tbuckley/cabot-search huggingface dataset:
Intraventricular Enzyme Replacement Improves Disease Phenotypes in a Mouse Model of Late Infantile Neuronal Ceroid Lipofuscinosis
Authors: Michael Chang, Jonathan D Cooper, David E Sleat, Seng H Cheng, James C Dodge, Marco A Passini, Peter Lobel, Beverly L Davidson
Journal: Molecular Therapy (2008)

Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive neurodegenerative disease caused by mutations in CLN2, which encodes the lysosomal protease tripeptidyl peptidase 1 (TPP1). LINCL is characterized clinically by progressive motor and cognitive decline, and premature death. Enzyme-replacement therapy (ERT) is currently available for lysosomal storage diseases affecting peripheral tissues, but has not been used in patients with central nervous system (CNS) involvement. Enzyme delivery through the cerebrospinal fluid is a potential alternative route to the CNS, but has not been studied for LINCL. In this study, we identified relevant neuropathological and behavioral hallmarks of disease in a mouse model of LINCL and correlated those findings with tissues from LINCL patients. Subsequently, we tested if intraventricular delivery of TPP1 to the LINCL mouse was efficacious. We found that infusion of recombinant human TPP1 through an intraventricular cannula led to enzyme distribution in several regions of the brain of treated mice. In vitro activity assays confirm increased TPP1 activity throughout the rostral-caudal extent of the brain. Importantly, treated mice showed attenuated neuropathology, and decreased resting tremor relative to vehicle-treated mice. This data demonstrates that intraventricular enzyme delivery to the CNS is feasible and may be of therapeutic value.
Liposome-Encapsulated Methotrexate Interactions With Human Chronic Lymphocytic Leukemia Cells&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: John A. Todd, Alexandra M. Levine, Zoltán A. Tökés
Journal: JNCI Journal of the National Cancer Institute (1980)

The uptake of free and liposome-entrapped methotrexate (MTX) by human chronic lymphocytic leukemia cells was compared under incubation conditions resembling those encountered in vivo. Liposome encapsulation enhanced up to 200 times the association of MTX with these cells. Autoradiographic studies established an association of [3H]MTX liposomes with the cells. Such a mode of delivery did not significantly increase the amount of drug available to inhibit dihydrotolate dehydrogenase, which suggested that the liposome content was not readily available to the cytoplasmic sites of action. Increased doses of encapsulated MTX resulted in enzyme inhibitions that were similar to those obtained with the free drug. This finding demonstrates that higher doses of MTX delivered by liposomes could be potentially useful in overcoming drug-transport resistance.
Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis
Authors: S I Nihtyanova, G M Brough, C M Black, C P Denton
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Background:</h3> Vascular damage is a key pathological process in systemic sclerosis (SSc) and accounts for significant disease-related morbidity. To determine the clinical burden of severe digital vasculopathy (SDV), we have reviewed hospital-based treatment for this important complication of SSc in a large single centre cohort. <h3>Methods:</h3> Cases were identified from a cohort of 1168 patients with a diagnosis of SSc who were reviewed during an 18-month period. Patients with recorded episodes of SDV-related complications (digital ulceration, critical digital ischaemia or digital gangrene), requiring surgical amputation, digital sympathectomy or admissions for intravenous prostacyclin or calcitonin gene related peptide (CGRP) and/or intravenous antibiotic treatment were identified. <h3>Results:</h3> From this large SSc cohort, 17.4% had SDV-related complications. Contrary to expectation, their frequency was significantly higher among the patients with the diffuse cutaneous subset of SSc (27.5%) compared with 13% among the patients with limited cutaneous SSc (p&lt;0.0001). 16.6% had at least one recorded episode of digital ulcers, and 12% required at least one hospitalisation during the 18 months for treatment with intravenous prostacyclin/CGRP. Overall, there were 242 admissions with a mean duration of 6 days. <h3>Conclusions:</h3> Digital vasculopathy is a serious complication of SSc contributing significant morbidity and often requiring hospital-based management.
Expression of Focal Adhesion Kinase in Acute Myeloid Leukemia Is Associated with Enhanced Blast Migration, Increased Cellularity, and Poor Prognosis
Authors: Christian Recher, Loïc Ysebaert, Odile Beyne-Rauzy, Véronique Mansat-De Mas, Jean-Bernard Ruidavets, Pascal Cariven, Cécile Demur, Bernard Payrastre, Guy Laurent, Claire Racaud-Sultan
Journal: Cancer Research (2004)

