tbuckley/cabot-search huggingface dataset:
CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non–Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3)
Authors: Yi-Long Wu, Myung-Ju Ahn, Marina Chiara Garassino, Ji-Youn Han, Nobuyuki Katakami, Hye Ryun Kim, Rachel Hodge, Paramjit Kaur, Andrew P. Brown, Dana Ghiorghiu, Vassiliki A. Papadimitrakopoulou, Tony S.K. Mok
Journal: Journal of Clinical Oncology (2018)

Purpose In patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC), there is an unmet need for EGFR-tyrosine kinase inhibitors with improved CNS penetration and activity against CNS metastases, either at initial diagnosis or time of progression. We report the first comparative evidence of osimertinib CNS efficacy versus platinum-pemetrexed from a phase III study (AURA3; ClinicalTrials.gov identifier: NCT02151981) in patients with EGFR T790M-positive advanced NSCLC who experience disease progression with prior EGFR-tyrosine kinase inhibitor treatment. Methods Patients with asymptomatic, stable CNS metastases were eligible for enrollment and were randomly assigned 2:1 to osimertinib 80 mg once daily or platinum-pemetrexed. A preplanned subgroup analysis was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiological review. The CNS evaluable for response set included only patients with one or more measurable CNS lesions. The primary objective for this analysis was CNS objective response rate (ORR). Results Of 419 patients randomly assigned to treatment, 116 had measurable and/or nonmeasurable CNS lesions, including 46 patients with measurable CNS lesions. At data cutoff (April 15, 2016), CNS ORR in patients with one or more measurable CNS lesions was 70% (21 of 30; 95% CI, 51% to 85%) with osimertinib and 31% (5 of 16; 95% CI, 11% to 59%) with platinum-pemetrexed (odds ratio, 5.13; 95% CI, 1.44 to 20.64; P = .015); the ORR was 40% (30 of 75; 95% CI, 29% to 52%) and 17% (7 of 41; 95% CI, 7% to 32%), respectively, in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 3.24; 95% CI, 1.33 to 8.81; P = .014). Median CNS duration of response in patients with measurable and/or nonmeasurable CNS lesions was 8.9 months (95% CI, 4.3 months to not calculable) for osimertinib and 5.7 months (95% CI, 4.4 to 5.7 months) for platinum-pemetrexed; median CNS progression-free survival was 11.7 months and 5.6 months, respectively (hazard ratio, 0.32; 95% CI, 0.15 to 0.69; P = .004). Conclusion Osimertinib demonstrated superior CNS efficacy versus platinum-pemetrexed in T790M-positive advanced NSCLC.
An early start of West Nile virus seasonal transmission: the added value of One Heath surveillance in detecting early circulation and triggering timely response in Italy, June to July 2018
Authors: Flavia Riccardo, Federica Monaco, Antonino Bella, Giovanni Savini, Francesca Russo, Roberto Cagarelli, Michele Dottori, Caterina Rizzo, Giulietta Venturi, Marco Di Luca, Simonetta Pupella, Letizia Lombardini, Patrizio Pezzotti, Patrizia Parodi, Francesco Maraglino, Alessandro Nanni Costa, Giancarlo Maria Liumbruno, Giovanni Rezza
Journal: Eurosurveillance (2018)

In Italy, the 2018 West Nile virus transmission season started early with a high number of cases reported. One-Health surveillance, within the Italian West Nile national preparedness and response plan, detected viral circulation 9 days before symptom-onset of the first confirmed human case; triggering timely implementation of blood and transplant safety measures. This is an example of how functional coordination allows health authorities to use early warning triggers from surveillance systems to implement preventive measures.
Investigation of Coronary Venous Anatomy by Retrograde Venography in Patients With Malignant Ventricular Tachycardia
Authors: EckhardMeisel, DietrichPfeiffer, LotharEngelmann, JürgenTebbenjohanns, BerndSchubert, StephenHahn, EckartFleck, ChristianButter
Journal: Circulation (2001)

