tbuckley/cabot-search huggingface dataset:
PTU-073 Dose Intensification with Anti-TNF Agents in Inflammatory Bowel Disease- a Secondary Care Experience
Authors: G Kothegal Marimahadevappa, J K Limdi
Journal: Gut (2013)

<h3>Introduction</h3> The efficacy of anti-TNF therapy, Infliximab (IFX) and Adalimumab (ADA) has been established in pivotal trials for induction and maintenance of remission of inflammatory bowel disease (IBD). Despite this a proportion of patients lose response and require dose intensification. The aim of our study was to assess the efficacy and durability of dose intensification with IFX/ADA. <h3>Methods</h3> A retrospective review of patients with IBD receiving IFX/ADA infusions from October 2011 until April 2012 at our institution was conducted through electronic and case note review, endoscopy, radiology and pathology reports. Patients losing response after 6 months or more of IFX/ADA maintenance therapy and in whom treatment was intensified were included. Dose intensification was defined as an increase in IFX dose per infusion from 5mg to 10mg/kg or increase in frequency of infusions from 8 weeks to 5 – 6 weeks. For ADA this was defined as increasing the dose from 40 mg to 80mg or increasing the frequency from biweekly to weekly. A positive response was defined by clinician assessment after 3 infusions. Non-response or loss of response was defined as persistent disease related symptoms requiring steroid therapy, hospitalisation, surgery or discontinuation of IFX/ADA. <h3>Results</h3> Of 208 patients receiving anti TNF therapy (IFX = 157, ADA = 51), 15 patients (12 female) received dose intensification (IFX = 12, ADA = 3). 6 had Ulcerative Colitis (UC) (4 pan-colonic, 2 left sided) and 9 had Crohn’s Disease (CD) with non stricturing, non penetrating disease (3), active stricturing (3), penetrating (1) and peri-anal (2) disease respectively. Disease location was ileal (1), colonic (2) and ileo-colonic in 6. The median age was 40 years (range 18–72 yrs). Response to intensification after approximately median duration of follow up of 12 months was noted in 8/9 CD and 2/6 UC patients. 9 patients (60%) remained on dose intensification and 5 lost response (33%). In 1 patient treatment was discontinued in the third trimester of pregnancy. Two patients (UC) reverted to their previous dose, 2 non-responders underwent surgery and 1 received Methotrexate. 2 patients are being evaluated for dose intensification. CRP was elevated in 5 patients prior to intensification. Endoscopic assessment of disease was performed in 4 patients with UC showing active colitis in 3. Four patients underwent enterography showing active disease in three. <h3>Conclusion</h3> A significant proportion of patients with CD respond to dose intensification but thorough disease assessment does not always appear to precede such critical decision. Anti-TNF trough and antibody levels, an astute assessment for active disease and search for alternative mechanistic explanations for symptoms are imperative prior to embarking on expensive therapy with its inherent risks. <h3>Disclosure of Interest</h3> None Declared
A Watershed Moment in the Treatment of Hepatitis C
Authors: Raymond T. Chung
Journal: New England Journal of Medicine (2012)

