tbuckley/cabot-search huggingface dataset:
Application of the 2010 ACR/EULAR classification criteria in patients with very early inflammatory arthritis: analysis of sensitivity, specificity and predictive values in the SAVE study cohort
Authors: Iuliia Biliavska, Tanja A Stamm, Jose Martinez-Avila, Thomas W J Huizinga, Robert B M Landewé, Günter Steiner, Daniel Aletaha, Josef S Smolen, Klaus P Machold
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> Performance of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) criteria was analysed in an internationally recruited early arthritis cohort (≤16 weeks symptom duration) enrolled in the 'Stop-Arthritis-Very-Early' trial. This sample includes patients with a variety of diseases diagnosed during follow-up. <h3>Methods</h3> Two endpoints were defined: Investigators' diagnosis and disease-modifying antirheumatic drug (DMARD) treatment start during the 12-month follow-up. The 2010 criteria were applied to score Patients' baseline data. Sensitivity, specificity, predictive values and areas under the receiver operating curves of this scoring with respect to both endpoints were calculated and compared to the 1987 criteria. The optimum level of agreement between the endpoints and the 2010 classification score ways estimated by Cohen's ϰ coefficients. <h3>Results</h3> 303 patients had 12-months follow-up. Positive predictive values of the 2010 criteria were 0.68 and 0.71 for RA-diagnosis and DMARD-start, respectively. Sensitivity for RA-diagnosis was 0.85, for DMARD-start 0.8, whereas the 1987 criteria's sensitivities were 0.65 and 0.55. The areas under the receiver operating curves of the 2010 criteria for RA-diagnosis and DMARD-start were 0.83 and 0.78. Analysis of inter-rater-agreement using Cohen's ϰ demonstrated the highest ϰ values (0.5 for RA-diagnosis and 0.43 for DMARD-start) for the score of 6. <h3>Conclusions</h3> In this international very early arthritis cohort predictive and discriminative abilities of the 2010 ACR/EULAR classification criteria were satisfactory and substantially superior to the 'old' 1987 classification criteria. This easier classification of RA in early stages will allow targeting truly early disease stages with appropriate therapy.
Two Proliferation-Related Proteins, TYMS and PGK1, Could Be New Cytotoxic T Lymphocyte-Directed Tumor-Associated Antigens of HLA-A2+ Colon Cancer
Authors: Shigeki Shichijo, Kouichi Azuma, Nobukazu Komatsu, Masaaki Ito, Yoshiaki Maeda, Yuki Ishihara, Kyogo Itoh
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this work was to provide a scientific basis for specific immunotherapy of colon cancer. Experimental Design: This study focused on identification of colon tumor-associated antigens and HLA-A2–restricted and tumor-reactive cytotoxic T lymphocytes (CTLs) generated from tumor-infiltrating lymphocytes of a colon cancer patient. A gene expression cloning method was used to identify genes coding for tumor antigens. Fifty-six peptides with HLA-A2–binding motifs encoded by these proteins were examined for their ability to induce HLA-A2–restricted and tumor-reactive CTLs. Results: We identified the following three genes coding for proliferation-related proteins: thymidylate synthase (TYMS), which is involved in chemoresistance (5-fluorouracil); 5′-aminoimidazole-4-carboxamide-1-β-d-ribonucleotide transfolmylase/inosinicase (AICRT/I); and phosphoglycerate kinase 1 (PKG1), which was secreted by tumor cells and involved in the angiogenic process. TYMS was preferentially expressed in tumor cells, whereas AICRT/I and PKG1 were equally expressed in both cancer cells and normal tissues at the mRNA level. Among 56 peptides with HLA-A2–binding motifs encoded by these proteins, 8 peptides were recognized by the CTLs, and 5 of 8 peptides were also recognized by the CTL precursors without ex vivo activation in the peripheral blood of colon cancer patients. Furthermore, four of them (one each from TYMS and PKG1 and two from AICRT/1) possessed the ability to induce HLA-A2–restricted and peptide-specific CTLs cytotoxic to colon tumor cells in peripheral blood mononuclear cells of colon cancer patients. Conclusions: TYMS and PGK1, as well as their epitope peptides, might be appropriate target molecules for specific immunotherapy of HLA-A2+ colon cancer patients because of the positive role of TYMS and PGK1 in chemoresistance (5-fluorouracil) and angiogenesis of tumor cells, respectively.
Credentialing Preclinical Pediatric Xenograft Models Using Gene Expression and Tissue Microarray Analysis
Authors: Craig C. Whiteford, Sven Bilke, Braden T. Greer, Qingrong Chen, Till A. Braunschweig, Nicola Cenacchi, Jun S. Wei, Malcolm A. Smith, Peter Houghton, Christopher Morton, C. Patrick Reynolds, Richard Lock, Richard Gorlick, Chand Khanna, Carol J. Thiele, Mikiko Takikita, Daniel Catchpoole, Stephen M. Hewitt, Javed Khan
Journal: Cancer Research (2007)

