tbuckley/cabot-search huggingface dataset:
Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor.
Authors: J A Koedam, J C Meijers, J J Sixma, B N Bouma
Journal: Journal of Clinical Investigation (1988)

Activated protein C (APC) acts as a potent anticoagulant enzyme by inactivating Factor V and Factor VIII. In this study, protein S was shown to increase the inactivation of purified Factor VIII by APC ninefold. The reaction rate was saturated with respect to the concentration of protein S when protein S was present in a 10-fold molar excess over APC. The heavy chain of Factor VIII was cleaved by APC and protein S did not alter the degradation pattern. Factor VIII circulates in a complex with the adhesive protein von Willebrand factor. When purified Factor VIII was recombined with von Willebrand factor, the inactivation of Factor VIII by APC proceeded at a 10-20-fold slower rate as compared with Factor VIII in the absence of von Willebrand factor. Protein S had no effect on the inactivation of the Factor VIII-von Willebrand factor complex by APC. After treatment of this complex with thrombin, however, the actions of APC and protein S towards Factor VIII were completely restored. In hemophilia A plasma, purified Factor VIII associated with endogenous von Willebrand factor, resulting in a complete protection against APC (4 nM). By mixing hemophilic plasma with plasma from a patient with severe von Willebrand's disease, we could vary the amount of von Willebrand factor. 1 U of von Willebrand factor was needed to provide protection of 1 U Factor VIII. Also in plasma from patients with the IIA-type variant of von Willebrand's disease, Factor VIII was protected. In von Willebrand's disease plasma, which was depleted of protein S, APC did not inactivate Factor VIII. These results indicate that protein S serves as a cofactor in the inactivation of Factor VIII and Factor VIIIa by APC and that von Willebrand factor can regulate the action of these two anticoagulant proteins.
Next generation sequencing analysis of platinum refractory advanced germ cell tumor sensitive to Sunitinib (Sutent®) a VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor in a phase II trial
Authors: Vivek Subbiah, Funda Meric-Bernstam, Gordon B Mills, Kenna R Mills Shaw, Ann Marie Bailey, Priya Rao, John F Ward, Lance C Pagliaro
Journal: Journal of Hematology & Oncology (2014)

Germ cell tumors (GCT) are the most common solid tumors in adolescent and young adult males (age 15 and 35 years) and remain one of the most curable of all solid malignancies. However a subset of patients will have tumors that are refractory to standard chemotherapy agents. The management of this refractory population remains challenging and approximately 400 patients continue to die every year of this refractory disease in the United States.Given the preclinical evidence implicating vascular endothelial growth factor (VEGF) signaling in the biology of germ cell tumors, we hypothesized that the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) may possess important clinical activity in the treatment of this refractory disease. We proposed a Phase II efficacy study of sunitinib in seminomatous and non-seminomatous metastatic GCT's refractory to first line chemotherapy treatment (ClinicalTrials.gov Identifier: NCT00912912). Next generation targeted exome sequencing using HiSeq 2000 (Illumina Inc., San Diego, CA, USA) was performed on the tumor sample of the unusual responder.Five patients are enrolled into this Phase II study. Among them we report here the clinical course of a patient (Patient # 5) who had an exceptional response to sunitinib. Next generation sequencing to understand this patient's response to sunitinib revealed RET amplification, EGFR and KRAS amplification as relevant aberrations. Oncoscan MIP array were employed to validate the copy number analysis that confirmed RET gene amplification.Sunitinib conferred clinical benefit to this heavily pre-treated patient. Next generation sequencing of this 'exceptional responder' identified the first reported case of a RET amplification as a potential basis of sensitivity to sunitinib (VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor) in a patient with refractory germ cell tumor. Further characterization of GCT patients using biomarkers for clinical response and patient selection is warranted.ClinicalTrials.gov Identifier: NCT00912912.
Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors
Authors: Garrett M. Frampton, Siraj M. Ali, Mark Rosenzweig, Juliann Chmielecki, Xinyuan Lu, Todd M. Bauer, Mikhail Akimov, Jose A. Bufill, Carrie Lee, David Jentz, Rick Hoover, Sai-Hong Ignatius Ou, Ravi Salgia, Tim Brennan, Zachary R. Chalmers, Savina Jaeger, Alan Huang, Julia A. Elvin, Rachel Erlich, Alex Fichtenholtz, Kyle A. Gowen, Joel Greenbowe, Adrienne Johnson, Depinder Khaira, Caitlin McMahon, Eric M. Sanford, Steven Roels, Jared White, Joel Greshock, Robert Schlegel, Doron Lipson, Roman Yelensky, Deborah Morosini, Jeffrey S. Ross, Eric Collisson, Malte Peters, Philip J. Stephens, Vincent A. Miller
Journal: Cancer Discovery (2015)

Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.
Mechanisms underlying the activation of L-type calcium channels by urocortin in rat ventricular myocytes
Authors: Tarik Smani, Eva Calderón-Sanchez, Nieves Gómez-Hurtado, María Fernández-Velasco, Victoria Cachofeiro, Vicente Lahera, Antonio Ordoñez, Carmen Delgado
Journal: Cardiovascular Research (2010)

The aim of this study was to elucidate the signalling pathways implicated in the modulation of cardiac L-type Ca2+ channels by urocortin (Ucn) in ventricular myocytes. Adult rat ventricular myocytes were stimulated in vitro with Ucn for 20–40 min. L-type calcium currents (ICaL) were measured with the patch-clamp technique, whereas quantification of activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was assessed by sandwich-ELISA. Ucn induced a significant increase in ICaL density that was not prevented by the protein kinase A (PKA) inhibitor KT-5720 or the non-selective antagonist of guanine nucleotide exchange factor brefeldin A. The Ucn effect was antagonized by astressin, a corticotropin-releasing factor receptor-2 (CRF-R2) antagonist, and significantly reduced by protein kinase C (PKC) and ERK1/2 inhibitors. The cyclic AMP (cAMP) analogue 8-pCPT-2′OMe-cAMP, which selectively activates the exchange protein activated by cAMP (Epac), was ineffective in modifying ICaL. Analysis of phospho-ERK1/2 showed that Ucn induced a significant activation of the ERK1/2 pathway in ventricular myocytes and this effect was prevented by pre-incubation with PKC inhibitors. The present study provides evidence of new mechanisms involved in the modulation of L-type Ca2+ channels by Ucn in adult ventricular myocytes. We propose that the marked increase in ICaL density induced by Ucn is mediated through CRF-R2 and involves PKC-dependent activation of the ERK1/2 pathway, whereas PKA and Epac signalling are not implicated.
Effect of bronchoconstrictor aerosols on the alveolar plateau of the single breath O2 test
Authors: D. C. Stanescu, D. B. Teculescu, R. Pacuraru, V. Popa
Journal: Thorax (1968)

In 17 subjects with bronchial asthma and chronic bronchitis measurements of the uneven ventilation using the single breath oxygen test, F.E.V.<sub>1·0</sub> and V.C. were performed before and after acetylcholine or allergen nebulization. An increase of the alveolar slope was noticed in five out of the seven patients with induced bronchospasm and a decrease in the remaining two. In two other subjects moderate dyspnoea not reflected by spirographic tests was accompanied by a definite increase of the N<sub>2</sub> gradient. One patient experienced a severe asthmatic attack after acetylcholine without significant increase of the N<sub>2</sub> gradient. In the last seven subjects the spirographic tests were not impaired but the N<sub>2</sub> gradient rose to a significant level in three. The various implications of these results are discussed. In one subject the alveolar nitrogen concentration decreased after acetylcholine with a concomitant increase in the residual volume. This finding was assumed to be the result of either a failure of inspired oxygen to mix with alveolar nitrogen or a decreased available lung space.
A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures
Authors: Todd H Baron, Gavin C Harewood, Ashwin Rumalla, Nicole L Pochron, Linda M Stadheim, Gregory J Gores, Terry M Therneau, Piet C De Groen, Thomas J Sebo, Diva R Salomao, Benjamin R Kipp
Journal: Clinical Gastroenterology and Hepatology (2004)
Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33
Authors: Monique A.M. Willart, Kim Deswarte, Philippe Pouliot, Harald Braun, Rudi Beyaert, Bart N. Lambrecht, Hamida Hammad
Journal: The Journal of Experimental Medicine (2012)

House dust mite (HDM) is one of the most common allergens worldwide. In this study, we have addressed the involvement of IL-1 in the interaction between HDM and the innate immune response driven by lung epithelial cells (ECs) and dendritic cells (DCs) that leads to asthma. Mice lacking IL-1R on radioresistant cells, but not hematopoietic cells, failed to mount a Th2 immune response and did not develop asthma to HDM. Experiments performed in vivo and in isolated air–liquid interface cultures of bronchial ECs showed that TLR4 signals induced the release of IL-1α, which then acted in an autocrine manner to trigger the release of DC-attracting chemokines, GM-CSF, and IL-33. Consequently, allergic sensitization to HDM was abolished in vivo when IL-1α, GM-CSF, or IL-33 was neutralized. Thymic stromal lymphopoietin (TSLP) became important only when high doses of allergen were administered. These findings put IL-1α upstream in the cytokine cascade leading to epithelial and DC activation in response to inhaled HDM allergen.
Sertraline in Children and Adolescents With Obsessive-Compulsive Disorder
Authors: J S March, J Biederman, R Wolkow, A Safferman, J Mardekian, E H Cook, N R Cutler, R Dominguez, J Ferguson, B Muller, R Riesenberg, M Rosenthal, F R Sallee, K D Wagner, H Steiner
Journal: JAMA (1998)