More than 170 million persons harbor chronic infection with hepatitis C virus (HCV), the leading indication for liver transplantation worldwide. For more than 20 years, treatment of chronic hepatitis C infection has relied on the use of the nonspecific antiviral cytokine interferon alfa, which induces hundreds of genes that collectively generate an antiviral state. In the early 1990s, treatment with interferon alfa resulted in a sustained virologic response in very few patients. The next two decades witnessed steady improvement; combining pegylated interferon alfa (peginterferon alfa) with ribavirin produced overall rates of sustained virologic response of 54 to 56%,1,2 with . . .
AB1435-HPR The contribution of assessing foot joints in early rheumatoid arthritis patients: Insights from item response theory
Authors: L. Siemons, P.M. ten Klooster, E. Taal, I.H. Kuper, P.L.C.M. van Riel, C.A.W. Glas, M.A.F.J. van de Laar
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The disease activity score for 28 joints (DAS-28) is a widely used index measure for evaluating the disease activity of individual rheumatoid arthritis (RA) patients and for determining appropriate treatment strategies aimed at reaching or sustaining a state of remission. However, despite the frequent involvement of the 28 joints included in the DAS-28, it has been argued that the omission of the foot joints causes the DAS-28 to underestimate actual disease activity in early RA patients predominantly suffering from disease activity in the feet [1]. Consequently, the exclusion of the foot joints remains a topic of debate and research. <h3>Objectives</h3> To evaluate the contribution of assessing foot joints to the measurement range and measurement precision of joint counts in early RA patients using item response theory. <h3>Methods</h3> Baseline measures of tender and swollen joint counts were analysed in 459 early RA patients who participated in the DREAM remission induction cohort. The contribution of foot joints was studied by evaluating their effect on the measurement range and measurement precision of the 28-joint counts. In addition, the alignment between the patient and joint distributions was investigated to determine whether the foot joints were informative for measuring an early RA patient's joint tenderness or swelling. <h3>Results</h3> Foot joints were commonly affected, with 233 patients (50.76%) experiencing tenderness and 200 patients (43.57%) experiencing swelling in at least one of the foot joints. Although foot joints appeared to be primarily informative for the measurement of joint tenderness and not so much for the measurement of joint swelling, the assessment of foot joints did not significantly improve the measurement range and measurement precision of the 28-joint counts. Furthermore, the inclusion of foot joints did not remove the existing discrepancy between the joint and patient distributions of both the 28-tender as well as the 28-swollen joint count. <h3>Conclusions</h3> Although foot joints were frequently affected on an individual level, the inclusion of foot joints did not significantly improve the measurement range or measurement precision of the tender and swollen joint counts in early RA patients. From a measurement perspective, reduced joint counts are appropriate to use on a population level. The contribution of assessing foot joints on an individual level requires further investigation. <h3>References</h3> Bakker MF, Jacobs JWG, Kruize AA, van der Veen MJ, van Booma-Frankfort C, Vreugdenhil SA, et al. Misclassification of disease activity when assessing individual patients with early rheumatoid arthritis using disease activity indices that do not include joints of feet. Ann Rheum Dis. 2011; In Press. <h3>Disclosure of Interest</h3> None Declared
Waldenström's Macroglobulinemia
Authors: G Wulf, S Pool
Journal: New England Journal of Medicine (2001)

Figure 1. A 65-year-old man had an 18-month history of slowly progressive swelling and discoloration of both ears, fatigue, night sweats, weight loss, occipital headaches, and photophobia. On examination, his ears were swollen and purplish and had several small cysts that were neither warm nor tender. The skin of his nose, cheeks, upper lip, and chin was also thickened and discolored (Panel A). He had diffuse peripheral lymphadenopathy. Funduscopy demonstrated tortuous arterioles, distended prominent veins bilaterally with diminished pulsations, and retinal hemorrhages. Serum immunoelectrophoresis revealed a monoclonal IgM spike with an IgM level of 7.7 g per liter and a . . .
Nation's Leaders Of Clinical Trials Discuss Future
Authors: F. Antoine
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Nation's Leaders Of Clinical Trials Discuss Future Get access Florence Antoine Florence Antoine Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 1, January 1989, Pages 9–11, https://doi.org/10.1093/jnci/81.1.9 Published: 01 January 1989
Meta-Analysis of the Effects of Soy Protein Intake on Serum Lipids
Authors: James W. Anderson, Bryan M. Johnstone, Margaret E. Cook-Newell
Journal: New England Journal of Medicine (1995)

In laboratory animals, the consumption of soy protein, rather than animal protein, decreases serum cholesterol concentrations, but studies in humans have been inconclusive. In this meta-analysis of 38 controlled clinical trials, we examined the relation between soy protein consumption and serum lipid concentrations in humans.
IMPAIRED LEFT VENTRICULAR GLOBAL LONGITUDINAL STRAIN IN PATIENTS WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION: INSIGHTS FROM THE RELAX TRIAL
Authors: Adam DeVore, Steven McNulty, Fawaz Alenezi, Mads Ersboll, Jae Oh, Grace Lin, Margaret Redfield, Gregory Lewis, Marc Semigran, Kevin Anstrom, Adrian F. Hernandez, Eric Velazquez
Journal: Journal of the American College of Cardiology (2015)
CUMULATIVE AND INDIVIDUAL EFFECTS OF SINGLE NUCLEOTIDE POLYMORPHISMS FOR ATRIAL FIBRILLATION BY META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IN PATIENTS WITH HEART FAILURE
Authors: Akira Fujii, Akiyoshi Ogimoto, Takayuki Nagai, Hiroshi Kawakami, Jun Suzuki, Katsuji Inoue, Kazuhisa Nishimura, Teruyoshi Uetani, Jun-ichi Funada, Yasuharu Tabara, Takafumi Okura, Jitsuo Higaki
Journal: Journal of the American College of Cardiology (2015)
P404Impaired response to calcium transients is compensated by improved inherent energetic homeostasis in chronic hypoxic hearts
Authors: V J Deschodt-Arsac, G Calmettes, M Chapolard, LM Arsac, P Dos Santos, PD Diolez
Journal: Cardiovascular Research (2014)

