tbuckley/cabot-search huggingface dataset:
The rheumatoid arthritis synovial microenvironment promotes differentiation of monocytes into pro-angiogenic macrophages responsive to angiopoietin signaling
Authors: Samuel García Pérez, Sarah Krausz, Carmen A Ambarus, Dominique L Baeten, Paul P Tak Paul Peter, Kris A Reedquist
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background and objectives</h3> Vascular remodeling promotes immune cell infiltration and provides nutrients to hyperplastic tissue in the synovial tissue of patients with rheumatoid arthritis (RA). In solid cancers, angiopoietin (Ang-1 and Ang-2) signaling to Tie2-expressing immunosuppressive monocytes (TEMs), is critical in allowing tumor establishment. A similar role for TEMs in chronic inflammatory disease has not been assessed, but the authors have recently found that macrophages are the primary cell types in which Tie2 is activated in RA synovial tissue. Here, the authors examined how the differentiation stimuli and the RA synovial microenvironment might regulate expression of Tie2 on macrophages, as well as their effects on expression of macrophage angiogenic factors and gene expression responses to Ang stimulation. <h3>Material and methods</h3> Human healthy donor peripheral blood monocytes were differentiated in the presence of pro-inflammatory/classically activating (GM-CSF, IFN-γ), anti-inflammatory/alternatively activating (M-CSF, IL-10) cytokines and RA synovial fluid (SF). Tie-2 expression was analysed by flow cytometry and quantitative PCR. Macrophage mRNA expression of 84 angiogenic factors in the absence or presence of TNF stimulation, alone or in combination with Ang-1 was analysed using low density quantitative PCR Array. <h3>Results</h3> Tie2 protein and mRNA expression was observed under all conditions, but expression levels failed to correspond to pro- or anti-inflammatory phenotypes – expression levels were equivalent and significantly highest in macrophages differentiated in IFN-γ and IL-10. Tie2 expression was also maintained in macrophages differentiated in the presence of RA SF.Gene expression analysis of angiogenic factors demonstrated distinct expression profiles under each polarisation condition, although macrophages differentiated in RA SF (RASF macrophages) showed significantly enhanced expression of pro-angiogenic chemokines (CXCL3, 5 and 6, IL-8 and CCL2) and decreased expression of antiangiogenic chemokines (CXCL2, 9, 10 and 11) (p values ranging from &lt; 0.05 to 0.0005 for each chemokine). TNF-treatment of RASF macrophages enhanced chemokine expression, and synergistic effects of TNF and Ang-1 were observed in promoting CXCL3, 6, and IL-8 expression. <h3>Conclusion</h3> Our results suggest that the RA synovial environment promotes pro-angiogenic macrophage differentiation, and potentiates macrophage production of chemokines which perpetuate synovial monocyte influx in response to TNF and Ang-1.
Abstract 1983: TP53 mutations in hepatocellular carcinoma: Association with survival and stem cell-like gene expression traits
Authors: Hyun Goo Woo, Xin Wei Wang, Anuradha Budhu, Zhao-You Tang, Zongtang Sun, Curtis C. Harris, Snorri S. Thorgeirsson
Journal: Cancer Research (2010)

Abstract PURPOSE Mutations of TP53, a tumor suppressor gene, are associated with prognosis of many cancers. However, the prognostic value of TP53 mutations in hepatocellular carcinoma (HCC) is still unclear, largely because of the enormous heterogeneity in the geographic and etiological backgrounds of the HCC patients. Here, we analyzed the prognostic values of TP53 mutations. Gene expression profiling analysis was performed to evaluate the effect of TP53 mutations at the molecular level. PATIENTS AND METHODS TP53 mutations were investigated in a total of 409 HCC patients including Chinese (n=336) and Caucasian (n=73) patients using direct sequencing method. RESULTS A total of 125 TP53 mutations were found in Chinese HCC patients (37.2 %). HCC patients harboring TP53 mutations showed shorter overall survival compared to patients with wild-type TP53 (Hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.37-2.52; P&amp;lt;0.001). The hotspot mutations at R249S and V157F were significantly associated with worse prognosis in both univariate (HR, 2.11; 95% CI, 1.51-2.94; P&amp;lt;0.001) and multivariate analyses (HR, 1.79; 95% CI, 1.29-2.51; P&amp;lt;0.001). In addition, gene expression profile analysis revealed the expression of stem cell-like traits in TP53 mutated tumors. This finding was validated in breast and lung cancers with TP53 mutations. CONCLUSION TP53 mutations, particularly hotspot mutations, are associated with poor prognosis in HCC. The acquisition of stem cell-like gene expression traits may contribute to the aggressive behavior of the TP53 mutated tumors. 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 1983.
