tbuckley/cabot-search huggingface dataset:
Interleukin-4 Protects against a Genetically Linked Lupus-like Autoimmune Syndrome
Authors: Marie-Laure Santiago, Liliane Fossati, Chantal Jacquet, Werner Müller, Shozo Izui, Luc Reininger
Journal: The Journal of Experimental Medicine (1997)

Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibodymediated autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW × C57BL/6.Yaa)F1 murine model of SLE. This was associated with marked changes in the serum levels of IgG subclasses, rather than in the total levels of anti-DNA antibodies, with a lack of IgG3, a decrease of IgG2a, and an increase in IgG1 subclasses, and by a strong reduction in the serum levels of gp70-antigp70 immune complexes. This effect of the transgene appears to result from a modulation of the Th1 versus Th2 autoimmune response, since the protected mice displayed comparably modified IgG2a and IgG3 antibody response against exogenous T cell–dependent antigen, but not against T cell–independent antigens. Thus, IL-4 prevents the development of this lupuslike autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.
The Tolerability, Safety, and Success of Sputum Induction and Combined Hypertonic Saline Challenge in Children
Authors: PETER D. JONES, ROBYN HANKIN, JODIE SIMPSON, PETER G. GIBSON, RICHARD L. HENRY
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Section:ChooseTop of pageAbstract <<METHODSRESULTSDISCUSSIONCONCLUSIONSReferencesCITING ARTICLES
Sleep in the Intensive Care Unit
Authors: Margaret A. Pisani, Randall S. Friese, Brian K. Gehlbach, Richard J. Schwab, Gerald L. Weinhouse, Shirley F. Jones
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Section:ChooseTop of pageAbstract <<Sleep Abnormalities in IC...Circadian Rhythm Alterati...Hormones, Cytokines, and ...Risk Factors for ICU Slee...Physiologic Effects of Sl...Tools to Measure Sleep in...Sleep-Promoting Intervent...Sleep after Critical Illn...ConclusionsReferencesCITING ARTICLES
Novel Roles of Unphosphorylated STAT3 in Oncogenesis and Transcriptional Regulation
Authors: Jinbo Yang, Moitreyee Chatterjee-Kishore, Susan M. Staugaitis, Hannah Nguyen, Karni Schlessinger, David E. Levy, George R. Stark
Journal: Cancer Research (2005)

Abstract Signal transducer and activator of transcription 3 (STAT3) is phosphorylated on tyrosine residue 705 in response to growth factors or cytokines to form activated homodimers that drive gene expression. Because the stat3 promoter has a binding site for STAT3 dimers, the amount of STAT3 protein increases when STAT3 is activated (e.g., in response to interleukin 6). Unphosphorylated STAT1 is known to drive the expression of certain genes. To explore the possibility of a similar role for the induced expression of unphosphorylated STAT3, we overexpressed either Y705F STAT3, which can not be phosphorylated on residue 705, or wild-type STAT3 in normal human mammary epithelial cells or STAT3-null mouse cells. The levels of many mRNAs were affected strongly by high levels of either form of STAT3. Some genes whose expression was increased by overexpressed STAT3, but not by activated STAT3 dimers, encode well-known oncoproteins (e.g., MRAS and MET). In many tumors, STAT3 is activated constitutively, and thus the unphosphorylated form is likely to be expressed highly, driving oncogene expression by a novel mechanism. In addition, expression of the stat3 gene is increased strongly in response to interleukin 6, and the high levels of unphosphorylated STAT3 that result drive a substantial late phase of gene expression in response to this cytokine. Thus, unphosphorylated STAT3, which activates gene expression by a novel mechanism distinct from that used by STAT3 dimers, is very likely to be an important transcription factor both in cancer and in responses to cytokines.
Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions
Authors: Lewis J Haddow, Robert Colebunders, Graeme Meintjes, Stephen D Lawn, Julian H Elliott, Yukari C Manabe, Paul R Bohjanen, Somnuek Sungkanuparph, Philippa J Easterbrook, Martyn A French, David R Boulware
Journal: The Lancet Infectious Diseases (2010)
Late-breaking abstract: Phase 2a randomized placebo-controlled trial of the oral prostaglandin D2 receptor (DP2/ CRTh2) antagonist QAWo39 in eosinophilic asthma
Authors: Sherif Gonem, Rachid Berair, Amisha Singapuri, Ruth Hartley, Marie Laurencin, Gerald Bacher, Chengxing Lu, Bjoern Holzhauer, Michelle Bourne, Vijay Mistry, Ian Pavord, Adel Mansur, Andrew Wardlaw, Salman Siddiqui, Richard Kay, Chris Brightling
Journal: European Respiratory Journal (2014)

