tbuckley/cabot-search huggingface dataset:
Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain.
Authors: G D Baura, D M Foster, D Porte, S E Kahn, R N Bergman, C Cobelli, M W Schwartz
Journal: Journal of Clinical Investigation (1993)

By acting in the central nervous system, circulating insulin may regulate food intake and body weight. We have previously shown that the kinetics of insulin uptake from plasma into cerebrospinal fluid (CSF) can best be explained by passage through an intermediate compartment. To determine if transport kinetics into this compartment were consistent with an insulin receptor-mediated transport process, we subjected overnight fasted, anesthetized dogs to euglycemic intravenous insulin infusions for 90 min over a wide range of plasma insulin levels (69-5,064 microU/ml) (n = 10). Plasma and CSF samples were collected over 8 h for determination of immunoreactive insulin levels, and the kinetics of insulin uptake from plasma into CSF were analyzed using a compartmental model with three components (plasma-->intermediate compartment-->CSF). By sampling frequently during rapid changes of plasma and CSF insulin levels, we were able to precisely estimate three parameters (average standard deviation 14%) characterizing the uptake of insulin from plasma, through the intermediate compartment and into CSF (k1k2); insulin entry into CSF and insulin clearance from the intermediate compartment (k2 + k3); and insulin clearance from CSF (k4). At physiologic plasma insulin levels (80 +/- 7.4 microU/ml), k1k2 was determined to be 10.7 x 10(-6) +/- 1.3 x 10(-6) min-2. With increasing plasma levels, however, k1k2 decreased progressively, being reduced sevenfold at supraphysiologic levels (5,064 microU/ml). The apparent KM of this saturation curve was 742 microU/ml (approximately 5 nM). In contrast, the rate constants for insulin removal from the intermediate compartment and from CSF did not vary with plasma insulin (k2 + k3 = 0.011 +/- 0.0019 min-1 and k4 = 0.046 +/- 0.021 min-1). We conclude that delivery of plasma insulin into the central nervous system is saturable, and is likely facilitated by an insulin-receptor mediated transport process.
Up-Regulation of EphB4 in Mesothelioma and Its Biological Significance
Authors: Guangbin Xia, S. Ram Kumar, Rizwan Masood, Michael Koss, Claire Templeman, David Quinn, Sutao Zhu, Ramachandra Reddy, Valery Krasnoperov, Parkash S. Gill
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Mesothelioma is a rare malignancy that is incurable and carries a short survival despite surgery, radiation, or chemotherapy. This study was designed to identify novel targets for diagnostic, prognostic, and therapeutic approaches. Experimental Design: The expression and functional significance of the receptor tyrosine kinase EphB4 was studied in vitro and in a murine model of mesothelioma. Results: EphB4 was highly expressed in mesothelioma cell lines and primary tumor tissues but not in normal mesothelium. Knockdown of EphB4 using small interfering RNA and antisense oligodeoxynucleotide showed reduction in cell survival, migration, and invasion. EphB4 knockdown initiated a caspase-8-mediated apoptosis and down-regulation of the antiapoptotic protein bcl-xl. EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription. In addition, murine tumor xenograft studies using EphB4 oligodeoxynucleotides showed a marked reduction in tumor growth accompanied by a specific decline in EphB4 protein levels, reduced cell division, apoptosis in tumor tissue, and decreased microvascular density. Conclusions: EphB4 is expressed in mesothelioma, provides a survival advantage to tumor cells, and is therefore a potential novel therapeutic target.
Suppression of Human Glioma Xenografts with Second-Generation IL13R-Specific Chimeric Antigen Receptor–Modified T Cells
Authors: Seogkyoung Kong, Sadhak Sengupta, Betty Tyler, Anthony J. Bais, Qiangzhong Ma, Saryn Doucette, Jinyuan Zhou, Ayguen Sahin, Bob S. Carter, Henry Brem, Richard P. Junghans, Prakash Sampath
Journal: Clinical Cancer Research (2012)

