tbuckley/cabot-search huggingface dataset:
Conventional and modified nasal potential-difference measurement in cystic fibrosis.
Authors: T Höfmann, O Bohmer, G Hüls, H G Terbrack, P Bittner, V Klingmüller, E Heerd, H Lindemann
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Cystic fibrosis (CF) is associated with impaired ion transport across epithelial membranes and an increased transepithelial potential difference (PD) that can be measured in airway epithelium. The aim of this study was to investigate the diagnostic value of nasal PD in CF, and to test a modified approach to the measurement of this PD. The reproducibility and diagnostic sensitivity and specificity of nasal PD measurements were tested with the perfusion technique and with a simplified modification of the technique done with a novel, solid-state exploring electrode. With the perfusion method, basal PD values were different in CF patients (mean +/- SEM: -51.6 +/- 0.9 mV, n = 104) than in normal (-15.5 +/- 0.9 mV, n = 58, p < 0.01) subjects. CF patients with acute rhinitis or other nasal pathology had mean PD values that were intermediate between those of the patients and normal and disease-control groups (-28.3 +/- 1.2 mV, n = 40, p < 0.01, different from normal). The diagnostic sensitivity of the perfusion method for CF was 91.3%, and the specificity was 96.4%. PD measurements with the modified technique correlated highly with the results achieved with the perfusion method (r = 0.94, n +/- 158). The measurement of nasal PD effectively distinguishes CF from control subjects. Care must be taken in the interpretation of measurements made on acutely inflamed epithelium. The modified method was simpler than the conventional perfusion technique, and equally effective.
Platelet Lipidomics
Authors: Valerie B. O’Donnell, Robert C. Murphy, Steve P. Watson
Journal: Circulation Research (2014)

Lipids are diverse families of biomolecules that perform essential structural and signaling roles in platelets. Their formation and metabolism are tightly controlled by enzymes and signal transduction pathways, and their dysregulation leads to significant defects in platelet function and disease. Platelet activation is associated with significant changes to membrane lipids, and formation of diverse bioactive lipids plays essential roles in hemostasis. In recent years, new generation mass spectrometry analysis of lipids (termed lipidomics) has begun to alter our understanding of how these molecules participate in key cellular processes. Although the application of lipidomics to platelet biology is still in its infancy, seminal earlier studies have shaped our knowledge of how lipids regulate key aspects of platelet biology, including aggregation, shape change, coagulation, and degranulation, as well as how lipids generated by platelets influence other cells, such as leukocytes and the vascular wall, and thus how they regulate hemostasis, vascular integrity, and inflammation, as well as contribute to pathologies, including arterial/deep vein thrombosis and atherosclerosis. This review will provide a brief historical perspective on the characterization of lipids in platelets, then an overview of the new generation lipidomic approaches, their recent application to platelet biology, and future perspectives for research in this area. The major platelet-regulatory lipid families, their formation, metabolism, and their role in health and disease, will be summarized.
Modulation of the ATPase and Transport Activities of Broad-Acting Multidrug Resistance Factor ABCC10 (MRP7)
Authors: Ekaterina V. Malofeeva, Natalya Domanitskaya, Mariya Gudima, Elizabeth A. Hopper-Borge
Journal: Cancer Research (2012)

