tbuckley/cabot-search huggingface dataset:
IgG4 anti‐infliximab in treated patients: Clinical impact and temporal evolution
Authors: A. Vultaggio, F. Nencini, A. Carraresi, S. Pratesi, R. Movérare, C. Eriksson, L. Venemalm, E. Maggi, A. Matucci
Journal: Allergy (2018)

Infliximab (IFX) carries potential risk of immunogenicity with the production of anti-drug antibodies (ADA). ADA may belong to different isotypes and are usually measured by ELISA bridging assay. This test is not designed to detect IgG4 antibodies. The aim was to measure IgG4 anti-IFX antibodies in a cohort of IFX-treated patients and to evaluate their relationship with ADA and their clinical impact.Anti-drug antibodies were detected using a bridging ELISA in the serum of 222 treated patients with different clinical outcomes to IFX. The same samples were analyzed for IgG4 anti-IFX antibodies using an experimental ImmunoCAP assay with reduced serum IgG4 background levels. A longitudinal evaluation was performed in a subgroup of 38 patients to define the temporal evolution of IgG4 anti-IFX.IgG4 anti-IFX was found in 26.6% of patients. Eighty of 222 patients were ADA+ (36%) and the majority (57/80, 71.3%) had IgG4 anti-IFX. Two IgG4-positive but ADA-negative patients were identified. IgG4 anti-IFX levels correlated with the serum levels of ADA. IgG4 anti-IFX was more common in both reactive and nonresponder patients than in tolerant/responder patients. Patients who had experienced IgE-mediated reactions displayed significantly higher IgG4 anti-IFX than IgE-negative reactive patients. The majority of patients tested positive for IgG4 anti-IFX after the first seven infusions.IgG4 anti-IFX is common in treated patients and a large part of ADA producing patients produce IgG4 antibodies. The IgG4 anti-IFX response does not prevent hypersensitivity reactions to IFX and correlates with the IgE anti-IFX response.
Combined Human Genome-wide RNAi and Metabolite Analyses Identify IMPDH as a Host-Directed Target against Chlamydia Infection
Authors: Marion Rother, Erik Gonzalez, Ana Rita Teixeira da Costa, Lea Wask, Isabella Gravenstein, Matteo Pardo, Matthias Pietzke, Rajendra Kumar Gurumurthy, Jörg Angermann, Robert Laudeley, Silke Glage, Michael Meyer, Cindrilla Chumduri, Stefan Kempa, Klaus Dinkel, Anke Unger, Bert Klebl, Andreas Klos, Thomas F. Meyer
Journal: Cell Host & Microbe (2018)
Next-Generation Drugs Targeting the Cereblon Ubiquitin Ligase
Authors: Sarah A. Holstein, Jens Hillengass, Philip L. McCarthy
Journal: Journal of Clinical Oncology (2018)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Pomalidomide Plus Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment: Results From a Phase II Trial. February 02, 2018 Errata. October 01, 2018 ARTICLE CITATION DOI: 10.1200/JCO.2018.77.9637 Journal of Clinical Oncology - published online before print May 1, 2018 PMID: 29715055 Next-Generation Drugs Targeting the Cereblon Ubiquitin Ligase Sarah A. HolsteinxSarah A. HolsteinSearch for articles by this author, Jens HillengassxJens HillengassSearch for articles by this author, and Philip L. McCarthyxPhilip L. McCarthySearch for articles by this author Show More Sarah A. Holstein, University of Nebraska Medical Center, Omaha, NE; and Jens Hillengass and Philip L. McCarthy, Roswell Park Comprehensive Cancer Center, Buffalo, NY https://doi.org/10.1200/JCO.2018.77.9637 First Page Full Text PDF Figures and Tables Supplements © 2018 by American Society of Clinical Oncology Companion Pomalidomide Plus Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment: Results From a Phase II Trial Errata Errata
Abstract 21294: Intrinsic Aerobic Capacity and Dynamic Exercise in Female Rats: Interaction on Early Vascular Remodeling in Hind Limb Ischemia
Authors: Madaniah Zakari, Caitlin Durr, Katherine Barefoot, Tyler Norvell, Musaad Alsahly, Lauren Koch, Stephen Britton, Laxmansa Katwa, Robert M Lust
Journal: Circulation (2017)

