tbuckley/cabot-search huggingface dataset:
The <i><scp>KIT</scp></i><scp>D</scp>816<scp>V</scp> allele burden predicts survival in patients with mastocytosis and correlates with the <scp>WHO</scp> type of the disease
Authors: G. Hoermann, K. V. Gleixner, G. E. Dinu, M. Kundi, G. Greiner, F. Wimazal, E. Hadzijusufovic, G. Mitterbauer, C. Mannhalter, P. Valent, W. R. Sperr
Journal: Allergy (2014)

Abstract KIT D816V is present in a majority of patients with systemic mastocytosis ( SM ). We determined the KIT D816V allele burden by quantitative real‐time PCR in bone marrow and peripheral blood of 105 patients with mastocytosis. KIT D816V was detected in 92/105 patients (88%). Significant differences in the median allele burden were observed between disease subgroups: cutaneous mastocytosis (0.042%), indolent SM (0.285%), smoldering SM (5.991%), aggressive SM (9.346%), and SM with associated hematologic non‐mast cell lineage disease (3.761%) ( P &lt; 0.001). The KIT D816V burden also correlated with serum tryptase ( R = 0.5, P &lt; 0.005) but not with mast cell infiltration in bone marrow or mediator symptoms. Moreover, the allele burden was of prognostic significance regarding survival ( P &lt; 0.01). Patients responding to cytoreductive therapy showed a significant decrease in KIT D816V ( P &lt; 0.05). To conclude, the KIT D816V burden correlates with the variant of mastocytosis, predicts survival, and is a valuable follow‐up parameter in SM .
95 EFFICACY AND SAFETY OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN COMBINATION WITH PEGYLATED INTERFERON ALPHA-2A AND RIBAVIRIN IN PREVIOUSLY NULL-RESPONDER GENOTYPE 1 HCV PATIENTS
Authors: D.R. Nelson, R.H. Ghalib, M. Sulkowski, E. Schiff, V. Rustgi, P.J. Pockros, C. Wang, G. Decosterd Kerhuel, P. Grosgurin, H. Porchet, R. Crabbe
Journal: Journal of Hepatology (2009)
Decreased Lung Fibroblast Growth Factor 18 and Elastin in Human Congenital Diaphragmatic Hernia and Animal Models
Authors: Olivier Boucherat, Alexandra Benachi, Anne-Marie Barlier-Mur, Marie-Laure Franco-Montoya, Jelena Martinovic, Bernard Thébaud, Bernadette Chailley-Heu, Jacques R. Bourbon
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Lung hypoplasia in congenital diaphragmatic hernia (CDH) seems to involve impaired alveolar septation. We hypothesized that disturbed deposition of elastin and expression of fibroblast growth factor 18 (FGF18), an elastogenesis stimulus, occurs in CDH.To document FGF18 and elastin in human CDH and ovine surgical and rat nitrofen models and to use models to evaluate the benefit of treatments.Human CDH and control lungs were collected post mortem. Diaphragmatic hernia was created in sheep at 85 days; fetal lungs were collected at 139 days (term = 145 days). Pregnant rats received nitrofen at 12 days; fetal lungs were collected at 21 days (term = 22 days). Some of the sheep fetuses with hernia underwent tracheal occlusion (TO); some of the nitrofen-treated pregnant rats received vitamin A. Both treatments are known to promote lung growth.Coincidental with the onset of secondary septation, FGF18 protein increased threefold in control human lungs, which failed to occur in CDH. FGF18 labeling was found in interstitial cells of septa. Elastin staining demonstrated poor septation and markedly decreased elastin density in CDH lungs. Consistently, lung FGF18 transcripts were diminished 60 and 83% by CDH in sheep and rats, respectively, and elastin density and expression were diminished. TO and vitamin A restored FGF18 and elastin expression in sheep and rats, respectively. TO restored elastin density.Impaired septation in CDH is associated with decreased FGF18 expression and elastic fiber deposition. Simultaneous correction of FGF18 and elastin defects by TO and vitamin A suggests that defective elastogenesis may result, at least partly, from FGF18 deficiency.
Intravenous Iron and Recombinant Human Erythropoietin in Cancer Patients
Authors: Yves Beguin
Journal: Journal of Clinical Oncology (2005)

randomized clinical trial of two methods of administration of single-agent irinotecan. 1 We concentrated on pretreatment levels since we wanted to determine if this "crude" measurement of glucuronidation activity could be used in clinical decision making when treating patients with irinotecan.Nonetheless, our database was limited in that we did not have routine bilirubin follow-up measurements available.We are intrigued by the results of Kramar et al, though would caution that they should be replicated in a larger patient population before advocating prophylactic granulocyte colonystimulating factor support (the result that 50% of patients with bilirubin Ͼ 1.5 mg/dL experienced grade 3/4 neutropenia is based on a group of three patients).
Allogeneic and Autologous Melanoma Vaccines: Where Have We Been and Where Are We Going?
Authors: Vernon K. Sondak, Michael S. Sabel, James J. Mulé
Journal: Clinical Cancer Research (2006)

