tbuckley/cabot-search huggingface dataset:
<i>In vitro</i> and <i>In vivo</i> Antitumor Effects of the Dual Insulin-Like Growth Factor-I/Insulin Receptor Inhibitor, BMS-554417
Authors: Paul Haluska, Joan M. Carboni, David A. Loegering, Francis Y. Lee, Mark Wittman, Mark G. Saulnier, David B. Frennesson, Kimberly R. Kalli, Cheryl A. Conover, Ricardo M. Attar, Scott H. Kaufmann, Marco Gottardis, Charles Erlichman
Journal: Cancer Research (2006)

Abstract The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to &amp;gt;8.5 μmol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo. (Cancer Res 2006; 66(1): 362-71)
PROCESS EVALUATION FOR COMMUNITY PARTICIPATION
Authors: Frances Dunn Butterfoss
Journal: Annual Review of Public Health (2005)

▪ Abstract This review provides a synthesis of published public health and social science literature to determine how process evaluation has been used to examine community participation and its intermediary role in health and social change outcomes. Community participation is defined, and its relationship to other community-development principles and evaluation and research methods is described. Then, case studies and research initiatives help answer questions such as who participates and why? What are the benefits and challenges of community participation? What qualitative and quantitative methods are used in process evaluations to measure community participation? What measures are used to help define the influence of community participation in community-based interventions? A better understanding of these issues is needed to ensure that community participation is valued and used effectively to plan and implement health-promotion initiatives and evaluate their processes and outcomes.
High-density genotyping study identifies four new susceptibility loci for atopic dermatitis
Authors: David Ellinghaus, Hansjörg Baurecht, Jorge Esparza-Gordillo, Elke Rodríguez, Anja Matanovic, Ingo Marenholz, Norbert Hübner, Heidi Schaarschmidt, Natalija Novak, Sven Michel, Laura Maintz, Thomas Werfel, Ulf Meyer-Hoffert, Melanie Hotze, Holger Prokisch, Katharina Heim, Christian Herder, Tomomitsu Hirota, Mayumi Tamari, Michiaki Kubo, Atsushi Takahashi, Yusuke Nakamura, Lam C Tsoi, Philip Stuart, James T Elder, Liangdan Sun, Xianbo Zuo, Sen Yang, Xuejun Zhang, Per Hoffmann, Markus M Nöthen, Regina Fölster-Holst, Juliane Winkelmann, Thomas Illig, Bernhard O Boehm, Richard H Duerr, Carsten Büning, Stephan Brand, Jürgen Glas, Maeve A McAleer, Caoimhe M Fahy, Michael Kabesch, Sara Brown, W H Irwin McLean, Alan D Irvine, Stefan Schreiber, Young-Ae Lee, Andre Franke, Stephan Weidinger
Journal: Nature Genetics (2013)
Functional Basis of Sinus Bradycardia in Congenital Heart Block
Authors: Keli Hu, Yongxia Qu, Yuankun Yue, Mohamed Boutjdir
Journal: Circulation Research (2004)

Congenital heart block (CHB) is a conduction abnormality characterized by complete atrioventricular (AV) block. CHB affects fetuses and/or newborn of mothers with autoantibodies reactive with ribonucleoproteins 48-kDa SSB/La, 52-kDa SSA/Ro, and 60-kDa SSA/Ro. We recently established animal models of CHB and reported, for the first time, significant sinus bradycardia preceding AV block. This unexpected observation implies that the spectrum of conduction abnormalities extends beyond the AV node to also affect the SA node. To test this hypothesis, we investigated the functional basis of this sinus bradycardia by characterizing the effects of antibodies from mothers with CHB children (positive IgG) on ionic currents that are known to significantly contribute to spontaneous pacing in SA node cells. We recorded L- (I(Ca.L)) and T- (I(Ca.T)) type Ca2+, delayed rectifier K+ (I(K)), hyperpolarization-activated (I(f)) currents, and action potentials (APs) from young rabbit SA node cells. We demonstrated that positive IgG significantly inhibited both I(Ca.T) and I(Ca.L) and induced sinus bradycardia but did not affect I(f) and I(K). Normal IgG from mothers with healthy children did not affect all the currents studied and APs. These results establish that IgG from mothers with CHB children causes substantial inhibition of I(Ca.T) and I(Ca.L), two important pacemaker currents in rabbit SA node cells and point to both I(Ca.T) and I(Ca.L) as major players in the ionic mechanism by which maternal antibodies induce sinus bradycardia in CHB. These novel findings have important clinical significance and suggest that sinus bradycardia may be a potential marker in the detection and prevention of CHB. The full text of this article is available online at http://circres.ahajournals.org
Flexible categorization requires the creation of relational features
Authors: Peter F. Dominey
Journal: Behavioral and Brain Sciences (1998)

