tbuckley/cabot-search huggingface dataset:
Application of Oligonucleotide Microarrays to Assess the Biological Effects of Neoadjuvant Imatinib Mesylate Treatment for Localized Prostate Cancer
Authors: Phillip G. Febbo, Aaron Thorner, Mark A. Rubin, Massimo Loda, Philip W. Kantoff, William K. Oh, Todd Golub, Daniel George
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Neoadjuvant administration of antineoplastic therapies is used to rapidly assess the clinical and biological activity of novel systemic treatments. To assess the feasibility of using microarrays to assess molecular end points following targeted treatment in a heterogeneous tumor, we measured global gene expression in localized prostate cancer before and following neoadjuvant treatment with imatinib mesylate. Patients and Methods: Patients with intermediate-risk to high-risk prostate cancer were treated for 6 weeks with 200 to 300 mg of oral imatinib mesylate. Frozen tissue was obtained from pretreatment ultrasound-guided biopsies and posttreatment radical prostatectomy specimens. Oligonucleotide microarray analysis following laser capture microdissection (LCM) and RNA amplification was used to assess gene expression changes associated with imatinib mesylate therapy. Immunohistochemistry was used to measure protein expression of MKP1 and CD31 and to assess cellular apoptosis. Results: Of the 11 patients enrolled, high-quality microarray data was obtained from both biopsies (n = 7) and radical prostatectomy specimens (n = 9). Technically introduced intrasample gene expression variability was found to be significantly less than intertumor biological variability. Large gene expression differences were observed, and the gene with the most consistent differential expression (MKP1) was validated by immunohistochemistry. Gene set enrichment analysis suggests that imatinib mesylate therapy results in apoptosis of microvascular endothelial cells, an observation anecdotally supported by immunohistochemistry. Conclusions: This study shows that high-quality microarray data can be generated using LCM and RNA amplification to discover potential mechanisms of targeted therapy in cancer.
Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG)
Authors: R. Forstpointner, M. Unterhalt, M. Dreyling, H.-P. Bock, R. Repp, H. Wandt, C. Pott, J. F. Seymour, B. Metzner, A. Hanel, T. Lehmann, F. Hartmann, H. Einsele, W. Hiddemann
Journal: Blood (2006)
For Bats and Dolphins, Hearing Gene Prestin Adapted for Echolocation
Authors: J. Caspermeyer
Journal: Molecular Biology and Evolution (2014)

A little over a decade ago, prestin was found to be a key gene responsible for hearing in mammals. Prestin makes a protein found in the hair cells of the inner ear that contracts and expands rapidly to transmit signals that help the cochlea, like an antique phonograph horn, amplify sound waves to make hearing more sensitivity. Now, Liu et al. (2014) have shown that prestin has also independently evolved to play a critical role in the ultrasonic hearing range of animal sonar, or echolocation, to help dolphins navigate through murky waters or bats find food in the dark. Although both toothed whales and echolocating bats can emit high-frequency echolocation calls, which show a substantial diversity in terms of their shape, duration, and amplitude, they receive and analyze the echoes returned from objects by their high-frequency hearing. The research team finely dissected the function of the prestin protein from two sonar guided bats and the bottlenose dolphin compared with nonsonar mammals. Evolutionary analyses of the prestin protein sequences showed that a single amino acid change in prestin, from a threonine (Thr or T) in all sonar mammals to an asparagine (Asn or N) in all nonsonar mammals, was subject to parallel evolution, suggesting that it may play a critical role for mammalian echolocation. Further experiments supported this assumption and identified four key amino acid differences among the sonar mammals, which may contribute to their unique features. Taken along side evolutionary analyses, these findings offered the first functional evidence supporting the notion that the hearing gene of prestin evolved to play a key role in the sonar system of mammals.
The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases
Authors: T ACKER, J FANDREY, H ACKER
Journal: Cardiovascular Research (2006)