Cardiac diseases are essentially multifactorial problems affecting numerous interactions and kinetic properties in highly organized cell, tissue and organ structures. Therefore, an exhaustive investigation of the effects of cardiac drugs and adaptations needs integrative approaches. Based on rigorously founded theory, metabolic control analysis (MCA) has the capacity to quantify kinetic responses of main energetic parts of the contractile system. In spite of impairments in contractile activity, mitochondrial content, cell energy status and calcium transients, we recently demonstrated an improved energy homeostasis in chronic hypoxic hearts explained by higher mitochondrial sensitivity to ATP/PCr changes, based on combined 31P-NMR spectroscopy and the analytical framework of metabolic control analysis (MoCA). In the present study, MoCA describes co-variations in cell energy status (PCr, ATP) and cardiac work (RPP), induced by calcium, adrenaline and ruthenium red, in perfused hearts of control rats vs. rats adapted for three weeks to a simulated altitude of 5500 m in a barochamber. In basal conditions, lower cardiac work and PCr concentration confirmed energetic impairments in chronic hypoxic hearts. At high calcium concentration in the perfusate, cardiac work increased by 40% in control as well as in hypoxic hearts but PCr drop less in hypoxic hearts thus indicating the improved energy homeostasis thanks to better mitochondrial sensitivity to PCr. Adrenaline, typically stimulating calcium transients and thereby parallel activation of supply and demand components, increased cardiac work twice as much in control hearts (RPP +100%) without any significant PCr variations. Ruthenium red, an inhibitor of MCU has the capacity to uncover the mitochondrial contribution in parallel activation by calcium transients. While ruthenium red added to adrenaline inhibited effects of calcium transients in control hearts (RPP -60%), the effect was absent in hypoxic hearts. We conclude that although chronic hypoxic hearts failed to use calcium transients to optimize their inotropic response to a specific adrenergic stimulation, they present specific adaptation of the energetic homeostasis based on improved energy supply sensitivity in the case of stimulation by calcium. Interestingly this better regulation of the energetic system is not explained by a direct effect on mitochondria by calcium but rather by an optimal metabolic feedback. We concluded that quantitative MCA applications have likely the potential to shape combined drugs therapy.
Role of 18F-DOPA PET/CT in Diagnosis and Follow-up of Adrenal and Extra-adrenal Paragangliomas
Authors: Alessandra Bacca, Serena Chiacchio, Virna Zampa, Davide Carrara, Valerio Duce, Caterina Congregati, Paolo Simi, Stefano Taddei, Gabriele Materazzi, Duccio Volterrani, Giuliano Mariani, Giampaolo Bernini
Journal: Clinical Nuclear Medicine (2013)

Purpose The objective of this study was to establish the clinical value of 18F-DOPA PET/CT in patients with adrenal and extra-adrenal paragangliomas (PGLs). Methods Twenty-six consecutive patients with suspected or recurrent PGL underwent MR (and/or CT) and 18F-DOPA PET/CT. Histopathology confirmation was obtained in 20 cases. Genetic analysis on known susceptibility genes for PGL (VHL, RET, SDHx, TMEM127) was available in 13 patients. Results Fourteen patients were affected by PGL (8 with head/neck location, 6 with abdominal/thoracic location), whereas 12 showed masses of other origin. Three patients proved to be SDHD, 1 SDHB, 2 SDHC, and 1 TMEM127 mutation carriers. 18F-DOPA PET/CT showed pathological uptake in 13 of 26 patients. The procedure identified all PGLs except one with bone metastases (previous malignant adrenal PGL). No uptake was found in patients without proven PGL. Thus, in the whole group, 18F-DOPA PET/CT sensitivity was 92.8%, and specificity was 100% with positive and negative predictive values of 100% and 92.3%, respectively. Total diagnostic accuracy was 96.2%. In the head/neck subgroup, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were 100%. In the abdominal location, sensitivity was 80% and specificity was 100%, and positive and negative predictive values were 100% and 91.7%, respectively. Abdominal diagnostic accuracy was 93.7%. Radiotracer uptake was superimposable in head/neck PGLs versus abdominal PGLs and in mutated versus wild-type patients. Conclusions The high diagnostic performance of 18F-DOPA PET/CT showed this technique to be a useful tool in detecting PGLs, above all those located at the head/neck site, regardless of the genetic pattern.
Pain-Related F-18 FDG Uptake of the Corrugator Supercilii Muscles in PET/CT
Authors: Irene A. Burger, Daniel T. Schmid, Thomas F. Hany
Journal: Clinical Nuclear Medicine (2011)

