tbuckley/cabot-search huggingface dataset:
Identification of shared citrullinated immunological targets in the lungs and joints of patients with rheumatoid arthritis
Authors: A Jimmy Ytterberg, Gudrun Reynisdottir, Elena Ossipova, Dorothea Rutishauser, Aase Hensvold, Anders Eklund, Magnus Sköld, Johan Grunewald, Karin Lundberg, Vivianne Malmström, Per Johan Jakobsson, Roman Zubarev, Lars Klareskog, Anca I Catrina
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The authors have previously demonstrated that smoking induces citrullination in the lungs of healthy smokers and they know that anticitrullinated protein antibodies (ACPA) develop in rheumatoid arthritis (RA) patients many years before disease onset. It was hypothesised that shared citrullinated targets are present in the lungs and joints of RA affected individuals and sought to investigate this by full-proteome analysis of synovial and lung biopsies of RA patients. <h3>Material and methods</h3> Proteins were extracted from synovial (n=7, five females and two males, median age 58, 66.7% ACPA positive) and lung (n=6, four females and two males, median age 63, 66.7% ACPA positive) biopsies of RA patients. Synovial biopsies were obtained at the time of open surgery from patients with long-standing RA (mean disease duration 24 years). Large bronchi biopsies were obtained by bronchoscopy from patients with newly diagnosed RA (three smokers and three non-smokers) with symptom duration less than 1 year. The proteins were reduced, alkylated and digested with Lys-C, separated by reverse-phase nanoflow-chromatography and analysed by LTQ-Velos-Orbitrap using multiple fragmentation methods. The data were searched against the human International Protein Index database using the Mascot search engine and all citrullinated peptides were manually verified. The degree of modification was quantified manually. The final results were expressed as ratios of citrullinated versus non-modified peptides. <h3>Results</h3> Over 3300 peptides and 500 proteins were identified in the different samples. The overall protein profiles varied between patients. Five of the identified proteins in the synovium (in total eight sites) and four in the lungs (in total four sites) contained citrullinated residues. Two vimentin derived citrullinated peptides were present in a majority of synovial and lung biopsies with slightly higher citrullinated/unmodified peptides ratios in smokers compared to non-smokers (median ratio of 0.03 in smokers and 0.02 in non-smokers for one of the peptides and a median ratio of 4.5 in the smokers and 0.04 in the non-smokers for the second vimentin peptide). While non-modified and citrullinated fibrinogen α-chain derived peptides were present in various amounts in the synovium, only the unmodified sites could be detected in the lungs of a subset of the patients (three out of six). <h3>Conclusions</h3> The authors demonstrate the presence of shared in vivo citrullinated proteins in the joints and lungs of RA individuals, providing further support for the important pathogenic link between joints and lungs in development of RA.
AB0677 How do parents of children with juvenile idiopathic arthritis (jia) perceive their therapies?
Authors: D. El Badri, B. Amine, S. Rostom, N. Mawani, M. Ezzahri, F. Moussa, S. Shyen, S. Gueddari, W. Moujibou, B. Chkirate, N. H. Hajjaj
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Compliance problems occur in most chronic diseases, especially in children. Facilitate adherence is an important issue. A positive perception of the parents for the treatment can help to improve the observance of their children, and to improve the control of the disease. <h3>Objectives</h3> This study describes the views of parents of patients with juvenile idiopathic arthritis (JIA) on different conventional treatments received by their children. <h3>Methods</h3> Forty seven patients with juvenile idiopathic arthritis (JIA) were included in a cross-sectional study. The diagnosis of JIA was made according to the criteria of the International League of Association of Rheumatology (ILAR). Information on disease activity, quality of life, sex, age, age at diagnosis, and duration of medication use were collected by use of a standardized questionnaire. Parents of children with JIA were surveyed. Questionnaires asked about patients’ use of different therapies in the past 30 days, their perceived helpfulness (0 = not helpful; 3 = very helpful), perceived side effects (0 = none; 3 = severe), and whether each therapy would be recommended to other patients with JIA (Yes, No, Not sure). <h3>Results</h3> Forty seven children with JIA were included (28 male, 19 female); the median of age of the patients was [5-16] years. AINS were used by 29 (53.7%) by patients, Corticosteroids in 25.9% of cases and DMARDs (Disease-modifying antirheumatic drugs) in 18.5%. Biologic medications were the most appreciated (50% of patients judge that it very efficient), monitoring of steroid treatment in 36.4% of cases, the non steroidal anti-inflammatory drugs (NSAIDs) in 34.5%, and DMARDs in 22.2%. For the side effects, the biologic medications weremore tolerated, tracking des DMARD’s in 66.7%, NSAIDs in 63.6% and corticosteroids in 45.5% of cases. Paradoxically, Corticosteroids and NSAIDs were more recommended to others families in 63.6% of cases, tracking des DMARDs. <h3>Conclusions</h3> This study suggests that parents of children with JIA viewed some symptomatic medications as being more helpful than some DMARD’s. <h3>Disclosure of Interest</h3> None Declared
In Search of a Cancer
Authors: P. Rudnick, W. D. Odell
Journal: New England Journal of Medicine (1971)

