tbuckley/cabot-search huggingface dataset:
Synergistic effects of combined platelet-activating factor receptor and epidermal growth factor receptor targeting in ovarian cancer cells
Authors: Yi Yu, Mingxing Zhang, Xiaoyan Zhang, Qingqing Cai, Shanshan Hong, Wei Jiang, Congjian Xu
Journal: Journal of Hematology & Oncology (2014)

Genetic alterations, including the overexpression of epidermal growth factor receptor (EGFR), play a crucial role in ovarian carcinogenesis. To date, EGFR targeting has shown limited antitumor effects in ovarian cancer when administered as monotherapy. We previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation. To determine whether PAFR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a PAFR antagonist (WEB2086) in conjunction with an EGFR inhibitor (AG1478). The expression of EGFR and PAFR in CAOV-3 and SKOV-3 ovarian cancer cell lines was measured by Western blot and immunocytochemistry. Synergy was determined using isobologram analysis. The effects of combined PAFR and EGFR targeting on both cells were assessed by using CCK-8, transwell, flow cytometry, western blot analysis. In vivo studies were conducted using CAOV-3 cells xenografted in nu/nu mice. Treatment with combination WEB2086 and AG1478 resulted in significantly greater inhibition of proliferation and invasion compared to either drug alone. When examining equipotent combinations of WEB2086 and AG1478 to determine potential synergy, a combination index (CI) of 0.49 was identified for CAOV-3 cells and a CI of 0.58 for SKOV-3 cells indicating synergy. This co-inhibition induced significantly more apoptosis and arrested the cells at G0/G1 phase in both cell lines. The activation of PAFR and/or EGFR induced phosphorylation of the mTOR, AKT, and MAPK pathways. Combined PAFR and EGFR targeting synergistically diminished the expression of PAFR and EGFR phosphorylation and downstream signaling. In vivo studies further verified the antitumor effects of combined PAFR and EGFR targeting in a CAOV-3 xenograft model. These results suggest that WEB2086 and AG1478 are synergistic in ovarian cancer cells with high expression of both PAFR and EGFR. The presented approach may have important therapeutic implications in the treatment of ovarian cancer patients.
Randomised trial of thiacetazone and rifampicin-containing regimens for pulmonary tuberculosis in HIV-infected Ugandans
Authors: A Okwera, F Byekwaso, R Mugerwa, A Okwera, F Byekwaso, J Ellner, M Vjecha, J Johnson, C Whalen, R Huebner
Journal: The Lancet (1994)
Vascular dysfunction and myocardial contractility in the JCR:LA-corpulent rat
Authors: F Brunner
Journal: Cardiovascular Research (2000)

Objective: The JCR:LA-corpulent rat is a unique animal model of human vascular disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular dysfunction. We tested the hypothesis that the defects affect endothelial and smooth muscle function of the coronary microvasculature as well as cardiac contractility. Coronary, myocardial and aortic function were assessed in obese (homozygous for the cp gene, cp/cp) and lean (heterozygous or homozygous normal, +/?) littermates aged 7 and 18 weeks. Methods: Coronary endothelial relaxation was examined in isolated perfused hearts by determining the effect of bradykinin (0.1–1000 nmoll−1) on coronary perfusion pressure (CPP), myocardial mechanical function was evaluated in terms of left-ventricular developed pressure (LVDevP), and aortic relaxation with the endothelium-dependent agonist, A 23187 (1–1000 nmoll−1). Results: In rats aged 7 weeks, bradykinin reduced CPP from 133±1 mmHg to 43±1 mmHg (−67%) in lean rats, but only to 64±3 mmHg (−52%) in corpulent rats (n=6, P<0.05). Similar differences were found in rats aged 18 weeks (n=8). Inhibition of NO synthase with NG-nitro-l-arginine (l-NNA; 0.2 mmoll−1) impaired, and tetrahydrobiopterin (0.1 mmoll−1), a NO synthase cofactor, restored relaxation in cp/cp rats. Spermine/NO equally reduced CPP in both groups (−58%). Mechanical function was similar in lean and corpulent rats, aortic endothelial relaxation was attenuated by ∼30% and aortic smooth muscle function was normal (7 weeks) or improved (18 weeks) in the cp/cp genotype. Conclusion: These results suggest that (i) there is a specific impairment of NO-mediated relaxation of the coronary resistance vessels in the JCR:LA-corpulent rat that is not associated with impaired baseline myocardial contractility, and (ii) exogenous tetrahydrobiopterin reversed the relaxation defects that are part of the vascular complications typical for the insulin resistance syndrome.
Purification and Preliminary Characterization of a Cardiac Kv1.5 Repressor Element Binding Factor
Authors: Paloma Valverde, Gideon Koren
Journal: Circulation Research (1999)