Flexible categorization clearly requires an adaptive component, but at what level of representation? We have investigated categorization in sequence learning that requires the extraction of abstract rules, but no modification of sensory primitives. This motivates the need to make explicit the distinction between sensory-level “atomic” features as opposed to concept-level “abstract” features, and the proposal that flexible categorization probably relies on learning at the abstract feature level.
Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): an open, prospective, randomised, multicentre trial
Authors: Carlo Di Mario, Dariusz Dudek, Federico Piscione, Waldemar Mielecki, Stefano Savonitto, Ernesto Murena, Konstantinos Dimopoulos, Antonio Manari, Achille Gaspardone, Andrzej Ochala, Krzysztof Zmudka, Leonardo Bolognese, Philippe Gabriel Steg, Marcus Flather
Journal: The Lancet (2008)
The frequency of NPM1 mutations in childhood acute myeloid leukemia
Authors: Maria Braoudaki, Chrissa Papathanassiou, Katerina Katsibardi, Natalia Tourkadoni, Kalliopi Karamolegou, Fotini Tzortzatou-Stathopoulou
Journal: Journal of Hematology & Oncology (2010)

Mutations in the nucleophosmin (NPM1) gene have been solely associated with childhood acute myeloid leukemia (AML). We evaluated the frequency of NPM1 mutations in childhood AML, their relation to clinical and cytogenetic features and the presence of common FLT3 and RAS mutations.NPM1 mutations were found in 8% of cases. They involved the typical type 'A' mutation and one novel mutation characterized by two individual base pair substitutions, which resulted in 2 amino acid changes (W290) and (S293) in the NPM protein. FLT3/ITD mutations were observed in 12% of the cases and in one NPM1-mutated case bearing also t(8;21) (q22;q22). No common RAS mutations were identified.A relatively consistent NPM1 mutation rate was observed, but with variations in types of mutations. The role of different types of NPM1 mutations, either individually or in the presence of other common gene mutations may be essential for childhood AML prognosis.
A Novel Prostaglandin E Receptor 4–Associated Protein Participates in Antiinflammatory Signaling
Authors: Kiyoshi Takayama, Galina K. Sukhova, Michael T. Chin, Peter Libby
Journal: Circulation Research (2006)

Prostaglandin E2 exerts an antiinflammatory action by ligation of the heptahelical receptor EP4 in human macrophages. Because the mechanism by which EP4 receptor stimulation suppresses inflammatory activation in macrophages remains undefined, we sought interactors with the carboxyl-terminal cytoplasmic domain of the EP4 receptor. Yeast 2-hybrid screening of the human bone marrow cDNA library with the EP4 receptor as a bait identified a cDNA clone encoding a 669-amino acid protein, designated here as EP4 receptor-associated protein (EPRAP), which contains 8 ankyrin motifs that might recruit other signaling molecules. EPRAP bound to the full-length EP4 receptor in HEK293 cells cotransfected with V5-tagged EPRAP and FLAG-tagged EP4 receptor cDNA, as anti-FLAG antibody coimmunoprecipitated EPRAP with the EP4 receptor from the lysates of cotransfected cells. Human macrophages derived from peripheral blood monocytes expressed an approximately 70-kDa protein detected by Western blotting with a polyclonal anti-EPRAP antibody. Fluorescence immunohistochemistry colocalized EPRAP with the EP4 receptor in human atheromata. Interference with EPRAP function by small interference RNA limited prostaglandin E2-mediated suppression of chemokine expression in macrophages activated with lipopolysaccharide and tumor necrosis factor alpha. In conclusion, the antiinflammatory action of prostaglandin E2 in macrophages involves EPRAP that associates directly with the cytoplasmic tail of EP4 receptor.
Pathophysiological findings in a model of persistent atrial fibrillation and severe congestive heart failure
Authors: A Bauer
Journal: Cardiovascular Research (2004)