Abstract Human tumor xenografts have been used extensively for rapid screening of the efficacy of anticancer drugs for the past 35 years. The selection of appropriate xenograft models for drug testing has been largely empirical and has not incorporated a similarity to the tumor type of origin at the molecular level. This study is the first comprehensive analysis of the transcriptome of a large set of pediatric xenografts, which are currently used for preclinical drug testing. Suitable models representing the tumor type of origin were identified. It was found that the characteristic expression patterns of the primary tumors were maintained in the corresponding xenografts for the majority of samples. Because a prerequisite for developing rationally designed drugs is that the target is expressed at the protein level, we developed tissue arrays from these xenografts and corroborated that high mRNA levels yielded high protein levels for two tested genes. The web database and availability of tissue arrays will allow for the rapid confirmation of the expression of potential targets at both the mRNA and the protein level for molecularly targeted agents. The database will facilitate the identification of tumor markers predictive of response to tested agents as well as the discovery of new molecular targets. [Cancer Res 2007;67(1):32–40]
The Opportunity and Obligation to Eliminate Rubella From the United States
Authors: Walter A. Orenstein
Journal: JAMA (1984)

The licensure of rubella vaccines in the United States in 1969 offered the opportunity to prevent the devastating consequences of congenital rubella infection, including miscarriages, therapeutic abortions, and congenital rubella syndrome (CRS), with its average lifetime cost of more than $220,000 per case. With the widespread use of vaccine, rubella transmission in the United States has been reduced to record low levels. Epidemics of rubella and CRS, previously reported every six to nine years, have not occurred, and since 1980, following decreases of rubella incidence rates in the postpubertal population, the endemic incidence rates of CRS have also begun to decrease. We have both the opportunity and the obligation to hasten elimination by (1) ensuring that susceptible females of childbearing age are vaccinated, (2) initiating and/or enforcing existing legislation requiring proof of rubella immunity for all children enrolled in schools, (3) intensifying surveillance for both acquired rubella and CRS, and (4) aggressively controlling rubella outbreaks.
Tc-99m MIBI Lung Imaging of a Large Pulmonary Hematoma
Authors: DRAGANA ŠOBIĆ-ŠARANOVIĆ, DRAGANA JOVANOVIĆ, SMILJANA PAVLOVIĆ, DRAGAN MANDARIĆ
Journal: Clinical Nuclear Medicine (1997)

The chest x-ray of a 47-year-old man showed a large density in the left lung and malignancy was suspected. Tc-99m MIBI lung imaging showed a photopenic area in the lower two thirds of the left lung. Lung perfusion scintigraphy with Tc-99m MAA performed before MIBI lung imaging showed a large perfusion defect in the lower two thirds of the left lung. CT showed a large cystic area in the left lung, bronchoscopy and bronchography showed displacement of the left sided bronchioles by the enormous cystic formation. Surgery showed organized intrapleural and pulmonary hematomas possibly caused by a prior thoracic injury or spontaneous rupture of an emphysematous bleb.
Current status of calcium in hepatocellular injury
Authors: Craig E. Thomas, Donald J. Reed
Journal: Hepatology (1989)

