tbuckley/cabot-search huggingface dataset:
Small-Conductance Calcium-Activated Potassium Channel and Recurrent Ventricular Fibrillation in Failing Rabbit Ventricles
Authors: Su-Kiat Chua, Po-Cheng Chang, Mitsunori Maruyama, Isik Turker, Tetsuji Shinohara, Mark J. Shen, Zhenhui Chen, Changyu Shen, Michael Rubart-von der Lohe, John C. Lopshire, Masahiro Ogawa, James N. Weiss, Shien-Fong Lin, Tomohiko Ai, Peng-Sheng Chen
Journal: Circulation Research (2011)

Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF).We hypothesized that activation of apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels is responsible for the postshock APD shortening in failing ventricles.A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca(2+) and membrane potential (V(m)) was performed in failing and nonfailing ventricles. Three failing ventricles developed SVF (SVF group); 9 did not (no-SVF group). None of the 10 nonfailing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF and increased postshock APD(80) in the SVF group from 126±5 to 153±4 ms (P<0.05) and from 147±2 to 162±3 ms (P<0.05) in the no-SVF group but did not change APD(80) in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K(+) current (I(KAS)) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial I(KAS) density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca(2+) response of I(KAS) was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca(2+) sensitivity of I(KAS) in failing ventricles. The K(d) was 232±5 nmol/L for failing myocytes and 553±78 nmol/L for normal myocytes (P=0.002).Heart failure heterogeneously increases the sensitivity of I(KAS) to intracellular Ca(2+), leading to upregulation of I(KAS), postshock APD shortening, and recurrent SVF.
Circulating endothelial progenitor cells and chronic pulmonary diseases
Authors: A. Huertas, P. Palange
Journal: European Respiratory Journal (2011)

Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells that contribute to vascular healing and remodelling under physiological and pathological conditions. Although controversies exist regarding the definition and origin of EPCs, it has been widely demonstrated that they are involved in several diseases and that they have therapeutic implications. Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation that is not fully reversible, associated with abnormalities of airways (bronchitis) and parenchyma (emphysema), reduced exercise tolerance and systemic inflammation. Growing evidence has also suggested that endothelial dysfunction may play a role in COPD. Although it is not clear whether endothelial dysfunction represents a cause or a consequence of COPD, several studies have highlighted the importance of EPCs in this disease, suggesting that the bone marrow could be a novel target of COPD. The present review summarises the role of EPCs in pulmonary diseases, with particular emphasis on COPD. The aim is to improve understanding as to the possible role of EPCs in COPD pathophysiology. This may help in the identification of novel diagnostic and therapeutic tools in COPD.
The importance of non-exercise physical activity for cardiovascular health and longevity
Authors: Elin Ekblom-Bak, Björn Ekblom, Max Vikström, Ulf de Faire, Mai-Lis Hellénius
Journal: British Journal of Sports Medicine (2013)

Background Sedentary time is increasing in all societies and results in limited non-exercise physical activity (NEPA) of daily life. The importance of low NEPA for cardiovascular health and longevity is limited, especially in elderly. Aim To examine the association between NEPA and cardiovascular health at baseline as well as the risk of a first cardiovascular disease (CVD) event and total mortality after 12.5 years. Study design Cohort study. Material and methods Every third 60-year-old man and woman in Stockholm County was invited to a health screening study; 4232 individuals participated (78% response rate). At baseline, NEPA and exercise habits were assessed from a self-administrated questionnaire and cardiovascular health was established through physical examinations and laboratory tests. The participants were followed for an average of 12.5 years for the assessment of CVD events and mortality. Results At baseline, high NEPA was, regardless of regular exercise and compared with low NEPA, associated with more preferable waist circumference, high-density lipoprotein cholesterol and triglycerides in both sexes and with lower insulin, glucose and fibrinogen levels in men. Moreover, the occurrence of the metabolic syndrome was significantly lower in those with higher NEPA levels in non-exercising and regularly exercising individuals. Furthermore, reporting a high NEPA level, compared with low, was associated with a lower risk of a first CVD event (HR=0.73; 95% CI 0.57 to 0.94) and lower all-cause mortality (0.70; 0.53 to 0.98). Conclusions A generally active daily life was, regardless of exercising regularly or not, associated with cardiovascular health and longevity in older adults.
Doxorubicin, Cardiac Risk Factors, and Cardiac Toxicity in Elderly Patients With Diffuse B-Cell Non-Hodgkin's Lymphoma
Authors: Dawn L. Hershman, Russell B. McBride, Andrew Eisenberger, Wei Yann Tsai, Victor R. Grann, Judith S. Jacobson
Journal: Journal of Clinical Oncology (2008)

