tbuckley/cabot-search huggingface dataset:
Combination of gastric atrophy, reflux symptoms and histological subtype indicates two distinct aetiologies of gastric cardia cancer
Authors: M H Derakhshan, R Malekzadeh, H Watabe, A Yazdanbod, V Fyfe, A Kazemi, N Rakhshani, R Didevar, M Sotoudeh, A A Zolfeghari, K E L McColl
Journal: Gut (2007)

Atrophic gastritis is a risk factor for non-cardia gastric cancer, and gastro-oesophageal reflux disease (GORD) for oesophageal adenocarcinoma. The role of atrophic gastritis and GORD in the aetiology of adenocarcinoma of the cardia remains unclear. We have investigated the association between adenocarcinoma of the different regions of the upper gastrointestinal tract and atrophic gastritis and GORD symptoms.138 patients with upper GI adenocarcinoma and age- and sex-matched controls were studied. Serum pepsinogen I/II was used as a marker of atrophic gastritis and categorised to five quintiles. History of GORD symptoms, smoking and H pylori infection were incorporated in logistic regression analysis. Lauren classification of gastric cancer was used to subtype gastric and oesophageal adenocarcinoma.Non-cardia cancer was associated with atrophic gastritis but not with GORD symptoms; 55% of these cancers were intestinal subtype. Oesophageal adenocarcinoma was associated with GORD symptoms, but not with atrophic gastritis; 84% were intestinal subtype. Cardia cancer was positively associated with both severe gastric atrophy [OR, 95% CI: 3.92 (1.77 to 8.67)] and with frequent GORD symptoms [OR, 95% CI: 10.08 (2.29 to 44.36)] although the latter was only apparent in the non-atrophic subgroup and in the intestinal subtype. The association of cardia cancer with atrophy was stronger for the diffuse versus intestinal subtype and this was the converse of the association observed with non-cardia cancer.These findings indicate two distinct aetiologies of cardia cancer, one arising from severe atrophic gastritis and being of intestinal or diffuse subtype similar to non-cardia cancer, and one related to GORD and intestinal in subtype, similar to oesophageal adenocarcinoma. Gastric atrophy, GORD symptoms and histological subtype may distinguish between gastric versus oesophageal origin of cardia cancer.
Anti-interleukin 1alpha autoantibodies
Authors: P Miossec
Journal: Annals of the Rheumatic Diseases (2002)

A natural treatment for rheumatoid arthritis

Prognostic markers are greatly needed to detect patients with rheumatoid arthritis (RA) at high risk of developing a destructive form of the disease as this may influence the choice of early treatment. Among the cytokines produced by the inflammatory synovium, interleukin 1 (IL1) appears to have a predominant role in joint destruction. Specific regulation of IL1 involves natural mechanisms, including soluble IL1 receptors, IL1 receptor antagonist (IL1ra), and anti-IL antibodies.1,2 Autoantibodies directed against cytokines were first described in 1989 as being mostly of the IgG isotype and binding with high affinity mainly to IL1α.

It is easy to imagine that defects in this natural regulation may contribute to changes in disease incidence and severity. However, definite demonstration of this association needs confirmation from different studies. With reference to the new study published in this issue of the Annals ,3 we will focus on the effect of autoantibodies to IL1α on disease presentation.

The classical way of detecting antibodies to IL1α is by a precipitation method, in which antibodies bind the radiolabelled human [125I]IL1α.4 The antibody-cytokine complex is then precipitated with polyethylene glycol (PEG). After centrifugation, radioactivity is measured in the pellet. Levels of antibodies are calculated as the percentage of [125I]IL1α precipitated.