Abstract The cell surface molecule ABCC10 is a broad-acting transporter of xenobiotics, including cancer drugs, such as taxanes, epothilone B, and modulators of the estrogen pathway. Abcc10−/− mice exhibit increased tissue sensitivity and lethality resulting from paclitaxel exposure compared with wild-type counterparts, arguing ABCC10 functions as a major determinant of taxane sensitivity in mice. To better understand the mechanistic basis of ABCC10 action, we characterized the biochemical and vectorial transport properties of this protein. Using crude membranes in an ABCC10 overexpression system, we found that the ABCC10 transport substrates estrogen estradiol-glucuronide (E217βG) and leukotriene C4 (LTC4) significantly stimulated ABCC10 beryllium fluoride (BeFx)-sensitive ATPase activity. We also defined the E217βG antagonist, tamoxifen, as a novel substrate and stimulator of ABCC10. In addition, a number of cytotoxic substrates, including docetaxel, paclitaxel, and Ara-C, increased the ABCC10 basal ATPase activity. We determined that ABCC10 localizes to the basolateral cell surface, using transepithelial well assays to establish that ABCC10-overexpressing LLC-PK1 cells exported [3H]-docetaxel from the apical to the basolateral side. Importantly, we found that the clinically valuable multikinase inhibitor sorafenib, and a natural alkaloid, cepharanthine, inhibited ABCC10 docetaxel transport activity. Thus, concomitant use of these agents might restore the intracellular accumulation and potency of ABCC10-exported cytotoxic drugs, such as paclitaxel. Overall, our work could seed future efforts to identify inhibitors and other physiologic substrates of ABCC10. Cancer Res; 72(24); 6457–67. ©2012 AACR.
Plasma and Urinary Heme Oxygenase-1 in AKI
Authors: Richard A. Zager, Ali C.M. Johnson, Kirsten Becker
Journal: Journal of the American Society of Nephrology (2012)

AKI induces upregulation of heme oxygenase 1 (HO-1), which exerts cytoprotective effects and modulates the renal response to injury, suggesting that a biomarker of intrarenal HO-1 activity may be useful. Because HO-1 largely localizes to the endoplasmic reticulum and has no known secretory pathway, it is unclear whether plasma or urinary levels of HO-1 reflect intrarenal HO-1 expression. We measured plasma and urinary levels of HO-1 by ELISA during the induction and/or maintenance phases of four mouse models of AKI: ischemia/reperfusion, glycerol-induced rhabdomyolysis, cisplatin nephrotoxicity, and bilateral ureteral obstruction. In addition, we measured levels of HO-1 mRNA and protein in the renal cortex. Each AKI model increased renal HO-1 gene expression, which corresponded with release of HO-1 into plasma and urine by 4 hours. Over time, the magnitudes of plasma and urinary HO-1 paralleled renal cortical gene expression. AKI and the associated uremia did not seem to affect extrarenal HO-1 gene activity assessed in the liver, lung, and spleen. In iron-challenged, cultured proximal tubule cells, we observed a positive correlation between HO-1 mRNA level and HO-1 release. In humans, 10 patients with AKI demonstrated markedly higher levels of plasma and urine HO-1 levels than 10 critically ill patients without AKI or 20 patients with CKD or ESRD. In summary, these data suggest that plasma and urinary HO-1 levels may serve as biomarkers of AKI and intrarenal HO-1 gene activity.
Identification of a Novel Major Histocompatibility Complex Class II–restricted Tumor Antigen Resulting from a Chromosomal Rearrangement Recognized by CD4+ T Cells
Authors: Rong-Fu Wang, Xiang Wang, Steven A. Rosenberg
Journal: The Journal of Experimental Medicine (1999)

CD4+ T cells play an important role in antitumor immune responses and autoimmune and infectious diseases. Although many major histocompatibility complex (MHC) class I–restricted tumor antigens have been identified in the last few years, little is known about MHC class II– restricted human tumor antigens recognized by CD4+ T cells. Here, we describe the identification of a novel melanoma antigen recognized by an human histocompatibility leukocyte antigen (HLA)-DR1–restricted CD4+ tumor-infiltrating lymphocyte (TIL)1363 using a genetic cloning approach. DNA sequencing analysis indicated that this was a fusion gene generated by a low density lipid receptor (LDLR) gene in the 5′ end fused to a GDP-l-fucose:β-d-galactoside 2-α-l-fucosyltransferase (FUT) in an antisense orientation in the 3′ end. The fusion gene encoded the first five ligand binding repeats of LDLR in the NH2 terminus followed by a new polypeptide translated in frame with LDLR from the FUT gene in an antisense direction. Southern blot analysis showed that chromosomal DNA rearrangements occurred in the 1363mel cell line. Northern blot analysis detected two fusion RNA transcripts present only in the autologous 1363mel, but not in other cell lines or normal tissues tested. Two minimal peptides were identified from the COOH terminus of the fusion protein. This represents the first demonstration that a fusion protein resulting from a chromosomal rearrangement in tumor cells serves as an immune target recognized by CD4+ T cells.
Effects of drive train stimulus intensity on ventricular refractoriness in humans.
Authors: J J Langberg, H Calkins, J Sousa, R el-Atassi, F Morady
Journal: Circulation (1991)

