tbuckley/cabot-search huggingface dataset:
Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer
Authors: Jan B. Vermorken, Ricard Mesia, Fernando Rivera, Eva Remenar, Andrzej Kawecki, Sylvie Rottey, Jozsef Erfan, Dmytro Zabolotnyy, Heinz-Roland Kienzer, Didier Cupissol, Frederic Peyrade, Marco Benasso, Ihor Vynnychenko, Dominique De Raucourt, Carsten Bokemeyer, Armin Schueler, Nadia Amellal, Ricardo Hitt
Journal: New England Journal of Medicine (2008)

Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck.We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first.Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P=0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths.As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00122460.)
<i>PCSK7</i> Genotype Modifies Effect of a Weight-Loss Diet on 2-Year Changes of Insulin Resistance: The POUNDS LOST Trial
Authors: Tao Huang, Jinyan Huang, Qibin Qi, Yanping Li, George A. Bray, Jennifer Rood, Frank M. Sacks, Lu Qi
Journal: Diabetes Care (2014)

OBJECTIVE A common variant rs236918 in the PCSK7 gene has the strongest association with iron homeostasis and is related to insulin resistance. Dietary carbohydrate (CHO) modulates the genetic effect on insulin resistance. We examined whether 2-year weight-loss diets modify the effect of PCSK7 genetic variants on changes in fasting insulin levels and insulin resistance in a randomized, controlled trial. RESEARCH DESIGN AND METHODS Data were analyzed in the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, which is a randomized, controlled 2-year weight-loss trial using diets that differed in macronutrient proportions. PCSK7 rs236918 was genotyped in 730 overweight or obese adults (80% whites) in this trial. We assessed the progression in fasting insulin and glucose levels, and insulin resistance by genotypes. RESULTS During the 6-month weight-loss phase, the PCSK7 rs236918 G allele was significantly associated with greater decreases in fasting insulin levels in the high–dietary CHO group (P for interaction = 0.04), while the interaction for changes in HOMA-insulin resistance (HOMA-IR) (P for interaction = 0.06) did not reach significant levels in white subjects. The G allele was significantly associated with a greater decrease in fasting insulin levels and HOMA-IR in response to high dietary CHO levels (P = 0.02 and P = 0.03, respectively). From 6 months to 2 years (weight-regain phase), the interactions became attenuated due to the regaining of weight (P for interactions = 0.08 and 0.06, respectively). In addition, we observed similar and even stronger results in the whole-study samples from the trial. CONCLUSIONS Our data suggest that PCSK7 genotypes may interact with dietary CHO intake on changes in insulin sensitivity in the white Americans.
Certain subphenotypes of aspirin-exacerbated respiratory disease distinguished by latent class analysis
Authors: Grazyna Bochenek, Joanna Kuschill-Dziurda, Krystyna Szafraniec, Hanna Plutecka, Andrzej Szczeklik, Ewa Nizankowska-Mogilnicka
Journal: Journal of Allergy and Clinical Immunology (2013)
Association of tyrosine protein kinase Zap-70 with the protooncogene product p120c-cbl in T lymphocytes.
Authors: M Fournel, D Davidson, R Weil, A Veillette
Journal: The Journal of Experimental Medicine (1996)

Accumulating data show that the tyrosine protein kinase Zap-70 plays an essential role in T cell receptor-mediated signal transduction. However, the model of action, as well as the physiologically relevant substrates of Zap-70, have not been determined. We have attempted to identify a 120-kD tyrosine-phosphorylated protein (p120) that associates with Zap-70 in activated T lymphocytes. The results of our analyses showed that p120 is largely encoded by the c-cbl protooncogene. Furthermore, the association of Zap-70 with c-Cbl was shown to be induced by T cell receptor stimulation, implying that it required posttranslational modification of one or both of these products. FynT, but not Lck, also associated with c-Cbl in activated T cells. Finally, using a heterologous system, it was demonstrated that the ability of Zap-70 to cause tyrosine phosphorylation of p120c-cbl was dependent on Lck- or FynT-mediated signals. As c-Cbl can associate with several other signaling molecules, it may couple Zap-70 to downstream effectors during T cell activation.
Comparison of twenty three nebulizer/compressor combinations for domiciliary use
Authors: EC Smith, J Denyer, AH Kendrick
Journal: European Respiratory Journal (1995)

