tbuckley/cabot-search huggingface dataset:
FRI0183 Long-term survival of tumor necrosis factor-alpha inhibitor therapies in a spanish cohort of rheumatoid arthritis patients
Authors: R. Caliz, MA Ferrer, MJ Soto, A Garcia, A Utrilla, P Salas, M Lopez-Sidro, L Romani, Z Acevedo, I Notario, J Sainz, R. Cáliz
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Several European studies have proven differences in long-term survival among the different anti-TNF treatments. These differences have been observed in our clinical practice. <h3>Objectives</h3> To investigate the safety and survival rate of tumor necrosis factor (TNF) α inhibitors Infliximab (INF), Adalimumab (ADA) and Etanercept (ETA) in patients with rheumatoid arthritis (RA). <h3>Methods</h3> Observational, retrospective study performed on RA patients treated with TNF-α inhibitors and followed between 2005 and 2011 in our hospital. Safety data were obtained analyzing the causes of discontinuations of treatment due to any causes or adverse events at 1, 2 and 5 years. Survival rates were assessed at 1, 2 and 5 years. Kaplan-Meier survival analysis was performed. Discontinuation from anti-TNF-α due to any cause was defined as final event. <h3>Results</h3> 297 patients were included, 246 are female (77.6%), with a mean age of 45 years: 85 (28.61%) patients received INF, 73 (24.57%) ETA and 139 (46.80%) ADA, which have been treated with DMARDs (46.4% Mtx; 42.9 leflunomide, 10.1% sulphasalazine). Patients treated with anti-TNF had no significant differences in the baseline HAQ and DAS-28. TNF-α inhibitor therapy resulted in a rapid clinical improvement associated with a reduction in inflammatory markers in the first year of the treatment. After 5 years the global retention rate of TNF-α inhibitor was 57. 3%. The mean survival rate in patients with ETA (42.6%) was significantly better than patients treated with INF (23.2%) or ADA (34.1%; p&lt;0.05). The mean duration of therapy was significantly longer for ETA (4.5 years: p&lt;0.05) when compared with ADA (3.25 years p&lt;0.05) or INF (2.5 years: p&lt;0.05). Main reasons for discontinuation were drug adverse events (35 patients: 5 ETA, 15 INF, 15 ADA), and inefficacy (133 patients: 38/85 INF, 61/139 ADA and 34/73 ETA). <h3>Conclusions</h3> TNF-α inhibitors constitute an effective therapeutic option for RA patients refractory to disease-modifying anti-rheumatic drugs. In our clinical practice, ETA has significantly higher survival rate over five years when compared with ADA and INF. All anti-TNF demonstrate an acceptable safety profile, but ETA showed lower rates of AEs and inefficiency unlike ADA and INF since the second year of treatment. Their survival rate remains high in the first years of treatment, decreasing considerably after the second year. <h3>References</h3> Brennan FM, Maini RN, Feldmann M: TNF-a pivotal role in rheumatoid arthritis Br J Rheumatol 1992; 31: 293-8. Freldmann M, Brenna FM, Malnl RN. Role of cytokines in rheumatoid arthritis Ann Rev Immunol 1996; 14: 397-440 <h3>Disclosure of Interest</h3> None Declared
Abstract LB-30: A functional analysis of the nuclear RhoGEF Ect2 in ovarian cancer
Authors: Molly J. DeCristo, Lauren E. Parker, Dimitri Trembath, Pei-Fen Kuan, Margaret Yim, Jinsong Liu, C. Ryan Miller, Channing J. Der, Adrienne D. Cox
Journal: Cancer Research (2012)

Abstract Ect2 is a guanine nucleotide exchange factor (GEF) and activator of Rho family small GTPases. Ect2 regulates RhoA, Rac1, and Cdc42, thereby playing an important role in the control of cell proliferation, survival, and migration. Originally identified as an oncogene in vitro, the role of Ect2 in regulating migration makes it of particular interest in ovarian cancer, in which local invasion and ascites are prevalent. Notably, ECT2 is located on 3q26.1-3q26.2, the most frequent amplicon in ovarian cancer, and it has been found to be overexpressed at the mRNA level in ovarian tumors. We first explored the role of Ect2 in ovarian cancer by knocking it down using shRNA and assessing anchorage-independent growth and both random and directed migration in a panel of ovarian cancer cell lines. Our findings reveal that Ect2 expression is required for each of these functions. Interestingly, we found that Ect2 utilization of specific Rho GTPase substrates is highly context-dependent. In addition, to investigate the potential clinical importance of