Introduction: The genotype associated with an inducible response to dynamic exercise is different from the genotype associated with the intrinsic capacity for aerobic exercise. The inducible response is an established component of rehab protocols after ischemic events, but the influence of the intrinsic capacity for exercise on the vascular response to active exercise following ischemic injury is unknown. Hypothesis: Reduced intrinsic aerobic exercise capacity will limit the early (2 week) inducible vascular response to active exercise after hind limb ischemia. Methods: Hind limb ischemic injury was created by unilateral femoral artery occlusion in previously established rat strains for high and low aerobic capacity phenotypes (HCR and LCR, Female, 40 weeks, n = 16 each). Beginning 3 days after the occlusion, 8 animals in each cohort began a 10 day, progressively increasing treadmill running protocol. Remaining animals served as sedentary post-ischemic controls. 14 days after occlusion, all animals were euthanized. Skeletal muscle was harvested from both hind limbs. Samples from the non-occluded contralateral hind limb were used as internal controls. All samples were stored in OCT at -80°C until processed for histologic assessment of capillarization (Rosenblatt staining). Results: LCR animals were about 80g heavier while HCRs had about 500% greater intrinsic running capacity (both p &lt; 0.01). HCRs showed 26% better preservation of muscle fiber area in the post-ischemic limb, but LCRs increased fiber area with exercise at least 2 fold more with active exercise (p &lt; 0.05). HCRs showed a greater increase (80%) in capillary density and perfusion exchange ratio (40%) in response to exercise. PCR for multiple angiogenic genes showed expression levels that were consistently higher in the LCRs, consistent with increased ongoing ischemic stress. Conclusions: Decreased baseline capillarization in the LCRs predisposed them to greater tissue loss following occlusion. The increased burden of exercise on the remaining fibers increased muscle growth in LCRs, but vasculogenic responses were delayed, despite stronger gene induction. Combining occlusion with exercise after occlusion in LCRs appeared to overwhelm the early angiogenic remodeling response.
High density lipoproteins production induced by selective intestinal LXR activation protects against the progression of liver injury by shifting M1 to M2 Kupffer cell phenotype
Authors: I. Pierantonelli, C. Pinto, C. Rychlicki, D.M. Giordano, L. Trozzi, M. Marzioni, A. Benedetti, G. Svegliati-Baroni
Journal: Journal of Hepatology (2018)
Gaps in Guidelines for the Management of Diabetes in Low- and Middle-Income Versus High-Income Countries—A Systematic Review
Authors: Mayowa O. Owolabi, Joseph O. Yaria, Meena Daivadanam, Akintomiwa I. Makanjuola, Gary Parker, Brian Oldenburg, Rajesh Vedanthan, Shane Norris, Ayodele R. Oguntoye, Morenike A. Osundina, Omarys Herasme, Sulaiman Lakoh, Luqman O. Ogunjimi, Sarah E. Abraham, Paul Olowoyo, Carolyn Jenkins, Wuwei Feng, Hernán Bayona, Sailesh Mohan, Rohina Joshi, Ruth Webster, Andre P. Kengne, Antigona Trofor, Lucia Maria Lotrean, Devarsetty Praveen, Jessica H. Zafra-Tanaka, Maria Lazo-Porras, Kirsten Bobrow, Michaela A. Riddell, Konstantinos Makrilakis, Yannis Manios, Bruce Ovbiagele
Journal: Diabetes Care (2018)

The extent to which diabetes (DM) practice guidelines, often based on evidence from high-income countries (HIC), can be implemented to improve outcomes in low- and middle-income countries (LMIC) is a critical challenge. We carried out a systematic review to compare type 2 DM guidelines in individual LMIC versus HIC over the past decade to identify aspects that could be improved to facilitate implementation.Eligible guidelines were sought from online databases and websites of diabetes associations and ministries of health. Type 2 DM guidelines published between 2006 and 2016 with accessible full publications were included. Each of the 54 eligible guidelines was assessed for compliance with the Institute of Medicine (IOM) standards, coverage of the cardiovascular quadrangle (epidemiologic surveillance, prevention, acute care, and rehabilitation), translatability, and its target audiences.Most LMIC guidelines were inadequate in terms of applicability, clarity, and dissemination plan as well as socioeconomic and ethical-legal contextualization. LMIC guidelines targeted mainly health care providers, with only a few including patients (7%), payers (11%), and policy makers (18%) as their target audiences. Compared with HIC guidelines, the spectrum of DM clinical care addressed by LMIC guidelines was narrow. Most guidelines from the LMIC complied with less than half of the IOM standards, with 12% of the LMIC guidelines satisfying at least four IOM criteria as opposed to 60% of the HIC guidelines (P < 0.001).A new approach to the contextualization, content development, and delivery of LMIC guidelines is needed to improve outcomes.
Noninvasvie prediction of oesophageal varics by liver stiffness measurement and platelet values in patients with liver cirrhosis due to nonalcoholic fatty liver disease: A multicenter cross-sectional study
Authors: S. Petta, G. Sebastiani, E. Bugianesi, M. Viganò, W. Sun, V. Wong, A. Berzigotti, A.L. Fracanzani, Q. Anstee, F. Marra, M. Barbara, V. Calvaruso, C. Camma, V. Di Marco, R. Lombardi, M.G. Rumi, A. Craxi, V. De Ledinghen
Journal: Journal of Hepatology (2018)
The death penalty.
Authors: P. Hall
Journal: BMJ (1992)