Abstract —We have previously demonstrated that the cell-specific expression of Kv1.5 promoter is regulated by a silencer (Kv1.5 repressor element; KRE) containing a dinucleotide-repetitive element, (GT) 19 (GA) 1 (CA) 15 (GA) 16 . Electromobility gel shift assays (EMSAs) of KRE with GH3 nuclear extracts detected a unique DNA-protein complex, which was not detectable in Chinese hamster ovary or COS-7 cells. We further delineated KRE and determined that a 52-bp fragment that contained a (GT) 10 (GA) 1 (CA) 10 dinucleotide-repetitive element was sufficient for silencer activity. EMSAs using nuclear extracts isolated from the heart and from GH3 cells demonstrated that the 52-bp element formed specific and identical gel shift effects. These complexes were not detectable in EMSA experiments with liver nuclear extracts. Magnetic DNA affinity purification and UV cross-linking experiments identified a 27-kDa KRE binding factor (KBF) in GH3 cell nuclear extracts. Purified KBF reacted specifically with double-stranded KRE, abolishing the formation of multimeric KRE-DNA complexes. Thus, the interaction between KRE and KBF may play an important role in regulating the GH3- and cardiac-specific expression of Kv1.5.
Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma1
Authors: Christine Billecke, Susan Finniss, Laura Tahash, Cathie Miller, Tom Mikkelsen, Nicholas P. Farrell, Oliver Bögler
Journal: Neuro-Oncology (2006)

We have evaluated the efficacy of the multinuclear platinum chemotherapeutics BBR3464, BBR3571, and BBR3610 against glioma cells in culture and animal models and investigated their mechanism of action at the cellular level. In a clonogenic assay, BBR3610, the most potent compound, had an IC90 dose (achieving 90% colony formation inhibition) that was 250 times lower than that of cisplatin for both LNZ308 and LN443 glioma cells. In subcutaneous xenografts of U87MG glioma cells, BBR3610 approximately doubled the time it took for a tumor to reach a predetermined size and significantly extended survival when these cells were implanted intracranially. Analysis of apoptosis and cell cycle distribution showed that BBR compounds induced G2/M arrest in the absence of cell death, while cisplatin predominantly induced apoptosis. Interestingly, the BBR compounds and cisplatin both induced extracellular signal-regulated kinase 1/2 phosphorylation, and inhibition of this pathway at the level of MEK antagonized the induction of G2/M arrest or apoptosis, respectively. Analysis of Chk1 and Chk2 status did not show any differential effects of the drugs, and it is thus unlikely to underlie the difference in response. Similarly, the drugs did not differentially modulate survivin levels, and knockdown of survivin did not convert the response to BBR3610 to apoptosis. Together, these findings support continued development of BBR3610 for clinical use against glioma and provide a framework for future investigation of mechanism of action.
Thymus reconstitution by c-kit-expressing hematopoietic stem cells purified from adult mouse bone marrow.
Authors: P de Vries, K A Brasel, H J McKenna, D E Williams, J D Watson
Journal: The Journal of Experimental Medicine (1992)

