tbuckley/cabot-search huggingface dataset:
Evaluation of a Weight-Adjusted Single-Bolus Plasminogen Activator in Patients With Myocardial Infarction
Authors: Peter den Heijer, Frank Vermeer, Ettore Ambrosioni, Zygmunt Sadowski, José L. López-Sendón, Rainer von Essen, Philippe Beaufils, Udho Thadani, Jennifer Adgey, Luc Pierard, Jeffrey Brinker, Richard F. Davies, Richard W. Smalling, Lars Wallentin, Abraham Caspi, Andreas Pangerl, Linda Trickett, Cynthia Hauck, David Henry, Paul Chew
Journal: Circulation (1998)

Background —Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. Methods and Results —InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P &lt;0.001). Similar results were observed at 90 minutes (26.1% to 57.1%, P &lt;0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase. Conclusions —Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.
Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01)
Authors: C. Le Péchoux, A. Laplanche, C. Faivre-Finn, T. Ciuleanu, R. Wanders, D. Lerouge, R. Keus, M. Hatton, G.M. Videtic, S. Senan, A. Wolfson, R. Jones, R. Arriagada, E. Quoix, A. Dunant
Journal: Annals of Oncology (2010)
Ebola virus disease: from epidemiology to prophylaxis
Authors: Wen Bin Liu, Zi Xiong Li, Yan Du, Guang Wen Cao
Journal: Military Medical Research (2015)

The outbreak of Ebola virus disease (EVD) continues to spread through West Africa. Since the first report of EVD in March 2014, the number of cases has increased rapidly, with the fatality rate of >50%. The most prevalent Ebola virus belongs to the species of Zaire ebolavirus, with a fatality rate as high as 90%. Although there were cases introduced into other continents, Africa is the endemic area where fruit bats and apes are suspected to be Ebola virus carriers. The virus might be transmitted from the host animals to humans if humans consume raw or not fully cooked and contaminated meats. However, human-to-human transmission via close contact is the major route of current outbreaks. EVD can occur during any season and affect people of any race and age group. Direct contact with body fluids of EVD patients or living in contaminated environments greatly increases the risk of being infected. Transmission via aerosol less likely, but transmission via virus-containing droplets is possible in humans. Thus, health care providers are facing danger of getting Ebola virus infection. To date, vaccines, drugs and/or therapies to prevent Ebola virus infection or treat EVD are limited. Medical workers should follow the current standard prophylactic procedures. The military can orchestrate efficient care to mass EVD patients. Although it is necessary to speed up the pace of developing effective vaccine and therapeutics for the prevention and treatment of EVD, public health prevention and management should be important issue at present to control the spread of this disease cost-effectively.
Epidermal Growth Factor Receptor Mutants from Human Lung Cancers Exhibit Enhanced Catalytic Activity and Increased Sensitivity to Gefitinib
Authors: Roseann Mulloy, Audrey Ferrand, Youngjoo Kim, Raffaella Sordella, Daphne W. Bell, Daniel A. Haber, Karen S. Anderson, Jeffrey Settleman
Journal: Cancer Research (2007)

Abstract Somatic mutations within the epidermal growth factor receptor (EGFR) kinase domain are detected in 10% to 30% of human non–small cell lung cancers and are correlated with striking clinical responses in a subset of patients treated with EGFR kinase inhibitors, such as gefitinib and erlotinib. Cell-based studies suggest that these mutant EGFRs promote increased autophosphorylating activity on a subset of EGFR COOH-terminal tyrosines and the consequent engagement of a subset of downstream effectors. Because EGFR function is regulated at multiple levels in vivo, and it is therefore difficult to assess the direct consequences of these mutations on EGFR enzyme function, we measured EGFR catalytic activity in in vitro kinase assays using purified recombinant proteins corresponding to the cytoplasmic domain of wild-type and two frequently detected EGFR mutants (DelL747-P753insS and L858R). Both mutants exhibit substantially increased autophosphorylating activity relative to wild-type EGFR, and they exhibit distinct reaction kinetics. In addition, the mutant kinases are more sensitive to kinase inhibition by gefitinib, which seems to reflect their increased drug affinity. These findings suggest that the altered signaling properties and drug sensitivity of these EGFR mutants that have been observed in vivo largely result from differences in the catalytic properties of the kinase. In addition, we find that the T790M secondary “drug resistance mutation” of EGFR, which frequently arises in relapsed patients that initially responded to treatment, confers enhanced kinase activity to primary activating EGFR alleles and may, therefore, be oncogenic in some contexts. [Cancer Res 2007;67(5):2325–30]
Effect of Different Doses of BCG on an Allogeneic Cell-Mediated Antitumor Response in Mice: Brief Communication2
Authors: Martin Davies, Edris Sabbadini
Journal: JNCI Journal of the National Cancer Institute (1977)