Current concepts of cellular oxygen-sensing include an isoform of the neutrophil NADPH oxidase, different electron carrier units of the mitochondrial electron transport chain (ETC), heme oxygenase-2 (HO-2), and a subfamily of 2-oxoglutarate dependent dioxygenases termed HIF (hypoxia inducible factor) prolyl hydroxylases (PHDs) and HIF asparagyl hydroxylase FIH-1 (factor-inhibiting HIF). Different oxygen sensitivities, cell-specific distribution and subcellular localization of specific oxygen-sensing cascades involving reactive oxygen species (ROS) as second messengers may help to tailor various adaptive responses according to differences in tissue oxygen availability. Herein, we propose an integrated model for these various oxygen-sensing mechanisms that very efficiently regulate HIF-α activity and plasma membrane potassium-channel (PMPC) conductivity.
Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer
Authors: Mario F Fraga, Esteban Ballestar, Ana Villar-Garea, Manuel Boix-Chornet, Jesus Espada, Gunnar Schotta, Tiziana Bonaldi, Claire Haydon, Santiago Ropero, Kevin Petrie, N Gopalakrishna Iyer, Alberto Pérez-Rosado, Enrique Calvo, Juan A Lopez, Amparo Cano, Maria J Calasanz, Dolors Colomer, Miguel Ángel Piris, Natalie Ahn, Axel Imhof, Carlos Caldas, Thomas Jenuwein, Manel Esteller
Journal: Nature Genetics (2005)
Human skin keratins are the major proteins in exhaled breath condensate
Authors: H. J. Hoffmann, L. M. Tabaksblat, J. J. Enghild, R. Dahl
Journal: European Respiratory Journal (2008)

Exhaled breath condensate (EBC) may be an attractive noninvasive alternative to bronchoscopy, bronchoalveolar lavage and induced sputum for diagnosis and monitoring of pulmonary disease. The aim of the present study was to identify proteins in EBC by mass spectrometry. Protein in EBC was characterised by gel electrophoresis of freeze-dried EBC samples, and individual proteins were identified by mass spectrometry. Saliva, ambient air condensate (AAC) and EBC were collected from normal human volunteers with or without a filter to remove particles from air. In some instances, EBC was condensed by breathing compressed air. Samples were freeze-dried and analysed by SDS-PAGE and peptide mass fingerprinting. Three major bands were seen in EBC and AAC, and were identified by peptide mass fingerprinting. The probability-based Mowse score was significant only for cytokeratin (CK) 1, CK2 and CK10. In the catalogue of human cytokeratins, CK1, CK2, CK9 and CK10 are described in keratinising epidermis. Saliva did not contain keratin and compressed air EBC contained markedly less keratin. Filtration of inspired air did not remove contaminating keratin. In conclusion, skin keratin in exhaled breath condensate derives from ambient air and not from the respiratory tract.
Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron
Authors: R. Gralla, M. Lichinitser, S. Van der Vegt, H. Sleeboom, J. Mezger, C. Peschel, G. Tonini, R. Labianca, A. Macciocchi, M. Aapro
Journal: Annals of Oncology (2003)
PrPSc accumulation in myocytes from sheep incubating natural scrapie
Authors: O Andréoletti, S Simon, C Lacroux, N Morel, G Tabouret, A Chabert, S Lugan, F Corbière, P Ferré, G. Foucras, H. Laude, F. Eychenne, J Grassi, F Schelcher
Journal: Nature Medicine (2004)
K562/GM-CSF Immunotherapy Reduces Tumor Burden in Chronic Myeloid Leukemia Patients with Residual Disease on Imatinib Mesylate
Authors: B. Douglas Smith, Yvette L. Kasamon, Jeanne Kowalski, Christopher Gocke, Kathleen Murphy, Carole B. Miller, Elizabeth Garrett-Mayer, Hua-Ling Tsai, Lu Qin, Christina Chia, Barbara Biedrzycki, Thomas C. Harding, Guang Haun Tu, Richard Jones, Kristen Hege, Hyam I. Levitsky
Journal: Clinical Cancer Research (2010)