Protein G immunoprecipitation is more specific than PEG precipitation, which allows precipitation of other than IgG complexes.5 It is antibody specific, binding to all IgG subclasses. In addition, it prevents interactions with other IL1 regulatory molecules, such as soluble IL1 receptors, IL1, or IL1ra. Antibodies can also be detected by an enzyme linked immunosorbent assay (ELISA), in which the cytokine bound to the ELISA plate is incubated with serum or plasma.6 After washes, the antibody bound to the cytokine is detected with …
MEDICARE AND MANAGED CARE
Authors: Harold S. Luft
Journal: Annual Review of Public Health (1998)

▪ Abstract Medicare offers nearly universal, but limited, coverage for the elderly. The vast majority of beneficiaries therefore obtain supplemental coverage, or they enroll in HMOs to gain extra benefits at substantially lower or zero cost. This is possible because of reduced utilization and costs, as well as favorable selection of lower-risk enrollees into HMOs. Competition from HMOs may lower local fee-for-service costs as well. Quality and satisfaction measures are quite balanced, with some results showing better HMO performance and some worse. The absence of adequate risk-adjusted payments to HMOs, however, gives them little incentive to develop high-quality programs for the sickest enrollees.
A cause of cholestatic jaundice
Authors: P G Wheeler, A Atrey, A Healey, K M Taylor, L R Jiao
Journal: Gut (2007)

A 44-year-old Romanian woman with a history of asthma, epilepsy, non-insulin dependent diabetes mellitus, and depression presented with a gradual weight loss over 1 year, pruritis over 3 months, and a history of dark urine and pale stools for several weeks. She denied any abdominal pain.

Clinical examination revealed a soft, non-tender abdomen with no organomegaly. The patient was not clinically …
Treatment of experimental murine pancreatic peritoneal carcinomatosis with fibroblasts genetically modified to express IL12: a role for peritoneal innate immunity
Authors: J M Peron, C Bureau, P Gourdy, H Lulka, A Souque, B Calippe, J Selves, T Al Saati, J Bernad, P Cordelier, B Couderc, L Pradayrol, B Pipy, L Buscail, J P Vinel
Journal: Gut (2006)

Peritoneal carcinomatosis from pancreatic cancer has a poor prognosis with a median survival of 3.1 months. This is mainly due to lack of effective treatment. Interleukin 12 (IL12) is a proinflammatory cytokine that has a potent antitumoral effect by stimulating innate and adoptive immunity.To examine the antitumoral effect and toxicity of intraperitoneal delivery of IL12 using an ex vivo gene therapy approach in a murine model of pancreatic peritoneal carcinomatosis.Peritoneal carcinomatosis was generated by direct intraperitoneal inoculation of the pancreatic cancer cell line Capan-1 in athymic mice. Syngenic fibroblasts were genetically modified in vitro to secrete IL12 using a polycistronic TFG murine IL12 retroviral vector coding for both p35 and p40 murine IL12 subunits. Ex vivo gene therapy involved injection of the genetically modified fibroblasts intraperitoneally twice a week for 4 weeks.Treatment of pre-established peritoneal carcinomatosis with fibroblasts genetically modified to express IL12 induced a marked inhibition of tumour growth as measured by comparison of the weights of the intraperitoneal tumour nodules in the treated and control animals (3.52 (SD 0.47) v 0.93 (SD 0.21) g, p<0.05) and improved survival. This effect was associated with infiltration of the peritoneal tumour nodules with macrophages. Peritoneal lavage confirmed enhancement of the innate peritoneal inflammatory activity, with an increased number of activated macrophages and natural killer cells. Moreover, macrophages harvested from animals with peritoneal carcinomatosis and treated with IL12-expressing fibroblasts expressed an activated proinflammatory antitumoral M1 phenotype that included strongly enhanced reactive oxygen species and nitric oxide production. There was no treatment-related toxicity.Multiple injections of genetically modified fibroblasts to express IL12 is an effective and well-tolerated treatment for experimental murine pancreatic peritoneal carcinomatosis via activated innate immunity and in particular activated M1 macrophages.
Muscarinic contraction in isolated guinea-pig trachea and antagonism by noradrenaline
Authors: A Walland, R Hammer
Journal: European Respiratory Journal (1997)

