tbuckley/cabot-search huggingface dataset:
Systemic Right Ventricle in Adults With Congenital Heart Disease
Authors: Margarita Brida, Gerhard-Paul Diller, Michael A. Gatzoulis
Journal: Circulation (2018)

The systemic right ventricle (SRV) is commonly encountered in congenital heart disease representing a distinctly different model in terms of its anatomic spectrum, adaptation, clinical phenotype, and variable, but overall guarded prognosis. The most common clinical scenarios where an SRV is encountered are complete transposition of the great arteries with previous atrial switch repair, congenitally corrected transposition of the great arteries, double inlet right ventricle mostly with previous Fontan palliation, and hypoplastic left heart syndrome palliated with the Norwood-Fontan protocol. The reasons for the guarded prognosis of the SRV in comparison with the systemic left ventricle are multifactorial, including distinct fibromuscular architecture, shape and function, coronary artery supply mismatch, intrinsic abnormalities of the tricuspid valve, intrinsic or acquired conduction abnormalities, and varied SRV adaptation to pressure or volume overload. Management of the SRV remains an ongoing challenge because SRV dysfunction has implications on short- and long-term outcomes for all patients irrespective of underlying cardiac morphology. SRV dysfunction can be subclinical, underscoring the need for tertiary follow-up and timely management of target hemodynamic lesions. Catheter interventions and surgery have an established role in selected patients. Cardiac resynchronization therapy is increasingly used, whereas pharmacological therapy is largely empirical. Mechanical assist device and heart transplantation remain options in end-stage heart failure when other management strategies have been exhausted. The present report focuses on the SRV with its pathological subtypes, pathophysiology, clinical features, current management strategies, and long-term sequelae. Although our article touches on issues applicable to neonates and children, its main focus is on adults with SRV.
Calcium Current Channels Induced by Catecholamines in Chick Embryonic Hearts Whose Fast Sodium Channels are Blocked by Tetrodotoxin or Elevated Potassium
Authors: Kokishigenobu, Nicksperelakis
Journal: Circulation Research (1972)

In isolated ventricles of old (9-19 day) chick embryonic hearts made inexcitable by inactivating the fast sodium channels with either tetrodotoxin (TTX) or elevated external potassium, catecholamines induced slow electrical responses and concomitant contractions within 1-3 minutes. These slow responses had a higher threshold and propagated at a slower velocity than did the normal action potential. They were often graded and quite variable from one region of the heart to another. They were blocked by lanthanum or manganese (1 mM) and showed a dependence on the external calcium level. Strontium and barium could substitute for calcium. The slow channels were not completely inactivated when the external potassium concentration was raised until low membrane potentials of -10 to -25 mv were reached. The catecholamine-induced responses had a shape similar to that of the plateau component of the normal action potential, and cooling affected both in a similar manner. In some cases, slow responses persisted in TTX-...
Abstract 16572: High Sensitive Cardiac Troponin T Predicts Long-Term Risk of Incident HF Independent of Cardiovascular Risk Factors and Cardiac Structure/Function in a Multi-Ethnic Population Without CVD: The Multi-Ethnic Study of Atherosclerosis
Authors: Stephen Seliger, Susie Hong-Zohlman, James deLemos, Robert Christenson, Joao Lima, Alain Bertoni, Lori B Daniels, Christopher deFillippi
Journal: Circulation (2016)

Introduction: Although small elevations of high sensitive cardiac troponin T (hs-cTnT) have been associated with incident heart failure (HF), the robustness of this finding across a large spectrum ...
Acetylcysteine Reduces Plasma Homocysteine Concentration and Improves Pulse Pressure and Endothelial Function in Patients With End-Stage Renal Failure
Authors: AlexandraScholze, ChristianeRinder, JoachimBeige, ReinerRiezler, WalterZidek, MartinTepel
Journal: Circulation (2004)

