tbuckley/cabot-search huggingface dataset:
OP0107 Ectopic Lymphoid Neogenesis is Specifically Associated with Activation of the IL-23/IL-17 Pathway in Rheumatoid Synovitis
Authors: N. Yeremenko, R. Celis, L. van Duivenvoorde, J. Ramírez, S. Marsal, J.L. Pablos, R. Sanmarti, J.D. Cañete, D. Baeten
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Ectopic lymphoid neogenesis (ELN) occurs in 30-50% of the rheumatoid synovial samples but its functional relevance remains unknown. As ELN correlates with the degree of tissue inflammation we investigated here whether ELN was associated with specific cytokine profiles. <h3>Methods</h3> Paired synovial tissue (ST) (n=63) and fluid (SF) (n=44) was obtained from the inflamed knee joints of rheumatoid arthritis (RA) patients. Synovial inflammation and ELN was determined by immunohistology. CD21L was used as molecular marker of ELN. Cytokine expression was determined by ELISA and quantitative PCR in SF and ST, respectively. <h3>Results</h3> 48% of ST displayed ELN by histology. ELN+ samples had increased T and B lymphocyte infiltration (p&lt;0.001) and CD21L expression (p=0.014). SF analysis showed higher expression of IL-23 (p=0.018) and IL-17F (p=0.028) in ELN+ versus ELN- samples, with a similar trend for IL-22 (p=0.070). Other cytokines, including IL-17A, IL-6, TNF, Th1 cytokines and Th2 cytokines, were not different. In ST, IL-23 (p=0.030) mRNA levels were increased in ELN+ samples. Moreover, CD21L expression as molecular marker of ELN correlated significantly with mRNA expression of IL-23 (r=0.70), IL-17F (r=0.42), IL-21 (r=0.30) and IL-22 (r=0.33), but not IL-17A, IL-6 and TNF. The strong correlation between CD21L and IL-23, IL-17F, IL-21 en IL-22 was confirmed in an independent RA ST sample set (n=36). <h3>Conclusions</h3> Synovial ELN in RA is specifically associated with increased expression of IL-23/IL-17-related cytokines. Whether patients depicting synovial ELN respond differently to therapeutic targeting of this pathway remains to be determined. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5179
P42 The relationship of home activity levels to psychological co-morbidity in COPD
Authors: T. Stuart, C. Rogers, G. Balanos, A. M. Wood
Journal: Thorax (2011)

<h3>Background</h3> Physical activity levels are often reduced in patients with COPD, but are partially amenable to intervention, predominantly by rehabilitation. Depression and anxiety are also commonly observed co-morbidities, which relate to outcomes such as mortality and admission rates.1 A recent meta-analysis of exercise as a treatment for depression suggested that it may improve depressive symptoms,2 hence it is recommended by NICE guidance for mild depression. We hypothesised that less active COPD patients would also have higher rates of psychological co-morbidity. <h3>Methods</h3> 59 consecutive COPD admissions or attendees to COPD clinic were recruited between January and March 2010, screened for anxiety and depression, and questioned regarding activity levels using the Modified Baecke Questionnaire (MBQ). Those who were already on treatment for anxiety or depression were excluded from further analysis (n=4). Home activity monitoring using the Actigraph was conducted in 20 patients and 6MWT distances recorded. <h3>Results</h3> 38.2% of patients were anxious and 36.4% depressed, according to HADS. Both related strongly to exacerbation and admission rates over the preceding 12 months (p&lt;0.01), and to QOL as measured by CAT (p&lt;0.01). Perceived activity as measured by MBQ was lower in depressed patients (p=0.02); this remained significant after regression analysis, adjusting for exacerbations and FEV<sub>1</sub> (p=0.03). However, actual activity from the Actigraph showed no relationship to either anxiety or depression (both p&gt;0.38). <h3>Conclusions</h3> Depressed patients perceive their symptoms to be more severe, and therefore their activity levels lower, than non-depressed patients. However, this did not translate into a difference in actual activity levels. Whether exercise programmes can impact on psychological co-morbidity in COPD requires further research.
Long-Term Evaluation of Single versus Multiple Courses of Actinomycin D Therapy of Wilms's Tumor
Authors: James A. Wolff, Giulio D'Angio, John Hartmann, William Krivit, William A. Newton
Journal: New England Journal of Medicine (1974)

