tbuckley/cabot-search huggingface dataset:
Efficacy of tocilizumab in patients with hand osteoarthritis: double blind, randomised, placebo-controlled, multicentre trial
Authors: Pascal Richette, Augustin Latourte, Jérémie Sellam, Daniel Wendling, Muriel Piperno, Philippe Goupille, Yves-Marie Pers, Florent Eymard, Sébastien Ottaviani, Paul Ornetti, René-Marc Flipo, Bruno Fautrel, Olivier Peyr, Jean Pierre Bertola, Eric Vicaut, Xavier Chevalier
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Objective</h3> To evaluate the efficacy of tocilizumab, an antibody against IL-6 receptor, in patients with hand osteoarthritis. <h3>Methods</h3> This was a multicentre, 12-week, randomised, double-blind, placebo-controlled study from November 2015 to October 2018. Patients with symptomatic hand osteoarthritis (pain ≥40 on a 0–100 mm visual analogue scale (VAS) despite analgesics and non-steroidal anti-inflammatory drugs; at least three painful joints, Kellgren-Lawrence grade ≥2) were randomised to receive two infusions 4 weeks apart (weeks 0 and 4) of tocilizumab (8 mg/kg intravenous) or placebo. The primary endpoint was changed in VAS pain at week 6. Secondary outcomes included the number of painful and swollen joints, duration of morning stiffness, patients' and physicians' global assessment and function scores. <h3>Results</h3> Of 104 patients screened, 91 (45 to tocilizumab and 46 to placebo; 82% women; mean age 64.4 (SD 8.7) years) were randomly assigned and 79 completed the 12-week study visit. The mean change between baseline and week 6 on the VAS for pain (primary outcome) was −7.9 (SD 19.4) and −9.9 (SD 20.1) in the tocilizumab and placebo groups (p=0.7). The groups did not differ for any secondary outcomes at weeks 4, 6, 8 or 12. Overall, adverse events were slightly more frequent in the tocilizumab than placebo group. <h3>Conclusion</h3> Tocilizumab was no more effective than placebo for pain relief in patients with hand osteoarthritis.
Lysyl Oxidase‐Like 4 Fosters an Immunosuppressive Microenvironment During Hepatocarcinogenesis
Authors: Hor‐Yue Tan, Ning Wang, Cheng Zhang, Yau‐Tuen Chan, Man‐Fung Yuen, Yibin Feng
Journal: Hepatology (2020)

Lysyl oxidase-like 4 (LOXL4) is an amine oxidase that is primarily involved in extracellular matrix remodeling and is highly expressed in HCC tissues, but its functional role in mediating liver carcinogenesis is poorly understood. Therefore, we aimed to investigate the role of LOXL4 in hepatocarcinogenesis.Here, we demonstrate that hepatic LOXL4 expression was increased during the liver carcinogenesis in mice concomitantly fed a choline-deficient, l-amino acid-defined diet. LOXL4 was secreted by the neoplastic cells and primarily localized within hepatic macrophages through exosome internalization. Supplementation of LOXL4 had minimal effect on neoplastic cells. In vitro exposure of macrophages to LOXL4 invoked an immunosuppressive phenotype and activated programmed death ligand 1 (PD-L1) expression, which further suppressed the function of CD8+ T cells. Injection of LOXL4 promoted macrophages infiltration into the liver and accelerated tumor growth, which was further abolished by adoptive T-cell transfer or PD-L1 neutralization. Label-free proteomics analysis revealed that the immunosuppressive function of LOXL4 on macrophages primarily relied on interferon (IFN)-mediated signal transducer and activator of transcription-dependent PD-L1 activation. Hydrogen peroxide scavenger or copper chelation on macrophages abolished the IFN-mediated PD-L1 presentation by LOXL4. In human HCC tissue, expression of LOXL4 in CD68+ cells was positively correlated with PD-L1 level. High expression of LOXL4 in CD68+ cells and low expression of CD8A in tumor tissue cooperatively predict poor survival of patients with HCC.LOXL4 facilitates immune evasion by tumor cells and leads to hepatocarcinogenesis. Our study unveils the role of LOXL4 in fostering an immunosuppressive microenvironment during hepatocarcinogenesis.
Tumor Microenvironment Sensitive Nanocarriers for Bioimaging and Therapeutics
Authors: Hyeongmok Park, Gurusamy Saravanakumar, Jinseong Kim, Junha Lim, Won Jong Kim
Journal: Advanced Healthcare Materials (2020)

