tbuckley/cabot-search huggingface dataset:
Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis
Authors: Jimmy Z Liu, Johannes Roksund Hov, Trine Folseraas, Eva Ellinghaus, Simon M Rushbrook, Nadezhda T Doncheva, Ole A Andreassen, Rinse K Weersma, Tobias J Weismüller, Bertus Eksteen, Pietro Invernizzi, Gideon M Hirschfield, Daniel Nils Gotthardt, Albert Pares, David Ellinghaus, Tejas Shah, Brian D Juran, Piotr Milkiewicz, Christian Rust, Christoph Schramm, Tobias Müller, Brijesh Srivastava, Georgios Dalekos, Markus M Nöthen, Stefan Herms, Juliane Winkelmann, Mitja Mitrovic, Felix Braun, Cyriel Y Ponsioen, Peter J P Croucher, Martina Sterneck, Andreas Teufel, Andrew L Mason, Janna Saarela, Virpi Leppa, Ruslan Dorfman, Domenico Alvaro, Annarosa Floreani, Suna Onengut-Gumuscu, Stephen S Rich, Wesley K Thompson, Andrew J Schork, Sigrid Næss, Ingo Thomsen, Gabriele Mayr, Inke R König, Kristian Hveem, Isabelle Cleynen, Javier Gutierrez-Achury, Isis Ricaño-Ponce, David van Heel, Einar Björnsson, Richard N Sandford, Peter R Durie, Espen Melum, Morten H Vatn, Mark S Silverberg, Richard H Duerr, Leonid Padyukov, Stephan Brand, Miquel Sans, Vito Annese, Jean-Paul Achkar, Kirsten Muri Boberg, Hanns-Ulrich Marschall, Olivier Chazouillères, Christopher L Bowlus, Cisca Wijmenga, Erik Schrumpf, Severine Vermeire, Mario Albrecht, John D Rioux, Graeme Alexander, Annika Bergquist, Judy Cho, Stefan Schreiber, Michael P Manns, Martti Färkkilä, Anders M Dale, Roger W Chapman, Konstantinos N Lazaridis, Andre Franke, Carl A Anderson, Tom H Karlsen
Journal: Nature Genetics (2013)
Endometrial receptivity markers, the journey to successful embryo implantation
Authors: Hanna Achache, Ariel Revel
Journal: Human Reproduction Update (2006)

Human embryo implantation is a three-stage process (apposition, adhesion and invasion) involving synchronized crosstalk between a receptive endometrium and a functional blastocyst. This ovarian steroid-dependant phenomenon can only take place during the window of implantation, a self-limited period of endometrial receptivity spanning between days 20 and 24 of the menstrual cycle. Implantation involves a complex sequence of signalling events, consisting in the acquisition of adhesion ligands together with the loss of inhibitory components, which are crucial to the establishment of pregnancy. Histological evaluation, now considered to add little clinically significant information, should be replaced by functional assessment of endometrial receptivity. A large number of molecular mediators have been identified to date, including adhesion molecules, cytokines, growth factors, lipids and others. Thus, endometrial biopsy samples can be used to identify molecules associated with uterine receptivity to obtain a better insight into human implantation. In addition, development of functional in vitro systems to study embryo–uterine interactions will lead to better definition of the interactions existing between the molecules involved in this process. The purpose of this review was not only to describe the different players of the implantation process but also to try to portray the relationship between these factors and their timing in the process of uterine receptivity.
Cytoskeletal damage during myocardial ischemia: changes in vinculin immunofluorescence staining during total in vitro ischemia in canine heart.
Authors: C Steenbergen, M L Hill, R B Jennings
Journal: Circulation Research (1987)

The role of cytoskeletal damage in the disruption of the plasma membrane observed during myocardial ischemia has been studied using antibodies to vinculin to identify changes in the distribution of this membrane associated cytoskeletal protein. Vinculin is a component of the cytoskeletal attachment complex between the plasma membrane and the Z-line of the underlying myofibrils. The effects of varying periods of total ischemia on the localization of vinculin were assessed by immunofluorescence and evidence of membrane disruption was evaluated by electron microscopy. Thin tissue slices prepared from the ischemic tissue were incubated in oxygenated Krebs-Ringer phosphate buffer at 37 degrees C to assess inulin permeability, ultrastructure, and any changes in the distribution of vinculin associated with incubation. The previously reported costameric pattern of vinculin staining was observed in longitudinal sections of control myocardium, myocardium subjected to 60 minutes of total ischemia, and myocardium subjected to 60 minutes of ischemia followed by 60 minutes of incubation in oxygenated media. Electron microscopy and inulin permeability measurements confirmed that plasma membrane integrity was preserved under these conditions. However, when the duration of total ischemia was extended to 120 minutes or longer, there was a progressive loss of vinculin staining along the lateral margin of myocytes. This change correlates with the appearance of subsarcolemmal blebs and breaks in the plasma membranes observed by electron microscopy and confirmed by the increase in inulin permeability observed in tissue slices.(ABSTRACT TRUNCATED AT 250 WORDS)
Myricetin Suppresses UVB-Induced Skin Cancer by Targeting Fyn
Authors: Sung Keun Jung, Ki Won Lee, Sanguine Byun, Nam Joo Kang, Sung Hwan Lim, Yong-Seok Heo, Ann M. Bode, G. Tim Bowden, Hyong Joo Lee, Zigang Dong
Journal: Cancer Research (2008)

