bluuebunny/crossref_metadata_2025 huggingface dataset:
Family History of Cancer in Relation to Breast Cancer Subtypes in African American Women
Authors: Bethea Traci N. , Rosenberg Lynn , Castro-Webb Nelsy , Lunetta Kathryn L. , Sucheston-Campbell Lara E. , Ruiz-Narváez Edward A. , Charlot Marjory , Park Song-Yi , Bandera Elisa V. , Troester Melissa A. , Ambrosone Christine B. , Palmer Julie R.
Published: January 2016

Background: The evidence on the relation of family history of cancers other than breast cancer to breast cancer risk is conflicting, and most studies have not assessed specific breast cancer subtypes.

Methods: We assessed the relation of first-degree family history of breast, prostate, lung, colorectal, ovarian, and cervical cancer and lymphoma or leukemia, to the risk of estrogen receptor–positive (ER+), ER−, and triple-negative breast cancer in data from the African American Breast Cancer Epidemiology and Risk Consortium. Multivariable logistic regression models were used to calculate ORs and 95% confidence intervals (CI).

Results: There were 3,023 ER+ and 1,497 ER− breast cancer cases (including 696 triple-negative cases) and 17,420 controls. First-degree family history of breast cancer was associated with increased risk of each subtype: OR = 1.76 (95% CI, 1.57–1.97) for ER+, 1.67 (1.42–1.95) for ER−, and 1.72 (1.38–2.13) for triple-negative breast cancer. Family history of cervical cancer was associated with increased risk of ER− (OR = 2.39; 95% CI, 1.36–4.20), but not ER+ cancer. Family history of both breast and prostate cancer was associated with increased risk of ER+ (3.40; 2.42–4.79) and ER− (2.09; 1.21–3.63) cancer, but family history of both breast and lung cancer was associated only with ER− cancer (2.11; 1.29–3.46).

Conclusions: A family history of cancers other than breast may influence the risk of breast cancer, and associations may differ by subtype.

Impact: Greater surveillance and counseling for additional screening may be warranted for women with a family history of cancer. Cancer Epidemiol Biomarkers Prev; 25(2); 366–73. ©2015 AACR.
New Strategies in Prostate Cancer: Prostate-Specific Membrane Antigen (PSMA) Ligands for Diagnosis and Therapy
Authors: Haberkorn Uwe , Eder Matthias , Kopka Klaus , Babich John W. , Eisenhut Michael
Published: January 2016

Key issues for prostate cancer patients are the detection of recurrent disease and the treatment of metastasized cancer. Early detection is a major challenge for all conventional imaging modalities. Furthermore, therapy of patients with hormone-resistant tumor lesions presents a major clinical challenge. Because the prostate-specific membrane antigen (PSMA) is frequently overexpressed in prostate cancer, several PSMA-targeting molecules are under development to detect and treat metastatic castration-resistant prostate cancer (mCRPC). mCRPC represents a situation where cure is no longer achievable and novel therapeutic approaches for palliation and increase of survival are needed. In this article, we discuss the recent development for noninvasive detection of recurrent disease and therapy of mCRPC with corresponding PSMA-targeted radioligands. Clin Cancer Res; 22(1); 9–15. ©2016 AACR.
Preclinical Evaluation of a Novel Orally Available SRC/Raf/VEGFR2 Inhibitor, SKLB646, in the Treatment of Triple-Negative Breast Cancer
Authors: Zheng Ming-Wu , Zhang Chun-Hui , Chen Kai , Huang Mei , Li Ya-Ping , Lin Wan-Ting , Zhang Rong-Jie , Zhong Lei , Xiang Rong , Li Lin-Li , Liu Xin-Yu , Wei Yu-Quan , Yang Sheng-Yong
Published: January 2016

Triple-negative breast cancer (TNBC) is the most aggressive and deadly breast cancer subtype. To date, chemotherapy is the only systemic therapy and prognosis remains poor. Herein, we report the preclinical evaluation of SKLB646 in the treatment of TNBC; SKLB646 is a novel multiple kinase inhibitor developed by us recently. This compound potently inhibited SRC and VEGFR2 with IC50 values of 0.002 μmol/L and 0.012 μmol/L, respectively. It also considerably inhibited B-Raf and C-Raf with IC50 values of 0.022 and 0.019 μmol/L, respectively. It exhibited significant antiproliferation and antiviability activities against TNBC cell lines. Studies of mechanism of action indicated that SKLB646 inhibited the activation of SRC signaling and blocked the MAPK signaling through inhibiting the Raf kinases. Interestingly, SKLB646 dose dependently downregulated the expression of Fra1, a transcriptional factor that plays a critical role in the epithelial-to-mesenchymal transition. In addition, SKLB646 could inhibit HUVEC proliferation, migration, and invasion. It effectively blocked the formation of intersegmental vessels in zebrafish embryos and displayed considerable antiangiogenic effects in the tumor-induced neovascularization zebrafish model. In TNBC xenograft models, SKLB646 suppressed the tumor growth in a dose-dependent manner. Moreover, SKLB646 could remarkably inhibit TNBC cell migration and invasion in vitro. Furthermore, in an experimental lung metastasis model, the overall survival time of groups treated with SKLB646 was much longer compared with the control-, dasatinib-, and paclitaxel-treated groups. In a preliminary pharmacokinetic study, SKLB646 showed good pharmacokinetic properties. Taken together, the preclinical data show that SKLB646 could be a promising lead compound for the treatment of TNBC. Mol Cancer Ther; 15(3); 366–78. ©2015 AACR.
Structure-Based Screen Identification of a Mammalian Ste20-like Kinase 4 (MST4) Inhibitor with Therapeutic Potential for Pituitary Tumors
Authors: Xiong Weipeng , Matheson Christopher J. , Xu Mei , Backos Donald S. , Mills Taylor S. , Salian-Mehta Smita , Kiseljak-Vassiliades Katja , Reigan Philip , Wierman Margaret E.
Published: January 2016

