tbuckley/cabot-search huggingface dataset:
CYR61 and αVβ5 Integrin Cooperate to Promote Invasion and Metastasis of Tumors Growing in Preirradiated Stroma
Authors: Yan Monnier, Pierre Farmer, Gregory Bieler, Natsuko Imaizumi, Thierry Sengstag, Gian Carlo Alghisi, Jean-Christophe Stehle, Laura Ciarloni, Snezana Andrejevic-Blant, Raphael Moeckli, René-Olivier Mirimanoff, Simon L. Goodman, Mauro Delorenzi, Curzio Rüegg
Journal: Cancer Research (2008)

Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of postradiation recurrences remains an unresolved issue. Tumors growing in preirradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. The transcription factor hypoxia inducible factor (HIF)-1 promotes invasion and metastasis of hypoxic tumors, but its role in the tumor bed effect has not been reported. Here, we show that tumor cells derived from SCCVII and HCT116 tumors growing in a preirradiated bed, or selected in vitro through repeated cycles of severe hypoxia, retain invasive and metastatic capacities when returned to normoxia. HIF activity, although facilitating metastatic spreading of tumors growing in a preirradiated bed, is not essential. Through gene expression profiling and gain- and loss-of-function experiments, we identified the matricellular protein CYR61 and alphaVbeta5 integrin as proteins cooperating to mediate these effects. The anti-alphaV integrin monoclonal antibody 17E6 and the small molecular alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a preirradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and alphaVbeta5 integrin as proteins that cooperate to mediate metastasis. They also identify alphaV integrin inhibition as a potential therapeutic approach for preventing metastasis in patients at risk for postradiation recurrences.
Nocturnal periodic breathing in primary pulmonary hypertension
Authors: R. Schulz, G. Baseler, H.A. Ghofrani, F. Grimminger, H. Olschewski, W. Seeger
Journal: European Respiratory Journal (2002)

Cheyne-Stokes respiration is frequently observed in congestive heart failure. Among other factors, prolongation of circulation time, hypocapnia and hypoxia are thought to underlie this sleep-related breathing disorder. Primary pulmonary hypertension (PPH) is also characterized by reduced cardiac output and blood gas alterations. Therefore, the aim of the present study was to determine whether a nocturnal periodic breathing (PB) occurs in PPH. A total of 20 consecutive patients with PPH who had been admitted for pharmacological investigation of pulmonary vasoreactivity were investigated by lung function testing, right heart catheterization and full-night attended polysomnography. PB was detected in six patients (30%) (mean +/- SEM: apnoea/hypopnoea index 37 +/- 5 h(-1); arterial oxygen saturation was <90% during 56 +/- 6.5% of total sleep time). The patients with PB had more severe haemodynamic impairment than those without. They also had a more marked reduction in the pulmonary diffusion capacity and greater arterial hypoxia. PB was markedly improved or even eradicated by nasal oxygen during the night. Periodic breathing occurs in patients with advanced primary pulmonary hypertension and can be reversed by nocturnal nasal oxygen. The clinical and prognostic significance of periodic breathing in primary pulmonary hypertension needs to be determined by further studies.
Mutational analysis of the CD2/CD58 interaction: the binding site for CD58 lies on one face of the first domain of human CD2.
Authors: C Somoza, P C Driscoll, J G Cyster, A F Williams
Journal: The Journal of Experimental Medicine (1993)

