tbuckley/cabot-search huggingface dataset:
Abstract 1098: Cys141 glutathionylation of human p53: Studies using specific polyclonal antibodies in cancer samples and cell lines
Authors: Mohammad A. Yusuf, Kalkunte S. Srivenugopal
Journal: Cancer Research (2010)

Abstract Purpose: We previously described that human p53 is functionally inactivated by S-glutathionylation at Cys 141 during oxidative and genotoxic stresses (Biochemistry 46, 7765-7780, 2007). To study the dynamics of this posttranslational modification in human cancers and normal tissues, polyclonal antibodies specifically recognizing the thiolated p53 were generated and characterized. Experimental Design: An 18 residue p53 peptide harboring a mixed disulfide with GSH at Cys141 was synthesized, and antibodies were raised in 5 rabbits. After initial assessment of the sera for the presence of specific (p53-glut) antibodies, it was affinity purified. The antibodies were tested in ELISA, immunoblotting and immunohistochemistry applications using human cancer cell lines and tumor tissue microarrays. Results: The p53-glut antibodies recognized the antigenic peptide but not the unmodified counterpart, with high sensitivity in ELISA. In immunoblot analyses, the purified antibodies did not react with unmodified p53 or recombinant p53 (rp53), but readily detected the glutathionylated or cysteinylated or small molecule ethanediol-modified rp53 only under non-reducing conditions. Western blotting and immunocytochemistry in HCT116 cells showed low basal levels of thiolated p53 in untreated cells which increased markedly after acute oxidative stress induced by H2O2, diamide and DNA damage by cisplatin or doxorubicin. The glut-p53 decreased sharply after passage of cells to oxidant-free media. The mutant p53 present in HT29 cells was also recognized. In human prostatatic tissues, the apparently normal prostate adjacent to the tumor and most prostate cancers showed abundant presence of glut-p53 in luminal epithelium, a site well known to generate reactive oxygen species, hydrogen peroxide, and lack antioxidant enzymes such as GST-pi. The melanoma and colon cancer were also positive while gastric cancers were negative. Further, the glut-p53 was degraded faster than unmodified p53 in the presence of rabbit reticulocyte lysates. Conclusions: Our findings provide first evidence for the presence of glut-p53 in human cells and cancer specimens. Glut-p53 found in prostate tissues may reflect the chronic oxidative stress and an alternative route to functional inactivation of p53. This is a first description of thiolation-specific antibodies for any protein. The glut-p53 antibodies should provide a valuable tool to study p53 inactivation in sustained redox imbalance states found in cancer and degenerative diseases, as well as the therapy-induced negative regulation of p53. 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 1098.
Case 76-1962
Authors: Allan L. Friedlich, Benjamin Castleman
Journal: New England Journal of Medicine (1962)

Presentation of Case First admission. A seventy-one-year-old man entered the hospital because of dyspnea.Gradually increasing exertional dyspnea accompanied by moderate ankle swelling began one year previously, and digitalis therapy was started six months later because of these symptoms. There was no history of chest pain, hypertension or rheumatic fever.Four years before entry the patient was seen in the clinic of this hospital because of an infrequent cough that was occasionally productive of blood-tinged sputum. The chest was clear to percussion and auscultation; no murmurs were heard. The blood pressure was 140 systolic, 80 diastolic, and the pulse . . .