In contrast to other muscarinic agonists, WAL 2014 FU does not induce bronchospasm in laboratory animals. The present investigation was intended to test the hypothesis that this is due to a particular susceptibility of the drug's effect to antagonism by catecholamines, as a result of partial M3-agonism. The tonic activity of the muscarinic agonists, aceclidine, arecoline, carbachol, McN-A-343, RS 86, thiopilocarpine and WAL 2014 FU, was tested in groups of isolated tracheal muscle of the guinea-pig. Susceptibility to functional antagonism by beta-adrenoceptor stimulation was measured by the displacement of the concentration-force curves by 3 microM noradrenaline. Evaluation of the concentration-force relationship revealed differences in potency and intrinsic activity (carbachol-100%) ranging from 114% for arecoline to 36% for thiopilocarpine (WAL 2014 FU-63%). The catecholamine increased the concentration of agonist which induced 5% of the maximum effect achievable (EC05) values fivefold (carbachol) to more than 4,680 fold (thiopilocarpine) (WAL 2014 FU: 2,860 fold). Regression analysis between the intrinsic activity of the seven compounds and the antagonistic effect of noradrenaline revealed a significant correlation (Spearman correlation coefficient (r[s])=-0.79; p=0.036). Inhibition of the effects of endogenous catecholamines by beta-adrenolysis with 50 microM toliprolol increased the maximal contraction induced by 1 mM WAL 2014 FU, but did not affect maximal contraction induced by 30 microM arecoline. Pretreatment with 0.3-1.0 mM dibutyrylcyclic adenosine monophosphate (DBcAMP) shifted the concentration-response curves of arecoline, WAL 2014 FU and thiopilocarpine in a similar manner to noradrenaline. The results exclude an important contribution of adenylate cyclase-coupled M2-receptors to the susceptibility of tracheal contraction by muscarinic agonists to functional antagonism by noradrenaline, but emphasize the importance of intrinsic activity at the M3-receptors. The pronounced susceptibility of WAL 2014 FU-induced contraction to functional antagonism by beta-adrenoceptor activation provides an explanation for the failure of the drug to induce bronchospasm in vivo.
Two novel rat liver membrane proteins that bind advanced glycosylation endproducts: relationship to macrophage receptor for glucose-modified proteins.
Authors: Z Yang, Z Makita, Y Horii, S Brunelle, A Cerami, P Sehajpal, M Suthanthiran, H Vlassara
Journal: The Journal of Experimental Medicine (1991)

Advanced glycosylation endproducts (AGEs), the glucose-derived adducts that form nonenzymatically and accumulate on tissue proteins, are implicated in many chronic complications associated with diabetes and aging. We have previously described a monocyte/macrophage surface receptor system thought to coordinate AGE protein removal and tissue remodeling, and purified a corresponding 90-kD AGE-binding protein from the murine RAW 264.7 cell line. To identify AGE-binding proteins in normal animals, the tissue distribution of 125I-AGE rat serum albumin taken up from the blood was determined in rats in vivo. These uptake studies demonstrated that the liver was a major site of AGE protein sequestration. Using a solid-phase assay system involving the immobilization of solubilized membrane proteins onto nitrocellulose to monitor binding activity, and several purification steps including affinity chromatography over an AGE bovine serum albumin matrix, two rat liver membrane proteins were isolated that specifically bound AGEs, one migrating at 60 kD (p60) and the other at 90 kD (p90) on SDS-PAGE. NH2-terminal sequence analysis revealed no significant homology between these two proteins nor to any molecules available in sequence databases. Flow cytometric analyses using avian antibodies to purified rat p60 and p90 demonstrated that both proteins are present on rat monocytes and macrophages. Competition studies revealed no crossreactivity between the two antisera; anti-p60 and anti-p90 antisera prevented AGE-protein binding to rat macrophages when added alone or in combination. These results indicate that rat liver contains at least two novel and distinct proteins that recognize AGE-modified macromolecules, although p90 may be related to the previously described 90-kD AGE receptor isolated from RAW 264.7 cells. The constitutive expression of AGE-binding proteins on rat monocytes and macrophages, and the sequestration of circulating AGE-modified proteins by the liver, provides further evidence in support of a role for these molecules in the normal removal of proteins marked as senescent by accumulated glucose-derived covalent addition products, or AGEs.
Intraspecific DNA sequence variation of the mitochondrial control region of white sturgeon (Acipenser transmontanus).
Authors: J R Brown, A T Beckenbach, M J Smith
Journal: Molecular Biology and Evolution (1993)

