tbuckley/cabot-search huggingface dataset:
uPAR regulates bronchial epithelial repair in vitro and is elevated in asthmatic epithelium
Authors: Ceri E Stewart, Hala S Nijmeh, Christopher E Brightling, Ian Sayers
Journal: Thorax (2011)

<h3>Background</h3> The asthma-associated gene urokinase plasminogen activator receptor (uPAR) may be involved in epithelial repair and airway remodelling. These processes are not adequately targeted by existing asthma therapies. A fuller understanding of the pathways involved in remodelling may lead to development of new therapeutic opportunities. uPAR expression in the lung epithelium of normal subjects and patients with asthma was investigated and the contribution of uPAR to epithelial wound repair in vitro was studied using primary bronchial epithelial cells (NHBECs). <h3>Methods</h3> Bronchial biopsy sections from normal subjects and patients with asthma were immunostained for uPAR. NHBECs were used in a scratch wound model to investigate the contribution of the plasminogen pathway to repair. The pathway was targeted via blocking of the interaction between urokinase plasminogen activator (uPA) and uPAR and overexpression of uPAR. The rate of wound closure and activation of intracellular signalling pathways and matrix metalloproteinases (MMPs) were measured. <h3>Results</h3> uPAR expression was significantly increased in the bronchial epithelium of patients with asthma compared with controls. uPAR expression was increased during wound repair in monolayer and air-liquid interface-differentiated NHBEC models. Blocking the uPA–uPAR interaction led to attenuated wound repair via changes in Erk1/2, Akt and p38MAPK signalling. Cells engineered to have raised levels of uPAR showed attenuated repair via sequestration of uPA by soluble uPAR. <h3>Conclusions</h3> The uPAR pathway is required for efficient epithelial wound repair. Increased uPAR expression, as seen in the bronchial epithelium of patients with asthma, leads to attenuated wound repair which may contribute to the development and progression of airway remodelling in asthma. This pathway may therefore represent a potential novel therapeutic target for the treatment of asthma.
Ragweed antigen causes interleukin-8 production in sensitized dog trachea.
Authors: T Kaneko, P R Massion, M Hara, J A Nadel
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Antigen challenge in allergic subjects and in sensitized animals causes recruitment of neutrophils as well as eosinophils into the airways. In this study, we asked whether interleukin-8 (IL-8) is involved in the recruitment of neutrophils into the airways after antigen challenge. We administered ragweed antigen to an isolated, superfused tracheal segment of ragweed-sensitized dogs. Local tracheal instillation of the antigen caused an increase in IL-8 concentration and increases in both the number of recruited neutrophils and myeloperoxidase activity (one indicator of neutrophil activation in the recruited cells). The increase in IL-8 concentration was observed earlier than both the neutrophil recruitment and the increase in myeloperoxidase activity in the tracheal superfusate. Superfusate removed from the trachea 8 h after antigen challenge showed marked neutrophil chemotactic activity in a microchemotaxis chamber, and this activity was inhibited (mean, 75.6%) by a blocking antibody to dog IL-8. We conclude that ragweed antigen causes neutrophil recruitment into the airways at least in part because of IL-8 production.
Predicting Clinical Outcome through Molecular Profiling in Stage III Melanoma
Authors: Thomas John, Michael A. Black, Tumi T. Toro, Debbie Leader, Craig A. Gedye, Ian D. Davis, Parry J. Guilford, Jonathan S. Cebon
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Patients with macroscopic stage III melanoma represent a heterogeneous cohort with average 5-year overall survival rates of &amp;lt;30%. With current algorithms, it is not possible to predict which patients will achieve longer-term survival. We hypothesized that molecular profiling could be used to identify prognostic groups within patients with stage III melanoma while also providing a greater understanding of the biological programs underpinning these differences. Experimental Design: Lymph node sections from 29 patients with stage IIIB and IIIC melanoma, with divergent clinical outcome including 16 “poor-prognosis” and 13 “good-prognosis” patients as defined by time to tumor progression, were subjected to molecular profiling using oligonucleotide arrays as an initial training set. Twenty-one differentially expressed genes were validated using quantitative PCR and the 15 genes with strongest cross-platform correlation were used to develop two predictive scores, which were applied to two independent validation sets of 10 and 14 stage III tumor samples. Results: Supervised analysis using differentially expressed genes was able to differentiate the prognostic groups in the training set. The developed predictive scores correlated directly with clinical outcome. When the predictive scores were applied to the two independent validation sets, clinical outcome was accurately predicted in 90% and 85% of patients, respectively. Conclusion: We describe a gene expression profile that is capable of distinguishing clinical outcomes in a previously homogeneous group of stage III melanoma patients.
Biology and Genetics of Adult Male Germ Cell Tumors
Authors: Jane Houldsworth, James E. Korkola, George J. Bosl, R. S. K. Chaganti
Journal: Journal of Clinical Oncology (2006)