Purpose Anthracycline-based chemotherapy, which improves survival for patients with non-Hodgkin's lymphoma, is often withheld from elderly patients because of its cardiotoxicity. We studied the cardiac effects of doxorubicin in a population-based sample of older patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Among patients age ≥ 65 years diagnosed with DLBCL from 1991 to 2002 in the Surveillance, Epidemiology, and End Results–Medicare database, we developed logistic regression models of the associations of doxorubicin with demographic, clinical, and cardiac variables. We then developed Cox proportional hazards models of the association between doxorubicin and subsequent congestive heart failure (CHF), taking predictors of CHF into account. Results Of 9,438 patients with DLBCL, 3,164 (42%) received doxorubicin-based chemotherapy. Any doxorubicin use was associated with a 29% increase in risk of CHF (95% CI, 1.02 to 1.62); CHF risk increased with number of doxorubicin claims, increasing age, prior heart disease, comorbidities, diabetes, and hypertension; hypertension intensified the effect of doxorubicin on risk of CHF (hazard ratio = 1.8; P &lt; .01). In the 8 years after diagnosis, the adjusted CHF-free survival rate was 74% in doxorubicin-treated patients versus 79% in patients not treated with doxorubicin. Conclusion Among patients receiving chemotherapy for DLBCL, those with prior heart disease were less likely than others to be treated with doxorubicin, and those who received doxorubicin were more likely than others to develop CHF. Various cardiac risk factors increased CHF risk, but only hypertension was synergistic with doxorubicin. Doxorubicin has dramatically improved survival of DLBCL patients; nonetheless, some subgroups may benefit from efforts to reduce doxorubicin-related CHF risk.
Risk of second primary malignancies following a diagnosis of cutaneous malignant melanoma or nonmelanoma skin cancer in Alberta, Canada from 1979 to 2009
Authors: G.W. Jung, D.C. Dover, T.G. Salopek
Journal: British Journal of Dermatology (2013)

Recent studies have revealed geographical variations with respect to the risk of second primary malignancies (SPMs) following cutaneous malignant melanoma (CMM) and nonmelanoma skin cancer (NMSC).To provide the largest analysis of the risk of SPM following skin cancers in Canada and to detect associations that may shed light on common pathogeneses between linked malignancies.Relative risks for development of SPMs following a diagnosis of CMM or NMSC were calculated via a retrospective analysis of data retrieved from the Alberta Cancer Registry (ACR) from 1979 to 2009.From 1979 to 2009, 85,967 NMSC and 6884 CMM incident cases were recorded in the ACR. In total 19,869 SPMs were identified following a primary NMSC (7709 cutaneous and 12,160 noncutaneous), while 1437 SPMs (908 cutaneous and 529 noncutaneous) followed CMM. Patients with a previous history of skin cancer had a 60% increased risk of developing an SPM compared with those without [observed/expected ratio (O/E) 1.6, 95% confidence interval (CI) 1.6-1.7; P < 0.001]. Thirty and 10 different SPMs were significantly identified to follow a diagnosis of NMSC and CMM, respectively. Patients under the age of 40 years with a prior history of CMM had a marked increased expectancy for SPM [O/E 5.6, 95% CI 4.5-7.0; P < 0.001).Further studies are warranted to identify environmental and molecular connections among linked cutaneous and noncutaneous malignancies, which may lead to earlier detection of related neoplasms via expanded screening protocols and development of shared treatment regimens. Heightened surveillance for the development of SPMs in patients with CMM under the age of 40 years should be considered.
Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets
Authors: Daphne de Launay, Marleen GH van de Sande, Maria JH de Hair, Aleksander M Grabiec, Gijs PM van de Sande, K Aad Lehmann, Carla A Wijbrandts, Lisa GM van Baarsen, Danielle M Gerlag, Paul P Tak, Kris A Reedquist
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naïve. Methods A total of 50 patients with early arthritis who were DMARD naïve (disease duration &lt;1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR). Results ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R 2 =0.59, p=0.02) after follow-up, and disease progression in early arthritis (R 2 =0.16, p&lt;0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44. Conclusions JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease process.
Exhaled Nitric Oxide Measurements in a Population Sample of Young Adults
Authors: CHERYL M. SALOME, ALYSON M. ROBERTS, NATHAN J. BROWN, JOHN DERMAND, GUY B. MARKS, ANN J. WOOLCOCK
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