Hypergonadotropic Hypogonadism in Female Patients with Galactosemia
Authors: Francine Ratner Kaufman, Maurice D. Kogut, George N. Donnell, Uwe Goebelsmann, Charles March, Richard Koch
Journal: New England Journal of Medicine (1981)

We evaluated gonadal function in 18 female and eight male patients with galactosemia due to transferase deficiency; it was normal in the males, but 12 females had signs of hypergonadotropic hypogonadism. All female patients had a 46,XX karyotype, normal levels of thyroid hormone and prolactin, and no anti-ovarian antibodies. The biologic activity of urinary gonadotropins was normal. Ultrasonography of the pelvis revealed that ovarian tissue was diminished or absent. Total estrogens increased in one of two patients after administration of human menopausal gonadotropin. The frequency of hypergonadotropic hypogonadism was higher in females in whom dietary treatment for galactosemia was delayed. Clinical course and mean erythrocyte galactose-1-phosphate and urinary galactitol levels did not correlate with ovarian function. We conclude that female patients with galactosemia have a high incidence of ovarian failure due to acquired ovarian atrophy. Galactose or its metabolites may be toxic to the ovarian parenchyma, particularly during the immediate neonatal period.
An intrinsic DFF40/CAD endonuclease deficiency impairs oligonucleosomal DNA hydrolysis during caspase-dependent cell death: a common trait in human glioblastoma cells
Authors: María Sánchez-Osuna, Laura Martínez-Escardó, Carla Granados-Colomina, Fina Martínez-Soler, Sònia Pascual-Guiral, Victoria Iglesias-Guimarais, Roser Velasco, Gerard Plans, Noemi Vidal, Avelina Tortosa, Carlos Barcia, Jordi Bruna, Victor J. Yuste
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) or grade IV astrocytoma is one of the most devastating human cancers. The loss of DFF40/CAD, the key endonuclease that triggers oligonucleosomal DNA fragmentation during apoptosis, has been linked to genomic instability and cell survival after radiation. Despite the near inevitability of GBM tumor recurrence after treatment, the relationship between DFF40/CAD and GBM remains unexplored. We studied the apoptotic behavior of human GBM-derived cells after apoptotic insult. We analyzed caspase activation and the protein levels and subcellular localization of DFF40/CAD apoptotic endonuclease. DFF40/CAD was also evaluated in histological sections from astrocytic tumors and nontumoral human brain. We showed that GBM cells undergo incomplete apoptosis without generating oligonucleosomal DNA degradation despite the correct activation of executioner caspases. The major defect of GBM cells relied on the improper accumulation of DFF40/CAD at the nucleoplasmic subcellular compartment. Supporting this finding, DFF40/CAD overexpression allowed GBM cells to display oligonucleosomal DNA degradation after apoptotic challenge. Moreover, the analysis of histological slices from astrocytic tumors showed that DFF40/CAD immunoreactivity in tumoral GFAP-positive cells was markedly reduced when compared with nontumoral samples. Our data highlight the low expression levels of DFF40/CAD and the absence of DNA laddering as common molecular traits in GBM. These findings could be of major importance for understanding the malignant behavior of remaining tumor cells after radiochemotherapy.