Intraspecific sequence variation in the D-loop region of mtDNA in white sturgeon (Acipenser transmontanus), a relict North American fish species, was examined in 27 individuals from populations of the Columbia and Fraser rivers. Thirty-three varied nucleotide positions were present in a 462-nucleotide D-loop sequence, amplified using the polymerase chain reaction. Bootstrapped neighbor-joining and maximum-parsimony trees of sequences from 19 haplotypes suggest that the two populations have recently diverged. This is consistent with the hypothesis that the Columbia River, a Pleistocene refugium habitat, was the source of founders for the Fraser River after the last glacial recession. On the basis of a divergence time of 10-12 thousand years ago, the estimated substitution rate of the white sturgeon D-loop region is 1.1-1.3 x 10(-7) nucleotides/site/year, which is comparable to rates for hypervariable sequences in the human D-loop region. Furthermore, the ratio of mean percent nucleotide differences in the D-loop (2.27%) to that in whole mtDNA (0.54%, as estimated from restriction-enzyme data) is 4.3, which is similar to the fourfold-to-fivefold-higher substitution rate estimated for the human D-loop. The high nucleotide substitution rate of the hypervariable region indicates that the vertebrate D-loop has potential as a genetic marker in molecular population studies.
Detection of tuberculosis in children
Authors: Valentina Vilc
Journal: European Respiratory Journal (2013)

Background: The detection of childhood TB remains a major challenge of TB control.  Aim: to evaluate methods of TB case detection in children and analysis of risk factors in childhood tuberculosis in Chisinau.  Materials and methods: This was a retrospective study (1994-2008) of 788 subjects (0-14 year ods) with confirmed TB. The discriminate analysis has been applied to determine the risc factors for TB in children.  Results: 594 (75,4%) children were diagnosed through active case finding and 194 (24,6%) have been diagnosed through passive case finding. It has been assed that out of 594 children detected through active case finding by applying Mantoux 2TU testing 267 (45,0%) have been diagnosed through systematic household contact investigation; 223 (37,5%) have been diagnosed after primary examination of contacts with TB patients; 93 (15,7%) of children have been registered as a result of screening of high-risk groups and 11 (1,8%) of cildren have been detected through the tuberculin skin test applied before BCG revaccination. Advanced forms of tuberculosis with complications were more frequently detected in the cases where the patients consulted the doctor 33,5±7,2%, p  Conclusions: To improve early detection of TB in children it is necessary to increase awareness in family doctors and physicians; increase knowledge on TB symptoms which can take the mask of other diseases and ensuring timely examination of risk groups.
Genomic Diversity and Fitness of <i>E. coli</i> Strains Recovered from the Intestinal and Urinary Tracts of Women with Recurrent Urinary Tract Infection
Authors: Swaine L. Chen, Meng Wu, Jeffrey P. Henderson, Thomas M. Hooton, Michael E. Hibbing, Scott J. Hultgren, Jeffrey I. Gordon
Journal: Science Translational Medicine (2013)

Comparative genomic and functional studies reveal that E. coli strains from women with recurrent urinary tract infection can move between gut and urinary tract without a fitness trade-off.
Identification of p53 as a strong predictor of survival for patients with malignant peripheral nerve sheath tumors
Authors: Helge R. Brekke, Matthias Kolberg, Rolf I. Skotheim, Kirsten S. Hall, Bodil Bjerkehagen, Björn Risberg, Henryk A. Domanski, Nils Mandahl, Knut Liestøl, Sigbjørn Smeland, Håvard E. Danielsen, Fredrik Mertens, Ragnhild A. Lothe
Journal: Neuro-Oncology (2009)