Background The coronary venous system is increasingly used for left ventricular or biventricular pacing in patients with severe heart failure. The present study investigated the structure of the coronary veins in patients presenting with structural heart disease and malignant ventricular tachyarrhythmias. The availability of veins for possible lead placement was assessed. Methods and Results The number, relative size, and location of coronary veins were evaluated by retrograde venography in 129 patients undergoing cardioverter-defibrillator implantation. Detailed x-ray image analysis was performed in 86 patients, for whom optimal coronary sinus occlusion and vein visualization was achieved. The anterior interventricular vein and the middle cardiac vein were visible in 85 (99%) of 86 patients and in 86 (100%) of 86 patients, respectively. Between these 2 veins, at least 1 additional prominent vein was visible in 85 (99%) of 86 patients. Just 1 vein was present in 44 (51%) of 86 patients. Two veins were obs...
Abstract 5133: Lipids and suppressive functions of MDSC in cancer
Authors: Filippo Veglia, Vladimir A. Tyurin, Valerian E. Kagan, Dmitry Gabrilovich
Journal: Cancer Research (2018)

Abstract Myeloid derived suppressor cells (MDSC) play an important role in the regulation of anti-tumor responses and their presence in cancer patients correlates with a poor prognosis. MDSC contribute to the failure of cancer therapies and favor tumor progression and metastasis. However, despite the recent advances in understanding the biology of MDSC, the mechanisms driving their expansion and suppressive function are not yet well defined. Polymorphonuclear, PMN-MDSC is by far the largest population of MDSC. Here, we found that PMN-MDSC from tumor bearing mice and from cancer patients have higher amount of lipids than their counterpart (neutrophils) in tumor free mice and healthy donors, respectively. The content of lipids in PMN-MDSC was much higher in MDSC infiltrating the tumor, and the accumulation of lipids in PMN-MDSC was caused by the uptake of extracellular lipids. Lipid profile of PMN-MDSC demonstrated accumulation of oxidized fatty acids as part of triglycerides and phospholipids. We demonstrated that fatty acids accumulated by PMN-MDSC are oxidized by myeloperoxidase (MPO) and reactive oxygen species (ROS) generated by Nox2. Genetic ablation of MPO or ROS in MDSC results in a drastic reduction of lipid oxidation and in an impaired ability of MDSC to suppress CD8 T cell responses. In line with these findings, unsaturated fatty acids, highly susceptible to oxidation, favor the expansion of highly suppressive MDSC from hematopoietic progenitors in vitro, contrary to non-oxidizable saturated fatty acids. Together, our data suggest that MDSC have increased ability to pick up lipids from the microenvironment and to oxidize them via their potent oxidative machinery. In turn oxygenated lipids contribute to the suppressive activity of MDSC. In conclusion, the regulation of the oxidation of lipids in MDSC could be an attractive therapeutic strategy in cancer. Citation Format: Filippo Veglia, Vladimir A. Tyurin, Valerian E. Kagan, Dmitry Gabrilovich. Lipids and suppressive functions of MDSC in 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 5133.
Abstract 18783: Hospitalization for Atrial Fibrillation Increases in the Elderly: Recent Analysis From TuRkish Atrial Fibrillation Data Base
Authors: Banu Evranos, Kudret Aytemir, BÜnyamin Yavuz, Emre Oto, Naim Ata, Deniz Katircioglu öztÜrk, Ergun Karaagaoglu, Altay GÜvenir, SelÇuk özcan, Emre Ertugay, Rasim Koselerli, AbdÜlkadir BÜrkan, Mustafa Kuruca, Yadigar Gokalp Ilhan, John A Camm, Ali M Oto
Journal: Circulation (2013)