Abstract Skin cancer is currently the most common type of human cancer in Americans. Myricetin, a naturally occurring phytochemical, has potent anticancer-promoting activity and contributes to the chemopreventive potential of several foods, including red wine. Here, we show that myricetin suppresses UVB-induced cyclooxygenase-2 (COX-2) expression in mouse skin epidermal JB6 P+ cells. The activation of activator protein-1 and nuclear factor-κB induced by UVB was dose-dependently inhibited by myricetin treatment. Western blot and kinase assay data revealed that myricetin inhibited Fyn kinase activity and subsequently attenuated UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays revealed that myricetin competitively bound with ATP to suppress Fyn kinase activity. Importantly, myricetin exerted similar inhibitory effects compared with 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, a well-known pharmacologic inhibitor of Fyn. In vivo mouse skin data also revealed that myricetin inhibited Fyn kinase activity directly and subsequently attenuated UVB-induced COX-2 expression. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Docking data suggest that myricetin is easily docked to the ATP-binding site of Fyn, which is located between the N and C lobes of the kinase domain. Overall, these results indicated that myricetin exerts potent chemopreventive activity mainly by targeting Fyn in skin carcinogenesis. [Cancer Res 2008;68(14):6021–9]
Patent Foramen Ovale and High-Altitude Pulmonary Edema
Authors: Yves Allemann, Damian Hutter, Ernst Lipp, Claudio Sartori, Hervé Duplain, Marc Egli, Stéphane Cook, Urs Scherrer, Christian Seiler
Journal: JAMA (2006)

Context Individuals susceptible to high-altitude pulmonary edema (HAPE) are characterized by exaggerated pulmonary hypertension and arterial hypoxemia at high altitude, but the underlying mechanism is incompletely understood.Anecdotal evidence suggests that shunting across a patent foramen ovale (PFO) may exacerbate hypoxemia in HAPE.Objective We hypothesized that PFO is more frequent in HAPE-susceptible individuals and may contribute to more severe arterial hypoxemia at high altitude.Design, Setting, and Participants Case-control study of 16 HAPE-susceptible participants and 19 mountaineers resistant to this condition (repeated climbing to peaks above 4000 m and no symptoms of HAPE). Main Outcome MeasuresPresence of PFO determined by transesophageal echocardiography, estimated pulmonary artery pressure by Doppler echocardiography, and arterial oxygen saturation measured by pulse oximetry in HAPE-susceptible and HAPE-resistant participants at low (550 m) and high altitude (4559 m). ResultsThe frequency of PFO was more than 4 times higher in HAPE-susceptible than in HAPE-resistant participants, both at low altitude (56% vs 11%, P=.004; odds ratio [OR], 10.9 [95% confidence interval {CI}, 1.9-64.0])and high altitude (69% vs 16%, P=.001; OR, 11.7 [95% CI, 2.3-59.5]).At high altitude, mean (SD) arterial oxygen saturation prior to the onset of pulmonary edema was significantly lower in HAPE-susceptible participants than in the control group (73% [10%] vs 83% [7%], P=.001).Moreover, in the HAPE-susceptible group, participants with a large PFO had more severe arterial hypoxemia (65% [6%] vs 77% [8%], P=.02) than those with smaller or no PFO.Conclusions Patent foramen ovale was roughly 4 times more frequent in HAPEsusceptible mountaineers than in participants resistant to this condition.At high altitude, HAPE-susceptible participants with a large PFO had more severe hypoxemia.We speculate that at high altitude, a large PFO may contribute to exaggerated arterial hypoxemia and facilitate HAPE.
Increased <i>MDR1</i> Expression in Normal and Malignant Peripheral Blood Mononuclear Cells Obtained from Patients Receiving Depsipeptide (FR901228, FK228, NSC630176)
Authors: Robert W. Robey, Zhirong Zhan, Richard L. Piekarz, Ganesh L. Kayastha, Tito Fojo, Susan E. Bates
Journal: Clinical Cancer Research (2006)

