM. In RegCAR-TTM, aptazymes are generated by in vitro selection/evolution of combinatory nucleic acid libraries and are used as molecular switches for controlling CAR expression. Aptazymes are RNA molecules consisting of an aptamer module and a ribozyme module, in which ribozyme self-cleavage can be allosterically regulated by the aptamer-ligand (e.g. a small molecule drug) interaction. With an aptazyme switch incorporated into the untranslated region (UTR) of a CAR gene, CAR expression can be temporally and dose-dependently controlled at mRNA level by a ligand, which may result in controllability of CAR-T efficacy and safety. Using RegCAR-TTM technology, we have generated aptazyme switches responsive to FDA-approved small molecules drugs with IC50 at micromolar level. Thus, next generation CAR-T therapies with aptazyme switches would be controllable by safe oral small molecules drugs. In conclusion, we have developed a technology platform (RegCAR-TTM) to generate aptazyme switches for enabling controllable CAR-T therapy. Citation Format: Xu Zhang, Ke Tang, Qingxuan Song, Si Chen, christopher Kasbek, Tianjiao Wang, Jun Huang. RegCAR-TTM: Enabling next-generation CAR-T 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 3579.
THU0231 Rheumatic disease as the cause of fever of unknown origin: an update of classical data
Authors: MA Oztürk, S Kiraz, I Ertenli, O Uzun, S Apras, M Çalgüneri, S Unal
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Fever of unknown origin (FUO) remains one of the major diagnostic challenges for the clinician. Although infection, malignancy and collagen vascular disease are accepted the 3 most important causes of FUO, the relative importance of these major categories might have changed because of improvements in serodiagnosis, culture techniques and radiologic imaging modalities. Rheumatic diseases not uncommonly present with fever. <h3>Objectives</h3> Our objective was to make an uptake of our knowledge regarding causes of FUO in our hospital together with more detailed analysis of collagen vascular and granulomatous disorders presenting with FUO. <h3>Methods</h3> In this clinical investigation, we retrospectively evaluated hospital records of patients who were hospitalised in our Infectious Diseases Service from January 1990 through September 2000 to investigate the cause of prolonged fever. One hundred forty-five patients (63 female, 82 male, mean age: 38.5, min-max: 16–80) meeting the classical criteria of FUO were included in the present study. <h3>Results</h3> Infections, rheumatic diseases and malign disorders were found in 93 (64.1%), 24 (16.6%) and 8 patients (5.5%), respectively. Infectious causes are the most common cause in all age groups, and rheumatic disease are the second. Malign diseases were diagnosed in 2.7% of patients under age 50, and percentage of these disorders increased to 15.6% among patients over 50. Miscellaneous conditions were found in 2 patients (1.4%), and despite detailed evaluation 18 patients (12.4%) remained undiagnosed. List of rheumatic diseases diagnosed as causes of FUO in the present study are given in Table 1. <h3>Conclusion</h3> In conclusion, despite widespread use of antibiotics and increasingly useful diagnostic technologies, infectious disease still remain the leading cause of FUO among our group of patients, and collagen vascular diseases together with granulomatous disorders are the second most common group. The percentage of tumours was higher in our elderly patients than in the younger ones but still clearly lower than other causes of FUO in adults. Infectious Diseases Department of Hacettepe University is one of the reference centres in Turkey, and many undiagnosed cases are being referred to our hospital. Therefore we believe that, although we performed the present study only from our hospital reports, the results may reflect the general population of central Anatolia.
Abstract 20735: Clinical Impact of Early Changes in von Willebrand Factor in Patients Supported With Left Ventricular Assist Device Therapy
Authors: Sarah Schettle, Barry Boilson, Simon Maltais, David Joyce, Lyle Joyce, Richard Daly, John Stulak
Journal: Circulation (2016)

