tbuckley/cabot-search huggingface dataset:
Constitutively Activated STAT3 Frequently Coexpresses with Epidermal Growth Factor Receptor in High-Grade Gliomas and Targeting STAT3 Sensitizes Them to Iressa and Alkylators
Authors: Hui-Wen Lo, Xinyu Cao, Hu Zhu, Francis Ali-Osman
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The goals of this study are to elucidate the relationship of the oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) with glioma aggressiveness and to understand the role of high STAT3 activity in the resistance of malignant gliomas and medulloblastomas to chemotherapy. Experimental Design: Immunohistochemical staining and biochemical methods were used to examine the extent of STAT3 activation and EGFR expression in primary specimens and cell lines, respectively. Cellular response to drug treatments was determined using cell cytotoxicity and clonogenic growth assays. Results: We found STAT3 to be constitutively activated in 60% of primary high-grade/malignant gliomas and the extent of activation correlated positively with glioma grade. High levels of activated/phosphorylated STAT3 were also present in cultured human malignant glioma and medulloblastoma cells. Three STAT3-activating kinases, Janus-activated kinase 2 (JAK2), EGFR, and EGFRvIII, contributed to STAT3 activation. An inhibitor to JAK2/STAT3, JSI-124, significantly reduced expression of STAT3 target genes, suppressed cancer cell growth, and induced apoptosis. Furthermore, we found that STAT3 constitutive activation coexisted with EGFR expression in 27.2% of primary high-grade/malignant gliomas and such coexpression correlated positively with glioma grade. Combination of an anti-EGFR agent Iressa and a JAK2/STAT3 inhibitor synergistically suppressed STAT3 activation and potently killed glioblastoma cell lines that expressed EGFR or EGFRvIII. JSI-124 also sensitized malignant glioma and medulloblastoma cells to temozolomide, 1,3-bis(2-chloroethyl)-1-nitrosourea, and cisplatin in which a synergism existed between JSI-124 and cisplatin. Conclusion: STAT3 constitutive activation, alone and in concurrence with EGFR expression, plays an important role in high-grade/malignant gliomas and targeting STAT3/JAK2 sensitizes these tumors to anti-EGFR and alkylating agents.
Expression of the NKTa clonotype in a series of human natural killer clones with identical cytotoxic specificity.
Authors: R E Schmidt, G T Bartley, S S Lee, J F Daley, H D Royer, H Levine, E L Reinherz, S F Schlossman, J Ritz
Journal: The Journal of Experimental Medicine (1986)

Over a period of 3 yr, a series of ten NK clones that express a unique clonotypic T cell receptor-like structure, termed NKTa, has been generated from a single individual. These clones were derived from either peripheral blood nonadherent cell fractions (JT9, JT10, JT11), NKH2-purified cells (CNK8, CNK9), or NKTa-purified cells (CNK11, CNK12, CNK13, CNK14, CNK15). Flow cytometric analysis of peripheral blood mononuclear cells from this individual showed that NKTa+ cells occur with a frequency of approximately 0.15%. The existence of NKTa+ cells in peripheral blood was confirmed by use of immunorosette enrichment techniques, flow cytometric purification, and subsequent clonal expansion of NKTa+ cells. Phenotypic analysis of NKTa+ clones showed that all expressed NKH1 as well as T3, T8, T11, T12, and Mo1 antigens. Only five of ten clones expressed NKH2 antigen. All NKTa+ clones had broad cytolytic activity against a series of seven different target cells that was similar to that of other NK clones. In addition, cytotoxicity of each clone could be inhibited by preincubation of effector cells with monoclonal anti-NKTa or by preincubation of target cells with monoclonal anti-TNKTAR. Although half of the NKTa+ clones appeared phenotypically different from the other half with regard to the expression of NKH2 antigen, analysis of T cell receptor gene rearrangements indicated that all NKTa+ clones contained identical gene rearrangements of C beta 2.
Chronic Salicylate Intoxication in Adults
Authors: Hugh D. Greer
Journal: JAMA (1965)

Chronic overdosage with salicylates can produce a syndrome of chronic salicylate intoxication. The main features of this syndrome are confused, sometimes bizarre, behavior and hyperventilation. The measurement of serum salicylate and carbon dioxide provides reliable laboratory confirmation of the diagnosis and may prevent mistaking the condition for frank hysteria, diabetic coma, or other causes of organic delirium. Five patients are reported who suffered from various primary diseases but were hospitalized for complaints directly related to salicylate poisoning. In one patient, papilledema appeared to be the result of the salicylate intoxication.
The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis
Authors: Jared M. Lucas, Cynthia Heinlein, Tom Kim, Susana A. Hernandez, Muzdah S. Malik, Lawrence D. True, Colm Morrissey, Eva Corey, Bruce Montgomery, Elahe Mostaghel, Nigel Clegg, Ilsa Coleman, Christopher M. Brown, Eric L. Schneider, Charles Craik, Julian A. Simon, Antonio Bedalov, Peter S. Nelson
Journal: Cancer Discovery (2014)