Glioblastoma multiforme (GBM) remains highly incurable, with frequent recurrences after standard therapies of maximal surgical resection, radiation, and chemotherapy. To address the need for new treatments, we have undertaken a chimeric antigen receptor (CAR) "designer T cell" (dTc) immunotherapeutic strategy by exploiting interleukin (IL)13 receptor α-2 (IL13Rα2) as a GBM-selective target.
Identification of seven new prostate cancer susceptibility loci through a genome-wide association study
Authors: Rosalind A Eeles, Zsofia Kote-Jarai, Ali Amin Al Olama, Graham G Giles, Michelle Guy, Gianluca Severi, Kenneth Muir, John L Hopper, Brian E Henderson, Christopher A Haiman, Johanna Schleutker, Freddie C Hamdy, David E Neal, Jenny L Donovan, Janet L Stanford, Elaine A Ostrander, Sue A Ingles, Esther M John, Stephen N Thibodeau, Daniel Schaid, Jong Y Park, Amanda Spurdle, Judith Clements, Joanne L Dickinson, Christiane Maier, Walther Vogel, Thilo Dörk, Timothy R Rebbeck, Kathleen A Cooney, Lisa Cannon-Albright, Pierre O Chappuis, Pierre Hutter, Maurice Zeegers, Radka Kaneva, Hong-Wei Zhang, Yong-Jie Lu, William D Foulkes, Dallas R English, Daniel A Leongamornlert, Malgorzata Tymrakiewicz, Jonathan Morrison, Audrey T Ardern-Jones, Amanda L Hall, Lynne T O'Brien, Rosemary A Wilkinson, Edward J Saunders, Elizabeth C Page, Emma J Sawyer, Stephen M Edwards, David P Dearnaley, Alan Horwich, Robert A Huddart, Vincent S Khoo, Christopher C Parker, Nicholas Van As, Christopher J Woodhouse, Alan Thompson, Tim Christmas, Chris Ogden, Colin S Cooper, Melissa C Southey, Artitaya Lophatananon, Jo-Fen Liu, Laurence N Kolonel, Loic Le Marchand, Tiina Wahlfors, Teuvo L Tammela, Anssi Auvinen, Sarah J Lewis, Angela Cox, Liesel M FitzGerald, Joseph S Koopmeiners, Danielle M Karyadi, Erika M Kwon, Mariana C Stern, Roman Corral, Amit D Joshi, Ahva Shahabi, Shannon K McDonnell, Thomas A Sellers, Julio Pow-Sang, Suzanne Chambers, Joanne Aitken, R A Gardiner, Jyotsna Batra, Mary Anne Kedda, Felicity Lose, Andrea Polanowski, Briony Patterson, Jürgen Serth, Andreas Meyer, Manuel Luedeke, Klara Stefflova, Anna M Ray, Ethan M Lange, Jim Farnham, Humera Khan, Chavdar Slavov, Atanaska Mitkova, Guangwen Cao, Douglas F Easton
Journal: Nature Genetics (2009)
Prognostic Value of Prostate Secretory Protein of 94 Amino Acids and its Binding Protein after Radical Prostatectomy
Authors: Jonathan R. Reeves, Hélène Dulude, Chandra Panchal, Luc Daigneault, Dharam M. Ramnani
Journal: Clinical Cancer Research (2006)