Pituitary tumors of the gonadotrope lineage are often large and invasive, resulting in hypopituitarism. No medical treatments are currently available. Using a combined genetic and genomic screen of individual human gonadotrope pituitary tumor samples, we recently identified the mammalian sterile-20 like kinase 4 (MST4) as a protumorigenic effector, driving increased pituitary cell proliferation and survival in response to a hypoxic microenvironment. To identify novel inhibitors of the MST4 kinase for potential future clinical use, computational-based virtual library screening was used to dock the SelleckChem kinase inhibitor library into the ATP-binding site of the MST4 crystal structure. Several inhibitor candidates were identified with the potential to bind with high affinity. Using a TR-FRET in vitro recombinant kinase assay, hesperadin, initially described as an Aurora kinase inhibitor, exhibited potent inhibition of the MST4 kinase at nanomolar concentrations. The LβT2 gonadotrope pituitary cell hypoxic model was used to test the ability of this inhibitor to antagonize MST4 actions. Under short-term severe hypoxia (1% O2), MST4 protection from hypoxia-induced apoptosis was abrogated in the presence of hesperadin. Similarly, under chronic hypoxia (5%), hesperadin blocked the proliferative and colony-forming actions of MST4 as well as the ability to activate specific downstream signaling and hypoxia-inducible factor-1 effectors. Together, these data identify hesperadin as the first potent, selective inhibitor of the MST4 kinase with the capacity to block pituitary tumor cell growth in a hypoxic microenvironment. Mol Cancer Ther; 15(3); 412–20. ©2015 AACR.
ФОТОАКТИВНІСТЬ БІОЛОГІЧНИХ МОЛЕКУЛ ЯК МОЖЛИВИЙ ФАКТОР КОРЕГУВАННЯ ТРИГЕРЗАЛЕЖНИХ СИСТЕМНИХ ПРОЦЕСІВ (ПЕРШЕ ПОВІДОМЛЕННЯ)
Authors: Mintser O. P. , Vatlitsov D. V.
Published: January 2016

The usage of a systemic approach for the investigation of the conceptual questions of the regulation and impact on certain
link create the conditions for accumulation and take into all of the known results of numerous studies. Using this approach were re-evaluated the targets of electromagnetic radiation of UV, visible and infrared spectra for correction of intracellular systems processes. The aim of this work was to create a concept of trigger biomolecules photoactivation of living cells as a correction factor of intracellular systems processes. Were used the content analysis, collocate analysis and the data obtained from the database of known and predicted biomolecules and interactions. It was developed the four resulting of light on trigger dependent systems processes of living cells: size; resonance; increasing of luminous flux power after polarization; asymmetric response of living systems. It was shown that physical and chemical properties of the biopolymers caused the possibilities for correction of trigger dependent processes and asymmetric response of living systems to the increase in total energy uptake to the system leads to activation of survival mechanisms.
ІНФОРМАЦІЙНІ АСПЕКТИ ОБҐРУНТУВАННЯ СТРУКТУРНИХ СКЛАДОВИХ БЕЗПЕКИ ПАЦІЄНТА
Authors: Babintseva L. Yu.
Published: January 2016

There was discussed the question of the safety of medical care. It was formalized terminology database problems and
proposed three-tier structure to ensure patient safety: quality of medical care; the organization action in unusual situations;
an individual approach to the management the patient care.
ПРО ПІДХІД ДО ЗАСТОСУВАННЯ НАУКОВИХ СОЦІАЛЬНИХ МЕРЕЖ ДЛЯ МАКСИМІЗАЦІЇ ПРЕДСТАВЛЕННЯ ІНФОРМАЦІЇ ПРО НАУКОВІ ПУБЛІКАЦІЇ
Authors: Semenets A. V. , Martsenyuk V. P.
Published: January 2016

Usage of the scientific social networks it are necessary component of the presentation the results of scientific research.
The importance of scientific social networks as tool for improvement of the bibliometrics citation quantity of the scientific
papers is shown. An approach for creating of the user profiles and its data integration through the scientific social networks
and open registries is presented. The maximization of visibility and bibliometrics citation increasing of the scientific papers
initiated by the given above approach is discussed. The methodology of usage of the desktop version of the reference
management software is also shown. The role and ways to receiving of the Altmetric rating indices are mentioned.
ПРИНЦИПИ ОРГАНІЗАЦІЇ ПРОБЛЕМНО-ОРІЄНТОВАНОГО НАВЧАННЯ НА КАФЕДРІ ГІСТОЛОГІЇ, ЦИТОЛОГІЇ ТА ЕМБРІОЛОГІЇ В УМОВАХ ВПРОВАДЖЕННЯ СУЧАСНИХ ІНФОРМАЦІЙНИХ ТЕХНОЛОГІЙ
Authors: Klyuchko S. S.
Published: January 2016

The article by questioning senior researchers and students of the Department of Histology, Cytology and Embryology
Authority identified the main approaches to the formation of the principles of problem-based learning students and objective 

control in the conditions of modern information technologies. Implementation at the Department of Histology, Cytology and
Embryology test control for control of knowledge and case studies for the evaluation of clinical thinking allows us to give an
objective assessment of how students understand the connection between the theoretical material and practical actions, are
able to analyze, synthesize the material and to predict development of the situation. To innovate the educational diagnosis can
be attributed to the successful use of the Department of Histology, Cytology and Embryology principles of modularity and rating
control training using computer programs. The undoubted advantages of the rating control are: evaluation of the individual
units of work ensures the reliability of the control (test control and situational problems, diagnostics 2 micropreparations and
electron diffraction); so its form satisfies the requirements of content and construct validity (compliance with the forms and
purposes); Extended Monitoring integrates and implements motivational and educational functions; detailed and phased
control procedure to develop students' skills of self-work, forms the experience of self-control in professional activities.
ВПРОВАДЖЕННЯ ВІРТУАЛЬНИХ МОДЕЛЕЙ У НАВЧАЛЬНИЙ ПРОЦЕС ВИВЧЕННЯ ФІЗІОЛОГІЇ
Authors: Guranych T. V.
Published: January 2016

