tbuckley/cabot-search huggingface dataset:
Abstract P4-05-03: Quantification of an Individual's Response to Drug Therapy Utilising a Novel Three-Dimensional Assay with Primary Breast Cancer Explants
Authors: AD Leeper, JSJ Thomas, JM Dixon, DJ Harrison, E. Katz
Journal: Cancer Research (2010)

Abstract Background: Breast cancer is not a single disease but one that displays both inter-and intra-tumoral heterogeneity. The principal models for breast cancer research are currently immortalised breast cancer cell lines as they are easily propagated, tractable to genetic modification and yield reproducible results However, it is not possible to use a cell line to predict the disease course of an individual patient. Moreover, epithelial cells grown on plastic in two dimensional cultures fail to recapitulate their three dimensional interaction with the tumour microenvironment, which is believed to be integral to tumour progression. Purpose: Using a collagen based three dimensional assay system and fresh breast cancer biopsies obtained at surgical resection, we have developed a novel assay which demonstrates ongoing proliferation and invasion of an individual's breast cancer. The proliferation and invasion of the breast cancer can be modified using currently available anti-cancer drugs. The effect of these drugs on an individual patient's cancer may then be quantified. Results: The model is amenable to investigation both in real-time and following formalin fixation. Using live microscopy and time delay image capture techniques we are able to study proliferation and invasion over a timecourse. Subsequent formalin fixation and sectioning enables two dimensional immunofluorescence quantification of drug effect at a cellular level. Three dimensional scanning and quantification, utilising Optical Projected Tomography and Velocity software enables one to demonstrate the effect of a drug on invasion at a macroscopic level. Conclusions: This assay has provided a method of sustaining an individual's primary breast tissue in long-term culture. Moreover, it provides a method of observing different patterns of invasion. Through the addition of currently available and novel therapeutics we are able to quantify how residual disease may respond to a battery of different treatments. In turn this may improve the ability of the clinician to decide on optimal adjuvant therapy, resulting in individually tailored therapy. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-05-03.
AB0055 Rho a protein and erk/jnk pathways regulate il-23 production by tlr2 in synovial macrophages from patients with rheumatoid arthritis
Authors: S. Y. Park, H. Y. Kim, H. R. Lee, S. H. Baek, C. D. Kim
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> TLR2 expression upon application of TNF-a, IL-1b, and LPSin synovial fibroblasts from joints of RA patients (1, 2).IL-23 is involved in autoimmune diseases such as RA and psoriasis, in which the cellular mechanism of IL-23 is associated with self-reactive production of IL-17, IL-6, and TNF-a, thereby playing a critical role in development of autoimmune inflammation (3, 4). <h3>Objectives</h3> This study aimed to elucidate the signaling pathways of TLR2-mediated IL-23 production in synovial fluid macrophages from patients with rheumatoid arthritis (RA). <h3>Methods</h3> Expression of IL-23 was measured by ELISA and immunofluorescence in synovial fluid macrophages from RA patients. RhoA activity was assessed by pull-down assay. The role of MAP kinase was investigated using selective inhibitors and western blot. <h3>Results</h3> TLR2 ligand LTA-stimulated IL-23 production measured by ELISAwas elevated time- and concentration-dependently. TLR2 stimulation by LTA significantly increased not only GTP-bound RhoA activity but also phosphorylation of ERK and JNK in RA macrophages in association with increased nuclear translocation and DNA-binding activity of NF-kB. Inhibition of RhoA by Y27632, and of ERK and JNK phosphorylation by PD98059 and SP600125, resulted in suppression of LTA-induced NF-kB activation and IL-23 production. <h3>Image/graph</h3> <h3>Conclusions</h3> TLR2-mediated IL-23 production in synovial fluid macrophages was mediated through activation of RhoA GTPase and phosphorylation of ERK/JNK in association with NF-kB activation. <h3>References</h3> Brentano F, Kyburz D, Schorr O, Gay R, Gay S. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol 2005, 233:90-96. Seibl R, Birchler T, Loeliger S, Hossle JP, Gay RE, Saurenmann T, Michel BA, Seger RA, Gay S, Lauener RP. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 2003, 162:1221-1227. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003, 198:1951-1957. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005, 201: 233-240. <h3>Disclosure of Interest</h3> None Declared
A memorable consultant: Perils of opera
Authors: J. Wright
Journal: BMJ (1998)

“I'm afraid I think that is a carcinoma of the larynx,” the ear, nose, and throat consultant leaned over the radiologist to point to an opacity on the barium swallow.

“I have to agree,” said the radiologist, taking the film from the screen to study it more closely.

