tbuckley/cabot-search huggingface dataset:
Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C
Authors: U Arena, F Vizzutti, J G Abraldes, G Corti, C Stasi, S Moscarella, S Milani, E Lorefice, A Petrarca, R G Romanelli, G Laffi, J Bosch, F Marra, M Pinzani
Journal: Gut (2008)

Background: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease. Aim: To assess the value of TE for predicting the stage of fibrosis. Methods: Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated. Results: The areas under the curve for the prediction of significant fibrosis (⩾F2), advanced fibrosis (⩾F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE <6 or ⩾12, <9 or ⩾12, and <12 or ⩾18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p<0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis. Conclusions: TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis.
Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters
Authors: Shuiying Hu, Zhaoyuan Chen, Ryan Franke, Shelley Orwick, Ming Zhao, Michelle A. Rudek, Alex Sparreboom, Sharyn D. Baker
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents. Experimental Design: Uptake of [3H]sorafenib or [3H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters. Results: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 μmol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9- and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls. Conclusions: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporter-related resistance mechanisms. (Clin Cancer Res 2009;15(19):6062–9)
From the Double Helix to Genomic Medicine
Authors: William N. Kelley
Journal: Annals of Internal Medicine (2003)

Editorials1 April 2003From the Double Helix to Genomic MedicineWilliam N. Kelley, MDWilliam N. Kelley, MDFrom University of Pennsylvania; Philadelphia, PA 19104Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-138-7-200304010-00019 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The monumental contribution of Watson and Crickproposing the structure of DNAis being celebrated this spring on the 50th anniversary of their classic publication in Nature(1). Expressed simply, clearly, and logically, their analysis was a signal event in the history of science. In the five decades that have followed, a series of truly remarkable discoveries have occurred throughout all of science based on the implications of their conclusions. While it is very difficult to quantify the effect of this progress on clinical medicine today or what it might be in the future, several observations may provide a perspective for the busy ...References1. Watson JD, Crick FH. A structure for deoxyribose nucleic acid. Nature. 1953;171:737-8. CrossrefMedlineGoogle Scholar2. Guttmacher AE, Collins FS. Genomic medicinea primer. N Engl J Med. 2002;347:1512-20. [PMID: 12421895] CrossrefMedlineGoogle Scholar3. McKusick VA. The anatomy of the human genome: a neo-Vesalian basis for medicine in the 21st century. JAMA. 2001;286:2289-95. [PMID: 11710895] CrossrefMedlineGoogle Scholar4. Srivastava IK, Liu MA. Gene vaccines. Ann Intern Med. 2003;138:550-9. LinkGoogle Scholar5. Murphy KM, Topel RH, eds. Measuring the Gains from Medical Research: An Economic Approach. Chicago: Univ Chicago Pr; 2003. Google Scholar Author, Article, and Disclosure InformationAffiliations: From University of Pennsylvania; Philadelphia, PA 19104Disclosures:Stock ownership or options (other than mutual funds): Merck & Co., Inc., Beckman Coulter, Inc., GenVec, Inc.; Patents received: Viral-Mediated Gene Transfer System (patent 5,672,344).Corresponding Author: William N. Kelley, MD, University of Pennsylvania School of Medicine, Suite 757, BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160; e-mail, [email protected]mail.med.upenn.edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byUnderstanding the new human genetics: A review of scientific editorials 1 April 2003Volume 138, Issue 7Page: 603-604KeywordsCloningCystic fibrosisDNAEnzymesGene therapyGenetic diseasesGeneticsMutationPolymerase chain reactionTumor necrosis factor ePublished: 1 April 2003 Issue Published: 1 April 2003 Copyright & PermissionsCopyright © 2003 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Molecular identification of Mucorales in human tissues: contribution of PCR electrospray-ionization mass spectrometry
Authors: A. Alanio, D. Garcia-Hermoso, S. Mercier-Delarue, F. Lanternier, M. Gits-Muselli, J. Menotti, B. Denis, A. Bergeron, M. Legrand, O. Lortholary, S. Bretagne
Journal: Clinical Microbiology and Infection (2015)
Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations
Authors: Pejman Soroosh, Taylor A. Doherty, Takanori So, Amit Kumar Mehta, Naseem Khorram, Paula S. Norris, Stefanie Scheu, Klaus Pfeffer, Carl Ware, Michael Croft
Journal: The Journal of Experimental Medicine (2011)