The purpose of this study was to identify new prognostic biomarkers with clinical impact in malignant peripheral nerve sheath tumor (MPNST), a highly aggressive malignancy for which no consensus therapy exists besides surgery. We have used tissue microarrays (TMAs) to assess in situ expression of 14 cell-cycle-regulating proteins in 64 well-characterized MPNST patients: 36 sporadic and 28 with neurofibromatosis type 1 (NF1). We developed a new software application for evaluation and logistics of the TMA images and performed a literature survey of cell cycle proteins in MPNST. For NF1-associated patients, there was a clear association between nuclear expression of p53 and poor survival (p = 0.004). Among the other proteins analyzed, we also found significant associations between survival and clinical variables, but none were as strong as that for p53. For the total series of MPNSTs, p53 was shown to be an independent predictor of survival, and patients without remission, with tumor size larger than 8 cm, and with positive p53 expression had a 60 times greater risk of dying within the first 5 years compared with the remaining patients (p = 0.000002). This is the most comprehensive study of in situ protein expression in MPNST so far, and expressed p53 was found to be a strong surrogate marker for outcome. Patients in complete remission with a primary p53-positive MPNST diagnosis may be considered in a high-risk subgroup and candidates for adjuvant treatment.
GP96 is a GARP chaperone and controls regulatory T cell functions
Authors: Yongliang Zhang, Bill X. Wu, Alessandra Metelli, Jessica E. Thaxton, Feng Hong, Saleh Rachidi, Ephraim Ansa-Addo, Shaoli Sun, Chenthamarakshan Vasu, Yi Yang, Bei Liu, Zihai Li
Journal: Journal of Clinical Investigation (2015)

Molecular chaperones control a multitude of cellular functions via folding chaperone-specific client proteins. CD4+FOXP3+ Tregs play key roles in maintaining peripheral tolerance, which is subject to regulation by multiple molecular switches, including mTOR and hypoxia-inducible factor. It is not clear whether GP96 (also known as GRP94), which is a master TLR and integrin chaperone, controls Treg function. Using murine genetic models, we demonstrated that GP96 is required for Treg maintenance and function, as loss of GP96 resulted in instability of the Treg lineage and impairment of suppressive functions in vivo. In the absence of GP96, Tregs were unable to maintain FOXP3 expression levels, resulting in systemic accumulation of pathogenic IFN-γ-producing and IL-17-producing T cells. We determined that GP96 serves as an essential chaperone for the cell-surface protein glycoprotein A repetitions predominant (GARP), which is a docking receptor for latent membrane-associated TGF-β (mLTGF-β). The loss of both GARP and integrins on GP96-deficient Tregs prevented expression of mLTGF-β and resulted in inefficient production of active TGF-β. Our work demonstrates that GP96 regulates multiple facets of Treg biology, thereby placing Treg stability and immunosuppressive functions strategically under the control of a major stress chaperone.
Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies
Authors: Murielle Mimeault, Surinder K. Batra
Journal: Pharmacological Reviews (2010)

The hedgehog (Hh)/glioma-associated oncogene (GLI) signaling network is among the most important and fascinating signal transduction systems that provide critical functions in the regulation of many developmental and physiological processes. The coordinated spatiotemporal interplay of the Hh ligands and other growth factors is necessary for the stringent control of the behavior of diverse types of tissue-resident stem/progenitor cells and their progenies. The activation of the Hh cascade might promote the tissue regeneration and repair after severe injury in numerous organs, insulin production in pancreatic β-cells, and neovascularization. Consequently, the stimulation of the Hh pathway constitutes a potential therapeutic strategy to treat diverse human disorders, including severe tissue injuries; diabetes mellitus; and brain, skin, and cardiovascular disorders. In counterbalance, a deregulation of the Hh signaling network might lead to major tissular disorders and the development of a wide variety of aggressive and metastatic cancers. The target gene products induced through the persistent Hh activation can contribute to the self-renewal, survival, migration, and metastasis of cancer stem/progenitor cells and their progenies. Moreover, the pivotal role mediated through the Hh/GLI cascade during cancer progression also implicates the cooperation with other oncogenic products, such as mutated K-RAS and complex cross-talk with different growth factor pathways, including tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), Wnt/β-catenin, and transforming growth factor-β (TGF-β)/TGF-β receptors. Therefore, the molecular targeting of distinct deregulated gene products, including Hh and EGFR signaling components and other signaling elements that are frequently deregulated in highly tumorigenic cancer-initiating cells and their progenies, might constitute a potential therapeutic strategy to eradicate the total cancer cell mass. Of clinical interest is that these multitargeted approaches offer great promise as adjuvant treatments for improving the current antihormonal therapies, radiotherapies, and/or chemotherapies against locally advanced and metastatic cancers, thereby preventing disease relapse and the death of patients with cancer.