tbuckley/cabot-search huggingface dataset:
LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation
Authors: Kenneth R. Cooke, Armin Gerbitz, James M. Crawford, Takanori Teshima, Geoffrey R. Hill, Amy Tesolin, Daniel P. Rossignol, James L.M. Ferrara
Journal: Journal of Clinical Investigation (2001)

Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT). Recent studies have demonstrated that the loss of gastrointestinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulation that contributes to GVHD. Using a mouse BMT model, we studied the effects of direct LPS antagonism on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of B975, a synthetic lipid-A analogue from day 0 to day +6, reduced serum TNF-α levels, decreased intestinal histopathology, and resulted in significantly improved survival and a reduction in clinical GVHD, compared with control-treated animals. Importantly, B975 had no effect on donor T cell responses to host antigens in vivo or in vitro. When mice received lethal doses of P815 tumor cells at the time of BMT, administration of B975 did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a critical role for LPS in the early inflammatory events contributing to GVHD and suggest that a new class of pharmacologic agents, LPS antagonists, may help to prevent GVHD while preserving T cell responses to host antigens and GVL activity.
Involvement of Peripheral Polymorphonuclear Leukocytes in Oxidative Stress and Inflammation in Type 2 Diabetic Patients
Authors: Revital Shurtz-Swirski, Shifra Sela, Avraham T. Herskovits, Shaul M. Shasha, Galina Shapiro, Lubna Nasser, Batya Kristal
Journal: Diabetes Care (2001)

OBJECTIVE— To determine the extent to which peripheral polymorphonuclear leukocytes (PMNs) contributed to oxidative stress (OS) and inflammation in type 2 diabetic patients. RESEARCH DESIGN AND METHODS— PMNs and plasma were separated from blood withdrawn from 18 type 2 diabetic patients and 16 age- and sex-matched normal control subjects. The rate of superoxide release from phorbol 12-myristate 13-acetate (PMA)-stimulated PMNs and the plasma glutathione (GSH) levels served as measures of OS. Inflammation was assessed by PMN recruitment, expressed by peripheral blood PMN counts, and the in vitro survival of PMNs, which reflects cell necrosis. RESULTS— PMA-stimulated PMNs from diabetes released superoxide significantly faster, and plasma-reduced GSH was lower in diabetic patients than in normal control subjects. The rate of superoxide release from diabetic PMNs showed no correlation with the plasma glucose concentrations, whereas a positive linear correlation with HbAlc was found. The in vitro survival of diabetic PMNs was lower than normal control PMNs when each was incubated in its own serum. The in vitro survival of normal control PMNs was reduced when incubated with diabetic serum, whereas normal control sera promoted the survival of diabetic PMNs. Peripheral PMN counts were higher in diabetic patients than in normal control patients. CONCLUSIONS— Type 2 diabetes is accompanied by a priming of PMNs, resulting in OS and increased self-necrosis. Necrosis starts a chain of inflammatory reactions that result in cell recruitment and in the long run,with OS, may result in endothelial dysfunction. Understanding the contribution of PMNs to OS and inflammation in diabetes may illuminate new mechanisms through which endothelial dysfunction evolves and causes angiopathy and atherosclerosis.
TAT Protein Transduction Into Isolated Perfused Hearts
Authors: Åsa B. Gustafsson, M. Richard Sayen, Scott D. Williams, Michael T. Crow, Roberta A. Gottlieb
Journal: Circulation (2002)