Memory T helper cells (Th cells) play an important role in host defense against pathogens but also contribute to the pathogenesis of inflammatory disorders. We found that a soluble decoy lymphotoxin β receptor (LT-βR)-Fc, which can block tumor necrosis factor (TNF)-related ligands LIGHT (TNFSF14) and LT-αβ binding to the herpesvirus entry mediator (HVEM) and the LT-βR, inhibited the accumulation of memory Th2 cells after antigen encounter and correspondingly reduced inflammatory responses in vivo. Showing that this was a function of the receptor for LIGHT, antigen-specific memory CD4 T cells deficient in HVEM were also unable to persist, despite having a normal immediate response to recall antigen. HVEM(-/-) memory Th2 cells displayed reduced activity of PKB (protein kinase B; Akt), and constitutively active Akt rescued their survival and restored strong inflammation after antigen rechallenge. This was not restricted to Th2 memory cells as HVEM-deficient Th1 memory cells were also impaired in surviving after encounter with recall antigen. Furthermore, the absence of LIGHT on T cells recapitulated the defect seen with the absence of HVEM, suggesting that activated T cells communicate through LIGHT-HVEM interactions. Collectively, our results demonstrate a critical role of HVEM signals in the persistence of large pools of memory CD4 T cells.
The acute phase protein α2-macroglobulin induces rat ventricular cardiomyocyte hypertrophy via ERK1,2 and PI3-kinase/Akt pathways☆
Authors: M PADMASEKAR, R NANDIGAMA, M WARTENBERG, K SCHLUTER, H SAUER
Journal: Cardiovascular Research (2007)

Alpha2-macroglobulin (alpha2M) is an acute phase protein released to the serum upon challenges such as cardiac hypertrophy and infarction. Here we report on the role of alpha2M in the induction of hypertrophic cell growth, contractile responsiveness of rat ventricular cardiomyocytes, and on the underlying extracellular regulated kinase 1,2 (ERK1,2) and phosphoinositide 3-kinase (PI3-kinase)/Akt pathways.Cell volume and cross-sectional areas were assessed as parameters of hypertrophic growth, and real time RT-PCR for the analysis of hypertrophy-related genes was performed. Protein synthesis was analyzed by 14C-phenylalanine incorporation. Activation of ERK1,2, PI3-kinase and Akt was assessed by immunohistochemical analysis of phosphorylated proteins. Contractile responsiveness was investigated by determination of cell shortening following electrical field stimulation. Intracellular calcium concentration [Ca2+]i was determined by fluo-3 microfluorometry.Treatment of ventricular cardiomyocytes for 24 h with alpha2M significantly increased cell volume and protein synthesis as well as expression of hypertrophy-associated genes [brain natriuretic protein (BNP), beta-myosin heavy chain (beta-MHC), myosin light chain-2 (MLC-2), atrial natriuretic factor (ANF), and skeletal alpha-actin]. Comparable effects were achieved by treatment of cells with an antibody directed against the alpha2M-receptor LDL receptor-related protein-1 (LRP-1) and counteracted upon coincubation with receptor-associated protein (RAP), suggesting an involvement of alpha2M-LRP-1 signalling. Furthermore, alpha2M treatment increased sarcoplasmic reticulum Ca2+-ATPase (SERCA-2a) expression, diastolic and systolic [Ca2+]i, and contractile responsiveness after electrical stimulation. Shortly after alpha2M stimulation, activation of ERK1,2, Akt, and PI3-kinase pathways was observed. Consequently, alpha2M-induced protein synthesis was inhibited upon treatment with the ERK1,2 inhibitor UO126 as well as by LY294002 and wortmannin, which inhibit PI3-kinase, and by rapamycin, which inhibits mammalian target of rapamycin (mTOR) downstream of Akt.Our data show that alpha2M induces hypertrophic cell growth in rat ventricular cardiomyocytes via ERK1,2 and PI3-kinase/Akt and improves cardiac cell function.
Histological and direct immunofluorescence study of cutaneous hyperreactivity in Behcet's disease
Authors: S. HAIM, J.D. SOBEL, R. FRIEDMAN-BIRNBAUM, C. LICHTIG
Journal: British Journal of Dermatology (1976)

