tbuckley/cabot-search huggingface dataset:
P101 Does Ivacaftor improve objective measurements of health in patients with the G551D cystic fibrosis transmembrane conductance regulator (CFTR) protein mutation? The experience of a UK cystic fibrosis centre
Authors: AE Ewence, CN Eruchie, AM Higton, TBL Ho
Journal: Thorax (2013)

<h3>Introduction and Objectives</h3> The CFTR potentiator, Ivacaftor, has recently been launched in England for use in adult cystic fibrosis patients with at least one copy of the G551D mutation. Formal clinical trials have demonstrated significant improvements in spirometry, weight and quality of life symptom scores in patients taking this new drug. We wish to report our experience of Ivacaftor in a standard clinic setting through longitudinal follow-up of our patients over a six month period. <h3>Methods</h3> 11 patients were started on Ivacaftor between December 2012 and February 2013. Before starting Ivacaftor we measured spirometry (FEV1 and FVC), weight, liver function tests, quality of life symptom scores and the number of antibiotic courses for infective exacerbations in the preceding 3 months. Repeat measurements were taken at 3 months after starting Ivacaftor and compared to baseline. Liver function tests were monitored as per manufacturer's advice, with the intention to stop Ivacaftor if there was a significant rise in liver function tests. <h3>Results</h3> 10 patients remained on Ivacaftor at 3 months (one patient was lost to follow-up). Baseline spirometry in these patients demonstrated an average percentage predicted FEV1 of 58.2% (SD ± 19.8) and average percentage predicted FVC of 77.9% (SD ± 22.2). Spirometry improved in all patients at 3 months compared to baseline; average increase in predicted FEV1 12.2% (p = 0.010) and average increase in predicted FVC 15.8% (p = 0.006). All but one patient gained weight with an average weight increase of 2.1 kg (p = 0.013). The use of antibiotics to treat exacerbations significantly improved; only 1 patient required antibiotics in the 3 months after starting Ivacaftor. One patient, whilst taking concomitant anabolic steroids, had to stop Ivacaftor after a six-time rise in alanine transaminase. After stopping steroids, he subsequently restarted Ivacaftor without deterioration in liver function. <h3>Conclusions</h3> At 3 months our patients demonstrated statistically significant improvements in spirometry and weight after starting Ivacaftor. Importantly, Ivacaftor has been well tolerated with reported improvements in symptom burden and reduced exacerbation rates; 3 patients have returned to work/changed jobs and one has starting full-time education. Further results from six month follow-up, including quality of life symptom scores, are awaited.
SAT0040 Arthritis induced by newly developed anti-type II collagen mabs associated with antigen affinity
Authors: S. Yoshino
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Polyclonal antibodies or a combination of 4 or 5 mAbs specific for type II collagen (CII) induce severe arthritis in mice (CAIA model). The induction of CAIA is associated with antigen affinity and complement activation. However, it is not completely clear that an anti-CII mAb itself or a combination of only 2 anti-CII mAbs is albe to induce severe arthritis. It is also not well understood whether the binding ability of anti-CII mAbs to CII is more important for the induction of CAIA than complement activation by the immune complexes. <h3>Objectives</h3> To establish new hybrydoma cells producing anti-CII mAbs, to test the ability of an anti-CII mAb alone or a combination of only two anti-CII mAbs to induce arthritis, and to investigate the association of the arthritogenicity of anti-CII mAbs with antigen affinity or complement activation. <h3>Methods</h3> DBA/1J mice were immunized with chicken CII and then the spleen cells were fused with myeloma cells before cloning cells producing anti-CII mAbs and determining their isotypes. An anti-CII mAb alone or a combination of two anti-CII mAbs that crossreacted with mouse CII were i.p. injected to attempt to induce arthritis. The binding ability of anti-CII mAbs to CII and complement activation were analyzed by ELISA in vitro. <h3>Results</h3> A number of hybydoma cells producing varying isotypes of anti-CII mAbs including IgG1, IgG2a, IgG2b, IgG3, IgM, and IgD were established. Two anti-CII IgG2b mAbs (C2B-9 and C2B-14) had markedly strong affinity to mouse CII. Two anti-CII IgG2a mAbs showed either moderate (C2A-7) or weak (C2A-12) affinity to the collagen. C2B-14 and C2A-12 showed more marked complement activation than C2B-9. I.p. injection of C2B-9 or C2B-14 alone induced weak arthritis while a combination of C2B-9 and C2B-14 caused severe joint inflammation. The animals injected i.p. with a combination of C2B-14 and C2A-12 had weak arthritis. <h3>Conclusions</h3> An anti-CII mAb alone is able to induce arthritis. A combination of two anti-CII mAbs is much more effective in causing severe joint inflammation. Induction of arthritis appears to be more importantly associated with the intensity of antigen affinity than complement activation. <h3>References</h3> Hutamekalin P., Saito, T., Yamaki, K., Mizutani, N., Brand, D.D., Waritani, T., Terato, K., Yoshino, S.: Collagen antibody-induced arthritis in mice: Development of a new arthritogenic cocktail of monoclonal anti-type II collagen antibodies. J. Immunol. Methods, 34:49-55, 2009. <h3>Disclosure of Interest</h3> None Declared
AB0463 Clinical significance of antibodies to infliximad in rheumatoid arthritis (RA) patients
Authors: G. Lukina, Y. Sigidin, E. Alexandrova, A. Novikov, E. Aronova, M. Kanonirova, S. Glukhova, E. Nasonov
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To assess efficacy and tolerability of infliximab (INF) in patients (pts) with RA depending on the presence of antibodies to INF (ATI) in the serum. <h3>Methods</h3> Twenty-two pts with active RA despite methotrexate therapy (19 women, mean age 45,8 years, mean disease duration 9,2 years, RF-positive 17, mean CRP 22 mg/L, mean HAQ 1,5, mean DAS28 6) were treated in one center with INF (3 mg/kg intravenously at weeks 0, 2, 6 and every 8 weeks thereafter). Pts were assessed by EULAR criteria at weeks 0, 14 and 22; ATI were measured by TNFα-Bloker-ADA ELISA kit (Immunodiagnostik AG, Germany) at the same points. Correlations between clinical results and the presence of ATI were analyzed. <h3>Results</h3> Before INF treatment no pt had ATI. Twenty pts completed the study. By the 22-nd week ATI were detected in 7 pts. Among them good results were registered in 2 pts; moderate results, 2 pts; no effect, 3 pts. Thirteen pts had no serum ATI. In this group clinical effect was assessed as good in 5 pts, and as moderate in 8 pts. No poor effect was noted among these pts. Positive (good and moderate) results were achieved in pts without ATI significantly more often (p=0,035). Frequency of adverse events was the same in both groups. <h3>Conclusions</h3> Presence of ATI can be considered as a risk factor for the reduction of the INF clinical effect. <h3>Disclosure of Interest</h3> None Declared
Transport and transportation pathways of hazardous chemicals from solid waste disposal.
Authors: R I Van Hook
Journal: Environmental Health Perspectives (1978)