Introduction: Left ventricular assist device (LVAD) therapy is known to alter von Willebrand factor (vWF) activity and function. Most data reflect changes late while on chronic support. Very limited data examine early changes in vWF stratified by device type with little correlation to adverse events. Methods: From February 2007 to December 2015, 321 patients underwent primary LVAD implant at our Clinic. Median age at implant was 62 years (range, 18-82) and 258 (80%) were male. Von Willebrand Factor activity and antigen measured before and early after LVAD were stratified by device type (HeartMate II (n=246) and HeartWare HVAD (n=43)), and correlated to thrombotic and hemorrhagic adverse events. Results: After HeartMate II implantation, vWF activity significantly decreased within a median of 2.3 months after implant (preop: 191 vs. postop: 130, p<0.001, while after HeartWare HVAD implantation, the decrease in vWF activity was not significantly reduced at a median of 2 months after implant (preop: 185 vs. p...
Abstract 19976: A New Combination of Nutraceutics Activates eNOS Through Plc/pkc-alpha/akt Signalling
Authors: Albino Carrizzo, Antonio Damato, Mariateresa Ambrosio, Antonia Alfano, Valentina Trimarco, Raffaele Izzo, Carmine Vecchione
Journal: Circulation (2017)

Introduction: Nutraceutics are medicinal foods that in certain components may exert a beneficial effect on cardiovascular system and represent a new opportunity for the maintenance of cardiovascular homeostasis. To date, despite its beneficial effects, the mechanisms involved are not completely clarified. Hypothesis: Here, we aimed to characterize the vascular action of AkP05 (IzzeK®, Akademy Pharma), a new nutraceutic that combines Bacopa monniera, Ginkgo biloba, phosphatidylserine and extract of Green tea leaves in a certain concentration and purification, patent based. Methods: We performed vascular reactivity studies on mice resistance vessels placed on pressure myograph evaluating the effects of increasing doses of AkP05 on phenylephrine-preconstricted vessels. In addition, to characterize the molecular mechanism we performed immunohistochemistry and Western Blot analyses. Results: We demonstrate that AkP05 was able to induce dose-dependent vasodilatation of the mice mesenteric arteries, which was si...
Association between physical exercise and mental health in 1·2 million individuals in the USA between 2011 and 2015: a cross-sectional study
Authors: Sammi R Chekroud, Ralitza Gueorguieva, Amanda B Zheutlin, Martin Paulus, Harlan M Krumholz, John H Krystal, Adam M Chekroud
Journal: The Lancet Psychiatry (2018)
Global Development Assistance for Adolescent Health From 2003 to 2015
Authors: Zhihui Li, Mingqiang Li, George C. Patton, Chunling Lu
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Growth in financing has underpinned progress in most areas of health. Adolescent health has recently become a global priority, with inclusion in the Global Strategy for Women's, Children's and Adolescents' Health, but little is known about patterns of financing and development assistance for adolescent health (DAAH). <h3>Objective</h3> To provide estimates of DAAH at global, regional, and country levels. <h3>Design, Setting, and Participants</h3> In this quality improvement study, data from the Creditor Reporting System were used to estimate flows of total DAAH and per-adolescent DAAH and to assess its distribution by donors, regions, and countries and the leading causes of burden of disease (ie, disability-adjusted life-years) in 132 developing countries between January 1, 2003, and December 31, 2015. Through use of a key word search and various funding allocation methods, 2 sets of estimates were produced: adolescent-targeted DAAH that included disbursements to projects with a primary adolescent health target and adolescent-inclusive DAAH that included disbursements to projects with either a primary or partial adolescent health target, as well as projects that could benefit adolescent health but did not include age-related key words. <h3>Main Outcomes and Measures</h3> Estimates of DAAH distinguishing between adolescent-targeted and adolescent-inclusive DAAH. <h3>Results</h3> There were 19 921 projects in 132 countries in the adolescent-targeted estimation between 2003 and 2015, with a total funding amount of $3634.6 million, accounting for 1.6% of total development assistance for health. The top 5 donors (Global Fund to Fight AIDS, Tuberculosis and Malaria, $806.8 million; United Nations Population Fund, $401.3 million; United States, $389.9 million; United Kingdom, $251.8 million; and International Development Association, $218.6 million) together provided 56.9% of all adolescent-targeted DAAH. Sub-Saharan Africa received the largest cumulative DAAH per adolescent ($5.37) during the period. In 2015, among the 10 leading causes of disability-adjusted life-years, HIV and AIDS received the largest DAAH, followed by interpersonal violence, tuberculosis, and diarrheal diseases. Other leading causes, including road injuries and depressive disorders, received few disbursements, especially among the low-income countries. <h3>Conclusions and Relevance</h3> Despite an increasing rate, DAAH composed a small proportion of total development assistance for health, suggesting that adolescent health has gained little donor attention. Moreover, recent allocations of DAAH have not aligned well with either the burden of disease or the areas where the benefits of investment are likely to be high.
Abstract 2775: A novel immunostimulatory OX40/PD-L1 bivalent bispecific antibody (MEDI1109) for the treatment of patients with cancer
Authors: Michael D. Oberst, Srinath Kasturirangan, Clifford Sachs, Catherine Auge, James Moynihan, Raymond Rothstein, James Hair, Francis Neal, Srinivas Mamidi, Shino Hanabuchi, Amanda Watkins, Yanan Zheng, Kim Rosenthal, Daniel J. Freeman, Scott Hammond
Journal: Cancer Research (2018)