My heart seemed to run south like a nervous squirrel as the implications sank in. Three weeks earlier I had become aware of a vague discomfort in the throat followed some days later, to the evident relief of my colleagues, …
Abstract 4863: The histone lysine-methyltransferase NSD1 and its functional role in non-small cell lung cancer (NSCLC)
Authors: Roy Joseph, Walter Stunkel, Mark Phong, Siew Chinn Fong, Lei Li, Robert M. Campbell
Journal: Cancer Research (2010)

Abstract NSD-1 (Nuclear receptor-binding SET domain protein 1) belongs to the epigenetic family of histone methyltransferases (HMTs), which are frequently found to be mutated in overgrowth syndromes. In cancer, NSD-1 is found as part of fusion proteins (e.g., NUP98-NSD1), which play a major role in the etiology of AML. In contrast to data from hematological tumors, little is known regarding the role of NSD-1 in cancers from solid origin, except that high level expression of NSD-1 has been correlated with poor survival in breast cancer patients (Miller, 2005). NSD-1 over-expression as well as copy number gain for the NSD-1 gene has been described in a variety of tumor cell lines. We studied the role of NSD-1 in the NSCLC line NCI-H460 using an inducible knockdown system (pSLIK). We found that knockdown of NSD-1 (&amp;gt;70% reduction in target mRNA expression) led to a significant decrease in cell proliferation as well as nearly 100% inhibition of anchorage-independent growth, whereas an empty vector transfected stable cell line did not. NSD-1 knockdown induced apoptosis in a time-dependent manner as measured by flow cytometry-based Annexin V staining. Cell death was found to follow a PARP-dependent mechanism suggesting that apoptosis is a contributor to growth inhibition/cell death. By conducting immuno-blot experiments against a panel of histone modifications, we examined putative in vivo histone substrates of NSD1. Our data suggest that NSD1 knockdown in NCI-H460 cells leads to a decrease in histone H4K20 trimethylation (64% inhibition after 24h), but did not affect H3K36 trimethylation as previously reported for NSD1 fusion proteins in AML. Further studies of changes in additional histone modifications are ongoing. In summary, we describe for the first time a functional role for NSD-1 in a NSCLC cell line with implications for this HMT in solid tumor growth/survival. 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 4863.
FRI0343 Safety and efficacy of varicella vaccine in patients with juvenile rheumatic diseases: A five years experience
Authors: G.S. Pileggi, C.B.S. de Souza, V.P.L. Ferriani
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> There are case reports of severe disseminated varicella-zoster virus (VZV) infections in patients on methotrexate (MTX) or anti-TNF therapy. The severity of these infections can be significantly reduced in those vaccinated <h3>Objectives</h3> The aims of this study were: to evaluate the safety and immunogenicity of a two dose protocol of varicella vaccine (VV) in susceptible patients with Juvenile Rheumatic Diseases (JRD) on MTX or anti-TNF therapy and to describe the vaccination efficacy over an observational 5-year follow-up period <h3>Methods</h3> Fifty patients with JRD (1-18 years) and no history of varicella were vaccinated with VV, 32 of them received two doses. IgG anti-VZV antibody (VZV-IgG) titers were measured by ELISA before, 4-6 weeks after each dose of VV, one and five years thereafter. Patients were monitored prospectively during 8 weeks for adverse events related to the vaccine and over a 5-year observational period for exposure to or occurrence of varicella <h3>Results</h3> All 50 patients were using MTX (mean dose 16 mg/m<sup>2</sup>/week, range 10 to 27); 23 were also receiving prednisone (range 5-20mg/day) and 5 were on anti-TNF therapy. Seroconversion rates were 50% after one dose of VV<sup>1</sup> and 87% (28/32) for patients who received two doses (p&lt;0,01). All 4/32 who did not reach protective titers after two VV doses were taking anti-TNF therapy (3/4 have systemic JIA). The vaccination neither induced overt varicella episodes or severe adverse events, nor underlying disease flare-ups after one or two doses. Twenty patients that received one dose of VV<sup>1</sup> completed the five-year period of follow-up. Eleven of them were seronegative after one year: 2/11 developed varicella, six received a VV booster and all became seropositive. Only the 3/20 that refused the booster remained susceptible in the evaluation after 5 years. Among the 28 seroconverted patients that received two doses of VV, only 55% maintained protective VZV-IgG titers after one year, however none of them developed herpes zoster or chickenpox during the follow-up period of 1-3 years, including those with direct exposure to the wild virus in their environmental <h3>Conclusions</h3> VV should be recommended for seronegative patients for whom immunosuppressive or biological therapy is planned and a protocol with 2 doses of VV should be considered to reach protective titers. If patients are on anti-TNF alpha therapy, additional boosters may be necessary. <h3>References</h3> Pileggi GCS; Souza, CBS; Ferriani, VPL. Safety and Immunogenicity of Varicella Vaccine in Patients With Juvenile Rheumatic Diseases Receiving Methotrexate and Corticosteroids. Arthritis Care &amp; Research, v. 62, p. 1034-1039, 2010. <h3>Disclosure of Interest</h3> None Declared
18F-FDG PET as a Monitoring Tool to Assess Treatment Response in Bilateral Adrenal Histoplasmosis
Authors: Rajeev Kasaliwal, Gaurav Malhotra, Amol Bukan, Ramesh V Asopa, Shashir Wanjare, Nalini S Shah
Journal: Clinical Nuclear Medicine (2014)