P219 Evaluating medical thoracoscopy services at a District General Hospital over the past 13 years
Authors: LM George, HJ Roberts, NJ Downer, GM Cox, NJ Ali, ME Roberts
Journal: Thorax (2013)

<h3>Introduction</h3> Medical thoracoscopy is an invaluable tool in the management of undiagnosed and known malignant pleural effusions. In the UK, increasing numbers of centres are offering the procedure We present the experience from a single district general hospital that has been offering medical thoracoscopy over the last 13 years. <h3>Methodology</h3> A retrospective analysis of 411 case notes of patients who had a medical thoracoscopy between July 2000 and April 2013. <h3>Results</h3> 291 patients (71%) were male. The median age was 70 years (24 to 92). In 321 patients (78%) the procedure was done for diagnostic purposes and the procedure was done on the right side (20%) had lung cancer, 94 (23%) had mesothelioma and 66 ( 16%) had other cancer. In the 231 patients that had operator observations as appearing malignant 198( 86%) were confirmed on histology. 34 ( 30%) patients had malignancy in operator observations that were reported as inflammation but reassuringly no patients had malignancy in the operator observations that were reported as appearing normal. Talc poudrage was done in 261 ( 64%)patients. 53 patients (13%) required a further pleural intervention within 12 months. Complications included empyema in 3 (0.7%), renal failure in 6 (1.4%) and trapped lung in 20 (5%) patients. 6 patients (1.4%) died within 15 days of the procedure and major contributors to mortality were hospital acquired infection. <h3>Conclusions</h3> Medical thoracoscopy is an effective procedure for diagnosing and managing pleural effusions. It is associated with a low complication rate and can be performed in patients with poor performance status. Caution should be exercised in patients with multiple comorbidities and careful management of cardiovascular status post-operatively could help reduce post-procedure kidney injury.
P480Antiatherogenic effect of quercetin is mediated by proteasome inhibition in the aorta and circulating leukocytes.
Authors: D Pashevin, LV Tumanovska, VE Dosenko, OO Moibenko
Journal: Cardiovascular Research (2014)

Proteasomal degradation of proteins contributes significantly to the regulation of the vital functions of cells. Disturbances in proteasomal proteolysis play pivotal role in pathologies of the cardiovascular system, such as atherosclerosis. Here, we report data showing the angioprotective properties of quercetin mediated by its effect on proteasomal proteolysis. Methods: Experiments were performed on 56 rabbits which divided on the next groups: control, cholesterol-rich diet and quercetin application with cholesterol-rich diet. Monocytes, lymphocytes and PMN were fractionated by centrifugation on a Percoll gradient and activities of proteasome were determined using fluorogenic substrates. The aorta and vena cava posterior was homogenized and used for biochemical analyses. The levels of cholesterol, triglyceride, LDL, and VLDL were determined using Bio System A25. Histological changes in aortic tissues were established using Oil Red and hematoxylin staining. Results: Our data clearly indicate the adequacy of our model, showing the increase of cholesterol, triglycerides, LDL and VLDL levels up to 32-, 2.2-, 30-, and 5-fold, respectively. We show proteasomal trypsin-like (TL) activity increased up to 2.4-fold, chymotrypsin-like (CTL) activity increased by up to 43% and peptidyl-glutamyl peptide-hydrolyzing (PGPH) activity increased by up to 10% after 8 weeks of a cholesterol-rich diet. Administration of quercetin (Quertin) to animals following a cholesterol-rich diet significantly decreased all types of proteolytic proteasome activities both in tissues and in circulating leukocytes and was associated with the reduction of atherosclerotic lesion areas in the aorta. Application of quercetin have not influence on lipids level. Also, Quercetin (Quertin) significantly decreased proteasomal TL activity 1.85-fold in monocytes, and decreased the CTL and PGPH activities more than 2-fold in polymorphonuclear leukocytes. Application of quercetin decrease proteasomal activity in aorta, in venous tissues activity of proteasome have not significantly changes in cholesterol-rich diet. Conclusions: These data indicate that the increase of proteasome activity in aorta and blood cells plays a pathogenic role during the development of atherosclerosis. Increase of proteasome activity was shown only in aortic tissues, not in venous tissiues (resistent to atherogenic factors) in CRD. Antiatherogenic action of quercetin is due to its inhibitory effect on proteasome activity.