Abstract Targeted immunotherapy utilizing agonist antibodies (Ab) to OX40 shows great promise in preclinical mouse models alone or in combination with various therapies including PD1/PD-L1 antagonist Abs. Ab-mediated signaling through OX40 requires higher-order clustering by Fcγ receptors to co-stimulate antitumor-specific T cells and attenuate regulatory T cell (Treg) immunosuppression, leading to antitumor activity. To date, OX40 agonists are well-tolerated but show limited activity alone or in combination with checkpoint blockade in clinical trials. We hypothesize that the antitumor activity of OX40 agonists in patients may be limited by insufficient intratumoral exposure and an inadequate amount of clustering by Fcγ receptors within the tumor microenvironment. To overcome these limitations, we engineered MEDI1109, a bivalent bispecific Ab composed of an OX40 agonist Ab molecularly fused to two single-chain variable fragments derived from a PD-L1 antagonist. The resulting bispecific Ab retained the functional properties of each parent Ab that included binding and agonizing OX40, binding and full blockage of the PD-L1/PD-1 pathway, depletion of OX40+ Tregs and overcoming Treg suppression. Emerging data suggest that the bispecific Ab also drives novel biology including (1) increased OX40 agonism through clustering by either PD-L1 and Fcγ receptors, (2) improved intratumoral exposure through PD-L1 targeting, (3) elimination of PD-L1 positive tumor cells by NK cell mediated antibody-dependent cellular cytotoxicity and (4) enhanced antitumor immunity through concurrent PD-L1/PD-1 blockade on tumor cells and OX40 co-stimulation of antitumor T cells. Intravenous administration of OX40/PD-L1 bispecific Abs to cynomolgus monkeys resulted in the proliferation of peripheral blood CD4+ and CD8+ total memory T-cell populations, and in the reduction of soluble PD-L1 levels in the plasma. These results demonstrate that MEDI1109 is a unique and potent immune modulating agent and may be utilized to enhance antitumor immunity in patients with cancer. Citation Format: Michael D. Oberst, Srinath Kasturirangan, Clifford Sachs, Catherine Auge, James Moynihan, Raymond Rothstein, James Hair, Francis Neal, Srinivas Mamidi, Shino Hanabuchi, Amanda Watkins, Yanan Zheng, Kim Rosenthal, Daniel J. Freeman, Scott Hammond. A novel immunostimulatory OX40/PD-L1 bivalent bispecific antibody (MEDI1109) for the treatment of patients with 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 2775.
Deficiency of Interleukin-1 Receptor Antagonist Promotes Neointimal Formation After Injury
Authors: KikuoIsoda, MasaruShiigai, NorioIshigami, TaizoMatsuki, ReikoHorai, KenichirouNishikawa, MasatoshiKusuhara, YasuhiroNishida, YoichiroIwakura, FumitakaOhsuzu
Journal: Circulation (2003)