We have assessed the physical and dynamic characteristics of 23 home jet nebulizer/compressor combinations currently available in the UK and Europe. The combinations were evaluated in terms of pressure-flow characteristics, aerosol mass distribution, volume output, electrical costs, and sound level. In addition, we determined the effect of nebulizer fill volume on aerosol mass distribution and volume output. One nebulizer was used with six different compressors, and four compressors were tested with three different nebulizers. The pressure-flow relationships showed a wide variation between models, as did flow-rate at the nebulizer (range 3.0-8.0 L.min-1). The mean +/- SD volume nebulized after 10 min using an initial fill volume of 2.5 and 5.0 mL was 46 +/- 9 and 34 +/- 12%, respectively. The mass median aerodynamic diameter (MMAD) over a 5 min nebulization ranged 2.6 to 10.2 microns. Nine of the nebulizations produced an MMAD of less than 5 microns at both fill volumes. Changing nebulizer/compressor combinations affected flow rate, MMAD and volume output. Sound levels varied between models. Running costs were low, with all using less than 74 kilowatt hours of energy per year. We conclude that there is a wide variation in performance of nebulizer/compressor combinations for use with nebulized bronchodilators. Correct matching of the nebulizer/compressor is seen to be important to ensure optimum performance.(ABSTRACT TRUNCATED AT 250 WORDS)
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
Authors: Heribert Schunkert, Inke R König, Sekar Kathiresan, Muredach P Reilly, Themistocles L Assimes, Hilma Holm, Michael Preuss, Alexandre F R Stewart, Maja Barbalic, Christian Gieger, Devin Absher, Zouhair Aherrahrou, Hooman Allayee, David Altshuler, Sonia S Anand, Karl Andersen, Jeffrey L Anderson, Diego Ardissino, Stephen G Ball, Anthony J Balmforth, Timothy A Barnes, Diane M Becker, Lewis C Becker, Klaus Berger, Joshua C Bis, S Matthijs Boekholdt, Eric Boerwinkle, Peter S Braund, Morris J Brown, Mary Susan Burnett, Ian Buysschaert, John F Carlquist, Li Chen, Sven Cichon, Veryan Codd, Robert W Davies, George Dedoussis, Abbas Dehghan, Serkalem Demissie, Joseph M Devaney, Patrick Diemert, Ron Do, Angela Doering, Sandra Eifert, Nour Eddine El Mokhtari, Stephen G Ellis, Roberto Elosua, James C Engert, Stephen E Epstein, Ulf de Faire, Marcus Fischer, Aaron R Folsom, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Solveig Gretarsdottir, Vilmundur Gudnason, Jeffrey R Gulcher, Eran Halperin, Naomi Hammond, Stanley L Hazen, Albert Hofman, Benjamin D Horne, Thomas Illig, Carlos Iribarren, Gregory T Jones, J Wouter Jukema, Michael A Kaiser, Lee M Kaplan, John J P Kastelein, Kay-Tee Khaw, Joshua W Knowles, Genovefa Kolovou, Augustine Kong, Reijo Laaksonen, Diether Lambrechts, Karin Leander, Guillaume Lettre, Mingyao Li, Wolfgang Lieb, Christina Loley, Andrew J Lotery, Pier M Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P McKeown, Christa Meisinger, Thomas Meitinger, Olle Melander, Pier Angelica Merlini, Vincent Mooser, Thomas Morgan, Thomas W Mühleisen, Joseph B Muhlestein, Thomas Münzel, Kiran Musunuru, Janja Nahrstaedt, Christopher P Nelson, Markus M Nöthen, Oliviero Olivieri, Riyaz S Patel, Chris C Patterson, Annette Peters, Flora Peyvandi, Liming Qu, Arshed A Quyyumi, Daniel J Rader, Loukianos S Rallidis, Catherine Rice, Frits R Rosendaal, Diana Rubin, Veikko Salomaa, M Lourdes Sampietro, Manj S Sandhu, Eric Schadt, Arne Schäfer, Arne Schillert, Stefan Schreiber, Jürgen Schrezenmeir, Stephen M Schwartz, David S Siscovick, Mohan Sivananthan, Suthesh Sivapalaratnam, Albert Smith, Tamara B Smith, Jaapjan D Snoep, Nicole Soranzo, John A Spertus, Klaus Stark, Kathy Stirrups, Monika Stoll, W H Wilson Tang, Stephanie Tennstedt, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Maciej Tomaszewski, Andre G Uitterlinden, Andre M van Rij, Benjamin F Voight, Nick J Wareham, George A Wells, H-Erich Wichmann, Philipp S Wild, Christina Willenborg, Jaqueline C M Witteman, Benjamin J Wright, Shu Ye, Tanja Zeller, Andreas Ziegler, Francois Cambien, Alison H Goodall, L Adrienne Cupples, Thomas Quertermous, Winfried März, Christian Hengstenberg, Stefan Blankenberg, Willem H Ouwehand, Alistair S Hall, Panos Deloukas, John R Thompson, Kari Stefansson, Robert Roberts, Unnur Thorsteinsdottir, Christopher J O'Donnell, Ruth McPherson, Jeanette Erdmann
Journal: Nature Genetics (2011)
Surface antigens of melanoma and melanocytes. Specificity of induction of Ia antigens by human gamma-interferon.
Authors: A N Houghton, T M Thomson, D Gross, H F Oettgen, L J Old
Journal: The Journal of Experimental Medicine (1984)