In epidemiologic studies of asthma there is a group with recent wheeze, but with no airway hyperresponsiveness (AHR), in whom it is unclear whether any significant airway abnormality exists. Exhaled nitric oxide (NO) has been proposed as a measure of airway inflammation. We measured exhaled NO in a population sample of 306 young adults who also underwent bronchial challenge with histamine or a bronchodilator test. Subjects blew into a 3-L Tedlar bag against a 2-mm-diameter resistance to close the soft palate and exclude nasal air. The NO content of expired gas from a single breath was analyzed by chemiluminescent analyzer. Exhaled NO was log-normally distributed in the population sample and duplicate measurements were highly reproducible (intraclass correlation coefficient = 0.98). Exhaled NO correlated significantly with airway responsiveness, measured as the dose-response ratio to histamine (r = 0.39, p < 0.001) and with peripheral blood eosinophils (r = 0.35, p < 0.001). Exhaled NO was significantly greater in asthmatic subjects (geometric mean, 22.2; 95% confidence intervals, 16.1 to 30.7 ppb) than in normal subjects (7.8, 7.1 to 8.4, p < 0.001) or in subjects with wheeze but no AHR (8.8, 7.5 to 10.3, p < 0.001). We conclude that exhaled NO is log-normally distributed, is highly reproducible and discriminates well among subjects, suggesting that it is both a feasible and useful measurement for epidemiologic studies of asthma. The findings suggest that wheeze in the absence of AHR is unlikely to be associated with airway inflammation.
Growth Factor Receptor–Bound Protein 2 Contributes to (Hem)Immunoreceptor Tyrosine-Based Activation Motif–Mediated Signaling in Platelets
Authors: Sebastian Dütting, Timo Vögtle, Martina Morowski, Sarah Schiessl, Carmen M. Schäfer, Stephanie K. Watson, Craig E. Hughes, Jochen A. Ackermann, Daniel Radtke, Heike M. Hermanns, Steve P. Watson, Lars Nitschke, Bernhard Nieswandt
Journal: Circulation Research (2013)