To evaluate the impact of hazardous chemicals in solid wastes on man and other organisms, it is necessary to have information about amounts of chemical present, extent of exposure, and chemical toxicity. This paper addresses the question of organism exposure by considering the major physical and biological transport pathways and the physicochemical and biochemical transformations that may occur in sediments, soils, and water. Disposal of solid wastes in both terrestrial and oceanic environments is considered. Atmospheric transport is considered for emissions from incineration of solid wastes and for wind resuspension of particulates from surface waste deposits. Solid wastes deposited in terrestrial environments are subject to leaching by surface and ground waters. Leachates may then be transported to other surface waters and drinking water aquifers through hydrologic transport. Leachates also interact with natural organic matter, clays, and microorganisms in soils and sediments. These interactions may render chemical constituents in leachates more or less mobile, possibly change chemical and physical forms, and alter their biological activity. Oceanic waste disposal practices result in migration through diffusion and ocean currents. Surface area-to-volume ratios play a major role in the initial distributions of chemicals in the aquatic environment. Sediments serve as major sources and sinks of chemical contaminants. Food chain transport in both aquatic and terrestrial environments results in the movement of hazardous chemicals from lower to higher positions in the food web. Bioconcentration is observed in both terrestrial and aquatic food chains with certain elements and synthetic organics. Bioconcentration factors tend to be higher for synthetic organics, and higher in aquatic than in terrestrial systems. Biodilution is not atypical in terrestrial environments. Synergistic and antagonistic actions are common occurrences among chemical contaminants and can be particularly important toxicity considerations in aquatic environments receiving runoff from several terrestrial sources.
Diffuse Renal 18F-FDG Uptake of a Patient With Fever of Unknown Origin Revealed Sarcoidosis
Authors: Takuya Toyonaga, Osamu Manabe, Florian C. Gaertner, Tasuku Nakagaki, Saori Nishio, Akira Suzuki, Nagara Tamaki
Journal: Clinical Nuclear Medicine (2014)