The effect of BCG on the development of cell-mediated cytotoxicity (CMC) in the spleens of allogeneic tumor-bearing (C57BL/6 X A)F1 mice was studied. BCG-treated tumor-bearing animals elicited a stronger CMC response than did the untreated tumor-bearing animals. Furthermore, the degree of activation was dependent on different doses of BCG, so that if the BCG was administered at doses above or below the optimum dose, a less marked stimulation of the CMC resulted. The combination of BCG given before the tumor implant plus an intratumor inoculation resulted in a significantly higher CMC than did either treatment alone.
Outcomes of Endoscopic Submucosal Dissection for Colorectal Epithelial Neoplasms in 200 Consecutive Cases
Authors: Mitsuhiro Fujishiro, Naohisa Yahagi, Naomi Kakushima, Shinya Kodashima, Yosuke Muraki, Satoshi Ono, Nobutake Yamamichi, Ayako Tateishi, Masashi Oka, Keiji Ogura, Takao Kawabe, Masao Ichinose, Masao Omata
Journal: Clinical Gastroenterology and Hepatology (2007)
Growth Factor Receptor Fusions Predict Therapeutic Sensitivity
Authors: Manmeet S. Ahluwalia, Jeremy N. Rich
Journal: Clinical Cancer Research (2015)

Dysregulated growth factor pathways promote tumor growth in many cancers, but receptor-targeting strategies frequently offer limited benefit despite activation by receptor overexpression or amplification. In contrast, tumors harboring growth factor receptor fusions display exquisite dependence on receptor activity, providing predictive markers for patient response to inform precise oncology treatment.
Rapid Evolution of Outer Egg Membrane Proteins in the Drosophila melanogaster Subgroup: A Case of Ecologically Driven Evolution of Female Reproductive Traits
Authors: Santosh Jagadeeshan, Rama S. Singh
Journal: Molecular Biology and Evolution (2007)

Although sexual selection has been predominantly used to explain the rapid evolution of sexual traits, eggs of oviparous organisms directly face both the challenges of sexual selection as well as natural selection (environmental challenges, survival in niches, etc.). Being the outermost membrane in most insect eggs, the chorion layer is the interface between the embryo and the environment, thereby serving to protect the egg. Adaptive ecological radiations such as divergence in ovipositional substrate usage and host-plant specializations can therefore influence the evolution of eggshell proteins. We can hypothesize that proteins localized on the outer eggshell may be affected to a greater degree by ecological challenges compared with inner eggshell proteins, and therefore, proteins localized in the outer eggshell (chorion membrane) may evolve differently (faster) than proteins localized in the inner egg membrane (vitelline membrane). We compared the evolutionary divergence of vitelline with chorion membrane proteins in species of the melanogaster subgroup and found that chorion proteins as a group are indeed evolving faster than vitelline membrane proteins. At least one vitelline membrane protein (Vm32E), specifically localized on the outer eggshell, is also evolving faster than other vitelline membrane proteins suggesting that all proteins localized on the outer eggshell may be evolving rapidly. We also found evidence that specific codons in chorion proteins cp15 and cp16 are evolving under positive selection. Polymorphism surveys of cp16 revealed inflated levels of divergence relative to polymorphism in specific regions of the gene, indicating that these regions are under strong selection. At the morphological level, we found notable difference in eggshell surface morphologies between specialist (Drosophila sechellia and Drosophila erecta) and generalist species of Drosophila. We do not know if any of the chorion proteins actually interact with spermatozoids, therefore leaving the possibility of rapid evolution through gametic interaction wide open. At this point, however, our results support previous suggestions that divergences in ecology, particularly, ovipositional substrate divergences may be a strong force driving the evolution of eggshell proteins.
Influence of Clinical Knowledge, Organizational Context, and Practice Style on Transfusion Decision Making
Authors: Susanne R. Salem-Schatz
Journal: JAMA (1990)