The introduction of clonal assays and long-term culture systems has resulted in considerable progress in the understanding of the early events that control self-renewal and commitment to differentiation of pluripotent hematopoietic stem cells (PHSC). Relatively little is known about the factors that control the commitment of PHSC to the lymphoid lineages, especially the T cell lineage. In the present study, the expression of the proto-oncogene c-kit was used to isolate and study the capacity of highly purified day 14 colony-forming units-spleen (CFU-S) to reconstitute the thymus of sublethally irradiated Thy-1 congenic recipient mice. We demonstrate here that one c-kit positive (c-kitpos) stem cell upon intrathymic transfer can effectively reconstitute the thymus of a sublethally irradiated recipient. After a lag phase of 15 d, high levels of donor-derived thymocytes (Thy-1.1pos) could be detected until 65 d after transplantation in Thy-1.2pos host mice. Donor-derived cells were only detected in the lobe of the thymus in which cells were previously injected and not in the noninjected lobe. These data suggest that c-kitpos stem cells do not migrate from one lobe to another and that they do not re-seed the thymus after having migrated to the bone marrow. The level and duration of reconstitution was found to be cell dose dependent, suggesting that, over time, endogenous stem cells compete with donor stem cells for available sites in the thymus microenvironment. The data presented in this paper demonstrate that commitment of purified adult bone marrow-derived c-kitpos stem cells to the T cell differentiation pathway can occur in the thymus and does not have to happen in the bone marrow.
Is tenure justified? An experimental study of faculty beliefs about tenure, promotion, and academic freedom
Authors: Stephen J. Ceci, Wendy M. Williams, Katrin Mueller-Johnson
Journal: Behavioral and Brain Sciences (2006)

The behavioral sciences have come under attack for writings and speech that affront sensitivities. At such times, academic freedom and tenure are invoked to forestall efforts to censure and terminate jobs. We review the history and controversy surrounding academic freedom and tenure, and explore their meaning across different fields, at different institutions, and at different ranks. In a multifactoral experimental survey, 1,004 randomly selected faculty members from top-ranked institutions were asked how colleagues would typically respond when confronted with dilemmas concerning teaching, research, and wrong-doing. Full professors were perceived as being more likely to insist on having the academic freedom to teach unpopular courses, research controversial topics, and whistle-blow wrong-doing than were lower-ranked professors (even associate professors with tenure). Everyone thought that others were more likely to exercise academic freedom than they themselves were, and that promotion to full professor was a better predictor of who would exercise academic freedom than was the awarding of tenure. Few differences emerged related either to gender or type of institution, and behavioral scientists' beliefs were similar to scholars from other fields. In addition, no support was found for glib celebrations of tenure's sanctification of broadly defined academic freedoms. These findings challenge the assumption that tenure can be justified on the basis of fostering academic freedom, suggesting the need for a re-examination of the philosophical foundation and practical implications of tenure in today's academy.
L-arginine evokes both endothelium-dependent and -independent relaxations in L-arginine-depleted aortas of the rat.
Authors: V B Schini, P M Vanhoutte
Journal: Circulation Research (1991)