Abstract In a 22-year-old man, who had minimal gynecomastia, serum immunoassayable luteinizing hormone activity was 500 to 1000 mIU per milliliter. A gonadotropin secreting neoplasm was diagnosed, but in spite of a thorough search over eight months' time, none was found. The search included all routine x-ray procedures, catheterization and measurement of gonadotropin concentrations in samples from femoral, inferior and superior vena caval veins and systemic arteries, abdominal arteriograms, measurement of testicular-vein gonadotropin concentrations, and surgical exploration of both testes and the mediastinum. Production rate of gonadotropin, estimated with radioiodinated chorionic gonadotropin, was sufficiently low that it would have been unlikely to detect differences between tumor venous concentrations and peripheral vein concentrations. One year after onset of symptoms, pulmonary metastases suddenly appeared, and within a few weeks he died with widespread metastases. At post-mortem examination, the lik...
Development of subsquamous cancer after hybrid endoscopic therapy for intramucosal Barrett's cancer
Authors: V. Konda, M. Gonzalez Haba Ruiz, J. Hart, I. Waxman
Journal: Endoscopy (2012)

A 60-year-old man presented for endoscopic management of a long-segment Barrett's esophagus with a visible lesion ([Fig. 1]). Endoscopic mucosal resection (EMR) of the lesion demonstrated intramucosal carcinoma (IMC) without submucosal invasion on histological examination. Endoscopic ultrasound (EUS) revealed no malignant adenopathy. Three subsequent sessions were performed with focal EMR of all visible lesions and radiofrequency ablation (RFA) of the remnant Barrett's esophagus segment. On a follow-up endoscopy 2 years after the initial intervention, neosquamous epithelium with no apparent Barrett's esophagus was seen and a rigorous biopsy protocol did not reveal any occult cancer. However, EUS demonstrated a 10-mm abnormal-looking gastrohepatic lymph node, diagnosed as metastatic adenocarcinoma by fine needle aspiration ([Fig. 2]). Subsequent computed tomography (CT) scan and colonoscopy did not demonstrate a primary site. A repeat esophagogastroduodenoscopy/EUS performed 6 months later demonstrated squamous mucosa with focal discoloration in the mid esophagus. Biopsies revealed neoplasia buried under squamous epithelium ([Fig. 3]).
Heterocyclic Amines in Cooked Foods: Candidates for Causation of Common Cancers
Authors: T. Sugimura, M. Nagao, K. Wakabayashi
Journal: JNCI Journal of the National Cancer Institute (1994)

This issue of the Journal has a report by Weisburger et al. (7) who have contributed much to our knowledge about chemical carcinogenesis as well as nutrition and its association with cancer prevention.Weisburger et al. describe the bacterial metabolite 2-amino-3,6-dihydro-3methyl-7//-imidazolo[4,5-/]quinolin-7-one (7-OHIQ), which is formed from a cooked food mutagen and carcinogen, 2-amino-3-methyl-3//-imidazo[4,5-/|quinoline (IQ).Although 7-OHIQ was suspected to induce colon cancer in rodents in vivo, no such result was obtained in this study.In contrast, IQ itself was shown to produce colon cancers by oral administration in rats in our experiments (2).It seems appropriate at this point to comment on the significance of recently found carcinogens existing in cooked food, i.e., heterocyclic amines (HCAs), which are possible candidates for producing commonly occurring human cancers.
P217 What's happening to lung cancer in females?
Authors: A. Ives, J. Verne
Journal: Thorax (2010)