The mechanism of skin hyperreactivity (pathergy) in Behçet's disease is unknown. It has been suggested that the response is due to an Arthus-like reaction. In 18 patients with active Behcet's disease, pathergy was induced and the skin biopsied after 24 h. The histological reaction was that of mold to intense round cell infiltration. perivascular in type. Direct immunofluorescence failed in all 18 patients to demonstrate the local presence of immunoglobulins and complement at the site of lesion. A marked increase in the number of mast cells was observed at the site of reaction and scattered throughout the dermis, the role of which is to be further investigated. The study failed to demonstrate a humoral mechanism in the production of the cutaneous hyperactivity.
IL-33 reduces the development of atherosclerosis
Authors: Ashley M. Miller, Damo Xu, Darren L. Asquith, Laura Denby, Yubin Li, Naveed Sattar, Andrew H. Baker, Iain B. McInnes, Foo Y. Liew
Journal: The Journal of Experimental Medicine (2008)

Atherosclerosis is a chronic inflammatory disease of the vasculature commonly leading to myocardial infarction and stroke. We show that IL-33, which is a novel IL-1–like cytokine that signals via ST2, can reduce atherosclerosis development in ApoE−/− mice on a high-fat diet. IL-33 and ST2 are present in the normal and atherosclerotic vasculature of mice and humans. Although control PBS-treated mice developed severe and inflamed atherosclerotic plaques in the aortic sinus, lesion development was profoundly reduced in IL-33–treated animals. IL-33 also markedly increased levels of IL-4, -5, and -13, but decreased levels of IFNγ in serum and lymph node cells. IL-33 treatment also elevated levels of total serum IgA, IgE, and IgG1, but decreased IgG2a, which is consistent with a Th1-to-Th2 switch. IL-33–treated mice also produced significantly elevated antioxidized low-density lipoprotein (ox-LDL) antibodies. Conversely, mice treated with soluble ST2, a decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE−/− mice compared with control IgG-treated mice. Furthermore, coadministration of an anti–IL-5 mAb with IL-33 prevented the reduction in plaque size and reduced the amount of ox-LDL antibodies induced by IL-33. In conclusion, IL-33 may play a protective role in the development of atherosclerosis via the induction of IL-5 and ox-LDL antibodies.
Role of small-bowel endoscopy in the management of patients with inflammatory bowel disease: an international OMED–ECCO consensus
Authors: A. Bourreille, A. Ignjatovic, L. Aabakken, E. Loftus Jr, R. Eliakim, M. Pennazio, Y. Bouhnik, E. Seidman, M. Keuchel, J. Albert, S. Ardizzone, S. Bar-Meir, R. Bisschops, E. Despott, P. Fortun, R. Heuschkel, J. Kammermeier, J. Leighton, G. Mantzaris, D. Moussata, S. Lo, V. Paulsen, J. Panés, G. Radford-Smith, W. Reinisch, E. Rondonotti, D. Sanders, J. Swoger, H. Yamamoto, S. Travis, J.-F. Colombel, A. Van Gossum
Journal: Endoscopy (2009)

Crohn's disease and ulcerative colitis are lifelong diseases seen predominantly in the developed countries of the world.
Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination
Authors: Taylor H. Schreiber, Vadim V. Deyev, Joseph D. Rosenblatt, Eckhard R. Podack
Journal: Cancer Research (2009)