Ect2, we studied its expression and localization in primary epithelial ovarian cancers, using over 300 histological tumor and cyst samples incorporated into a tissue microarray (TMA). Ect2 is unusual among the RhoGEFs because of its localization. A critical regulator of cytokinesis, it is sequestered to the nucleus in interphase cells. It has been hypothesized that the overexpression and mislocalization of Ect2 into the cytoplasm leads to aberrant Rho activation and oncogenesis. Unexpectedly, our recently completed TMA data analysis suggests that malignant serous ovarian cancer is instead associated with nuclear Ect2, while benign disease is associated with mislocalized, cytosolic Ect2. We are currently exploring a possible nuclear mechanism to explain these findings. Although standard immunohistochemical analyses typically report only total protein levels, our new data reveal that unrestricted subcellular localization of Ect2 is likely to be more important than total protein levels for ovarian pathology. 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 LB-30. doi:1538-7445.AM2012-LB-30
Treatment of Rheumatoid Arthritis with Methotrexate Alone, Sulfasalazine and Hydroxychloroquine, or a Combination of All Three Medications
Authors: James R. O'Dell, Claire E. Haire, Nils Erikson, Walter Drymalski, William Palmer, P. James Eckhoff, Vernon Garwood, Pierre Maloley, Lynell W. Klassen, Steven Wees, Harry Klein, Gerald F. Moore
Journal: New England Journal of Medicine (1996)

Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality. The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug, such as methotrexate, are often suboptimal. Despite limited data, many patients are treated with combinations of these drugs.We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year, double-blind, randomized study of treatment with methotrexate alone (7.5 to 17.5 mg per week), the combination of sulfasalazine (500 mg twice daily) and hydroxychloroquine (200 mg twice daily), or all three drugs. The dose of methotrexate was adjusted in an attempt to achieve remission in all patients. The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity.Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity. Among them were 24 of 31 patients treated with all three drugs (77 percent), 12 of 36 patients treated with methotrexate alone (33 percent, P < 0.001 for the comparison with the three-drug group), and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine (40 percent), P = 0.003 for the comparison with the three-drug group). Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity.In patients with rheumatoid arthritis, combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine, and hydroxychloroquine.
FRI0356 Patients with takayasu’s arteritis having persistent acute phase response usually have an increased major vessel uptake by 18f-fdg-pet/ct
Authors: F. Alibaz-Oner, F. Dede, T. Ones, H. Turoglu, H. Direskeneli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) is a sensitive imaging tool for large-vessel vasculitis. Although not uniformly accepted, an increased uptake by 18F-FDG PET/CT in large-vessels is accepted to be a sign of active disease in Takayasu's arteritis (TAK). <h3>Objectives</h3> In this study, we aimed to investigate the value of 18F-FDG-PET/CT for clinical assessment in a subset of TAK patients having a persistent acute phase response (APR) without any signs or symptoms of clinical disease activity. <h3>Methods</h3> We studied 12 patients with TAK (mean age: 39.2±14.8 years, F/M: 10/2, disease duration: 5.4 years). Patients were clinically inactive (according to the definition of activity by <i>Kerr et al</i>), while categorized as having "persistent" disease activity by physician's global assessment due only to APR. All patients were under immunosupressive treatments including corticosteroids. The severity of large-vessel 18F-FDG uptake was graded using a four-point scale from grade 0 (no uptake present) to grade III (high-grade: uptake higher than liver). Any uptake in major vessels with a grade ≥2 was accepted to be "active." <h3>Results</h3> Mean ESR was 55.5 (30-86) mm/h and mean CRP was 29.6 (7.7-90) mg/L. Active vasculitic lessions were observed by 18F-FDG-PET/CT in 8 of 12 (66%) of the study group, with a mean number of 2.6 (1-4) active vascular lesions. Arcus aorta was involved in 25%, ascending aorta in 20%, right brachiocephalic artery in 20%, descending aorta in 15%, abdominal aorta in 10% and left and right subclavian arteries in 5% each of the investigated vessels. A step-up treatment change was decided in 7 patients according to 18F-FDG-PET/CT results. <h3>Conclusions</h3> We observed increased 18F-FDG uptake in the majority of TAK patients with an increased APR, but clinically silent disease. 