A 60-year-old woman with clinical and biochemical features suggestive of adrenal insufficiency was found to have bilateral adrenal masses on CT scan and was subjected to F-FDG PET scan. The scan showed hypermetabolic mediastinal nodes in addition to intense tracer uptake in bilateral adrenal masses. CT-guided adrenal biopsy grew Histoplasma capsulatum on Sabouraud dextrose agar culture. A second F-FDG PET scan after 6 months of appropriate antifungal therapy showed a significant decrease in intensity of uptake consistent with the clinical outcome.
MB-04 * EXPRESSION OF CRMP1 INHIBITS CELL PROLIFERATION OF MEDULLOBLASTOMA AND IS REGULATED BY HMGA1
Authors: H.-K. Ng, K. W. K. Li, Y. Qi, X. Tian, Y. Yao, L. Zhou, K.-M. Lau
Journal: Neuro-Oncology (2015)

Many facets of the tumor biology of medulloblastoma (MB) have not been fully elucidated. Collapsin response mediator protein 1 (CRMP1) is a member of cytoplasmic family that regulates the development of central nervous system. Recent studies demonstrated that CRMP1 functioned as an invasion suppressor. We reported that high mobility group AT-hook 1 (HMGA1) contributed to tumor biology of MB and regulated cell growth and migration/invasion. Transcriptional profiling and quantitative RT-PCR revealed the increased expression of CRMP1 in HMGA1-depleted cells, suggesting that CRMP1 may be a downstream target of HMGA1 in MB. In this study, we showed HMGA1 is associated with the CRMP1 promoter by chromatin immunoprecipitation (ChIP) assay. Luciferase assay demonstrated a marked enhancement of CRMP1 transcription activity in HMGA1-depleted cells. Furthermore, quantitative RT-PCR revealed a significant negative correlation between HMGA1 and CRMP1 in 32 MB samples. To investigate the biological roles of CRMP1 in MB pathogenesis, we established MB clones stably expressing CRMP1. Functional analysis revealed that expression of CRMP1 significantly inhibited cell proliferation, migration, invasion, and formation of filopodia and stress fibers. Our data suggest that HMGA1 regulates CRMP1 expression and CRMP1 is involved in MB pathogenesis.
SHORT TERM AND LONG TERM FOLLOW UP OF CORONARY ARTERY BYPASS GRAFT(CABG) PATIENTS BY 256-SLICE MULTI-DETECTOR CT ANGIOGRAPHY: ASSESSMENT OF PATENCY AND PREDICTORS OF GRAFT OCCLUSION
Authors: Zahra Azizi, Alireza Alizadeh Ghavidel, Ali Mohammadzadeh, Rohollah Salehian
Journal: Journal of the American College of Cardiology (2016)
CONCENTRATIONS OF PRO-NEUROTENSIN, CARDIAC STRUCTURE, AND CORONARY ARTERY CALCIUM IN THE COMMUNITY: THE FRAMINGHAM HEART STUDY
Authors: James L. Januzzi, Hanna Gaggin, Asya Lyass, April Trebnick, Joseph Massaro, Ralph D’Agostino, Christopher O’Donnell, Thomas Wang, Vasan Ramachandran
Journal: Journal of the American College of Cardiology (2016)
A pilot study of in vivo identification of pancreatic cystic neoplasms with needle-based confocal laser endomicroscopy under endosonographic guidance
Authors: Vani Konda, Alexander Meining, Laith Jamil, Marc Giovannini, Joo Hwang, Michael Wallace, Kenneth Chang, Uzma Siddiqui, John Hart, Simon Lo, Michael Saunders, Harry Aslanian, Kirsten Wroblewski, Irving Waxman
Journal: Endoscopy (2013)