Develop and evaluate a model of persistent atrial fibrillation (AF) and severe congestive heart failure (CHF).A single-chamber atrial pacemaker was implanted in pigs (20-30 kg). Burst atrial pacing at 42 Hz led to development of persistent AF. Immediately and 20 days after activation of the burst pacing protocol, animals underwent echocardiography. Heart rate, rhythm and general condition were monitored on a daily basis. After 20 days of atrial fibrillation, the animals were sacrificed. Conventional histological methods were used to evaluate microscopic structural changes.In the pig model, persistent atrial fibrillation developed 5 +/- 0.7 days after initiation of the burst protocol. Ventricular response rate was 274 +/- 5 bpm during atrial fibrillation, leading to a tachycardiomyopathy. Heart failure symptoms occurred approximately 15 days after initiation of burst pacing. Increases in QT interval on electrocardiogram, heart weight-to-body weight ratio, and laboratory values suggestive of a hypercatecholaminergic state, as well as liver and kidney dysfunction occurred during the 20-day duration of the study. Microstructural changes consistent with cellular hypertrophy, variable fibrosis, myolysis and apoptosis were found in the atria and ventricles of the study animals.The combined entity of atrial fibrillation and severe congestive heart failure leads to multiple organ dysfunction, ultrastructural and microscopic cardiac changes. Cellular hypertrophy, fibrosis and apoptosis are more prominent in this combined entity than previously reported models of lone atrial fibrillation or heart failure. This model can be used for further investigation into the pathophysiology and treatment of atrial fibrillation and advanced heart failure.
Prioritised research agenda for prevention and control of chronic respiratory diseases
Authors: J. Bousquet, J. Kiley, E. D. Bateman, G. Viegi, A. A. Cruz, N. Khaltaev, N. Ait Khaled, C. E. Baena-Cagnani, M. L. Barreto, N. Billo, G. W. Canonica, K.-H. Carlsen, N. Chavannes, A. Chuchalin, J. Drazen, L. M. Fabbri, M. W. Gerbase, M. Humbert, G. Joos, M. R. Masjedi, S. Makino, K. Rabe, T. To, L. Zhi
Journal: European Respiratory Journal (2010)

The 2008-2013 World Health Organization (WHO) action plan on noncommunicable diseases (NCDs) includes chronic respiratory diseases as one of its four priorities. Major chronic respiratory diseases (CRDs) include asthma and rhinitis, chronic obstructive pulmonary disease, occupational lung diseases, sleep-disordered breathing, pulmonary hypertension, bronchiectiasis and pulmonary interstitial diseases. A billion people suffer from chronic respiratory diseases, the majority being in developing countries. CRDs have major adverse effects on the life and disability of patients. Effective intervention plans can prevent and control CRDs, thus reducing morbidity and mortality. A prioritised research agenda should encapsulate all of these considerations in the frame of the global fight against NCDs. This requires both CRD-targeted interventions and transverse NCD programmes which include CRDs, with emphasis on health promotion and disease prevention.
A High-Affinity Fully Human Anti–IL-6 mAb, 1339, for the Treatment of Multiple Myeloma
Authors: Mariateresa Fulciniti, Teru Hideshima, Claudine Vermot-Desroches, Samantha Pozzi, Puru Nanjappa, Zhenxin Shen, Nipun Patel, Ernest S. Smith, Wei Wang, Rao Prabhala, Yu-tzu Tai, Pierfrancesco Tassone, Kenneth C. Anderson, Nikhil C. Munshi
Journal: Clinical Cancer Research (2009)