Chronic myeloid leukemia (CML) can be responsive to T-cell-mediated immunity. K562/granulocyte macrophage-colony stimulating factor (GM-CSF) is a GM-CSF producing vaccine derived from a CML cell line that expresses several CML-associated antigens. A pilot study was developed to determine if K562/GM-CSF immunotherapy could improve clinical responses to imatinib mesylate (IM) in patients with chronic myeloid leukemia.Patients with chronic phase CML who achieved at least a major cytogeneic response but remained with persistent, measurable disease despite one or more years on imatinib mesylate were eligible. Each was given a series of four vaccines administered in three-week intervals, with or without topical imiquimod, while remaining on a stable dose of imatinib mesylate. CML disease burden was measured serially before and after vaccination.Nineteen patients were vaccinated, with a median duration of previous imatinib mesylate therapy of 37 (13-53) months. Mean PCR measurements of BCR-ABL for the group declined significantly following the vaccines (P = 0.03). Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable.K562/GM-CSF vaccine appears to improve molecular responses in patients on imatinib mesylate, including achieving complete molecular remissions, despite long durations of previous imatinib mesylate therapy.
Inflammation as a Mediator of the Link between Mild to Moderate Renal Insufficiency and Endothelial Dysfunction in Essential Hypertension
Authors: Carmine Zoccali, Raffaele Maio, Giovanni Tripepi, Francesca Mallamaci, Francesco Perticone
Journal: Journal of the American Society of Nephrology (2006)

The relationship among inflammation (plasma high-sensitivity C-reactive protein [CRP]), endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm), and renal function (serum creatinine and GFR [Modification of Diet in Renal Disease formula]) was investigated in 264 never-treated individuals with uncomplicated essential hypertension and serum creatinine within the normal range. Multiple regression models of renal function (creatinine) were constructed in sequence including Framingham risk factors as well the hemodynamic response to ACh and plasma CRP. The inclusion of endothelial function into a model based on Framingham risk factors added highly significant (P < 0.001) power to this model (+5%). Of note, in an alternative model that included CRP (instead of endothelial function), the creatinine variance explained by this factor was two times higher (+10%) than that associated with endothelial function in the first model. In the full model that included both endothelial function and CRP, CRP maintained a much stronger independent link with the outcome measure than endothelial function. In individuals with untreated, uncomplicated essential hypertension, multivariate modeling indicated that inflammation is a crucial mechanism mediating the endothelial-renal function link. The proatherogenic potential of inflammation associated with subtle impairment in renal function may contribute to the cardiovascular risk of essential hypertension.
S100A4 and Bone Morphogenetic Protein-2 Codependently Induce Vascular Smooth Muscle Cell Migration via Phospho–Extracellular Signal-Regulated Kinase and Chloride Intracellular Channel 4
Authors: Edda Spiekerkoetter, Christophe Guignabert, Vinicio de Jesus Perez, Tero-Pekka Alastalo, Janine M. Powers, Lingli Wang, Allan Lawrie, Noona Ambartsumian, Ann-Marie Schmidt, Mark Berryman, Richard H. Ashley, Marlene Rabinovitch
Journal: Circulation Research (2009)

S100A4/Mts1 is implicated in motility of human pulmonary artery smooth muscle cells (hPASMCs), through an interaction with the RAGE (receptor for advanced glycation end products).We hypothesized that S100A4/Mts1-mediated hPASMC motility might be enhanced by loss of function of bone morphogenetic protein (BMP) receptor (BMPR)II, observed in pulmonary arterial hypertension.Both S100A4/Mts1 (500 ng/mL) and BMP-2 (10 ng/mL) induce migration of hPASMCs in a novel codependent manner, in that the response to either ligand is lost with anti-RAGE or BMPRII short interference (si)RNA. Phosphorylation of extracellular signal-regulated kinase is induced by both ligands and is required for motility by inducing matrix metalloproteinase 2 activity, but phospho-extracellular signal-regulated kinase 1/2 is blocked by anti-RAGE and not by BMPRII short interference RNA. In contrast, BMPRII short interference RNA, but not anti-RAGE, reduces expression of intracellular chloride channel (CLIC)4, a scaffolding molecule necessary for motility in response to S100A4/Mts1 or BMP-2. Reduced CLIC4 expression does not interfere with S100A4/Mts1 internalization or its interaction with myosin heavy chain IIA, but does alter alignment of myosin heavy chain IIA and actin filaments creating the appearance of vacuoles. This abnormality is associated with reduced peripheral distribution and/or delayed activation of RhoA and Rac1, small GTPases required for retraction and extension of lamellipodia in motile cells.Our studies demonstrate how a single ligand (BMP-2 or S100A4/Mts1) can recruit multiple cell surface receptors to relay signals that coordinate events culminating in a functional response, ie, cell motility. We speculate that this carefully controlled process limits signals from multiple ligands, but could be subverted in disease.
Bisphosphonates act on rat bone resorption through the mediation of osteoblasts.
Authors: M Sahni, H L Guenther, H Fleisch, P Collin, T J Martin
Journal: Journal of Clinical Investigation (1993)