This study was designed to investigate the effects of L-arginine (the substrate for the formation of endothelium-derived nitric oxide) in vascular tissues. Rat aortic rings, with or without endothelium, were suspended in organ chambers for the measurement of isometric tension; they were contracted with phenylephrine (10(-6) M). After a short incubation period (0.5 hour) in physiological salt solution, L-arginine induced minor changes in both types of rings. In contrast, when the incubation time was increased (2, 4, 6, and 8 hours), L-arginine evoked concentration- and time-dependent relaxations in aortic rings both with and without endothelium. The relaxations were larger in rings with endothelium. The presence of L-arginine (10(-3) M) in the incubation medium inhibited subsequent relaxations evoked by the amino acid. The concentration-relaxation curves associated with acetylcholine in rings with endothelium and the curves associated with Sin-1, a spontaneous donor of nitric oxide, in rings with or without endothelium were slightly but significantly shifted to the right after a 6-hour incubation. Nitro-L-arginine (3 x 10(-5) M) and methylene blue (3 x 10(-7) M) attenuated the relaxations evoked by L-arginine in rings both with and without endothelium. Other basic amino acids (D-arginine, L-homoarginine, L-citrulline, L-lysine, and L-ornithine; all tested at 10(-3) M) either had no effect or induced small relaxations and did not affect the response to L-arginine. These observations suggest that L-arginine specifically and stereoselectively relaxes aortic rings with and without endothelium, probably by restoring the endogenous pool of the amino acid, which is likely depleted by prolonged incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
Pelvic/Retroperitoneal Salvage Lymph Node Dissection for Patients Treated With Radical Prostatectomy With Biochemical Recurrence and Nodal Recurrence Detected by [11C]Choline Positron Emission Tomography/Computed Tomography
Authors: Patrizio Rigatti, Nazareno Suardi, Alberto Briganti, Luigi F. Da Pozzo, Manuela Tutolo, Luca Villa, Andrea Gallina, Umberto Capitanio, Firas Abdollah, Vincenzo Scattoni, Renzo Colombo, Massimo Freschi, Maria Picchio, Cristina Messa, Giorgio Guazzoni, Francesco Montorsi
Journal: European Urology (2011)
Clonal status of actionable driver events and the timing of mutational processes in cancer evolution
Authors: Nicholas McGranahan, Francesco Favero, Elza C. de Bruin, Nicolai Juul Birkbak, Zoltan Szallasi, Charles Swanton
Journal: Science Translational Medicine (2015)

Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal "actionable" mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)-AKT-mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS-MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.
Précis of<i>Neuroconstructivism: How the Brain Constructs Cognition</i>
Authors: Sylvain Sirois, Michael Spratling, Michael S. C. Thomas, Gert Westermann, Denis Mareschal, Mark H. Johnson
Journal: Behavioral and Brain Sciences (2008)

Abstract Neuroconstructivism: How the Brain Constructs Cognition proposes a unifying framework for the study of cognitive development that brings together (1) constructivism (which views development as the progressive elaboration of increasingly complex structures), (2) cognitive neuroscience (which aims to understand the neural mechanisms underlying behavior), and (3) computational modeling (which proposes formal and explicit specifications of information processing). The guiding principle of our approach is context dependence , within and (in contrast to Marr [1982]) between levels of organization. We propose that three mechanisms guide the emergence of representations: competition, cooperation, and chronotopy; which themselves allow for two central processes: proactivity and progressive specialization. We suggest that the main outcome of development is partial representations, distributed across distinct functional circuits. This framework is derived by examining development at the level of single neurons, brain systems, and whole organisms. We use the terms encellment , embrainment , and embodiment to describe the higher-level contextual influences that act at each of these levels of organization. To illustrate these mechanisms in operation we provide case studies in early visual perception, infant habituation, phonological development, and object representations in infancy. Three further case studies are concerned with interactions between levels of explanation: social development, atypical development and within that, developmental dyslexia. We conclude that cognitive development arises from a dynamic, contextual change in embodied neural structures leading to partial representations across multiple brain regions and timescales, in response to proactively specified physical and social environment.
Bla g 2 Hypoallergens Retaining the Native Fold and Capacity to Modulate T Cell Reactivity Provide Candidates for Cockroach Immunotherapy
Authors: Anna Pomés, Jill Glesner, Judith A. Woodfolk, Paul Wright, Christopher L. Kepley, Mi Li, Martin Himly, Alla Gustchina, Alexander Wlodawer, Martin D. Chapman
Journal: Journal of Allergy and Clinical Immunology (2015)
Randomized, Controlled Trial of the Effectiveness of Short-Term Dynamic Psychotherapy and Cognitive Therapy for Cluster C Personality Disorders
Authors: Martin Svartberg, Tore C Stiles, Michael H Seltzer
Journal: American Journal of Psychiatry (2004)