The necessity to modernize the educational process of physiology studying by the introduction of innovative teaching
methods, in particular virtual modeling is considered in the article. Such method can improve the quality of the discipline
studying and more accurately reflect the vital processes in the human body.
ПОЛЯРИЗОВАНЕ СВІТЛО У ФІЗІОТЕРАПІЇ
Authors: Tondiy L. D. , Tondiy O. L. , Kas I. V. , Zemlyanaya O. V. , Zakrevskaya E. L. , Zhuravlev V. A.
Published: January 2016

The data on polarized light (PS) - a new promising treatment, rehabilitation and prevention, which took its deserved place among the known therapeutic physical factors and may even compete with laser radiation of low and LED therapy.

It is reflected the significant contribution of domestic scientists in the study of aircraft action on the body, its introduction in the treatment, rehabilitation and prevention of grippe, ARI. These action's mechanisms of the aircraft on the electro-physiological processes in the body that have the leading role in the regulation of its life.

The new moment in the study of aircraft on the body is the evidence of its positive impact on the mechanisms of self body - its different units: the disease's banning - a revitalization of the stress-protective, stress-limiting system antioxidial, detoxification and other protection systems, the formation by the body antiviral and antimicrobial specific substances (interferon and lysozyme), activation of the immune system, phagocytosis, protective functions of skin.

The protective and mobilizing role of the second link is studied: which is triggered in case of occurrence of disease or preexisting diseases: PL mobilized processes of restitution, reparations, compensation, immunity and microcirculation.

The authors studied the possibility of aircraft's using to enhance performance, reduce side effects of physical factors, which are often used in the treatment (electric methods, treatment by sound, fresh and mineral water, etc.).
ПОРІВНЯЛЬНИЙ АНАЛІЗ КІРЛІАНОГРАФІЧНОГО СВІТІННЯ БІОЛОГІЧНОЇ ТКАНИНИ З БІОХІМІЧНИМИ ПРОЦЕСАМИ
Authors: Pesotskaya L. A. , Glukhovа N. V. , Povstyanoy V. A. , Evdokimenko N. M. , Chernenko G. P.
Published: January 2016

Kirlian diagram samples Conducted. Achilles tendon dead people with various postmorbidnym period (from 5:0 until 22 days) and optoelectronics is part of the standard terms of the x-ray film developer. The results obtained were compared with biochemical indicators of the level of enzymes and content of degradation products of proteins, trace elements, derived from 
the investigated samples. For kirlianograficeskih studies used an experimental device, RIVERS 1, developed by Ukrainian Scientific Research Institute of mechanical engineering technologies (Dnepropetrovsk). For mathematical processing of results using Matlab program.

The growing shortage of ATP causes the breach and termination of ion exchange, increases reactive oxygen generation, lipid peroxidation destroys cell membranes. The process of self digestion (autoliza) tissue tendons, as shown by the results of the experiments, had cyclical changes metabolism enzyme activity (ALT), carbohydrate (LDH), nucleotides, of total protein and micronutrients.
КІБЕРНЕТИЧНЕ ПРОГНОЗУВАННЯ ЯК ЗАСІБ ОПТИМІЗАЦІЇ ЛІКУВАЛЬНО- ДІАГНОСТИЧНОГО ПРОЦЕСУ В ХІРУРГІЇ
Authors: Veselyy S. V. , Yudin O. I. , Klimanskyi R. P.
Published: January 2016

The paper shows the relevance of the use of medical forecasting in diagnostic and treatment process. The urgency of the use of mathematical models in the organization of the treatment process were reflects. It carried out a literature review of the importance of using modern medical prediction, along with instrumental and pharmacological methods of diagnosis and treatment.
ДОСВІД ФАНТОМНО-СИМУЛЯЦІЙНОГО НАВЧАННЯ СТУДЕНТІВ ІЗ ДИСЦИПЛІНИ «АКУШЕРСТВО ТА ГІНЕКОЛОГІЯ»
Authors: Potapov V. A. , Donskaya Yu. V. , Medvediev M. V. , Petulko А. Р.
Published: January 2016

The article presents the results of simulation trainings at the Department of Obstetrics and Gynecology of State Establishment «Dnipropetrovsk Medical Academy of Health Ministry of Ukraine». In order to improve the quality of knowledge of students a lot of time to the development of practical skills of modern high-tech simulation equipment was given. During the 2013-
2015 academic years the department staff has conducted more than 7 thousands practical trainings for students of IV, V and VI years using modern simulation equipment. Analysis of the data showed that significant proportion of students has
improved the results of the basic skills after undergoing training. The introduction in the educational process of simulation training promotes quality practical skills and more efficient formation of students' motivation to learn.
ЗАСТОСУВАННЯ ІНФОРМАЦІЙНИХ ТЕХНОЛОГІЙ ДЛЯ ОЦІНКИ ОСОБЛИВОСТЕЙ РЕАКТИВНОСТІ ОРГАНІЗМУ МОЛОДИХ ЩУРІВ ПРИ ЕКСПЕРИМЕНТАЛЬНІЙ ГІПОКСІЇ
Authors: Volkova N. M.
Published: January 2016