We report about the usefulness of F-FDG PET for the detection and therapy response evaluation of renal sarcoidosis. A 55-year-old woman presented with a condition diagnosed with pulmonary and ocular sarcoidosis 2 years before having anemia and acute deterioration of renal function. FDG PET revealed diffuse increased FDG uptake in both kidneys and the spleen. Histopathologic examination of a renal biopsy sample revealed granulomatous interstitial nephritis with sarcoidosis. After methylprednisolone treatment, the abnormal FDG uptake resolved completely with improvement of symptoms. FDG PET is a useful tool to detect active sarcoidosis regions and to monitor treatment efficacy.
Four-Year Follow-up after Two-Year Dietary Interventions
Authors: Dan Schwarzfuchs, Rachel Golan, Iris Shai
Journal: New England Journal of Medicine (2012)

This follow-up study, conducted 4 years after a 2-year trial that involved healthy dietary changes, showed that the interventions had long-lasting, favorable effects, particularly in those receiving the Mediterranean or low-carbohydrate diet, despite partial weight regain.
P95Effects of dabrafenib and trametinib, cancer therapies that target BRaf and MEK, on cardiac signalling
Authors: A Clerk, L Connell, M Pipe, SJ Fuller, PH Sugden
Journal: Cardiovascular Research (2014)

Background: The extracellular signal-regulated kinase (ERK1/2) cascade is implicated in cardioprotection and cardiac hypertrophy. Enhanced ERK1/2 signalling is associated with cancer, particularly in melanoma in which ~50% of cancers result from mutations of the upstream kinase BRaf that signals through MEK to ERK1/2. Inhibitors of BRaf (e.g. dabrafenib, DAB) and/or MEK (trametinib, TRAM) are in clinical use as cancer therapies. Early studies failed to identify BRaf in the heart and, whilst BRaf and MEK inhibitors are known to affect cardiac function, their molecular effects remain to be established. Materials and methods. Expression of BRaf was assessed in neonatal rat cardiomyocytes and adult rat hearts by immunoblotting. BRaf activities were measured following immunoprecipitation. Adult rat hearts were perfused in the Langendorff mode under control conditions, with DAB or TRAM alone, with fibroblast growth factor (FGF) or with FGF in the presence of DAB or TRAM. Signalling through the ERK1/2 cascade and potential off-target effects on the cytoprotective Akt pathway were assessed by immunoblotting. Results and discussion. BRaf protein was detected in extracts from adult rat hearts or cardiomyocytes as a doublet of ~90 kDa (predicted 89 kDa). Activity assays confirmed that BRaf has high basal activity that was further increased by peptide growth factors. Perfusion of rat hearts with DAB inhibited baseline phosphorylation (i.e. activation) of MEK and ERK1/2, whilst TRAM inhibited baseline activation of ERK1/2. These data suggest that BRaf activity is required for basal ERK1/2 activation in the heart. Both inhibitors prevented activation of ERK1/2 and downstream kinases (p90 RSK, p70 S6K) by FGF further indicating that growth factor signalling is mediated by BRaf in the heart. Interestingly, whilst DAB inhibited basal Akt phosphorylation, TRAM enhanced Akt signalling in control and FGF-perfused hearts. Conclusions. BRaf is expressed in cardiomyocytes and adult hearts at significant levels, has high basal activity and is activated by peptide growth factors. BRaf and MEK inhibitors in use for cancer therapy suppress basal and growth factor induced activation of ERK1/2 signalling suggesting that they are likely to have cardiotoxic effects. However, potentially damaging inhibition of ERK1/2 signalling by TRAM may be mitigated in part by enhanced cytoprotection via Akt if this pathway is not compromised.
PTU-187 Is Plasma Citrulline Concentration a Reliable Marker for Diagnosis and Clinical Management of Coeliac Disease ?
Authors: C Papadia, F Fonaroli, F Lanzarotto, M Salemme, A Di Sabatino, V Villanacci, G R Corazza, A Forbes
Journal: Gut (2013)