Bisphosphonates are generally considered to act on bone resorption by binding to bone mineral and subsequently inhibiting the activity of the osteoclasts which ingest them. This has been supported by the fact that bisphosphonates adsorbed on mineralized tissue inhibit the resorbing activity of isolated osteoclasts in vitro. However, the effectiveness of different bisphosphonates determined in this system does not reflect their relative potencies in vivo. Employing the well-described isolated osteoclast resorption pit assay, with ivory as the resorption substrate, we show here that this lack of correlation prevails only when the bisphosphonates are added to the mineral before addition of osteoclasts, but not when the cells are treated for a short time (5 min) before allowing them to adhere onto ivory. By using this approach with five different bisphosphonates, a stringent correlation of relative potencies was obtained with those found, both in the rat and in the human, in vivo. Furthermore, by using an osteoblastic cell line (CRP 10/30) which is a powerful promoter of osteoclastic resorption in vitro, we obtained evidence that the inhibitory effect of bisphosphonates was the result of an action on osteoblasts rather than on osteoclasts. Thus, in experiments in which the osteoblastic cells were pretreated for 5 min with bisphosphonates and then cocultured with osteoclasts, inhibition of osteoclastic resorbing activity was obtained. Moreover, it was found that this treatment resulted in a decrease of the stimulatory effect found in CRP 10/30-conditioned medium. In conclusion the present study shows that part of the osteoclast inhibiting action of the bisphosphonates is mediated through an action on osteoblasts.
The Psychological Impact of Terrorism: An Epidemiologic Study of Posttraumatic Stress Disorder and Associated Factors in Victims of the 1995–1996 Bombings in France
Authors: Pierre Verger, William Dab, Donna L Lamping, Jean-Yves Loze, Céline Deschaseaux-Voinet, Lucien Abenhaim, Frédéric Rouillon
Journal: American Journal of Psychiatry (2004)

A wave of bombings struck France in 1995 and 1996, killing 12 people and injuring more than 200. The authors conducted follow-up evaluations with the victims in 1998 to determine the prevalence of and factors associated with posttraumatic stress disorder (PTSD).Victims directly exposed to the bombings (N=228) were recruited into a retrospective, cross-sectional study. Computer-assisted telephone interviews were conducted to evaluate PTSD, per DSM-IV criteria, and to assess health status before the attack, initial injury severity and perceived threat at the time of attack, and psychological symptoms, cosmetic impairment, hearing problems, and health service use at the time of the follow-up evaluation. Factors associated with PTSD were investigated with univariate logistic regression followed by multiple logistic regression analyses.A total of 196 respondents (86%) participated in the study. Of these, 19% had severe initial physical injuries (hospitalization exceeding 1 week). Problems reported at the follow-up evaluation included attack-related hearing problems (51%), cosmetic impairment (33%), and PTSD (31%) (95% confidence interval=24.5%-37.5%). Results of logistic regression analyses indicated that the risk of PTSD was significantly higher among women (odds ratio=2.54), participants age 35-54 (odds ratio=2.83), and those who had severe initial injuries (odds ratio=2.79) or cosmetic impairment (odds ratio=2.74) or who perceived substantial threat during the attack (odds ratio=3.99).The high prevalence of PTSD 2.6 years on average after a terrorist attack emphasizes the need for improved health services to address the intermediate and long-term consequences of terrorism.
Clozapine‐induced symmetrical drug‐related intertriginous and flexural exanthema: first reported cases
Authors: A. Rao, N. Francis, N. Morar
Journal: British Journal of Dermatology (2011)