Research of adaptation mechanisms in young body to factors such as hypoxic effect is an actual scientific problem. The aim of the experiment was to determine the functional consequences of changes in ion permeability of cell membranes in the associative cortex in young rats ufter incubation at hypoxic environment under conditions of low atmospheric pressure.
Incubation of rats in the hypoxic environment under conditions of moderately low atmospheric pressure leads to increased permeability of cell membranes for Na + and Cl- ions at the associative cortex. This is a functional feature of hypoxic damage to membrane structures of nerve tissue that causes compensatory limit the activity of the central contour regulation of heart rate and decrease activity of the sympathetic regulation. Peculiarities in reactivity of young rats exist due to the immaturity of fronto-thalamic brain system.
ЗАСТОСУВАННЯ ВІДКРИТОГО ПРОГРАМНОГО КОМПЛЕКСУ ДЛЯ ОБРОБКИ МЕДИЧНИХ ЗОБРАЖЕНЬ MEVISLAB ПРИ ВИВЧЕННІ КУРCУ «МЕДИЧНА ІНФОРМАТИКА»
Authors: Kravets N. O. , Semenets A. V. , Sverstyuk A. S.
Published: January 2016

The main capabilities of the MeVisLab image analysis suite to the medical images processing are shown. The application software package structure and the user interface are described. The methodology of the MeVisLab software package usage
to the studying of the corresponded topics of the Medical Informatics course is presented. An approach of the implementation of the image elements recognition algorithm is demonstrated.
APPLICATION OF UKRAINIAN GRID INFRASTRUCTURE FOR ELECTROENCEPHALOGRAM AND ULTRASONIK DIAGNOSTIC IMAGES ANALYSIS
Authors: Byvalkevych R. V. , Gaidar V. O. , Radchenko S. P. , Sudakov O. О.
Published: January 2016

Ultrasonic introscopic imaging (USI) and electroencephalography (EEG) are powerful tools for diagnostics of different pathologies. In the same time USI and EEG equipment is available in almost all clinical and even in many educational institutions. Development of ultrasonic images and EEG data processing algorithms providing physicians with additional specific clinical parameters is a popular current research subject. Successful operation of these
algorithms needs fast procession of large information volumes. These algorithms are based on an analysis of large databases with information about the patients. Grid infrastructures can provide distributed data
archiving, procession and access facilities for such
databases.
MOLECULAR SIGNATURES OF LUNG CANCER BASED ON GENE EXPRESSION RANKING OF RNA-SEQ DATA
Authors: Bondarenko V. , Emmert-Streib Frank
Published: January 2016

Whole Transcriptome Shotgun Sequencing or RNA-Seq is an experimental methodology which allows quantification of all transcripts expressed in a population of cells. In biomedicine, it is gradually gaining popularity to become a prevalent method
for transcriptome analysis. Sequencing of individual human transcriptomes has become a powerful tool in disease biomarkers discovery and setting up individual
treatment therapy of cancer and other disorders.
THE EXPERIENCE OF THE INTRODUCTION OF «DOCTOR ELEKS»
Authors: Ventskivska N. I. , Korobchinska N. V. , Tumanina S. V.
Published: January 2016

The need for a single medical information space in Vinnitsa there was a long time, however, the actual implementation of the automated medical information system was made possible with
the debugging of the program «Doctor Eleks.» The «Doctor Eleks» provides automation and linking all the main processes of the medical institutions. The goal of creating a unified information space of urban health by implementing the program «Doctor Eleks» improve the quality of medical services in Vinnitsya.
INFORMATIONAL TECHNOLOGIES IN THE DOCTOR'S WORK IN MUNICIPAL CHILDREN'S CLINICAL HOSPITAL
Authors: Semenyuk O. O.
Published: January 2016

The implementation of IT in combination with organizational changes in our hospital has contributed to: increase of
efficiency in the organization of work of the institution; speed up of diagnostics and treatment according to modern criteria of quality of medical care to the patient in compliance with clinical protocols and routes of the patient according to nosologies diseases; speed up and simplification of the documents circulation, conducting of the analytical data processing, formation of statements necessary for making decision by the administration of the hospital; protection of personal data of the patient in accordance with current legislation; information that contains electronic patient's card, can be transmitted electronically for consultation with the specialists of leading clinics, as well as to conduct telemedicine consultation online; implementation of the electronic patient's card puts our clinic along with the most advanced European clinics.
APPLICATION OF UKRAINIAN GRID INFRASTRUCTURE FOR INVESTIGATION OF NONLINEAR DYNAMICS IN LARGE NEURONAL NETWORKS
Authors: Sudakov O. О. , Maistrenko V. L.
Published: January 2016

In present work the Ukrainian National Grid (UNG) infrastructure was applied for investigation of synchronization in large networks of interacting neurons. This application is important for solving of modern neuroscience problems related to mechanisms of nervous system activities (memory, cognition etc.) and nervous pathologies (epilepsy, Parkinsonism, etc.). Modern non-linear dynamics theories and applications provides powerful basis for computer simulations
of biological neuronal networks and investigation of phenomena which mechanisms hardly could be clarified by other approaches. Cubic millimeter of brain tissue contains about 105 neurons, so realistic (Hodgkin-Huxley model) and phenomenological (Kuramoto-Sakaguchi, FitzHugh-Nagumo, etc. models) simulations require consideration of large
neurons numbers.
ІНФОРМАЦІЙНІ ТЕХНОЛОГІЇ ВИВЧЕННЯ АДАПТАЦІЙНОЇ ЗДАТНОСТІ СЕРЦЕВО-СУДИННОЇ СИСТЕМИ ДО ФІЗИЧНОГО НАВАНТАЖЕННЯ ЗА МОРФОЛОГІЧНИМ, ЧАСОВИМ ТА СПЕКТРАЛЬНИМ АНАЛІЗОМ ОСЦИЛОГРАМ
Authors: Martsenyuk V. P. , Vakulenko D. V. , Vakulenko L. O.
Published: January 2016