Abstract The increased expression of markers associated with a differentiated phenotype, such as P-glycoprotein (Pgp), follows treatment with histone deacetylase inhibitors. Because depsipeptide (FR901228, FK228, NSC630176) is a substrate for Pgp, up-regulation of the gene that encodes it, MDR1, would mean that depsipeptide induces its own mechanism of resistance. To examine the effect of depsipeptide on expression of ATP-binding cassette transporters associated with multidrug resistance, the kidney cancer cell lines 108, 121, 127, and 143 were treated with depsipeptide and evaluated by quantitative reverse transcription-PCR. Increased levels of MDR1 (1.3- to 6.3-fold) and ABCG2 (3.2- to 11.1-fold) but not MRP1 (0.9- to 1.3-fold) were observed. The induced Pgp transported the fluorescent substrates rhodamine 123, bisantrene, calcein-AM, BODIPY-vinblastine, and BODIPY-paclitaxel. In normal peripheral blood mononuclear cells (PBMC) and circulating tumor cells obtained from patients receiving depsipeptide, increased levels of histone H3 acetylation were found. We next examined MDR1 levels in normal and malignant PBMCs obtained from 15 patients enrolled in clinical trials with depsipeptide and detected up to a 6-fold increase in normal PBMCs and up to an 8-fold increase in circulating tumor cells after depsipeptide administration. In one patient with Sézary syndrome, increased MDR1 gene expression was accompanied by increased cell surface Pgp expression in circulating Sézary cells as determined by measurement of MRK-16 staining by flow cytometry. These studies suggest that depsipeptide induces its own mechanism of resistance and thus provide a basis for clinical trials evaluating depsipeptide in combination with a Pgp inhibitor.
Perfluorochemical emulsions decrease Kupffer cell phagocytosis
Authors: Lori A. Bottalico, Hannah T. Betensky, Young B. Min, Shelley B. Weinstock
Journal: Hepatology (1991)

One drawback to using perfluorochemical emulsions as blood substitutes is that perfluorochemical particles are cleared from the blood by the reticuloendothelial system, primarily liver and spleen. We measured the impact of two perfluorochemical emulsions on clearance of colloidal carbon (&lt; 1 μm) and 51 Cr-sheep red blood cells (about 8 μm) by the reticuloendothelial system in vivo and in the isolated perfused liver. Male rats were injected with 2 ml/100 gm body wt of Fluosol-DA or Oxypherol-ET for 4 consecutive days. Carbon (1 ml/100 gm body wt) or sheep red blood cells (0.05 ml of 5% vol/vol/100 gm body wt) were then injected intravenously ( in vivo ) or added to perfusate. Samples were taken at several time points for 1 hr. In the isolated perfused liver, carbon clearance was depressed by 25% 1 day after treatment. Rates returned to control levels by 12 days in Fluosol-DA—treated rats but remained depressed by 67% in Oxypherol-ET—treated rats. Sheep red blood cell (8 μm) clearance was two to five times slower than carbon clearance and depressed by 40% in livers from Fluosol-DA rats 1 day and 12 days after treatment. Added serum did not improve phagocytosis. In vivo carbon clearance remained normal in Fluosol-DA—treated rats but decreased by 74% in Oxypherol-ET—treated rats 1 day after treatment, returning to normal by 12 days. Clearance rates were similar in control rats in vivo and in the perfused liver. We conclude that the isolated perfused liver is a good model to measure liver clearance function. Although low doses of perfluorochemical emulsions may depress Kupffer cell phagocytosis, general reticuloendothelial system function is not significantly compromised. (HEPATOLOGY 1991;14:169-174.)
Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
Authors: Michael A Jacobetz, Derek S Chan, Albrecht Neesse, Tashinga E Bapiro, Natalie Cook, Kristopher K Frese, Christine Feig, Tomoaki Nakagawa, Meredith E Caldwell, Heather I Zecchini, Martijn P Lolkema, Ping Jiang, Anne Kultti, Curtis B Thompson, Daniel C Maneval, Duncan I Jodrell, Gregory I Frost, H M Shepard, Jeremy N Skepper, David A Tuveson
Journal: Gut (2012)

<h3>Objective</h3> Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. <h3>Methods</h3> Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. <h3>Results</h3> PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. <h3>Conclusions</h3> The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.
DNA Methylation as an Adjunct to Histopathology to Detect Prevalent, Inconspicuous Dysplasia and Early-Stage Neoplasia in Barrett's Esophagus
Authors: Muhammad A. Alvi, Xinxue Liu, Maria O'Donovan, Richard Newton, Lorenz Wernisch, Nicholas B. Shannon, Kareem Shariff, Massimiliano di Pietro, Jacques J.G.H.M. Bergman, Krish Ragunath, Rebecca C. Fitzgerald
Journal: Clinical Cancer Research (2012)