Oncogene Links Seen to Heart Disease, Cholesterol
Authors: E. Blume
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Oncogene Links Seen to Heart Disease, Cholesterol Get access Elaine Blume Elaine Blume Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 19, 4 October 1989, Pages 1442–1443, https://doi.org/10.1093/jnci/81.19.1442 Published: 04 October 1989
FRI0169 Influence of anti-tnf therapy on the risk of myocardial infarction in subjects with rheumatoid arthritis: results from the bsrbr-ra
Authors: A. Low, M. Lunt, L. Mercer, E. Bruce, B. C. C. Consortium, W. Dixon, K. Hyrich, D. Symmons
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Subjects with RA are at increased risk of premature cardiovascular disease (CVD) including myocardial infarction (MI), partly through shared inflammatory mechanisms. Anti-TNF therapy may influence this risk through control of inflammation and mediation of other CV risk factors. <h3>Objectives</h3> The aim of the analysis was to study the association of anti-TNF therapy with the risk of MI in routine UK clinical practice. <h3>Methods</h3> The BSRBR-RA is an ongoing national prospective observational cohort study. Subjects with RA starting anti-TNF (etanercept, infliximab, adalimumab) and a biologic-naïve comparator cohort of subjects exposed to nbDMARD were recruited 2001-2009. All were followed by clinician &amp; patient questionnaires 6-monthly for 3 years, annual clinician questionnaires thereafter and linked to the national death register. All reported MIs from any source were validated against the 2007 AHA/ESC MI criteria. Additional criteria were acute thrombolysis/angioplasty for MI or MI as the underlying cause of death on death certificates. Subjects were censored at 20/4/2010, death, incident MI or date of last clinician follow-up, whichever came first. Subjects with prior CVD were excluded from analysis. Risk of MI was compared between nbDMARD and subjects ever exposed to anti-TNF therapy using Cox regression adjusted by propensity score deciles (PD; Table). The PD included age, gender, RA-related factors, CV risk factors &amp; drugs. Risk of MI was explored further with different drug exposure models and also modelled over time. 30-day and 1-year all-cause mortality post-MI was compared between nbDMARD and anti-TNF subjects using multivariate logistic regression, adjusted for the same confounders. <h3>Results</h3> 235 verified incident MIs were analysed; nbDMARD: 43 in 10337 person-years (pyrs), anti-TNF: 192 in 55636 pyrs (42 v 35 per 10,000 pyrs; Table). There was a trend for a reduced risk of MI in subjects ever exposed to anti-TNF compared to nbDMARD: PD-adjusted hazard ratio 0.65 (0.42-1.01). Risk estimates were similar when limited to periods receiving anti-TNF drug only and did not vary over time. 30-day and 1-year mortality post-MI was not associated with ever-exposure to anti-TNF: adjusted odds ratios (OR) 0.93 (0.29-2.95), OR 0.97 (0.33-2.79) respectively. <h3>Conclusions</h3> Subjects with RA ever exposed to anti-TNF experienced a reduced risk of MI over the medium term, further supporting the role of TNF and inflammation in CVD. <h3>Disclosure of Interest</h3> None Declared
SP0203 Molecular mechanisms of fibrogenesis in pulmonary fibrosis
Authors: O. Eickelberg
Journal: Annals of the Rheumatic Diseases (2013)

Interstitial lung diseases, most importantly idiopathic pulmonary fibrosis (IPF) share similar pathomechanistic principles, including progressive fibrosis of the pulmonary interstitium, distortion of normal lung architecture, and respiratory failure. Fibrotic alterations in IPF can occur secondary to acute or chronic lung injury. The prevalence and incidence of interstitial lung disease is often underestimated: up to 750.000 patients may suffer from interstitial lung disease in the Western World. IPF alone affects up to 150.000 patients in Europe and exhibits an average survival time of 3-5 years after diagnosis. This seminar will review initial trigger events and secondary hits in IPF, describe early cellular responses during the development of fibrosis, including regenerative responses, developmental pathways, cellular plasticity, trafficking and crosstalk, fibroblast activation, and matrix deposition. Finally, the seminar will highlight novel molecular concepts and targets for the treatment of fibrosis in general and IPF in particular. <h3>Disclosure of Interest</h3> None Declared
A1.29 Normal and rheumatoid arthritis neutrophil extracellular TRAPS are both pro- and anti-inflammatory via mechanisms involving the C1Q complement protein but independently of ACPA, ll-37 or the inflammasome
Authors: M Ribon, S Seninet, K Matyja, M Sebbag, C Clavel, J Mussard, G Serre, MC Boissier, P Decker