18F-FDG-PET/CT showed the presence and localisation of active vascular inflammation in the aorta and its branches. Although specificity of observed lesions are not clear, 18F-FDG-PET/CT imaging may influence physician's assessment of clinical activity and treatment choices in TAK. <b>Disclosure of Interest</b>: None Declared
Risk of Infection after Penetrating Abdominal Trauma
Authors: Ronald Lee Nichols, Jeffrey W. Smith, Daniel B. Klein, Donald D. Trunkey, Ronald H. Cooper, Michael F. Adinolfi, John Mills
Journal: New England Journal of Medicine (1984)

To identify the risk factors for the development of postoperative septic complications in patients with intestinal perforation after abdominal trauma, and to compare the efficacies of single-drug and dual-drug prophylactic antibiotic therapy, we studied 145 patients who presented with abdominal trauma and intestinal perforation at two hospitals between July 1979 and June 1982. Logistic-regression analysis showed that a higher risk of infection (P<0.05) was associated with increased age, injury to the left colon necessitating colostomy, a larger number of units of blood or blood products administered at surgery, and a larger number of injured organs. The presence of shock on arrival, which was found to increase the risk of infection when this factor was analyzed individually, did not add predictive power. Patients with postoperative sepsis were hospitalized significantly longer than were patients without infection (13.8 vs. 7.7 days, P<0.0001). Both treatment regimens — cefoxitin given alone and clindamycin and gentamicin given together—resulted in similar infection rates, drug toxicity, duration of hospitalization, and costs. (N Engl J Med 1984; 311: 1065–70.)
Abstract 3079: Estrogen signaling promotes cancer stem cell expansion via microRNA-140 targeting of pluripotency-associated factor SOX2 in ERα positive breast cancer cells.
Authors: Yongshu Zhang, Gabriel L. Eades, Yuan Yao, Qinglin Li, Qun Zhou
Journal: Cancer Research (2013)

Abstract Multiple reports indicate that the prospective tumor suppressor miR-140 is down regulated in breast tumors compared to normal breast tissues; however, the role of miR-140 in breast tumorigenesis remains unclear. We have identified a novel target for miR-140 in mammary epithelium, the core pluripotency transcription factor SOX2. It is well known that SOX2 regulates the self-renewal of embryonic stem cells, however, less is known concerning possible oncogenic roles of SOX2 in breast cancer. We found that miR-140 and SOX2 target mRNA exhibited inverse expression in breast tumors and normal breast tissues, which was also correlated with estrogen receptor alpha (ERα) status. We investigated the role of ERα signaling in the regulation of miR-140 and SOX2 in breast tumors and found that estrogen stimulation resulted in decreased miR-140 and increased SOX2 expression in mammary epithelium and breast cancer cells. We performed bioinformatics promoter analyses of the miR-140 promoter revealing several predicted estrogen response elements (ERE) in the miR-140 promoter. We examined estrogen-induced activation of these prospective EREs using luciferase reporters for a miR-140 promoter deletion series. Furthermore, we used chromatin-immunoprecipitation to reveal that ERα binds to an ERE flanking the miR-140 promoter, consequently suppressing miR-140 transcription. As estrogen signaling was previously implicated in the regulation of breast cancer stem cells (CSCs), we investigated whether the miR-140/SOX2 pathway might provide a mechanistic link between ERα signaling and CSC maintenance. We found that forced activation of the miR-140/SOX2 pathway decreased mammosphere formation (a surrogate measure of CSC self-renewal) and opposed estrogen-induced expansion of the well-characterized CD44(high)/CD24(low) CSC subpopulation in ERα+ breast cancer cells. These results indicate that an ERα/miR-140/SOX2 pathway critically regulates breast CSC maintenance in ERα+ breast tumors. Citation Format: Yongshu Zhang, Gabriel L. Eades, Yuan Yao, Qinglin Li, Qun Zhou. Estrogen signaling promotes cancer stem cell expansion via microRNA-140 targeting of pluripotency-associated factor SOX2 in ERα positive breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3079. doi:10.1158/1538-7445.AM2013-3079