Linkage of the 11-amino-acid transduction domain of HIV TAT to a heterologous protein allows the protein to be transduced readily into cells.In this study, we inserted the apoptosis repressor with caspase recruitment domain (ARC) or beta-galactosidase (beta-gal) cDNA into the pTAT-hemagglutinin bacterial expression vector to produce genetic in-frame TAT-ARC or TAT-beta-gal fusion proteins for use in cell culture and in Langendorff perfusion of adult rat hearts. TAT-beta-gal and TAT-ARC were conjugated with Texas Red and could be detected in >95% of cells. TAT-ARC was able to protect H9c2 cells against cell death mediated by hydrogen peroxide, as measured by protection against the loss of mitochondrial membrane potential and preservation of nuclear morphology. Isolated adult hearts were perfused with recombinant TAT-beta-gal or TAT-ARC (20 nmol/L) for 15 minutes and then subjected to 30 minutes of global no-flow ischemia, followed by 2 hours of reperfusion. Protein transduction was assessed by Western blotting of cell lysates and cytosolic and mitochondrial fractions and by fluorescence microscopy of Texas Red-conjugated TAT proteins. TAT-beta-gal and TAT-ARC readily transduced into perfused hearts and were homogeneously distributed. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining, and creatine kinase release was measured. Transduction of TAT-ARC was cardioprotective when administered before global ischemia and reperfusion.Our results demonstrate that TAT-linked fusion protein transduction into the myocardium is feasible and that transduction of TAT-ARC is protective in cell culture and in the perfused heart.
Major conceptual change required to improve lung cancer: see a respiratory physician
Authors: J.S. Vourlekis, E. Szabo
Journal: European Respiratory Journal (2003)

To the Editor: 

We fully agree with the discussion of Field and Brambilla 1 regarding effective strategies that could lead to important reductions in lung cancer mortality. We would like to add a fifth strategy, chemoprevention, which can be used in parallel with screening of high risk individuals. Chemoprevention is the medicinal use of natural …
Thrombin Stimulates Synthesis of Type IV Collagen and Tissue Inhibitor of Metalloproteinases-1 by Cultured Human Mesangial Cells
Authors: Mitsuaki Kaizuka, Hideaki Yamabe, Hiroshi Osawa, Ken Okumura, Noboru Fujimoto
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Glomerular accumulation of extracellular matrix (ECM) is the common pathologic feature following glomerular injury, and the alteration in the synthesis and degradation of ECM may be involved in the glomerular accumulation of ECM. Glomerular fibrin formation occurs in various forms of human and experimental glomerulonephritis, and it may play an important role in progressive glomerular injury. Thrombin, a multifunctional serine proteinase that is generated at the site of vascular injury, has central functions in hemostasis and it also shows various biologic effects. In this study, it is hypothesized that thrombin may alter the production and the degradation of type IV collagen, which is an important component of ECM in the glomeruli. Human mesangial cells (HMC) were cultured, and the levels of type IV collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), and matrix metalloproteinase-2 (MMP-2) in the culture supernatants were measured by enzyme immunoassay using specific antibodies. MMP-2 activity was also evaluated by zymography using polyacrylamide/sodium dodecyl sulfate gel-containing gelatin. Thrombin increased the production of type IV collagen and TIMP-1 in a dose- and time-dependent manner, but it did not increase MMP-2. Thrombin also stimulated the gene expressions of the type IV collagen and TIMP-1 in HMC in a dose- and time-dependent manner. Thrombin treated with diisopropylfluorophosphate, a serine proteinase inhibitor, did not show any of these effects. Hirudin, a natural thrombin inhibitor, and anti-transforming growth factor-β-neutralizing antibody inhibited the stimulating effect of thrombin. These findings suggest that thrombin may contribute to the excessive accumulation of ECM and progression of glomerulosclerosis through an increase of type IV collagen production and a decreased matrix degradation presumably via a transforming growth factor-β-dependent mechanism.
Cryptic MHC Polymorphism Revealed but Not Explained by Selection on the Class IIB Peptide-Binding Region
Authors: V. Llaurens, M. McMullan, C. van Oosterhout
Journal: Molecular Biology and Evolution (2012)