The strength-interval relation between the intensity of premature stimulus and the ventricular effective refractory period (VERP) has been well characterized. The effects of variation in the intensity of the basic drive train stimuli (S1) on VERP are not as well defined. This relation was studied in 44 patients undergoing clinically indicated electrophysiological study.The outputs of two stimulus isolation units were connected in parallel, allowing the intensity of S1 to be varied independently of intensity of the extrastimulus (S2). To prevent confounding effects from cycle length change, continuous overdrive pacing was performed for 3 minutes before each measurement of VERP. The effect of S1 intensity on VERP was assessed in 24 patients with S2 intensity kept constant at twice threshold. VERP shortened from 232 +/- 19 msec at an S1 intensity of 1.5 times threshold to 219 +/- 20 msec at 5 mA and 211 +/- 19 msec at 10 mA (p less than 0.0001 for baseline versus 5 mA and for 5 mA versus 10 mA). Autonomic blockade with atropine and propranolol blunted but did not completely eliminate this effect. To assess whether the effect of S1 intensity on VERP was independent of S2 intensity, S2 strength-interval curves were generated in 10 patients at low (1.5 times threshold) and high (10 mA) S1 intensities. All portions of the strength-interval curve were shifted to the left by an increase in S1 intensity. The time course of change in VERP after an abrupt increase in S1 intensity was assessed in an additional 10 patients. VERP changed slowly, requiring 18 +/- 28 seconds to shorten by 2 msec and 64 +/- 46 seconds to decrease by 10 msec after a change in S1 intensity from 1.5 times threshold to 10 mA. In a final group of 10 patients, VERP was measured using an eight-beat drive train and a 4-second intertrain interval. With this more conventional protocol, VERP shortened by 14 +/- 8 msec with an increase in S1 intensity from 1.5 times threshold to 10 mA.Increasing S1 intensity results in clinically significant, progressive shortening of VERP in man. This effect is independent of S2 intensity. The prolonged time course of the change in VERP after an increase in S1 intensity and the attenuation of this effect by autonomic blockade are consistent with stimulation of sympathetic nerve terminals and catecholamine release as a result of intense stimulation.
Fcγ receptors are required for NF-κB signaling, microglial activation and dopaminergic neurodegeneration in an AAV-synuclein mouse model of Parkinson's disease
Authors: Shuwen Cao, Shaji Theodore, David G Standaert
Journal: Molecular Neurodegeneration (2010)

Abstract Overexpression of alpha-synuclein (α-SYN), a protein which plays an important role in the pathogenesis of Parkinson's disease (PD), triggers microglial activation and adaptive immune responses, and leads to neurodegeneration of dopaminergic (DA) neurons. We hypothesized a link between the humoral adaptive immune response and microglial activation in α-SYN induced neurodegeneration. To test this hypothesis, we employed adeno-associated virus serotype 2 (AAV2) to selectively over-express human α-SYN in the substantia nigra (SN) of wild-type mice and FcγR-/- mice, which lack high-affinity receptors for IgG. We found that in wild-type mice, α-SYN induced the expression of NF-κB p65 and pro-inflammatory molecules. In FcγR-/- mice, NF-κB activation was blocked and pro-inflammatory signaling was reduced. Microglial activation was examined using immunohistochemistry for gp91PHOX. At four weeks, microglia were strongly activated in wild-type mice, while microglial activation was attenuated in FcγR-/- mice. Dopaminergic neurodegeneration was examined using immunohistochemistry for tyrosine hydroxylase (TH) and unbiased stereology. α-SYN overexpression led to the appearance of dysmorphic neurites, and a loss of DA neurons in the SN in wild-type animals, while FcγR-/- mice did not exhibit neuritic change and were protected from α-SYN-induced neurodegeneration 24 weeks after injection. Our results suggest that the humoral adaptive immune response triggered by excess α-SYN plays a causative role in microglial activation through IgG-FcγR interaction. This involves NF-κB signaling, and leads to DA neurodegeneration. Therefore, blocking either FcγR signaling or specific intracellular signal transduction events downstream of FcγR-IgG interaction, such as NF-κB activation, may be viable therapeutic strategies in PD.
Specialized antigen-presenting cells. Splenic dendritic cells and peritoneal-exudate cells induced by mycobacteria activate effector T cells that are resistant to suppression.
Authors: J S Britz, P W Askenase, W Ptak, R M Steinman, R K Gershon
Journal: The Journal of Experimental Medicine (1982)

We have tested the ability of several types of trinitrophenyl (TNP)-labeled Ia+ cells to induce contact hypersensitivity (CS) after intravenous injection. Most labeled cell types (spleen cells, splenic macrophages, various types of peritoneal-exudate cells) not only fail to induce CS after this type of inoculation but, rather, activate T suppressor cells leading to specific immunological tolerance. Occasionally, some of these immunizing cells managed to bypass the T suppressor system and induced CS. In those cases the response was short-lived and could be blocked by concomitant injection of trinitrobenzelsulphonic acid (TNBS), a potent inducer of T suppressor cells. In sharp contrast to these results, TNP-labeled splenic dendritic cells and TNP-labeled peritoneal-exudate cells induced by complete Freund's adjuvant had the following distinctive features: (a) They were always able to sensitize when injected intravenously, and the degree of sensitization they produced was roughly equivalent to that achieved by cutaneous application of picryl chloride, the chemically reactive form of TNP. (b) The response they elicited was long lived (i.e., lasted for greater than 3 wk). (c) Their sensitizing capacity could not be blocked by the concomitant injection of TNBS. (d) They elicited a response that could be adoptively transferred to untreated, normal recipients. These results indicate that the type of cell that first presents antigen to the immune system plays an important, even essential, role in determining the strength and duration of the subsequent immune response. In particular, the results suggest that some special antigen-presenting cells can induce a response that is relatively resistant to host suppressor mechanisms. Evidence that they do so by activating contrasuppressor cells is discussed.
Pathogenic role of anti- 2-glycoprotein I antibodies in antiphospholipid associated fetal loss: characterisation of 2-glycoprotein I binding to trophoblast cells and functional effects of anti- 2-glycoprotein I antibodies in vitro
Authors: N Di Simone
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> Antiphospholipid antibodies reacting with β2-glycoprotein I (β2GPI) have been associated with recurrent fetal loss and pregnancy complications. <b>Objective:</b> To investigate whether specific mutations in the phospholipid binding site of β2GPI might affect its binding to trophoblast and in turn the anti-β2GPI antibody induced functional effects. <b>Methods:</b> β2GPI adhesion to trophoblast was evaluated as human monoclonal IgM or polyclonal IgG anti-β2GPI antibody binding to trophoblast monolayers cultured (1) in complete medium; (2) in serum-free medium; (3) after serum starvation in the presence of purified human β2GPI; or (4) in the presence of β2GPI with single or multiple mutations in the amino acid loop Cys<sup>281</sup>-Lys-Asn-Lys-Glu-Lys-Lys-Cys<sup>288</sup>. The effect of anti-β2GPI binding to trophoblast was evaluated as chorionic gonadotropin (hCG) mRNA expression, and protein release by RT-PCR and radioimmunoassay, respectively. <b>Results:</b> β2GPI adhesion to trophoblast and its consequent recognition by the specific antibodies were inversely proportional to the mutation number in the phospholipid binding site. Anti-β2GPI antibodies reduced gonadotropin release, hormone dependent hCG mRNA expression, and protein synthesis in the presence of β2GPI, while the addition of the mutants or the absence of β2GPI had no effect. <b>Conclusions:</b> β2GPI binds to trophoblast in vitro through its fifth domain, as reported for endothelial cells, and can be recognised by anti-β2GPI antibodies; the antibody binding downregulates trophoblast hCG synthesis and secretion. Such a mechanism might contribute to defective placentation in women with fetal loss associated with the antiphospholipid syndrome.
Effects of Acute Hypoglycemia on Inflammatory and Pro-atherothrombotic Biomarkers in Individuals With Type 1 Diabetes and Healthy Individuals
Authors: Nino Gogitidze Joy, Maka S. Hedrington, Vanessa J. Briscoe, Donna B. Tate, Andrew C. Ertl, Stephen N. Davis
Journal: Diabetes Care (2010)

Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals.Thirty-five healthy volunteers (19 male and 16 female subjects age 32 +/- 2 years, BMI 26 +/- 2 kg/m(2), A1C 5.1 +/- 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 +/- 3 years, BMI 24 +/- 2 kg/m(2), A1C 7.7 +/- 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1)) euglycemic or hypoglycemic (2.9 +/- 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study.Insulin levels were similar (602 +/- 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 +/- 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 +/- 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes.In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.
Metachronous gastric MALT lymphoma and early gastric cancer: is residual lymphoma a risk factor for the development of gastric carcinoma?
Authors: C. Copie-Bergman, C. Locher, M. Levy, M.T. Chaumette, C. Haioun, M.H. Delfau-Larue, K. Leroy, P. Gaulard, J.C. Delchier
Journal: Annals of Oncology (2005)
IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner
Authors: S Chikano
Journal: Gut (2000)

<h3>BACKGROUND</h3> In murine models of inflammatory bowel disease, colonic inflammation is considered to be caused by an aberrant Th1-type immune response. <h3>AIM</h3> To investigate if systemic administration of interleukin (IL)-12 and IL-18 to wild-type BALB/c mice induces liver injury and intestinal inflammation, and if pathological changes are observed, what cytokines are involved. <h3>METHODS</h3> Mice (BALB/c-wild-type (wt), MRL-lpr/lpr, BALB/c-interferon γ knock out (IFN-γ KO), C57BL/6-inducible nitric oxide synthase (iNOS) KO, and BALB/c tumour necrosis factor α (TNF-α) KO) were injected intraperitoneally each day with IL-12 (20 ng/g/mouse) and/or IL-18 (200 ng/g/mouse). <h3>RESULTS</h3> Administration of IL-12 and IL-18 to BALB/c-wt mice induced prominent intestinal mucosal inflammation and fatty liver, leading to piloerection, bloody diarrhoea, and weight loss. IL-12 and IL-18 induced striking elevations in serum levels of IFN-γ that caused NO production, although increased NO had no exacerbating effect on mice. Moreover, iNOS KO mice, or MRL lpr/lpr mice lacking functional Fas were equally susceptible to IL-12 and IL-18. Administration of IL-12 and IL-18 did not induce TNF-α production in wild-type mice, and the same treatment to TNF-α KO mice induced intestinal mucosal inflammation. Furthermore, they had diffuse and dense infiltration of small fat droplets in their hepatocytes associated with an increase in serum levels of liver enzymes. In contrast, the same treatment in IFN-γ KO BALB/c mice and iNOS KO mice did not induce these changes. <h3>CONCLUSIONS</h3> Our study strongly indicates that IL-18 together with IL-12 induces intestinal mucosal inflammation in an IFN-γ dependent but TNF-α, NO, and Fas ligand independent manner, and fatty liver is dependent on IFN-γ and NO.