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Activated neutrophils (PMN) form neutrophil extracellular traps (NET), expelled chromatin fibres. NETosis is dependent on citrullination and may be pathogenic in rheumatoid arthritis (RA), which is characterised by the production of anti-citrullinated protein autoantibodies (ACPA). However, the potential pathogenic mechanisms triggered by NET are not elucidated. Therefore, we have analysed the antigenic and inflammatory properties of NET in RA. <h3>Materials and methods</h3> Primary blood PMN and monocytes were freshly purified from 115 independent healthy donors (HD) and RA patients. IgG were purified from HD, ACPA-positive RA patients or ACPA-negative patients. Monocytes were differentiated into macrophages. NETosis was induced <i><i>in vitro</i></i> by PMA on adherent PMN and analysed by fluorescence microscopy, together with IgG binding. To produce soluble NET (sNET), NET were detached from glass by mild nuclease digestion. They were enriched, quantified by spectrophotometry, and characterised by SDS-PAGE and agarose gel. Macrophages/PMN were cultured with sNET in the presence/absence of LPS, IgG, NH<sub>4</sub>Cl, LL-37, ATP or C1q. Cell purity, IgG binding and cell activation were estimated by flow cytometry. Cytokine secretion was measured by ELISA. <h3>Results</h3> Low binding of IgG was observed on untreated PMN. Upon activation, a strong recognition by ACPA+ IgG was observed on NET. The NET staining with ACPA from RA patients was stronger than with ACPA-negative IgG. HD NET were as antigenic as RA NET. NETosis was higher with RA PMN. Soluble NET activated steady-state macrophages and PMN, independently of ACPA+ IgG or soluble LL-37. The stimulatory activity of sNET on macrophages was increased in the presence of C1q but was not influenced by inhibition of endosomal acidification/TLR in PMN. Both HD NET and RA NET induced cell activation, although RA NET were more potent. Likewise, both HD and RA PMN and macrophages responded to sNET but IL-1β secretion was not induced. On the contrary, sNET specifically inhibited LPS-induced IL-6 secretion by macrophages. <h3>Conclusions</h3> ACPA+ IgG from RA patients recognise NET and not untreated PMN. NET are antigenic and possess both pro- and anti-inflammatory properties. Therefore, an excess of NETosis together with higher NET activity may be pathogenic in RA.
THU0378 Interleukin-6 blocking therapy by tocilizumab in patients with multicentric castleman’s disease results in a significant decrease in serum levels of IgG4 and IGE
Authors: M. Murakami, T. Matsutani, C. Aoki, H.-M. Lee, Y. Li, N. Nishimoto
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder characterized by systemic lymphadenopathy, constitutional inflammatory symptoms, and abnormal laboratories such as hyper-γ-globulinemia, increases in various auto-antibodies as well as acute phase proteins. While the symptoms are closely associated with dysregulated overproduction of interleukin (IL)-6, an increase in serum IgG4 and/or IgE levels in MCD patients is frequently observed. Blocking IL-6 with anti-IL-6 receptor antibody, tocilizumab (TCZ), ameliorates not only systemic inflammatory symptoms but also abnormal laboratories including hyper-γ-globulinemia. <h3>Objectives</h3> 1) To clarify differences in clinical features between MCD patients with high serum IgG4 and those with normal serum IgG4. 2) To analyze changes in serum IgG subclasses as well as IgE levels of MCD patients with TCZ treatment. <h3>Methods</h3> Serum levels of total IgG and four IgG subclasses as well as IgE of 18 MCD patients were measured. Eleven of 18 patients were treated with TCZ. Serum IgG subclass levels (n=11) and serum IgE levels (n=9) were compared before and after the treatment. <h3>Results</h3> Serum IgG4 levels at baseline were elevated in 12 of 18 MCD patients (542.2±387.7 mg/dl, n=12 vs. 45.2±39.8 mg/dl, n=6; the normal range is less than 105 mg/dl). Clinical features between MCD patients with high serum IgG4 and those with normal serum IgG4 were not distinct. Serum IgE levels at baseline were elevated in 12 of 16 MCD patients (3414.0±7198.2 IU/ml, n=12 vs. 95.8±66.4 IU/ml, n=4). All the 12 patients with high serum IgG4 showed elevated levels of IgE while only 2 out of 4 patients with normal IgG4 showed high IgE levels. IgG4 and IgE levels were significantly correlated. The mean absolute numbers of all IgG subclasses were significantly decreased after TCZ treatment. Furthermore, the mean ratio of IgG4 to total IgG was significantly decreased (7.4% vs. 5.5%, p&lt;0.05, n=11), while those of the other subclasses did not change. The mean absolute number of IgE levels was also significantly decreased by TCZ treatment (1316.7 IU/ml vs. 481.0 IU/ml, p&lt;0.05, n=9). <h3>Conclusions</h3> Decreases in the serum IgG4/IgG ratios and IgE levels after TCZ treatment suggests that IL-6 may be involved in the class switch to IgG4 and IgE. <h3>Disclosure of Interest</h3> M. Murakami: None Declared, T. Matsutani: None Declared, C. Aoki: None Declared, H.-M. Lee: None Declared, Y. Li: None Declared, N. Nishimoto Grant/Research support from: Chugai and Roche group, the product company of TCZ., Consultant for: Chugai and Roche group, the product company of TCZ.
ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF GLIOBLASTOMA
Authors: M. Gromeier, E. Dobrikova, M. Dobrikov, M. Brown, J. Bryant, S. Threatt, S. Boulton, K. Carter, J. Herndon, A. Desjardins, H. Friedman, J. Sampson, A. Friedman, D. Bigner
Journal: Neuro-Oncology (2014)

BACKGROUND: With the exception of Burkitt lymphoma, almost all solid cancers are susceptible to infection with poliovirus, due to widespread ectopic expression of the poliovirus receptor, the onco-fetal cell adhesion molecule Necl5/CD155. We engineered a profoundly CNS-incompetent and genetically stable variant of polio through recombination of the cognate internal ribosomal entry site (IRES) with its counterpart from human rhinovirus type 2. The resulting PVSRIPO chimera is incapable of causing poliomyelitis or encephalitis in non-human primates or human subjects, even after high-dose intracerebral inoculation, but retains excellent cytotoxic properties in malignant cells. This is due to constitutively active signal transduction pathways via Raf-Erk MAPKs to the MAPK-interacting kinase, Mnk, and the translation apparatus. METHODS: Raf-Erk-Mnk signals favor translation of mRNAs with highly structured, encumbered 5' untranslated regions, typical for mRNAs encoding potent biological response modifiers, survival factors, growth factors or oncogenes. They afford an enormous advantage to PVSRIPO translation, causing irreversible lethal cytotoxicity as early as 60 min after infection. PVSRIPO infection of GBM produces drastic, violent cytotoxicity and a wide range of pro-inflammatory and immunogenic host responses. These are due to virally-induced ‘immunogenic cell death’, forceful activation of innate antiviral type 1 interferon responses, non-lethal infection and pro-inflammatory stimulation of tumor-associated macrophages/dendritic cells and stimulation of cytotoxic T-cell responses directed against the tumor. RESULTS: A currently accruing Phase-1 clinical trial of PVSRIPO with intratumoral, CED-mediated infusion in recurrent GBM is showing promise with the first patients experiencing durable complete clinical and near-complete radiographic responses >20 months post PVSRIPO infusion. The key to PVSRIPO oncolytic immunotherapy is the early acute phase of viral cytotoxicity after intratumoral infusion. Unhinged translation control, enabling unfettered viral, IRES-mediated initiation, is independent of the notorious intratumoral and inter-individual heterogeneity of advanced, treatment-refractory cancers. To define the molecular mechanism of PVSRIPO-mediated immunogenic cell death, we unraveled a signaling network centered on Raf-Erk-Mnk signals and their control over the Ser-Arg-rich protein kinase. CONCLUSIONS: Provided a solid mechanistic rationale exists for their use, oncolytic viruses such as PVSRIPO may induce tumor-cytotoxic, immune-modulatory and immune-stimulatory effects with an extent and biological range that are difficult to achieve with any other type of anti-cancer agent. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
Abstract 2081: Mechanisms of the acquisition of anoikis resistance in breast cancer: Lessons from small molecule inhibitors
Authors: Winston West, Margaret A. Park
Journal: Cancer Research (2012)