REMOTE MYOCARDIAL TISSUE CHANGES AFTER ACUTE MYOCARDIAL INFARCTION AND ITS ROLE IN CARDIAC REMODELING: A CMR T1-MAPPING STUDY
Authors: Stefan Biesbroek, Raquel Amier, Lourens Robbers, Paul Teunissen, Aernout Beek, Albert van Rossum, Mark Hofman, Niels Van Royen, Robin Nijveldt
Journal: Journal of the American College of Cardiology (2016)
OC-031 Using Genome-Wide Studies to Identify Novel Foxm1 Transcription Factor Target Genes in Oesophageal Cancer
Authors: E F Wiseman, N Han, Y S Ang, A S Sharrocks
Journal: Gut (2013)

<h3>Introduction</h3> The prognosis of oesophageal cancer remains poor with &lt; 10% 5-year survival. Delineating the molecular pathogenesis of oesophageal cancer could inform future research into targeted therapies and may uncover novel biomarkers to aid management decisions. As a transcription factor with important roles in the control of cell cycle transcription, FOXM1 regulates cellular proliferation and chromosome stability. FOXM1 is frequently overexpressed in human cancers and this aberrant expression has been implicated in cancer initiation, progression and resistance to chemotherapy. Overexpression of FOXM1 mRNA and protein has recently been described in oesophageal adenocarcinoma (OAC) tissues. We aim to identify novel gene targets of FOXM1 to better understand the molecular pathogenesis of OAC. <h3>Methods</h3> Chromatin immunoprecipitation (ChIP) followed by deep sequencing (ChIP-seq) of FOXM1 binding sites was performed in OE33 OAC cells. FOXM1 binding at target gene promoters was confirmed with ChIP-qPCR studies. Target gene expression in OE33 cells after siRNA-mediated FOXM1 depletion was examined using qRT-PCR and western blotting. Target gene expression in OAC tissues was examined by analysis of microarray gene expression data. Statistical significance (<i>p</i>)in knockdown studies was calculated by Student’s <i>t</i>-test. The Pearson correlation coefficient (r) was used to measure strength of correlation of gene expression. <h3>Results</h3> Putative novel FOXM1 targets identified from an existing FOXM1 ChIP-seq dataset in U2OS osteosarcoma cells were validated by ChIP-seq in OE33 cells. A large overlap between the genes bound by FOXM1 in both cell types was observed. Genes with FOXM1 binding in both cell types whose expression was highly correlated with FOXM1 in OAC tissues such as <i>ETV4</i>, <i>SKA2</i> and <i>NUCKS1</i> (r = 0.83, 0.84 and 0.72) were analysed further with ChIP-qPCR and FOXM1 knockdown gene expression studies. OE33 cells demonstrated significant FOXM1 binding at the <i>ETV4</i> promoter and a reduction in <i>ETV4</i> mRNA in FOXM1 depleted cells was observed compared to control (<i>p</i> = 0.0006). However, despite highly significant FOXM1 binding at the <i>SKA2</i> and <i>NUCKS1</i> promoters the reduction in <i>SKA2</i>/<i>NUCKS1</i> mRNA following FOXM1 knockdown was modest and not significant. <h3>Conclusion</h3> We have identified <i>ETV4</i> as a novel FOXM1 target in oesophageal cancer. We found strong correlation with FOXM1 expression in clinical tissues, <i>in vivo</i> FOXM1 binding to its regulatory regions and evidence of regulation by FOXM1 in OE33 cells. Our studies also highlight the importance of validating ChIP-seq data with gene expression analysis since transcription factor binding at gene promoters does not always correlate with transcriptional regulation by that transcription factor. <h3>Disclosure of Interest</h3> None Declared
Abstract 3732: New aspirin analogs for targeted therapy of ER+ breast cancers with activated NFkB inflammatory pathway
Authors: Irida Kastrati, Vladislav A. Litosh, Gregory R.J. Thatcher, Jonna Frasor
Journal: Cancer Research (2012)

