tbuckley/cabot-search huggingface dataset:
SP0047 Type i interferon system in autoimmunity
Authors: L Rönnblom
Journal: Annals of the Rheumatic Diseases (2017)

The type I interferon (IFN) system is our main defense against viral infections and can be activated by a large number of sensors of nucleic acid, triggering the production of more than 15 different proteins with antiviral and immunostimulatory capacity. There are several observations suggesting an important role for this system in the etiopathogenesis of SLE and other autoimmune diseases. Among these are the reported development of autoimmune diseases during treatment with IFN-alpha, a prominent increase in the expression of type I IFN regulated genes (an IFN signature) in a number of rheumatic diseases, the existence of endogenous or self derived IFN inducers in SLE patients and a genetic association between autoimmune diseases and gene variants within the type I IFN signaling pathway. The type I IFN system is closely connected to a number of cytokine and chemokine pathways, which all can contribute to both the IFN signature and the type I IFN effects. Important type I IFN effects are maturation and differentiation of dendritic cells, activation of T and B cells with enhanced antibody production and induction of increased expression of autoantigens. Consequently, type I IFNs can act as an immune adjuvant and promote an autoimmune process. Recent data have also shown that the regulation of the type I IFN system is abnormal in SLE, which all together suggests that inhibition of the type I IFN system could be beneficial in SLE and possible also other autoimmune diseases. Many different therapeutic targets exists and several studies are in progress aiming to block, or down-regulate, the activated type I IFN system in SLE. A number of studies with monoclonal anti-IFN-alpha antibodies have been reported, and a small study investigating vaccination with an interferon-alpha-kinoid against IFN-alpha has been published. Recently, a phase IIb study targeting the type I IFN receptor in moderate to severe SLE was published, reporting substantially reduced disease activity. Other therapeutic possibilities include elimination of the endogenous IFN inducers and inhibition of key molecules in the type I IFN signaling pathway. The results so far shows that it9s possible to suppress the IFN signature and improve several biomarkers in SLE patients without major safety problems. The challenge for the future is to modulate the interferon system in autoimmune diseases more precisely and realize that different treatments may be appropriate in various patients. <h3>Disclosure of Interest</h3> L. Rönnblom Grant/research support from: AstraZeneca
ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis
Authors: Guojun Shi, Diane Somlo, Geun Hyang Kim, Cristina Prescianotto-Baschong, Shengyi Sun, Nicole Beuret, Qiaoming Long, Jonas Rutishauser, Peter Arvan, Martin Spiess, Ling Qi
Journal: Journal of Clinical Investigation (2017)

Peptide hormones are crucial regulators of many aspects of human physiology. Mutations that alter these signaling peptides are associated with physiological imbalances that underlie diseases. However, the conformational maturation of peptide hormone precursors (prohormones) in the ER remains largely unexplored. Here, we report that conformational maturation of proAVP, the precursor for the antidiuretic hormone arginine-vasopressin, within the ER requires the ER-associated degradation (ERAD) activity of the Sel1L-Hrd1 protein complex. Serum hyperosmolality induces expression of both ERAD components and proAVP in AVP-producing neurons. Mice with global or AVP neuron-specific ablation of Se1L-Hrd1 ERAD progressively developed polyuria and polydipsia, characteristics of diabetes insipidus. Mechanistically, we found that ERAD deficiency causes marked ER retention and aggregation of a large proportion of all proAVP protein. Further, we show that proAVP is an endogenous substrate of Sel1L-Hrd1 ERAD. The inability to clear misfolded proAVP with highly reactive cysteine thiols in the absence of Sel1L-Hrd1 ERAD causes proAVP to accumulate and participate in inappropriate intermolecular disulfide-bonded aggregates, promoted by the enzymatic activity of protein disulfide isomerase (PDI). This study highlights a pathway linking ERAD to prohormone conformational maturation in neuroendocrine cells, expanding the role of ERAD in providing a conducive ER environment for nascent proteins to reach proper conformation.
PEGylated human IL-10 (AM0010) in combination with pembrolizumab in anti-PD1 and CTLA-4 refractory melanoma.