intervention can be recommended.In addition, use of a daytime average of 160/95mmHg must deny treatment to many patients who would receive it on the basis of the World Health Organisation criteria,8 and may deny some of them the benefits in terms of preventing stroke.Furthermore, as a separate issue, we are concerned that the common assumption that patients with "white coat" hypertension are not at risk may be flawed.9We believe that there is a need for prospectively collected data on the clinical outcome of patients managed on the basis of ambulatory rather than clinic pressures and suggest that this is an urgent concern.Such data might be collected by the joint action of academic centres working in this research area.Until such data have been collected, wholesale introduction of this technique in clinical practice may be premature.
A simple AGED score for risk classification of primary liver cancer: development and validation with long-term prospective HBsAg-positive cohorts in Qidong, China
Authors: Chunsun Fan, Mengge Li, Yu Gan, Taoyang Chen, Yan Sun, Jianhua Lu, Jinbing Wang, Yan Jin, Jianquan Lu, Gengsun Qian, Jianren Gu, Jianguo Chen, Hong Tu
Journal: Gut (2018)

We read with great interest the recent publication by Kim et al 1 showing that patients with untreated immune tolerant (IT) chronic hepatitis B with normal alanine aminotransferase (ALT) levels had significantly higher risks of hepatocellular carcinoma (HCC) and death/transplantation than treated immune active (IA) patients who had elevated ALT levels. These results indicate that ALT is not a sensitive surrogate marker for liver cell damage, and the IT phase of HBV infection cannot be considered fully benign.2 Chu and Liaw3 have challenged this view because they speculated that the IT group in that study might include IA patients who were in remission state after experiencing unrecognised minimal ALT elevations. Apparently, the highly dynamic nature of ALT perturbation makes it inadequate to act as a predictor for HCC.

We have developed and validated an easy-to-use scoring system for primary liver cancer (PLC) risk prediction. The development data set was set up in 1996 based on a community-based prospective cohort (qidong hepatitis B infection cohort (QBC)) established in Qidong, China.4 It contained …
Disulfiram thermosensitive in-situ gel based on solid dispersion for cataract
Authors: Chunjuan Zhang, Tonghua Xu, Donglei Zhang, Wei He, Siling Wang, Tongying Jiang
Journal: Asian Journal of Pharmaceutical Sciences (2018)

To improve the corneal permeability and water-solubility of disulfiram (DSF), which is an ocular drug for cataract, P188 was selected as a matrix to prepare solid dispersion of DSF (DSFSD) by hot melt method. The DSFSD was characterized by DSC, XRD, and IR, and the results suggested that DSF was amorphous in DSFSD. The DSFSD was added to borate buffer solution (BBS) contained 20% poloxamer P407 and 1.2% poloxamer P188 to form in-situ gel. In vitro and in vivo experiments revealed that DSFSD combined with in-situ gel (DSFSD/in-situ gel) increased the residence time and the amount of DSF penetrated through the corneal. The pharmacodynamics studies exhibited DSFSD/in-situ gel delayed the development of selenium-induced cataract at some content. These results investigated that DSFSD/in-situ gel as a drug delivery system can improve DSF ocular permeability.
The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma
Authors: Javier Vaquero, Cindy Lobe, Sylvana Tahraoui, Audrey Clapéron, Martine Mergey, Fatiha Merabtene, Dominique Wendum, Cédric Coulouarn, Chantal Housset, Christèle Desbois-Mouthon, Françoise Praz, Laura Fouassier
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Cholangiocarcinoma (CCA) is a desmoplastic tumor of the biliary tree in which epidermal growth factor receptor (EGFR) is overexpressed and contributes to cancer progression. Although EGFR has been envisaged as a target for therapy, treatment with tyrosine kinase inhibitors (TKI) such as erlotinib did not provide therapeutic benefit in patients with CCA, emphasizing the need to investigate resistance mechanisms against EGFR inhibition. Experimental Design: Resistant CCA cells to EGFR inhibition were obtained upon long-time exposure of cells with erlotinib. Cell signaling, viability, migration, and spheroid growth were determined in vitro, and tumor growth was evaluated in CCA xenograft models. Results: Erlotinib-resistant CCA cells displayed metastasis-associated signatures that correlated with a marked change in cell plasticity associated with an epithelial–mesenchymal transition (EMT) and a cancer stem cell (CSC)–like phenotype. Resistant cells exhibited an upregulation of insulin receptor (IR) and insulin-like growth factor (IGF) 1 receptor (IGF1R), along with an increase in IGF2 expression. IR/IGF1R inhibition reduced EMT and CSC-like traits in resistant cells. In vivo, tumors developed from resistant CCA cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF). Pharmacological coinhibition of EGFR and IR/IGF1R reduced tumor growth and stromal compartment in resistant tumors. Modeling of CCA-CAF crosstalk showed that IGF2 expressed by fibroblasts boosted IR/IGF1R signaling in resistant cells. Furthermore, IR/IGF1R signaling positively regulated fibroblast proliferation and activation. Conclusions: To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch, involving a contribution of stromal cells. Clin Cancer Res; 24(17); 4282–96. ©2018 AACR.
Preliminary results from TRASTYVERE study: A retrospective analysis of HER2-positive (HER2) metastatic breast cancer (MBC) patients treated in Spain with lapatinib (L) plus trastuzumab (T).
Authors: Joaquin Gavila, Begoña Bermejo, Luis Manso, Eva Muñoz, Antonio Anton, Joan Brunet, Alvaro Rodriguez-Lescure, Cesar Augusto Rodriguez, Ana Santaballa, Pedro Sanchez-Rovira, Juan de la Haba-Rodriguez, Marta Santisteban, Manuel Ruiz Borrego, Javier Cortes, Antonio Llombart-Cussac
Journal: Journal of Clinical Oncology (2014)