Abstract Approximately 75% of breast cancers express estrogen receptor (ER), classified as either ER+ luminal A or luminal B. Five year survival rate of luminal B breast cancers is ∼50% compared to ∼95% for luminal A, making luminal B subtype a target for better understanding the mechanisms of carcinogenicity and improved therapy. Inflammation and activation of its nuclear factor NFkB, is linked clinically and epidemiologically to cancer. Activation of NFkB in a subset of ER+ cancers is associated with poor prognosis and resistance to therapy. We were the first to show synergy between ER and NFkB in a specific gene signature that highly correlates with luminal B ER+ breast cancers, suggesting a potential functional role for NFkB inhibition in this subset. Based on these findings, we hypothesized that co-targeting ER and NFkB may achieve clinical efficacy in luminal B breast cancer. To target the ER, a selective estrogen receptor modulator (SERM) was employed. To target NFkB pathway, an NSAID-based therapy would be safe and, based on epidemiological data, is suggested to be chemopreventive in breast cancer. For NFkB targeting, we characterized a family of aspirin (ASA)-based analogs (x-ASA) that also serve as pro-drugs for quinone methide formation. We found that x-ASA analogs inhibited TNFa induction of NFkB via a reporter assay in a dose-dependent fashion in MCF-7 cells, and also shut down several genes typically up-regulated by the ER-NFkB crosstalk. Next we tested the co-targeting approach in mammosphere formation assays: the combination significantly reduced overall mammosphere number and size. While the mechanisms of action remains to be elucidated, the aspirin analogs in combination with a SERM show promise in treating ER+ breast cancers with activated NFkB where standard endocrine therapy alone fails. 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 3732. doi:1538-7445.AM2012-3732
MS-22 * NEOPLASTIC MENINGITIS FROM EPENDYMOMAS OF THE ADULT: A RETROSPECTIVE ANALYSIS
Authors: R. Ruda, M. Magistrello, L. Bertero, C. Bosa, A. Pellerino, E. Nicolotto, F. Moretto, D. Garbossa, R. Soffietti
Journal: Neuro-Oncology (2014)

BACKGROUND: There is lack of information regarding the natural history and treatment outcome of neoplastic meningitis (NM) from ependymomas of the adult. AIM OF THE STUDY: To retrospectively analyze all patients with biopsy proven adult ependymomas with NM, who were diagnosed and treated at a single neuro-oncological Institution over the last decade. PATIENTS AND METHODS: We collected from the database and follow-up visits 15 evaluable patients (12 males, 3 females) with a median age of 45 (range 20-72). Histological diagnosis was as follows: 6 grade III (40%), 4 grade II (27%) and 5 grade I (myxopapillary) (33%) ependymomas. Overall, median time to NM was 2 years (range: 0-24). NM occurred at diagnosis in 5/15 (33%) and during follow-up in 10/15 (67%): among these latter the primary tumor was under control in 6/10 (60%) and progressive in 4/10 (40%). All but 4 patients were symptomatic and MRI of the whole CNS was available in all patients. The diagnosis of NM was CSF-based in 7/15 (47%) and radiologically-based in 8/15 (53%). RT to the bulky disease was applied in 7/15 (47%) and surgery in 2/15 (13%). Medical therapies consisted variably in intrathecal Depocyte, temozolomide, nitrosourea-based regimens and bevacizumab. Four out of 12 symptomatic patients had a significant clinico-radiological response. Median survival was 20 months (range: 1 month-7 years), and 7/15 patients are still alive. CONCLUSIONS: NM from ependymomas in the adult is more indolent compared with other NM types, with longer survivals after multimodality treatment. Prospective studies are warranted.
Posttreatment Neuropathy in Diabetic Subjects With Mitochondrial tRNA (Leu) Mutation
Authors: Yoshihiko Suzuki, Hiroko Kadowaki, Hideki Katagiri, Makoto Suematsu, Yoshihito Atsumi, Kazuhiro Hosokawa, Takasi Kadowaki, Yoshitomo Oka, Yoshio Yazaki, Kempei Matsuoka
Journal: Diabetes Care (1994)
Osteochondromas after Total-Body Irradiation
Authors: Marisa K. Matthys, Jane E. Benson
Journal: New England Journal of Medicine (2011)

To the Editor: A 9-year-old boy received the diagnosis of acute biphenotypic leukemia. Once remission was induced, treatment proceeded to bone marrow transplantation with donation from the child's HLA-identical sister. The patient received total-body irradiation consisting of four fractions of 300 cGy for a total dose of 1200 cGy. The patient did well initially, but at the age of 14 years, the leukemia relapsed. At the staging workup, he was found to have bilateral osteochondromas, benign tumors composed of bone projecting from endochondral bones, in the iliac wings. On the right side, one lesion had posterior projection, and on the . . .