To establish the prognostic value of total and free prostate secretory protein of 94 amino acids (PSP94) and the PSP94-binding protein (PSPBP) following radical prostatectomy.One hundred and eighty-five serum samples were obtained from patients with localized prostate cancer prior to treatment with radical prostatectomy at Virginia Urology (Richmond, VA). Patients were followed up for a median of 48 months (range, 1-66 months) and biochemical relapse was indicated as total prostate-specific antigen (tPSA) levels increasing to > 0.1 ng/mL. The available clinical variables included initial tPSA, Gleason score, surgical margin status, and clinical stage. Total PSP94, free PSP94, and the PSPBP were quantified in the pretreatment serum using new ELISA tests (Medicorp, Inc. and Ambrilia Biopharma, Inc., Montreal, Quebec, Canada). Univariate and multivariate Cox proportional hazards models were used to assess the ability of PSP94 and PSPBP to predict time to recurrence.Thirty-one patients had biochemical recurrence. Gleason score, margin status, clinical stage, and initial tPSA significantly predicted recurrence risk (all P < 0.001). In addition, PSPBP was negatively associated with recurrence risk (P = 0.005), and, consistent with previous studies, the bound/free PSP94 ratio was positively associated with recurrence risk (P = 0.008). Multivariate analysis showed that PSPBP, as well as the bound/free PSP94 ratio, were independent predictors of biochemical relapse risk adjusting for tPSA, Gleason score, and margin status.Bound/free PSP94 and PSPBP are novel and independent prognostic markers following radical prostatectomy for prostate cancer.
Role of Endogenous Fas (CD95/Apo-1) Ligand in Balloon-Induced Apoptosis, Inflammation, and Neointima Formation
Authors: Christian M. Matter, Christos E. Chadjichristos, Patricia Meier, Tobias von Lukowicz, Christine Lohmann, Pia K. Schuler, Dongming Zhang, Bernhard Odermatt, Eugen Hofmann, Thomas Brunner, Brenda R. Kwak, Thomas F. Lüscher
Journal: Circulation (2006)

Fas (CD95/Apo-1) ligand (FasL)-induced apoptosis in Fas-bearing cells is critically involved in modulating immune reactions and tissue repair. Apoptosis has also been described after mechanical vascular injury such as percutaneous coronary intervention. However, the relevance of cell death in this context of vascular repair remains unknown.To determine whether FasL-induced apoptosis is causally related to neointimal lesion formation, we subjected FasL-deficient (generalized lymphoproliferative disorder [gld], C57BL/6J) and corresponding wild-type (WT) mice to carotid balloon distension injury, which induces marked endothelial denudation and medial cell death. FasL expression in WT mice was induced in injured vessels compared with untreated arteries (P<0.05; n=5). Conversely, absence of functional FasL in gld mice decreased medial and intimal apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling [TUNEL] index) at 1 hour and 7 days after balloon injury (P<0.05; n=6). In addition, peritoneal macrophages isolated from gld mice showed no apoptosis and enhanced migration (P<0.05; n=4). In parallel, we observed increased balloon-induced macrophage infiltrations (anti-CD68) in injured arteries of FasL-deficient animals (P<0.05; n=6). Together with enhanced proliferation (bromodeoxyuridine index; P<0.05), these events resulted in a further increase in medial and neointimal cells (P<0.01; n=8) with thickened neointima in gld mice (intima/media ratio, x3.8 of WT; P<0.01).Our data identify proapoptotic and antiinflammatory effects of endogenous FasL as important factors in the process of neointimal lesion formation after balloon injury. Moreover, they suggest that activation of FasL may decrease neointimal thickening after percutaneous coronary intervention.
Oxidative stress induces the generation of tissue factor bearing microparticles by airway epithelial cells in vitro
Authors: Concettina Noce, Tommaso Neri, Federica Novelli, Cinzia Cordazzo, Silvia Petrini, Yuri Carmazzi, Laura Tavanti, Pierluigi Paggiaro, Alessandro Celi
Journal: European Respiratory Journal (2011)

Background: Activation of the coagulation cascade is involved in the pathogenesis of pulmonary fibrosis. Although, according to the traditional view, coagulation factors present in the lung are derived from the general circulation, recent data indicate that factor (F) X is locally increased in fibrotic lung tissue in its active form (FXa), where it is capable of signaling a fibrotic response via proteinase activated receptor1 (PAR1) (Scotton, 2009). While oxidative stress has been shown to induce FX synthesis by A549 alveolar cells, the mechanisms of FX activation are not clear. Microparticles (MP) are procoagulant and proinflammatory vesicles shed by eukariotic cells. It is not known whether alveolar cells generate microparticles capable of FX activation.

Aim: To investigate whether oxidative stress can also induce the generation of procoagulant microparticles by A549 cells.