Abstract The past three decades have seen substantial research on vaccines for the treatment of metastatic melanoma and the prevention of recurrence following resection. Despite their enormous promise, the actual results have been disappointing, with several high-profile vaccine clinical trials failing to show a benefit. Nonetheless, enthusiasm for melanoma vaccines remains and has increased with our expanding understanding of the immune response to tumor. Cellular vaccines can be divided into autologous, derived from the patient's own tumor and allogeneic vaccines. Autologous vaccines have the advantage of containing all potentially relevant tumor-associated antigens for that particular patient. However, autologous vaccines are difficult to obtain from most patients with advanced disease and impossible to obtain from patients who present after resection of all clinically evident disease. No consensus exists for how tumors should be processed, preserved, modified, and delivered to serve as an effective vaccine. The amount of autologous tumor available is rarely enough to produce more than two or three vaccination doses, and the time between initial tumor harvest and ultimate availability of the vaccine may result in interval tumor progression that diminishes the likelihood of vaccine efficacy. All these drawbacks of autologous tumor vaccination limit its applicability and also limit the ability to test autologous vaccines in prospective trials. Allogeneic vaccines avoid many of these problems, but may not contain all of the tumor-associated antigens present on the patient's own tumor. In particular, neoantigens created by mutations in the patient's tumor would be unlikely to be represented in an allogeneic vaccine. Although allogeneic vaccines can be manufactured in sufficient quantities to allow large-scale trials, there remain significant limiting issues in the manufacture and standardization of the vaccine product.
Induction of MET by Ionizing Radiation and Its Role in Radioresistance and Invasive Growth of Cancer
Authors: Francesca De Bacco, Paolo Luraghi, Enzo Medico, Gigliola Reato, Flavia Girolami, Timothy Perera, Pietro Gabriele, Paolo M. Comoglio, Carla Boccaccio
Journal: JNCI Journal of the National Cancer Institute (2011)

Ionizing radiation (IR) is effectively used in cancer therapy. However, in subsets of patients, a few radioresistant cancer cells survive and cause disease relapse with metastatic progression. The MET oncogene encodes the hepatocyte growth factor (HGF) receptor and is known to drive "invasive growth", a regenerative and prosurvival program unduly activated in metastasis.Human tumor cell lines (MDA-MB-231, MDA-MB-435S, U251) were subjected to therapeutic doses of IR. MET mRNA, and protein expression and signal transduction were compared in treated and untreated cells, and the involvement of the DNA-damage sensor ataxia telangiectasia mutated (ATM) and the transcription factor nuclear factor kappa B (NF-κB) in activating MET transcription were analyzed by immunoblotting, chromatin immunoprecipitation, and use of NF-κB silencing RNA (siRNA). Cell invasiveness was measured in wound healing and transwell assays, and cell survival was measured in viability and clonogenic assays. MET was inhibited by siRNA or small-molecule kinase inhibitors (PHA665752 or JNJ-38877605). Combinations of MET-targeted therapy and radiotherapy were assessed in MDA-MB-231 and U251 xenografts (n = 5-6 mice per group). All P values were from two-sided tests.After irradiation, MET expression in cell lines was increased up to fivefold via activation of ATM and NF-κB. MET overexpression increased ligand-independent MET phosphorylation and signal transduction, and rendered cells more sensitive to HGF. Irradiated cells became more invasive via a MET-dependent mechanism that was further enhanced in the presence of HGF. MET silencing by siRNA or inhibition of its kinase activity by treatment with PHA665752 or JNJ-38877605 counteracted radiation-induced invasiveness, promoted apoptosis, and prevented cells from resuming proliferation after irradiation in vitro. Treatment with MET inhibitors enhanced the efficacy of IR to stop the growth of or to induce the regression of xenografts (eg, at day 13, U251 xenografts, mean volume increase relative to mean tumor volume at day 0: vehicle = 438%, 5 Gy IR = 151%, 5 Gy IR + JNJ-38877605 = 76%; difference, IR vs JNJ-38877604 + IR = 75%, 95% CI = 59% to 91%, P = .01).IR induces overexpression and activity of the MET oncogene through the ATM-NF-κB signaling pathway; MET, in turn, promotes cell invasion and protects cells from apoptosis, thus supporting radioresistance. Drugs targeting MET increase tumor cell radiosensitivity and prevent radiation-induced invasiveness.
Neutrophilic eccrine hidradenitis with an unusual presentation
Authors: L.S. OSTLERE, J. WELLS, H.P. STEVENS, G. PRENTICE, M.H.A. RUSTIN
Journal: British Journal of Dermatology (1993)