Context.—The serotonin reuptake inhibitors are the treatment of choice for patients with obsessive-compulsive disorder; however, empirical support for this assertion has been weaker for children and adolescents than for adults.Objective.—To evaluate the safety and efficacy of the selective serotonin reuptake inhibitor sertraline hydrochloride in children and adolescents with obsessive-compulsive disorder.Design.—Randomized, double-blind, placebo-controlled trial.Patients.—One hundred eighty-seven patients: 107 children aged 6 to 12 years and 80 adolescents aged 13 to 17 years randomized to receive either sertraline (53 children, 39 adolescents) or placebo (54 children, 41 adolescents).Setting.—Twelve US academic and community clinics with experience conducting randomized controlled trials.Intervention.—Sertraline hydrochloride was titrated to a maximum of 200 mg/d during the first 4 weeks of double-blind therapy, after which patients continued to receive this dosage of medication for 8 more weeks. Control patients received placebo.Main Outcome Measures.—The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH GOCS), and the NIMH Clinical Global Impressions of Severity of Illness (CGI-S) and Improvement (CGI-I) rating scales.Results.—In intent-to-treat analyses, patients treated with sertraline showed significantly greater improvement than did placebo-treated patients on the CY-BOCS (adjusted mean, −6.8 vs −3.4, respectively; P = .005), the NIMH GOCS (−2.2 vs −1.3, respectively; P = .02), and the CGI-I (2.7 vs 3.3, respectively; P = .002) scales. Significant differences in efficacy between sertraline and placebo emerged at week 3 and persisted for the duration of the study. Based on CGI-I ratings at end point, 42% of patients receiving sertraline and 26% of patients receiving placebo were very much or much improved. Neither age nor sex predicted response to treatment. The incidence of insomnia, nausea, agitation, and tremor were significantly greater in patients receiving sertraline; 12 (13%) of 92 sertraline-treated patients and 3 (3.2%) of 95 placebo-treated patients discontinued prematurely because of adverse medical events (P = .02). No clinically meaningful abnormalities were apparent on vital sign determinations, laboratory findings, or electrocardiographic measurements.Conclusion.—Sertraline appears to be a safe and effective short-term treatment for children and adolescents with obsessive-compulsive disorder.
Chylothorax after high translumbar aortography.
Authors: P A Dupont
Journal: Thorax (1975)

Two patients who had high translumbar aortograms for suspected arterial disease developed shortness of breath 48 hours after aortography and were found to have chylothoraces. Conservative management was initially adopted for both, but surgery had to be resorted to, although the first patient died before arriving in the operating theatre. The literature and the management of this condition are reviewed.
Hand and Wrist
Authors: Joe Coyle, Ali Naraghi, Otto Chan
Journal: BMJ (2014)

The decidua of human term placenta contains a cell population with highly immunomodulatory properties regulating viability, growth and invasion important for the fetal development, remarkably resembling the tumor-microenvironment. Prompted by previously published data from our group demonstrating the pro-apoptotic potential of placenta-derived supernatant on human lung cancer in vitro, the anti-tumor activity of placenta-conditioned medium was studied in more detail. For this purpose, human NSCLC cell lines A549 and H838 were challenged for 17h with placenta-derived conditioned medium, obtained from human fresh term placenta incubated overnight in DMEM with 2%FCS. Viability was analysed either by MTT assay or FACS using 7-AAD. For tumor growth, expression of proliferation marker Ki-67 was analysed, induction of apoptosis was determined by expression of annexin V and/or cleaved caspase 3 using immunofluorescence or FACS analysis. Overall, both suppression of Ki-67 expression and increase of apoptotic cells were induced by all placentas (n=6), although to strikingly varying extent. Based on these preliminary but promising results demonstrating consistent inhibitory effects on lung tumor cells, placenta-derived anti-tumor activity will be further studied including human NSCLC specimens and by using fractionated placenta-derived supernatants that will be also analysed by mass spectrometry to identify potential immunosuppressive mediators. Thus, these studies could result in the development of new therapeutic agents for a more effective treatment of NSCLC.
T cell aging
Authors: Janko Nikolich-Žugich
Journal: The Journal of Experimental Medicine (2005)