A major question being addressed in hepatocellular injury is whether a unifying mechanism exists which involves a loss of regulation of cellular Ca++ levels.In this regard, alterations of Ca++ homeostasis have been proposed to play a major role in cell injury induced by a diversity of situations such as chemical intoxication and abnormal physiological states such as ischemia.In this review, we will discuss some of the available literature concerning hepatocellular Ca++ homeostasis, means by which it can be disrupted and how such disruptions may lead to loss of cell viability.Recent studies suggest that the ability of certain pathological conditions to intensify hepatocellular damage appears to be related to activation of molecular oxygen, a process termed oxidative stress (1, 2).We will present evidence which highlights the complex interrelationship between Ca++ homeostasis and oxidative stress in cell injury.In spite of intensive research effort, a complete understanding of the events resulting in a perturbation of Ca++ homeostasis, and its consequences, remains elusive.It is apparent that much more information concerning the effects of pathological conditions on the distribution and functions of Ca++ in the liver and its various cell types is needed. NORMAL HEPATOCELLULAR Ca++ HOMEOSTASISPlasma Membrane Ca" Transport.Mammalian cells are typically bathed in extracellular fluid (plasma or media) containing upwards of 2 mM Ca++.It is this fact that highlights the remarkable ability of cells to regulate and maintain free, ionized intracellular Ca+ + levels in the low micromolar range (Fig. 1).Maintenance of this 10,000-fold Ca++ gradient is vital to cell viability; thus, it is conceivable that processes leading to hepatocellular injury may include alterations in Ca++ homeostasis.For this reason, considerable attention has been focused on identifying and understanding the cellular machinery which serves to control cellular Ca++ fluxes.Ca++ transport systems of the plasma membrane appear to vary widely with tissue, and perhaps even cell
Observational study on efficacy, safety, and drug survival of anakinra in rheumatoid arthritis patients in clinical practice
Authors: A A den Broeder
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> The efficacy and safety of anakinra, a recombinant human interleukin 1 (IL1) receptor antagonist used in rheumatoid arthritis, has been documented in five randomised controlled studies. However, long term post-marketing efficacy data are lacking. <b>Objective:</b> To evaluate the efficacy, safety, and drug survival of anakinra in clinical practice. <b>Methods:</b> All patients with rheumatoid arthritis who started anakinra in six hospitals between May 2002 and February 2004 were included in a two year prospective, in part retrospective, cohort study. Efficacy was assessed using the 28 joint disease activity score (DAS28) and the EULAR response criteria. Safety was evaluated using the common toxicity criteria. Drug survival and prognostic factors were analysed using Kaplan–Meier and Cox proportional hazard analyses. <b>Results:</b> After three months, 55% of the patients (n = 146) showed a response (43% moderate, 12% good). A subset of patients continuing anakinra after 18 months had a sustained clinical response compared with patients who switched to other disease modifying antirheumatic drug treatment (DAS28 improvement, 2.46 <i>v</i> 1.79). Drug survival was 78%, 54%, and 14% after three, six, and 24 months, respectively. The reason for discontinuation was lack of efficacy in 78% and adverse events in 22%. Except for higher drug survival in women (odds ratio = 0.51, 95% confidence interval, 0.27 to 0.97), no prognostic factors were found. Adverse events were reported 206 times in 111 patients, the most common being injection site reactions (36%). Serious adverse events occurred in 12% of the patients, with one classified as related. <b>Conclusions:</b> The short term efficacy and safety profile of anakinra are comparable to those found in randomised clinical studies. However, the drug survival of anakinra after two years is low, mostly because of lack of efficacy.
A severe defect in CRAC Ca2<b>+</b> channel activation and altered K<b>+</b> channel gating in T cells from immunodeficient patients
Authors: Stefan Feske, Murali Prakriya, Anjana Rao, Richard S. Lewis
Journal: The Journal of Experimental Medicine (2005)