The adhesion interaction between the immunoglobulin superfamily molecules CD2 and CD58 (lymphocyte function-associated antigen 3) plays an important role in T cell and natural killer cell interaction with various antigen-presenting and target cells. Determination of the solution structure of rat CD2 domain 1 has allowed a model of human CD2 domain 1 to be generated, and a series of mutants based on this model have been made. Residues of domain 1 of human CD2 predicted to be solvent exposed were substituted with the equivalent residues present in the rat CD2 molecule. The ability of these mutants to mediate rosetting with human and sheep erythrocytes was studied. Results show that the binding site of CD2 for both human and sheep CD58 maps to the beta sheet containing beta strands CC'C"F and G. Residues K34 and E36 in beta strand C, R48 and K49 in beta strand C', and K91 and N92 in the loop connecting beta strands F and G are shown to be critical in the interaction. The data support the proposition that the interaction between CD2 and CD58 involves the major beta sheet face of CD2.
Distinct behavior of mutant triosephosphate isomerase in hemolysate and in isolated form: molecular basis of enzyme deficiency
Authors: Ferenc Orosz, Judit Oláh, Marco Alvarez, György M. Keserű, Beáta Szabó, Gábor Wágner, Zoltán Kovári, Margit Horányi, Klára Baróti, Joseph A. Martial, Susan Hollán, Judit Ovádi
Journal: Blood (2001)
Population Pharmacokinetics of the Novel Anticancer Agent E7070 During Four Phase I Studies: Model Building and Validation
Authors: Ch. van Kesteren, R. A.A. Mathôt, E. Raymond, J. P. Armand, Ch. Dittrich, H. Dumez, H. Roché, J. P. Droz, C. Punt, M. Ravic, J. Wanders, J. H. Beijnen, P. Fumoleau, J. H.M. Schellens
Journal: Journal of Clinical Oncology (2002)

N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters.Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model.The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model.A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.
Promoter Methylation in <i>APC</i>, <i>RUNX3</i>, and <i>GSTP1</i> and Mortality in Prostate Cancer Patients
Authors: Lorenzo Richiardi, Valentina Fiano, Loredana Vizzini, Laura De Marco, Luisa Delsedime, Olof Akre, Anna Gillio Tos, Franco Merletti
Journal: Journal of Clinical Oncology (2009)