Long-term analysis of the value of a single course (36 patients) versus multiple courses (37 patients) of actinomycin D in the treatment of Wilms's tumor showed that the relapse rate was significantly less in subjects given multiple-course chemotherapy. There was no significant difference in long-term survival between the two groups. Multiple courses appeared to suppress pulmonary metastases. Because of fewer relapses, fewer additional control measures were needed, and morbidity from the disease and its treatment was therefore lessened. Multiple-course therapy is preferred to a single course in Wilms's tumor. (N Engl J Med 290:84–86, 1974)
P08.01 * RESPONSE TO T-DM1 IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BM)
Authors: A. S. Berghoff, R. Bartsch, E. Bergen, M. Rudas, M. Gnant, K. Dieckmann, K. Pinker, C. C. Zielinski, G. G. Steger, M. Preusser
Journal: Neuro-Oncology (2014)

BACKGROUND: Management of BM mainly relies on local treatment approaches including whole brain radiotherapy (WBRT), radiosurgery, and neurosurgery depending on number and size of BM. Of note, WBRT is associated with severe late-toxicity. Recently, lapatinib plus capecitabine (LapCap) as primary systemic treatment in oligosymptomatic patients (pts) with multiple Her2-positive BM was shown to achieve considerable response and delay the need for WBRT. T-DM1 (trastuzumab-emtansine) is an antibody-drug conjugate linking trastuzumab (T) to an anti-microtubule agent. T-DM1 provides activity in pts progressing upon T and has lower toxicity as compared to LapCap. Here, we investigated the activity of T-DM1 in newly diagnosed or progressive BM. PATIENTS AND METHODS: Six pts (median age 55 years) with Her2-positive breast cancer and BM were treated with T-DM1. Two asymptomatic pts received T-DM1 as first line therapy for brain metastatic disease, while four pts received local therapy before and had documented CNS progression at inclusion. T-DM1 was administered intravenously at a dose of 3.6 mg/kg body weight every three weeks; re-assessment of disease status was performed every three cycles. At baseline and restaging, MRI was performed. CNS response was defined as a reduction of lesion size of ≥50%. RESULTS: Median follow-up was 6 months (m). All pts had received prior T, 3/6 (50%) had already received LapCap, and 2/6 (33.3%) pertuzumab. Currently, 4/6 pts (66.6%) are assessable for CNS response. Two/4 pts (50%) had partial remission, while one patient progressing upon prior local therapy had stable disease. One/6 (16.6%) patient had minor response on MRI but no reduction of pre-existing brain oedema and increasing cortisol doses and was therefore deemed PD. A significant LVEF drop was observed in one heavily pretreated patient. CONCLUSION: This prospective case series again indicates that systemic therapy offers activity in Her2-positive BM. Currently, primary systemic treatment with LapCap remains the standard of care. Still, T-DM1 is well tolerated and offers relevant clinical activity; therefore, the role of T-DM1 in BM should be investigated in larger studies.
P16.22 * DIFFERENTIAL DIAGNOSIS OF TUMOR RECURRENCE AND RADIATION NECROSIS AFTER RADIOSURGERY FOR BRAIN METASTASES WITH 320-ROW AREA DETECTOR CT PERFUSION IMAGING
Authors: K. Mitsuya, Y. Nakasu, N. Hayashi, H. Harada, T. Nishimura, I. Ito, A. Urikura, Y. Nakaya, M. Endo
Journal: Neuro-Oncology (2014)