Abstract TMPRSS2 is an androgen-regulated cell-surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastases. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries, we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-MET receptor tyrosine kinase signaling, and initiated a proinvasive epithelial-to-mesenchymal transition phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment. Significance: The vast majority of prostate cancer deaths are due to metastasis. Loss of TMPRSS2 activity dramatically attenuated the metastatic phenotype through mechanisms involving the HGF–c-MET axis. Therapeutic approaches directed toward inhibiting TMPRSS2 may reduce the incidence or progression of metastasis in patients with prostate cancer. Cancer Discov; 4(11); 1310–25. ©2014 AACR. See related commentary by Rubin, p. 1262 This article is highlighted in the In This Issue feature, p. 1243
House dust mite sublingual immunotherapy is safe and appears to be effective in moderate, persistent asthma
Authors: L. Wang, J. Yin, R. Fadel, A. Montagut, O. de Beaumont, P. Devillier
Journal: Allergy (2014)

Abstract Background The efficacy and safety of sublingual immunotherapy in house dust mite–induced asthma have yet to be firmly established. We report the results of a double‐blind, placebo‐controlled, randomized clinical trial performed in mainland China. Methods After a three‐month baseline period, 484 asthmatic adults were randomized 2 : 1 to 12 months of daily treatment with either an aqueous, standardized, 300 index of reactivity mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae extracts or a placebo. The primary efficacy criterion was well‐controlled asthma for at least 16 of the last 20 weeks of treatment. Results In the active ( n = 308) and placebo ( n = 157) groups, well‐controlled asthma was achieved by 85.4% and 81.5% of the patients, respectively ( P = 0.244). A subsequent post hoc analysis by asthma severity revealed significant clinical benefits in actively treated subjects with moderate, persistent asthma at baseline [401–800 μg budesonide/day ( n = 175)], with greater achievement of well‐controlled asthma (80.5% and 66.1% for the active treatment and placebo groups, respectively; P = 0.021) and totally controlled asthma (54.0% and 33.9%, respectively, P = 0.008), a higher percentage of patients with an asthma control questionnaire score &lt; 0.75 (56.6% and 40.0%, respectively; P = 0.039) and a greater mean reduction in inhaled corticosteroid use (218.5 μg and 126.2 μg, respectively; P = 0.004). The active vs placebo differences in disease control and corticosteroid use were not significant for mild, persistent asthma. No treatment‐related serious adverse events were reported. Conclusions Sublingual mite allergen immunotherapy was well tolerated in adult asthmatics and effectively controlled disease in patients with moderate (but not mild) persistent asthma (ClinicalTrials.gov: NCT 00660452).
Measurement of instantaneous blood-flow velocity in the human aorta using pulsed Doppler ultrasound
Authors: S E GISVOLD, A O BRUBAKK
Journal: Cardiovascular Research (1982)

The reproducibility and ease of use of a pulsed Doppler system has been investigated in 27 normal subjects. Measurements were performed in the ascending aorta and the aortic arch in the sitting and supine position. Good quality recordings were obtained in over 90% of the subjects. Maximum velocities of 120 and 108 cm·s−1 were found in the supine position of the ascending aorta in males and females respectively, while the corresponding acceleration were 2254 and 2148 cm·s−2. When moving from the sitting to the supine position, changes in integral under the mean and maximum velocity curve, which is supposed to be proportional to stroke volume, were approximately 30% both in the ascending aorta and in the aortic arch. Making certain assumptions about dimensions of the aorta, reasonable values for cardiac output could be calculated in all subjects. The reproducibility of the measurements was tested by making ten repeat measurements in five subjects. The mean variation coefficient was between 6 and 11% for all measured variables. It is concluded that blood-flow velocity can be measured in the ascending aorta and the aortic arch using pulsed ultrasound and that the method has a reproducibility which permits measurements of changes in the flow and flow velocity of over 10%.
Selection of Patients with Chronic Drug-Resistant Epilepsy for Resective Surgery: 5 Years’ Experience
Authors: C E Polkey
Journal: Journal of the Royal Society of Medicine (1981)