Platelets are anuclear cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity but may also cause pathological vessel occlusion. One major pathway of platelet activation is triggered by 2 receptors that signal through an (hem)immunoreceptor tyrosine-based activation motif (ITAM), the activating collagen receptor glycoprotein (GP) VI and the C-type lectin-like receptor 2 (CLEC-2). Growth factor receptor-bound protein 2 (Grb2) is a ubiquitously expressed adapter molecule involved in signaling processes of numerous receptors in different cell types, but its function in platelets and MKs is unknown.We tested the hypothesis that Grb2 is a crucial adapter protein in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets.Here, we show that genetic ablation of Grb2 in MKs and platelets did not interfere with MK differentiation or platelet production. However, Grb2-deficiency severely impaired glycoprotein VI-mediated platelet activation because of defective stabilization of the linker of activated T-cell (LAT) signalosome and activation of downstream signaling proteins that resulted in reduced adhesion, aggregation, and coagulant activity on collagen in vitro. Similarly, CLEC-2-mediated signaling was impaired in Grb2-deficient platelets, whereas the cells responded normally to stimulation of G protein-coupled receptors. In vivo, this selective (hem)immunoreceptor tyrosine-based activation motif signaling defect resulted in prolonged bleeding times but affected arterial thrombus formation only after concomitant treatment with acetylsalicylic acid, indicating that defective glycoprotein VI signaling in the absence of Grb2 can be compensated through thromboxane A2-induced G protein-coupled receptor signaling pathways.These results reveal an important contribution of Grb2 in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets in hemostasis and thrombosis by stabilizing the LAT signalosome.
The antagonism between MCT-1 and p53 affects the tumorigenic outcomes
Authors: Ravi Kasiappan, Hung-Ju Shih, Meng-Hsun Wu, ChikOn Choy, Tai-Du Lin, Linyi Chen, Hsin-Ling Hsu
Journal: Molecular Cancer (2010)

Abstract Background MCT-1 oncoprotein accelerates p53 protein degradation via a proteosome pathway. Synergistic promotion of the xenograft tumorigenicity has been demonstrated in circumstance of p53 loss alongside MCT-1 overexpression. However, the molecular regulation between MCT-1 and p53 in tumor development remains ambiguous. We speculate that MCT-1 may counteract p53 through the diverse mechanisms that determine the tumorigenic outcomes. Results MCT-1 has now identified as a novel target gene of p53 transcriptional regulation. MCT-1 promoter region contains the response elements reactive with wild-type p53 but not mutant p53. Functional p53 suppresses MCT-1 promoter activity and MCT-1 mRNA stability. In a negative feedback regulation, constitutively expressed MCT-1 decreases p53 promoter function and p53 mRNA stability. The apoptotic events are also significantly prevented by oncogenic MCT-1 in a p53-dependent or a p53-independent fashion, according to the genotoxic mechanism. Moreover, oncogenic MCT-1 promotes the tumorigenicity in mice xenografts of p53-null and p53-positive lung cancer cells. In support of the tumor growth are irrepressible by p53 reactivation in vivo , the inhibitors of p53 (MDM2, Pirh2, and Cop1) are constantly stimulated by MCT-1 oncoprotein. Conclusions The oppositions between MCT-1 and p53 are firstly confirmed at multistage processes that include transcription control, mRNA metabolism, and protein expression. MCT-1 oncogenicity can overcome p53 function that persistently advances the tumor development.
The cultural evolution of prosocial religions
Authors: Ara Norenzayan, Azim F. Shariff, Will M. Gervais, Aiyana K. Willard, Rita A. McNamara, Edward Slingerland, Joseph Henrich
Journal: Behavioral and Brain Sciences (2014)

Abstract We develop a cultural evolutionary theory of the origins of prosocial religions and apply it to resolve two puzzles in human psychology and cultural history: (1) the rise of large-scale cooperation among strangers and, simultaneously, (2) the spread of prosocial religions in the last 10–12 millennia. We argue that these two developments were importantly linked and mutually energizing. We explain how a package of culturally evolved religious beliefs and practices characterized by increasingly potent, moralizing, supernatural agents, credible displays of faith, and other psychologically active elements conducive to social solidarity promoted high fertility rates and large-scale cooperation with co-religionists, often contributing to success in intergroup competition and conflict. In turn, prosocial religious beliefs and practices spread and aggregated as these successful groups expanded, or were copied by less successful groups. This synthesis is grounded in the idea that although religious beliefs and practices originally arose as nonadaptive by-products of innate cognitive functions, particular cultural variants were then selected for their prosocial effects in a long-term, cultural evolutionary process. This framework (1) reconciles key aspects of the adaptationist and by-product approaches to the origins of religion, (2) explains a variety of empirical observations that have not received adequate attention, and (3) generates novel predictions. Converging lines of evidence drawn from diverse disciplines provide empirical support while at the same time encouraging new research directions and opening up new questions for exploration and debate.
THE SUSCEPTIBILITY OF INFANT RHESUS MONKEYS TO POLIOMYELITIS VIRUS ADMINISTERED BY MOUTH
Authors: Dorothy M. Horstmann, Joseph L. Melnick, Robert Ward, M. José Sá Fleitas
Journal: The Journal of Experimental Medicine (1947)