Introduction  There is a high unmet need for safe, effective and convenient therapies to control symptoms and reduce the impact of exacerbations in severe asthma. Eosinophilic inflammation is common in asthma and attenuation of sputum eosinophilia is strongly associated with reduced exacerbation frequency.  Methods  In this single-center, double-blind, randomized controlled study, asthmatics (GINA II-V), with a sputum eosinophil count ≥2% at baseline, were randomised to QAW039 225mg BID or placebo for 12 weeks after a 2-week placebo run-in. The primary endpoint was the reduction of sputum eosinophils. Secondary, exploratory and post-hoc outcomes included changes in Asthma Control Questionnaire score (ACQ7), Asthma Quality of Life score (AQLQ) and FEV1.  Results  61 patients were randomized (30 to QAW039 and 31 to placebo); 90% were ≥GINA IV; and 25% were GINA V requiring up to 10 mg prednisolone daily. The primary endpoint was met, with QAW039 reducing sputum eosinophils 3.5-fold over placebo (95% CI: 1.7-7.0, p=0.001). The AQLQ improved in those treated with QAW039 compared to placebo (0.59 points; p=0.008) with non-significant improvements in ACQ7 in the group as a whole (0.40 points; p=0.084), which was greater in those with poor asthma control (ACQ≥1.5) at baseline (0.56 points; p=0.046). FEV1 improved in those receiving QAW039 versus placebo (0.074L; p=0.408; pre-bronchodilator (BD), 0.163L; p=0.022; post-BD). AEs were mild/moderate, balanced between both groups with no SAEs or deaths.  Conclusion  QAW039 is effective at attenuating eosinophilic airway inflammation, improves health status and lung function and has a favourable safety profile.
Analysis of tissue-specific gene delivery by recombinant adenoviruses containing cardiac-specific promoters
Authors: W Franz
Journal: Cardiovascular Research (1997)

Objective: To approach heart muscle diseases by gene transfer, an adenoviral vector system was intended to be established suitable for gene expression in ventricular and/or atrial myocardium. Methods: Two adenoviral vectors (Ad-mhcLuc, Ad-mlcLuc) were constructed, in which the luciferase reporter gene is under control of either the ventricle-specific myosin light chain-2 (mlc-2v) or the atrial- and ventricular-specific α-myosin heavy chain (α-mhc) promoter. For controls, a recombinant adenovirus without promoter (Ad-Luc) and one with the Rous sarcoma virus (rsv) promoter (Ad-rsvLuc) were generated. A volume of 20 μl containing 2×109 plaque forming units (pfu) of the recombinant adenoviruses Ad-mhcLuc, Ad-mlcLuc, Ad-rsvLuc or Ad-Luc was injected into the cardiac cavity or the quadriceps femoris muscle of neonatal rats. After five days animals were sacrificed and nine different tissues were analyzed for reporter gene expression by detection of light activity relative to mg of tissue. Results: Injections of recombinant adenoviruses into the cardiac cavity of neonatal rats resulted in heart-specific gene expression of Ad-mlcLuc (20 fold of Ad-Luc; 11% of Ad-rsvLuc), whereas Ad-mhcLuc gave mainly luciferase activity in the heart (6.5 fold of Ad-Luc; 3% of Ad-rsvLuc) with additional activity in lung and liver (2–4 fold of Ad-Luc). In the ventricular tissue Ad-mlcLuc revealed a 35-fold higher luciferase activity, whereas Ad-mhcLuc, Ad-rsvLuc and Ad-Luc showed only 2-fold higher luciferase activities compared to the atrium. Viral DNA in atrial and ventricular tissue was detected by PCR at approximately the same abundance independent of the injected type of adenovirus. Direct injection of Ad-mhcLuc and Ad-mlcLuc into the thigh muscle revealed only background luciferase activities. Conclusions: In the adenoviral system only the mlc-2v promoter may fulfil the safety requirements for a myocardial specific gene expression with a high selectivity for the ventricular myocardium, thus providing a promising tool for future gene therapy of cardiomyopathies.
Induction of tolerance to one determinant on a synthetic peptide does not affect the response to a second linked determinant. Implications for the mechanism of neonatal tolerance induction.
Authors: G M Gammon, A Oki, N Shastri, E E Sercarz
Journal: The Journal of Experimental Medicine (1986)