F-18 fluorodeoxyglucose (FDG) is still the most commonly used radiotracer in positron emission tomography/CT imaging in oncologic patients. The high sensitivity with a limited specificity of increased FDG uptake is well known. Therefore, knowledge of different physiological uptake patterns is mandatory to prevent false-positive interpretations. In the presented case, a 39-year-old male patient suffered from back-pain due to an infection of the endovascular stent-graft. The high FDG-uptake on his forehead was located in the corrugator supercilii muscle on both sides and was pain-related, as this muscle typically contracts in patients suffering from pain.
A1.19 Identification of macrophage subsets in zebrafish larvae
Authors: M Nguyen-Chi, B Laplace-Builhe, J Travnickova, P Luz-Crawford, G Tejedor, I Richard, K Kissa, G Lutfalla, C Jorgensen, F Djouad
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Zebrafish have emerged as a powerful model system to study leukocyte recruitment and inflammation. In human and mouse, several subsets of the macrophage lineage have been described. The two extremes in the range of macrophage function are characterised by the pro-inflammatory (M1) and the anti-inflammatory (M2) phenotypes. M1 macrophages, efficient producers of inflammatory cytokines such as TNF-α, exert cytotoxic functions, whereas M2 are anti-inflammatory or associated with tissue remodelling. In zebrafish embryos, primitive macrophages have been identified, however, although the existence of different macrophage subtypes has been suggested they are not fully characterised. <h3>Materials, Methods and results</h3> To assess the phenotype of activated macrophages in zebrafish, we generated a double transgenic line to visualise TNF-α expressing macrophages. Using 4D-confocal microscopy, we showed that both wound induced inflammation and E. coli infection triggered the recruitment of macrophages, which started to express TNF-α few hours following stimulation. These results are the first showing in real time the mobilisation of pro-inflammatory macrophages (referred as M1-like) at the inflammation site. To further characterise macrophage subsets at the molecular level, we sorted by FACS TNF-α<sup>+</sup> and TNF-α<sup>-</sup> macrophages from transgenic larvae to enrich in M1- or M2-like macrophages. RT-qPCR analysis revealed that TNF-α<sup>+</sup> and TNF-α<sup>-</sup> macrophages express markers of human M1 and M2 subsets, respectively. <h3>Conclusion</h3> Our data suggests a high conservation in the phenotypes of macrophages in vertebrates. We thus propose that these findings combined with the specific advantages of the larval zebrafish model system – transparency, genetic tractability – should facilitate the study of inflammation, infection, and leukocyte biology.
Abstract 1628: Tumor cell specific inhibition of oncogenic Wnt signaling
Authors: Yutaka Takigawa, Damon K. Love, Anthony M. C. Brown
Journal: Cancer Research (2010)

Abstract Aberrant activation of the Wnt/β-catenin pathway is one of the most frequent signaling abnormalities known in human cancer and contributes to both tumor initiation and tumor maintenance. In normal tissues, however, the Wnt/β-catenin pathway plays widespread and important roles in the regulation of stem cell behavior, differentiation, and homeostasis. Consequently, a challenge in developing strategies for antagonizing Wnt signaling in cancer will be to minimize harmful side-effects on normal tissues. In many human cancers the canonical Wnt pathway is activated by single base missense mutations in β-catenin located near N-terminal phosphorylation sites that control the protein's stability. These mutant forms of β-catenin represent targets that are unique to cancer cells. We have screened RNAi reagents designed specifically to target individual mutant β-catenin sequences found in cancer cells while having minimal impact on wild-type β-catenin. We have used colorectal and hepatoma cell lines with defined β-catenin mutations for initial evaluation of the efficacy and specificity of knock-down, in conjunction with signaling assays based on nuclear accumulation of β-catenin and TCF-responsive reporter assays. We find that mutation-specific siRNA or shRNA reagents can be identified that substantially reduce β-catenin levels in cancer cells bearing the respective mutation, but have little or no effect on cells that are wild-type for β-catenin or which carry a different mutation. We also observe mutation-specific inhibitory effects on cell growth. These results provide encouragement for developing this strategy as a means of silencing oncogenic mutations in cancer while causing only minimal collateral damage to normal tissues. 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 1628.
Cerebrospinal Fluid Rhinorrhea Caused by a Congenital Defect of Stapes Mimicking Otorrhea
Authors: S Kim, C H Park, K Park
Journal: Clinical Nuclear Medicine (2000)