<h3>Aim</h3> To examine trends in female lung cancer incidence. <h3>Introduction</h3> Lung cancer incidence in men has been decreasing for the past 2–3 decades, while for females it has increased. Furthermore, to achieve the national cancer mortality target reduction, it is essential that lung cancer incidence reduces as this is a major contributor to the mortality target. Mortality trends closely mirror that of incidence due to the poor prognosis of lung cancer. <h3>Methodology</h3> The UK Association of Cancer Registries dataset was used to identify female lung cancer cases diagnosed between 1985 and 2006 in England and its constituent Regions. Three year rolling directly age-standardised rates (standardised to the European population) was calculated. National deprivation quintiles were used, where deprivation was based on the income domain of Indices of Multiple Deprivation 2007. The postcode of residence of each patient was used to assign the relevant deprivation quintile. <h3>Results</h3> England lung cancer incidence for females significantly increased (p&lt;0.01) from 1985 to 1987 (32.3 per 100 000) and 2004–2006 (35.4 per 100 000). Incidence and trends across Regions varies significantly. Further analysis at Network/LA level shows even more extreme variation in trends. By 2030, it is anticipated that lung cancer incidence will be similar for both males and females in the South West Region. In the past 20 years the inequalities gap for females is widening. Incidence rates have increased in the most deprived population (30%) of the South West, while remaining relatively stable in the most affluent population of the region. Each Region shows different inequalities. <h3>Conclusion</h3> Smoking prevention is the key to reducing lung cancer. A lot of effort to encourage people to give up smoking has focused on men. Evidence of increasing female rates, more so in deprived areas; show that targeted efforts to support women need to be increased in order for large health gains to be achieved.
Ectopic Production of Prolactin
Authors: Roger W. Turkington
Journal: New England Journal of Medicine (1971)

Markedly elevated serum prolactin levels were observed in a patient with undifferentiated bronchogenic carcinoma and in a patient with galactorrhea and hypernephroma. Irradiation of the bronchogenic carcinoma was associated with a decrease in the serum prolactin concentration from 100 to 20 ng per milliliter, and surgical resection of the hypernephroma reduced the serum prolactin concentration from 150 to less than 2 ng per milliliter. Production of prolactin was directly demonstrated in tissue cultures of the hypernephroma. The prolactin activity was found to be identical to authentic prolactin by its biologic activity on organ cultures of mammary gland and by the specificity of its immunologic reactivity with antiprolactin antibodies. These studies demonstrate the ectopic production of prolactin by human cancer cells, and the results suggest that carcinoma should be considered in the differential diagnosis of patients with galactorrhea or hyperprolactinemia.
Abstract 5062: Integrated analysis of the whole exome sequencing (WES) identifies novel mutations and suggests patient selection hypothesis
Authors: Sergey Lezhnin
Journal: Cancer Research (2012)