Background— Increased oxidative stress, elevated plasma homocysteine concentration, increased pulse pressure, and impaired endothelial function constitute risk factors for increased mortality in patients with end-stage renal failure. Methods and Results— We investigated the metabolic and hemodynamic effects of intravenous administration of acetylcysteine, a thiol-containing antioxidant, during a hemodialysis session in a prospective, randomized, placebo-controlled crossover study in 20 patients with end-stage renal failure. Under control conditions, a hemodialysis session reduced plasma homocysteine concentration to 58±22% predialysis (mean±SD), whereas in the presence of acetylcysteine, the plasma homocysteine concentration was significantly more reduced to 12±7% predialysis (P<0.01). The reduction of plasma homocysteine concentration was significantly correlated with a reduction of pulse pressure. A 10% decrease in plasma homocysteine concentration was associated with a decrease of pulse pressure by 2.5...
Abstract 14070: Combination of Clinical, Electrocardiographic and Echocardiographic Parameters Predict the Onset of Atrial Fibrillation
Authors: Takeshi Soeki, Sachiko Bando, Tomomi Matsuura, Takeshi Tobiume, Etsuko Uematsu, Kenya Kusunose, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Tetsuzo Wakatsuki, Michio Shimabukuro, Masataka Sata
Journal: Circulation (2015)

Bacground: The ability to identify risk markers for first atrial fibrillation (AF) is critical to the development of preventive strategies. Prior studies have demonstrated that advanced age, diabetes, hypertension, and cardiovascular disease increase the risk of developing AF. Echocardiographic left atrial (LA) size and diastolic dysfunction are also shown to predict the onset of AF. Furthermore, a recent study has revealed that the addition of premature atrial contraction (PAC) count to a validated AF risk algorithm provides superior AF risk discrimination. However, it remains unknown whether a combination of clinical, electrocardiographic, and echocardiographic parameters predict the onset of AF. In the present study, we evaluated the predictive value of the combined score including these parameters. Methods: We retrospectively studied 1,040 patients without AF in whom both echocardiography and 24-hour Holter electrocardiography were performed from May 2005 to December 2010 and could be followed thereafter. During the follow-up period of 70.0±29.1 months, we investigated the new onset of AF. Results: Of the 1,040 patients, 103 developed AF. Patients who developed AF were older than patients who did not. Total heart rate, PAC count, max RR interval, and frequency of sinus arrest quantified by 24-hour electrocardiography were associated with the new onset of AF. Left atrial diameter (LAD) determined by echocardiography was also associated with the development of AF. In multivariate Cox analyses, age, PAC count, max RR interval, and LAD were independently associated with the development of AF (multivariable-adjusted hazard ratios per SD: age 1.49, PAC count 1.16, max RR interval 1.21, and LAD 1.34). Furthermore, the predictive value of the combined score using these 4 parameters (hazard ratios per SD: 1.80) was higher than that of each parameter. Conclusion: The combined score using age, PAC count, max RR interval, and LAD could help to identify risk of the new onset of AF.
E-cadherin signal sequence disruption: a novel mechanism underlying hereditary cancer
Authors: Joana Figueiredo, Soraia Melo, Kimberley Gamet, Tanis Godwin, Susana Seixas, João M. Sanches, Parry Guilford, Raquel Seruca
Journal: Molecular Cancer (2018)

The aim of this study was to uncover the pathogenic relevance and the underlying molecular mechanism of a novel CDH1 variant found in a Hereditary Diffuse Gastric Cancer family (p.L13_L15del), which affects the signal peptide of E-cadherin without changing the remaining predicted sequence. We verified that p.L13_L15del cells yield low levels of E-cadherin, decreased cell adhesion and enhanced cell invasion. Further, we demonstrated that the disruption of the highly conserved hydrophobic core of the signal peptide hampers the binding of cellular components crucial for E-cadherin translation and translocation into the endoplasmic reticulum, constituting a new molecular basis for the loss of a tumour suppressor gene causative of hereditary cancer.
Abstract LB-113: Enhanced anti-tumor efficacy of CEACAM1-targeting antibody after affinity maturation
Authors: So-Young Eun, Mijung Lee, Hye-Young Park, Miyoung Oh, Hye In Yum, Aerin Yoon, Eunhee Lee, Hyemi Nam, Sungtae Yun, Hyunjung Cho, Minkyu Hur, Jaehwan Kim, Byoung Chul Cho, Jonghwa Won
Journal: Cancer Research (2018)

