tbuckley/cabot-search huggingface dataset:
FRI0240 SIRT-1 Regulates TGF-β Induced Dermal Fibroblast Migration via Modulation of CYR61 Expression
Authors: W. Jeong, E.-J. Park, E.-J. Kwon, M. Cho, J. Kim
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> SIRT1 is a NAD-dependent protein deacetylase that participate in cellular regulation. The increased migration of fibroblast is important phenotype in fibroblast activation. The role of SIRT1 in cell migration remains controversial whether SIRT1 act as a activator or suppressor for cell migration. <h3>Objectives</h3> The aim of this study was to establish the role of SIRT1 in human dermal fibroblast migration and explore a target of SIRT1 for dermal fibroblast migration. <h3>Methods</h3> Levels of SIRT1 expression were analysed in human dermal fibroblast by RT-PCR and western blotting before and after stimulation with tumour gowth factor-β (TGF-β) and resveratol. Human dermal fibroblasts were transfected with active SIRT1 expression vectors or with siRNA targeting SIRT1 or were treated with nicotinamide. Cyr61 expression analysis was performed by western blotting to study the role of SIRT1 on cell migration. The wound healing assay was performed due to analyze migration of human dermal fibroblasts. <h3>Results</h3> SIRT1 and Cyr61 was expressed in human dermal fibroblasts and the stimulation of TGF-β further induced expression levels of SIRT1 and Cyr61 (figure a). Treatment of resveratol, SIRT1 agonist or overexpression of SIRT1 also promoted expression of SIRT1 and Cyr61 in human dermal fibroblasts, whereas inhibition of SIRT1 activity by nicotinamide or knock down of SIRT1 down-regulated Cyr61 basal level as well as TGF-β or resveratol-induced Cyr61expression. Blocking of ERK signaling by PD98509 reduced TGF-β or resveratol-induced Cyr61 expression. Resveratol increased migration and nicotinamide attenuated resveratol-induced migration of human dermal fibroblasts. Furthermore, SIRT1 overexpression promoted cell migration whereas blocking Cyr61 attenuated SIRT1-stimulated migration of human dermal fibroblasts (figure b and c). <h3>Conclusions</h3> We suggested a role of SIRT1 in human dermal fibroblast migration. SIRT1 increased cell migration by stimulated Cyr61 expression for their target through the ERK signaling. SIRT1-induced Cyr61 production is very important for human dermal fibroblasts migration. <h3>References</h3> Wei J, Ghosh AK, Chu H, Fang F, Hinchcliff ME, Wang J et al. The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor beta Signaling. Arthritis Rheumatol. 2015;67(5):1323–34. doi:10.1002/art.39061 Akgedik R, Akgedik S, Karamanli H, Uysal S, Bozkurt B, Ozol D et al. Effect of resveratrol on treatment of bleomycin-induced pulmonary fibrosis in rats. Inflammation. 2012;35(5):1732–41. doi:10.1007/s10753-012-9491–0. Katherine T., Andrew L. CCN1 Expression By Fibroblasts is Required for Bleomycin-Induced Skin Scleroderma. Rheumatology 2015;doi: 10.1093/rheumatology/kev090.003 <h3>Disclosure of Interest</h3> None declared
Children with Down Syndrome (DS) and NCI Standard Risk (SR) Acute Lymphoblastic Leukemia (ALL) Have a Superior Five-Year Event-Free Survival (EFS) When Treated with Escalating Intravenous Methotrexate on the Children's Cancer Group (CCG) Study 1991
Authors: Yousif Matloub, Bruce C. Bostrom, Stephen Hunger, Anne Angiolillo, Meenakshi Devidas, Mei La, Nyla A. Heerema, Naomi Winick, James Nachman, Harland Sather, William L. Carroll, Paul S Gaynon
Journal: Blood (2010)
Genome-Wide Single-Nucleotide Polymorphism-Array Based Karyotyping Detects Clonal Aberrations, and Predicts the Risk of Imatinib Failure In Chronic Myeloid Leukemia.