To investigate the mechanism underlying neonatal T cell tolerance, we used synthetic peptides to induce tolerance. We found that induction of tolerance to one determinant on a 23-amino acid peptide did not affect the response to an adjacent determinant on the same peptide. There was no evidence of suppression of the response to the second determinant. Furthermore, even small peptides near the minimal size for a determinant, which would be very unlikely to possess a suppressor T cell-inducing determinant as well as a proliferative T cell-inducing determinant, could induce tolerance. These studies provide in vivo experiments supporting clonal inactivation as the mechanism of neonatal tolerance to immunogenic peptides.
Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation
Authors: Gaoping Zhao, Daniel J. Moore, James I. Kim, Kang Mi Lee, Matthew R. O’Connor, Patrick E. Duff, Maozhu Yang, Ji Lei, James F. Markmann, Shaoping Deng
Journal: Science Translational Medicine (2011)

Immune senescence causes resistance to transplantation tolerance that can be functionally restored by targeting sex steroid production.
Involvement of Pax-2 in the Action of Activin A on Tubular Cell Regeneration
Authors: Akito Maeshima, Kyoko Maeshima, Yoshihisa Nojima, Itaru Kojima
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. It has been recently shown that in ischemic rat kidneys activin A is induced in tubular cells and inhibits their regeneration. The present study was conducted to further investigate the action of activin A in tubular cells during regeneration. Among genes thought to be critical for kidney development, Pax-2 was upregulated in tubular cells during regeneration after renal ischemia. Pax-2 protein was localized in nuclei of tubular and interstitial cells, some of which co-expressed a mesenchymal cell marker, vimentin, suggesting that a population of Pax-2–positive cells have properties of immature progenitor-like tubular cells. The Pax-2–expressing cells co-expressed a cell proliferation marker, BrdU, activin A, and the type II activin receptor. Activin A modulated growth of BrdU/Pax-2 double-positive cells since an administration of follistatin increased; conversely, exogenous activin A decreased the number of BrdU/Pax-2 double-positive cells after renal ischemia. Activin A also reduced the expression of Pax-2 in cultured metanephroi. A proximal tubular cell line, LLC-PK1 cells, was used to further study the mode of action of activin A. The expression of Pax-2 was not detected in quiescent LLC-PK1 cells, but it was markedly increased when growth was stimulated. Under this condition, activin A significantly inhibited DNA synthesis and reduced the expression of Pax-2 in LLC-PK1 cells. In contrast, blockade of the activin signaling by overexpressing dominantly negative mutant receptor enhanced the expression level of Pax-2 in LLC-PK1 cells and induced an immature phenotype. These results suggest that activin A regulates tubular cell growth and differentiation by modulating the expression of Pax-2 during regeneration.
Analysis of Genome-Wide Association Studies of Alzheimer Disease and of Parkinson Disease to Determine If These 2 Diseases Share a Common Genetic Risk
Authors: Valentina Moskvina, Denise Harold, Gian Carlo Russo, Alexey Vedernikov, Manu Sharma, Mohamad Saad, Peter Holmans, Jose M. Bras, Francesco Bettella, Margaux F. Keller, Nayia Nicolaou, Javier Simón-Sánchez, J. Raphael Gibbs, Claudia Schulte, Alexandra Durr, Rita Guerreiro, Dena Hernandez, Alexis Brice, Hreinn Stefánsson, Kari Majamaa, Thomas Gasser, Peter Heutink, Nick Wood, Maria Martinez, Andrew B. Singleton, Michael A. Nalls, John Hardy, Michael J. Owen, Michael C. O'Donovan, Julie Williams, Huw R. Morris, Nigel M. Williams
Journal: JAMA Neurology (2013)