Methods: The generation of MP by A549 was investigated through a prothrombinase assay, that measures the concentration of negative charges on the cell membrane, expressed as phosphatidylserine (PS) concentration, and a one-stage clotting assay, that investigates the procoagulant activity mediated by tissue factor (TF).

Results: Incubation of A549 cells with H2O2 (100 μM) for 20 hours caused a significant increase in PS-containing MP (731±173 vs. 170±31 pM; mean±SEM; p<.05); N acetyl cysteine (1 μM) inhibited the effect (260±54 pM). MP-associated TF activity was also increased (197±98 vs. 19±14 arbitrary U).

Conclusions: Oxidative stress induces the generation of functionally active, MP-associated TF by A549 alveolar cells, demonstrating a possible mechanism of local FX activation.
A Novel B Lymphocyte–Associated Adaptor Protein, Bam32, Regulates Antigen Receptor Signaling Downstream of Phosphatidylinositol 3-Kinase
Authors: Aaron J. Marshall, Hiroaki Niiro, Cara G. Lerner, Theodore J. Yun, Sushma Thomas, Christine M. Disteche, Edward A. Clark
Journal: The Journal of Experimental Medicine (2000)

We have identified and characterized a novel src homology 2 (SH2) and pleckstrin homology (PH) domain-containing adaptor protein, designated Bam32 (for B cell adaptor molecule of 32 kD). cDNAs encoding the human and mouse Bam32 coding sequences were isolated and the human bam32 gene was mapped to chromosome 4q25-q27. Bam32 is expressed by B lymphocytes, but not T lymphocytes or nonhematopoietic cells. Human germinal center B cells show increased Bam32 expression, and resting B cells rapidly upregulate expression of Bam32 after ligation of CD40, but not immunoglobulin M. Bam32 is tyrosine-phosphorylated upon B cell antigen receptor (BCR) ligation or pervanadate stimulation and associates with phospholipase Cgamma2. After BCR ligation, Bam32 is recruited to the plasma membrane through its PH domain. Membrane recruitment requires phosphatidylinositol 3-kinase (PI3K) activity and an intact PI(3,4, 5)P(3)-binding motif, suggesting that membrane association occurs through binding to 3-phosphoinositides. Expression of Bam32 in B cells leads to a dose-dependent inhibition of BCR-induced activation of nuclear factor of activated T cells (NF-AT), which is blocked by deletion of the PH domain or mutation of the PI(3,4,5)P(3)-binding motif. Thus, Bam32 represents a novel B cell-associated adaptor that regulates BCR signaling downstream of PI3K.
Clinical response to therapy with thymopoietin pentapeptide (TP-5) in rheumatoid arthritis
Authors: E.M. Veys, E.C. Huskisson, M. Rosenthal, T.L. Vischer, H. Mielants, P.A. Thrower, J. Scott, H. Ott, H. Scheijgrond, J. Symoens
Journal: Annals of the Rheumatic Diseases (1982)

The effect of thymopoietin pentapeptide (TP-5) was evaluated in patients with rheumatoid arthritis (RA). Ninety-two patients were divided into 3 groups, namely, placebo, TP-5 intramuscularly (IM) 1 mg, TP-5 intravenously (IV) 50 mg, and were evaluated for 6 measures of disease activity at the beginning of the study and at 3 and 6 months. No difference was observed between the placebo group and the group treated with TP-5 IM 1 mg. However, in the group treated with TP-5 IV 50 mg a statistically significant improvement of all parameters except the ESR was observed.
Treatment of the later stages of Parkinson’s disease – pharmacological approaches now and in the future
Authors: Peter Jenner
Journal: Translational Neurodegeneration (2015)