<b>Background and study aims:</b> Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) of pancreatic cystic lesions (PCL) is flawed by inadequate diagnostic yield. Needle-based confocal laser endomicroscopy (nCLE) utilizes a sub-millimeter probe that is compatible with an EUS needle and enables real-time imaging with microscopic detail of PCL. The aims of the In vivo nCLE Study in the Pancreas with Endosonography of Cystic Tumors (INSPECT) pilot study were to assess both the diagnostic potential of nCLE in differentiating cyst types and the safety of the technique. <b>Patients and methods:</b> Eight referral centers performed nCLE in patients with PCL. Stage 1 defined descriptive terms for structures visualized by an off-line, unblinded consensus review. Cases were reviewed with a gastrointestinal pathologist to identify correlations between histology and nCLE. Stage 2 assessed whether the specific criteria defined in Stage 1 could identify pancreatic cystic neoplasms (PCN) including intraductal papillary mucinous neoplasms, mucinous cystic adenoma, or adenocarcinoma in an off-line blinded consensus review. <b>Results:</b> A total of 66 patients underwent nCLE imaging and images were available for 65, 8 of which were subsequently excluded due to insufficient information for consensus reference diagnosis. The presence of epithelial villous structures based on nCLE was associated with PCN (<i>P</i> = 0.004) and provided a sensitivity of 59 %, specificity of 100 %, positive predictive value of 100 %, and negative predictive value of 50 %. The overall complication rate was 9 % and included pancreatitis (1 mild case, 1 moderate case), transient abdominal pain (n = 1), and intracystic bleeding not requiring any further measures (n = 3). <b>Conclusions:</b> These preliminary data suggested that nCLE has a high specificity in the detection of PCN, but may be limited by a low sensitivity. The safety of nCLE requires further evaluation.
AB0239 Autoantibody profile in a cohort of adult patients with inflammatory myophaties:
Authors: M. Fredi, A. Ceribelli, M. Taraborelli, M. Quinzanini, I. Cavazzana, A. Tincani, E.K. Chan, M. Satoh, F. Franceschini
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Specific autoantibodies in patients with polymyositis/dermatomyositis (PM/DM) are associated with unique subsets, and they are useful in monitoring clinical course and predicting outcome. <h3>Objectives</h3> to analyze the prevalence of myositis specific antibodies (MSA) and their clinical significance in a cohort of adult PM/DM patients. <h3>Methods</h3> Autoantibodies in sera from 58 consecutive adult PM/DM patients (74% female, mean age 43±17, mean follow up 55 months) were analyzed by immunoprecipitation of <sup>35</sup>S-labeled K562 cell extracts, ELISA (anti-MJ, Ro52, La, Jo-1), Western Blot and Indirect Immunofluorescence (IIF). Clinical association of antibody specificity was analyzed using information from charts and database. <h3>Results</h3> Autoantibody prevalence in our cohort is shown in table 1. Anti-MJ antibodies are the most prevalent specificity (10/58;17%) in our PM/DM patients, followed by anti-Jo-1 (10%),-p155/140 (5%),-SRP (5%),-EJ (4%), and anti-Mi2,-SMN complex,-OJ with one case each. Anti-MJ was found in 30% of DM and 8% of PM (P=0.02). Among 10 cases of anti-MJ, 8 were DM and 2 were PM. When clinical features of 10 cases of anti-MJ (+) vs 48 cases anti-MJ(-) were compared, DM is more common (P=0.03) and no overlap syndrome patients were found in anti-MJ(+) group (0% vs 13%). Age of onset (25.5 vs 46.1 years) and age at initial visit (37.6 vs 54.6 years) were younger in anti-MJ(+) group (P=0.002), and 2 anti-MJ(+) were pediatric onset DM. In anti-MJ(+) patients, heliotrope rash (P=0.01) and calcinosis (P=0.057) were common, however, none of them had heart involvement (0% vs 27%, P=0.03), interstitial lung disease (0% vs 33%, P=0.048), or cancer (0% vs 8%). Myopathy in anti-MJ (+) patients was well responsive to steroid therapy and elevated CPK in the last visit was not seen (0% vs 25%). 4 patients had cancer, two were negative one was anti-Mi2 and one –OJ positive. <h3>Conclusions</h3> Anti-MJ antibodies have been described in pediatric population with DM (1,2) but are detected also in adult PM/DM, and they are the most frequent specificity in our cohort, found in 17% of PM/DM (30% in DM and 4% in PM). Anti-MJ(+) patients have DM of young onset, severe calcinosis, no internal organ involvement and good response of myopathy to steroid. No association between MSA and cancer was found. Anti-MJ will be a useful new addition of MSA to help clinical monitoring of patients with adult PM/DM. <h3>References</h3> Oddis CV et al. Arthritis Rheum 1997;40:S139. Gunawardena H et al. Arthritis Rheum 2009;60:1807-14. <h3>Disclosure of Interest</h3> None Declared
Abstract 1666: Regorafenib (BAY 73-4506): preclinical pharmacology and clinical identification and quantification of its major metabolites
Authors: Dieter Zopf, Roland Heinig, Karl-Heinz Thierauch, Claudia Hirth-Dietrich, Frank-Thorsten Hafner, Olaf Christensen, Tiffany Lin, Scott Wilhelm, Martin Radtke
Journal: Cancer Research (2010)