Authors: Aung Naing, Deborah Jean Lee Wong, Jeffrey R. Infante, Manish R. Patel, Shubham Pant, Bartosz Chmielowski, Filip Janku, Coya Tapia, Navneet Ratti, Peter Van Vlasselaer, Gail Linda Brown, Annie Hung, Martin Oft, Adi Diab
Journal: Journal of Clinical Oncology (2017)

3084 Background: Melanoma has a high response rate to anti-PD-1 alone. More than 50% of melanoma on anti-PD-1 progress within one year. IL-10 inhibits inflammation and stimulates the cytotoxicity and proliferation of tumor infiltrating CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are induced on activated CD8 T cells, providing a mechanistic rationale for combining AM0010 and anti-PD1. AM0010 alone has established tolerability and anti-tumor activity in a phase 1 study. Objective responses were observed in 4 of 15 pts with RCC, one patient with uveal melanoma and cutaneous T cell lymphoma, each. Methods: 25 melanoma pts who had progressed on prior anti-CTLA4 and on prior anti-PD-1 containing regimen were treated with AM0010 (20mg/kg qd, SQ) and pembrolizumab (2mg/kg, q3wk IV). Patients had a median of 3.5 prior therapies (range 2-6) and a median of 2 prior immune therapies (range 1-6). Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AM0010 plus pembrolizumab was well tolerated. All treatment related adverse events (TrAE) were reversible. DLTs and SAEs leading to study discontinuation were not observed. G3/4 TrAEs were observed in 11 of 25 pts and included fatigue (8) thrombocytopenia (6), anemia (4), rash (1) and hypertriglyceridemia (1). There were no objective tumor responses. 9 of 20 evaluable pts had stable disease (DCR = 45%). As of Jan. 31 2017, the mPFS was 2.0 mo. and the mOS was not reached, with a mFU of 15.5 mos (range 10.0-18.4). AM0010 plus pembrolizumab increased Th1 cytokines as well as the number and proliferation of PD1+ Lag3+ activated CD8 T cells in the blood while reducing inflammatory cytokines and TGFb. A de-novo oligoclonal expansion of T cell clones in the blood and an increase of tumor infiltrating Granzyme+ PD1+ CD8+ T cells in tumor biopsies of treated patients was observed. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in refractory melanoma pts. The clinical activity and the observed CD8+ T cell activation may suggest to study AM0010 in combination with an anti-PD-1 in melanoma patients with less prior treatments. Clinical trial information: NCT02009449.
Nomogram for predicting overall survival (OS) in patients (pts) treated with <i>nab</i>-paclitaxel (<i>nab</i>-P) plus gemcitabine (Gem) or Gem alone for metastatic pancreatic cancer (MPC).
Authors: David Goldstein, Daniel D. Von Hoff, E. Gabriela Chiorean, Michele Reni, Josep Tabernero, Ramesh K. Ramanathan, Abdalla Aly, Marc Botteman, Julia Wilkersen, Sandra Margunato-Debay, Brian Lu, Chrystal Ursula Louis, Markus Frederic Renschler, Desmond Micahel Thomas McGovern, Chee Khoon Lee
Journal: Journal of Clinical Oncology (2017)

4109 Background: Prognostic nomograms have been developed in various cancers, including ovarian, breast, and gastrointestinal; however, there is limited information on nomograms in MPC. The large, phase 3 MPACT study of nab-P + Gem vs Gem alone for the treatment of MPC provides a robust database for the development of a nomogram to predict OS using baseline patient variables. Methods: A multivariable Cox model was created from MPACT data using factors that were significantly predictive of OS in univariable analysis or considered clinically important (stepwise selection to remain in model). From the Cox model, a nomogram was derived that assigned points equal to the weighted sum of relative significance of each variable. The nomogram was internally validated using bootstrapping, a concordance index (c-index), and calibration plots. Results: Data from all 861 pts were used. Seven of the 34 considered variables were retained in the multivariable analysis (Table; all factors significant at the P &lt; 0.01 level, except for analgesic use [ P = 0.07]). The resulting nomogram was able to distinguish low (n = 216), medium (n = 430), and high (n = 215) risk groups (c-index: 0.69; CI: 0.67-0.71) with median OS values of 12.9, 8.2, and 3.7 months, respectively. Calibration curves showed that the nomogram’s predicted probabilities were mostly consistent with observed probabilities for 6-, 9-, and 12-month OS. Conclusions: Treatment arm, Karnofsky performance status (KPS), neutrophil-to-lymphocyte ratio (NLR), albumin level, sum of longest tumor diameters (SLD), and presence of liver metastasis were the key predictors of OS. This nomogram, which will be presented in visual format in the final presentation, may help physicians and pts make informed treatment decisions. Clinical trial information: NCT00844649. [Table: see text]