This study compared the effectiveness of short-term dynamic psychotherapy and cognitive therapy for outpatients with cluster C personality disorders.Patients (N=50) who met the criteria for one or more cluster C personality disorders and not for any other personality disorders were randomly assigned to receive 40 weekly sessions of short-term dynamic psychotherapy or cognitive therapy. The most common axis I disorders in the patient group were anxiety and depression diagnoses. Therapists were experienced, full-time clinicians and were receiving manual-guided supervision. Outcome variables included symptom distress, interpersonal problems, and core personality pathology. Measures were administered repeatedly during and after treatment, and change was assessed longitudinally by means of growth modeling procedures.The overall patient group showed, on average, statistically significant improvements on all measures during treatment and also during a 2-year follow-up period. Significant changes in symptom distress after treatment were found for the group of patients who received short-term dynamic psychotherapy but not for the cognitive therapy patients. Despite these differences in intragroup changes, no statistically significant differences between the short-term dynamic psychotherapy group and cognitive therapy group were found on any measure for any time period. Two years after treatment, 54% of the short-term dynamic psychotherapy patients and 42% of the cognitive therapy patients had recovered symptomatically, whereas approximately 40% of the patients in both groups had recovered in terms of interpersonal problems and personality functioning.Both short-term dynamic psychotherapy and cognitive therapy have a place in the treatment of patients with cluster C personality disorders. However, factors other than treatment modality may discriminate better between successful and poor outcomes. Such factors should be explored in future studies.
CD99-Positive “Ewing's Sarcoma” from Mouse Bone Marrow–Derived Mesenchymal Progenitor Cells?
Authors: Heinrich Kovar, Alain Bernard
Journal: Cancer Research (2006)

To the Editor: 

One of the unsolved enigmas of Ewing's sarcoma family of tumors (ESFT) is its histogenetic origin. Lately, evidence has been accumulating that bone- or bone marrow–derived mesenchymal progenitor cells (MPC) can be transformed by EWS-FLI1 causing small-round cell-like tumors in
Distribution patterns of small-molecule ligands in the protein universe and implications for origin of life and drug discovery
Authors: Hong-Fang Ji, De-Xin Kong, Liang Shen, Ling-Ling Chen, Bin-Guang Ma, Hong-Yu Zhang
Journal: Genome biology (2007)

Abstract Background Extant life depends greatly on the binding of small molecules (such as ligands) with macromolecules (such as proteins), and one ligand can bind multiple proteins. However, little is known about the global patterns of ligand-protein mapping. Results By examining 2,186 well-defined small-molecule ligands and thousands of protein domains derived from a database of druggable binding sites, we show that a few ligands bind tens of protein domains or folds, whereas most ligands bind only one, which indicates that ligand-protein mapping follows a power law. Through assigning the protein-binding orders (early or late) for bio-ligands, we demonstrate that the preferential attachment principle still holds for the power-law relation between ligands and proteins. We also found that polar molecular surface area, H-bond acceptor counts, H-bond donor counts and partition coefficient are potential factors to discriminate ligands from ordinary molecules and to differentiate super ligands (shared by three or more folds) from others. Conclusion These findings have significant implications for evolution and drug discovery. First, the chronology of ligand-protein binding can be inferred by the power-law feature of ligand-protein mapping. Some nucleotide-containing ligands, such as ATP, ADP, GDP, NAD, FAD, dihydro-nicotinamide-adenine-dinucleotide phosphate (NDP), nicotinamide-adenine-dinucleotide phosphate (NAP), flavin mononucleotide (FMN) and AMP, are found to be the earliest cofactors bound to proteins, agreeing with the current understanding of evolutionary history. Second, the finding that about 30% of ligands are shared by two or more domains will help with drug discovery, such as in finding new functions from old drugs, developing promiscuous drugs and depending more on natural products.
Impact of left ventricular outflow tract area on systolic outflow velocity in hypertrophic cardiomyopathy
Authors: Jian Xin Qin, Takahiro Shiota, Harry M Lever, David N Rubin, Fabrice Bauer, Yong Jin Kim, Marta Sitges, Neil L Greenberg, Jeanne K Drinko, Maureen Martin, Deborah A Agler, James D Thomas
Journal: Journal of the American College of Cardiology (2002)