Although rhesus monkeys have been generally regarded as refractory to infection with poliomyelitis virus administered by the oral route, two of seven infant rhesus developed paralytic poliomyelitis when fed murine-adapted strains of virus. Preliminary intranasal treatment with zinc sulfate and negative serial sections of the olfactory bulbs of the positive animals ruled out the possibility that infection occurred by way of the olfactory pathway. Studies on the distribution of virus in the tissues of the infected animals yielded positive results in one animal only. In this instance, virus was widely distributed throughout the body being isolated from spinal cord, buccal mucosa, duodenal wall, colon contents, superficial lymph nodes, spleen, heart, and adrenals.
α7-Nicotinic Acetylcholine Receptor Agonists for Cognitive Enhancement in Schizophrenia
Authors: Robert Freedman
Journal: Annual Review of Medicine (2013)

α7-Nicotinic acetylcholine receptors have emerged as a potential therapeutic target for the treatment of neurocognitive dysfunctions in schizophrenia that are often resistant to existing antipsychotic drugs. Molecular evidence for involvement in schizophrenia of CHRNA7, the gene for the receptor subunit, in the neurobiology of deficits in attention is a critical rationale for the clinical study of α7-nicotinic receptor agonists to improve neurocognition. Initial clinical trials show enhancement of inhibitory neuron function related to sensory gating and increased attention and working memory, as well as improvement in negative symptoms such as anhedonia and alogia. Further development of this therapeutic strategy requires assessment of interactions with patients' heavy cigarette smoking and the relationship of this mechanism to the therapeutic effects of clozapine and olanzapine, both highly effective therapeutics with significant side effects.
Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors
Authors: L Rhoda Molife, Li Yan, Joanna Vitfell-Rasmussen, Adriane M Zernhelt, Daniel M Sullivan, Philippe A Cassier, Eric Chen, Andrea Biondo, Ernestina Tetteh, Lillian L Siu, Amita Patnaik, Kyriakos P Papadopoulos, Johann S de Bono, Anthony W Tolcher, Susan Minton
Journal: Journal of Hematology & Oncology (2014)

Inhibition of AKT with MK-2206 has demonstrated synergism with anticancer agents. This phase 1 study assessed the MTD, DLTs, PK, and efficacy of MK-2206 in combination with cytotoxic and targeted therapies. Advanced solid tumor patients received oral MK-2206 45 or 60 mg (QOD) with either carboplatin (AUC 6.0) and paclitaxel 200 mg/m2 (arm 1), docetaxel 75 mg/m2 (arm 2), or erlotinib 100 or 150 mg daily (arm 3); alternative schedules of MK-2206 135-200 mg QW or 90-250 mg Q3W were also tested. MTD of MK-2206 (N = 72) was 45 mg QOD or 200 mg Q3W (arm 1); MAD was 200 mg Q3W (arm 2) and 135 mg QW (arm 3). DLTs included skin rash (arms 1, 3), febrile neutropenia (QOD, arms 1, 2), tinnitus (Q3W, arm 2), and stomatitis (QOD, arm 3). Common drug-related toxicities included fatigue (68%), nausea (49%), and rash (47%). Two patients with squamous cell carcinoma of the head and neck (arm 1; Q3W) demonstrated a complete and partial response (PR); additional PRs were observed in patients (1 each) with melanoma, endometrial, neuroendocrine prostate, NSCLC, and cervical cancers. Six patients had stable disease ≥6 months. MK-2206 plus carboplatin and paclitaxel, docetaxel, or erlotinib was well-tolerated, with early evidence of antitumor activity. ClinicalTrials.gov: NCT00848718 .