Annals Story Slam - I Remember
Authors: Bikrampal Sidhu
Journal: Annals of Internal Medicine (2017)

Web Exclusives19 September 2017Annals Story Slam - I RememberFREEBikrampal Sidhu, MDBikrampal Sidhu, MDFrom University of Toronto, Toronto, Ontario, Canada.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0050 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - I Remember "I Remember," by Dr. Bikrampal Sidhu (Duration 05:16)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From University of Toronto, Toronto, Ontario, Canada.Current Author Address: Bikrampal Sidhu, MD, University of Toronto, Toronto, Ontario, Canada; e-mail, bikrampal.[email protected]utoronto.ca. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 September 2017Volume 167, Issue 6Page: SS1 ePublished: 19 September 2017 Issue Published: 19 September 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Exposure to Ambient Particulate Matter during Specific Gestational Periods Produces Adverse Obstetric Consequences in Mice
Authors: Jason L. Blum, Lung-Chi Chen, Judith T. Zelikoff
Journal: Environmental Health Perspectives (2017)

Background: Epidemiological studies associate inhalation of fine-sized particulate matter (PM2.5) during pregnancy with preterm birth (PTB) and low birth weight (LBW) but disagree over which time frames are most sensitive, or if effects are cumulative. Objectives: Our objective was to provide experimental plausibility for epidemiological observations by testing the hypothesis that exposure to PM2.5 during discrete periods of pregnancy results in PTB and LBW. Methods: For the first study, timed-pregnant B6C3F1 mice were exposed to concentrated ambient PM2.5 (CAPs) or filtered air (FA) throughout pregnancy [6 h/d from gestational day (GD) 0.5 through GD16.5]. A follow-up study examined the effects of CAPs exposure during discrete gestational periods (1: GD0.5–5.5; 2: GD6.5–14.5; 3: GD14.5–16.5; 4: GD0.5–16.5) aligning to milestones during human development. Results: In the first experiment, exposure to 160 μg CAPs/m3 throughout pregnancy decreased gestational term by 0.5 d (∼1.1 wk decrease for humans) and birth weight by 11.4% compared with FA. The follow-up experiment investigated timing of CAPs exposure (mean concentrations at 178, 193, 171, and 173 μg/m3 for periods 1–4, respectively). Pregnancy was significantly shortened (vs. FA) by ∼0.4d when exposure occurred during gestational periods 2 and 4, and by ∼0.5d if exposure occurred during period 3. Exposure during periods 1, 2, and 4 reduced birth weight by ∼10% compared with FA, and placental weight was reduced (∼8%) on GD17.5 if exposure occurred only during period 3. Conclusions: Adverse PM2.5-induced outcomes such as PTB and LBW are dependent upon the periods of maternal exposure. The results of these experimental studies could contribute significantly to air pollution policy decisions in the future. https://doi.org/10.1289/EHP1029
Metabolically Healthy Obese and Incident Cardiovascular Disease Events Among 3.5 Million Men and Women
Authors: Rishi Caleyachetty, G. Neil Thomas, Konstantinos A. Toulis, Nuredin Mohammed, Krishna M. Gokhale, Kumarendran Balachandran, Krishnarajah Nirantharakumar
Journal: Journal of the American College of Cardiology (2017)
AB1042 Dynamic contrast-enhanced magnetic resonance imaging in a randomized placebo-controlled rheumatoid arthritis trial – impact of applying joint coverage quality criteria
Authors: MB Axelsen, H Bliddal, LTH Jacobssen, MS Hansen, A Dudek, M Rell-Bakalarska, M Boesen, J Stefanek, B Sundman-Engberg, M Østergaard