<h3>Introduction</h3> In chronic villous atrophy plasma citrulline concentration (PCC) is decreased at the same severity and extent of mucosal lesions of villous architecture. Marsh-Oberhuber classification is conventionally used for grading villous atrophy in coeliac disease and a correlation with plasma citrulline concentrations has been found in pioneering studies. The Corazza-Villanacci classification gives better inter-observer agreement then Marsh-Oberhuber classification. Our primary aim was to correlate PCC to Corazza-Villanacci classification in coeliac disease. We aimed also to yield information in respect of PCC after one year of gluten free diet. <h3>Methods</h3> Forty subjects with a diagnosis of acute celiac disease have been studied. Nine out of forty patients were on gluten challenge diet. All patients underwent OGD with multiple biopsies and a blood test for plasma citrulline concentration at baseline and after one year of gluten free diet (GFD). Routine haematological and biochemical investigations were performed including, IgA tTG, IgA EMA and IgA/G antigliadin, ESR, haemoglobin and haematinics, albumin, liver function tests and creatinine. BMI and clinical symptoms were monitored. Histology was interpreted according to Marsh-Oberhuber and Corazza-Villanacci Classification. Plasma citrulline concentration was analysed by High Performance Liquid Chromatography <h3>Results</h3> Mean plasma citrulline concentration was lower (15.12 μmol/l) at baseline, in patients with active celiac disease, than in the same group of patients after one year of GFD (16.47 μmol/l) however we did not observe any overall change in citrulline concentration after one year of gluten-free diet. All patients were only partially histopathologically and clinically responsive to one year of GFD. Plasma citrulline concentrations correlated with Villanacci-Corazza classification (P = 0.05) in patients on gluten challenge diet. Patients with a score of 2 had lower citrulline values compared to those with a score of 1, on average 4 units. Correlation was not found between plasma citrulline concentrations and Marsh-Oberhuber classification at baseline and after one year of gluten-free diet. <h3>Conclusion</h3> Plasma citrulline concentration may be considered a reliable marker of severity and extent of small bowel villous atrophy in acute coeliac disease, more data are warranted to determine its role in the long-term management. <h3>Disclosure of Interest</h3> None Declared.
Abstract 5187: Migration and proliferation of colon carcinoma cells are importantly affected by leptin and adiponectin via diverse pathways
Authors: Janina Ratke, Bernd Niggemann, Kurt S. Zänker, Thomas Dittmar, Kerstin Lang
Journal: Cancer Research (2010)

Abstract Obesity is a dramatically increasing public health problem worldwide. Traditionally, fat tissue was considered to be solely an energy storage depot. However, recent studies have shown that adipose tissue exerts important endocrine functions, which are predominantly mediated by a network of various soluble factors derived from adipocytes. New evidence has come to light elucidating a modulatory role of this adipocytokines in the regulation of cancer development. The most prominent adipocytokines are leptin and adiponectin, which are predominantly secreted by differentiated adipocytes. Depending on the energy status of adipocytes, the secreted concentrations of leptin and adiponectin vary drastically. In obesity, serum level of leptin is considerable increased (greater than or equal to 100 nanogram/ml), whereas the adiponectin concentration is very low. In contrast, adiponectin concentration accelerates by weight reduction (greater than or equal to 10 microgram/ml). The aim of our study was to investigate the influence of adipocytokines on cancer cells. Using our three-dimensional, collagen-based migration assay we found a strong impact of leptin and adiponectin on the migration of colon cancer cells. Both adipocytokines alone significantly enhanced the migratory activity of SW480 colon carcinoma cells from 30.3±7.4% spontaneously locomoting cells to 50.9±8.2%. In contrast, both adipocytokines in combination reduced the migration of colon carcinoma cells to control level. Moreover, treatment of the cells with leptin alone enhanced the proliferation of SW480 cells up to 50%, whereas adiponectin mediated an anti-proliferative function by 30%. Surprisingly, addition of leptin and adiponectin together did not have any effect on the proliferation. On the molecular level, leptin-induced migration was mediated by phosphorylation of focal adhesion kinase (FAK) and activation of phosphatidyl-inositol-3-kinase (PI3K). The pro-migratory effect of adiponectin was accompanied by an activation of PI3K/AKT and various transcription factors. In contrast, incubation with both adipocytokines in combination led to a decreased phosphorylation of FAK and AKT. Understanding the impact of leptin and adiponectin alone and their interplay on the carcinogenesis of colon cancer as well as the underlying molecular mechanisms have a major clinical significance, and provide the basis for the development of novel therapeutics to treat obesity-associated colorectal cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5187.
Retrieval of a sharp foreign body from the stomach: a novel approach
Authors: Adam Bledsoe, Brett Baloun, Jeffrey Murray, Muslim Atiq
Journal: Endoscopy (2014)