614 Background: Dual blockade with L and T in heavily pretreated HER2 MBC patients obtains impressive survival gain (Blackwell, 2012), yielding to the EMA approval for the HR-negative subgroup. Nevertheless, the benefit of the combination is unknown in L pretreated patients. Methods: We conducted a retrospective, post-authorized, multicenter study including patients treated in Spain by compassionate uses for the combination of T-L. The inclusion criteria were (1) HER2-positive metastatic or locally advanced MBC; (2) progression on at least one prior line of trastuzumab for advanced disease; and (3) T-L treatment started before DEC/2012. Concomitant endocrine therapy for HR-positive patients was allowed as well as patients with brain metastasis. Combinations with cytotoxic agents were excluded. A total of 111 patients were predefined for the primary objective: Clinical Benefit rates (CBR). In JAN/2014 independently monitored data from 72 patients was confirmed. Results: The median age was 59 years (39 - 83); Mean number of prior T lines 4 (range 1-13); 72% previously treated with L; 58% HR-positive; 78% visceral disease; 35% CNS involvement; 44% 3 or more organs involved. A total of 31 patients (43%) achieved a CBR (95% CI 31% – 54%); 1 CR, 12 PR and 18 SD lasting >24 weeks. The median time to progression (TTP) was 5.5 months (95% CI 4.63 – 6.54) and the median overall survival (OS) was 14.5 months (95% CI 9.69 – 17.64). The CBR was independent of L exposition: (50% L naïve vs. 40% L pretreated; p=0.46) or HR-status (HR-positive 43% vs. HR-negative 41%; p=0.86). No significant trends were observed in any pre-specified condition for ORR, TTP or OS. No cardiac toxicity occurred and less than 10% of G3 or G4 toxicity were recovered during the T-L treatment. Conclusions: The combination of T-L is active in heavily pretreated patients. Benefit was independent of previous treatment with L and HR-status. Future research may focus on the potential synergism of endocrine therapy in HR-positive patients.
Lung Metastases of Intracranial Atypical Meningioma Diagnosed on Posttherapeutic Imaging After 177Lu-DOTATATE Therapy
Authors: Philipp Backhaus, Sebastian Huss, Volkan Kösek, Matthias Weckesser, Kambiz Rahbar
Journal: Clinical Nuclear Medicine (2018)