IFN-gamma is known to induce expression of Ia antigens on a variety of cell types. In the present study, this activity of IFN-gamma has been analyzed with a panel of 36 melanoma cell lines, normal melanocytes, and 97 cell lines representing a range of other differentiation lineages. 55% of the melanoma cell lines express Ia antigens in a constitutive manner without IFN-gamma induction. Of the 16 Ia-melanoma lines, 13 could be induced to express Ia antigens by IFN-gamma, whereas three were noninducible. Melanocytes, which do not normally express Ia antigens, are converted to Ia expression by IFN-gamma. Ia antigens expressed constitutively or after IFN-gamma induction were identified with antibodies detecting monomorphic and allomorphic products of DR and DC loci. IFN-gamma appeared to be unique in its ability to induce Ia expression on melanoma and melanocytes; 14 other agents (including IFN-alpha and IFN-beta) known to influence growth or differentiation did not have Ia-inducing activity. Equally striking is the restriction of antigenic changes following IFN-gamma induction to HLA-associated products; of the 38 systems of cell surface antigens examined, only HLA-A,B,C, beta 2m, and Ia antigens were affected. A variety of other Ia- cell types were shown to be Ia-inducible by IFN-gamma; these included established lines of breast, colon, pancreas, bladder, kidney, ovary, and brain cancers, and cultures of normal fibroblasts, kidney epithelia, and epidermal keratinocytes. In contrast, three tumor types, teratocarcinoma, choriocarcinoma, and neuroblastoma, were not inducible for Ia expression, even though IFN-gamma could induce expression of HLA-A,B,C products. The broad representation of Ia antigens on most somatic cell types expressed either constitutively or after IFN-gamma can be viewed in an immunological context (antigen presentation/immune regulatory signals) or could indicate that Ia products have functions other than those related to immune reactions.
Activation of human lung mast cells by monomeric immunoglobulin E
Authors: G. Cruse, D. Kaur, W. Yang, S. M. Duffy, C. E. Brightling, P. Bradding
Journal: European Respiratory Journal (2005)