Purpose There is a need to better understand prostate cancer progression and identify new prognostic markers for this tumor. We investigated the association between promoter methylation in a priori selected genes and survival in two independent large series of prostate cancer patients. Methods We followed up with two cohorts of patients (216 patients diagnosed in 1982 to 1988 and 243 patients diagnosed in 1993 to 1996) diagnosed at one hospital pathology ward in Turin, Italy. DNA was obtained from paraffin-embedded tumor tissues and evaluated for promoter methylation status in glutathione S-transferase (GSTP1), adenomatous polyposis coli (APC), and runt-related transcription factor 3 (RUNX3). Results The two cohorts had different prevalences of methylation in APC (P = .047), GSTP1 (P = .002), and RUNX3 (P &lt; .001). Methylation in APC was associated with an increased risk of prostate cancer–specific mortality (hazard ratio [HR] = 1.42; 95% CI, 0.98 to 2.07 in the 1980s cohort; HR = 1.57; 95% CI, 0.95 to 2.62 in the 1990s cohort; HR = 1.49; 95% CI, 1.11 to 2.00 in the two cohorts combined). In subgroup analyses, the HRs were higher among patients with a Gleason score less than 8 (HR = 1.52; 95% CI, 0.85 to 2.73 in the 1980s cohort; HR = 2.09; 95% CI, 1.02 to 4.28 in the 1990s cohort). Methylation in RUNX3 was associated with prostate cancer mortality only in the 1990s cohort, and methylation in GSTP1 did not predict mortality in either cohort. Conclusion The pattern of hypermethylation may have changed after the introduction of prostate-specific antigen testing in the beginning of the 1990s. Promoter methylation in APC was identified as a marker for prostate cancer progression.
Anti-inflammatory effects of cell-based therapy with tyrosine hydroxylase-positive catecholaminergic cells in experimental arthritis
Authors: Zsuzsa Jenei-Lanzl, Silvia Capellino, Frieder Kees, Martin Fleck, Torsten Lowin, Rainer H Straub
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Studies in rheumatoid arthritis (RA), osteoarthritis (OA) and mice with arthritis demonstrated tyrosine hydroxylase-positive (TH<sup>+</sup>) cells in arthritic synovium and parallel loss of sympathetic nerve fibres. The exact function of TH<sup>+</sup> cells and mode of TH induction are not known. <h3>Methods</h3> Synovial cells of RA/OA were isolated and cultured under normoxic/hypoxic conditions with/without stimulating enzyme cofactors of TH and inhibitors of TH. We studied TH expression and release of cytokines/catecholamines. In vivo function was tested by cell therapy with TH<sup>+</sup> neuronal precursor cells (TH<sup>+</sup> neuronal cells) in DBA/1 mice with collagen type II-induced arthritis (CIA). <h3>Results</h3> Compared with normoxic conditions, hypoxia increased TH protein expression and catecholamine synthesis and decreased release of tumour necrosis factor (TNF) in OA/RA synovial cells. This inhibitory effect on TNF was reversed by TH inhibition with α-methyl-para-tyrosine (αMPT), which was particularly evident under hypoxic conditions. Incubation with specific TH cofactors (tetrahydrobiopterin and Fe<sup>2+</sup>) increased hypoxia-induced inhibition of TNF, which was also reversed by αMPT. To address a possible clinical role of TH<sup>+</sup> cells, murine TH<sup>+</sup> neuronal cells were generated from mesenchymal stem cells. TH<sup>+</sup> neuronal cells exhibited a typical catecholaminergic phenotype. Adoptive transfer of TH<sup>+</sup> neuronal cells markedly reduced CIA in mice, and 6-hydroxydopamine, which depletes TH<sup>+</sup> cells, reversed this effect. <h3>Conclusions</h3> The anti-inflammatory effect of TH<sup>+</sup> neuronal cells on experimental arthritis has been presented for the first time. In RA/OA, TH<sup>+</sup> synovial cells have TH-dependent anti-inflammatory capacities, which are augmented under hypoxia. Using generated TH<sup>+</sup> neuronal cells might open new avenues for cell-based therapy.
Biology of Cardiac Arrhythmias
Authors: Brian P. Delisle, Blake D. Anson, Sridharan Rajamani, Craig T. January
Journal: Circulation Research (2004)

The mechanisms underlying normal and abnormal cardiac rhythms are complex and incompletely understood. Through the study of uncommon inheritable arrhythmia syndromes, including the long QT and Brugada syndromes, new insights are emerging. At the cellular and tissue levels, we now recognize that ion channel current is the sum of biophysical (gating, permeation), biochemical (phosphorylation, etc), and biogenic (biosynthesis, processing, trafficking, and degradation) properties. This review focuses on how heart cells process ion channel proteins and how this protein trafficking may be altered in some cardiac arrhythmia diseases. In this review, we honor Dr Harry A. Fozzard, a modern pioneer in cardiac arrhythmias, cell biology, and molecular electrophysiology. As a scientist and physician, his writings and mentorship have served to foster a generation of investigators who continue to bring this complex field toward greater scientific understanding and impact on humankind.
Effect of terbutaline on mucociliary clearance in asthmatic and healthy subjects after inhalation from a pressurised inhaler and a dry powder inhaler.
Authors: J Mortensen, S Groth, P Lange, F Hermansen
Journal: Thorax (1991)