We investigated the in vitro and in vivo anti-multiple myeloma activity of monoclonal antibody (mAb) 1339, a high-affinity fully humanized anti-interleukin 6 mAb (immunoglobulin G1), alone and in combination with conventional and novel anti-multiple myeloma agents, as well as its effect on bone turnover.We examined the growth inhibitory effect of 1339 against multiple myeloma cell lines in the absence and in the presence of bone marrow stromal cells, alone or in combination with dexamethasone, bortezomib, perifosine, and Revlimid. Using the severe combined immunodeficient (SCID)-hu murine model of multiple myeloma, we also examined the effect of 1339 on multiple myeloma cell growth and multiple myeloma bone disease.mAb 1339 significantly inhibited growth of multiple myeloma cell in the presence of bone marrow stromal cell in vitro, associated with inhibition of phosphorylation of signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, and Akt. In addition, mAb 1339 enhanced cytotoxicity induced by dexamethasone, as well as bortezomib, lenalidomide, and perifosine, in a synergistic fashion. Importantly mAb 1339 significantly enhanced growth inhibitory effects of dexamethasone in vivo in SCID-hu mouse model of multiple myeloma. mAb 1339 treatment also resulted in inhibition of osteoclastogenesis in vitro and bone remodeling in SCID-hu model.Our data confirm in vitro and in vivo anti-multiple myeloma activity of, as well as inhibition of bone turnover by, fully humanized mAb 1339, as a single agent and in combination with conventional and novel agents, providing a rationale for its clinical evaluation in multiple myeloma.
Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation
Authors: Sichen Li, Arthur P. Chou, Weidong Chen, Ruihuan Chen, Yuzhong Deng, Heidi S. Phillips, Julia Selfridge, Mira Zurayk, Jerry J. Lou, Richard G. Everson, Kuan-Chung Wu, Kym F. Faull, Timothy Cloughesy, Linda M. Liau, Albert Lai
Journal: Neuro-Oncology (2012)

Mutations in isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) are found in a subset of gliomas. Among the many phenotypic differences between mutant and wild-type IDH1/2 gliomas, the most salient is that IDH1/2 mutant glioma patients demonstrate markedly improved survival compared with IDH1/2 wild-type glioma patients. To address the mechanism underlying the superior clinical outcome of IDH1/2 mutant glioma patients, we investigated whether overexpression of the IDH1R132H protein could affect response to therapy in the context of an isogenic glioma cell background. Stable clonal U87MG and U373MG cell lines overexpressing IDH1WT and IDH1R132H were generated, as well as U87MG cell lines overexpressing IDH2WT and IDH2R172K. In vitro experiments were conducted to characterize baseline growth and migration and response to radiation and temozolomide. In addition, reactive oxygen species (ROS) levels were measured under various conditions. U87MG-IDH1R132H cells, U373MG-IDH1R132H cells, and U87MG-IDH2R172K cells demonstrated increased sensitivity to radiation but not to temozolomide. Radiosensitization of U87MG-IDH1R132H cells was accompanied by increased apoptosis and accentuated ROS generation, and this effect was abrogated by the presence of the ROS scavenger N-acetyl-cysteine. Interestingly, U87MG-IDH1R132H cells also displayed decreased growth at higher cell density and in soft agar, as well as decreased migration. Overexpression of IDH1R132H and IDH2R172K mutant protein in glioblastoma cells resulted in increased radiation sensitivity and altered ROS metabolism and suppression of growth and migration in vitro. These findings provide insight into possible mechanisms contributing to the improved outcomes observed in patients with IDH1/2 mutant gliomas.
Reciprocal regulation of iNOS and PARP-1 during allergen-induced eosinophilia
Authors: A. S. Naura, R. Datta, C. P. Hans, M. Zerfaoui, B. M. Rezk, Y. Errami, M. Oumouna, K. Matrougui, A. H. Boulares
Journal: European Respiratory Journal (2008)