BACKGROUND AND PURPOSE: Radiation necrosis occurs from 6 months to several years following stereotactic radiosurgery (SRS) for brain metastases when tumor recurrences are also most likely. Conventional MR imaging does not provide sufficient information to differentiate between radiation necrosis and tumor recurrence. Tl-SPECT, FDG-PET, MET-PET and MR spectroscopy sometimes lead to false positive findings. We applied 320-row area detector CT perfusion imaging for the differentiation because it shows vascularity of lesions in the whole brain. METHODS: Between October 2008 and September 2013, 275 patients with metastatic brain tumors underwent SRS at our institute. Follow-up MR images were taken at 1 and 3 months and successive every three months after radiosurgery. Twenty-eight lesions enlarged in 26 patients 3 to 26 months (median: 8 months) after treatment. They underwent CT perfusion imaging. To calculate the normalized cerebral blood volume ratio (nCBV ratio), the regions of interest (ROIs) were located in the enhanced areas and in the contralateral normal white matter. Serial MR imaging with gadolinium was done at one- to two-month intervals afterward. Lesions progressively increased in size or became symptomatic were resected and diagnosed by pathological examination. On the other hands, lesions decreased or stable on MR images over three months were diagnosed as radiation necrosis. RESULTS: Surgical removal of the lesions revealed 16 of 18 patients had tumor recurrence. Serial MR imaging (10 patients) and surgery (2 patients) revealed 12 patients suffered radiation necrosis. CT perfusion images showed nCBV ratios higher than 3.0 in all 14 patients with recurrent metastases; whereas it demonstrated nCBV ratios lower than 3.0 in the 12 patients with radiation necrosis. An cut off value nCBV ratio of greater than 3.0 analyzed by ROC curve provided the best sensitivity and specificity for identifying recurrent metastatic tumors, at 81.3% and 100%, respectively. CONCLUSION: Perfusion CT imaging demonstrated a threshold of nCBV ratio reflecting microvascular information about the lesions, and is a reliable method for differentiating tumor recurrence from radiation necrosis after radiosurgery.
P726Coronary NET burden and DNase activity in ST-elevation acute coronary syndrome are predictors of infarct size
Authors: A Mangold, T Scherz, S Alias, T Hofbauer, J Jakowitsch, C Bangert, S Pfaffenberger, MP Winter, KT Preissner, IM Lang
Journal: Cardiovascular Research (2014)

Background: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome (STE-ACS) are poorly understood. We have previously reported accumulation of neutrophils (polymorphonuclear cells [PMNs]) in culprit lesion site thrombi. The goal of the present study was to quantify PMNs, their formation of neutrophil extracellular traps (NETs), and to examine the relationships of extracellular DNA, DNase and clinical outcomes. Methods and Results: We analyzed coronary thrombectomy aspirates from 112 patients undergoing primary percutaneous coronary intervention. Compared to systemic PMNs, coronary thrombus PMNs were characterized by high expression of activation markers and by the formation of aggregates with platelets. Nucleosomes, neutrophil elastase, myeloperoxidase and myeloid-related protein 8/14 were increased in coronary plasma, and NETs significantly contributed to the scaffolds of particulate coronary thrombi. Thrombus NET burden was directly correlated with infarct size, while culprit site DNase activity showed a reverse correlation with infarct size. Recombinant DNase accelerated lysis of coronary thrombi ex vivo. Conclusion: PMNs are highly activated in STE-ACS and undergo NETosis at the culprit lesion site. Coronary NET burden and DNase activity are predictors of myocardial infarct size.
AB0301 Dyslipidaemia in seropositive arthralgia patients predicts the development of arthritis:
Authors: L.A. van de Stadt, A.M. van Sijl, D. van Schaardenburg, M.T. Nurmohamed
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic inflammatory disease that is strongly associated with cardiovascular (CV) disease. In early active arthritis, an unfavourable lipid profile has been found. A strong association exists between the development of arthritis and auto-antibodies, such as Rheumatoid Factor (RF) and anti-cyclic citrullinated protein (aCCP). <h3>Objectives</h3> Considering the relation between inflammation and lipid profiles, we sought to investigate whether differences in lipid profile were also associated with the development of arthritis. <h3>Methods</h3> Total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), apolipoprotein (apo) A1 and apoB were determined at baseline in sera of 348 arthralgia patients positive for RF and/or aCCP. Statin use and cardiovascular co-morbidities were recorded at baseline. Development of arthritis was followed over a median (IQR) of 24 (14-49) months. Differences in lipid profiles between patients who developed arthritis and patients who did not, and differences between aCCP positive and aCCP negative patients were analysed with Student's T test or Mann Whitney U tests as appropriate. Predictive properties of lipid profiles for the development of arthritis were analysed with Cox proportional hazard analyses. <h3>Results</h3> One hundred sixteen patients developed arthritis after a median (IQR) follow-up of 12 (6-23) months, of whom 91% were diagnosed with RA according to the 2010 ACR/EULAR criteria. Lower lipid levels were observed in patients who developed arthritis than in patients who did not, although the difference did not reach statistical significance for all lipids. HDL levels and ApoA1 levels were significantly lower in the arthritis group. Total Cholesterol and ApoA1 were predictive for arthritis development as continuous variables (hazard ratios (HR); 95%CI: 0.84; 0.71-1.00; and 0.44; 0.26-0.79, respectively). HDL was predictive for arthritis development only when analysed as categorical variable (HR; 95%CI: 0.64; 0.43-0.94). aCCP status was a confounder for all lipids. No other confounders were found. aCCP positive patients had significantly lower total cholesterol levels. For the other lipids, trends were seen towards lower lipid levels in aCCP positive patients. After adjustment for aCCP status, only ApoA1 was significantly predictive for arthritis development (HR; 95%CI: 0.52; 0.29-0.92) whereas for HDL an obvious trend was observed (HR; 95%CI: 0.70; 0.47-1.02). <h3>Conclusions</h3> Seropositive arthralgia patients who developed arthritis had overall lower lipid levels than those who did not develop arthritis. Lower lipid levels were also inversely associated with aCCP status. ApoA1 and HDL levels add to the predictive value of aCCP for the development of arthritis. <h3>Disclosure of Interest</h3> None Declared
Researchers Engineering New Cancer Drug Delivery Systems
Authors: L. Seachrist
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Researchers Engineering New Cancer Drug Delivery Systems Get access Lisa Seachrist Lisa Seachrist Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 22, 17 November 1993, Pages 1797–1798, https://doi.org/10.1093/jnci/85.22.1797 Published: 17 November 1993
Abstract B2: Coup-tf1 is suppressed by androgen receptor in prostate cancer epithelial and normal stromal cells
Authors: Ruth Perets, Guy Hidas, Itamar Simon, Eli Pikarsky
Journal: Cancer Research (2009)