Offer Author Information Technology morphological, temporal and spectral analysis of waveforms (recorded at rest and after exercise), the introduction of analytical treated for clinical interpretation of the results, evaluation and decision-making to doctors significantly increases the information content of the procedure of blood pressure measurement. Can be used for early detection and prenosological premorbid state and functional reserve of the circulatory system, help more effectively to plan preventive, diagnostic and therapeutic process.
Dipeptidyl Peptidase 4 Inhibition Alleviates Shortage of Circulating Glucagon-Like Peptide-1 in Heart Failure and Mitigates Myocardial Remodeling and Apoptosis via the Exchange Protein Directly Activated by Cyclic AMP 1/Ras-Related Protein 1 Axis
Authors: Aoyama Morihiko , Kawase Haruya , Bando Yasuko K. , Monji Akio , Murohara Toyoaki
Published: January 2016

Background—

Ample evidence demonstrates cardiovascular protection by incretin-based therapy using dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 (GLP-1) under either diabetic or nondiabetic condition. Their action on myocardium is mediated by the cyclic AMP (cAMP) signal; however, the pathway remains uncertain. This study was conducted to address the effect of DPP4i/GLP-1/cAMP axis on cardiac dysfunction and remodeling induced by pressure overload (thoracic aortic constriction [TAC]) independently of diabetes mellitus.

Methods and Results—

DPP4i (alogliptin, 10 mg/kg per day for 4 weeks) prevented TAC-induced contractile dysfunction, remodeling, and apoptosis of myocardium in a GLP-1 receptor antagonist (exendin [9-39])–sensitive fashion. In TAC, circulating level of GLP-1 (in pmol/L; 0.86±0.10 for TAC versus 2.13±0.54 for sham control) unexpectedly declined and so did the myocardial cAMP concentration (in pmol/mg protein; 33.0±1.4 for TAC versus 42.2±1.5 for sham). Alogliptin restored the decline in the GLP-1/cAMP levels observed in TAC, thereby augmented cAMP signaling effectors (protein kinase A [PKA] and exchange protein directly activated by cAMP 1 [EPAC1]). In vitro assay revealed distinct roles of PKA and EPAC1 in cardiac apoptosis. EPAC1 promoted cardiomyocyte survival via concomitant increase in B cell lymphoma-2 (Bcl-2) expression and activation of small G protein Ras-related protein 1 (Rap1) in a cAMP dose–dependent and PKA–independent fashion.

Conclusions—

DPP4i restores cardiac remodeling and apoptosis caused by the pathological decline in circulating GLP-1 in response to pressure overload. EPAC1 is essential for cardiomyocyte survival via the cAMP/Rap1 activation independently of PKA.
Association of Serum Erythropoietin With Cardiovascular Events, Kidney Function Decline, and Mortality
Authors: Garimella Pranav S , Katz Ronit , Patel Kushang V , Kritchevsky Stephen B , Parikh Chirag R , Ix Joachim H , Fried Linda F , Newman Anne B , Shlipak Michael G , Harris Tamara B , Sarnak Mark J
Published: January 2016

Background—

Studies suggest that in patients with heart failure (HF), high serum erythropoietin is associated with risk of recurrent HF and mortality. Trials of erythropoietin-stimulating agents in persons with kidney disease have also suggested an increased incidence of adverse clinical events. No large studies of which we are aware have evaluated the association of endogenous erythropoietin levels with clinical outcomes in the community-living older adults.

Methods and Results—

Erythropoietin concentration was measured in 2488 participants aged 70–79 years in the Health, Aging and Body Composition Study. Associations of erythropoietin with incident HF, coronary heart disease, stroke, mortality, and ≥30% decline in estimated glomerular filtration rate were examined using Cox proportional hazards and logistic regression over 10.7 years of follow-up. Mean (SD) age was 75 (3) years and median (quartile 1, quartile 3) erythropoietin was 12.3 (9.0, 17.2) mIU/mL. There were 503 incident HF events, and each doubling of serum erythropoietin was associated with a 25% increased risk of incident HF 1.25 (95% confidence interval 1.13, 1.48) after adjusting for demographics, prevalent cardiovascular disease, cardiovascular disease risk factors, kidney function, and serum hemoglobin. There was no interaction of serum erythropoietin with chronic kidney disease or anemia (
P
>0.50). There were 330 incident coronary heart disease events, 161 strokes, 1112 deaths, and 698 outcomes of ≥30% decline in estimated glomerular filtration rate. Serum erythropoietin was not significantly associated with these outcomes.

Conclusions—

Higher levels of endogenous erythropoietin are associated with incident HF in older adults. Studies need to elucidate the mechanisms through which endogenous erythropoietin levels associate with specific outcomes.
Health Literacy Mediates the Relationship Between Age and Health Outcomes in Patients With Heart Failure
Authors: Wu Jia-Rong , Moser Debra K. , DeWalt Darren A. , Rayens Mary Kay , Dracup Kathleen
Published: January 2016

Background—

Previous studies have linked frequent rehospitalizations for heart failure (HF) and increased mortality with older age, higher severity of HF, lack of an evidence-based medication regimen, and inadequate health literacy. However, the pathway between age and health outcomes in patients with HF remains unknown. Therefore, the purpose of this study was to test whether the association between age and health outcomes can be explained by severity of HF, evidence-based medication use, and health literacy in patients with HF.

Methods and Results—

This was a longitudinal study of 575 rural patients with HF recruited from outpatient clinics and hospitals. Demographics, clinical data, and health literacy were collected at baseline. HF readmissions and cardiac mortality were followed for 2 years; 57% of patients were ≥65 years of age. Older patients with HF were more likely to have low health literacy and less likely to be prescribed angiotensin-converting enzyme inhibitors or β-blockers. Using Kaplan–Meier survival curves with log-rank tests, health outcomes were significantly worse in patients who were ≥65 years and in those with low health literacy. Separate Cox regressions revealed that age and health literacy predicted worse health outcomes (
P
=0.006 and <0.001, respectively). When health literacy was entered into the model, the hazard ratio for age changed from 1.49 to 1.29 (a 41% reduction); age was no longer a significant predictor of health outcomes, but health literacy remained significant (
P
<0.001), demonstrating mediation.