Abstract The tumor microenvironment (TME), which is composed of cancer cells, stromal cells, immune cells, and extracellular matrices, plays an important role in tumor growth and progression. Thus, targeting the TME using a well‐designed nano‐drug delivery system is emerging as a promising strategy for the treatment of solid tumors. Compared to normal tissues, the TME presents several distinguishable physiological features such as mildly acidic pH, hypoxia, high level of reactive oxygen species, and overexpression of specific enzymes, that are exploited as stimuli to induce specific changes in the nanocarrier structures, and thereby facilitates target‐specific delivery of imaging or chemotherapeutic agents for the early diagnosis or effective treatment, respectively. Recently, smart nanocarriers that respond to more than one stimulus in the TME have also been designed to elicit a more desirable spatiotemporally controlled drug release. This review highlights the recent progress in TME‐sensitive nanocarriers designed for more efficient tumor therapy and imaging. In particular, the design strategies, challenges, and critical considerations involved in the fabrication of TME‐sensitive nanocarriers, along with their in vitro and in vivo evaluations are discussed.
Scientific consensus on the COVID-19 pandemic: we need to act now
Authors: Nisreen A Alwan, Rochelle Ann Burgess, Simon Ashworth, Rupert Beale, Nahid Bhadelia, Debby Bogaert, Jennifer Dowd, Isabella Eckerle, Lynn R Goldman, Trisha Greenhalgh, Deepti Gurdasani, Adam Hamdy, William P Hanage, Emma B Hodcroft, Zoë Hyde, Paul Kellam, Michelle Kelly-Irving, Florian Krammer, Marc Lipsitch, Alan McNally, Martin McKee, Ali Nouri, Dominic Pimenta, Viola Priesemann, Harry Rutter, Joshua Silver, Devi Sridhar, Charles Swanton, Rochelle P Walensky, Gavin Yamey, Hisham Ziauddeen
Journal: The Lancet (2020)
OP0335-PARE MODERNISATION OF PATIENT ORGANIZATION THROUGH ONLINE COURSES
Authors: N. Unesi
Journal: Annals of the Rheumatic Diseases (2020)

Background: A big and very crucial part of every membership organization is the continuing education of members and elected representatives in regional and local chapters. Given the geographical long distances in Sweden, attending courses in person can be difficult, and expensive for the Swedish Rheumatism Association, the SRA. In 2019 the SRA developed a method to modernise our educational efforts by offering online courses to our elected representatives. Thus making it possible for anyone who has access to a computer to participate when it suits him or her. The courses can be done individually or in groups. Objectives: The goal is to offer modern and cost effective ways to educate in matters selected by the SRA, and for elected representatives and members to be able to attend courses at any times. Methods: The courses consists of films, texts and study exercises. The staff of the SRA record films and make as much of the content themselves as possible. The content must be relaxed, easy to do and enhance the feeling of familiarity. Those who complete the courses should feel like they are in the same room as the lecturers. Results: In 2019, the SRA completed two courses for elected representatives. The first course was on the matter of democratic structures at the annual general meeting of the SRA, and all decision making that applies for the SRA, for example, statutes, how to elect new board members and decide on an activity plan for the coming year. The course circled around these topics: How do you write a motion and how do you send it to the annual meeting? How do you prepare as a representative? What happens at an annual general meeting? How do you ask for the word and how do you argue for your cause? How do you report from a general meeting to your local organization? During the evaluation, the SRA received positive comments from those who attended. By the end of 2019, the SRA finished developing an online course on membership recruitment. Conclusion: In 2020, the SRA plan to do three more online courses on the topic of systemic sclerosis, rheumatoid arthritis and fibromyalgia. Online courses will not replace physical meetings, but offer a good alternative in the field of patient education. Disclosure of Interests: None declared
Thrombotic and Bleeding Outcomes of Pregnancy in Women With a Fontan Circulation
Authors: Andrea K Girnius, Dominica Zentner, Magalie Ladouceur, Mary Canobbio, Jamil Aboulhosn, Anne Marie Valente, Wendy Book, Elisa Bradley, Jasmine Grewal, Sara Partington, Morgan Venuti, Yonatan Buber, Barbara J Mulder, Berto Bouma, Nicholas Ollberding, Amita Mirani, Michelle Faust, Gruschen Veldtman
Journal: Circulation (2018)
Solitary pulmonary nodule imaging approaches and the role of optical fibre-based technologies
Authors: Susan Fernandes, Gareth Williams, Elvira Williams, Katjana Ehrlich, James Stone, Neil Finlayson, Mark Bradley, Robert R. Thomson, Ahsan R. Akram, Kevin Dhaliwal
Journal: European Respiratory Journal (2020)