Abstract Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase playing an important role in cell motility and survival. However, very little is known about FAK in normal and leukemic myeloid cells. In this study, FAK protein expression and mRNA were detected in 25 of 60 cases (42%) of acute myeloid leukemia (AML). Whereas FAK was expressed in 46% of CD34+ AML cells, it was not detected in normal purified CD34+ cells. Conversely, the FAK homologue proline-rich tyrosine kinase 2 (PYK2) was found to be expressed both in normal and leukemic myeloid cells. When expressed, FAK displayed phosphorylation on Tyr-397, an important step for its activation. Moreover, FAK expression was correlated with the phosphorylation of PYK2 on Tyr-881, a critical site for the PYK2 function in cell migration. FAK+ AML cells displayed significantly higher migration capacities and resistance to daunorubicin, compared with FAK− cells. The implication of FAK in both cell motility and drug resistance was demonstrated by small interfering RNA experiments with the FAK-positive KG1 cell line. However, adhesion on fibronectin efficiently protected FAK− AML cells from daunorubicin-mediated killing, suggesting that cellular adhesion mediated-drug resistance is not mediated by FAK. Finally, in a retrospective cohort of 60 AML patients, FAK expression was significantly correlated with high blast cell count, early death, and shorter survival rate. Altogether, this study shows that FAK is aberrantly expressed and activated in about half of the cases of AML and suggests that FAK may contribute to the regulation of AML cell transit from the marrow to blood compartment and that it may influence clinical outcome.
Surface properties related to concanavalin A-induced agglutination. A comparative study of several Entamoeba strains.
Authors: D Trissl, A Martínez-Palomo, C Argüello, M de la Torre, R de la Hoz
Journal: The Journal of Experimental Medicine (1977)

Pathogenic strains of Entamoeba histolytica are more easily agglutinated with concanavalin A (Con A) than strains isolated from human asymptomatic carriers. All three pathogenic strains studied here were found to agglutinate with low concentrations of Con A in contrast to various nonpathogenic axenic strains of amebas, characterized by their ability to grow at room temperature. Our present observations suggest that the extreme susceptibility of pathogenic strains of E. histolytica to agglutinate with Con A is related to their higher capacity for lectin binding and to their lack of detectable repulsive charges at the cell surface. The amount of fluorescein-tagged Con A bound to the surface was much higher in pathogenic strains. Only nonpathogenic strains showed a detectable negative surface charge as studied both by means of cell microelectrophoresis and by labeling cells with cationized ferritin at 0 degrees C. The mobility of surface Con A receptors estimated as the percentage of caps was comparable in all strains. Results of one strain cultured in axenic and monoxenic conditions suggested that bacteria can modify the behaviour of E. histolytica trophozoites by altering surface properties of the amebas.
Inhibition of Glioblastoma Growth in a Highly Invasive Nude Mouse Model Can Be Achieved by Targeting Epidermal Growth Factor Receptor but not Vascular Endothelial Growth Factor Receptor-2
Authors: Tobias Martens, Yvonne Laabs, Hauke S. Günther, Dirk Kemming, Zhenping Zhu, Larry Witte, Christian Hagel, Manfred Westphal, Katrin Lamszus
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Major shortcomings of traditional mouse models based on xenografted human glioblastoma cell lines are that tumor cells do not invade and that genetic alterations, such as amplification of the epidermal growth factor receptor (EGFR) gene, are not maintained. Such models are thus of limited value for preclinical studies. We established a highly invasive model to evaluate the effect of antibodies against EGFR (cetuximab) and vascular endothelial growth factor receptor-2 (antibody DC101). Experimental Design: After short-term culture, glioblastoma spheroids were implanted into the brains of nude mice. Animals were treated either i.c. with cetuximab or i.p. with DC101. Tumor burden was determined histologically using image analysis of 36 different landmark points on serial brain sections. Results: Invasive xenografts were obtained from nine different glioblastomas. Three of seven cases treated with cetuximab responded with significant tumor growth inhibition, whereas four did not. All responsive tumors were derived from glioblastomas exhibiting EGFR amplification and expression of the truncated EGFRvIII variant, which were maintained in the xenografts. All nonresponsive tumors lacked EGFR amplification and EGFRvIII expression. The proportion of apoptotic cells was increased, whereas proliferation and invasion were decreased in responsive tumors. None of four xenograft cases treated with DC101 responded to treatment, and the diffusely invading tumors grew independent of angiogenesis. Conclusions: Inhibition of glioblastoma growth and invasion can be achieved using i.c. delivery of an anti-EGFR antibody, but tumor response depends on the presence of amplified and/or mutated EGFR. Antiangiogenic treatment with DC101 is not effective against diffusely invading tumors.
Primary Anal Melanoma Associated With Melanosis of the Upper Gastrointestinal Tract
Authors: M. Horowitz, M. M. Nobrega
Journal: Endoscopy (1998)