Selection criteria are the key to success in resective surgery for intractable epilepsy. Using such criteria about 50% of patients admitted for assessment are considered unsuitable, half of these for neurophysiological reasons or because there is evidence of more than one area of structural abnormality. Selection for a good result from temporal lobectomy can be judged, both on the proportion of positive pathological lesions in the resected temporal lobes and on a high degree of seizure relief together with a low incidence of side effects. The same holds for other resections. The relationship between these factors is reviewed.
NICOTINE ADDICTION AND TREATMENT
Authors: Jed E. Rose, Ph.D
Journal: Annual Review of Medicine (1996)

The persistence of cigarette smoking despite widespread awareness of adverse health effects results from an underlying addiction to nicotine. Unaided attempts to quit smoking are generally unsuccessful. This article discusses nicotine addition and therapeutic techniques that have been or are being developed to relieve smoking withdrawal symptoms and promote abstinence from smoking. These techniques include nicotine chewing gum, skin patches, nasal sprays, and inhalers, as well as pharmacotherapies such as mecamylamine and clonidine, serotonergic treatments such as buspirone, and antidepressants such as buproprion. A nondrug approach using cigarette substitutes that mimic the airway sensations produced by cigarette smoke is also discussed.
Physiotherapists' use of information in identifying a concussion: an extended Delphi approach
Authors: S J Sullivan, A G Schneiders, P McCrory, A Gray
Journal: British Journal of Sports Medicine (2007)

To determine the relative importance of signs and symptoms that a selected cohort of sports physiotherapists use to identify a sports concussion.A two-round Delphi methodology was used to achieve consensus in a cohort of 21 sports physiotherapists. A subsequent round involving an educational intervention provided the participants with an opportunity to modify their knowledge base through the provision of a relevant resource article.Participants provided 123 responses, which were grouped into eight descriptive categories with consensus (>80%) being reached for the importance of: cognition/orientation, memory, motor dysfunction and state of consciousness. The category "state of consciousness" remained the most important information source at the completion of the study.Participants placed considerable importance on the player's level of consciousness in their decision making. This would appear to be in conflict with recent trends to place greater importance on the role of symptoms in identifying a concussion.
Telepsychiatry: Psychiatric Consultation by Interactive Television
Authors: THOMAS F. DWYER
Journal: American Journal of Psychiatry (1973)

The author describes an interactive television (IATV) system set up between Massachusetts General Hospital and a medical station in Boston. The system has proven to be feasible and acceptable to individuals and institutions in the community, providing psychiatric skills on a much wider scale, in a more accessible way, and faster than any other system. The author delineates the implications and future uses that appropriately placed IATV links could have, such as significantly multiplying existing manpower and more evenly distributing psychiatric care without placing greater demands on manpower.
Scientists produce genetically engineered, cloned pigs for xenotransplantation
Authors: R. Dobson
Journal: BMJ (2002)

Two groups of scientists have produced genetically engineered, cloned pigs whose tissue may be suitable for transplanting into humans. Both teams have reported having bred pigs that lack the gene that causes rejection.

PPL Therapeutics, which is based in Edinburgh, has produced five pigs that lack the gene, while Immerge BioTherapeutics and a team from the …
Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study
Authors: Henk M. Lokhorst, Bronno van der Holt, Jan J. Cornelissen, Marie-José Kersten, Marinus van Oers, Reinier Raymakers, Monique C. Minnema, Sonja Zweegman, Jeroen J. Janssen, Mark Zijlmans, Gerard Bos, Nicolaas Schaap, Shulamiet Wittebol, Okke de Weerdt, Rianne Ammerlaan, Pieter Sonneveld
Journal: Blood (2012)
Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression
Authors: Phillip M. Garfin, Dullei Min, Jerrod L. Bryson, Thomas Serwold, Badreddin Edris, Clare C. Blackburn, Ellen R. Richie, Kenneth I. Weinberg, Nancy R. Manley, Julien Sage, Patrick Viatour
Journal: The Journal of Experimental Medicine (2013)

Thymic involution during aging is a major cause of decreased production of T cells and reduced immunity. Here we show that inactivation of Rb family genes in young mice prevents thymic involution and results in an enlarged thymus competent for increased production of naive T cells. This phenotype originates from the expansion of functional thymic epithelial cells (TECs). In RB family mutant TECs, increased activity of E2F transcription factors drives increased expression of Foxn1, a central regulator of the thymic epithelium. Increased Foxn1 expression is required for the thymic expansion observed in Rb family mutant mice. Thus, the RB family promotes thymic involution and controls T cell production via a bone marrow–independent mechanism, identifying a novel pathway to target to increase thymic function in patients.
Gene Expression Profiling–Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome
Authors: Göran Jönsson, Christian Busch, Stian Knappskog, Jürgen Geisler, Hrvoje Miletic, Markus Ringnér, Johan R. Lillehaug, Åke Borg, Per Eystein Lønning
Journal: Clinical Cancer Research (2010)