Solitary pulmonary nodules (SPNs) are a clinical challenge, given there is no single clinical sign or radiological feature that definitively identifies a benign from a malignant SPN. The early detection of lung cancer has a huge impact on survival outcome. Consequently, there is great interest in the prompt diagnosis, and treatment of malignant SPNs. Current diagnostic pathways involve endobronchial/transthoracic tissue biopsies or radiological surveillance, which can be associated with suboptimal diagnostic yield, healthcare costs and patient anxiety. Cutting-edge technologies are needed to disrupt and improve, existing care pathways. Optical fibre-based techniques, which can be delivered via the working channel of a bronchoscope or via transthoracic needle, may deliver advanced diagnostic capabilities in patients with SPNs. Optical endomicroscopy, an autofluorescence-based imaging technique, demonstrates abnormal alveolar structure in SPNs in vivo . Alternative optical fingerprinting approaches, such as time-resolved fluorescence spectroscopy and fluorescence-lifetime imaging microscopy, have shown promise in discriminating lung cancer from surrounding healthy tissue. Whilst fibre-based Raman spectroscopy has enabled real-time characterisation of SPNs in vivo . Fibre-based technologies have the potential to enable in situ characterisation and real-time microscopic imaging of SPNs, which could aid immediate treatment decisions in patients with SPNs. This review discusses advances in current imaging modalities for evaluating SPNs, including computed tomography (CT) and positron emission tomography-CT. It explores the emergence of optical fibre-based technologies, and discusses their potential role in patients with SPNs and suspected lung cancer.
First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia
Authors: Olga Salamero, Pau Montesinos, Christophe Willekens, José Antonio Pérez-Simón, Arnaud Pigneux, Christian Récher, Rakesh Popat, Cecilia Carpio, César Molinero, Cristina Mascaró, Joaquim Vila, M. Isabel Arévalo, Tamara Maes, Carlos Buesa, Francesc Bosch, Tim C. P. Somervaille
Journal: Journal of Clinical Oncology (2020)

Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML).
FRI0233 Low back pain from “the joint and bone decade perspective”
Authors: RM Baddoura
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Low back pain (LBP) is a common health problem yet it still raises controversies about rationales for appropriate and cost effective management. LBP burden is reported to be higher in developing compared to developed countries in the absence of an adequate work leave compensation system. <h3>Objectives</h3> Estimate LBP prevalence, assess risk factors and evaluate the impact in term of work leave. <h3>Methods</h3> Three observational studies were conducted between 1997 and 1999. The first was population based on a random sample of 1035 adults asked to report on LBP over the past week. The second was conducted among nursing profession looking at LBP occurrence fever the past month in a sample of 633 subjects. The third was in an occupational setting addressing past history of LBP and included 201 individuals. <h3>Results</h3> Among adults, prevalence of LBP at any given day was 13.1 (CI:11.0–14.2). Mean age is 41.8(SD:16.3) and M/F ratio is 0.7. A history of trauma was recorded by 13.2% (7.5–18.9) of LBP cases. Among nurses, 54% had experienced LBP over the past month. Handling patients was related to LBP by 60% (CI:55–65) of nurses. In an occupational setting, heavy workload is associated with higher frequency of LBP. 30.7% of those seeking medical care were offered a sick leave. <h3>Conclusion</h3> At any given day,13.1% (CI: 11.0–14.2) of adult population would report acute LBP. Workload is related to LBP occurrence. Sick leave is commonly prescribed for LBP.
RNA splicing alteration in the response to platinum chemotherapy in ovarian cancer: A possible biomarker and therapeutic target
Authors: Ilenia Pellarin, Barbara Belletti, Gustavo Baldassarre
Journal: Medicinal Research Reviews (2020)