A 49-year old severely ill man, with no digestive complaints, was admitted to our hospital. Abdominal ultrasound was suggestive of hepatic metastases. Endoscopy revealed multiple, flat and polypoid, pigmented lesions in the esophagus, stomach and duodenum. Biopsy showed only melanotic pigment, without malignant cells. A bone marrow biopsy confirmed the diagnosis of metastatic melanoma. A flexible rectosigmoidoscopy revealed a dark polypoid lesion. Histological analysis confirmed the diagnosis of anal melanoma. These findings demonstrate that melanosis can occur concomitantly with anal melanoma and in different segments of the upper gastrointestinal tract.
A standard variation file format for human genome sequences
Authors: Martin G Reese, Barry Moore, Colin Batchelor, Fidel Salas, Fiona Cunningham, Gabor T Marth, Lincoln Stein, Paul Flicek, Mark Yandell, Karen Eilbeck
Journal: Genome biology (2010)

Abstract Here we describe the Genome Variation Format (GVF) and the 10Gen dataset. GVF, an extension of Generic Feature Format version 3 (GFF3), is a simple tab-delimited format for DNA variant files, which uses Sequence Ontology to describe genome variation data. The 10Gen dataset, ten human genomes in GVF format, is freely available for community analysis from the Sequence Ontology website and from an Amazon elastic block storage (EBS) snapshot for use in Amazon's EC2 cloud computing environment.
Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta
Authors: Elke Dworatzek, Shokoufeh Mahmoodzadeh, Carola Schubert, Christina Westphal, Joachim Leber, Angelika Kusch, Georgios Kararigas, Daniela Fliegner, Maryline Moulin, Renée Ventura-Clapier, Jan-Ake Gustafsson, Mercy M. Davidson, Duska Dragun, Vera Regitz-Zagrosek
Journal: Cardiovascular Research (2014)

Oestrogen receptor alpha (ERα) and beta (ERβ) are involved in the regulation of pathological myocardial hypertrophy (MH). We hypothesize that both ER are also involved in physiological MH. Therefore, we investigated the role of ER in exercise-induced physiological MH in loss-of-function models and studied potential mechanisms of action. We performed 1 and 8 weeks of voluntary cage wheel running (VCR) with male and female C57BL/6J wild-type (WT), ERα- and ERβ-deleted mice. In line with other studies, female WT mice ran more than males (P ≤ 0.001). After 8 weeks of VCR, both sexes showed an increase in left ventricular mass (females: P ≤ 0.01 and males: P ≤ 0.05) with more pronounced MH in females (P < 0.05). As previously shown, female ERα-deleted mice run less than female WT mice (P ≤ 0.001). ERβ-deleted mice showed similar running performance as WT mice (females vs. male: P ≤ 0.001), but did not develop MH. Only female WT mice showed an increase in phosphorylation of serine/threonine kinase (AKT), ERK1/2, p38-mitogen-activated protein kinase (MAPK), and ribosomal protein s6, as well as an increase in the expression of key regulators of mitochondrial function and mitochondrial respiratory chain proteins (complexes I, III, and V) after VCR. However, ERβ deletion abolished all observed sex differences. Mitochondrial remodelling occurred in female WT-VCR mice, but not in female ERβ-deleted mice. The sex-specific response of the heart to exercise is modulated by ERβ. The greater increase in physiological MH in females is mediated by induction of AKT signalling, MAPK pathways, protein synthesis, and mitochondrial adaptation via ERβ.
Genetic Associations with Valvular Calcification and Aortic Stenosis
Authors: George Thanassoulis, Catherine Y. Campbell, David S. Owens, J. Gustav Smith, Albert V. Smith, Gina M. Peloso, Kathleen F. Kerr, Sonali Pechlivanis, Matthew J. Budoff, Tamara B. Harris, Rajeev Malhotra, Kevin D. O'Brien, Pia R. Kamstrup, Børge G. Nordestgaard, Anne Tybjaerg-Hansen, Matthew A. Allison, Thor Aspelund, Michael H. Criqui, Susan R. Heckbert, Shih Jen Hwang, Yongmei Liu, Marketa Sjogren, Jesper Van Der Pals, Hagen Kälsch, Thomas W. Mühleisen, Markus M. Nöthen, L. Adrienne Cupples, Muriel Caslake, Emanuele Di Angelantonio, John Danesh, Jerome I. Rotter, Sigurdur Sigurdsson, Quenna Wong, Raimund Erbel, Sekar Kathiresan, Olle Melander, Vilmundur Gudnason, Christopher J. O'Donnell, Wendy S. Post
Journal: New England Journal of Medicine (2013)

Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently.Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
Bronchoprovocation testing for diagnosis of EIB in Athletes: Is one test enough?
Authors: Oliver J. Price, Les Ansley, James H. Hull
Journal: European Respiratory Journal (2013)