Established tumors suppress antitumor immune responses and induce tolerance by incompletely characterized mechanisms, and this phenomenon is an important barrier to tumor immunotherapy. Single vaccination with tumor cells expressing gp96-Ig stimulates robust expansion of tumor-specific CTLs in tumor-naïve mice and this expansion is inhibited by established tumors. Interestingly, frequent vaccinations restore antitumor immune responses in the presence of established tumors. Syngeneic EG7 tumor-bearing mice have heterogeneous responses to frequent vaccination with EG7-gp96-Ig, with 32% complete responders and 68% partial responders. Comparison of responders to nonresponders revealed an inverse correlation between tumor-specific CTL expansion in the peripheral blood and tumor size. To identify immune cells and molecules associated with effective antitumor immune responses, reverse transcription-PCR arrays were performed using cells isolated from the vaccination site. ELISAs, cellular phenotyping, and tumor immunohistochemistry were also performed comparing vaccine responders to nonresponders. These data show that up-regulation of T-bet, RORgammat, IFNgamma, CCL8, CXCL9, and CXCL10 at the vaccination site are associated with vaccine-induced antitumor immunity. These data correlate with increased CTL expansion in the peripheral blood of responders, increased infiltration of responder tumors by CD8+ cells and interleukin-17+ cells, and decreased infiltration of responder tumors by CD11b+Gr-1+ cells and FoxP3+ cells. Furthermore, serum ELISAs revealed a significant elevation of transforming growth factor-beta in nonresponders as compared with responders. Interestingly, CD8+ T cells isolated from responders and nonresponders have equivalent cytotoxic activity in vitro. Taken together, our data suggest that established tumors may escape immunosurveillance by preventing clonal expansion of tumor-specific CTL without inducing anergy.
Effect of oral contraceptives and hormone replacement therapy on bone mineral density in premenopausal and perimenopausal women: a systematic review
Authors: S L Liu, C M Lebrun
Journal: British Journal of Sports Medicine (2005)

Seventy five articles on the effect of oral contraceptives and other hormone replacement on bone density in premenopausal and perimenopausal women were reviewed. The evidence was appraised using the Oxford Centre for Evidence-Based Medicine levels of evidence. There is good evidence for a positive effect of oral contraceptives on bone density in perimenopausal women, and fair evidence for a positive effect in "hypothalamic" oligo/amenorrhoeic premenopausal women. There is limited evidence for a positive effect in healthy and anorexic premenopausal women. In hypothalamic oligo/amenorrhoeic women, baseline bone density has been shown to be significantly lower than that in healthy controls, therefore the decision to treat is clinically more important. The ideal formulation(s) and duration of treatment remain to be determined by further longitudinal and prospective randomised controlled trials in larger subject populations.
Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas
Authors: Hinke F van Thuijl, Ilari Scheinin, Daoud Sie, Agusti Alentorn, Hendrik F van Essen, Martijn Cordes, Ruth Fleischeuer, Anja M Gijtenbeek, Guus Beute, Wimar A van den Brink, Gerrit A Meijer, Miek Havenith, Ahmed Idbaih, Khê Hoang-Xuan, Karima Mokhtari, Roel GW Verhaak, Paul van der Valk, Mark A van de Wiel, Jan J Heimans, Eleonora Aronica, Jaap C Reijneveld, Pieter Wesseling, Bauke Ylstra
Journal: Genome biology (2014)