Objective: Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhytmia and constitutes a major public health problem. Patients with AF often have a variety of co-morbidities and need frequent hospitalizations. The present retrospective cohort study used medical claims data to evaluate the rates of hospitalization in patients with AF in Turkey. Methods: We analyzed the records of patients over the age 18 who had the diagnosis of non-valvular atrial fibrillation (AF) according to ICD-10 code I48 from a claims and utilization management system called MEDULA which processes claims for all health insurance funds in Turkey since 2007. Covering close to 100 % of the population, MEDULA is comprised of pharmacy, inpatient, outpatient and laboratory claims and covers 23,500 pharmacies, 20,000 general practitioners, 850 government hospitals, 60 university hospitals and 500 private hospitals. In this study we have used completely anonymized data Results: Of an eligible study population of 402674 patients with AF (mean age 68,3 years, 44,2% men), 102334 patients (25,4%) were hospitalized, 68951 (17,1%) were rehospitalized. Seventy seven percent of females and sixty seven percent of males older than 65 years were hospitalized. The most common admission diagnoses were congestive heart failure (47,1%), ischemic stroke or transient ischemic attack (21,1%), gastrointestinal bleeding (5%), hemorrhagic stroke (1,5%) and thromboemboli (1,4%). Twenty nine percent of coumadin users, 27,2% of aspirin users, 23,9% klopidogrel users 23,3 % of clopidogrel+aspirin users and 21,1% of none user patients were hospitalized. When we performed time-to event analysis we found that the earliest hospitalizations were for coumadin users due to bleeding (p&lt;0.001). Conclusions: Elderly patients, especially females, with AF underwent frequent hospitalization both for CV and non-CV causes. Anticoagulant therapy with warfarin did not reduce hospitalization rate as a result of increased hospitalizations due to bleeding complications. Therefore, measures that lower bleedings and inpatient readmission rates may reduce the increasing cost of treating patients with AF and reduce the burden on health economics.
The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia
Authors: Nicolas Duployez, Alice Marceau-Renaut, Céline Villenet, Arnaud Petit, Alexandra Rousseau, Stanley W. K. Ng, Agnès Paquet, Fanny Gonzales, Adeline Barthélémy, Frédéric Leprêtre, Nicolas Pottier, Brigitte Nelken, Gérard Michel, André Baruchel, Yves Bertrand, Guy Leverger, Hélène Lapillonne, Martin Figeac, John E. Dick, Jean C. Y. Wang, Claude Preudhomme, Meyling Cheok
Journal: Leukemia (2018)
Abstract 5618: Anti-FGFR4 antibody drug conjugate for immune therapy of rhabdomyosarcoma and hepatocellular carcinoma
Authors: Adam Cheuk, Nitya Shivaprasad, Martin Skarzynski, Sivasubramanian Baskar, Peter Azorsa, Javed Khan
Journal: Cancer Research (2018)

Abstract Rhabdomyosarcoma (RMS), an aggressive soft tissue sarcoma originating from skeletal muscle in children and adolescent young adults. It is divided in two main histological subtypes including embryonal RMS driven by RAS pathway mutations and alveolar RMS driven by a chimeric fusion gene involving PAX3 or PAX7 with FOXO1. FGFR4 is a cell surface tyrosine kinase receptor that is a critical molecule in RMS biology. In RMS it is a direct target and strongly induced by PAX3-FOXO1 as well as PAX3, and PAX7. By immunohistochemistry we found high expression of FGFR4 in RMS cancers but low expression in normal human organs. Of note FGFR4 has been reported overexpressed in hepatocellular carcinoma (HCC). We therefore hypothesized that FGFR4 will provide a rational target for immune therapy in cancers with high expression. We generated fifteen binders against FGFR4 and characterized them further as candidates for immunotherapy. We found that 3A11, a mouse IgG antibody, bound to FGFR4 positive cell lines with an observed avidity of 1.9nM. By ELISA using the extra cellular domain of human FGFR1, FGFR2, FGFR3 or FGFR4, 3A11 showed dose dependent binding to FGFR4 only. 3A11 was also found internalized upon binding to FGFR4 positive cell lines. The VL and VH domain of 3A11 was cloned and chimeric 3A11 scFvFc (mouse Fv and Human IgG1 Fc) construct was made. The chimeric form of 3A11 antibody was successfully produced in vitro and retained its specificity. To investigate FGFR4-mediated cytotoxicity in RMS cell lines, we cultured RH30 (a RMS cell line expresses FGFR4) in the presence of the chimeric 3A11 and polyclonal anti-mouse 2°ADC conjugated to Duocarmycin DM for 72 hours. Dose-dependent cytotoxicity was observed in RH30, suggesting that chimeric form of 3A11 could deliver a cytotoxic payload to FGFR4 positive cells. We are currently developing antibody drug conjugate using the cytotoxic drug, pyrrolobenzodiazepine which will be tested in vitro and in vivo models of RMS. We have thus developed a chimeric antibody that may provide effective immune therapy for cancers with high FGFR4 expression including RMS and HCC Citation Format: Adam Cheuk, Nitya Shivaprasad, Martin Skarzynski, Sivasubramanian Baskar, Peter Azorsa, Javed Khan. Anti-FGFR4 antibody drug conjugate for immune therapy of rhabdomyosarcoma and hepatocellular carcinoma [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 5618.
Anti-Cardiolipin Antibodies and Risk of Myocardial Infarction in a Prospective Cohort of Middle-Aged Men
Authors: OutiVaarala, MattiMänttäri, VesaManninen, LeenaTenkanen, MarjaPuurunen, KimmoAho, TimoPalosuo
Journal: Circulation (1995)