Journal Article Neutrophilic eccrine hidradenitis with an unusual presentation Get access L.S. OSTLERE, L.S. OSTLERE Departments of Dermatology, The Royal Free Hospital and School of Medicine, Pond St, London NW3 2QG, U.K. Search for other works by this author on: Oxford Academic Google Scholar J. WELLS, J. WELLS Departments of Haematology, The Royal Free Hospital and School of Medicine, Pond St, London NW3 2QG, U.K. Search for other works by this author on: Oxford Academic Google Scholar H.P. STEVENS, H.P. STEVENS Departments of Dermatology, The Royal Free Hospital and School of Medicine, Pond St, London NW3 2QG, U.K. Search for other works by this author on: Oxford Academic Google Scholar G. PRENTICE, G. PRENTICE Departments of Haematology, The Royal Free Hospital and School of Medicine, Pond St, London NW3 2QG, U.K. Search for other works by this author on: Oxford Academic Google Scholar M.H.A. RUSTIN M.H.A. RUSTIN Departments of Dermatology, The Royal Free Hospital and School of Medicine, Pond St, London NW3 2QG, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 128, Issue 6, 1 June 1993, Pages 696–698, https://doi.org/10.1111/j.1365-2133.1993.tb00269.x Published: 01 June 1993 Article history Accepted: 05 January 1993 Published: 01 June 1993
Chronic aortic regurgitation: reassessment of the prognostic value of preoperative left ventricular end-systolic dimension and fractional shortening.
Authors: W G Daniel, W P Hood, A Siart, D Hausmann, U Nellessen, H Oelert, P R Lichtlen
Journal: Circulation (1985)

The prognostic significance of a preoperative echocardiographic left ventricular end-systolic dimension (ESD) greater than 55 mm and/or fractional shortening (FS) of 25% or less was evaluated retrospectively in 84 patients who had undergone aortic valve replacement for isolated chronic aortic regurgitation due to various causes. Postoperative survival, improvement in symptoms, and echocardiographic evidence of regression of left ventricular dilatation and hypertrophy were compared between patients with a preoperative ESD greater than 55 mm (category 1) and those with an ESD of 55 mm or less (category 2) and between patients with FS of 25% or less (category 3) and those with FS greater than 25% (category 4). Patients in categories 1 and 3 had a higher preoperative left ventricular end-diastolic dimension (EDD) and cross-sectional area than those in categories 2 and 4, respectively, but their preoperative functional impairment (NYHA class) was similar. There were 13 deaths, only two of which (one early, one late) could be attributed to left ventricular dysfunction. In both, FS was 25% or less and in one ESD was greater than 55 mm. There was a weak association without useful positive predictive value between the echocardiographic variables and postoperative death due to all causes. Among 42 patients with a preoperative ESD greater than 55 mm and/or FS of 25% or less, 33 (79%) were alive at a mean follow-up of 29.5 months. Symptoms improved in all categories of survivors, with the postoperative NYHA class being similar between categories 1 and 2 and between categories 3 and 4. Among 48 survivors with high-quality echocardiograms both before and after surgery, EDD fell in all groups but fell to a lesser extent in category 3 than in category 4. Postoperative cross-sectional area fell to the same level in all categories. Follow-up intervals were similar in all categories. We conclude that in patients undergoing aortic valve replacement for chronic aortic regurgitation, a preoperative ESD greater than 55 mm or an FS of 25% or less does not reliably predict early or late death, does not correlate with lack of improvement in symptoms, and does not preclude postoperative regression of left ventricular dilatation and hypertrophy. Thus these echocardiographic criteria alone cannot be used for the timing of surgical intervention in these patients.
1413 SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR TREATMENT OF CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NAÏVE PATIENTS: RESULTS FROM QUEST-2, A PHASE III TRIAL
Authors: M. Manns, P. Marcellin, F.P. Fred Poordad, E. Stanislau Affonso de Araujo, M. Buti, Y. Horsmans, E.J. Ewa Janczewska, F. Villamil, M. Peeters, O. Lenz, S. Ouwerkerk-Mahadevan, R. Kalmeijer, M. Beumont-Mauviel
Journal: Journal of Hepatology (2013)
Dr. Franko and Colleagues Reply
Authors: DEBRA L. FRANKO, MARK A. BLAIS, ANNE E. BECKER, SHERRIE SELWYN DELINSKY, DARA N. GREENWOOD, ANDREAS T. FLORES, ELIZABETH R. EKEBLAD, KAMRYN T. EDDY, DAVID B. HERZOG
Journal: American Journal of Psychiatry (2002)
Dissociation constant of the norepinephrine-receptor complex in normotensive and hypertensive rats.
Authors: R B Strecker, W C Hubbard, A M Michelakis
Journal: Circulation Research (1975)