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Dynamic contrast-enhanced MRI (DCE-MRI) has been proposed for evaluating treatment response in RA. In a 16-week anti-TNF trial, DCE-MRI measures of inflammation analyzed for regions of interest (ROIs) covering MCP joints 2–5 and PIP joints 2–5 detected improvements at week 16, but not at earlier time point<sup>1</sup>. <h3>Objectives</h3> To investigate if solely analyzing joints fulfilling predefined MRI quality criteria for joint visualization would increase the responsiveness and discrimination between treatments of DCE-MRI. <h3>Methods</h3> Patients with active RA despite stable DMARD therapy for ≥12 weeks were randomized 2:1 to certolizumab pegol (CZP) or 2 weeks of placebo (PBO) followed by CZP (CZP+PBO). MRIs were obtained at weeks 0 (baseline), 1, 2, 4, 8 and 16. Only joints fulfilling MRI joint quality criteria (≥3MCP/≥2PIP joint slices including the distal and/or the proximal bone of the joint and part of the joint cavity) were included in analyses. ROIs covering each joint were analyzed for number of enhancing voxels (Nvoxel), initial rate of enhancement (IRE) and maximum enhancement (ME) using the DYNAMIKA software (Image Analysis, UK). <h3>Results</h3> For 38 (CZP: 26; PBO+CZP: 12) of the 40 randomized patients, ≥1 joint fulfilled the quality criteria at baseline. 31 MCP2, 28 MCP3, 23 MCP4, 7 MCP5, 29 PIP2, 29 PIP3, 28 PIP4 and 12 PIP5 joints were included. No individual joints showed significant changes over time or differences between groups. Analyses by joint group (MCP2–4 and PIP2–4) had few data available. Nvoxel and ME decreased numerically, but not significantly, for PIP2–4. <h3>Conclusions</h3> There were no statistically significant changes in DCE-MRI on joint level or joint group level or between groups. Applying strict joint coverage quality criteria compromises the statistical power of the DCE-MRI analyses underlining the importance of standardization of the method. <h3>References</h3> Østergaard. Arthritis Rheum 2014;66(Suppl. 10):518. <h3>Disclosure of Interest</h3> M. B. Axelsen Grant/research support from: UCB Nordic funded the study, H. Bliddal Grant/research support from: UCB Nordic, L. T. H. Jacobssen Consultant for: Abbvie, Celegen, MSD, Novartis and UCB, M. Hansen: None declared, A. Dudek: None declared, M. Rell-Bakalarska: None declared, M. Boesen Consultant for: Chairman of the clinical advisory board Image Analysis, LTD London, J. Stefanek: None declared, B. Sundman-Engberg: None declared, M. Østergaard Grant/research support from: and/or speaking/consultant fees: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, and Wyeth
FRI0665 Anti-heterogenous nuclear ribonucleoproteins (ANTI- HNRNP) and other autoantibodies for detection of erosive arthropathy in systemic lupus erythematosus with joint involvement in comparison by joint X-ray
Authors: SY Hussein, NA Fathi, SH Goma, NA Mohammed, E Mosad
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Joint involvement in SLE is very common, affecting 90% of patients at some stage in the course of their disease (1).Arthritis featuring prominent radiological erosion in SLE is less common; however, in a small subset of patients an erosive pattern similar to RA develops (2). Anti- heterogenous nuclear ribonucleoprotein A2 (anti-hnRNP-A2) occur in about one-third of patients with RA but rarely in other arthritides such as OA, PsA or reactive arthritis. Interestingly, in SLE patients anti-hnRNP-A2 autoantibodies were found to be significantly associated with erosive arthritis (3). <h3>Objectives</h3> To investigate joint involvement in SLE and its relationship with autoantibodies to the hnRNP Ab A1 and A2, rheumatoid factor (R.F), Antinuclear antibody (A.N.A) and Anti-double stranded DNA (Anti-DSDNA) and correlation with articular involvement by joint x-ray. <h3>Methods</h3> Case series study comparing diagnosis of arthritis by hand and wrist x-ray with anti-hnRNP A1 and A2 in Fourty SLE patients aged 17–60 years old with disease duration 1–17 years complaining of arthralgia or arthritis. A controlled group of 21 clinically normal persons, age and sex matched and blood samples are drawn and centrifuged. RF and auto-antibodies to nuclear antigens anti-nuclear antibodies (ANA) and anti-double stranded DNA were determined in all the patients. All patients underwent X-rays of the hands and wrists. <h3>Results</h3> Anti-hnRNP A1 showed highly significant difference between study and control. Anti-hnRNP A2 showed significant difference between study and