Abstract Since the huge success of PD-1 blocking antibodies in clinical studies, anti-cancer therapy has changed its strategic gear to immunotherapy, which showed the strongest potential to eradicate cancer without detrimental side effects. Antibodies targeting similar immune checkpoint proteins with immunosuppressive functions have started to surge into clinical trials. CEACAM1 (CCM1) is also a potential target for anti-cancer immunotherapy because it is an ITIM-containing inhibitory molecule expressed on activated T cells and NK cells, on which it suppresses T/NK cell-mediated pro-inflammatory immune responses. CCM1-CCM1 homophilic interaction inhibits ZAP-70 phosphorylation in the TCR proximal signaling complex, thereby suppressing T cell activation. The anti-cancer therapeutic potential of CCM1-blockade has already been demonstrated in mouse models and one of the anti-human CCM1 antibodies entered into a phase I clinical trial once. As previously reported, our clone C25 (an anti-CCM1 monoclonal antibody) activated T cells and enhanced T/NK cell-mediated tumor cell-killing in a CCM1-dependent manner. The clone C25 was further engineered to have higher efficacies through mutagenesis within the variable regions of heavy and light chains. Here, we describe mutated variants of C25 with improved in vitro tumor-killing efficacies as well as higher binding affinities while maintaining fundamental characteristics of their parental clone C25. Most importantly, C25 and its variants exclusively bind to CCM1, but not to any other homologs of the CCM family. Such strong target-specificity will be a crucial point that distinguishes our clones from the other anti-CCM1 antibodies having off-target binding activities. We are currently investigating the CCM1-dependent anti-cancer therapeutic efficacy of our final clone on the patient-derived tumor xenografts implanted in a humanized mouse model. The target-ligand expression profiling on tumor tissues from lung cancer patients revealed strong clues for patient selection criteria and co-treatment options. Citation Format: So-Young Eun, Mijung Lee, Hye-Young Park, Miyoung Oh, Hye In Yum, Aerin Yoon, Eunhee Lee, Hyemi Nam, Sungtae Yun, Hyunjung Cho, Minkyu Hur, Jaehwan Kim, Byoung Chul Cho, Jonghwa Won. Enhanced anti-tumor efficacy of CEACAM1-targeting antibody after affinity maturation [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-113.
Abstract 2317: Palbociclib monotherapy exhibits potent activity in cervical cancer cell lines
Authors: Peter Van Dam, An Wouters, Luc Dirix, Christian Rolfo
Journal: Cancer Research (2018)

Abstract Background: Over the last decades, little progress has been made in the systemic treatment of patients with advanced or recurrent cervical cancer. We recently performed an silico analysis to identify potential driver pathways of cervical carcinogenesis and candidate targets for treatment.1 Expression2Kinases (E2K) analysis revealed a protein-protein interaction (PPI) network of 162 nodes (including 20 druggable kinases) consisting of 5 signaling modules associated with MYC signaling (module 1), cell cycle deregulation and cyclin signaling (module 2), TGFβ-signaling (module 3), a PI3K - MAPK signaling (module 4) and chromatine modeling (module 5). Methods: The cervical cancer cell lines included in the study were CaSki, SiHa and HeLa. Cells were incubated for 24 or 72 hours with the PI3K pathway inhibitor BYL719 (Novartis), the multiple pathway inhibitor INC280 (inhibits cMET-dependent PI3K and RAS signaling, Novartis), or the CDK4/6 inhibitor PD-0332991 (palbociclib, Selleck Chemicals) in monotherapy. Sensitivity to drug treatment (0 - 10 μM) was investigated using the colorimetric sulforhodamine B (SRB) assay. IC50 values were calculated using WinNonlin Software. Results: Incubation with BYL719 or INC280 for 24 or 72 hours in concentrations up to 10 μM was not able to establish a distinct cytotoxic effect in the three cervical cancer cell lines included in the study. Incubation with 10 μM BYL719 for 72h resulted in only 20% cell kill, while 10 μM INC280 for 72h caused around 30% cell kill in all three cell lines. However, incubation with palbociclib for 72 hours clearly induced a concentration-dependent cytotoxic effect, with IC50 values of 5.32 ± 0.03 μM, 7.69 ± 0.02 μM and 5.68 ± 0.12 μM for HeLa, SiHa and CaSki cells, respectively. Conclusion: CDK4/6 inhibition seems effective in cervical cancer cell lines and should be further evaluated alone and in combination with chemotherapy for the treatment of advanced and recurrent cervical cancer. References: Van Dam P, van Dam PJ, Rolfo C, Giallombardo M, Van Berckelaer C, Trin XB, Altintas S, Huizing M, Papadimitriou K, Tjalma W, Van Laere S. In silico pathway analysis in cervical carcinoma reveals potential new targets for treatment. Oncotarget 2016;7(3):2780-2795 Citation Format: Peter Van Dam, An Wouters, Luc Dirix, Christian Rolfo. Palbociclib monotherapy exhibits potent activity in cervical cancer cell lines [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 2317.
Biological material collection to advance translational research and treatment of children with CNS tumours: position paper from the SIOPE Brain Tumour Group
Authors: Stefan Rutkowski, Piergiorgio Modena, Daniel Williamson, Kornelius Kerl, Karsten Nysom, Barry Pizer, Ute Bartels, Stephanie Puget, François Doz, Antony Michalski, Katja von Hoff, Mathilde Chevignard, Shivaram Avula, Matthew J Murray, Stefan Schönberger, Thomas Czech, Antoinette Y N Schouten-van Meeteren, Uwe Kordes, Christof M Kramm, Dannis G van Vuurden, Esther Hulleman, Geert O Janssens, Guirish A Solanki, Marie-Luise C van Veelen, Ulrich Thomale, Martin U Schuhmann, Chris Jones, Felice Giangaspero, Dominique Figarella-Branger, Torsten Pietsch, Steve C Clifford, Stefan M Pfister, Stefaan W Van Gool
Journal: The Lancet Oncology (2018)
A novel global health fellowship elective in oncology in Rwanda: A multi-faceted model in education.
Authors: Frederick Lansigan, Cristiana A. Costa, Egide Mpanumusingo, Catherine Kigonya, John Butonzi, Fidel Sebahungu, Cyprien Shyirambere, Tharcisse Mpunga, Jennifer Haley, Kurt Figueroa, Paul Park, Thomas H. Davis, Mary D. Chamberlin
Journal: Journal of Clinical Oncology (2017)