Abstract Since its discovery, alternative splicing has been recognized as a powerful way for a cell to amplify the genetic information and for a living organism to adapt, evolve, and survive. We now know that a very high number of genes are regulated by alternative splicing and that alterations of splicing have been observed in different types of human diseases, including cancer. Here, we review the accumulating knowledge that links the regulation of alternative splicing to the response to chemotherapy, focusing our attention on ovarian cancer and platinum‐based treatments. Moreover, we discuss how expanding information could be exploited to identify new possible biomarkers of platinum response, to better select patients, and/or to design new therapies able to overcome platinum resistance.
Colloid Transfusion, Natural Anticoagulant Depletion, and Symmetric Peripheral Gangrene
Authors: Theodore E Warkentin, Shuoyan Ning, Wendy Lim
Journal: New England Journal of Medicine (2020)

Gangrene from Anticoagulant Dilution The use of colloid for volume expansion in two patients with hemodynamic shock led to dilution of antithrombin, free protein S, and protein C and the subsequent...
Re: Alfonso Gómez de Liaño Lista, Nick van Dijk, Guillermo de Velasco Oria de Rueda, et al. Clinical Outcome After Progressing to Frontline and Second-line Anti–PD-1/PD-L1 in Advanced Urothelial Cancer. Eur Urol 2020;77:269–76
Authors: Alessia Cimadamore, Liang Cheng, Marina Scarpelli, Antonio Lopez-Beltran, Veronica Mollica, Rodolfo Montironi, Francesco Massari
Journal: European Urology (2020)
Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer’s disease
Authors: Lutgarde Serneels, Dries T’Syen, Laura Perez-Benito, Tom Theys, Matthew G. Holt, Bart De Strooper
Journal: Molecular Neurodegeneration (2020)