Abstract Regorafenib is a novel diphenylurea oral multikinase inhibitor of angiogenic, stromal, and oncogenic kinases with potent preclinical antitumor activity and long-lasting antiangiogenic activity (as measured by dynamic contrast-enhanced magnetic resonance imaging). Regorafenib treatment has recently shown to result in a 31% partial response (PR) rate and 50% stabilization rate in patients with metastatic renal cell carcinoma in a Phase II study. Promising clinical activity was shown in a Phase I study in 27 evaluable patients with advanced refractory colorectal cancer (median 4 prior regimens) with a 74% overall disease control rate (PR + stable disease). The biotransformation of regorafenib was investigated in vitro with liver microsomes and hepatocytes, and in vivo in the plasma of several species. In man, the N-oxide (M-2) and the demethylated N-oxide (M-5) appear significant as both metabolites show systemic exposure (area under the curve [AUC], mg*h/L) at steady state similar to regorafenib (the parent compound) in patients at a dose of 160 mg in a 3 weeks on/1 week off Phase I study. Characterization of both M-2 and M-5 demonstrated potent pharmacologic activities. In biochemical kinase assays, M-2 and M-5 showed an inhibition profile similar to but distinct from regorafenib. In cellular assays, M-2 and M-5 inhibited key targets such as vascular endothelial growth factor (VEGF) receptor 2, TIE-2, and mutant and wild-type c-KIT and B-RAF, with IC50 values very similar to regorafenib for M-2 and somewhat higher for M-5. Regorafenib and both M-2 and M-5 dosed iv at 1 mg/kg showed significant activity in a rat VEGF hypotensive pharmacodynamic model. Both metabolites dosed orally exhibited potent dose-dependent tumor growth inhibition (TGI) in preclinical murine HT-29 colorectal and MDA-MB-231 breast cancer xenografts, achieving significant TGI of 62/58% and 54/50%, respectively, compared with vehicle controls at 10 mg/kg. Regorafenib revealed 66-77% TGI at 10 mg/kg in these models. On oral administration of regorafenib to mice, the N-oxide (M-2) plasma level accounted for ∼20% of the AUC of regorafenib; conversely, on administration of M-2, regorafenib exposure reached ∼20% of M-2 exposure, indicating that oxidation to and reduction of the N-oxide are metabolic pathways in vivo. In summary, these data demonstrate that the metabolites M-2 and M-5, exhibiting similar exposure as regorafenib, their parent compound, in man, are pharmacologically active and therefore most likely contribute to the clinical antitumor activity of regorafenib. 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 1666.
STATINS AND EXERCISE TRAINING RESPONSE IN HEART FAILURE PATIENTS: INSIGHTS FROM THE HF-ACTION TRIAL
Authors: Jacob P. Kelly, Robert Mentz, Phillip Schulte, Allison Dunning, Mona Fiuzat, Steven Keteyian, Jerome Fleg, Eric Leifer, Ileana Pina, Lawton Cooper, Dalane Kitzman, William Kraus, David Whellan, Christopher O’Connor
Journal: Journal of the American College of Cardiology (2015)
The Yin and Yang of Interleukin-2–Mediated Immunotherapy
Authors: Jeffrey A. Bluestone
Journal: New England Journal of Medicine (2011)

In this issue of the Journal, the findings of two case series suggest that in vivo treatment with interleukin-2 can suppress immune-mediated diseases. In one study, Koreth et al.1 found that low-dose interleukin-2 was associated with reversal of glucocorticoid-refractory chronic graft-versus-host disease (GVHD) in patients who had undergone allogeneic hematopoietic stem-cell transplantation (HSCT) for the treatment of lymphomas and leukemias. The control of chronic GVHD was not accompanied by the relapse of cancer in any patient.1 In a second small case series, Saadoun et al.2 found that treatment of patients with hepatitis C virus (HCV)–related vasculitis with low-dose interleukin-2 led . . .