Authors: Boram Han, Jungwon Huh, Jun Ho Yi, Ha Yeon Lee, Jong-Won Kim, Hee-Jin Kim, Yeo-Kyeoung Kim, Hyeoung Joon Kim, Joon Ho Moon, Sang Kyun Sohn, Chul Won Jung, Dong Hwan (Dennis) Kim
Journal: Blood (2010)
THU0266 Cgamp and Cgas Are Expressed in A Subset of Patients with Systemic Lupus Erythematosus and Associate with Disease Activity
Authors: J. An, L. Durcan, R.M. Karr, J.J. Woodward, K. Elkon
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Type I interferon (IFN-I) is strongly implicated in the pathogenesis of Systemic Lupus Erythematosus (SLE) and "interferonopathies" such as Aicardi-Goutieres Syndrome (AGS). A recently discovered DNA-activated IFN-I pathway, cyclic GMP-AMP (cGAMP) synthase (cGAS), which is crucial in viral immunity, has been linked to AGS and mouse models of SLE. Whether this pathway plays a role in human SLE is unknown. <h3>Objectives</h3> Given the pivotal role played by interferon in the pathogenesis of SLE, our initial aim was to determine whether cGAS expression and subsequent cGAMP production contribute to IFN-I production in SLE. A further objective was to establish whether there is a specific disease phenotype associated with activation of this pathway. <h3>Methods</h3> There were three phases to this work. Initially, we evaluated cGAS mRNA expression by QPCR from stored cDNA in 51 SLE patients and 20 normal controls. Peripheral blood mononuclear cells (PBMC) were obtained from a second cohort comprising 17 SLE patients, 10 RA patients and 9 healthy volunteers. Extracts from these PBMC were tested for cGAMP by a Multiple Reaction Monitoring (MRM) assay developed on a mass spectrometer coupled with Ultra-Performance Liquid Chromatogram (UPLC). In a third cohort, cGAS and cGAMP were examined in the same SLE patients (n=31). Disease activity was determined by SELENA-SLEDAI and organ involvement, serology and medications recorded. Categorical variables were compared using Fischer9s exact test, mean data was compared using a t-test or the Wilcoxon Sum-Rank test for normal or non-normally distributed data respectively. <h3>Results</h3> Phase 1 revealed that cGAS expression in PBMC was significantly higher in SLE patients (n=51) when compared to normal controls (n=20) (p=0.0045). cGAS expression positively correlated with IFN response gene (ISG) expression in SLE patients (p=1.8 x 10<sup>–5</sup>). When PBMC from healthy controls were incubated with IFN-I, cGAS mRNA increased in a dose response manner consistent with it being an IFN stimulated gene. Targeted measurement of cGAMP by mass spectrometery detected cGAMP in 14.6% (7/48) SLE patients but not in any of the normal (n=19) or RA (n=22) controls. Disease activity was significantly higher in SLE patients with cGAMP detected versus those in which it was not detected (SLEDAI=7.0, SD 5.09 versus 3.52, SD 2.78, p=0.0102). <h3>Conclusions</h3> Although cGAS appears to be a prominent cytosolic DNA sensor responsible for inducing IFN in response to infection, its role in human autoimmune diseases is unknown. Here, we describe for the first time, evidence of cGAS/cGAMP activation in human SLE. We demonstrated high disease activity associated with activation of this pathway. The inducing stimulus, cell type of production and overall importance in generating the IFN signature in SLE remain to be determined. <h3>Disclosure of Interest</h3> None declared
A Modified HIV1-Based Lentiviral Vector Can Transduce Rhesus Hematopoietic Repopulating Cells as Efficiently as An SIV Vector in An Autologous Transplantation Model.
Authors: Naoya Uchida, Phillip W Hargrove, Kareem Washington, Coen J. Lap, Matthew M. Hsieh, Aylin C. Bonifacino, Sandra D. Price, Allen E. Krouse, Mark E. Metzger, Robert E. Donahue, Derek Persons, John F. Tisdale
Journal: Blood (2009)
Subcutaneous Injections of Low-Dose Anti-CD20 Veltuzumab for Treatment of Relapsed Immune Thrombocytopenia (ITP).