e18086 Background: Despite the rising burden of cancer, opportunities for global health education (GHE) at the fellowship level are lacking in hematology and oncology (HO). The Geisel School of Medicine at Dartmouth (GSMD) is pioneering a supervised one-month elective in Rwanda for HO fellows enrolled in U.S. programs. The goals are to expose fellows to a wider spectrum of disease states, improve clinical acumen, cultural sensitivity, and learn about health delivery in low-resource countries, while providing educational support for the local staff in a multidirectional learning paradigm. Methods: In partnership with the Rwandan Ministry of Health (MOH) and Partners in Health (PIH), GSMD created a one month elective rotation at the Butaro Cancer Center of Excellence (BCCOE) in Rwanda. HO Fellows with an interest in GHE apply to work in the outpatient clinic and inpatient wards in at BCCOE under direct supervision by GSMD faculty to provide input on cancer management including diagnosis, treatment, and chemotherapy administration. Fellows and attendings give lectures to hospital faculty and staff on topics requested by the leadership of BCCOE and participate in weekly telemedicine tumor boards. Fellows are evaluated using ACGME clinical competencies. Feedback from the Rwandan staff is obtained through customized evaluations. Results: The HO fellow gained exposure to advanced cancers including HIV-related malignancies, rare sarcomas and gestational trophoblastic disease, adhered to locally developed staging and treatment pathways, and gained confidence in guiding medical decisions. Fellows and faculty gave didactic presentations and provided bedside teaching. The local MOH and PIH staff gained new insight about approaches to management of complex disease states. This program promoted a multidirectional exchange of ideas related to patient care, disease states, and collaborative research projects. Conclusions: The institution of a global health fellowship elective in oncology has measurable benefits to HO fellows, cancer care providers in Rwanda and American faculty sub-specialists. This novel educational program will help to bridge the gap in global health disparities in a multifaceted approach.
Body Mass Index, Surgery, and Risk of Venous Thromboembolism in Middle-Aged Women
Authors: LianneParkin, SiânSweetland, AngelaBalkwill, JaneGreen, GillianReeves, ValerieBeral
Journal: Circulation (2012)

Background—Obesity and surgery are known risk factors for venous thromboembolism (VTE), but there is limited information about the independent effects of obesity on the incidence of postoperative VTE. We linked questionnaire data from the Million Women Study with hospital admission and death records to examine the risk of VTE in relation to body mass index (BMI) both in the absence of surgery and in the first 12 weeks following an operation. Methods and Results—Overall, 1 170 495 women (mean age, 56.1 years) recruited in 1996 to 2001 through the National Health Service Breast Screening Programme in England and Scotland were followed for an average of 6 years, during which time 6438 were admitted to hospital or died of VTE. The adjusted relative risks of VTE increased progressively with increasing BMI and women with a BMI ≥35 kg/m2 were 3–4 times as likely to develop VTE as those with a BMI 22.5 to 24.9 (relative risk 3.45 [95% CI 3.09–3.86]). Overweight and obese women were more likely than lean women to ...
Abstract 17314: Impact of Mild Therapeutic Hypothermia on Platelet Inhibition in Acute Coronary Syndrome
Authors: JanKaufmann, HelenaStockmann, PhilippStawowy, KristofGraf, EckartFleck, TimSchroeder, ChristianStorm
Journal: Circulation (2014)