Endoscopic surveillance of Barrett's esophagus is problematic because dysplasia/early-stage neoplasia is frequently invisible and likely to be missed because of sampling bias. Molecular abnormalities may be more diffuse than dysplasia. The aim was therefore to test whether DNA methylation, especially on imprinted and X-chromosome genes, is able to detect dysplasia/early-stage neoplasia.27K methylation arrays were used to find genes best able to differentiate between 22 Barrett's esophagus and 24 esophageal adenocarcinoma (EAC) samples. These were validated using pyrosequencing on a retrospective cohort (60 Barrett's esophagus, 36 dysplastic, and 90 EAC) and then in a prospective multicenter study (98 Barrett's esophagus patients, including 28 dysplastic and 9 early EAC) designed to utilize biomarkers to stratify patients according to their prevalent dysplasia/EAC status.Genes (23%) on the array, including 7% of X-linked and 69% of imprinted genes, have shown statistically significant changes in methylation in EAC versus Barrett's esophagus (Wilcoxon P < 0.05). 6/7 selected candidate genes were successfully internally (Pearson's P < 0.01) and externally validated (ANOVA P < 0.001). Four genes (SLC22A18, PIGR, GJA12, and RIN2) showed the greatest area under curve (0.988) to distinguish between Barrett's esophagus and dysplasia/EAC in the retrospective cohort. This methylation panel was able to stratify patients from the prospective cohort into three risk groups based on the number of genes methylated (low risk: <2 genes, intermediate: 2, and high: >2).Widespread DNA methylation changes were observed in Barrett's carcinogenesis including ≈70% of known imprinted genes. A four-gene methylation panel stratified patients with Barrett's esophagus into three risk groups with potential clinical utility.
Surgical Management of Hepatocellular Carcinoma
Authors: Steven A. Curley
Journal: Liver Cancer (1998)

Hepatocellular carcinoma (HCC) is one of the 10 most common cancers in the world. Although relatively uncommon in Western Countries, HCC is probably the most common solid cancer in the world.1,2 Worldwide annual incidence of HCC is estimated to be at least one million new patients.3–5 HCC is also one of the most lethal human malignancies, with a mortality index of 0.94.6
Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma
Authors: Alice L. Yu, Andrew L. Gilman, M. Fevzi Ozkaynak, Wendy B. London, Susan G. Kreissman, Helen X. Chen, Malcolm Smith, Barry Anderson, Judith G. Villablanca, Katherine K. Matthay, Hiro Shimada, Stephan A. Grupp, Robert Seeger, C. Patrick Reynolds, Allen Buxton, Ralph A. Reisfeld, Steven D. Gillies, Susan L. Cohn, John M. Maris, Paul M. Sondel
Journal: New England Journal of Medicine (2010)

Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma.Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis.A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses).Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)
Differences in bone structure between rheumatoid arthritis and psoriatic arthritis patients relative to autoantibody positivity
Authors: Roland Kocijan, Stephanie Finzel, Matthias Englbrecht, Klaus Engelke, Juergen Rech, Georg Schett
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To investigate whether trabecular and cortical bone structure differ between patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). So far, no study has performed a detailed comparative analysis of bone structure in patients with RA and PsA. <h3>Methods</h3> 110 patients (60 RA, 50 PsA) received high-resolution peripheral quantitative CT of the distal radius. Demographic and disease-specific parameters including anti-rheumatic treatment, bone erosion status and previous fractures were recorded. <h3>Results</h3> RA and PsA patients were comparable in age, gender, body mass index, disease duration, disease activity, functional status, antirheumatic treatment and bone erosion status. No significant differences were found for volumetric bone mineral density (BMD), including total BMD (300±77 vs 316±62 mgHA/cm<sup>3</sup>), trabecular BMD (152±46 vs 165±40 mgHA/cm<sup>3</sup>) and cortical BMD (787±113 vs 818±76 mgHA/cm<sup>3</sup>) when comparing RA patients to PsA patients, respectively. However, in contrast to seronegative RA, seropositive RA showed significantly reduced trabecular BMD (p=0.007), bone volume per tissue volume (p=0.007) and trabecular number (p=0.044), as well as a strong trend towards higher trabecular inhomogeneity compared to PsA patients. In the regression analysis, higher age, female gender and presence of autoantibodies were independently associated with trabecular bone loss. <h3>Conclusions</h3> Seropositive RA exhibits more profound changes in trabecular bone architecture than seronegative RA or PsA. The data support the concept that seropositive RA is a disease entity that is distinct from seronegative RA and PsA.