Evidence shows that blood products, like other health care resources, are often used inappropriately, but the reasons for this have not been well studied. We conducted a face-to-face survey of 122 general surgeons, orthopedic surgeons, and anesthesiologists in three hospitals to evaluate the influence of several clinical and nonclinical factors on transfusion decision making. We found widespread deficiencies in physicians' knowledge of transfusion risks and indications. Each transfusion risk was estimated correctly by fewer than half of the physicians surveyed, and only 31% responded correctly to a set of four questions regarding transfusion indications. Attending physicians routinely had lower knowledge scores than did residents, yet they exhibited more confidence in their knowledge. Residents' transfusion decisions, however, were strongly influenced by the desires of their attending physicians, resulting in their ordering potentially inappropriate transfusions. Of the residents surveyed, 61% indicated that they ordered transfusions that they judged unnecessary at least once a month because a more senior physician suggested that they do so. These findings provide insights for the development of strategies to improve transfusion practices, which would address the dual concerns of quality of care and cost containment.
Ancestral Ca2+ Signaling Machinery in Early Animal and Fungal Evolution
Authors: X. Cai, D. E. Clapham
Journal: Molecular Biology and Evolution (2011)

Animals and fungi diverged from a common unicellular ancestor of Opisthokonta, yet they exhibit significant differences in their components of Ca2+ signaling pathways. Many Ca2+ signaling molecules appear to be either animal-specific or fungal-specific, which is generally believed to result from lineage-specific adaptations to distinct physiological requirements. Here, by analyzing the genomic data from several close relatives of animals and fungi, we demonstrate that many components of animal and fungal Ca2+ signaling machineries are present in the apusozoan protist Thecamonas trahens, which belongs to the putative unicellular sister group to Opisthokonta. We also identify the conserved portion of Ca2+ signaling molecules in early evolution of animals and fungi following their divergence. Furthermore, our results reveal the lineage-specific expansion of Ca2+ channels and transporters in the unicellular ancestors of animals and in basal fungi. These findings provide novel insights into the evolution and regulation of Ca2+ signaling critical for animal and fungal biology.
Cross-bridge kinetics in respiratory muscles
Authors: GC Sieck, YS Prakash
Journal: European Respiratory Journal (1997)

In respiratory muscles, force generation and shortening depend on the cyclical interaction of actin and myosin (cross-bridge cycling). During cross-bridge cycling, adenosine triphosphate (ATP) is hydrolysed. The globular head region of the myosin heavy chain (MyHC) possesses both the binding site to actin and the site for ATP hydrolysis. Therefore, the MyHC is both a structural and enzymatic protein. Different isoforms of MyHC are expressed in skeletal muscle fibres, and these MyHC isoforms provide mechanical and metabolic diversity. In the present study, the relationships between MyHC isoform expression in single rat diaphragm muscle fibres and their mechanical and energetic properties were evaluated. The expression of MyHC isoforms in single diaphragm muscle fibres was identified using electrophoretic and immunohistochemical techniques. Cross-bridge cycling kinetics in diaphragm muscle fibres clearly depend on MyHC isoform expression, and these differences are interpreted in the context of Huxley's two-state cross-bridge model. It is concluded that the unique mechanical and energetic properties of myosin heavy chain isoforms are designed to accomplish different motor behaviours of the diaphragm muscle, and that, as a result of these unique properties, a selective recruitment of diaphragm muscle fibres is essential to avoid fatigue.
PGI2-induced Th17 cell differentiation in connective tissue disease: a comment
Authors: Yaguo Zheng, Changming Xiong, Jianguo He
Journal: Annals of the Rheumatic Diseases (2013)