Conclusions—

Health literacy mediates the relationship between age and health outcomes in adults with HF.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00415545.
Antiplatelet Therapy and Adverse Hematologic Events During Heart Mate II Support
Authors: Saeed Omar , Shah Aman , Kargoli Faraj , Madan Shivank , Levin Allison P. , Patel Snehal R. , Jermyn Rita , Guerrero Cesar , Nguyen Jenni , Sims Daniel B. , Shin Julia , D’Alessandro David , Goldstein Daniel J. , Jorde Ulrich P.
Published: January 2016

Background
—

Hematologic adverse events are common during continuous flow left ventricular assist device support; yet, their relation to antiplatelet therapy, including aspirin (ASA) dosing, is uncertain.

Methods and Results—

A single-center retrospective review of all patients supported by a continuous flow left ventricular assist device (Heart Mate II) from June 2006 to November 2014 was conducted. Patients were categorized into 3 groups: (1) ASA 81 mg+dipyridamole 75 mg daily (n=26) with a target international normalized ratio (INR) of 2 to 3 from June 2006 to August 2009; (2) ASA 81 mg daily (n=18) from September 2009 to August 2011 with a target INR of 1.5 to 2; and (3) ASA 325 mg daily from September 2011 to November 2014 with a target INR of 2 to 3 (n=70). Hemorrhagic and thrombotic outcomes were retrieved ≤365 days after implantation. Cumulative survival free from adverse events was calculated using Kaplan–Meier curves and Cox proportional hazard ratios were generated. Hemorrhagic events occurred in 6 patients on ASA 81 mg+dipyridamole (26%; 0.42 events per patient year; mean INR at event, 2.2), 4 patients on ASA 81 mg (22%; 0.38 events per patient year; mean INR at event, 2.0), and in 38 patients on ASA 325 mg (54%; 1.4 events per patient year; mean INR at event, 2.2);
P
=0.004. Patients on ASA 325 mg had a higher adjusted hazard ratio of 2.9 (95% confidence interval, 1.2–7.0 versus ASA 81 mg+dipyridamole;
P
=0.02) and 3.4 (95% confidence interval, 1.2–9.5 versus ASA 81 mg;
P
=0.02) for hemorrhagic events. Thrombotic events rates were not different between groups.

Conclusions—

High-dose ASA in Heart Mate II patients treated concomitantly with warfarin is associated with an increased hazard of bleeding but does not reduce thrombotic events.
Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure
Authors: Testani Jeffrey M. , Hanberg Jennifer S. , Cheng Susan , Rao Veena , Onyebeke Chukwuma , Laur Olga , Kula Alexander , Chen Michael , Wilson F. Perry , Darlington Andrew , Bellumkonda Lavanya , Jacoby Daniel , Tang W.H. Wilson , Parikh Chirag R.
Published: January 2016

Background—

Removal of excess sodium and fluid is a primary therapeutic objective in acute decompensated heart failure and commonly monitored with fluid balance and weight loss. However, these parameters are frequently inaccurate or not collected and require a delay of several hours after diuretic administration before they are available. Accessible tools for rapid and accurate prediction of diuretic response are needed.

Methods and Results—

Based on well-established renal physiological principles, an equation was derived to predict net sodium output using a spot urine sample obtained 1 or 2 hours after loop diuretic administration. This equation was then prospectively validated in 50 acute decompensated heart failure patients using meticulously obtained timed 6-hour urine collections to quantify loop diuretic-induced cumulative sodium output. Poor natriuretic response was defined as a cumulative sodium output of <50 mmol, a threshold that would result in a positive sodium balance with twice-daily diuretic dosing. Following a median dose of 3 mg (2–4 mg) of intravenous bumetanide, 40% of the population had a poor natriuretic response. The correlation between measured and predicted sodium output was excellent (
r
=0.91;
P
<0.0001). Poor natriuretic response could be accurately predicted with the sodium prediction equation (area under the curve =0.95, 95% confidence interval 0.89–1.0;
P
<0.0001). Clinically recorded net fluid output had a weaker correlation (
r
=0.66;
P
<0.001) and lesser ability to predict poor natriuretic response (area under the curve =0.76, 95% confidence interval 0.63–0.89;
P
=0.002).

Conclusions—

In patients being treated for acute decompensated heart failure, poor natriuretic response can be predicted soon after diuretic administration with excellent accuracy using a spot urine sample.
Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure
Authors: Grodin Justin L , Verbrugge Frederik H , Ellis Stephen G , Mullens Wilfried , Testani Jeffrey M , Tang W.H. Wilson
Published: January 2016

Background—

The aim of this analysis was to determine the long-term prognostic value of lower serum chloride in patients with stable chronic heart failure. Electrolyte abnormalities are prevalent in patients with chronic heart failure. Little is known regarding the prognostic implications of lower serum chloride.

Methods and Results—

Serum chloride was measured in 1673 consecutively consented stable patients with a history of heart failure undergoing elective diagnostic coronary angiography. All patients were followed for 5-year all-cause mortality, and survival models were adjusted for variables that confounded the chloride–risk relationship. The average chloride level was 102±4 mEq/L. Over 6772 person-years of follow-up, there were 547 deaths. Lower chloride (per standard deviation decrease) was associated with a higher adjusted risk of mortality (hazard ratio 1.29, 95% confidence interval 1.12–1.49;
P
<0.001). Chloride levels net-reclassified risk in 10.4% (
P
=0.03) when added to a multivariable model (with a resultant C-statistic of 0.70), in which sodium levels were not prognostic (
P
=0.30). In comparison to those with above first quartile chloride (≥101 mEq/L) and sodium (≥138 meq/L), subjects with first quartile chloride had a higher adjusted mortality risk, whether they had first quartile sodium (hazard ratio 1.35, 95% confidence interval 1.08–1.69;
P
=0.008) or higher (hazard ratio 1.43, 95% confidence interval 1.12–1.85;
P
=0.005). However, subjects with first quartile sodium but above first quartile chloride had no association with mortality (
P
=0.67).