Journal Article Clozapine‐induced symmetrical drug‐related intertriginous and flexural exanthema: first reported cases Get access A. Rao, A. Rao Department of Dermatology, Chelsea and Westminster Hospital, Fulham Road, London SW10 9NH, U.K Search for other works by this author on: Oxford Academic Google Scholar N. Francis, N. Francis Department of Histopathology, Imperial College NHS Trust, London, U.K. E‐mail: archana22vs@yahoo.com Search for other works by this author on: Oxford Academic Google Scholar N. Morar N. Morar Department of Dermatology, Chelsea and Westminster Hospital, Fulham Road, London SW10 9NH, U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 166, Issue 5, 1 May 2012, Pages 1142–1143, https://doi.org/10.1111/j.1365-2133.2011.10758.x Published: 01 May 2012
Neurogenic coronary vasoconstrictor effects of digitalis during acute global ischemia in dogs.
Authors: K B Sagar, E C Hanson, W J Powell
Journal: Journal of Clinical Investigation (1977)

The rapid i.v. administration of digitalis has recently been shown to cause a substantial increase in coronary vascular resistance in the normal heart. This neurogenically mediated decrease in coronary blood flow would be potentially detrimental if it occurred during ischemia. The present study evaluates the effects of i.v. acetylstrophanthidin and digoxin on coronary vascular resistance during acute global ischemia in 29 dogs anesthetized with chloralose and urethane. Under these conditions, 0.5 mg of i.v. acetylstrophanthidin in 15 dogs resulted in erratic increases in coronary vascular resistance. The peak rise was 12+/-5% above control (P less than 0.01). In 7 of the 15 dogs, the initial erratic rise in coronary vascular resistance culminated in a steep rise associated with acute elevation in left ventricular end-diastolic pressure, which in four dogs terminated in ventricular fibrillation. During the nonischemic control periods, the peak rise in coronary vascular resistance with acetylstrophanthidin was 16+/-1% above control (P less than 0.01). In five dogs, prior alpha adrenergic receptor blockade with phenoxybenzamine prevented the rise in coronary vascular resistance with acetylstrophanthidin during ischemia. Similar erratic increases in coronary vascular resistance were observed with i.v. digoxin (1 mg) during ischemia in three dogs. In two of these dogs, there was a progressive rise in coronary vascular resistance associated with elevation of left ventricular end-diastolic pressure and ventricular fibrillation. The increase in coronary vascular resistance with digoxin during ischemia was abolished with phenoxybenzamine in two additional dogs. Thus, i.v. digitalis in the ischemic heart results in potentially detrimental increases in coronary vascular resistance mediated through alpha adrenergic receptor stimulation.
Treatment of Patients with the Hypereosinophilic Syndrome with Mepolizumab
Authors: Marc E. Rothenberg, Amy D. Klion, Florence E. Roufosse, Jean Emmanuel Kahn, Peter F. Weller, Hans-Uwe Simon, Lawrence B. Schwartz, Lanny J. Rosenwasser, Johannes Ring, Elaine F. Griffin, Ann E. Haig, Paul I.H. Frewer, Jacqueline M. Parkin, Gerald J. Gleich
Journal: New England Journal of Medicine (2008)

The hypereosinophilic syndrome is a group of diseases characterized by persistent blood eosinophilia, defined as more than 1500 cells per microliter with end-organ involvement and no recognized secondary cause. Although most patients have a response to corticosteroids, side effects are common and can lead to considerable morbidity.We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an anti-interleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome. Patients were negative for the FIP1L1-PDGFRA fusion gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a stable clinical status and a blood eosinophil count of less than 1000 per microliter. Patients received either intravenous mepolizumab or placebo while the prednisone dose was tapered. The primary end point was the reduction of the prednisone dose to 10 mg or less per day for 8 or more consecutive weeks.The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001) with no increase in clinical activity of the hypereosinophilic syndrome. A blood eosinophil count of less than 600 per microliter for 8 or more consecutive weeks was achieved in 95% of patients receiving mepolizumab, as compared with 45% of patients receiving placebo (hazard ratio, 3.53; 95% CI, 1.94 to 6.45; P<0.001). Serious adverse events occurred in seven patients receiving mepolizumab (14 events, including one death; mean [+/-SD] duration of exposure, 6.7+/-1.9 months) and in five patients receiving placebo (7 events; mean duration of exposure, 4.3+/-2.6 months).Our study shows that treatment with mepolizumab, an agent designed to target eosinophils, can result in corticosteroid-sparing for patients negative for FIP1L1-PDGFRA who have the hypereosinophilic syndrome. (ClinicalTrials.gov number, NCT00086658 [ClinicalTrials.gov].).