Dear Editor

We read with interest the study conducted by Truchetet et al on the regulation of prostaglandin I2 (PGI2) in Th17 cell differentiation in systemic sclerosis (SSc). Actually, previous in vitro studies have found that synthetic PGI2 enhanced Th17 cell differentiation.1 Zhou et al 2 have also demonstrated that PGI2 induced Th17 cell differentiation through modulating the ratio of interleukin 23 (IL-23)/interleukin 12 in a mouse model of experimental autoimmune encephalitis. However, in this study, Truchetet et al 3 treated SSc-related digital ulcers with iloprost, providing evidence for the first time that iloprost increases the frequency of Th17 cells in human …
Serological and molecular survey for HTLV-I infection in a high-risk Middle Eastern group
Authors: D. Meytes, M. Elgat, B. Schochat, Y. Sidi, M. Shaklai, Y. Kilim, Y. Danon, G. Nadel, H. Lee, M. Cerney, P. Swanson, E. Chin, J.D. Rosenblatt
Journal: The Lancet (1990)
Questionnaires, spirometry and PEF monitoring in epidemiological studies on elderly respiratory patients
Authors: V. Bellia, F. Pistelli, D. Giannini, N. Scichilone, F. Catalano, M. Spatafora, R. Hopps, L. Carrozzi, S. Baldacci, F. Di Pede, P. Paggiaro, G. Viegi
Journal: European Respiratory Journal (2003)

Questionnaires are the most used subjective instrument of measurement in respiratory epidemiology. The standardisation of the questionnaires aims to limit bias by maximising validity and reliability, and comparability. Within the European Union project BIOMED1, a compendium of respiratory standard questionnaires (CORSQ) was developed for adults covering 18 topics from general information to early life events, through environmental risk factors and respiratory symptoms and diseases. Reliable spirometry data needs a rigorous quality control programme, as in the "Salute Respiratoria nell'Anziano" (Sa.R.A.) project, Italian for "Respiratory Health in the Elderly". Reproducibility rates were 95.8% for forced expiratory volume in one second (FEV1). Male sex and age were independent risk factors for a poorer reproducibility, as well as cognitive and physical impairment (shorter 6-min walking distance) and lower educational level for a poorer acceptability. Reference values for people aged 65-85 yrs have been produced; these results suggest that the effect of aging should be corrected for physical and mental disability. A revision of interpretative strategies included in current guidelines is needed. Peak expiratory flow monitoring has several methodological problems: reliability and sensitivity of the measurement in order to detect changes in airway calibre; compliance with long-term monitoring; choice of the best variability index; difference between asthmatic and nonasthmatic subjects; age-related differences. Despite these methodological problems, peak expiratory flow monitoring has been successfully used in the evaluation of the effects of air pollution in normal and asthmatic subjects, and in the elderly.
THE MEDIAL TEMPORAL LOBE
Authors: Larry R. Squire, Craig E.L. Stark, Robert E. Clark
Journal: Annual Review of Neuroscience (2004)