Meningiomas are typically benign solitary intracranial tumors. Atypical (World Health Organization [WHO] grade II) or malignant/anaplastic (WHO grade III) meningiomas are seldom, and distant metastases occur only in rare exceptions. We present a case of a 54-year-old male patient with atypical (WHO grade II) meningioma who underwent 1 cycle of peptide receptor radionuclide therapy. Previous imaging studies were confined to the head, but posttherapeutic whole-body Lu-DOTATATE scintigraphy revealed thoracic uptake arising from previously undetected pulmonic meningioma metastases. The case highlights the importance of consideration of rare/untypical metastatic sides and the value of radiotracer whole-body imaging in identifying these.
Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder
Authors: Ditte Demontis, Raymond K Walters, Joanna Martin, Manuel Mattheisen, Thomas D Als, Esben Agerbo, Gísli Baldursson, Rich Belliveau, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Ashley Dumont, Nicholas Eriksson, Michael Gandal, Jacqueline I Goldstein, Katrina L Grasby, Jakob Grove, Olafur O Gudmundsson, Christine S Hansen, Mads Engel Hauberg, Mads V Hollegaard, Daniel P Howrigan, Hailiang Huang, Julian B Maller, Alicia R Martin, Nicholas G Martin, Jennifer Moran, Jonatan Pallesen, Duncan S Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Elise B Robinson, F Kyle Satterstrom, Hreinn Stefansson, Christine Stevens, Patrick Turley, G Bragi Walters, Hyejung Won, Margaret J Wright, Ole A Andreassen, Philip Asherson, Christie L Burton, Dorret I Boomsma, Bru Cormand, Søren Dalsgaard, Barbara Franke, Joel Gelernter, Daniel Geschwind, Hakon Hakonarson, Jan Haavik, Henry R Kranzler, Jonna Kuntsi, Kate Langley, Klaus-Peter Lesch, Christel Middeldorp, Andreas Reif, Luis Augusto Rohde, Panos Roussos, Russell Schachar, Pamela Sklar, Edmund J S Sonuga-Barke, Patrick F Sullivan, Anita Thapar, Joyce Y Tung, Irwin D Waldman, Sarah E Medland, Kari Stefansson, Merete Nordentoft, David M Hougaard, Thomas Werge, Ole Mors, Preben Bo Mortensen, Mark J Daly, Stephen V Faraone, Anders D Børglum, Benjamin M Neale
Journal: Nature Genetics (2018)
Posttranscriptional Regulation of Interleukin-33 Expression by MicroRNA-200 in Bronchial Asthma
Authors: Xin Tang, Feng Wu, Jinshuo Fan, Yang Jin, Jianjun Wang, Guanghai Yang
Journal: Molecular Therapy (2018)

The importance of understanding how interleukin-33 (IL-33) is regulated (particularly by miRs) is critical in IL-33 biology, and evidence of this in asthma pathology is limited. MicroRNA profiling of cells isolated from bronchoalveolar lavage of 14 asthmatic patients and 11 healthy controls revealed miR-200b and miR-200c were significantly reduced in asthmatic patients compared with healthy controls. The reduction was validated in two independent models of allergen-induced allergic airway inflammation and further demonstrated to be inversely correlated with asthma severity, as well as increased IL-33 production in asthmatic patients. In addition, the miR-200b and miR-200c binding sites in the 3' UTR of IL-33 mRNA were identified by bioinformatics analysis and reporter gene assay. More importantly, introduction of miR-200b and miR-200c reduced, while inhibition of endogenous miR-200b and miR-200c increased, the induction of IL-33 expression in lung epithelial cells. Exogenous administration of miR-200b to lungs of mice with allergic inflammation resulted in a decrease in IL-33 levels and resolution of airway inflammation phenotype. In conclusion, miR-200b and miR-200c by regulating the expression of IL-33 have a role in bronchial asthma, and dysregulation of expression of miR-200b/c may be the underlying mechanism resulting in the asthmatic phenotype.
ROP: dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues
Authors: Serghei Mangul, Harry Taegyun Yang, Nicolas Strauli, Franziska Gruhl, Hagit T. Porath, Kevin Hsieh, Linus Chen, Timothy Daley, Stephanie Christenson, Agata Wesolowska-Andersen, Roberto Spreafico, Cydney Rios, Celeste Eng, Andrew D. Smith, Ryan D. Hernandez, Roel A. Ophoff, Jose Rodriguez Santana, Erez Y. Levanon, Prescott G. Woodruff, Esteban Burchard, Max A. Seibold, Sagiv Shifman, Eleazar Eskin, Noah Zaitlen
Journal: Genome biology (2018)

High-throughput RNA-sequencing (RNA-seq) technologies provide an unprecedented opportunity to explore the individual transcriptome. Unmapped reads are a large and often overlooked output of standard RNA-seq analyses. Here, we present Read Origin Protocol (ROP), a tool for discovering the source of all reads originating from complex RNA molecules. We apply ROP to samples across 2630 individuals from 54 diverse human tissues. Our approach can account for 99.9% of 1 trillion reads of various read length. Additionally, we use ROP to investigate the functional mechanisms underlying connections between the immune system, microbiome, and disease. ROP is freely available at https://github.com/smangul1/rop/wiki .