<h3>Importance</h3> Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders. <h3>Objective</h3> To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD. <h3>Design</h3> Combined GWA analysis. <h3>Setting</h3> Data sets from the United Kingdom, Germany, France, and the United States. <h3>Participants</h3> Thousands of patients with AD or PD and their controls. <h3>Main Outcomes and Measures</h3> Meta-analysis of GWA studies of AD and PD. <h3>Methods</h3> To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies. We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD. <h3>Results</h3> Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD. <h3>Conclusions and Relevance</h3> Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.
Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial
Authors: Chaitanya R Divgi, Neeta Pandit-Taskar, Achim A Jungbluth, Victor E Reuter, Mithat Gönen, Shutian Ruan, Christine Pierre, Andrew Nagel, Daniel A Pryma, John Humm, Steven M Larson, Lloyd J Old, Paul Russo
Journal: The Lancet Oncology (2007)
A multi-center prospective phase II study of high-dose chemotherapy in germ-cell cancer patients relapsing from complete remission
Authors: S. Rodenhuis, R. de Wit, P.H.M. de Mulder, H.J. Keizer, D.T. Sleijfer, R.I. Lalisang, P.J.M. Bakker, I. Mandjes, M. Kooi, E.G.E. de Vries
Journal: Annals of Oncology (1999)
T Cell Death and Transforming Growth Factor β1
Authors: Pierre Golstein, Andrew H. Wyllie
Journal: The Journal of Experimental Medicine (2001)

The TGF-␤ family comprises many cytokines involved in the control of cell fate (1).Some of these have been shown to control cell death.For instance, at least one of the members of the BMP subfamily of the TGF-␤ family is required in interdigital death, a classical model of developmentally programmed cell death (2).Another TGF-␤ family member, TGF-␤ 1, entertains a complicated relationship with cell death, of lymphocytes in particular.When added extracellularly, it has been reported to induce death of B lymphocytes (3, 4) and to prevent T lymphocyte death (5-7).A new, and at times somewhat heretical twist, is now reported (8).In mice homozygous for a TGF-␤ 1 null mutation (9, 10), thus not expressing TGF-␤ 1, W.J. Chen et al. ( 8) found that apparently spontaneous apoptosis of both thymic and peripheral T cells was increased compared with wild-type controls.These findings might seem relatively trivial, since TGF-␤ 1 had previously been shown to prevent T cell death (see above).However, not only was spontaneous T cell death impressive in both thymus and peripheral organs, but results were even more striking when T cells were challenged with anti-CD3 antibody (mimicking stimulation through the TCR).In vitro experiments already showed an increased sensitivity of T cells from TGF-␤ 1 knockout mice, resulting in marked activation-induced cell death.The most spectacular results were obtained with in vivo injection of anti-CD3 antibody into TGF-␤ 1 knockout mice, leading to massive apoptosis in both thymus and spleen, visible as terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells within hours, and effecting considerable reduction in lymphoid organ cell numbers.This was accompanied by an increase in expression of Fas and Fas ligand in spleen cells, and increase in sensitivity to the Fas pathway and in some situations to the TNFR2 pathway of cell death.These results demonstrated that activated lymphocytes in vivo require TGF-␤ 1 to protect them from death.
Placental Vascular Dysfunction, Fetal and Childhood Growth, and Cardiovascular Development
Authors: Romy Gaillard, Eric A.P. Steegers, Henning Tiemeier, Albert Hofman, Vincent W.V. Jaddoe
Journal: Circulation (2013)