The problems associated with the pharmacological treatment of the later stages of Parkinson's disease (PD) remain those seen over many years. These centre on a loss of drug effect ('wearing off') with disease progression, the occurrence of dyskinesia, notably with L-dopa use and the appearance of non-motor symptoms that are largely refractory to dopaminergic medication. Treatment strategies in late PD have been dominated by the use of drug combinations and the subtle manipulation of drug dosage. However, change is occurring as the understanding of the basis of motor complications and fluctuations and non-motor symptoms improves. New pharmacological options are expanding with the advent of longer acting versions of existing dopaminergic drugs, new drug delivery systems and the introduction of non-dopaminergic agents able to manipulate motor function both within the basal ganglia and in other brain regions. Non-dopaminergic agents are also being investigated for the treatment of dyskinesia and for the relief of non-motor symptoms. However, while therapy continues to improve, the treatment of late stage PD remains problematic with non-motor symptoms dominating the unmet need in this patient group.
Intrathecal heat shock protein 60 mediates neurodegeneration and demyelination in the CNS through a TLR4- and MyD88-dependent pathway
Authors: Karen Rosenberger, Paul Dembny, Katja Derkow, Odilo Engel, Christina Krüger, Susanne A Wolf, Helmut Kettenmann, Eckart Schott, Andreas Meisel, Seija Lehnardt
Journal: Molecular Neurodegeneration (2015)

Toll-like receptors (TLR) constitute a highly conserved class of receptors through which the innate immune system responds to both pathogen- and host-derived factors. Although TLRs are involved in a wide range of central nervous system (CNS) disorders including neurodegenerative diseases, the molecular events leading from CNS injury to activation of these innate immune receptors remain elusive. The stress protein heat shock protein 60 (HSP60) released from injured cells is considered an endogenous danger signal of the immune system. In this context, the main objective of the present study was to investigate the impact of extracellular HSP60 on the brain in vivo. We show here that HSP60 injected intrathecally causes neuronal and oligodendrocyte injury in the CNS in vivo through TLR4-dependent signaling. Intrathecal HSP60 results in neuronal cell death, axonal injury, loss of oligodendrocytes, and demyelination in the cerebral cortex of wild-type mice. In contrast both mice lacking TLR4 and the TLR adaptor molecule MyD88 are protected against deleterious effects induced by HSP60. In contrast to the exogenous TLR4 ligand, lipopolysaccharide, intrathecal HSP60 does not induce such a considerable inflammatory response in the brain. In the CNS, endogenous HSP60 is predominantly expressed in neurons and released during brain injury, since the cerebrospinal fluid (CSF) from animals of a mouse stroke model contains elevated levels of this stress protein compared to the CSF of sham-operated mice. Our data show a direct toxic effect of HSP60 towards neurons and oligodendrocytes in the CNS. The fact that these harmful effects involve TLR4 and MyD88 confirms a molecular pathway mediated by the release of endogenous TLR ligands from injured CNS cells common to many forms of brain diseases that bi-directionally links CNS injury and activation of the innate immune system to neurodegeneration and demyelination in vivo.
Comparison of Biomarkers in Exhaled Breath Condensate and Bronchoalveolar Lavage
Authors: Abigail S. Jackson, Alessandra Sandrini, Charlotte Campbell, Sharron Chow, Paul S. Thomas, Deborah H. Yates
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Exhaled breath condensate (EBC) is increasingly studied as a noninvasive research method of sampling the lungs, measuring several biomarkers. The exact site of origin of substances measured in EBC is unknown, as is the clinical applicability of the technique. Special techniques might be needed to measure EBC biomarkers.To assess biomarker concentrations in clinical disease and investigate the site of origin of EBC, we compared EBC and bronchoalveolar lavage (BAL) biomarkers in 49 patients undergoing bronchoscopy for clinical indications.We measured exhaled nitric oxide, 8-isoprostane, hydrogen peroxide, total nitrogen oxides, pH, total protein, and phospholipid (n = 33) and keratin (n = 15) to assess alveolar and mucinous compartments, respectively. EBC was collected over 10 min using a refrigerated condenser according to European Respiratory Society/American Thoracic Society recommendations, and BAL performed immediately thereafter.8-Isoprostane, nitrogen oxides, and pH were significantly higher in EBC than in BAL (3.845 vs. 0.027 ng/ml, 28.4 vs. 3.8 microM, and 7.35 vs. 6.4, respectively; p < 0.001). Hydrogen peroxide showed no difference between EBC and BAL (17.5 vs. 20.6 microM, p = not significant), whereas protein was significantly higher in BAL (33.8 vs. 183.2 microg/ml, p < 0.001). Total phospholipid was also higher in EBC, but keratin showed no difference. No significant correlation was found between EBC and BAL for any of the biomarkers evaluated either before or after correction for dilution.In clinical disease, markers of inflammation and oxidative stress are easily measurable in EBC using standard laboratory techniques and EBC is readily obtained. However, EBC and BAL markers do not correlate.
Breathing during Sleep in Patients with Nocturnal Desaturation
Authors: HEINRICH F. BECKER, AMANDA J. PIPER, WENDY E. FLYNN, STEPHEN G. McNAMARA, RON R. GRUNSTEIN, J. HERMANN PETER, COLIN E. SULLIVAN
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The mechanisms leading to hypoxemia during sleep in patients with respiratory failure remain poorly understood, with few studies providing a measure of minute ventilation (V I) during sleep. The aim of this study was to measure ventilation during sleep in patients with nocturnal desaturation secondary to different respiratory diseases. The 26 patients studied had diagnoses of chronic obstructive pulmonary disease (COPD) (n = 9), cystic fibrosis (CF) (n = 2), neuromusculoskeletal disease (n = 4), and obesity hypoventilation syndrome (OHS) (n = 11). Also reported are the results for seven normal subjects and seven patients with effectively treated obstructive sleep apnea (OSA) without desaturation during sleep. Ventilation was measured with a pneumotachograph attached to a nasal mask. In the treated patients with OSA and in the normal subjects, only minor alterations in V I were observed during sleep. In contrast, mean V I for the group with nocturnal desaturation decreased by 21% during non-rapid-eye-movement (NREM) sleep and by 39% during rapid-eye-movement (REM) sleep as compared with wakefulness. This reduction was due mainly to a decrease in tidal volume (V T). Hypoventilation was most pronounced during REM sleep, irrespective of the underlying disease. These data indicate that hypoventilation may be the major factor leading to hypoxia during sleep, and that reversal of hypoventilation during sleep should be a major therapeutic strategy for these patients.
Diagnostic yield of cytology in malignant pleural effusion: Impact of volume and repeated thoracentesis
Authors: Mehrdad Solooki
Journal: European Respiratory Journal (2011)