Background— The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via the IL-1 receptor antagonist (IL-1Ra). The role of IL-1Ra in neointima formation after injury, however, is poorly understood. Methods and Results— Using IL-1Ra–deficient (IL-1Ra−/−; backcrossed 8 generations into the C57BL/6J background) and wild-type (IL-1Ra+/+) mice, we investigated neointimal formation 3 weeks after femoral artery injury induced by an external vascular cuff model. Intima and media thicknesses were measured, and the intima/media ratio was calculated. The mean intimal thickness and the intima/media ratio of IL-1Ra−/− mice increased by 249% (31.8±2.9 μm [n=10] versus 9.1±0.7 μm [n=10]; P<0.0001) and 257% (2.5±0.2 versus 0.7±0.1; P<0.0001), respectively, compared with IL-1Ra+/+ mice. No significant differences were observed in the medial thickness. Control immunostaining for IL-1Ra in injured vessels localized IL-1β and the...
Relative Apical Sparing of Myocardial Longitudinal Strain Is Explained by Regional Differences in Total Amyloid Mass Rather Than the Proportion of Amyloid Deposits
Authors: Paco E. Bravo, Kana Fujikura, Marie Foley Kijewski, Michael Jerosch-Herold, Sophia Jacob, Mohamed Samir El-Sady, William Sticka, Shipra Dubey, Anthony Belanger, Mi-Ae Park, Marcelo F. Di Carli, Raymond Y. Kwong, Rodney H. Falk, Sharmila Dorbala
Journal: JACC. Cardiovascular imaging (2018)
Impact of Body Mass Index and the Metabolic Syndrome on the Risk of Cardiovascular Disease and Death in Middle-Aged Men
Authors: JohanÄrnlöv, ErikIngelsson, JohanSundström, LarsLind
Journal: Circulation (2010)

Background— The purpose of this study was to investigate associations between combinations of body mass index (BMI) categories and metabolic syndrome (MetS) and the risk of cardiovascular disease and death in middle-aged men. Methods and Results— At age 50 years, cardiovascular risk factors were assessed in 1758 participants without diabetes in the community-based Uppsala Longitudinal Study of Adult Men (ULSAM). According to BMI-MetS status, they were categorized as normal weight (BMI  30 kg/m2) without MetS (n=30), or obese with MetS (n=66). During follow-up (median 30 years), 788 participants died, and 681 developed cardiovascular disease (composite of cardiovascular death or hospitalization for myocardial infarction, stroke, or heart failure). In Cox proportional-hazards models that adjusted for a...
Reinduction of Atrial Fibrillation Immediately After Termination of the Arrhythmia Is Mediated by Late Phase 3 Early Afterdepolarization–Induced Triggered Activity
Authors: AlexanderBurashnikov, CharlesAntzelevitch
Journal: Circulation (2003)

Background— Atrial fibrillation (AF) at times recurs immediately after termination of the arrhythmia. The mechanism(s) responsible for the extrasystole that reinduces AF is largely unknown. We hypothesized that abbreviation of action potential duration (APD) would permit very rapid rates of excitation, known to induce intracellular calcium loading, which in turn could promote delayed and/or early afterdepolarizations (EADs). Methods and Results— Acetylcholine (ACh, 1 μmol/L) was used to abbreviate atrial APD and permit rapid-pacing induction of AF in isolated coronary-perfused canine right atria. Transmembrane action potentials, pseudo-ECG, and tension development were recorded. AF or rapid pacing was associated with an increase in tonic tension. Termination of AF or rapid pacing (cycle length, 150 to 80 ms) resulted in a dramatic rise of phasic tension, prolongation of repolarization of the initial beats at the regular rate (cycle length, 700 ms), and the development of late phase 3 EADs and extrasystole...
Abstract 4782: Inhibition of FGFR in breast cancer metastasis
Authors: Hang Lin, Saeed S. Akhand, Michael K. Wendt
Journal: Cancer Research (2018)