Inducible nitric oxide synthase (iNOS) inhibition was recently shown to exert no effect on allergen challenge in human asthma, raising serious concerns about the role of the protein in the disease. The present study investigated the role of iNOS in ovalbumin-induced eosinophilia from the perspective of its relationship with poly(ADP-ribose) polymerase-1 (PARP-1) and oxidative DNA damage. A mouse model of ovalbumin-induced eosinophilia was used to conduct the studies. iNOS-associated protein nitration and tissue damage were partially responsible for allergen-induced eosinophilia. iNOS expression was required for oxidative DNA damage and PARP-1 activation upon allergen challenge. PARP-1 was required for iNOS expression and protein nitration, and this requirement was connected to nuclear factor-κB. PARP-1 was an important substrate for iNOS-associated by-products after ovalbumin-challenge. PARP-1 nitration blocked its poly(ADP-ribosyl)ation activity. Interleukin-5 re-establishment in ovalbumin-exposed PARP-1<sup>-/-</sup> mice reversed eosinophilia and partial mucus production without a reversal of iNOS expression, concomitant protein nitration or associated DNA damage. The present results demonstrate a reciprocal relationship between inducible nitric oxide synthase and poly(ADP-ribose) polymerase-1 and suggest that expression of inducible nitric oxide synthase may be dispensable for eosinophilia after interleukin-5 production. Inducible nitric oxide synthase may be required for oxidative DNA damage and full manifestation of mucus production. Such dispensability may explain, in part, the reported ineffectiveness of inducible nitric oxide synthase inhibition in preventing allergen-induced inflammation in humans.
Relative responsiveness of condition specific and generic health status measures in juvenile idiopathic arthritis
Authors: C Moretti
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objectives:</b> To compare the relative responsiveness of condition specific measures with that of a generic health status instrument for outcome assessment of intra-articular corticosteroid (IAC) injection in patients with juvenile idiopathic arthritis (JIA). <b>Methods:</b> We examined 44 consecutive patients with oligoarticular JIA before an IAC injection and after 6 months. Condition specific measures included physician's and parent's global assessments, the Childhood Health Assessment Questionnaire (CHAQ), the articular indices, and laboratory indicators of systemic inflammation. The generic health status instrument was the Child Health Questionnaire (CHQ), which was divided into two parts: the physical score (PhS) and the psychosocial score (PsS). Responsiveness statistics were the standardised response mean, the effect size, and Guyatt's method. The discriminative ability of the clinical measures in distinguishing improved from non-improved patients was evaluated with the correlation and the receiver operating characteristic methods, using the physician's and the parent's judgements of the treatment outcome as external criteria. <b>Results:</b> All responsiveness statistics and discriminative ability assessments consistently ranked the physician's global assessment of the disease activity as the most responsive measure. The CHQ-PhS revealed superior ability in detecting baseline versus 6 month change compared with the CHAQ and the CHQ-PsS; both summary scales of the CHQ revealed better discriminative ability than the CHAQ. <b>Conclusions:</b> The physician's global assessment of the disease activity proved the most responsive outcome measure in our patients with JIA. The relative evaluative properties of the generic health status instrument and the CHAQ should be further investigated.
Deep nephron function after release of acute unilateral ureteral obstruction in the young rat.
Authors: J Buerkert, D Martin, M Head, J Prasad, S Klahr
Journal: Journal of Clinical Investigation (1978)

The effects of acute unilateral ureteral obstruction (UUO) of 18 h duration on deep nephron function was evaluated in 14 weanling rats with the technique of micropuncture. After release of UUO, 3.4 +/- 0.66% (SE) of the filtered water remained at the tip of the collecting duct nearly fivefold greater than in controls (0.75 +/- 0.10%). Similar differences were seen in fractional sodium that remained at this site. The ratio of tubular fluid osmolality to that of plasma was also reduced in the UUO group (1.53 +/- 0.06 vs. 4.60 +/- 0.26 in controls, P less than 0.001). Single nephron glomerular filtration rate of cortical and deep nephrons was significantly less (P less than 0.001) after release of UUO. Although the percentage of filtering nephrons was significantly reduced in both nephron populations, the decline in glomerular filtration rate was greater in cortical than in juxtamedullary nephrons (cortical:juxtamedullary nephrons = 27.6 +/- 4.5% vs. 53.3 +/- 5.2% in controls, P less than 0.005) which suggests that single nephron glomerular filtration rate is redistributed to deep nephrons after release of UUO. In contrast to cortical nephrons, the amount of tubular fluid which remains near the bend of the loop of Henle of deep nephrons was greater after release of UUO. This appeared to be the result of a decrease in the reabsorption of both water (tubular fluid:plasma inulin = 2.41 +/- 0.16 vs. 7.94 +/- 0.69 in controls, P less than 0.001) and sodium (52.3 +/- 4% vs. 40.7 +/- 2.9% of the filtered sodium in controls, P less than 0.02). It is suggested that this altered reabsorption occurs along both the proximal tubule and descending limb of the loop of Henle of juxtamedullary nephrons. Inner medullary plasma flow (IMPF), as measured with the [125I]albumin-accumulation technique, was significantly depressed before release of UUO, but exceeded control values 90 min postrelease. Such changes imply that the filtration fraction of deep nephrons is decreased and that physical factors in the proximal tubular reabsorption of sodium have been altered. When papillary solute content was measured before release of UUO it was low (428 +/- 23 vs. 1,205 +/- 106 mosmol/kg in controls, P less than 0.001) which indicates that the decline in papillary osmolality is not a consequence of the increased IMPF seen after ureteral release, but rather precedes it. In fact, the decline in papillary osmolality may contribute to the increase in IMPF after release of UUO and to the decreased reabsorption of fluid along the descending limb of the loop of Henle.