Authors: Mansoor N Saleh, Howard Liebman, Zale P. Bernstein, O. George Negrea, James B. Bussel, Anthony C. Onyegbula, Charles M Farber, Rashid Abassi, Thomas M. Cosgriff, Kenneth Pennington, Heather Horne, Nick Teoh, Asraf Gomaa, William A Wegener, David M Goldenberg
Journal: Blood (2009)
A Phase II Study of Elacytarabine/Idarubicin As Second Course Remission-Induction in Patients with Acute Myeloid Leukemia Who Failed Cytarabine/Anthracycline, and Evaluation of the Impact of the Nucleoside Transporter hENT1 on Response
Authors: David A. Rizzieri, Norbert Vey, Richard F. Schlenk, Xavier Thomas, Françoise Huguet, Bjorn Gjertsen, Jürgen Krauter, Igor Wolfgang Blau, Malin Johansen, Athos Gianelli-Borradori, Tove Flem Jacobsen, Jianyu Rao, Utz Krug
Journal: Blood (2011)
A New Dosing Scheme of ATG-F Prevents Rejection and Maintains Immune Recovery in Haploidentical T and B Cell Depleted Stem Cell Transplantation
Authors: Peter Lang, Tobias F. Feuchtinger, Patrick Schlegel, Heiko-Manuel Teltschik, Roland Meisel, Friedhelm R. Schuster, Bernd Gruhn, Wolfgang Schwinger, Christian E. Urban, Holger Martinius, Ulrike Pflückhahn, Rouwen Teltschik, Christina Kyzirakos, Michael Schumm, Rupert Handgretinger
Journal: Blood (2012)
SAT0108 Methotrexate and Anti-TNF Treatment Improve Endothelial Function in Patients with Rheumatoid Arthritis, Psoriatic Arthritis and Ankylosing Spondylitis
Authors: G. Deyab, I. Hokstad, M.C. Småstuen, S. Agewall, I. Hollan
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Inflammatory rheumatic diseases (IRD) are associated with accelerated atherosclerosis, which progression is related to inflammation. One of the first stages in atherogenesis is endothelial dysfunction (ED). <h3>Objectives</h3> We wanted to examine the effects of methotrexate (MTX) and anti-tumor necrosis factor (TNF) treatment (with or without MTX co-medication) on endothelial function (EF) in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). <h3>Methods</h3> From the data registry from PSARA (an observational study), we evaluated patients with RA (n=64), PsA (n=30) and AS (n=20) who completed a 6 month follow-up. All patients required treatment with either MTX monotherapy or anti-TNF±MTX, due to clinical indication. EF was assessed by finger plethysmography (RH-PAT): reactive hyperemia index (RHI) &lt;1,67 was considered as ED. In patients with ED at baseline (n=40), we searched for change in EF after 6 weeks and 6 months of anti-rheumatic therapy. <h3>Results</h3> In IRD patients with ED, RHI improved from baseline to 6 weeks (mean change=0.56, p&lt;0.005) and 6 months (mean change=0.46, p&lt;0.005), with the greatest improvements within the RA subgroup in whom RHI significantly improved at both control visits. In PsA, RHI improved at both control visits, but the change was statistically significant only at the 6 months visits. AS patients had a statistically non-significant trend towards RHI improvement at both control visits. At 6 months, RHI improved more in the MTX group than in the anti-TNF±MTX group (mean change 0.74 vs. 0.24; p=0.010), and this difference remained statistically significant after adjustments for potential confounders. There was no significant difference between the treatment regimens at 6 weeks.Id significantly gtly greater thhe The improvement in RHI was independent of changes in disease activity and of traditional CV risk factors. <h3>Conclusions</h3> Treatment with MTX and anti-TNF±MTX appears to relatively fast improve EF in IRD patients with ED, independently of improvement of disease activity. After 6 month, the EF improvement was more pronounced in the MTX users than in the anti TNF±MTX users. Among other factors, this might be due to a better effect of MTX on the vasculature, or due to differences in the MTX and anti-TNF±MTX populations. It remains to be examined in further studies if the lack of significant effect of the treatment on ED in AS is due to specific features of vascular disease in AS, or due to other factors, such as Type-2 error. <h3>Disclosure of Interest</h3> None declared
Combined magnetic resonance elastography and collagen molecular magnetic resonance imaging accurately stage liver fibrosis in a rat model
Authors: Bo Zhu, Lan Wei, Nicholas Rotile, Helen Day, Tyson Rietz, Christian T. Farrar, Gregory Y. Lauwers, Kenneth K. Tanabe, Bruce Rosen, Bryan C. Fuchs, Peter Caravan
Journal: Hepatology (2016)

Hepatic fibrosis is associated with an overproduction of matrix proteins and a pathological increase of liver stiffness. Noninvasive magnetic resonance (MR) quantification of matrix can be assessed with a collagen‐binding molecular MR probe and stiffness by MR elastography, complementary techniques. This study used both imaging techniques to more accurately stage hepatic fibrosis in a rat model. Thirty rats with varying levels of diethylnitrosamine‐induced liver fibrosis were imaged before and 45 minutes after injection of collagen‐specific probe EP‐3533. MR elastography was performed in the same imaging session. Changes in liver relaxation rate post–EP‐3533 and liver stiffness were compared to the collagen proportional area determined by histology and to Ishak scoring using receiver operating characteristic analysis. Collagen imaging was most sensitive to early fibrosis, while elastography was more sensitive to advanced fibrosis. This complementary feature enabled the formulation of a composite model using multivariate analysis of variance. This model incorporated the discriminating advantages of both MR techniques, resulting in more accurate staging throughout fibrotic progression. Conclusion : Collagen molecular MR imaging is complementary to MR elastography, and combining the two techniques in a single exam leads to increased diagnostic accuracy for all stages of fibrosis. (H epatology 2017;65:1015‐1025)
Obesity Adversely Affects Survival of Pediatric Patients with Severe Aplastic Anemia After Hematopoietic Cell Transplantation.