Background: Mild therapeutic hypothermia (MTH) improves outcome for patients with acute coronary syndrome (ACS) after cardiac arrest (CA). Previous data point to an interaction between hypothermia and drug metabolism, thus potentially impacting on platelet function under antiplatelet therapy. Purpose: The aim of the study is to determine clopidogrel metabolism and platelet function in clopidogrel naive ACS patients treated with mild hypothermia (33°C, n=12) compared with ACS patients (troponin positive) with normal body temperature (n=14). Methods: Platelet function was measured by light transmittance aggregometry (LTA), multiple electrode platelet aggregometry (MEA) and VASP phosphorylation analysis before, 2h, 4h and 24h after administration of a 600 mg clopidogrel loading dose. Furthermore, plasma concentrations of clopidogrel, the active thiol metabolite and the inactive carboxyl metabolite were determined. All patients were screened for CYP2C19*2 polymorphism and scheduled for PCI. Mild hypothermia w...
Optimal Windows of Statin Use for Immediate Infarct Limitation
Authors: ShojiSanada, HiroshiAsanuma, TetsuoMinamino, KoichiNode, SeijiTakashima, HirokoOkuda, YoshiroShinozaki, AkikoOgai, MasashiFujita, AkioHirata, JiyoongKim, YoshihiroAsano, HidezoMori, HitonobuTomoike, SoichiroKitamura, MasatsuguHori, MasafumiKitakaze
Journal: Circulation (2004)

Background— Although statins are reported to have a cardioprotective effect, their immediate direct influence on ischemia-reperfusion injury and the underlying mechanisms remain obscure. We investigated these issues an in vivo canine model. Methods and Results— Dogs were subjected to coronary occlusion (90 minutes) and reperfusion (6 hours) immediately after injection of pravastatin (0.2, 2, or 10 mg/kg), pitavastatin (0.01, 0.1, or 0.5 mg/kg), or cerivastatin (0.5, 5, or 50 μg/kg). Then myocardial phosphatidylinositol 3-kinase (PI3-K) and 5′-nucleotidase activities were measured, as well as infarct size. After 15 minutes of reperfusion, pravastatin caused dose-dependent activation of Akt and ecto-5′-nucleotidase in the ischemic zone, and the effect was significant at higher doses. Pitavastatin also significantly increased these activities, and its optimal dose was within the clinical range, whereas cerivastatin caused activation at the lowest dose tested. In all cases, both Akt and ecto-5′-nucleotidase s...
Effects of Ghrelin Administration on Left Ventricular Function, Exercise Capacity, and Muscle Wasting in Patients With Chronic Heart Failure
Authors: NoritoshiNagaya, JunjiMoriya, YoshioYasumura, MasaakiUematsu, FumiakiOno, WataruShimizu, KazuyukiUeno, MasafumiKitakaze, KunioMiyatake, KenjiKangawa
Journal: Circulation (2004)

Background— Ghrelin is a novel growth hormone–releasing peptide that also induces vasodilation, inhibits sympathetic nerve activity, and stimulates feeding through growth hormone–independent mechanisms. We investigated the effects of ghrelin on left ventricular (LV) function, exercise capacity, and muscle wasting in patients with chronic heart failure (CHF). Methods and Results— Human synthetic ghrelin (2 μg/kg twice a day) was intravenously administered to 10 patients with CHF for 3 weeks. Echocardiography, cardiopulmonary exercise testing, dual x-ray absorptiometry, and blood sampling were performed before and after ghrelin therapy. A single administration of ghrelin elicited a marked increase in serum GH (25-fold). Three-week administration of ghrelin resulted in a significant decrease in plasma norepinephrine (1132±188 to 655±134 pg/mL; P<0.001). Ghrelin increased LV ejection fraction (27±2% to 31±2%; P<0.05) in association with an increase in LV mass and a decrease in LV end-systolic volume. Treatmen...