Abstract The Cox-2 inhibitor Celecoxib has been reported to possess chemopreventive and chemotherapeutic properties, specifically in hormonally-regulated tumors. OSU-03012 is a novel celecoxib derivative, with no COX-2 inhibitory activity, but an order of magnitude greater cell killing ability. We here show that this novel compound has a greater cytotoxicity against a model of anoikis-resistant (AnR) breast cancer. In parallel, anoikis resistance reduces AnR cell sensitivity to the ErbB1/2 dual inhibitor Lapatinib (GW572016, Tykerb, GSK). The two compounds synergize in parental breast cancer cells. Cell killing is achieved partially via induction of ER stress, as measured by eIF2-alpha phosphorylation. We have found that lapatinib resistance may be induced by the aberrant splicing of BCL-X, and that the sensitivity to OSU-03012 is likely due to PTEN dysregulation. In conclusion, these data identify a molecule that may be more efficacious against metastatic tumors, and partially defined its mechanism of action. 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 2081. doi:1538-7445.AM2012-2081
PROPHYLACTIC INTRA-AORTIC BALLOON PUMP INSERTION PRIOR TO SURGICAL LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION
Authors: Ravi Prasad Avati Nanjundappa, Rajan Patel, Aditya Bansal, Hamang Patel, Daniel Masvidal, Patrick Campbell, Sapna Desai, Stacy Mandras, Tyrone Collins, Christopher White, Hector Ventura
Journal: Journal of the American College of Cardiology (2015)
AB0666 The Survival of the anti Tumor Necrosis Factor Alpha in Patients with Ankylosing Spondylitis as First Line Treatment in Slovenian Nationwide Registry
Authors: I. Holc, M. Koren Kraqjnc, A. Pahor
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Ankylosing spondylitis is potentially debilitating rheumatic disease. The introduction of biologics in treatment armamentarium made a radical change in prognosis. Anti tumor necrosis factor alpha (TNF-a) are the only biologics approved for treating NSAID resistant ankylosing spondylitis so far. That9s why the survival of the drug is very important issue. <h3>Objectives</h3> To estimate the time of drug survival of first line anti TNF-a in patients with ankylosing spondylitis resistant to NSAIDs according to Slovenia nationwide registry (Biorx). <h3>Methods</h3> All the patients treated with biologics for rheumatic diseases in Slovenia are registered in nationwide registry. We included all patients treated with anti TNF-a agent as first line therapy between May 2010 and October 2013, namely adalimumab, golimumab, etanercept and infliximab. <h3>Results</h3> In observed period 377 patients (37,55% female patients, 80,92% HLA-B27 positive) with ankylosing spondilitis were treated with biologics, median age at baseline was 46, 6 years. Mean disease duration at baseline was 8,12 years. Survival rates in 180 weeks of treatment were 82%, 72%, 72% and 66% for adalimumab, etanercept, golimumab and infliximab, respectively. <h3>Conclusions</h3> Survival of first line therapy anti TNF a agent in ankylosing spondylitis is 76%. These results are in concordance with the previous published studies. <h3>References</h3> Braun J et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis Ann Rheum Dis 2011;70:896-904 Davis J e tal. Efficacy and safety of up to 192 weeks of etanercept therapy in patients with ankylosing spondylitis. Ann Rheum Dis. 2008 Mar;67(3):346-52 Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, Hetland ML: Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years9 surveillance in the Danish nationwide DANBIO registry. Ann Rheum Dis 2010, 69:2002-2008. Seiper J et al. Tocilizumab (tcz) is not effecitve for the treatment f ankylosing spondlitis (AS): results of a phase 2, international, multicenre, randomised, double-blind, placebo-controlled trial.Ann Rheum Dis 2012;71(Suppl3):110 Glintborg B. et al. Clinical response, drug survival and predictors thereof in 432 patients with ankylosing spondilitis switching anti tumor necrosis factor alpha therapy. results from the Danish nationwide Danbio registry. Ann Rheum Dis. 2010 Nov;69(11):2002-8 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4596