Suboptimal fetal nutrition may influence early growth and cardiovascular development. We examined whether umbilical and uterine artery resistance indices, as measures of feto-placental and utero-placental vascular function, respectively, are associated with fetal and childhood growth and cardiovascular development.This study was embedded in a population-based prospective cohort study among 6716 mothers and their children. Umbilical artery pulsatility index and uterine artery resistance index and fetal growth were measured in third trimester. Childhood growth was repeatedly assessed from birth to the age of 6 years. We measured body fat distribution, left ventricular mass, and blood pressure at the age of 6 years. Higher third trimester umbilical and uterine artery vascular resistance were associated with lower fetal length and weight growth in third trimester resulting in a smaller size at birth among boys and girls (P values < 0.05). These differences in length and weight growth became smaller from the age of 6 months onwards, but were still present at the age of 6 years. Higher third trimester umbilical artery vascular resistance, but not uterine artery vascular resistance, was associated with higher childhood body mass index, total fat mass, android/gynoid fat mass ratio, and systolic blood pressure, and with a lower left ventricular mass (P values<0.05). These associations were not explained by birth weight. Stronger associations tended to be present among girls as compared with boys.Higher third trimester feto-placental vascular resistance, but not utero-placental vascular resistance, was associated with slower fetal growth rates and cardiovascular adaptations in childhood.
Colonoscopic polypectomy and the incidence of colorectal cancer
Authors: S J WINAWER, A G ZAUBER
Journal: Gut (2001)

See article on page 812 

It has long been believed that colorectal cancer evolves from a precursor lesion, the adenomatous polyp. This concept was based on the elegant pathology studies from the St Mark's Hospital, London, published by Lockhart-Mummery and Dukes in 1928,1 and culminating in the concept of the polyp-cancer sequence published in 1975 by Muto and colleagues.2 The introduction of colonoscopy in the early 1970s, followed by the demonstration of the feasibility of colonoscopic polypectomy, provided the technology for the application of this concept to clinical practice.3 The entire colon could be examined, polyps identified and removed and, it was believed, colorectal cancer prevented. Evidence for this belief was provided by observations from the prospective National Polyp Study (NPS) in the USA that demonstrated a reduction in the incidence of colorectal cancer by 76–90% following colonoscopic polypectomy.4 

The paper in this issue of Gut by Citarda et al addressed a common question—that is, can efficacy observed in a clinical trial be translated to effectiveness in clinical practice (see page 812).5 The study was a retrospective analysis of the incidence of colorectal cancer …
Effects of Growth Hormone on Leptin Metabolism and Energy Expenditure in Hemodialysis Patients with Protein-Calorie Malnutrition
Authors: GIACOMO GARIBOTTO, ANTONINA BARRECA, ANTONELLA SOFIA, RODOLFO RUSSO, FULVIO FIORINI, GIORGIO CAPPELLI, FOSCO CAVATORTA, ARIANNA CESARONE, ROBERTO FRANCESCHINI, PAOLO SACCO, FRANCESCO MINUTO, TOMASO BARRECA
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The relationships among growth hormone (GH), leptin, and resting energy expenditure (REE) are not understood. It has been reported that in malnourished hemodialysis patients, GH increases muscle protein synthesis, a process that requires energy. The present study evaluated the arterial levels and the forearm exchange of leptin, as well as the REE of the same patients during their participation in the same study, in four sequential 6-wk periods: I, baseline; II, GH treatment; III, washout; and IV, GH + intradialytic parenteral nutrition. During periods II and IV, patients received GH (5 mg three times per week). REE rose by 5% in period II, declined during period III, and rose by 7% during period IV. Basal leptin levels were low (2.0 ± 0.19 ng/L). Insulin and leptin levels, as well as leptin release from the forearm, were unchanged during periods I through III but rose (+ 36%; P &lt; 0.05) during period IV. Changes in arterial leptin were directly related to changes in forearm leptin release ( P &lt; 0.002), indicating a role of leptin production by peripheral tissues on leptinemia. Changes in leptin release were directly related to insulin ( P &lt; 0.001) and, less consistently, to insulin-like growth factor-binding protein-1 levels ( P &lt; 0.02). Similarly, variations in leptin levels were directly related to insulin ( P &lt; 0.01). Variations in REE were not related to variations in leptin or insulin levels but to changes in muscle protein synthesis ( P &lt; 0.025). The data show that in malnourished hemodialysis patients, treatment with GH is not invariably associated with an increase in leptin production. An increase in leptin release by peripheral tissues and leptin levels occurs only in the setting of hyperinsulinemia. The increase in REE that is induced by treatment with GH is not dependent on changes in leptin but is largely accounted for by the energy cost of the stimulation of muscle protein synthesis.