BACKGROUND: beta Agonists have been shown to increase mucociliary clearance in some studies but not all. Whether the formulation of beta agonists affects mucociliary clearance is not known but may be important as the use of dry powder inhalers increases. METHODS: The effect of different methods of administration of inhaled terbutaline on mucociliary clearance and forced expiratory volume in one second (FEV1) was assessed in 10 patients with asthma and 10 healthy subjects. Terbutaline (1 mg) was administered through a metered dose inhaler with a spacer (Nebuhaler) or a dry powder inhaler (Turbuhaler), or both treatments were given, in a four way double blind, double dummy trial. Mucociliary clearance was measured by bronchoscintigraphy. RESULTS: Clearance of radioactivity from the lobar bronchi increased in the asthmatic patients by a median of 32% after terbutaline was given by metered dose inhaler and 55% after a combined dose of 2 mg from both inhalers (1 mg from each) compared with placebo but by only 9% after 1 mg of terbutaline was given by a dry powder inhaler. In the healthy subjects mucociliary clearance increased by 51% when terbutaline was given by a dry powder inhaler, by 66% when given by a metered dose inhaler, and by 66% when given by both inhalers combined. The effect of terbutaline on FEV1 was the same with each of the inhalers. CONCLUSION: Despite similar changes in FEV1 with the two formulations terbutaline increased mucociliary clearance significantly in asthmatic and healthy subjects when inhaled from a metered dose inhaler whereas when it was inhaled from a dry powder inhaler its effect was significant only in healthy subjects. The reason for the difference in asthmatic subjects is unclear, but may be associated with differences in the deposition of terbutaline.
Langerhans cell histiocytosis in a child presenting as a pustular eruption
Authors: P. Gottlöber, L. Weber, W. Behnisch, G. Bezold, R.U. Peter, M. Kerscher
Journal: British Journal of Dermatology (2000)

Journal Article Langerhans cell histiocytosis in a child presenting as a pustular eruption Get access P. Gottlöber, P. Gottlöber Departments of Dermatology and *Paediatrics, University of Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany Search for other works by this author on: Oxford Academic Google Scholar L. Weber, L. Weber Departments of Dermatology and *Paediatrics, University of Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany Search for other works by this author on: Oxford Academic Google Scholar W. Behnisch, W. Behnisch Departments of Dermatology and *Paediatrics, University of Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany Search for other works by this author on: Oxford Academic Google Scholar G. Bezold, G. Bezold Departments of Dermatology and *Paediatrics, University of Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany Search for other works by this author on: Oxford Academic Google Scholar R.U. Peter, R.U. Peter Departments of Dermatology and *Paediatrics, University of Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany Search for other works by this author on: Oxford Academic Google Scholar M. Kerscher M. Kerscher Departments of Dermatology and *Paediatrics, University of Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 6, 1 June 2000, Pages 1234–1235, https://doi.org/10.1046/j.1365-2133.2000.03556.x Published: 01 June 2000
Incorporation of Bevacizumab in the Primary Treatment of Ovarian Cancer
Authors: Robert A. Burger, Mark F. Brady, Michael A. Bookman, Gini F. Fleming, Bradley J. Monk, Helen Huang, Robert S. Mannel, Howard D. Homesley, Jeffrey Fowler, Benjamin E. Greer, Matthew Boente, Michael J. Birrer, Sharon X. Liang
Journal: New England Journal of Medicine (2011)

Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a humanized anti–vascular endothelial growth factor monoclonal antibody, has shown single-agent activity in women with recurrent tumors. Thus, we aimed to evaluate the addition of bevacizumab to standard front-line therapy.
Neuronal Intermediate Filaments
Authors: M K Lee, D W Cleveland
Journal: Annual Review of Neuroscience (1996)

Neurofilaments (NFs) are the most abundant structural components in large-diameter myelinated axons. Assembled as obligate heteropolymers requiring NF-L and substoichiometric amounts of NF-M and/or NF-H, NF investment into axons is essential for establishment of axonal caliber, itself a key determinant of conduction velocity. Use of transgenic mice to increase axonal accumulation of NFs or to express mutant NFs subunits has proven that aberrant organization or assembly of NFs is sufficient to cause disease arising from selective dysfunction and degeneration of motor neurons. Because aberrant accumulation of NFs is a common pathology in a series of motor neuron diseases-including amyotrophic lateral sclerosis-NF misaccumulation, and the resultant disruption in axonal transport, is probably a key intermediate in the pathogenesis of these diseases.
Review of Radiofrequency Ablation for Renal Cell Carcinoma
Authors: Andrew Hines-Peralta, S. Nahum Goldberg
Journal: Clinical Cancer Research (2004)