Previous reports have suggested that smooth muscle obtained from the thoracic aorta of spontaneously hypertensive rats is less responsive to vasoconstrictive agents than that obtained from normotensive rats. The present study was undertaken to determine whether the responsiveness of aortic muscles from normotensive and spontaneously hypertensive rats correlates with a difference in the affinity of the adrenergic receptors for norepinephrine and whether antihypertensive therapy alters the affinity of the adrenergic receptors for norepinephrine. The affinity of the adrenergic receptors for norepinephrine was determined by computing the dissociation constant of the norepinephrine-receptor complex (KDR). The values computed for KDR in aortic muscles from normotensive and spontaneously hypertensive rats that had received no antihypertensive therapy were 1.07 X 10(-7)M and 1.17 X 10(-7)M, respectively. The values computed for KDR in aortic muscles from normotensive and spontaneously hypertensive rats that had received antihypertensive therapy were 1.38 X 10(-7)M and 1.29 X 10(-7)M, respectively. The differences in these values for KDR are not significant. These results indicate that the difference in the contractility of aortic muscles from normotensive and spontaneously hypertensive rats is not related to an alteration in the affinity of the adrenergic receptors for norepinephrine and that the affinity of the adrenergic receptors for norepinephrine is not altered by antihypertensive therapy. Thus, it appears that the etiology of hypertension cannot be directly correlated with a difference in the affinity of the adrenergic receptors for norepinephrine.
Bevacizumab Has Differential and Dose-Dependent Effects on Glioma Blood Vessels and Tumor Cells
Authors: Louisa von Baumgarten, David Brucker, Anca Tirniceru, Yvonne Kienast, Stefan Grau, Steffen Burgold, Jochen Herms, Frank Winkler
Journal: Clinical Cancer Research (2011)

Bevacizumab targets VEGF-A and has proved beneficial in glioma patients, improving clinical symptoms by the reduction of tumor edema. However, it remains controversial whether or not bevacizumab exerts antitumor effects in addition to (and potentially independent of) its effects on tumor vessels, and it is unknown what doses are needed to achieve this.We established a novel orthotopic glioma mouse model that allowed us to simultaneously study the kinetics of the morphologic and functional vascular changes, tumor growth, and the viability of individual tumor cells during the course of anti-VEGF therapy in the same microscopic tumor region in real-time. Three doses of bevacizumab were compared, a subclinical dose and two clinical doses (medium and high).Low (subclinical) doses of bevacizumab led to a significant reduction of the total vascular volume without affecting tumor cell viability or the overall tumor growth rates. Medium and high doses triggered a similar degree of vascular regression but significantly decreased tumor growth and prolonged survival. Remaining vessels revealed morphologic features of vascular normalization, reduced permeability, and an increase in blood flow velocity; the latter was dose dependent. We observed an uncoupling of the antitumoral and the antivascular effects of bevacizumab with the high dose only, which showed the potential to cause microregional glioma cell regression. In some tumor regions, pronounced glioma cell regression occurred even without vascular regression. In vitro, there was no effect of bevacizumab on glioma cell proliferation.Regression of glioma cells can occur independently from vascular regression, suggesting that high doses of bevacizumab have indirect anticancer cell properties in vivo.
Natural selection to sports, later physical activity habits, and coronary heart disease
Authors: Urho M Kujala, Seppo Sarna, Jaakko Kaprio, Heikki O Tikkanen, Markku Koskenvuo
Journal: British Journal of Sports Medicine (2000)