The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. Although spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers in selecting patients for immune therapy.We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization, we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus, and NRAS/BRAF mutation screening.The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation, or stromal composition genes. Although all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (P < 0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by a high frequency of CDKN2A homozygous deletions (P < 0.01). We observed a different prognosis between the subtypes (P = 0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared with the others (P = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III and IV melanomas. Moreover, low expression of an a priori defined gene set associated with immune response signaling was significantly associated with poor outcome (P = 0.001).Our data reveal a biologically based taxonomy of malignant melanomas with prognostic effect and support an influence of the antitumoral immune response on outcome.
Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98
Authors: Sherene Loi, Nicolas Sirtaine, Fanny Piette, Roberto Salgado, Giuseppe Viale, Françoise Van Eenoo, Ghizlane Rouas, Prudence Francis, John P.A. Crown, Erika Hitre, Evandro de Azambuja, Emmanuel Quinaux, Angelo Di Leo, Stefan Michiels, Martine J. Piccart, Christos Sotiriou
Journal: Journal of Clinical Oncology (2013)

Purpose Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT—in this case, anthracycline-only CT—in selected BC subtypes. Patients and Methods We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. Results There was no significant prognostic association in the global nor estrogen receptor (ER) –positive/human epidermal growth factor receptor 2 (HER2) –negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). Conclusion In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.
The arginine-552-cysteine (R1315C) mutation within the A1 loop of von Willebrand factor induces an abnormal folding with a loss of function resulting in type 2A–like phenotype of von Willebrand disease: study of 10 patients and mutated recombinant von Willebrand factor
Authors: Anne-Sophie Ribba, Lysiane Hilbert, Jean-Maurice Lavergne, Edith Fressinaud, Catherine Boyer-Neumann, Catherine Ternisien, Irène Juhan-Vague, Jenny Goudemand, Jean-Pierre Girma, Claudine Mazurier, Dominique Meyer
Journal: Blood (2001)
Ulysses - an application for the projection of molecular interactions across species.
Authors: Danielle Kemmer, Yong Huang, Sohrab P Shah, Jonathan Lim, Jochen Brumm, Macaire MS Yuen, John Ling, Tao Xu, Wyeth W Wasserman, BF Francis Ouellette
Journal: Genome biology (2005)

Abstract We developed Ulysses as a user-oriented system that uses a process called Interolog Analysis for the parallel analysis and display of protein interactions detected in various species. Ulysses was designed to perform such Interolog Analysis by the projection of model organism interaction data onto homologous human proteins, and thus serves as an accelerator for the analysis of uncharacterized human proteins. The relevance of projections was assessed and validated against published reference collections. All source code is freely available, and the Ulysses system can be accessed via a web interface http://www.cisreg.ca/ulysses .
Reappraisal of bicarbonate secretion by the human oesophagus.
Authors: A Mertz-Nielsen, J Hillingso, K Bukhave, J Rask-Madsen
Journal: Gut (1997)

BACKGROUND AND AIMS: Administration of omeprazole to healthy volunteers was recently reported to increase proximal duodenal mucosal bicarbonate secretion. As human oesophagus also secretes bicarbonate, the hypothesis was tested that omeprazole may stimulate oesophageal bicarbonate secretion and thus contribute to the therapeutic efficacy of the drug in gastro-oesophageal reflux disease. SUBJECTS AND METHODS: In nine healthy volunteers, oesophageal "steady state" perfusion of a 10 cm open segment of distal oesophagus was performed twice in random order. The volunteers were pretreated with either 60 mg/day omeprazole for three days and 80 mg intravenous omeprazole before perfusion or 600 mg/day ranitidine for three days and 50 mg/h intravenously during the perfusion. Saliva and samples of aspirate from the perfused oesophagus and stomach were collected and bicarbonate concentrations were measured. RESULTS: The median rates (95% confidence intervals) of intrinsic oesophageal bicarbonate secretion, corrected for contaminating salivary and gastric bicarbonate, were 89 (33-150) and 121 (63-203) mumol/h/10 cm (p &gt; 0.5) in omeprazole and ranitidine treated subjects respectively. Salivary and gastric bicarbonate contaminating the oesophagus accounted for 14% and 3%, respectively, of total oesophageal bicarbonate output. CONCLUSIONS: Bicarbonate secretory capacity of the human oesophagus is less than previously assumed, and the clinical relevance of intrinsic oesophageal bicarbonate for mucosal defence may be overestimated. As omeprazole and ranitidine did not affect bicarbonate secretion differently there was no evidence that omeprazole acts on bicarbonate secretory cells in the oesophageal mucosa.