control. <h3>Conclusions</h3> This study showed a high frequency of erosive arthropathy and autoantibody to both hnRNP antigens might become useful marker for joint involvement in SLE patients and identify SLE patients prone to develop joint damage <h3>References</h3> Pipili C, Sfritzeri A, Cholongitas E. Deforming arthropathy in systemic lupus erythematosus. Eur J Intern Med 2008;19(7):482–7. Pipili C, Sfritzeri A, Cholongitas E. Deforming arthropathy in SLE: review in the literature apropos of one case. Rheumatol Int 2009;29(10):1219–21. Hassfeld W, Steiner G, Graninger W, Witzmann G, Schweitzer H, Smolen JS. Autoantibody to the nuclear antigen RA33 – a marker for early rheumatoid arthritis.Br J Rheumatol 1993;86:19–203. <h3>Disclosure of Interest</h3> None declared
THU0635 Precise and simple algorithm to identify ra cases in electronic medical records
Authors: R Knevel, S Raychaudhuri, K Liao, TW Huizinga
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Electronic medical records (EMR) have emerged as a large-scale data collection option for observational studies. These huge data registries create new opportunities to study the rheumatologic phenotype and the real-life implications for these diseases. EMR usage poses new questions of quality management, such as how to reliably identify patients with the disease or phenotype of interest, as well as bioinformatic tools to handle the magnitude of data. Thusfar, the algorithms used to identify cases are often not validated and overly simplify by using one financial code, or they are well-validated but require very specific information which hampers the applicability to other datasets. <h3>Objectives</h3> <i>Aim I:</i> Test the accuracy of the identification of patients with rheumatoid arthritis (RA) using the financial coding system. <i>Aim II:</i> Develop a simple and precise algorithm to select patients with RA that is easy to implement at other centers. <h3>Methods</h3> <i>Aim I:</i> Out of the 16,183 Rheumatology patients in the Leiden out-patient EMR system 400 charts were randomly selected and reviewed for the rheumatologic diagnosis. Next, the charts were reviewed for 200 randomly selected patients that were labeled as RA in the financial system. <i>Aim II:</i> To enable generalizability, only codified data that was obtained at regular outpatient clinic visits was used. Lasso regression was applied to identify the most discriminative variables. <h3>Results</h3> <i>Aim I:</i> Since 2008, 16,183 patients were enrolled in the EMR system of the Leiden rheumatology outpatient clinic. 2,845 of these patients were classified as having RA in the financial system. 63/400 (16.3%) of the reviewed charts concerned patients with RA. The majority (n=57) were registered as having RA in the financial system. Still, 33% of the patients with the financial code RA did not have RA. <i>Aim II:</i> Using Least Absolute Shrinkage and Selection Operator (LASSO) regression anti CCP, MTX prescription and number of visits were identified as the most discriminative variables. Combining these with the presence of the financial code for RA improved the algorithm from an accuracy of 67% to 90%. <h3>Conclusions</h3> The vast majority of patients that are classified as having RA are registered as such in the financial system. However, a substantial number of patients are registered as RA in the financial system are not classified as RA in clinical charts. Using widely available data on anti-CCP status, MTX prescription and visit count improved the selection of RA patients from a 67% to 90% accuracy. The combination of these variables provides a widely applicable algorithm, as they are broadly registered in Rheumatology clinics. Subsequent replications are ongoing. <h3>Disclosure of Interest</h3> None declared
Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis
Authors: Robert D Gray, Gareth Hardisty, Kate H Regan, Maeve Smith, Calum T Robb, Rodger Duffin, Annie Mackellar, Jennifer M Felton, Lily Paemka, Brian N McCullagh, Christopher D Lucas, David A Dorward, Edward F McKone, Gordon Cooke, Seamas C Donnelly, Pradeep K Singh, David A Stoltz, Christopher Haslett, Paul B McCray, Moira K B Whyte, Adriano G Rossi, Donald J Davidson
Journal: Thorax (2017)

Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation.