tbuckley/cabot-search huggingface dataset:
Circulating Mesothelin Protein and Cellular Antimesothelin Immunity in Patients with Pancreatic Cancer
Authors: Fabian Mc. Johnston, Marcus C.B. Tan, Benjamin R. Tan, Matthew R. Porembka, Elizabeth M. Brunt, David C. Linehan, Peter O. Simon, Stacey Plambeck-Suess, Timothy J. Eberlein, Karl Erik Hellstrom, Ingegerd Hellstrom, William G. Hawkins, Peter Goedegebuure
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Mesothelin is a glycoprotein expressed on normal mesothelial cells and is overexpressed in several histologic types of tumors including pancreatic adenocarcinomas. A soluble form of mesothelin has been detected in patients with ovarian cancer and malignant mesothelioma, and has prognostic value. Mesothelin has also been considered as a target for immune-based therapies. We conducted a study on the potential clinical utility of mesothelin as a biomarker for pancreatic disease and therapeutic target pancreatic cancer. Experimental Design: Tumor cell–bound and soluble mesothelin in patients was evaluated by immunohistochemistry and ELISA, respectively. The in vitro cellular immune response to mesothelin was evaluated by INFγ ELISA and intracellular cytokine staining for IFNγ in CD4+ and CD8+ T cells. The level of circulating antibodies to mesothelin was measured by ELISA. Results: All tumor tissue from patients with pancreatic adenocarcinoma expressed mesothelin (n = 10). Circulating mesothelin protein was detected in patients with pancreatic adenocarcinoma (73 of 74 patients) and benign pancreatic disease (5 of 5) but not in healthy individuals. Mesothelin-specific CD4+ and CD8+ T cells were generated from peripheral blood lymphocytes of patients with pancreatic cancer in 50% of patients compared with only 20% of healthy individuals. Antibodies reactive to mesothelin were detected in &amp;lt;3% of either patients or healthy individuals. Conclusions: Circulating mesothelin is a useful biomarker for pancreatic disease. Furthermore, mesothelin-specific T cells can be induced in patients with pancreatic cancer. This suggests that mesothelin is a potential target for immune-based intervention strategies in pancreatic cancer. (Clin Cancer Res 2009;15(21):6511–8)
Lysosomal accumulation of gliadin p31-43 peptide induces oxidative stress and tissue transglutaminase-mediated PPAR downregulation in intestinal epithelial cells and coeliac mucosa
Authors: A. Luciani, V. R. Villella, A. Vasaturo, I. Giardino, M. Pettoello-Mantovani, S. Guido, O. N. Cexus, N. Peake, M. Londei, S. Quaratino, L. Maiuri
Journal: Gut (2009)

<h3>Background</h3> An unresolved question in coeliac disease is to understand how some toxic gliadin peptides, in particular p31–43, can initiate an innate response and lead to tissue transglutaminase (TG2) upregulation in coeliac intestine and gliadin sensitive epithelial cell lines. <h3>Aim</h3> We addressed whether the epithelial uptake of p31–43 induces an intracellular pro-oxidative envoronment favouring TG2 activation and leading to the innate immune response. <h3>Methods</h3> The time course of intracellular delivery to lysosomes of p31–43, pα-2 or pα-9 gliadin peptides was analysed in T84 and Caco-2 epithelial cells. The effects of peptide challenge on oxidative stress, TG2 and peroxisome proliferator-activated receptor (PPAR)γ ubiquitination and p42/44–mitogen activated protein (MAP) kinase or tyrosine phosphorylation were investigated in cell lines and cultured coeliac disease biopsies with/without anti-oxidant treatment or TG2 gene silencing by immunoprecipitation, western blot, confocal microscopy and Fluorenscence Transfer Resonance Energy (FRET) analysis. <h3>Results</h3> After 24 h of challenge p31–43, but not pα-2 or pα-9, is still retained within LAMP1-positive perinuclear vesicles and leads to increased levels of reactive oxygen species (ROS) that inhibit TG2 ubiquitination and lead to increases of TG2 protein levels and activation. TG2 induces cross-linking, ubiquitination and proteasome degradation of PPARγ. Treatment with the antioxidant EUK-134 as well as TG2 gene silencing restored PPARγ levels and reversed all monitored signs of innate activation, as indicated by the dramatic reduction of tyrosine and p42/p44 phosphorylation. <h3>Conclusion</h3> p31–43 accumulation in lysosomes leads to epithelial activation via the ROS–TG2 axis. TG2 works as a rheostat of ubiquitination and proteasome degradation and drives inflammation via PPARγ downregulation.
Ligation of Endothelial α <sub>v</sub> β <sub>3</sub> Integrin Increases Capillary Hydraulic Conductivity of Rat Lung
Authors: Hiroshi Tsukada, Xiaoyou Ying, Chenzhong Fu, Shigemi Ishikawa, Paula McKeown-Longo, Steven Albelda, Sunita Bhattacharya, Bonnie Anderson Bray, Jahar Bhattacharya
Journal: Circulation Research (1995)

Complement-mediated pulmonary edema results from increases in lung capillary hydraulic conductivity (Lp), possibly by receptor-mediated mechanisms. We considered the Lp effects of vitronectin and the vitronectin-containing complement complex SC5b-9, which ligate the integrin alpha v beta 3. Vitronectin, SC5b-9, and SC5b-9-enriched zymosan-activated serum all rapidly increased Lp, as determined by the split-drop technique in single lung capillaries of rat lung. The Lp increases were inhibited by a monospecific (LM609) and a polyclonal (R838) antibody against the alpha v beta 3 integrin but not by an irrelevant monoclonal antibody isotype matched with LM609, by a monoclonal antibody against the alpha v beta 5 integrin, or by preimmune rabbit serum. Vitronectin monomers failed to increase Lp. The tyrosine kinase blockers genistein and methyl 2,5-dihydroxycinnamate caused significant concentration-dependent inhibitions of Lp increases due to vitronectin and zymosan-activated serum. By contrast, the protein kinase C blocker calphostin C had no major effect. We conclude that (1) multivalent ligation of the luminally located alpha v beta 3 integrin of lung capillary endothelium increases transcapillary liquid flux, and (2) the dominant signal transduction pathway for this effect occurs through tyrosine kinase activation.
Dendritic Cells in the Kidney
Authors: Rohan John, Peter J. Nelson
Journal: Journal of the American Society of Nephrology (2007)

Dendritic cells (DC) in nonlymphoid organs function at the crossroads of innate and adaptive immunity, self-tolerance, and tissue homeostasis. This review provides an overview of the study of DC in the kidney, tracing its history leading to the current knowledge of the origins, migration, and function of renal DC. Together, these studies suggest that renal DC play a critical role in the health and disease of the kidney, opening the way to direct targeting of renal DC for therapeutic benefit.
Case of Acute Hydrocephalus: Iodine: Cure
Authors: E. Copeman
Journal: BMJ (1848)

CASE OF ACUTE HYDROCEPHALUS.Pergat.She is improving, but the excretions are still black.1 p.m.The gallic acid produced vomiting; and effervescing draughts with Sulpbate of Magnesia, aud Liq.Opii Sed., Battlei, were substituted.The following day she commenced quinine and acid.The urine was become of natural color, and the motions althougb still dark had lost their blackness.5th.The catamenia appeared, and for a few hours assumed an hmmorrhagic character, but were checked by half-grain doses of opium.17th.She was able to go home, there had been no return, of the hmmorrhage and she was graduallygaining strength; the excretions were healthy, and the spots on ber body had nearly disappeared.She was ordered to take quinine, iron, and sulphuric acid, while in the country.August 15th.She returned to Plymouth, and I then examined into the state of the various organs of the body as exactly as possible with the following results:- The heart is large and powerful, but otherwise beal- thy.The right lung healthy, with the exception of slight sibilous rales on deep inspiration.In the left
CRP and ASDAS are associated with future elevated arterial stiffness, a risk marker of cardiovascular disease, in patients with ankylosing spondylitis: results after 5-year follow-up
Authors: Inger Jorid Berg, Anne Grete Semb, Désirée van der Heijde, Tore K Kvien, Inge C Olsen, Hanne Dagfinrud, Sella A Provan
Journal: Annals of the Rheumatic Diseases (2015)

To identify factors associated with elevated arterial stiffness in a 5-year follow-up of patients with ankylosing spondylitis (AS).C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath AS disease activity index (BASDAI) and AS disease activity score (ASDAS) were recorded in 2003, and arterial stiffness (Augmentation Index (AIx) and pulse wave velocity (PWV)) in 2008/2009. Patients were grouped into quartiles according to baseline CRP, ESR and BASDAI and four ASDAS groups. Trend analyses were performed using ANCOVA (AIx/PWV as dependent variable) with separate models for CRP, ESR, BASDAI and ASDAS (age and gender adjusted). Independent predictors of future AIx and PWV levels were identified in multivariate linear regression models.In total, 85 patients participated. Increasing baseline values of CRP, ESR and ASDAS were associated with elevated AIx on follow-up (p(trend) 0.01, 0.05 and 0.04, respectively). Similar non-significant patterns were seen for PWV. In the multivariate analyses, baseline CRP and ASDAS were independently associated with future elevated AIx (p=0.03 and0.02, respectively). In the multivariate PWV model, results for CRP and ASDAS were non-significant.Baseline CRP and ASDAS were associated with future elevated arterial stiffness measured as AIx, supporting that disease activity is related to future risk of cardiovascular disease in patients with AS.
Mixed Multiple Endocrine Neoplasia Syndromes
Authors: W. Michael Alberts
Journal: JAMA (1980)

ERDHEIM first reported the occurrence of multiple endocrine tumors in a single patient. Since that time, many such patients have been described, with the endocrine tumors most frequently occurring in one of two patterns. Type I, also known as Wermer's syndrome, consists of involvement of the pituitary gland, the pancreatic islets, and the parathyroid glands. Occurring less often, but still considered part of the multiple endocrine neoplasia (MEN) I syndrome, is involvement of the thyroid and adrenal cortex, bronchial and intestinal carcinoid tumors, lipomas, brown fat tumors, gastric polyps, schwannomas, and thymomas. Type II has been divided into type IIa, also known as Sipple's syndrome, which consists of pheochromocytoma, medullary carcinoma of the thyroid, and hyperparathyroidism, and into type IIb or type III,<sup>1</sup>which consists of medullary carcinoma of the thyroid, pheochromocytoma, mucosal neuromas, hyperplastic corneal nerves, Marfan-like appearance, and, rarely, parathyroid disorders. According to Schimke,<sup>2</sup>these MEN
THE ROLE OF HYPOVENTILATION AND VENTILATION-PERFUSION REDISTRIBUTION IN OXYGEN-INDUCED HYPERCAPNIA DURING ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Authors: David Feller-Kopman, Richard Schwartzstein
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The detailed mechanisms of oxygen-induced hypercapnia were examined in 22 patients during an acute exacerbation of chronic obstructive pulmonary disease. Ventilation, cardiac output, and the distribution of ventilation-perfusion (V A/Q ) ratios were measured using the multiple inert gas elimination technique breathing air and then 100% oxygen through a nose mask. Twelve patients were classified as retainers (R) when Pa(CO(2)) rose by more than 3 mm Hg (8.3 +/- 5.6; mean +/- SD) after breathing 100% oxygen for at least 20 min. The other 10 patients showed a change in Pa(CO(2)) of -1.3 +/- 2.2 mm Hg breathing oxygen and were classified as nonretainers (NR). Ventilation fell significantly from 9.0 +/- 1.5 to 7.2 +/- 1.2 L/min in the R group breathing oxygen (p = 0.007), whereas there was no change in ventilation in the NR group (9.8 +/- 1.8 to 9.9 +/- 1.8 L/min). The dispersion of V A/Q ratios as measured by log SD of blood flow (log SD Q) increased significantly in both R (0.96 +/- 0. 17 to 1.13 +/- 0.17) and NR (0.77 +/- 0.20 to 1.04 +/- 0.23, p < 0.05) groups breathing oxygen, whereas log SD of ventilation (log SD Q ) increased only in the R group (0.97 +/- 0.24 to 1.20 +/- 0.46, p < 0.05). This study suggests that an overall reduction in ventilation characterizes oxygen-induced hypercapnia, as an increased dispersion of blood flow from release of hypoxic vasoconstriction occurred to a significant and similar degree in both groups. The significant increase in wasted ventilation (alveolar dead space) in the R group only may be secondary to the higher carbon dioxide tension, perhaps related to bronchodilatation.
P64 The effect of wood smoke on the ability of human macrophages to phagocytose and kill Mycobacterium tuberculosis
Authors: J. E. Scriven, D. G. Fullerton, A. Warman, S. B. Gordon
Journal: Thorax (2011)

<h3>Introduction</h3> Half of the world9s population are exposed to household air pollution from biomass fuels, which are increasingly recognised as a global risk factor for impaired respiratory health. Data from case-control studies has associated Tuberculosis (TB) with biomass fuel exposure. We hypothesised that particulate matter (PM) within alveolar macrophages of individuals exposed to biomass smoke detrimentally affects macrophage function by: (A) Reduced phagocytosis of TB, leading to increased infectivity and (B) Impaired macrophage killing of TB, leading to increased susceptibility to disease. This study assessed the ability of wood smoke exposed human monocyte-derived macrophages (MDMs) to phagocytose and kill TB in vitro. <h3>Methods</h3> MDMs, from buffy coats, were cultured in vitro for 12 days and then exposed to suspensions of wood smoke PM (Malawian (MW) and Norwegian (NW) wood, 10 μg/ml or 50 μg/ml) for 8 h. The PM loaded cells were then challenged with TB. Phagocytosis was assessed by manually counting infected macrophages, using fluorescent microscopy and by quantitative culture of day 1 supernatant and macrophage lysate. Remaining cells were maintained in culture for 7 days before lysis and quantitative culture to assess intracellular growth. <h3>Results</h3> Microscopy data showed a reduced proportion of infected macrophages in the high dose NW smoke group (Abstract P64 figure 1A), and fewer TB bacilli per macrophage in the two MW smoke groups (Abstract P64 figure 1B). Quantitative culture of day 1 supernatant and cell lysate showed no difference between the groups (Abstract P64 figure 1C). Quantitative culture of day 7 lysate showed reduced <i>Mycobacteria</i> loads in the high dose NW smoke group (Abstract P64 figure 1D). <h3>Discussion</h3> We have developed an in vitro model to assess the interaction between TB and wood smoke exposed macrophages. Phagocytic data does not fully support increased TB infectivity in biomass smoke exposed individuals. Quantitative culture data does not demonstrate a difference in the ability of wood smoke exposed MDMs to kill TB; high dose NW smoke led to a reduced intra-macrophage growth of TB probably as a result of the toxic effect of PM on <i>Mycobacteria</i> growth. Modifications of this model are required to provide mechanistic evidence of an association of TB with wood smoke exposure.
Randomized Comparison of Megestrol Acetate Versus Dexamethasone Versus Fluoxymesterone for the Treatment of Cancer Anorexia/Cachexia
Authors: Charles L. Loprinzi, John W. Kugler, Jeff A. Sloan, James A. Mailliard, James E. Krook, Mary B. Wilwerding, Kendrith M. Rowland, John K. Camoriano, Paul J. Novotny, Bradley J. Christensen
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetites in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0.75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetites and drug toxicities. RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P = .03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P = .06). CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.
Epidermal growth factor reduces multiorgan failure induced by thioacetamide
Authors: M E Caballero
Journal: Gut (2001)

Multiorgan failure is a severe life threatening state where present therapeutic approaches are suboptimal. Epidermal growth factor (EGF) is a potent stimulant of repair in in vitro and in vivo models. We therefore examined its potential beneficial effect in reducing mortality and injury induced by the noxious agent thioacetamide (TAA).Mice (20 per group) were fasted overnight and received a single intraperitoneal dose of human recombinant EGF at 10 or 30 microg/kg or saline (control). Either 30 minutes before or after EGF, all animals also received TAA (40 mg/kg intraperitoneally). Twenty four hours later, surviving animals were killed, tissues collected, and degree of organ injury assessed.Fifty per cent (10/20) of control animals died within the first 24 hour period. Mortality was almost completely prevented by the higher dose of EGF whether given before or after TAA (p<0.01) and was reduced by about 50% with the lower dose of EGF. In control animals, the entire length of the jejunum and ileum had necrosis with or without mucosal denudation. In contrast, necrosis affected only about 10-20% of the total length in EGF treated groups (both p<0.01 v control). Control animals showed marked glomerular tuft collapse, interstitial haemorrhage, and increased plasma creatinine levels. These effects were significantly reduced in animals given EGF (30 microg/kg; p<0.01). All groups showed similar changes in liver histology (centrilobular necrosis) and alanine transaminase levels (10-fold increase).Although EGF did not prevent the hepatotoxicity associated with TAA, it reduced mortality, renal injury, and gastrointestinal damage. These studies provide preliminary evidence that EGF may be a novel approach for the prevention and/or treatment of multiorgan failure.
Cholesterol synthesis in the squirrel monkey: relative rates of synthesis in various tissues and mechanisms of control
Authors: John M. Dietschy, Jean D. Wilson
Journal: Journal of Clinical Investigation (1968)

Cholesterol synthesis has been extensively investigated in various tissues of lower mammals; however, there is little specific information concerning cholesterologenesis in the primate. Furthermore, experiments in whole animals suggest that important differences may exist in the features of cholesterologenesis in the dog and rat versus the monkey and man. Using the new world squirrel monkey, therefore, we performed the present studies to determine the rates of cholesterologenesis in various tissues per unit weight, to define the relative rates of whole organ synthesis, and to evaluate the operation of control mechanisms in these tissues.In control animals fed a low cholesterol chow diet, the liver and ileum were the two most active sites for cholesterologenesis followed, in order, by the colon, esophagus, and proximal small bowel. Rates of synthesis in 10 other tissues tested were considerably lower than these found in the gastrointestinal tract. When rates of whole organ synthesis were calculated, three tissues, i.e., liver, bowel, and skin, accounted for 92% of the total demonstrable synthetic activity.Following cholesterol feeding utilizing either a solid chow or liquid formula diet, marked suppression of hepatic cholesterologenesis occurred while synthesis in other organs remained essentially unaltered. Similarly, fasting animals for periods up to 96 hr resulted in suppression of synthesis in the liver, but not in various levels of the intestine. Finally, biliary diversion for 48 hr caused a twofold increase in hepatic cholesterologenesis and a six- to eightfold increase in sterol synthesis in the small but not the large intestine.
Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial
Authors: D. Tripathy, M. Lichinitzer, A. Lazarev, S.A. MacLachlan, J. Apffelstaedt, M. Budde, B. Bergstrom
Journal: Annals of Oncology (2004)
Interobserver reliability of ultrasonography in the assessment of cartilage damage in rheumatoid arthritis
Authors: E. Filippucci, K. R. da Luz, L. Di Geso, F. Salaffi, M. Tardella, M. Carotti, J. Natour, W. Grassi
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> To evaluate the interobserver reliability of ultrasonography (US) in the assessment of cartilage damage at metacarpophalangeal (MCP) joint level in patients with rheumatoid arthritis (RA). <h3>Methods</h3> US examinations were performed on 80 MCP joints of 20 patients with RA using a MyLab70 XVG (Esaote Biomedica, Genoa, Italy), equipped with a broadband linear probe (6–18 MHz). For each patient, second and third MCP joints of both hands were examined independently on the same day by two rheumatologists (an experienced musculoskeletal sonographer and an investigator with limited US training). A multiplanar scanning technique on dorsal, lateral and volar aspects of the MCP joints was adopted. All US pathological findings were documented on at least two perpendicular scanning planes. Each joint was assessed by quadrant for the presence or absence of cartilage damage. Cartilage damage was also scored per quadrant on a five-grade semiquantitative scoring system on which investigators reached a consensus prior to the study. <h3>Results</h3> Exact agreement between investigators was found in 173 out of 200 quadrants (86.5%) with regard to presence or absence of cartilage damage. Percentages of exact agreement for cartilage damage semiquantitative assessment at dorsal, lateral and volar quadrants were 72.5%, 52.5% and 85%, respectively, while unweighted κ values were 0.561, 0.366 and 0.766, respectively. <h3>Conclusions</h3> The present study demonstrated moderate to good interobserver reproducibility of a semiquantitative scoring system based on qualitative morphological changes for cartilage damage at MCP joint level in patients with RA.