The immune genes of the major histocompatibility complex (MHC) are characterized by extraordinarily high levels of nucleotide and haplotype diversity. This variation is maintained by pathogen-mediated balancing selection that is operating on the peptide-binding region (PBR). Several recent studies have found, however, that some populations possess large clusters of alleles that are translated into virtually identical proteins. Here, we address the question of how this nucleotide polymorphism is maintained with little or no functional variation for selection to operate on. We investigate circa 750–850 bp of MHC class II DAB genes in four wild populations of the guppy Poecilia reticulata. By sequencing an extended region, we uncovered 40.9% more sequences (alleles), which would have been missed if we had amplified the exon 2 alone. We found evidence of several gene conversion events that may have homogenized sequence variation. This reduces the visible copy number variation (CNV) and can result in a systematic underestimation of the CNV in studies of the MHC and perhaps other multigene families. We then focus on a single cluster, which comprises 27 (of a total of 66) sequences. These sequences are virtually identical and show no signal of selection. We use microsatellites to reconstruct the populations' demography and employ simulations to examine whether so many similar nucleotide sequences can be maintained in the populations. Simulations show that this variation does not behave neutrally. We propose that selection operates outside the PBR, for example, on linked immune genes or on the "sheltered load" that is thought to be associated to the MHC. Future studies on the MHC would benefit from extending the amplicon size to include polymorphisms outside the exon with the PBR. This may capture otherwise cryptic haplotype variation and CNV, and it may help detect other regions in the MHC that are under selection.
Bioartificial Sinus Node Constructed via In Vivo Gene Transfer of an Engineered Pacemaker HCN Channel Reduces the Dependence on Electronic Pacemaker in a Sick-Sinus Syndrome Model
Authors: Hung-Fat Tse, Tian Xue, Chu-Pak Lau, Chung-Wah Siu, Kai Wang, Qing-Yong Zhang, Gordon F. Tomaselli, Fadi G. Akar, Ronald A. Li
Journal: Circulation (2006)

Background— The normal cardiac rhythm originates in the sinoatrial (SA) node that anatomically resides in the right atrium. Malfunction of the SA node leads to various forms of arrhythmias that necessitate the implantation of electronic pacemakers. We hypothesized that overexpression of an engineered HCN construct via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing in vivo. Methods and Results— Using various electrophysiological and mapping techniques, we examined the effects of in situ focal expression of HCN1-ΔΔΔ, the S3-S4 linker of which has been shortened to favor channel opening, on impulse generation and conduction. Single left ventricular cardiomyocytes isolated from guinea pig hearts preinjected with the recombinant adenovirus Ad-CMV-GFP-IRES-HCN1-ΔΔΔ in vivo uniquely exhibited automaticity with a normal firing rate (237±12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-ΔΔΔ–injected Langendorff-perfused hearts revealed the generation of spontaneous action potentials from the transduced region in the left ventricle. To evaluate the efficacy of our approach for reliable atrial pacing, we generated a porcine model of sick-sinus syndrome by guided radiofrequency ablation of the native SA node, followed by implantation of a dual-chamber electronic pacemaker to prevent bradycardia-induced hemodynamic collapse. Interestingly, focal transduction of Ad-CGI-HCN1-ΔΔΔ in the left atrium of animals with sick-sinus syndrome reproducibly induced a stable, catecholamine-responsive in vivo “bioartificial node” that exhibited a physiological heart rate and was capable of reliably pacing the myocardium, substantially reducing electronic pacing. Conclusions— The results of the present study provide important functional and mechanistic insights into cardiac automaticity and have further refined an HCN gene–based therapy for correcting defects in cardiac impulse generation.
Human self-reactive T cell clones expressing identical T cell receptor beta chains differ in their ability to recognize a cryptic self-epitope.
Authors: S Quaratino, M Feldmann, C M Dayan, O Acuto, M Londei
Journal: The Journal of Experimental Medicine (1996)