Abstract 3813: DNA polymerase eta and a novel anticancer selenophene compound
Authors: Yih-wen Chen, Jang-yang Chang, Kai-Ming Chou
Journal: Cancer Research (2012)

Abstract Human DNA polymerase ≤ (pol α) plays a key role in replicating across the UV radiation induced cyclobutane pyrimidine dimers (CPD) in DNA and mutations in pol ≤ gene result in a syndrome called Xeroderma Pigmentosum Variant (XP-V). In the absence of pol β, the DNA replication forks collapse after prolonged stalling at CPD sites, which consequently lead to DNA breakages and cell death. Therefore, pol ≤ has been considered to serve as a cellular protection mechanism to enhance cell survival and reduce mutagenesis. In addition to UV-induced CPD lesion, pol ≤ has the ability to handle DNA lesions introduced by chemotherapeutic anticancer agents, such as platinum based compounds and nucleoside analogs. Such damage tolerance ability of pol ≤ has been shown to reduce cell sensitivity to these DNA targeting agents. D-501036 [2,5-bis(5-hydroxymethyl-2-selenienyl)-3-hydroxymethyl-N-methylpyrrole] is a selenophene compounds that demonstrated promising antitumor activity against various human cancer cells and in vivo xenograft mouse model. Mechanistic studies have shown that D-501036 induced DNA adduct(s) and caused genome instability, which result in cell cycle accumulation in the S-phase, DNA breakage, and subsequently lead to cell death. Interestingly, the IC50 for human fibroblast XP30RO cells derived from XP-V patients was &amp;gt;50 fold higher than the XP30RO cells that stably transfected with a pol ≤ expressing vector (XP30RO-EGFP-pol α). In addition, D-501036 caused an increased amount of DNA breakage in the XP30RO-EGFP-pol ≤ cells as compared to its parental XP30RO cells in both DNA fragmentation and comet assays. These results revealed a novel role of pol ≤ in the action of D-501036 that is very different from its protective role against UV irradiation or cisplatin. 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 3813. doi:1538-7445.AM2012-3813
AB0224 Treating rheumatoid arthritis to target: a singapore survey
Authors: F. L. Chia, S. C. Ng, H.-L. Low, A. Lateef, K. H. Leong
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In recent years, the treatment paradigm for rheumatoid arthritis (RA) has changed significantly. Treat to Target (T2T) is a global initiative that aims to provide guidance to treat RA to specific therapeutic goals <h3>Objectives</h3> This study aims to assess the agreement and application of the 10 T2T recommendations in Singapore practice. <h3>Methods</h3> An online survey of rheumatologists in Singapore was conducted, asking rheumatologists to score their agreement with each recommendation on a 10-point Likert scale (1= fully disagree, 10= fully agree) and to asses the extent of application in their daily practice on a 4 point Likert scale (Always, very often, not very often, never). Those who were not applying the recommendations were asked if they were willing to change their practice, with qualitative comments captured if they were not willing to change. <h3>Results</h3> 33 out of 41 (80.5%) rheumatologists contacted responded. Of these, 87.9% were in government or restructured hospitals and the rest in private practice. There was high agreement with the recommendations, with average agreement scores ranging from 8.30 (+/- 1.61) for recommendation #6 (composite measures of disease activity are necessary) to 9.27 (+/- 1.40) for recommendation #1 (the target of treatment is remission). A majority of rheumatologists indicated that they apply the T2T recommendations in their practice, but recommendations #5 and #6 (regarding frequency of visits and use of composite measures) had the highest number of responses indicating that they were infrequently applied (24.2% and 33.3%). There was no difference between rheumatologists in private practice or government hospitals. Lack of time and manpower, inability of the patient to relate to abstract composite scores and the fact that ultrasonography may be more useful than composite scores to assess activity were reasons given for not applying these recommendations, although most were willing to change their practice. <h3>Conclusions</h3> Most rheumatologists in Singapore agreed with and applied the T2T recommendations, although there were specific recommendations that some rheumatologists felt were contentious. A workgroup has been formed to formulate local guidelines for the treatment of RA. <h3>References</h3> Smolen JS, Aletaha D, Bijlsma JWJ, Breedveld FC, Boumpas D, Burmester G et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Annals of Rheumatic Diseases 2010; 69:631 Haraoui B, Smolen JS, Aletaha D, Breedveld FC, Burmester G, Codreanu C, Da Silva JP et al. Treating rheumatoid arthritis to target: multinational recommendations assessment questionnaire. Ann Rheum Dis 2011; 70: 1999 <h3>Disclosure of Interest</h3> None Declared