Objectives —To investigate the associations between natural selection to sports at a young age, continuity of physical activity, and occurrence of coronary heart disease. Design —Prospective cohort study. Setting —Finland. Participants —Former top level male athletes participating at a young age (1920–1965) in different types of sport (endurance (n = 166), power speed (n = 235), “other” (n = 834)) and controls healthy at the age of 20 years (n = 743). Main outcome measures —Data on the occurrence of coronary heart disease were obtained from death certificates, three nationwide registers, and questionnaire studies in 1985 and 1995, and data on later physical activity were obtained from the questionnaires. Results —In 1985 all groups of former athletes were more physically active than controls (p&lt;0.001). Despite similar total volumes of physical activity, compared with power speed athletes, former endurance athletes participated more often in vigorous activity (p = 0.006) and had less coronary heart disease (adjusted odds ratio 0.34, 95% confidence interval 0.17 to 0.73; p = 0.004). In 1985 and 1995, both endurance and other athletes had less coronary heart disease than controls. From 1986 to 1995, the incidence of new coronary heart disease was lower among those who participated in vigorous physical activity in 1985. Conclusions —Both a previous aptitude for endurance athletic events and continuity of vigorous physical activity seem to be associated with protection against coronary heart disease, but an aptitude for power speed events does not give protection against coronary heart disease.
Characterization of the Regulation and Functional Consequences of p21ras Activation in Neutrophils by Antineutrophil Cytoplasm Antibodies
Authors: Julie M. Williams, Caroline O. S. Savage
Journal: Journal of the American Society of Nephrology (2004)

Antineutrophil cytoplasm antibodies (ANCA) are implicated in the pathogenesis of systemic vasculitis. ANCA are directed against antigens expressed on the surface of cytokine-primed neutrophils. It was shown previously that whole IgG ANCA and its fraction antigen binding [F(ab′)2] fragment can activate the GTPase p21ras. This study shows a functional involvement of this molecule in the ANCA activation of neutrophils by inhibiting the production of superoxide with farnesylthiosalicylic acid. Using the ras activation assay, farnesylthiosalicylic acid inhibits p21ras binding to its substrate at comparable concentrations to those seen for superoxide inhibition. It is also shown that activation of p21ras by ANCA is transient, peaking at 5 to 10 min and returning to baseline by 30 min. The use of ras isoform–specific antibodies in Western blots established, for the first time, that Harvey-ras is not present in human neutrophils, but both Kirsten-ras (K-ras) and Neuronal-ras are. Stimulation with ANCA is able to differentially activate K-ras without effects on neuronal-ras. The activation of p21ras by ANCA and its F(ab′)2 is prevented by inhibition of both Src kinases and phosphatidylinositol-3-kinase, indicating a cooperative role for both molecules in the G protein pathway activated by ANCA F(ab′)2 upstream of p21ras. It is concluded that ANCA selectively activates K-ras during induction of a respiratory burst via pathways involving multiple upstream kinases.
RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome
Authors: Nina Bögershausen, I-Chun Tsai, Esther Pohl, Pelin Özlem Simsek Kiper, Filippo Beleggia, E. Ferda Percin, Katharina Keupp, Angela Matchan, Esther Milz, Yasemin Alanay, Hülya Kayserili, Yicheng Liu, Siddharth Banka, Andrea Kranz, Martin Zenker, Dagmar Wieczorek, Nursel Elcioglu, Paolo Prontera, Stanislas Lyonnet, Thomas Meitinger, A. Francis Stewart, Dian Donnai, Tim M. Strom, Koray Boduroglu, Gökhan Yigit, Yun Li, Nicholas Katsanis, Bernd Wollnik
Journal: Journal of Clinical Investigation (2015)

The genetic disorder Kabuki syndrome (KS) is characterized by developmental delay and congenital anomalies. Dominant mutations in the chromatin regulators lysine (K)–specific methyltransferase 2D (KMT2D) (also known as MLL2) and lysine (K)–specific demethylase 6A (KDM6A) underlie the majority of cases. Although the functions of these chromatin-modifying proteins have been studied extensively, the physiological systems regulated by them are largely unknown. Using whole-exome sequencing, we identified a mutation in RAP1A that was converted to homozygosity as the result of uniparental isodisomy (UPD) in a patient with KS and a de novo, dominant mutation in RAP1B in a second individual with a KS-like phenotype. We elucidated a genetic and functional interaction between the respective KS-associated genes and their products in zebrafish models and patient cell lines. Specifically, we determined that dysfunction of known KS genes and the genes identified in this study results in aberrant MEK/ERK signaling as well as disruption of F-actin polymerization and cell intercalation. Moreover, these phenotypes could be rescued in zebrafish models by rebalancing MEK/ERK signaling via administration of small molecule inhibitors of MEK. Taken together, our studies suggest that the KS pathophysiology overlaps with the RASopathies and provide a potential direction for treatment design.
Effects of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German, 12-month, prospective, randomised substudy
Authors: P. Hadji, M. Ziller, D.G. Kieback, W. Dornoff, H.W. Tessen, T. Menschik, J. Kuck, F. Melchert, A. Hasenburg
Journal: Annals of Oncology (2009)