Recognition of self-antigens by T lymphocytes is a central event in autoimmunity. Understanding of the molecular interactions between T cell receptors (TCR) and self-epitopes may explain how T cells escape thymic education and initiate an autoimmune reaction. We have studied five human in vivo activated T cell clones specific for the region 535-551 of human thyroid peroxidase (TPO) established from a Graves' patient. Three clones (37, 72, and 73) expressed identical TCR beta and alpha chains rearranging V beta 1.1 and V alpha 15.1, and were considered sister clones. Clone 43 differed from clone 37 and its sisters in the J alpha region only. Clone NP-7 expressed V beta 6.5 but rearranged two in-frame TCR alpha chain, both using the V alpha 22.1 segment. Fine epitope mapping using nested peptides showed that clones using identical TCR beta chains, identical V alpha, but a different J alpha recognized distinct, nonoverlapping epitopes in the TPO 535-551 region. This finding shows that a different J alpha region alone leads to a heterogeneous pattern of recognition. This indicates that the "restricted" TCR V region usage sometimes found in autoimmune diseases may not always correspond to identical epitope recognition. To confirm that clones 37 (and its sisters) and 43 recognize different epitopes, the T cell clones were stimulated with a TPO-transfected autologous Epstein-Barr virus (EBV) cell line (TPO-EBV) that presents TPO epitopes afer endogenous processing. Only clone 37 and its sisters recognizes the TPO-EBV cell line, suggesting that the epitope recognized by clone 43 is not presented upon endogenous processing. We have shown that thyroid epithelial cells (TEC), the only cells that produce TPO, express HLA class II molecules in Graves' disease and can act as an antigen-presenting cells, presenting TPO after endogenous processing to autoantigen-reactive T cell clones. We tested, therefore, whether autologous TEC induced the same pattern of stimulation as TPO-EBV; T cell clone 37 recognizes the TEC, whereas it is stimulated poorly by the TPO loaded to autologous peripheral blood mononuclear cells (PBMC). Clone 43, which fails to recognize the TPO-EBV, also fails to recognize the TEC, but is activated by exogenous TPO presented by autologous PBMC. These results show that exogenous versus endogenous processing in vivo generates a different TPO epitope repertoire, producing a "cryptic" epitope (epitope not always available for recognition). Our findings define a route by which human self-reactive T cells may escape thymic selection and become activated in vivo, thus possibly leading to autoimmunity.
Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T cell acute lymphoblastic leukemia by real-time quantitative PCR assay
Authors: TJ M'soka, J Nishioka, A Taga, K Kato, H Kawasaki, Y Yamada, A Yu, Y Komada, T Nobori
Journal: Leukemia (2000)
Developing a novel in vitro 3D airway model to provide a viable alternative to animal use in asthma research
Authors: Gavin Morris, Leigh-Anne Carroll, Alan Knox, John Aylott, Amir Ghaemmaghami, Felicity Rose
Journal: European Respiratory Journal (2012)

Studies into airway disease have been limited to whole animal  in vivo  or single cell-type  in vitro  studies. In asthma, mouse immunological studies have lead to our understanding of the Th2 paradigm, but this reveals only a modest proportion of the human condition.  In vitro  primary cells studies provide insight into the underlying signaling mechanisms in airway disease, but tissue cultured-plastic restricts cell growth to a 2D monolayer. Reliance on these traditional platforms is decreasing as current protocols (such as using electrospun matrices) provide a better 3D environment for cells to inhabit  in vitro .  We are developing a tissue engineered 3D model of an airway bronchiole containing the three main structural cells (epithelial, fibroblast, and smooth muscle) sourced from both healthy and asthmatic patients. Using defined electrospinning parameters we have developed both nano- and micro-fibrous scaffolds to support the cell types within a 3D environment. Once the cell types have been grown on their tailored scaffolds, they are combined to form a simple construct of the bronchiole and held in a flow perfusion bioreactor to provide effective nutrient exchange and metabolic waste removal.  We have optimized a nanofibrous polyethylene tetraphthalate (PET) electrospun scaffold for epithelial cell growth and differentiation. Fibroblast and smooth muscle cells have been successfully cultured on a microfibrous PET electrospun scaffold. The scaffold system provides a platform to investigate cell-cell interactions within a bi- or tri-culture system. Preliminary data suggest fibroblasts play an important role in epithelial cell responses to airway inflammatory mediators.
Autocrine interaction between IL-5 and IL-1β mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle
Authors: Hakon Hakonarson, Neil Maskeri, Carrie Carter, Sing Chuang, Michael M. Grunstein
Journal: Journal of Clinical Investigation (1999)