Abstract Chicken ovalbumin upstream promoter-transcription factor 1 (Coup-tf1) is a transcription repressor previously known to play a role in neurogenesis and adipogenesis. It mainly acts through suppression of thyroid hormone receptor and vitamin D receptor. Coup-tf1 was implicated before in breast cancer as a negative regulator of the Aromatase gene, and in gastric cancer cell lines as a positive regulator of vegf-d. We performed a genome wide location analysis of androgen receptor (AR) target genes in prostate cancer cells treated with androgen, an AR antagonist or androgen deprivation. This analysis revealed ligand dependent binding of the coup-tf1 promoter and enhancer by the AR which was confirmed by specific chromatin immunoprecipitation studies. AR activation by a ligand is correlated with decreasing mRNA levels implying that AR is a negative regulator of coup-tf1 in prostate cancer cells. Using immunohistochemistry we have seen coup-tf1 staining in 21/28 primary human prostate cancer samples, regardless of Gleason score or prognosis. Coup-tf1 staining was in a nucleolar pattern and its levels in malignant cells were substantially higher than in the adjacent benign prostate glands. Stromal cells both in human and mouse prostate show nuclear coup-tf1 staining. There is an inverse correlation between Coup-tf1 staining and the rising levels of androgen with advancing puberty. These results implicate coup-tf1 in prostate cancer for the first time, and show a novel AR repressed gene, that might play a role in prostate cancer. Citation Information: Cancer Res 2009;69(23 Suppl):B2.
Polymyositis Detected by Ga-67 Scintigraphy
Authors: Yuko Kodama, Yukiko Arisaka, Kotaro Higashi, Suzuka Taki, Mitura Taniguchi, Manabu Oguchi, Hisao Tonami, Itaru Yamamoto, Ariyuki Hori, Nozomu Kurose
Journal: Clinical Nuclear Medicine (2002)

KODAMA, YUKO M.D.*; ARISAKA, YUKIKO M.D.*; HIGASHI, KOTARO M.D.*; TAKI, SUZUKA M.D.*; TANIGUCHI, MITURU M.D.*; OGUCHI, MANABU M.D.*; TONAMI, HISAO M.D.*; YAMAMOTO, ITARU M.D.*; HORI, ARIYUKI M.D.*†; KUROSE, NOZOMU M.D.*‡ Author Information
Abstract 3414: Role of FGFR2 in invasion and metastasis through different activation of downstream signaling in gastric cancer
Authors: Won Suk Lee, Kyu Hyun Park, Jeong Min Kim, Myung Eun Lee, Tae Soo Kim, Hyo Song Kim, Hei Cheul Jeung, Hyun Cheol Chung, Sun Young Rha
Journal: Cancer Research (2012)