The immune system exhibits profound age-related changes, collectively termed immunosenescence. The most visible of these is the decline in protective immunity, which results from a complex interaction of primary immune defects and compensatory homeostatic mechanisms. The sum of these changes is a dysregulation of many processes that normally ensure optimal immune function. Recent advances suggest that old mice can produce fully functional new T cells, opening both intriguing inquiry avenues and raising critical questions to be pursued.
Molecular Pathobiology of Gastrointestinal Stromal Sarcomas
Authors: Christopher L. Corless, Michael C. Heinrich
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Gastrointestinal stromal tumors (GISTs) form an interesting group of sarcomas whose unique pathobiology provides a model of how molecularly targeted therapeutics can have a major impact on patient welfare. Approximately 85% of GISTs are driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT or platelet-derived growth factor receptor alpha. We review the pivotal relationship between specific mutations in these kinase genes, the origin and pathologic spectrum of GISTs, and the response of these tumors to treatment with kinase inhibitors such as imatinib and sunitinib. Mechanisms of resistance to kinase inhibitor therapy are discussed, and targets for the next generation of therapeutics are considered. The rapid evolution in our understanding of GISTs, which stems directly from the close alliance of basic and clinical researchers in the field, illustrates the growing role of the molecular classification of solid tumors in the development of modern oncological treatments.
EVALUATION OF THE RENAL TOXICITY OF HEME PROTEINS AND THEIR DERIVATIVES: A ROLE IN THE GENESIS OF ACUTE TUBULE NECROSIS
Authors: Sheldon R. Braun, Frederick R. Weiss, Allen I. Keller, J. Richard Ciccone, Harry G. Preuss
Journal: The Journal of Experimental Medicine (1970)

This investigation studies the toxicity of heme proteins and/or their break-down products on renal function. Heme proteinemia precedes acute tubule necrosis at a frequency great enough to suggest a causal relationship between the two events. Physiological and metabolic functions of kidney slices are investigated in several models of acute tubule necrosis. Organic acid and organic base transport is depressed earliest. These alterations in tubule function cannot be explained by ischemia or obstruction alone. Heme proteinemia in rats or incubation of renal slices in medium containing heme proteins yields several interesting observations. Neither in vivo or in vitro do hemoglobin and methemoglobin alone produce a depressive effect on the transport systems studied. However, parallel to many clinical situations, when such secondary insults as hypoxia and elevated ammonia concentrations are included in the experimental design, transport functions are depressed. Ferrihemate, a molecule smaller than hemoglobin or methemoglobin, depresses transport function without secondary insults. From these studies it is concluded that heme proteins play a role in tubule dysfunction seen in acute tubule necrosis. A model is presented that collates these data with other factors known to play a part in the pathogenesis of this renal syndrome.
The Role of Media Violence in Violent Behavior
Authors: L. Rowell Huesmann, Laramie D. Taylor
Journal: Annual Review of Public Health (2006)

Media violence poses a threat to public health inasmuch as it leads to an increase in real-world violence and aggression. Research shows that fictional television and film violence contribute to both a short-term and a long-term increase in aggression and violence in young viewers. Television news violence also contributes to increased violence, principally in the form of imitative suicides and acts of aggression. Video games are clearly capable of producing an increase in aggression and violence in the short term, although no long-term longitudinal studies capable of demonstrating long-term effects have been conducted. The relationship between media violence and real-world violence and aggression is moderated by the nature of the media content and characteristics of and social influences on the individual exposed to that content. Still, the average overall size of the effect is large enough to place it in the category of known threats to public health.
Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype
Authors: M. Gnant, I. Sestak, M. Filipits, M. Dowsett, M. Balic, E. Lopez-Knowles, R. Greil, P. Dubsky, H. Stoeger, M. Rudas, R. Jakesz, S. Ferree, J.W. Cowens, T. Nielsen, C. Schaper, C. Fesl, J. Cuzick
Journal: Annals of Oncology (2015)
Neutrophils are essential for early anti-Listeria defense in the liver, but not in the spleen or peritoneal cavity, as revealed by a granulocyte-depleting monoclonal antibody.
Authors: J W Conlan, R J North
Journal: The Journal of Experimental Medicine (1994)

This study shows that in mice selectively depleted of neutrophils by treatment with a monoclonal antibody, RB6-8C5, listeriosis is severely exacerbated in the liver, but not in the spleen or peritoneal cavity during the crucial first day of infection. At sites of infection in the livers of neutrophil-depleted mice, Listeria monocytogenes grew to large numbers inside hepatocytes. By contrast, in the livers of normal mice neutrophils rapidly accumulated at infectious foci and this was associated with the lysis of infected hepatocytes that served to abort infection in these permissive cells. In the spleen the situation was different, in that depletion of neutrophils did not result in appreciable exacerbation of infection. In this organ intact infected cells, many of which appeared to be fibroblast-like stromal cells, were found at foci of infection in the presence or absence of large numbers of neutrophils. This suggests that neutrophils are less effective at destroying L. monocytogenes-infected target cells in the spleen than in the liver. Consequently, at least during the first day, the organism remained free to multiply intracellularly in the spleen in cells that are permissive for its growth. Presumably, the same situation exists in the peritoneal cavity, because depleting neutrophils did not severely exacerbate infection initiated at this site.