Engagement of the TCR triggers sustained Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, which helps drive gene expression underlying the T cell response to pathogens. The identity and activation mechanism of CRAC channels at a molecular level are unknown. We have analyzed ion channel expression and function in T cells from SCID patients which display 1–2% of the normal level of Ca2+ influx and severely impaired T cell activation. The lack of Ca2+ influx is not due to deficient regulation of Ca2+ stores or expression of several genes implicated in controlling Ca2+ entry in lymphocytes (kcna3/Kv1.3, kcnn4/IKCa1, trpc1, trpc3, trpv6, stim1). Instead, electrophysiologic measurements show that the influx defect is due to a nearly complete absence of functional CRAC channels. The lack of CRAC channel activity is correlated with diminished voltage sensitivity and slowed activation kinetics of the voltage-dependent Kv1.3 channel. These results demonstrate that CRAC channels provide the major, if not sole, pathway for Ca2+ entry activated by the TCR in human T cells. They also offer evidence for a functional link between CRAC and Kv1.3 channels, and establish a model system for molecular genetic studies of the CRAC channel.
CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer
Authors: Xavier Pivot, Alexey Manikhas, Bogdan Żurawski, Ewa Chmielowska, Boguslawa Karaszewska, Rozenn Allerton, Stephen Chan, Alessandra Fabi, Paolo Bidoli, Stefania Gori, Eva Ciruelos, Magdolna Dank, Lajos Hornyak, Sara Margolin, Arnd Nusch, Roma Parikh, Fareha Nagi, Michelle DeSilvio, Sergio Santillana, Ramona F. Swaby, Vladimir Semiglazov
Journal: Journal of Clinical Oncology (2015)

Purpose CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. Patients and Methods Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m 2 per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m 2 per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). Results The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, −1.6%; 95% CI, −2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. Conclusion CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.
Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis.
Authors: J M Lindstrom, B L Einarson, V A Lennon, M E Seybold
Journal: The Journal of Experimental Medicine (1976)

Immunization of Lewis rats with acetylcholine receptor (AChR) purified from either Electrophorus electricus electric organ or syngeneic rat muscle induced experimental autoimmune myasthenia gravis (EAMG). This was demonstrated by clinical signs of weakness and by electromyographic evidence of imparied neuromuscular transmission. The amount of rat AChR required to induce an autoimmune response was comparable to the amount of eel AChR required. In vitro complexing of rat AChrR with antibody reduced its immunogenicity. Autoantibody to muscle AChR was present in serum and complexed with AChR in muscle. Antibody was not bound to the ACh binding site of AChR, since antibody-AChR complexes extracted from muscle could still bind 125I-alpha-bungarotoxin. The amount of AChR extracted from muscle of rats with EAMG was diminished. The amount of AChR and antibody-AChR complexes in muscle was measured at intervals after immunization with eel AChR. The amount of AChR decreased in rats with acute EAMG, then transiently increased to more than normal amounts during remission, and finally decreased to only about 20% of normal in rats with chronic EAMG. At least half of the AChR remaining in animals with chronic EAMG was complexed with antibody. Thus, both a decrease in amount of AChR and the formation of antibody-AChR complexes contribute to impairment of neuromuscular transmission in rats with EAMG. The possible mechanisms involved in the changes in AChR content are discussed.
Upper airway obstruction due to inoperable intrathoracic goitre treated by tracheal endoprosthesis.
Authors: M Noppen, M Meysman, E Dhondt, L Gepts, B Velkeniers, L Vanhaelst, W Vincken
Journal: Thorax (1994)