T-helper type 2 (Th2) cytokines have been implicated in the pathogenesis of the pulmonary inflammatory response and altered bronchial responsiveness in allergic asthma. To elucidate the mechanism of Th2-dependent mediation of altered airway responsiveness in the atopic asthmatic state, the expression and actions of specific cytokines were examined in isolated rabbit and human airway smooth muscle (ASM) tissues and cultured cells passively sensitized with sera from atopic asthmatic patients or nonatopic/nonasthmatic (control) subjects. Relative to control tissues, the atopic asthmatic sensitized ASM exhibited significantly enhanced maximal isometric contractility to acetylcholine and attenuated relaxation responses to isoproterenol. These proasthmatic changes in agonist responsiveness were ablated by pretreating the atopic sensitized tissues with either an IL-5 receptor blocking antibody (IL-5ra) or the human recombinant IL-1 receptor antagonist (IL-1ra), whereas an IL-4 neutralizing antibody had no effect. Moreover, relative to controls, atopic asthmatic sensitized ASM cells demonstrated an initial, early (after 3 hours of incubation) increased mRNA expression and protein release of IL-5. This was followed (after 6 hours of incubation) by an enhanced mRNA expression and release of IL-1β protein, an effect that was inhibited in sensitized cells pretreated with IL-5ra. Extended studies demonstrated that naive ASM exposed to exogenously administered IL-5 exhibited an induced upregulated mRNA expression and protein release of IL-1β associated with proasthmatic-like changes in ASM constrictor and relaxant responsiveness, and that these effects were ablated in tissues pretreated with IL-1ra. Taken together, these observations provide new evidence that (a) the Th2 cytokine IL-5 and the pleiotropic proinflammatory cytokine IL-1β are endogenously released by atopic asthmatic sensitized ASM and mechanistically interact to mediate the proasthmatic perturbations in ASM responsiveness; and (b) the nature of this interaction is given by an initial endogenous release of IL-5, which then acts to induce the autologous release of IL-1β by the sensitized ASM itself, resulting in its autocrine manifestation of the proasthmatic phenotype.
THE EFFECT OF TREATMENT ON THE MENTAL LEVEL OF PATIENTS WITH GENERAL PARESIS
Authors: Samuel H. Epstein, Harry C. Solomon
Journal: American Journal of Psychiatry (1939)

1. Analysis of the psychometric determinations in 78 cases of general paresis shows that the change in intelligence quotient following treatment is relatively small in the majority of the cases, but there is a little greater likelihood for the intelligence rating to be increased than for it to fall. 2. The greatest increase in intelligence quotient occurred in those patients having an original quotient of between 60 and 90, and the great majority of the cases fell within this range. Patients with an originally relatively high or a very low rating are more likely to show a drop than a rise in the intelligence quotient following treatment. 3. There is suggestive evidence that the psychometric results are better in those patients who had, in the course of their treatment, fever combined with chemotherapy than those who had chemotherapy alone. 4. A comparison of the general clinical results with the psychometric results shows that the ability to return to work depends, in some degree, upon the final level of intelligence; and unless the final intelligence quotient reaches at least 70, the ability to be self-supporting is unlikely. It is also evident that if the original pre-treatment intelligence quotient is much below 70, the likelihood of restoring a patient to working efficiency is relatively slight. 5. It is probable that those patients who have a distinct decrease in their intelligence quotient prior to the beginning of treatment are unlikely to make a good clinical recovery. 6. Delusional trends, if they are well established, interfere with the clinical result even if the final intelligence quotient is high enough and near enough to the original level to presage a satisfactory result. 7. There is relatively little variance in psychometric results in the various mental pictures of the patients in this study, but the euphoric grandiose patients showed a little greater increase in the psychometric rating when this did occur. 8. The psychometric results do not parallel the changes in the spinal fluid, thus corroborating the well established experience that clinical outcome and spinal fluid results show no correlation. 9. If a change in the psychometric rating occurs, it becomes manifest within a few months after treatment, and the level remains relatively stable thereafter.
Epstein–Barr virus in Hodgkin’s disease
Authors: A.L.N. Chapman, A.B. Rickinson
Journal: Annals of Oncology (1998)

Epstein-Barr virus (EBV), a B-lymphotropic herpesvirus widespread in human populations, is carried by most individuals as an asymptomatic lifelong infection.Much progress has been made in our understanding of virus infection/persistence, and in the role of the cytotoxicT lymphocyte response in control of that infection.This same virus is linked to several malignancies, including endemic Burkitt's lymphoma, post-transplant lymphoproliferative disease and to many cases of Hodgkin's disease (HD).Recent evidence showing that HD, like the other EBV-associated lymphomas, is of B-cell origin suggests that the pathogenesis of these malignancies may share more com-mon ground than previously thought.The biology and cytotoxic T-cell control of primary and persistent EBV infection, and the links between EBV and all three lymphomas are reviewed.The expression of viral antigens in EBV-positive HD raises the possibility of developing tumour immunotherapy, using relevant components of the EBV-specific T-cell response; progress to date, and future prospects for immune control of EBV-positive HD are discussed.