Adult male germ cell tumors (GCTs) arise by transformation of totipotent germ cells. They have the unique potential to activate molecular pathways, in part mimicking those occurring during gametogenesis and normal human development, as evidenced by the array of histopathologies observed in vivo. Recent expression profiling studies of GCTs along with advances in embryonic stem-cell research have contributed to our understanding of the underlying biology of the disease. Gain of the short arm of chromosome 12 detected in almost all adult GCTs appears to be multifunctional in germ cell tumorigenesis on the basis of the observed overexpression of genes mapped to this region involved in maintenance of pluripotency and oncogenesis. Expression signatures associated with the different histopathologies have yielded clues as to the functional mechanisms involved in GCT invasion, loss of pluripotency, and lineage differentiation. Genomic and epigenomic abnormalities that contribute to or cause these events have been identified by traditional genome analyses and continue to be revealed as genome-scanning technologies develop. Given the high sensitivity of most GCTs to cisplatin-based treatment, these tumors serve as an excellent model system for the identification of factors associated with drug resistance, including differentiation status and acquisition of genomic alterations. Overall, adult male GCTs provide a unique opportunity for the examination of functional links between transformation and pluripotency, genomic and epigenomic abnormalities and lineage differentiation, and the identification of genetic features associated with chemotherapy resistance.
Induction of p53-Specific Immunity by a p53 Synthetic Long Peptide Vaccine in Patients Treated for Metastatic Colorectal Cancer
Authors: Frank M. Speetjens, Peter J.K. Kuppen, Marij J.P. Welters, Farah Essahsah, Anne Marie E.G. Voet van den Brink, M. Graziella Kallenberg Lantrua, A. Rob P.M. Valentijn, Jaap Oostendorp, Lorraine M. Fathers, Hans W. Nijman, Jan W. Drijfhout, Cornelis J.H. van de Velde, Cornelis J.M. Melief, Sjoerd H. van der Burg
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The tumor-associated self-antigen p53 is commonly overexpressed in cancer, including colorectal cancer, and can serve as a target for immunotherapy. The safety and immunogenicity of a p53 synthetic long peptide (p53-SLP) vaccine were investigated in patients treated for metastatic colorectal cancer. Experimental Design: Ten patients were vaccinated twice with a set of 10 overlapping p53-SLP in a phase I/II trial. Both the safety and the breadth, magnitude, and polarization of vaccine-induced p53-specific T cells was evaluated in blood samples drawn before and after vaccination by IFN-γ enzyme-linked immunospot, proliferation, cytokine secretion, and multiparameter flow cytometry. The migratory capacity of p53-specific T cells was evaluated by assessing their presence in a biopsy of the second vaccination site. Results: Toxicity was limited to grade 1/2, mostly at the vaccination site. p53-specific T-cell responses were induced in 9 of 10 colorectal cancer patients as measured by IFN-γ enzyme-linked immunospot, proliferation, and cytokine bead array. In 6 of 9 tested patients, p53-specific T-cell reactivity persisted at least 6 months. Furthermore, p53-specific T cells isolated from the vaccination site were characterized as CD4+ T cells producing both T-helper types 1 and 2 cytokines on stimulation with p53 peptide and p53 protein. Multiparameter flow cytometry revealed that only a minor population of the p53-specific CD4+ T cells was optimally polarized. Conclusions: The p53-SLP vaccine is safe and capable to induce p53-specific T-cell responses in patients treated for colorectal cancer. New trials should focus on improving the polarization of the p53-SLP vaccine-induced T-cell response.
Fall in admission rate of old people to psychiatric units.
Authors: K Shulman, T Arie
Journal: BMJ (1978)