Abstract Background Three amino acid differences between rodent and human APP affect medically important features, including β-secretase cleavage of APP and Aβ peptide aggregation (De Strooper et al., EMBO J 14:4932-38, 1995; Ueno et al., Biochemistry 53:7523-30, 2014; Bush, 2003, Trends Neurosci 26:207–14). Most rodent models for Alzheimer’s disease (AD) are, therefore, based on the human APP sequence, expressed from artificial mini-genes randomly inserted in the rodent genome. While these models mimic rather well various biochemical aspects of the disease, such as Aβ-aggregation, they are also prone to overexpression artifacts and to complex phenotypical alterations, due to genes affected in or close to the insertion site(s) of the mini-genes (Sasaguri et al., EMBO J 36:2473-87, 2017; Goodwin et al., Genome Res 29:494-505, 2019). Knock-in strategies which introduce clinical mutants in a humanized endogenous rodent APP sequence (Saito et al., Nat Neurosci 17:661-3, 2014) represent useful improvements, but need to be compared with appropriate humanized wildtype (WT) mice. Methods Computational modelling of the human β-CTF bound to BACE1 was used to study the differential processing of rodent and human APP. We humanized the three pivotal residues we identified G676R, F681Y and R684H (labeled according to the human APP770 isoform) in the mouse and rat genomes using a CRISPR-Cas9 approach. These new models, termed mouse and rat App hu/hu , express APP from the endogenous promotor. We also introduced the early-onset familial Alzheimer’s disease (FAD) mutation M139T into the endogenous Rat Psen 1 gene. Results We show that introducing these three amino acid substitutions into the rodent sequence lowers the affinity of the APP substrate for BACE1 cleavage. The effect on β-secretase processing was confirmed as both humanized rodent models produce three times more (human) Aβ compared to the original WT strain. These models represent suitable controls, or starting points, for studying the effect of transgenes or knock-in mutations on APP processing (Saito et al., Nat Neurosci 17:661-3, 2014). We introduced the early-onset familial Alzheimer’s disease (FAD) mutation M139T into the endogenous Rat Psen 1 gene and provide an initial characterization of Aβ processing in this novel rat AD model. Conclusion The different humanized APP models (rat and mouse) expressing human Aβ and PSEN1 M139T are valuable controls to study APP processing in vivo allowing the use of a human Aβ ELISA which is more sensitive than the equivalent system for rodents. These animals will be made available to the research community.
SAT0217 Experimental arthritis in lewis rats induced by repeated injections of yersinia enterocolitica o:8 in different doses
Authors: E Bernotiene, R Bradunaite, L Leonaviciene, V Astrauskas, A Venalis, D Vaitkiene, A Valickas
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The incidence of experimental arthritis induced by Yersinia enterocolitica O:8 (YeO8) in animals of different species and strains varies greatly, depending on the the susceptibility of the strain and the dose.<sup>1,2</sup> The susceptibility is easily affected by many factors. To increase the incidence of arthritis we used repeated injections of YeO8. <h3>Objectives</h3> To evaluate the ability to cause reactive arthritis (ReA) in Lewis rats by repeated i.v. injections of various doses of live YeO8. <h3>Methods</h3> 3 experiments were performed on 30 male Lewis rats. Bacterial culture of virulent YeO8 for each experiment were prepared according to usual methods and injected into the tail veins of rats in doses 4 × 10 7 ? 6 × 10 9. The limbs of animals were examined 5 times/week, the severity of joint swelling was assessed by score from 0 to 4. At the end of experiment rats were decapitated and pathomorphological examination of joints and YeO8 detection in the internal organs were performed. <h3>Results</h3> In the first experiment 10 male rats were i.v. injected with YeO8 in a dose 4 × 10 7, but no signs of ReA were observed. Injection of YeO8 was repeated two weeks later in a dose 8 × 10 8, but it also showed no joint swelling. Third inoculation (6 × 10 9) of YeO8 induced arthritis in 40% of rats on day 10 after the last injection (swelling scores 1.5–3). Joint swelling decreased to the level of 1 score in 3 weeks. In the 2nd experiment, injection of YeO8 in a dose of 1 × 10 8 induced joint swelling in 20% of rats. Repeared injection of higher dose (3 × 10 8) two weeks later induced ReA in 40% of animals (swelling scores 1.5–4), but 3 weeks after the last injection it was observed only in 20% of rats (swelling score 2). In the 3rd experiment high dose of YeO8 (1 × 10 9) was used and it caused the lethality of 50% of rats. One week after Ye inoculation joint swelling (score 2) developed in 20% of animals. All arthritides were confirmed by histology. <h3>Conclusion</h3> The incidence of arthritis varied by using different bacterial doses. Although i.v. injection of YeO8 in lower doses showed no signs of joint swelling, repeated injections were able to cause ReA, but the doses of bacteria were extremely high. The use of high doses of YeO8 for previously non-infected animals, showed high lethality, which didn't correlate with a high incidence of arthritis. <h3>References</h3> Gripenberg-Lerche C, Toivanen P. Variability in the induction of the experimental arthritis: Yersinia associated arthritis in Lewis rats. Scand J Rheumatol. 1994;23:124–7 Di Genaro MS, Escudero ME, Muñoz E, <i>et al</i>. Arthritogenicity of Yersinia enterocolitica O:8 in hamsters: analysis of the immune response. Folia Microbiol (Praha) 1998;43(6):690–6
Illegal Online Opioids Are Targeted
Authors: Mary Chris Jaklevic
Journal: JAMA (2020)

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