Abstract Whole exome sequencing was done on 257 breast and 102 ovarian tumors using next generation sequencing. Seven gigabases of sequencing data were generated for each sample or 100x coverage of the whole exome, which enable to determine sequence variations with &amp;gt;99% confidence. The results of the mutation calls were compared with recently published TCGA breast and ovarian datasets. Genes with large number of passenger mutations were called out and frequency of passenger mutations per sample was linked to MMR signature. In ovarian tumors, a high prevalence of p53 and BRCA1 mutation was confirmed in serous tumors. A signature of BRCA1/2 deficient tumors was developed and cross-validated between the datasets. In no-serous tumors, a high prevalence of mutations MAPK pathway and beta-catenin pathway were found. FOXL2 mutation was identified in 100% of granulose ovarian tumors and linked to high levels of EMT signature. In addition we showed a significant overlap between genes found to be mutated in TCGA datasets and in our dataset, suggesting a larger number of potentially significantly mutated genes than previously reported. In breast tumors, known high frequency of mutations was confirmed in PIK3CA and TP53 genes and validated with respective pathway specific gene expression signatures. In addition, prevalent mutations were identified in MAPK and PI3K pathways and linked with respective pathway signatures. These findings strengthen and enrich our understanding of molecular subtypes of ovarian and breast tumors and can be used for identification of novel targets and for development of responder hypothesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5062. doi:1538-7445.AM2012-5062
AB0088 Regulatory b cell is negatively associated with disease activity in rheumatoid arthritis
Authors: I. S. Yoo, S. T. Song, H. J. Lee, J. Kim, S. W. Kang, J. H. Lee
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The regulatory function of B cells is beginning to be understood, and several subsets of regulatory B cells have been suggested. A recent study suggested that the human B cell secreting IL-10 may have a central role in the regulatory function in immune system. However, the roles of regulatory B cells secreting IL-10 (B10 cells) was not established in rheumatoid arthritis (RA) pathogenesis. <h3>Objectives</h3> To know the exact status of IL-10+ B cells, we investigated the induction of B10 cells in the RA patients and analyzed disease activity. <h3>Methods</h3> CD19+ cells in peripheral blood mononuclear cells were purified from blood samples of RA patients and age and sex matched healthy controls, and stimulated with CD40 ligand and CpG for 48 hours. Intracellular IL-10 was analyzed using flow cytometry. <h3>Results</h3> The proportion of IL-10+ B cells to total B cells in RA patients was significantly higher than those in controls (RA, 4.44% ± 3.44% vs. healthy control 2.44% ± 1.64%, p = 0.033). However, the proportion of IL-10+ B cells to total B cells was correlated negatively with disease activity (r = –0.398, p = 0.040). Although age was correlated with IL-10+ B cells positively (r = –0.525, p = 0.004), age was also correlated with disease activity (r = 0.409, p = 0.031) in RA patients in this study. In healthy controls, age was not correlated with IL-10+ B cells (r = 0.035, p = 0.895). Thus, the association could be attributed to disease activity. To evaluate the effect of soluble factors in serum, IL-10+ B cell was induced with adding patients' serum. The proportion of IL-10+ B cells was increased with serum. However, there were no differences between active RA and inactive RA group. <h3>Conclusions</h3> The proportion of induced IL-10+ B cell increased in RA patients compared to healthy control and was negatively correlated with disease activity in rheumatoid arthritis. Adding active and inactive RA patients' sera, the proportion of IL-10+ B cell did not different between two groups. <h3>Disclosure of Interest</h3> None Declared
PREVALENCE OF OSTEOPOROSIS AMONGST A LARGE COELIAC COHORT SUPPORTS EARLY BONE MINERAL DENSITY ASSESSMENT FOR ALL PATIENTS
Authors: J Collum, M Corrigan, A Smith, K Martin
Journal: Gut (2013)

<h3>Introduction</h3> Coeliac disease is associated with osteoporosis and osteoporosis is a significant public health problem (1). However, debate exists concerning the routine use of bone mineral density (BMD) assessment at time of coeliac diagnosis. <h3>Aims/Background</h3> To determine the prevalence of osteoporosis in patients with coeliac disease, as defined by BMD assessment, and the impact of factors such as gender, age &amp; disease duration. <h3>Method</h3> We retrospectively analysed dietitian held data sets, which are kept for all patients with coeliac disease. <h3>Results</h3> The data sets for 232 patients were available for analysis. The index BMD assessment was recorded. The prevalence of osteoporosis was 23%. Overall, males were found to have lower average BMD than females. BMD decreased with advancing age. This finding was statistically significant (p&lt;0.01). Greater duration of disease was associated with low BMD, but this did not reach statistical significance. (p=0.42) <h3>Conclusion</h3> Due to a period of undiagnosed coeliac disease with latent calcium malabsorption, reduced BMD is likely to be present at time of diagnosis. Whilst osteoporosis is often asymptomatic until fracture, when fractures do occur they carry a significant morbidity and mortality. Screening allows identification of reduced BMD prior to fracture and subsequent management strategies can be instigated to improve this. The use of BMD assessment at diagnosis is gaining widespread support, but has not been formalised in UK guidelines (4). This screening strategy is likely to be cost effective, due to the widespread availability of BMD assessment and the markedly decreased cost of bisphosphonate therapy (6).
Abstract 523: Modeling the crosstalk between head and neck carcinomas and fibroblasts that underlies malignant invasion and drug resistance
Authors: Kati A. Räsänen, Devraj Basu, Kathleen Montone, Gao Zhang, Anil Rustgi, Meenhard Herlyn
Journal: Cancer Research (2011)