A 13-year-old boy with congenital hearing loss of the left ear presented with watery rhinorrhea. He had two episodes of bacterial meningitis. The results of computed tomographic (CT) cisternography were unremarkable. Radionuclide cisternography using Tc-99m DTPA depicted abnormal radioactivity in the region of the left ear, suggesting cerebrospinal fluid (CSF) otorrhea, but there was no scintigraphic evidence of CSF rhinorrhea. At surgery, a common cavity anomaly of the left inner ear with CSF leakage into the middle ear through the perilymph fistula was found. This was repaired successfully with bone wax. The patient is doing well without rhinorrhea, but the hearing loss of the affected ear is permanent.
Abstract 1221: Targeting interferon-λ1 with a stabilized dimer of anti-tumor Fab .
Authors: Donglin Liu, Edmund A. Rossi, Thomas M. Cardillo, David M. Goldenberg, Chien-Hsing Chang
Journal: Cancer Research (2013)

Abstract Background: The type-III interferons (IFNs), comprising IFN-λ1, IFN-λ2, and IFN-λ3, are functionally similar to the type-I IFN-α in eliciting anti-viral, anti-tumor, and immune-modulating activities. Due to its more restricted cellular targets, IFN-λ is being considered as a potential alternative to existing therapeutic regimens based on IFN-α, whose adverse effects in patients limit its use. The development of antibody-targeted IFN-λ may further improve its safety, potency and pharmacokinetics. Methods: We generated three DOC-AND-LOCKTM (DNLTM) complexes, designated (E1)-λ1, (15)-λ1, and (C2)-λ1, by conjugating IFN-λ1 site-specifically to a stabilized dimer of humanized Fab derived from hRS7 (anti-Trop-2), hMN-15 (anti-CEACAM6), and hL243 (anti-HLA-DR), respectively, which were affinity-purified and evaluated in human malignant cell lines of cervix (ME-180), colon (HT-29), esophagus (TE-11, T.Tn), lung (SK-MES-1, A549), liver (HepG2, Huh-7), and skin (A375). Results: As determined by flow cytometry, Trop-2 was highly expressed on the surface of ME-180, TE-11, and T.Tn; moderately on SK-MES-1 and HT-29; and negligibly on HepG2, Huh-7, A549, and A375. In comparison, CEACAM6 was undetectable on SK-MES-1 and A375, but positive on the remaining 7 cell lines, yet at a considerably lower level than Trop-2. Targeting of these immunocytokines to antigen-expressing cells markedly increased the amount of IFN-λ1 localized at the cell surface, as demonstrated by (E1)-λ1 on ME-180 (Trop-2+), (15)-λ1 on HepG2 (CEACAM6+), and (C2)-λ1 on A375 (HLA-DR+), respectively. In MTS assays, (E1)-λ1 inhibited the in vitro proliferation of ME-180, SK-MES-1, and TE-11, with EC50 &amp;lt;1 pM, which was 1,000-fold more potent than commercial IFN-λ1. Likewise, the anti-proliferation activity of (15)-λ1 was enhanced ∼100-fold in ME-180 and TE-11, but not in CEACAM6-negative SK-MES-1. The observed potency was further substantiated by enhanced cell signaling, including STAT phosphorylation and MHC-I up-regulation induced by (15)-λ1 in HepG2 cells. In the Pk study, (E1)-λ1 showed a mean residence time of 12 h with a T1/2 of 8.6 h, and clearance of 2.2 ml/h in mouse serum, which is comparable to PEG-IFN-λ1. Conclusions: These promising results, attributable to increased localization and stronger binding to antibody-targeted cells, warrant further exploration of these novel immunocytokines as potential cancer therapeutics. Citation Format: Donglin Liu, Edmund A. Rossi, Thomas M. Cardillo, David M. Goldenberg, Chien-Hsing Chang. Targeting interferon-λ1 with a stabilized dimer of anti-tumor Fab . [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 1221. doi:10.1158/1538-7445.AM2013-1221