Background Data concerning the relation between anti-phospholipid (aPL) antibodies and myocardial infarction in subjects without evidence of overt autoimmune disease are conflicting. All published studies have been performed on survivors of myocardial infarction or in patients with established coronary heart disease. The purpose of the present study was to determine whether the presence of aPL antibodies, namely, anti-cardiolipin (aCL) antibodies, carries a risk for myocardial infarction in a prospective cohort. Methods and Results The sera to be studied were drawn at entry from middle-aged dyslipidemic men (non–high-density lipoprotein cholesterol, ≥5.2 mmol/L) participating in the Helsinki Heart Study, a 5-year coronary primary prevention trial with gemfibrozil. Samples were tested for IgG-class antibodies to cardiolipin by an ELISA. The risk was estimated with logistic regression analysis using a nested case-control design with 133 patients (myocardial infarction or cardiac death) and 133 control subje...
Abstract LB-279: Efficacy of fractionated injections of CLR 131 in a OPM-2 SCID nude mouse model
Authors: Jarrod Longcor, Maria Banach, John Friend
Journal: Cancer Research (2018)

Abstract Background: Multiple myeloma remains an incurable disease. Treatment with immunomodulators and proteasome inhibitors have provided significant benefits to patients but they still relapse. The introduction of new treatments like daratumumab have provided further benefit. However, patients continue to experience issues and relapse. CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells to provide targeted delivery of iodine-131 directly to tumor cells. This study evaluates the effect of fractionated injections of CLR 131 in OPM-2 tumor bearing mice in comparison to equivalent doses of CLR 131 and the standard dosing of bortezomid. Methods: The OPM-2 cell line (human multiple myeloma) was purchased from American Type Culture Collection (ATCC, Rockville, MD) and maintained in McCoy's 5a media supplemented with 10% fetal bovine serum. Female CB17 SCID mice approximately 5-7 weeks of age were injected subcutaneously with 1x107 viable cells (in ~100 µL Dulbecco's PBS) into the right flank. The study was initiated when tumor size had reached a pre-determined size (approximately 150-200 mm3). The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation three days prior to injection and continuing through two weeks post-injection. Results: All treatment groups showed a reduction in tumor growth with the fractionated dose of CLR 131 producing the greatest inhibition. The control group showed exponential growth throughout the study, increasing in volume by an average 11 fold from baseline. This compared with a 3.5 fold increase from baseline in the fractionated dose group and 7.5 fold for the bortezomid group. Conclusions: The results of the study indicated that a fractioned injection of CLR 131 (2 injections of ~50 µCi) on human multiple myeloma (OPM-2) tumor bearing model showed a significant inhibition of tumor growth as well as a survival benefit. While a single injection of CLR 131 at either ~50 uCi and ~100 uCi were effective, there was an important improvement with by using fractionated dosing. The implication is that in this clinically predictive in vivo model CLR 131, which is currently in a Phase 2 clinical trial for multiple myeloma, might show improved clinical efficacy in patients if a fractionated dose is utilized. Citation Format: Jarrod Longcor, Maria Banach, John Friend. Efficacy of fractionated injections of CLR 131 in a OPM-2 SCID nude mouse 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-279.
Heart Failure With Preserved Ejection Fraction Expert Panel Report
Authors: Kishan S. Parikh, Kavita Sharma, Mona Fiuzat, Howard K. Surks, Jyothis T. George, Narimon Honarpour, Christopher Depre, Patrice Desvigne-Nickens, Richard Nkulikiyinka, Gregory D. Lewis, Mardi Gomberg-Maitland, Christopher M. O’Connor, Norman Stockbridge, Robert M. Califf, Marvin A. Konstam, James L. Januzzi, Scott D. Solomon, Barry A. Borlaug, Sanjiv J. Shah, Margaret M. Redfield, G. Michael Felker
Journal: JACC Heart Failure (2018)