Pleural effusions are a common finding in patients with cancer,and the diagnosis is important in view of prognosis and management.We conducted this study to determine the sensitivity of pleural fluid cytology and also to check the minimum volume required for best diagnostic yield of cytology and the effect of repeated thoracentesis on the results.   Methods:  This prospective - descriptive study in patients with exudative pleural effusion during a period of 24 months (from September 2007 to August 2009) had been admitted in massih-daneshvari hospital in Tehran-Iran.The patients underwent thoracentesis and pleural fluid cytology and subsequently followed up for six months. Diagnostic value of cytology in general and also of different volume of pleural fluid and impact of repeated thoracentesis were investigated.   Results:  A total of 318 patients were studied. Sensitivity of cytology for diagnosis of pleural malignancy was 40.8% (p=0.004). The sensitivity of first, second and third cytologic exam was 11.6%, 16.8% and 23.8% respectively. Sensitivity of tests with increasing the volume of fluid was increased (p=0.004)).   Discussion and conclusion:  The sensitivity of cytology based on the study was 40.8%, and it is necessary to consider a minimum volume of fluid (31-40 cc) and to repeat the test to achieve the best results.
Increased apoptosis in bone marrow B lymphocytes but not T lymphocytes in myelodysplastic syndrome
Authors: Hesham M. Amin, Iman Jilani, Elihu H. Estey, Michael J. Keating, Amanda L. Dey, Taghi Manshouri, Hagop M. Kantarjian, Zeev Estrov, Jorge E. Cortes, Deborah A. Thomas, Francis J. Giles, Maher Albitar
Journal: Blood (2003)