This review will discuss how minimally invasive, image-guided radiofrequency (RF) tumor ablation [i.e., coagulating tumor using short-duration heating (<15 minutes) by directly applying temperatures >50 degrees C via needle electrodes] is being incorporated as a clinical tool for the treatment of renal cell carcinoma. RF ablation has been used to treat focal liver tumors. Potential benefits of this thermal therapy include reduced morbidity and mortality compared with standard surgical resection and the ability to treat nonsurgical patients. More recently, this technique has been introduced to treat focal renal tumors, particularly incidental lesions smaller than 3 cm in elderly patients and those with comorbid conditions. Other uses have included treatment in patients with von Hippel-Lindau syndrome and other diseases that predispose patients to multiple renal carcinomas, where renal parenchymal preservation is desired. Techniques, complications, and results will be discussed. Additionally, strategies that we are currently studying to improve RF outcomes and enable the potential treatment of larger tumors will be addressed. Most notably, recent data on increased coagulation achieved by combining RF ablation with antivascular/antiangiogenic therapies, such as arsenic trioxide, that reduce blood flow and promote heat retention are provided.
Automatic Border Detection Identifies Subclinical Anthracycline Cardiotoxicity in Children With Malignancy
Authors: Ikuo Hashimoto, Fukiko Ichida, Masayoshi Miura, Takashi Okabe, Hirokazu Kanegane, Kei-ichiro Uese, Yuji Hamamichi, Takuro Misaki, Shoichi Koizumi, Toshio Miyawaki
Journal: Circulation (1999)

Background —Anthracycline drugs for cancer therapy often cause functional myocardial impairment even in relatively low doses. We investigated the left ventricular function in asymptomatic anthracycline-treated children by automatic border detection (ABD) to assess its clinical usefulness for unmasking latent anthracycline-induced myocardial damage. Methods and Results —Thirty-four children (0.7 to 17.6 years old) during or after anthracycline chemotherapy (26 to 1100 mg/m 2 ) for malignancy (Chemo group) were studied, and 40 children (2.8 to 15.6 years old) without cardiac involvement served as normal control subjects (Control group). All patients underwent complete echocardiographic examination, including M-mode, Doppler, and ABD. Conventional echocardiography disclosed no difference between groups with regard to ejection fraction and the ratio of early to late transmitral flow velocity. In marked contrast, an investigation using ABD revealed that the Chemo group appeared to have some anthracycline-induced myocardial damage. In the apical 4-chamber view, peak filling rate in the Chemo group [2.3±0.4 end-diastolic area (EDA)/s] was significantly lower than that in the Control group (3.1±0.5 EDA/s) ( P &lt;0.0001), and time to peak filling rate in the Chemo group (106±31 ms) was clearly prolonged compared with that in the Control group (74±22 ms) ( P &lt;0.0001). Conclusions —Echocardiographic ABD may be a sensitive and useful noninvasive approach for evaluating subclinical anthracycline cardiotoxicity.
Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial
Authors: Mark R. Gilbert, Meihua Wang, Kenneth D. Aldape, Roger Stupp, Monika E. Hegi, Kurt A. Jaeckle, Terri S. Armstrong, Jeffrey S. Wefel, Minhee Won, Deborah T. Blumenthal, Anita Mahajan, Christopher J. Schultz, Sara Erridge, Brigitta Baumert, Kristen I. Hopkins, Tzahala Tzuk-Shina, Paul D. Brown, Arnab Chakravarti, Walter J. Curran, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2013)

Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P &lt; .001), PFS (8.7 v 5.7 months; HR, 1.63; P &lt; .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P &lt; .001), mostly lymphopenia and fatigue. Conclusion This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.