Thyroidectomy is the treatment of choice in patients with thyroid enlargement complicated by compression or displacement of the trachea because of the risk of complete airway obstruction due to sudden enlargement of the goitre by, for example, haemorrhage. In patients who are medically inoperable an endoscopically inserted tracheal endoprosthesis may provide longstanding airway patency, as reported here.
Why we should talk about compliance with assisted reproductive technologies (ART): a systematic review and meta-analysis of ART compliance rates
Authors: S. Gameiro, C.M. Verhaak, J.A.M. Kremer, J. Boivin
Journal: Human Reproduction Update (2012)

The goal of this systematic review and meta-analysis was to estimate the rate of compliance with assisted reproductive technologies (ART) and examine its relationship with treatment success rates. Six databases were systematically searched from 1978 to December 2011. Studies were included if they reported data on patient progression through three consecutive standard ART cycles. Compliance was estimated for the first three ART cycles (typical ART Regimen Compliance, TARC) and after the first and the second failed cycles (CAF1, CAF2). Treatment success rates for all patients who started ART and for those who fully complied with the three ART cycles were estimated. Ten studies with data for 14 810 patients were included. TARC was 78.2% [95% confidence interval (CI) 68.8–85.3%], CAF1 was 81.8% (73.3–88.1%) and CAF2 was 75.3% (68.2–81.2%). The overall success rate was 42.7% (32.6–53.6%) for all patients starting ART and 57.9% (49.4–65.9%) for those who complied with three ART cycles. Compliance rates did not vary according to study quality, but TARC was higher for studies that reported data on doctor-censored patients versus those that did not (84.2% 95% CI 75.5–90.2 versus 70.6% 95% CI 58.3–80.5, P = 0.043). Analysis of funnel plots and the Egger test indicated publication bias for CAF1. Findings from this meta-analysis should reassure clinics and patients that most patients are able to comply with three cycles of ART. Compliers could increase their chances of success by as much as 15%. A more detailed assessment of compliance requires monitoring long-term treatment trajectories through the creation of national registries.
Pharmacology of serotonin: what a clinician should know
Authors: F De Ponti
Journal: Gut (2004)

The pharmacology of serotonin (5-hydroxytryptamine or 5-HT) in the gut has been the centre of intense interest and research for several decades.Although it is now recognised that 5-HT is contained in intrinsic enteric neurones (where it works as a neurotransmitter), enterochromaffin cells of the mucosa are the main source (more than 90%) of the body's 5-HT.In the gut, 5-HT is an important mucosal signalling molecule targeting enterocytes, smooth muscle cells, and enteric neurones.Application of exogenous 5-HT evokes so many responses that it is difficult to determine which are physiologically relevant.This bewildering range of effects is largely due to the presence of multiple receptor subtypes, which appear to be present on several classes of myenteric neurones, on smooth muscle cells, and on epithelial cells.5-HT is thought to be involved in the pathophysiology of several clinical entities such as functional gut disorders (namely, irritable bowel syndrome), carcinoid diarrhoea, and chemotherapy induced emesis.In this review, the possible targets for pharmacological intervention are analysed in the light of the most recent advances of our understanding of the role of 5-HT in gut pathophysiology.Indeed, the recent regulatory interventions on cisapride (a 5-HT 4 receptor partial agonist) and alosetron (a 5-HT 3 receptor antagonist) have prompted a rethinking of our approaches to the pharmacological modulation of serotonergic pathways.In gut disorders, the most interesting targets for pharmacological intervention are: (1) the 5-HT receptor subtypes known to affect gut function such as those belonging to the 5-HT 1 , 5-HT 3 , 5-HT 4 , and 5-HT 7 subtypes; and (2) the 5-HT reuptake mechanism which, apart from the central nervous system, is expressed in enteric neurones and enterocytes and is blocked by antidepressants. 5-HT: enteric neurotransmitter and mucosal signalling moleculeBecause so many responses are seen when exogenous 5-HT is applied to the gut, it is difficult to determine which of these are physiologically relevant (box 2).5-HT works both as neurotransmitter and a mucosal signalling molecule.