The numbers of the elderly, and particularly the very old, have been increasing and continue to increase rapidly; but admission rates of old people to psychiatric hospitals in England and Wales suddenly started to fall in 1970. They were still generally falling in 1974 (the most recent year for which figures are available). There is no evidence that the incidence of dementia has suddenly fallen, or that expansion of extramural or other non-psychiatric services is everywhere coping with the severely demented. It is probably becoming more difficult for demented people to be admitted to psychiatric hospitals that are often still overcrowded, in view of the greater scrutiny of institutional care that has become established since the Ely Report of 1969. If this is so the cost to the demented and those who care for them of the undoubted improvements in conditions in psychiatric hospitals needs to be counted.
Electrical properties of the rabbit cortical collecting duct from obstructed kidneys after unilateral ureteral obstruction. Effects of renal decapsulation.
Authors: S Muto, Y Asano
Journal: Journal of Clinical Investigation (1994)

Ureteral obstruction causes impaired salt wastage and K+ secretion in the distal nephron segments, including the cortical collecting duct (CCD). Recently, we demonstrated that conductances of Na+ and K+ in the apical membrane, as well as the electrogenic Na(+)-K+ pump activity and the relative K+ conductance in the basolateral membrane of the collecting duct cell, were inhibited in the obstructed kidney after unilateral ureteral obstruction (UUO). To examine whether the increased intrarenal pressure might be causally related to these abnormalities in the CCD, the effects of unilateral renal decapsulation, a maneuver that partially blocks the increase in renal pressure, were evaluated with microelectrode techniques in isolated CCDs from UUO and sham-operated (control) rabbits 24 h after operation. Renal decapsulation had no effects on barrier voltages and conductances in the CCD from control animals. The lumen-negative transepithelial (VT) and basolateral membrane (VB) voltages as well as the transepithelial (GT) and the apical membrane (GA) conductances were decreased in the CCD from UUO animals compared with control animals. Pretreatment of renal decapsulation partially corrected the decreases in VT, VB, GT, and GA seen in the CCD from UUO animals. The changes in apical membrane voltage and GT upon addition of luminal amiloride and Ba2+, and the changes in VB upon addition of bath ouabain, were also decreased in the CCD from UUO animals compared with control animals. Pretreatment of renal decapsulation also partially corrected the above abnormalities seen in UUO animals, whereas it had no effect in control animals. The transference numbers for Cl- (tCl) and K+ (tK) in the basolateral membrane were, respectively, increased and decreased in the CCD from UUO animals compared with control animals. Pretreatment of renal decapsulation also partially corrected the changes in tCl and tK seen in UUO animals, whereas it had no effect in control animals. We conclude that, in UUO animals, renal decapsulation partially corrects the inhibition of apical Na+ and K+ conductances as well as basolateral Na(+)-K+ pump activity and relative K+ conductance seen after UUO, whereas in control animals it has no effect. The increased renal pressure may partly contribute to the defects in Na+ and K+ transport in the CCD from obstructed kidneys. Renal decapsulation has protective effects on impaired Na+ and K+ transports in the CCD after ureteral obstruction.
2,4-Dienoyl-coenzyme A reductase deficiency: a possible new disorder of fatty acid oxidation.
Authors: C R Roe, D S Millington, D L Norwood, N Kodo, H Sprecher, B S Mohammed, M Nada, H Schulz, R McVie
Journal: Journal of Clinical Investigation (1990)