The mechanism of chronic mast cell activation in asthma is unclear. Monomeric immunoglobulin (Ig)E in the absence of allergen induces mediator release from rodent mast cells, indicating a possible role for IgE in the continued activation of mast cells within the asthmatic bronchial mucosa. In this study it was investigated whether monomeric IgE induces Ca 2+ influx and mediator release from human lung mast cells (HLMC). Purified HLMC were cultured for 4 weeks and then exposed to monomeric human myeloma IgE. Ratiometric Ca 2+ imaging was performed on single fura-2-loaded cells. Histamine release was measured by radioenzymatic assay; leukotriene C 4 (LTC 4 ) and interleukin (IL)-8 were measured by ELISA. At concentrations experienced in vivo , monomeric IgE induced dose-dependent histamine release, LTC 4 production and IL-8 synthesis. This was associated with a rise in cytosolic free Ca 2+ . Enhanced histamine release was still evident 1 week after initial exposure to IgE suggesting that continued exposure maintains enhanced secretion. Monomeric immunoglobulin E alone activates cultured human lung mast cells initiating Ca 2+ influx, degranulation, arachidonic acid metabolism and cytokine synthesis. These findings support the hypothesis that immunoglobulin E loading of mast cells within the asthmatic airway contributes to the disordered airway physiology of this disease.
Deregulation of microRNA-503 Contributes to Diabetes Mellitus–Induced Impairment of Endothelial Function and Reparative Angiogenesis After Limb Ischemia
Authors: Andrea Caporali, Marco Meloni, Christine Völlenkle, Desiree Bonci, Graciela B. Sala-Newby, Roberta Addis, Gaia Spinetti, Sergio Losa, Rachel Masson, Andrew H. Baker, Reuven Agami, Carlos le Sage, Gianluigi Condorelli, Paolo Madeddu, Fabio Martelli, Costanza Emanueli
Journal: Circulation (2011)

Background— Diabetes mellitus impairs endothelial cell (EC) function and postischemic reparative neovascularization by molecular mechanisms that are not fully understood. microRNAs negatively regulate the expression of target genes mainly by interaction in their 3′ untranslated region. Methods and Results— We found that microRNA-503 (miR-503) expression in ECs is upregulated in culture conditions mimicking diabetes mellitus (high D-glucose) and ischemia-associated starvation (low growth factors). Under normal culture conditions, lentivirus-mediated miR-503–forced expression inhibited EC proliferation, migration, and network formation on Matrigel (comparisons versus lentivirus.GFP control). Conversely, blocking miR-503 activity by either adenovirus-mediated transfer of a miR-503 decoy ( Ad.decoymiR-503 ) or by antimiR-503 (antisense oligonucleotide) improved the functional capacities of ECs cultured under high D-glucose/low growth factors. We identified CCNE1 and cdc25A as direct miR-503 targets which are downregulated by high glucose/low growth factors in ECs. Next, we obtained evidence that miR-503 expression is increased in ischemic limb muscles of streptozotocin-diabetic mice and in ECs enriched from these muscles. Moreover, Ad.decoymiR-503 delivery to the ischemic adductor of diabetic mice corrected diabetes mellitus–induced impairment of postischemic angiogenesis and blood flow recovery. We finally investigated miR-503 and target gene expression in muscular specimens from the amputated ischemic legs of diabetic patients. As controls, calf biopsies of nondiabetic and nonischemic patients undergoing saphenous vein stripping were used. In diabetic muscles, miR-503 expression was remarkably higher, and it inversely correlated with cdc25 protein expression. Plasma miR-503 levels were also elevated in the diabetic individuals. Conclusions— Our data suggest miR-503 as a possible therapeutic target in diabetic patients with critical limb ischemia.
Hypoxia and Adipocyte Physiology: Implications for Adipose Tissue Dysfunction in Obesity
Authors: Paul Trayhurn
Journal: Annual Review of Nutrition (2014)

Hypoxia develops in white adipose tissue in obese mice, resulting in changes in adipocyte function that may underpin the dysregulation that leads to obesity-associated disorders. Whether hypoxia occurs in adipose tissue in human obesity is unclear, with recent studies contradicting earlier reports that this was the case. Adipocytes, both murine and human, exhibit extensive functional changes in culture in response to hypoxia, which alters the expression of up to 1,300 genes. These include genes encoding key adipokines such as leptin, interleukin (IL)-6, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2), which are upregulated, and adiponectin, which is downregulated. Hypoxia also inhibits the expression of genes linked to oxidative metabolism while stimulating the expression of genes associated with glycolysis. Glucose uptake and lactate release by adipocytes are both stimulated by hypoxia, and insulin sensitivity falls. Preadipocytes and macrophages in adipose tissue also respond to hypoxia. The hypoxia-signaling pathway may provide a new target for the treatment of obesity-associated disorders.
Continuous flow leukapheresis induces expression of stress genes in lymphocytes: impact on microarray analyses
Authors: Susan Moir, Eileen T. Donoghue, Oxana K. Pickeral, Angela Malaspina, Marie A. Planta, Tae-Wook Chun, Surekha R. Krishnan, Shyamasundaran Kottilil, Charles E. Birse, Susan F. Leitman, Anthony S. Fauci
Journal: Blood (2003)
Arterial smooth muscle cells express nitric oxide synthase in response to endothelial injury.
Authors: G K Hansson, Y J Geng, J Holm, P Hårdhammar, A Wennmalm, E Jennische
Journal: The Journal of Experimental Medicine (1994)