Background: Exercise-induced bronchoconstriction (EIB) is highly prevalent in athletes and impacts on their health and performance. The gold-standard means for diagnosing EIB is indirect bronchoprovocation testing, however the repeatability of this methodology is not established. Aims and objectives: To evaluate the short-term test-retest repeatability of eucapnic voluntary hyperpnea (EVH). Methods: Twenty-five recreationally active men (n=21) and women (n=4) were recruited. Participants were required to attend on two separate occasions separated by a period of fourteen days. Participants performed spirometry before and following (at 3,5,10 and 15 mins) an EVH challenge (6 minutes at 85% maximum voluntary ventilation). Difference in forced expiratory volume in one second (FEV1) between visits was analysed using Bland-Altman methodology. Results: 22 subjects completed both visits (n=3 excluded - unwell), mean (SD) age 25 (±4) yrs, FEV1 102 (±8.6) % predicted. There was no significant difference in maximum fall in FEV1 post EVH between visits (P>0.05), however Bland-Altman analysis revealed wide limits of agreement (-10.36-7.9%) for the difference in fall in FEV1 between visits. A diagnosis of EIB (>10% fall in FEV1) was established in two athletes at visit one whereas this increased to five athletes at visit 2. Importantly, only one athlete had a diagnosis of EIB confirmed at both visits. Conclusion: In this cohort of athletes EVH demonstrated poor repeatability over a fixed two-week period. The findings highlight the need for caution when considering confirming or refuting a diagnosis of EIB based on a solitary indirect bronchoprovocation test and a cut-off value of 10% fall in FEV1.
IBD/Colorectal/IBS Free Papers
Authors: S.L. Jowett, C.J. Seal, J.R. Barton, M.R. Welfare
Journal: Gut (2001)

Background: Several tools exist to assess disease activity in patients with UC. The Simple Clinical Colitis Activity Index (SCCAI; Walmsley RS et al. Gut 1998;43:29–32) is a validated symptom based index (score 0–19) which has a good correlation with more complicated disease activity indices. However the score which defines a relapse has not been determined.

Aims: To determine a) the validity of the SCCAI when self-administered, b) the score that defines a relapse c) the correlation with existing disease activity indices.

Method: UC patients routinely attending hospital completed a 6 point questionnaire, the same questionnaire was later administered by the attendant physician who was blinded to the scoring process. As no gold standard for defining relapse exists the attendant physician made a global assessment of relapse/ remission status using the available clinical, laboratory & endoscopic evidence.

Results: Scores were obtained for 74 presentations; age range 16–79 years, 51% male, 34% relapse rate. The mean patient score was 4.1 (range 0–14) & mean physician score 3.7 (0–14). There was excellent correlation between the scores obtained by the patient & physician (mean difference of 0.38, 95% CI 0.10–0.65). The self-administered SCCAI correlated well with a more complicated symptom & laboratory based activity index (Seo M et al. Am J Gastroenterol 1992;87:971–6) (r=0.77, p<0.01). The receiver-operator curve demonstrates the performance of the SCCAI scores in determining relapse. A score of 5 or more defines relapse with 92% sensitivity, 91% specificity, 85% positive predictive value & 89% negative predictive value. 





Conclusions: The SCCAI is a simple tool that can be accurately self administered, correlates well with a more complicated disease activity index, & can be used to define relapse of UC with high specificity & sensitivity.

# 2. A RANDOMISED TRIAL OF INTRAVENOUS PAMIDRONATE AND CALCIUM & VITAMIN D IN THE TREATMENT OF OSTEOPOROSIS ASSOCIATED WITH CROHN'S DISEASE {#article-title-2}

Introduction: Osteoporosis is recognised as a common complication of Crohn's disease, affecting 10–42% of patients. Several groups have …
Cost, Coverage, and Comparative Effectiveness Research: The Critical Issues for Oncology
Authors: Steven D. Pearson
Journal: Journal of Clinical Oncology (2012)

A new national initiative in comparative effectiveness research (CER) is part of a broad and long-term evolution toward greater reliance on scientific evidence in clinical practice and medical policy. But CER has been controversial because of its high profile in the health care reform effort, its instantiation in a prominent new national research institute, and lingering concerns that the ultimate goal of CER is to empower the government and private insurers to reduce health care costs by restricting access to expensive new medical tests and treatments. This article presents an analysis of the policy development behind CER and focuses on its potential impact on insurance coverage and payment for oncology services. By itself, CER will not solve the tension that exists between the goal of innovative, personalized care and the eroding affordability of cancer treatment in the United States. But CER does offer an important opportunity for progress. Oncologists have taken important first steps in acknowledging their responsibility for addressing cost issues; as a professional society, they should now move forward to assume leadership in the effort to integrate clinical evidence with considerations of cost effectiveness to guide clinical practice and insurer policies.