Abstract Metastatic breast cancer is the most advanced stage of breast cancer. This type of cancer can spread other organs and cause 90% of cancer-related death. However, little is known about the molecular mechanisms which drive metastasis in breast cancer. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) promote tumor invasion and metastasis. Previously, it has been reported that fibroblast growth receptor 1 plays a key role during EMT: MET cycle. Therefore, optimizing FGFR inhibitors is crucial for therapeutic targeting of late-stage breast cancer. Here, we examined the efficacies of three FGFR kinase inhibitors, AZD4547, JNJ-42756493 and FIIN4, in the 4TO7 cell line both in vitro and in vivo. The 4TO7 cell line is a syngeneic model of systemic dormancy. Mammary fat pad engraftment of the 4T07 cells onto immune competent Balb/C mice results in systemic dissemination, but no macroscopic metastasis. In contrast, the 4T07 cells can escape cellular dormancy in 3D culture and form robust pulmonary tumors in mice upon tail vein inoculation. Furthermore, the 4TO7 cell line robustly responses to exogenous stimulation with FGF2. The phosphorylation of Erk1/2 downstream of FGFR was stimulated after a five-minute treatment with FGF2 and was effectively blocked with all the inhibitors tested. Furthermore, we developed a 3D culture approach that combines tumor spheroid formation in a non-adherent round bottom dish followed by placement on a bed of matrix. Our in vitro results demonstrate that both JNJ-42756493 and FIIN4 have more potent anti-proliferative activities in 3D culture and longer residence time as compared to AZD4547. In vivo, inhibition of FGFR is highly effective against 4TO7 tumors in the pulmonary microenvironment. Importantly, FIIN4 showed the least toxicity. This result suggested that covalent inhibition of FGFR is a promising cancer therapy for patients with metastatic breast cancer. Citation Format: Hang Lin, Saeed S. Akhand, Michael K. Wendt. Inhibition of FGFR in breast cancer metastasis [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 4782.
Ventricular Hypertrophy Plus Neurohumoral Activation Is Necessary to Alter the Cardiac β-Adrenoceptor System in Experimental Heart Failure
Authors: KirstenLeineweber, KatjaBrandt, BeateWludyka, AnjaBeilfuß, KlausPönicke, IngridHeinroth-Hoffmann, Otto-ErichBrodde
Journal: Circulation Research (2002)

Treatment of rats with monocrotaline (MCT) leads to pulmonary hypertension, right ventricular (RV) hypertrophy, and finally to RV heart failure. This is associated with characteristic changes in right ventricular β-adrenoceptors (β-AR), neuronal noradrenaline transporter (NAT) density and activity (uptake1), and G protein–coupled receptor kinase (GRK) activity. This study aimed to find out factors that determine β-AR, uptake1, and GRK changes. Thus, 6-week-old rats were treated with 50 mg/kg MCT subcutaneous or 0.9% saline. Within 13 to 19 days after MCT application (group A), RV weight (222±6 versus 147±5 mg) and RV/left ventricular (LV) weight ratio (0.42±0.01 versus 0.29±0.01) were significantly increased, whereas plasma noradrenaline, RV β-AR density, RV NAT density and activity, and RV GRK activity were not significantly altered. Twenty-one to twenty-eight days after MCT (group B), however, not only RV weight (316±4 versus 148±2 mg) and RV/LV weight ratio (0.61±0.01 versus 0.3±0.01) were markedly inc...
Molecular Basis for the Association of Group IIA Phospholipase A2 and Decorin in Human Atherosclerotic Lesions
Authors: PeterSartipy, BeritJohansen, KathrineGåsvik, EvaHurt-Camejo
Journal: Circulation Research (2000)

Abstract—Group IIA secretory nonpancreatic phospholipase A2 (snpPLA2) is associated with collagen fibers in the extracellular matrix of human atherosclerotic plaques. Decorin, a small proteoglycan (PG) carrying chondroitin/dermatan sulfate glycosaminoglycans (GAGs), forms part of the collagen network in human arteries. To explore whether snpPLA2 may be associated with collagen fibers via interaction with decorin, we performed (1) immunohistochemistry to compare the relative in vivo localization of snpPLA2 and decorin in human atherosclerotic tissue and (2) in vitro experiments to study the interaction between snpPLA2 and decorin. In atherosclerotic lesions, decorin was detected within the snpPLA2-positive part of the intima close to the media. Electrophoretic mobility shift assay showed that snpPLA2 binds to decorin synthesized by human fibroblasts. Native and GAG-depleted decorin enhanced the association of snpPLA2 to collagen types I and VI in a solid-phase binding assay. Furthermore, snpPLA2 bound effi...