Authors: Collin C. Barker, Manza- A Agovi, Brent Logan, Vikas Gupta, Hillard M. Lazarus, Karen K Ballen, Gregory A. Hale, Haydar Frangoul, J. Douglas Rizzo, Marcelo C. Pasquini
Journal: Blood (2009)
SP0063 Clinical Trial Design in Pediatric Rheumatology
Authors: N. Ruperto
Journal: Annals of the Rheumatic Diseases (2016)

This lecture will present a general overview, with pros and cons, of the different study design that could be employed for drug evaluation in pediatric rheumatic diseases. Among the multitude of study designs that could be considered in pediatric rheumatology, the major trial designs are the classic parallel randomized clinical trial (RCT) with placebo or active comparator and the randomized withdrawal design. While the parallel design still remain the gold standard for establishing the efficacy and short-term safety of an experimental agent, disadvantages include ethical concerns due to the use of placebo in children with chronic condition for which alternative treatments are available. The option of using an active control is not feasible due to the high sample size that are required by these kind of trial. The double-blind, controlled, randomized withdrawal design was proposed for the first time by Dr Lovell and Dr Giannini for use in pediatric rheumatology studies in particular for juvenile idiopathic arthritis. Eligible children are treated in an open label fashion with the experimental therapy to be tested in the trial for a few months after which responders (typically defined as those demonstrating an ACR Pediatric 30 response) are randomized in a double-blind fashion either to continue the experimental therapy or to switch to placebo. In this segment of the study, called the double-blind withdrawal phase, patients who demonstrate a pre-defined definition of disease worsening (e.g. “flare”) are withdrawn from the double-blind withdrawal phase and usually re-treated with the experimental therapy in an open label fashion. The withdrawal design has proven to be very effective design and has been used in nearly all recent trials of biologic agents in children with JIA. Data gathered by use of this design led to the approval of biologic agents for children with JIA by both the FDA and EMA. <h3>Disclosure of Interest</h3> N. Ruperto Grant/research support from: The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the following industries: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Speakers bureau: The undersigned Dr Nicolino Ruperto received honoraria for consultancy or speaker9s bureau from the following pharmaceutical companies: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, Vertex.
WHO refers $29m Oxford research project to GMC for misconduct
Authors: Nigel Hawkes
Journal: BMJ (2016)

The World Health Organization has referred leading Oxford University researchers to the UK General Medical Council after an independent review found that they committed research ethics misconduct.

The referral is the culmination of a long running dispute involving Jose Villar of the Nuffield Department of Obstetrics and Gynaecology at Oxford and Stephen Kennedy, head of the department and professor of reproductive medicine. They lead Intergrowth-21st, an international study of fetal growth funded by a $29m (£23.2m; €26m) grant from the Gates Foundation.

Ever since they won the grant in 2008 there have been grumbles from rival researchers that they did so by exploiting ideas developed as part of a WHO project with the same aim. Villar worked at WHO as coordinator of maternal and perinatal health before his appointment to an Oxford chair in 2006, and both men were involved in developing the protocol for a proposed extension of WHO’s child …
Efficacy of Fluconazole Prophylaxis for Autologous Peripheral Blood Stem Cell Transplantation: Results of a Prospective, Randomized, Controlled, Multicenter, Open Label Study.