Conclusions—

Lower serum chloride levels are independently and incrementally associated with increased mortality risk in patients with chronic heart failure. A better understanding of the biological role of serum chloride is warranted.
Heart Failure With Preserved Ejection Fraction Induces Beiging in Adipose Tissue
Authors: Valero-Muñoz María , Li Shanpeng , Wilson Richard M. , Hulsmans Maarten , Aprahamian Tamar , Fuster José J. , Nahrendorf Matthias , Scherer Philipp E. , Sam Flora
Published: January 2016

Background—

Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there are no evidence-based therapies for HFpEF. Clinical studies suggest a relationship between obesity-associated dysfunctional adipose tissue (AT) and HFpEF. However, an apparent obesity paradox exists in some HF populations with a higher body mass index. We sought to determine whether HFpEF exerted effects on AT and investigated the involved mechanisms.

Methods and Results—

Mice underwent
d
-aldosterone infusion, uninephrectomy, and were given 1% saline for 4 weeks. HFpEF mice developed hypertension, left ventricular hypertrophy, and diastolic dysfunction and had higher myocardial natriuretic peptide expression. Although body weights were similar in HFpEF and sham-operated mice, white AT was significantly smaller in HFpEF than in sham (epididymal AT, 7.59 versus 10.67 mg/g; inguinal AT, 6.34 versus 8.38 mg/g). These changes were associated with smaller adipocyte size and increased beiging markers (ucp-1, cidea, and eva) in white AT. Similar findings were seen in HFpEF induced by transverse aortic constriction. Increased activation of natriuretic peptide signaling was seen in white AT of HFpEF mice. The ratio of the signaling receptor, natriuretic peptide receptor type A, to the clearance receptor, nprc, was increased as was p38 mitogen-activated protein kinase activation. However, HFpEF mice failed to regulate body temperature during cold temperature exposure. In HFpEF, despite a larger brown AT mass (5.96 versus 4.50 mg/g), brown AT showed reduced activity with decreased uncoupling protein 1 (ucp-1), cell death-inducing DFFA-like effector a (cidea), and epithelial V-like antigen (eva) expression and decreased expression of lipolytic enzymes (hormone-sensitive lipase, lipoprotein lipase, and fatty acid binding protein 4) versus sham.

Conclusions—

These findings show that HFpEF is associated with beiging in white AT and with dysfunctional brown AT.
Partial Liver Kinase B1 (LKB1) Deficiency Promotes Diastolic Dysfunction, De Novo Systolic Dysfunction, Apoptosis, and Mitochondrial Dysfunction With Dietary Metabolic Challenge
Authors: Miller Edward J. , Calamaras Timothy , Elezaby Aly , Sverdlov Aaron , Qin Fuzhong , Luptak Ivan , Wang Ke , Sun Xinxin , Vijay Andrea , Croteau Dominique , Bachschmid Markus , Cohen Richard A. , Walsh Kenneth , Colucci Wilson S.
Published: January 2016

Background

Myocardial hypertrophy and dysfunction are key features of metabolic heart disease due to dietary excess. Metabolic heart disease manifests primarily as diastolic dysfunction but may progress to systolic dysfunction, although the mechanism is poorly understood. Liver kinase B1 (
LKB
1) is a key activator of
AMP
‐activated protein kinase and possibly other signaling pathways that oppose myocardial hypertrophy and failure. We hypothesized that
LKB
1 is essential to the heart's ability to withstand the metabolic stress of dietary excess.

Methods and Results

Mice heterozygous for cardiac
LKB
1 were fed a control diet or a high‐fat, high‐sucrose diet for 4 months. On the control diet, cardiac
LKB
1 hearts had normal structure and function. After 4 months of the high‐fat, high‐sucrose diet, there was left ventricular hypertrophy and diastolic dysfunction in wild‐type mice. In cardiac
LKB
1 (versus wild‐type) mice, high‐fat, high‐sucrose feeding caused more hypertrophy (619 versus 553 μm
2
,
P
<0.05), the de novo appearance of systolic dysfunction (left ventricular ejection fraction; 41% versus 59%,
P
<0.01) with left ventricular dilation (3.6 versus 3.2 mm,
P
<0.05), and more severe diastolic dysfunction with progression to a restrictive filling pattern (E/A ratio; 5.5 versus 1.3,
P
=0.05). Myocardial dysfunction in hearts of cardiac
LKB
1 mice fed the high‐fat, high‐sucrose diet was associated with evidence of increased apoptosis and apoptotic signaling via caspase 3 and p53/
PUMA
(p53 upregulated modulator of apoptosis) and more severe mitochondrial dysfunction.

Conclusions

Partial deficiency of cardiac
LKB
1 promotes the adverse effects of a high‐fat, high‐sucrose diet on the myocardium, leading to worsening of diastolic function and the de novo appearance of systolic dysfunction.
LKB
1 plays a key role in protecting the heart from the consequences of metabolic stress.
Circulating Galectin‐3 Is Associated With Cardiometabolic Disease in the Community
Authors: Nayor Matthew , Wang Na , Larson Martin G. , Vasan Ramachandran S. , Levy Daniel , Ho Jennifer E.
Published: January 2016

Background

Circulating Galectin‐3 (Gal‐3) concentrations are associated with an increased incidence of heart failure, atrial fibrillation, chronic kidney disease, and mortality. Recent evidence suggests that Gal‐3 may also be an important modulator of cardiometabolic traits such as adiposity, insulin resistance, and hyperglycemia. We examined the associations of blood Gal‐3 concentrations and cardiometabolic disease traits in the Framingham Heart Study.