Abstract 3679: Targeting drug-resistant GIST cells with a quadruplex-binding small molecule
Authors: Mekala Gunaratnam, Gavin Collie, Anthony Reszka, Alan Todd, Gary Parkinson, Jonathan Fletcher, Stephen Neidle
Journal: Cancer Research (2010)

Abstract Gastrointestinal tumours (GIST) originate, at least in part, from disregulation and consequent aberrant expression of the c-kit oncogene. Imatinib is an effective inhibitor of the ATP-binding activity of the kinase domain in the c-kit protein, and is used clinically to treat GIST patients. However acquired resistance to Imatinib is a severe problem hindering long-term patient survival. We have previously reported on an alternative approach to c-kit therapy that involves targeting and stabilising quadruplex DNA sequences with a small molecule, (i) in two sequences within the c-kit promoter so that c-kit expression is down-regulated, and (ii) in the single-stranded overhang of telomeric DNA, inhibiting telomerase activity in GIST cells. We have previously reported that both of these are targeted by a potent (IC50 ≪ 1μM) tetra-substituted naphthalene diimide compound in the Imatinib-sensitive GIST882 patient-derived cell line. This compound is equally potent in the patient-derived GIST48 Imatinib-resistant line; we report here that it has no effect on c-kit expression, telomerase activity, or the expression of other oncogenes in which promoter quadruplexes have been identified. Instead we find that the translation of the apoptosis-related bcl-2 gene is profoundly affected, but not its transcription. The bcl-2 gene has a potential quadruplex-forming region in the 5′-UTR sequence, and we report here that this forms a stable RNA quadruplex structure, which is further stabilised by the binding of the naphthalene diimide ligand. A reporter assay approach using a dual luciferase psiCHECK-2 vector, containing the bcl-2 5′-UTR sequence, is being used to validate the key concept that this G-rich sequence is involved in modulating translation in vitro, and in vivo through transfection into mammalian cells. Our current experiments in an Imatinib-resistant GIST cell line in the presence of the compound are enabling us to substantiate this cellular target and characterize the mode of action. 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 3679.
PARE0011 Living with A Strange `'Roommate” in Your Body – A Journey through Life with A Chronic Disease
Authors: S. Makri
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Pain had began during the most productive years of age (30-45). Ten years of everyday pain mainly on the neck. Then it spread all over the body. Very strong headaches, non restorative sleep, fatigue, pain killers on an everyday basis. Coping with every day activities at home proved difficult. Working and meeting Job demands on a full time working schedule also was exhausting. Diagnosis came after one year and after visiting various Doctors and health professionals9. I refused to accept my condition. Ifelt sad and was Wondering `9Why me"!! <h3>Objectives</h3> Acceptance Find a way to cope with everyday activities Return to work Be a good parent Return to social activities Return to social life Avoid depression Control stress Control anxiety Deal with fatigue Avoid isolation Find happiness without really knowing how <h3>Methods</h3> I Sought help from the local patient association. Started following Self management workshops. I had to change my profession and my way of thinking and living. I followed different approaches to treatment and started learning about the disease and finding my own way of dealing with it. <h3>Results</h3> Return to action and came out of isolation. New experiences and new people came into my life to offer their help in various ways. More self confident, began travelling again, I followed a new `9life" with new targets, new objectives, new and exciting experiences. I met new interesting people. The family and the social environment came to understand that I was suffering from a real disease and that it was not only in my mind. I started meeting the `9right" people who could support me ... The question was not `9Why me" anymore but `9why not me?". <h3>Conclusions</h3> Personal effort by the patients is needed in order to stay active, fit and productive even with a chronic disease. You can grow older and still have a lot to offer to yourself, to the family and the social environment. To do this you have to look "inside" you, get to know your feelings, your real self. Happiness is not somewhere around you, it is inside you. a lot therefore depends on you and on your own efforts. You must keep in mind always that you are not alone, there always people ready to support you !! <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1036