The number of persons with heart failure has continued to rise over the last several years. Approximately one-half of those living with heart failure have heart failure with preserved ejection fraction, but critical unsolved questions remain across the spectrum of basic, translational, clinical, and population research in heart failure with preserved ejection fraction. In this study, the authors summarize existing knowledge, persistent controversies, and gaps in evidence with regard to the understanding of heart failure with preserved ejection fraction. Our analysis is based on an expert panel discussion "Think Tank" meeting that included representatives from academia, the National Institutes of Health, the U.S. Food and Drug Administration, the Centers for Medicare & Medicaid Services, and industry.
Oral Anti-CD3 Antibody Treatment Induces Regulatory T Cells and Inhibits the Development of Atherosclerosis in Mice
Authors: NaotoSasaki, TomoyaYamashita, MasafumiTakeda, MasakazuShinohara, KenjiNakajima, HidetoTawa, TakashiUsui, Ken-ichiHirata
Journal: Circulation (2009)

Background— Accumulating evidence suggests that several subsets of regulatory T cells that actively mediate immunologic tolerance play crucial roles in atherogenesis. Recently, orally administered anti-CD3 monoclonal antibody has been shown as an inducer of novel regulatory T cells expressing latency-associated peptide (LAP) on their surface, which potently prevents systemic autoimmunity. In the present study, we hypothesized that oral anti-CD3 antibody treatment may inhibit atherosclerosis in mice. Methods and Results— Six-week-old apolipoprotein E–deficient mice on a standard diet were orally given anti-CD3 antibody or control immunoglobulin G on 5 consecutive days, and atherosclerosis was assessed at age 16 weeks. Oral administration of anti-CD3 antibody significantly reduced atherosclerotic lesion formation and accumulations of macrophages and CD4+ T cells in the plaques compared with controls. We observed a significant increase in LAP+ cells and CD25+Foxp3+ cells in the CD4+ T-cell population in anti...
Leukocyte Depletion Attenuates Reperfusion Injury in Patients With Left Ventricular Hypertrophy
Authors: YoshikiSawa, KazuhiroTaniguchi, KeishiKadoba, MotonobuNishimura, HajimeIchikawa, AkiraAmemiya, ThoruKuratani, HikaruMatsuda
Journal: Circulation (1996)

Background Reperfusion injury can occur after a long period of aortic cross-clamping in patients with left ventricular hypertrophy during open-heart surgery, even with the most up-to-date techniques of myocardial protection. In the present study, we examined whether leukocyte depletion as an adjunct to terminal blood cardioplegia (LDTC) attenuates reperfusion injury in patients with left ventricular hypertrophy (LV mass, >300 g; left ventricular end-systolic volume index, >100 mL/m2) in a group of 30 patients undergoing aortic valve replacement. Methods and Results We used basic cold potassium crystalloid cardioplegic solution. Terminal blood cardioplegic solution (TC) or LDTC was accomplished by mixing a cold potassium crystalloid cardioplegic solution with warm arterial blood obtained through cardiopulmonary bypass and administered to the aortic root for the first 10 minutes of reperfusion. During delivery of LDTC, warm arterial blood was passed through a leukocyte-removal filter. Patients were randomiz...
Effects of Erythrol Tetranitrate and Amotriphene on Exercise Tolerance Tests in Angina Pectoris
Authors: Arthurruskin
Journal: Circulation (1961)

Sublingual erythrol tetranitrate is a potent drug in counteracting coronary insufficiency, as evidenced by reversal of positive electrocardiographic exercise tolerance tests in 72 per cent of 36 cases and reduction of anginal attacks in them by more than 50 per cent. Comparative studies with amotriphene indicate some subjective alleviation of angina, but objective reversals of the electrocardiographic effects of exercise in only 16 per cent of the cases. Side effects of erythrol tetranitrate, particularly headache, are seen in a minority of cases and are often circumvented by starting with a small dose and gradually increasing it as necessary. Alleviation of ectopic beats on exercise occurred equally in a minority of cases on the two drugs.