The medial temporal lobe includes a system of anatomically related structures that are essential for declarative memory (conscious memory for facts and events). The system consists of the hippocampal region (CA fields, dentate gyrus, and subicular complex) and the adjacent perirhinal, entorhinal, and parahippocampal cortices. Here, we review findings from humans, monkeys, and rodents that illuminate the function of these structures. Our analysis draws on studies of human memory impairment and animal models of memory impairment, as well as neurophysiological and neuroimaging data, to show that this system (a) is principally concerned with memory, (b) operates with neocortex to establish and maintain long-term memory, and (c) ultimately, through a process of consolidation, becomes independent of long-term memory, though questions remain about the role of perirhinal and parahippocampal cortices in this process and about spatial memory in rodents. Data from neurophysiology, neuroimaging, and neuroanatomy point to a division of labor within the medial temporal lobe. However, the available data do not support simple dichotomies between the functions of the hippocampus and the adjacent medial temporal cortex, such as associative versus nonassociative memory, episodic versus semantic memory, and recollection versus familiarity.
Multihistology, Target-Driven Pilot Trial of Oral Topotecan as an Inhibitor of Hypoxia-Inducible Factor-1α in Advanced Solid Tumors
Authors: Shivaani Kummar, Mark Raffeld, Lamin Juwara, Yvonne Horneffer, Agnes Strassberger, Deborah Allen, Seth M. Steinberg, Annamaria Rapisarda, Shawn D. Spencer, William D. Figg, Xiaohong Chen, Ismail Baris Turkbey, Peter Choyke, Anthony J. Murgo, James H. Doroshow, Giovanni Melillo
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Hypoxia-inducible factor 1 (HIF-1) α is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1α expression in preclinical models. We designed a pilot trial to measure HIF-1α inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1α, after treatment with oral topotecan. Experimental Design: Topotecan was administered orally at 1.6 mg/m2 once daily for 5 days/week for 2 weeks, in 28-day cycles. Objectives were to determine inhibition of expression of HIF-1α and HIF-1 target genes in tumor; to assess tumor blood flow by dynamic contrast–enhanced magnetic resonance imaging (DCE-MRI); and to measure pharmacokinetics. Tumor biopsies were collected at baseline and during the second cycle of treatment. Results: Sixteen patients were enrolled. The dose of topotecan was reduced to 1.2 mg/m2/day due to myelosuppression. Seven patients had paired tumor biopsies. In 4 patients, HIF-1α nuclear staining became undetectable after treatment (7.5%–50% staining at baseline). Decreased levels of VEGF and GLUT-1 mRNA were measured in 4 patients; the changes were concordant with reduction in HIF-1α in 3 patients. Decreased tumor blood flow and permeability were observed by DCE-MRI in 7 of 10 patients after 1 cycle. One patient had a partial response accompanied by inhibition of HIF-1α in tumor and reduction in tumor blood flow on DCE-MRI. Conclusions: This multihistology, target assessment trial of a small molecule inhibitor of HIF-1α showed that topotecan could decrease HIF-1α expression in advanced solid tumors. Clin Cancer Res; 17(15); 5123–31. ©2011 AACR.
Electromechanical Dyssynchrony and Resynchronization of the Failing Heart
Authors: Jonathan A. Kirk, David A. Kass
Journal: Circulation Research (2013)

Patients with heart failure and decreased function frequently develop discoordinate contraction because of electric activation delay. Often termed dyssynchrony, this further decreases systolic function and chamber efficiency and worsens morbidity and mortality. In the mid- 1990s, a pacemaker-based treatment termed cardiac resynchronization therapy (CRT) was developed to restore mechanical synchrony by electrically activating both right and left sides of the heart. It is a major therapeutic advance for the new millennium. Acute chamber effects of CRT include increased cardiac output and mechanical efficiency and reduced mitral regurgitation, whereas reduction in chamber volumes ensues more chronically. Patient candidates for CRT have a prolonged QRS duration and discoordinate wall motion, although other factors may also be important because ≈30% of such selected subjects do not respond to the treatment. In contrast to existing pharmacological inotropes, CRT both acutely and chronically increases cardiac systolic function and work, yet it also reduces long-term mortality. Recent studies reveal unique molecular and cellular changes from CRT that may also contribute to this success. Heart failure with dyssynchrony displays decreased myocyte and myofilament function, calcium handling, β-adrenergic responsiveness, mitochondrial ATP synthase activity, cell survival signaling, and other changes. CRT reverses many of these abnormalities often by triggering entirely new pathways. In this review, we discuss chamber, circulatory, and basic myocardial effects of dyssynchrony and CRT in the failing heart, and we highlight new research aiming to better target and implement CRT, as well as leverage its molecular effects.
Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-FU, and infusional 5-FU alone in advanced pancreatic carcinoma patients
Authors: M. Ducreux, E. Mitry, M. Ould-Kaci, V. Boige, J.F. Seitz, R. Bugat, J.L. Breau, O. Bouché, P.L. Etienne, J.M. Tigaud, F. Morvan, E. Cvitkovic, P. Rougier
Journal: Annals of Oncology (2004)