An 82-year-old man presented to the emergency room following an episode of dark tarry stools. Esophagogastroduodenoscopy (EGD) revealed an 8-mm nonbleeding, cratered ulcer in the gastric antrum. A piece of glass was noted to be embedded in the antral wall within the ulcer base ([Fig. 1 a]).
PWE-157 Two Dimensional Mapping of Mutant Clones in Human Colonic Crypts Reveal Stem Cell Dynamics and Migration Patterns
Authors: B Cereser, A-M C Baker, P J Tadrous, A Humphries, M Novelli, M Rodriguez-Justo, T A Graham, S A McDonald, N A Wright
Journal: Gut (2013)

<h3>Introduction</h3> Deficiency in the enzyme cytochrome C oxidase (CCO) has proven to be a versatile marker of clonal population in human tissues. CCO is encoded entirely by the mitochondrial DNA (mtDNA) and deficiency in CCO expression is usually attributable to mutation in the mtDNA. CCO-deficient cells are easily detectable by two-colour enzyme histochemistry. This staining provides means to identify clonal patches of CCO-deficient cells. Subsequent sequencing of mtDNA from individual cells within the patch and revealing the same somatic mutation in each cell confirms the clonality of a patch. In the human intestine, crypts are composed of a population of a contiguous CCO-deficient mtDNA-mutated cells, and also non-mutant CCO-proficient cells are frequently observed: from the small clones occupying only a few cell positions on the crypt circumference (partially-mutated crypts), to crypts composed only CCO-deficient cells (wholly-mutated crypts). Patches of adjacent and clonal CCO-deficient crypts are also observed. Larger patches are more common in older patients indicating that CCO-deficient crypts continue to divide in the ageing colon. <h3>Methods</h3> To study stem cells dynamics within intestinal crypts, we aim to characterise the shape and the size of clones in partially CCO-deficient crypts, by combining the two-colour enzyme histochemical staining with image analysis and computer reconstruction. Multiple serial sections in the transverse plain were taken through frozen samples. Digital images were then taken of each serial section and used to create a ‘crypt map’ using in-house analytical software. A crypt map is a representation of the whole 3D tubular crypt unfurled and laid flat with colour enhancement post-processing. <h3>Results</h3> Our results in normal and diseased human colon show that clone size can be approximated by the percentage of the crypt circumference measured from crypt transverse sections and occupied by a CCO-deficient clone. <h3>Conclusion</h3> We envisage that analysis of such clonal distributions in the context of a branching process model could be used to determine the patterns of stem cell division within the human colon. <h3>Disclosure of Interest</h3> None Declared.
Racial and Occupational Variations in Cancer of the Testis: San Francisco, 1956–65
Authors: Piero Mustacchi, Don Millmore
Journal: JNCI Journal of the National Cancer Institute (1976)

During 1956-65, white and nonwhite San Francisco male residents did not have equal risks of developing testicular cancer. The lower risk observed for nonwhites could not be attributed entirely to genetic factors, since among whites a risk gradient seemed to correlate directly with broad socioeconomic indices such as occupation and census tract of residence. Although incidence rates for testicular cancer have progressively increased in the United States and now parallel rates in Danish towns and rural areas, they are still lower than rates observed in Copenhagen, where a "technology" effect has been postulated. In this perspective, the San Francisco findings are compatible with a hypothesis that certain occupational groups may have become epidemiologic indicators of testicular carcinogens in a changing environment.