Abstract Activation of fibroblast growth factor receptors (FGFRs), the family of receptor tyrosine kinase (RTK), initiates intracellular signaling networks for key cellular processes. Previous reports show that FGFR2 amplification induces activation of downstream signaling in gastric cancer influencing cell proliferation and survival. In this study, we evaluated activation of FGFRs and related downstream pathways, and also determine the effect of FGFRs in tumor invasion and metastasis in gastric cancer. First, we performed phospho-RTK array in 25 gastric cancer cell lines and found that FGFR2 and FGFR3 were more frequently phosphorylated than FGFR1 or FGFR4 in gastric cancer. Next, we observed genomic amplification status and phosphorylation level of FGFR2 using real-time PCR and Western blot. KATO III and SNU-16 with higher expression of FGFR2 showed high correlation between DNA amplification and phosphorylation status. Then, using invasion assay, cells with higher FGFR3 showed higher invasiveness compare to cells with FGFR2 overexpression. When we observed the activation status of downstream signaling molecules, cells with higher FGFR2 were more dependent on PI3K-AKT-mTOR pathway, while cells with higher FGFR3 were more dependent on ERK pathway. In conclusion, FGFRs have various biological roles through different signaling pathways in gastric cancer, suggesting that FGFRs are the potential molecular targets in gastric cancer. 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 3414. doi:1538-7445.AM2012-3414
Abstract 1512: Hypoxic activation of <i>FVII</i> gene in cancer cells mediated by interaction among HIF2α, Sp1, and HDAC4
Authors: Shiro Koizume, Etsuko Miyagi, Fumiki Hirahara, Yoshiyasu Nakamura, Yasuo Takano, Wolfram Ruf, Yohei Miyagi
Journal: Cancer Research (2011)

Abstract Blood coagulation factor VII (fVII) is a key enzyme of the extrinsic coagulation cascade that is produced predominantly by hepatocytes. Tissue factor/fVIIa complex formation on the cell surface initiates key pathogenic mechanisms in cancer, including cell motility, invasion, cell survival, and angiogenesis. We have shown that various cancer cells ectopically synthesize fVII, resulting in activation of cell motility and invasion [1]. We have also shown that fVII expression is ectopically induced in ovarian cancer cells under hypoxia, potentially leading to a major complication of cancer patients, thromboembolism via secretion of fVII-positive microparticles [2]. Hypoxia inducible factors HIF1α and HIF2α are known to form a heterodimeric complex with a constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-ARNT complex binds to hypoxia response elements (HREs) within gene regulatory regions, resulting in transcriptional activation. We previously found that fVII gene (FVII) is inducible under hypoxia by HIF2α dependent mechanism. Unexpectedly, chromatin immunoprecipitation (ChIP) analysis revealed that HIF2α but not HIF1α was found to bind to FVII promoter without HRE [1]. In this study, we further investigated this characteristic transcriptional activation mechanism. Reporter gene, ChIP, and RNA interference (RNAi) experiments revealed that interaction between Sp1 and HIF2α in the promoter region is essential for FVII induction. Histone acetylation is known as a major mechanism for transcriptional activation. Thus, we additionally investigated effect of histone acetylation within the promoter region on HIF2α-Sp1 mediated transcriptional activation. We unexpectedly found that unlike typical transcriptional activation mechanisms, acetylation of histones negatively regulates FVII gene induction. ChIP and RNAi, followed by real-time PCR analysis revealed that a class II histone deacetylase HDAC4 is recruited to FVII promoter under hypoxia and is a coactivator responsible for this transcriptional induction. Furthermore, immunohistochemical experiments with an ovarian cancer xenograft model revealed that fVII presents in tissues strongly expressing HIF2α. These results suggest that hypoxic activation of FVII gene in cancer cells involves novel deacetylation dependent mechanism mediated by HIF2α-Sp1 interaction. References [1] Koizume, S. et al. Cancer Res. 66: 9453-9460, 2006. [2] Yokota, N. et al. Br. J. Cancer, 101: 2023-2029, 2009. 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 1512. doi:10.1158/1538-7445.AM2011-1512