The disease course of patients with diffuse low-grade glioma is notoriously unpredictable. Temporal and spatially distinct samples may provide insight into the evolution of clinically relevant copy number aberrations (CNAs). The purpose of this study is to identify CNAs that are indicative of aggressive tumor behavior and can thereby complement the prognostically favorable 1p/19q co-deletion.Genome-wide, 50 base pair single-end sequencing was performed to detect CNAs in a clinically well-characterized cohort of 98 formalin-fixed paraffin-embedded low-grade gliomas. CNAs are correlated with overall survival as an endpoint. Seventy-five additional samples from spatially distinct regions and paired recurrent tumors of the discovery cohort were analyzed to interrogate the intratumoral heterogeneity and spatial evolution. Loss of 10q25.2-qter is a frequent subclonal event and significantly correlates with an unfavorable prognosis. A significant correlation is furthermore observed in a validation set of 126 and confirmation set of 184 patients. Loss of 10q25.2-qter arises in a longitudinal manner in paired recurrent tumor specimens, whereas the prognostically favorable 1p/19q co-deletion is the only CNA that is stable across spatial regions and recurrent tumors.CNAs in low-grade gliomas display extensive intratumoral heterogeneity. Distal loss of 10q is a late onset event and a marker for reduced overall survival in low-grade glioma patients. Intratumoral heterogeneity and higher frequencies of distal 10q loss in recurrences suggest this event is involved in outgrowth to the recurrent tumor.
A Proton MRSI Study of Brain &lt;char aid="99804048" id="ital"&gt;N&lt;/char&gt;-Acetylaspartate Level After 12 Weeks of Citalopram Treatment in Drug-Naive Patients With Obsessive-Compulsive Disorder
Authors: Joon Jang
Journal: American Journal of Psychiatry (2006)

Objective: Reductions in the level of N -acetylaspartate within subcortical structures of patients with obsessive-compulsive disorder (OCD) have been reported in several studies. However, there have been, as yet, no reports regarding N -acetylaspartate levels in the prefrontal cortex of adult drug-naive OCD patients. The authors used proton magnetic resonance spectroscopic imaging ( 1 H-MRSI) to investigate regional N -acetylaspartate level abnormalities and changes after 12 weeks of pharmacotherapy with citalopram in drug-naive OCD patients. Method: Thirteen drug-naive OCD patients and 13 age- and sex-matched healthy comparison subjects were included in this study. N -acetylaspartate levels (obtained from ratios of N -acetylaspartate with creatine, choline, and creatine plus choline) in the prefrontal cortex, parietal cortex, anterior cingulate, posterior cingulate, frontal white matter, and parietal white matter were measured by 1 H-MRSI. In OCD patients, measurements were taken before and after 12 weeks of citalopram treatment. Correlations between N -acetylaspartate concentrations in regions of interest and clinical measures were also assessed. Results: Drug-naive OCD patients exhibited significantly lower N -acetylaspartate levels in the prefrontal cortex, frontal white matter, and anterior cingulate at baseline than did comparison subjects. Significant increases in N -acetylaspartate level were detected in the prefrontal cortex and frontal white matter in OCD patients after 12 weeks of citalopram treatment. Conclusions: These data suggest that reductions in neuronal viability occur in the frontal region of OCD patients and that these reductions may be partly reversible.
Observations on the Ventricular Dysrhythmia Associated with Atrial Fibrillation in the Dog Heart
Authors: G. K. MOE, J. A. ABILDSKOV
Journal: Circulation Research (1964)

The distribution of ventricular cycle lengths and the incidence of "long" cycles were studied during episodes of atrial fibrillation induced by electrical stimulation of the right atrium in exposed dog hearts. It was concluded that the ventricular dysrhythmia can be interpreted in terms of concealed conduction. Long cycles (bracketing one or more responses concealed in the A-V node) tend to favor the occurrence of subsequent long cycles. The probability of occurrence of long cycles is shown to be a function of the duration of the "concealment zone" and of the atrial input frequency.
Re-emergence of early pandemic Staphylococcus aureus as a community-acquired meticillin-resistant clone
Authors: D Ashley Robinson, Angela M Kearns, Anne Holmes, Donald Morrison, Hajo Grundmann, Giles Edwards, Frances G O'Brien, Fred C Tenover, Linda K McDougal, Alastair B Monk, Mark C Enright
Journal: The Lancet (2005)