Abstract There is an ongoing need to advance in vitro models of carcinoma invasion and drug resistance, which are both processes likely to be shaped by the complex crosstalk between normal and malignant cells at stromal interfaces. Epithelial to mesenchymal transition (EMT) generates a mesenchymal-like malignant subpopulation within carcinomas with enhanced invasive potential. Here this subpopulation is hypothesized to play a critical role in a tumor-fibroblast crosstalk that enhances invasion and resistance to chemotherapy. To assess the biologic and therapeutic significance of this subpopulation, we have defined head and neck squamous cell carcinoma (HNSCC) cell lines where ongoing EMT sustains an “Ecad-lo” subset; these cells are distinguished by a mesenchymal-like overall gene expression profile and also display key markers typically associated with activated fibroblasts. The mesenchymal-like (Ecad-lo) subset is separable from epithelial-like (Ecad-hi) cells based on loss of surface E-cadherin and expression of vimentin. As an in vivo correlate of Ecad-lo cells, we identified a subpopulation of vimentin-positive malignant cells in primary advanced stage human HNSCCs. In vitro, the Ecad-lo subset showed resistance to cytotoxic and EGFR-targeted therapy; comparable findings were seen in vivo, where treatment led to enrichment of vimentin positive cells in direct xenografts of human HNSCCs. Interactions of stroma with Ecad-hi versus Ecad-lo cells were compared using collagen embedded tumor spheroids and organotypic 3D reconstructs. Here Ecad-lo cells were shown necessary to create an invasive front into collagen matrix. Ecad-lo cells were also needed to drive fibroblast migration and formed a direct interface with fibroblasts in the collagen layer of organotypic 3D cultures. Activated stromal fibroblasts subsequently participated in a feedback loop by promoting EMT in the epithelial-like Ecad-hi subpopulation of cancer cells, increasing the size of the invasive, treatment-resistant Ecad-lo subset. These results define systems for modeling the coordinated acquisition of mesenchymal-like features, invasiveness, and drug resistance by HNSCC cells via active crosstalk with stromal fibroblasts. In this capacity, the models will serve as a platform for identifying targetable mechanisms underlying these central features of malignant behavior. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 523. doi:10.1158/1538-7445.AM2011-523
P17.68 * CHARACTERISATION OF A NOVEL ASPIRIN ANALOGUE IN MALIGNANT GLIOMA
Authors: V. Petinou, C. J. Perry, I. D. Nicholl, J. Singh, R. W. Lea, P. J. Welsby
Journal: Neuro-Oncology (2014)

Gliomas are the most common intracranial brain tumours and are associated with poor prognosis and median survival time of less than 15 months from first diagnosis. Clinical and preclinical research has suggested a role for aspirin in the treatment or prevention of cancer, with a recent focus on the development of novel aspirin analogues. Established (U87 MG, 1321N1, GOS-3& SVG-p12) and primary cell lines (BTNW911 & BTNW914) were treated with the novel aspirin analogue PN517, aspirin and cisplatin for 24 and 48 hr at 0.1 and 1mM. Cells were subsequently harvested and cell cycle distribution determined by flow cytometry following PI (50 mg/ml) and RNAse (100 mg/ml) treatment, and apoptosis examined by flow cytometry following staining with annexin-V and PI (50 mg/ml), or the mitochondrial membrane potential marker JC-1 (5 mM). Migration was examined over 18 hr using scratch assay and Boyden chamber technique. A two-way ANOVA test was used to analyse the significance between treatments with significance set at p < 0.05. PN517 induced apoptosis in the primary and established cell lines with a similar efficacy to cisplatin following 24 hours treatment at 0.1 mM. The induction of apoptosis was also assessed over a period of 48 hours and it was found to be the predominant mode of cell death at both 0.1 and 1mM concentrations and at early time points, with necrosis being observed at higher drug concentrations and after 24 hours of drug treatment. Following 48 hours of treatment PN517 (1 mM) significantly increased the sub G1 phase apoptotic population as determined by cell cycle analysis and decreased both the G1 and G2/M phase populations when compared to control. Treatment with the aspirin analogue (0.1 mM) also reduced migration significantly when compared to control. The novel aspirin analogue PN517 induced apoptosis, caused cell cycle arrest and reduced migration in both primary and established glioma cell lines. These results show that PN517 has therapeutic potential in the treatment of glioma.