Several inherited disorders of fatty acid beta-oxidation have been described that relate mainly to saturated precursors. This study is the first report of an enzyme defect related only to unsaturated fatty acid oxidation and provides the first in vivo evidence that fat oxidation in humans proceeds by the reductase-dependent pathway. The patient was a black female, presenting in the neonatal period with persistent hypotonia. Biochemical studies revealed hyperlysinemia, hypocarnitinemia, normal organic acid profile, and an unusual acylcarnitine species in both urine and blood. The new metabolite was positively identified by mass spectrometry as 2-trans,4-cis-decadienoylcarnitine, derived from incomplete oxidation of linoleic acid. In spite of dietary therapy, the patient died of respiratory acidosis at four months of age. Samples of liver and muscle from the autopsy were assayed for 2,4-dienoyl-coenzyme A reductase activity. Using the substrate 2-trans,4-cis-decadienoylcoenzyme A, the reductase activity was 40% of the control value in liver and only 17% of that found in normal muscle. It is suggested that unsaturated substrates should be used for in vitro testing to cover the full range of potential beta-oxidation defects and that acylcarnitine species identification be used for in vivo detection of this disorder.
Chromatin Remodeling by the T Cell Receptor (Tcr)-β Gene Enhancer during Early T Cell Development
Authors: Noëlle Mathieu, William M. Hempel, Salvatore Spicuglia, Christophe Verthuy, Pierre Ferrier
Journal: The Journal of Experimental Medicine (2000)

Gene targeting studies have shown that T cell receptor (TCR)-β gene expression and recombination are inhibited after deletion of an enhancer (Eβ) located at the 3′ end of the ∼500-kb TCR-β locus. Using knockout mouse models, we have measured, at different regions throughout the TCR-β locus, the effects of Eβ deletion on molecular parameters believed to reflect epigenetic changes associated with the control of gene activation, including restriction endonuclease access to chromosomal DNA, germline transcription, DNA methylation, and histone H3 acetylation. Our results demonstrate that, in early developing thymocytes, Eβ contributes to major chromatin remodeling directed to an ∼25-kb upstream domain comprised of the Dβ-Jβ locus regions. Accordingly, treatment of Eβ-deleted thymocytes with the histone deacetylase inhibitor trichostatin A relieved the block in TCR-β gene expression and promoted recombination within the Dβ-Jβ loci. Unexpectedly, however, epigenetic processes at distal Vβ genes on the 5′ side of the locus and at the 3′ proximal Vβ14 gene appear to be less dependent on Eβ, suggesting that Eβ activity is confined to a discrete region of the TCR-β locus. These findings have implications with respect to the developmental control of TCR-β gene recombination, and the process of allelic exclusion at this locus.
Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G&gt;A
Authors: F Auer, F Rüschendorf, M Gombert, P Husemann, S Ginzel, S Izraeli, M Harit, M Weintraub, O Y Weinstein, I Lerer, P Stepensky, A Borkhardt, J Hauer
Journal: Leukemia (2013)
Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology
Authors: Irina G. Stavrovskaya, Malini V. Narayanan, Wenhua Zhang, Boris F. Krasnikov, Jill Heemskerk, S. Stanley Young, John P. Blass, Abraham M. Brown, M. Flint Beal, Robert M. Friedlander, Bruce S. Kristal
Journal: The Journal of Experimental Medicine (2004)

Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury.
Quantitative Detection of Human Cytomegalovirus DNA in Lung Transplant Recipients
Authors: A.THOMAS C. KOTSIMBOS, VINCENT SINICKAS, ERIC M. GLARE, DONALD S. ESMORE, GREGORY I. SNELL, E. HAYDN WALTERS, TREVOR J. WILLIAMS
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Human cytomegalovirus (HCMV) disease remains a major cause of morbidity and mortality after lung transplantation. Currently, routine diagnostic tests for HCMV are inefficient and insensitive or nonspecific for HCMV disease. We describe an efficient, highly sensitive, quantitative polymerase chain reaction (PCR) assay for HCMV using competitive PCR and fluorescently labeled primers, and we have used this to measure HCMV DNA load in donor and recipient tissues of six lung transplant recipients at the time of transplantation, and 2 wk after transplantation when clinically stable. Total DNA yield was adequate for analysis in transbronchial biopsy, bronchoalveolar lavage, and peripheral blood leukocytes, but the endobronchial biopsy specimens did not consistently produce sufficient DNA for analysis. There was a large intersubject and intrasubject variability between tissues in HCMV DNA load, with a tendency for greater levels in lung tissue compared with BAL or peripheral blood cells. All six HCMV IgG seronegative donors or recipients were found to have HCMV DNA present. One of the three seronegative matched transplant recipients developed histopathologically proven HCMV disease, and HCMV DNA levels were shown to increase at that time point and subsequently decrease with ganciclovir treatment. This assay will allow prospective studies to confirm the predictive value of HCMV DNA load in donor and recipient tissues for HCMV disease.
CERTAIN CONDITIONS DETERMINING ENHANCED INFECTION WITH THE RABBIT PAPILLOMA VIRUS
Authors: William F. Friedewald
Journal: The Journal of Experimental Medicine (1944)

The infection of normal or hyperplastic rabbit skin with the papilloma virus can be greatly enhanced by protecting the scarified and inoculated area with a layer of paraffined gauze until healing occurs. In this way the necrosis which follows upon scarification and also the scabbing are almost entirely prevented and in consequence epithelial regeneration is usually complete within 24 hours. Not only are many susceptible cells provided to the virus far earlier than would otherwise be the case,-and collateral tests have shown that it becomes associated with them within a few hours instead of after many,-but the inoculum is itself conserved, instead of becoming largely lost amidst necrotic tissue and scab, as under ordinary circumstances. The effective titer of the virus is increased by the procedure from 10 to 100 times over that attained when hyperplastic skin is allowed to dry after inoculation. Since the results under the latter circumstances are 10 to 100 times better than those when normal skin is treated in the same way it follows that a 100- to 10,000-fold increase in the effectiveness of the virus has now been obtained.
Differential Expression of Transforming Growth Factor-α during Prenatal Development of the Mouse
Authors: Daniel R. Twardzik
Journal: Cancer Research (1985)

Transforming growth factors (TGFs) are differentially expressed in the mouse during neonatal development. Highest levels are seen early at Day 7, and lower levels, at Day 13. Both small- and large-molecular-weight forms of TGF are found; they share many biochemical properties with rat TGF-alpha, including a similar high-pressure liquid chromatography elution profile. Although the embryo-derived activities compete with epidermal growth factor for binding to epidermal growth factor membrane receptors, they are immunologically distinct from epidermal growth factor. These embryonic polypeptides, however, do cross-react in a competitive radioimmunoassay developed using a synthetic peptide corresponding to the carboxy-17 amino acids of rat TGF-alpha as the immunogen. The highly conserved TGF-alpha family of peptides produced by some tumor cells may therefore represent derepressed forms of these embryonic growth factors. A functional role in neonatal development is proposed.
Inflammatory cell microlocalisation and airway dysfunction: cause and effect?
Authors: S. Siddiqui, F. Hollins, S. Saha, C. E. Brightling
Journal: European Respiratory Journal (2007)

Airway inflammation is a critical feature of the airway diseases asthma and chronic obstructive pulmonary disease (COPD). There is emerging evidence that structural cells play a key role in the development and perpetuation of the inflammatory response and are pivotal in the development of the changes in the airway structures that lead to airway remodelling. To date, little attention has been given to the localisation of inflammatory cells to airway structures or the potential interactions between these intimately located cells. However, it is likely that interactions between inflammatory and structural cells in the airway contribute enormously to the pathophysiology of asthma and COPD. Indeed, recent evidence suggests that mast cells localised to the airway smooth muscle bundle may be important in the development of airway hyperresponsiveness in asthma. In the present article, the authors aim to summarise: 1) the current understanding of which inflammatory cells locate to airway structures; 2) the proposed mechanisms that may be involved in mediating this microlocalisation; 3) the possible consequences of interactions between inflammatory and structural cells; and 4) the pressing need to investigate whether modulating these interactions is beneficial in asthma and chronic obstructive pulmonary disease.