Authors: Tracey L. Walsh, Carlos Bachier, Paul Shaughnessy, Cesar O. Freytes, Natalie Callander, C. Fred LeMaistre, Michael Grimley, Patrick Bradshaw
Journal: Blood (2004)
WT1 Full Length Protein Vaccination Shows High Immunogenicity and In Vivo Anti-Tumour Activity.
Authors: Daniela Cilloni, Ilaria Defilippi, Paolo Nicoli, Enrico Bracco, Raffaella Reviglione, Antonella Roetto, Alessandro Bondi, Daniela Di Giovanni, Erika Decklic, Elisa Girola, Rosa Maria Pellegrino, Francesca Arruga, Francesca Messa, Giuseppe Saglio
Journal: Blood (2006)
Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes
Authors: S. Alice Long, Jerill Thorpe, Hannah A. DeBerg, Vivian Gersuk, James A. Eddy, Kristina M. Harris, Mario Ehlers, Kevan C. Herold, Gerald T. Nepom, Peter S. Linsley
Journal: Science Immunology (2016)

Biologic treatment of T1D typically results in transient stabilization of C-peptide levels (a surrogate for endogenous insulin secretion) in some patients, followed by progression at the same rate as in untreated control groups. Here, we used integrated systems biology and flow cytometry approaches with clinical trial blood samples to elucidate pathways associated with C-peptide stabilization in T1D subjects treated with the anti-CD3 monoclonal antibody teplizumab. We identified a population of CD8 T cells that accumulated in subjects with the best response to treatment (responders) and showed that these cells phenotypically resembled exhausted T cells by expressing high levels of the transcription factor EOMES, effector molecules, and multiple inhibitory receptors (IRs), including TIGIT and KLRG1. These cells expanded after treatment, with levels peaking after 3-6 months. To functionally characterize these exhausted-like T cells, we isolated memory CD8 TIGIT+KLRG1+ T cells from responders and showed that they exhibited expanded TCR clonotypes, indicative of prior in vivo expansion; recognized a broad-based spectrum expressed of environmental and auto-antigens; and were hypo-proliferative during polyclonal stimulation, increasing expression of IR genes and decreasing cell cycle genes. Triggering these cells with a recombinant ligand for TIGIT during polyclonal stimulation further downregulated their activation, demonstrating their exhausted phenotype was not terminal. These findings identify and functionally characterize a partially exhausted cell type associated with response to teplizumab therapy and suggest that pathways regulating T cell exhaustion may play a role in successful immune interventions for T1D.
GENO-24ONCOGENIC PTPRZ1-MET FUSIONS PROMOTE MALIGNANT PROGRESS OF GLIOMAS
Authors: Yanwei Liu, Huimin Hu, Wei Zhang, Tao Jiang
Journal: Neuro-Oncology (2015)

We have recently identified a recurrent PTPRZ1-MET (ZM) fusions presenting in a subgroup of gliomas. Patients afflicted with ZM fusions harboring glioblastomas survived poorly relative to those afflicted with non-ZM harboring sGBMs. In the present study, we collected and analyzed a cohort of 339 patients with gliomas from 4 institutions (including 153 grade II, 104 grade III gliomas and 82 sGBM). We found 41 tumors with ZM fusions, of which 26 were sGBM (31.71%), 9 were grade II gliomas (5.88%) and 5 grade III gliomas (4.81%). RNA transcript fusing exon1and exon 2 of PTPRZ1 to exon 2 of MET (ZM1-2 and ZM 2-2) were the largest number and proportion. Two patients (grade II and III gliomas) without ZM fusions in each initial tumor, however, of which the fusions were detected in progressive tumors (sGBM). ZM fusions were associated with strong MET expression. The ZM fusion displays oncogenic activity when introduced into glioma cells or stereotactically transduced in the mouse brain by hyperactivated MET signaling. The ZM enhanced MET signaling can be significantly blocked by MET kinase inhibitors, Crizotinib and CAD-1001. The latter is a highly specific and single-target inhibitor of MET kinase under clinical investigation. ZM-transformed gliomas cells were more sensitive to the two inhibitors. These results suggest that PTPRZ1-MET fusions could potentially identify a subset of gliomas patients who would benefit from targeted MET kinase inhibition.