Endothelial cells regulate vascular tone by secreting paracrine mediators that control the contractility of arterial smooth muscle cells. Nitric oxide (NO) is an important vasodilating agent that is generated from L-arginine by the enzyme nitric oxide synthase (NOS), which is expressed constitutively by the endothelium. NO also inhibits platelet aggregation, contributing to the antithrombotic properties of the endothelial surface. It would therefore be expected that loss of the endothelium during arterial injury would lead to vasospasm and thrombosis but instead, the neointima formed after injury has a nonthrombogenic surface and a maintained vascular patency. We report here that arterial smooth muscle cells in the neointima formed after a deendothelializing balloon injury to the rat carotid artery express the cytokine-inducible isoform of NOS. Expression was detectable by reverse transcription-polymerase chain reaction from day 1-14 after injury and in situ hybridization showed expression of NOS mRNA by neointimal smooth muscle cells, particularly at the surface of the lesion. This was associated with systemically detectable NO production as revealed by electron paramagnetic resonance spectroscopic analysis of nitrosylated red cell hemoglobin. Local NO production by intimal smooth muscle cells after endothelial injury could represent an important mechanism for the maintenance of arterial patency and nonthrombogenicity in the injured artery.
The usefulness of non-invasive liver stiffness measurements in predicting clinically significant portal hypertension in cirrhotic patients: Korean data
Authors: Won Ki Hong, Moon Young Kim, Soon Koo Baik, Seung Yong Shin, Jung Min Kim, Yong Seok Kang, Yoo Li Lim, Young Ju Kim, Youn Zoo Cho, Hye Won Hwang, Jin Hyung Lee, Myeong Hun Chae, Hyoun A Kim, Hye Won Kang, Sang Ok Kwon
Journal: Clinical and Molecular Hepatology (2013)

Liver stiffness measurement (LSM) has been proposed as a non-invasive method for estimating the severity of fibrosis and the complications of cirrhosis. Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard for assessing the presence of portal hypertension, but its invasiveness limits its clinical application. In this study we evaluated the relationship between LSM and HVPG, and the predictive value of LSM for clinically significant portal hypertension (CSPH) and severe portal hypertension in cirrhosis.LSM was performed with transient elastography in 59 consecutive cirrhotic patients who underwent hemodynamic HVPG investigations. CSPH and severe portal hypertension were defined as HVPG ≥10 and ≥12 mmHg, respectively. Linear regression analysis was performed to evaluate the relationship between LSM and HVPG. Diagnostic values were analyzed based on receiver operating characteristic (ROC) curves.A strong positive correlation between LSM and HVPG was observed in the overall population (r(2)=0.496, P<0.0001). The area under the ROC curve (AUROC) for the prediction of CSPH (HVPG ≥10 mmHg) was 0.851, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for an LSM cutoff value of 21.95 kPa were 82.5%, 73.7%, 86.8%, and 66.7%, respectively. The AUROC at prediction of severe portal hypertension (HVPG ≥12 mmHg) was 0.877, and the sensitivity, specificity, PPV, and NPV at LSM cutoff value of 24.25 kPa were 82.9%, 70.8%, 80.6%, and 73.9%, respectively.LSM exhibited a significant correlation with HVPG in patients with cirrhosis. LSM could be a non-invasive method for predicting CSPH and severe portal hypertension in Korean patients with liver cirrhosis.