Methods and Results

In cross‐sectional analyses of 2946
Framingham Heart Study
participants (mean age 59 years, 55% women), higher Gal‐3 concentrations were associated with higher body mass index, waist circumference, and triglycerides (
P
<0.0001 for all). Higher Gal‐3 was associated with greater odds of obesity (multivariable‐adjusted odds ratio 1.16 per 1‐SD increase in log–Gal‐3, 95%
CI
1.06–1.28,
P
=0.002) and hypertension (odds ratio 1.18, 95%
CI
1.07–1.29,
P
=0.0006). In prospective analyses, Gal‐3 was associated with incident metabolic syndrome (hazard ratio 1.22, 95%
CI
1.10–1.36,
P
=0.0002) and diabetes (hazard ratio 1.21, 95%
CI
1.04–1.41,
P
=0.02), in age‐ and sex‐adjusted, but not multivariable‐adjusted models.

Conclusions

In this large, community‐based sample, circulating Gal‐3 was associated with abdominal adiposity, dyslipidemia, and hypertension in cross‐sectional analyses, but Gal‐3 did not predict incident cardiometabolic disease after adjusting for cardiometabolic risk factors. Future investigations should focus on further elucidating mechanisms linking Gal‐3 with cardiometabolic disease and on assessing whether modulation of the Gal‐3 pathway might have positive cardiometabolic effects.
Rac1 Signaling Is Required for Anterior Second Heart Field Cellular Organization and Cardiac Outflow Tract Development
Authors: Leung Carmen , Liu Yin , Lu Xiangru , Kim Mella , Drysdale Thomas A. , Feng Qingping
Published: January 2016

Background

The small
GTP
ase Rac1 regulates diverse cellular functions, including both apicobasal and planar cell polarity pathways; however, its role in cardiac outflow tract (
OFT
) development remains unknown. In the present study, we aimed to examine the role of Rac1 in the anterior second heart field (
SHF
) splanchnic mesoderm and subsequent
OFT
development during heart morphogenesis.

Methods and Results

Using the Cre/loxP system, mice with an anterior
SHF
‐specific deletion of
Rac1
(
Rac1

SHF

) were generated. Embryos were collected at various developmental time points for immunostaining and histological analysis. Intrauterine echocardiography was also performed to assess aortic valve blood flow in embryos at embryonic day 18.5. The
Rac1

SHF

splanchnic mesoderm exhibited disruptions in
SHF
progenitor cellular organization and proliferation. Consequently, this led to a spectrum of
OFT
defects along with aortic valve defects in
Rac1

SHF

embryos. Mechanistically, it was found that the ability of the
Rac1

SHF

OFT

myocardial cells to migrate into the proximal
OFT
cushion was severely reduced. In addition, expression of the neural crest chemoattractant semaphorin 3c was decreased. Lineage tracing showed that anterior
SHF
contribution to the
OFT
myocardium and aortic valves was deficient in
Rac1

SHF

hearts. Furthermore, functional analysis with intrauterine echocardiography at embryonic day 18.5 showed aortic valve regurgitation in
Rac1

SHF

hearts, which was not seen in control hearts.

Conclusions

Disruptions of Rac1 signaling in the anterior
SHF
results in aberrant progenitor cellular organization and defects in
OFT
development. Our data show Rac1 signaling to be a critical regulator of cardiac
OFT
formation during embryonic heart development.
Ambulatory Monitoring and Arrhythmic Outcomes in Pediatric and Adolescent Patients With Duchenne Muscular Dystrophy
Authors: Villa Chet R. , Czosek Richard J. , Ahmed Humera , Khoury Philip R. , Anderson Jeffrey B. , Knilans Timothy K. , Jefferies John L. , Wong Brenda , Spar David S.
Published: January 2016

Background

Patients with Duchenne Muscular Dystrophy (
DMD
) develop cardiac fibrosis and dilated cardiomyopathy. We described the frequency of significant Holter findings in
DMD
, the relationship between cardiac function and arrhythmia burden, and the impact of these findings on clinical management.

Methods and Results

A retrospective review was done of patients with
DMD
who received a Holter from 2010 to 2014. Clinical and arrhythmic outcomes were analyzed. Patients were classified based on left ventricular ejection fraction (
LVEF
): ≥55%, 35% to 54% and <35%. Significant Holter findings included atrial tachycardia, ventricular tachycardia and atrial fibrillation/flutter. Logistic regression was used to assess predictors of significant Holter findings and change in care. The study included 442 Holters in 235 patients. Mean age was 14±4 years. Patients with cardiac dysfunction were older, and had increased late gadolinium enhancement and left ventricular dilation (
P
<0.01). There were 3 deaths (1%), all with normal function and none cardiac. Patients with
LVEF
<35% had more arrhythmias including nonsustained atrial tachycardia (
P
=0.01), frequent premature ventricular contractions, ventricular couplets/triplets, and nonsustained ventricular tachycardia (
P
<0.001) compared to the other groups.
LVEF
<35% (
P
<0.001) was the only predictor of clinically significant Holter finding. Four patients (40%) had change in medication in the
LVEF
<35% group compared to 9 (3%) in the ≥55% and 4 (4%) in the 35% to 54% groups (
P
<0.001).

Conclusions

Sudden cardiac events are rare in
DMD
patients with an
LVEF
>35%. Significant Holter findings are rare in patients with
DMD
who have an
LVEF
>35%, and cardiac dysfunction appears to predict significant Holter findings. Holter monitoring is highest yield among
DMD
patients with cardiac dysfunction.