tbuckley/cabot-search huggingface dataset:
Abstract B14: Variations in the proteasome activity are associated with human papilloma virus (HPV) gene expression and patient survival in HPV+ oropharyngeal tumors
Authors: Frederico O. Gleber-Netto, Meng Gao, Li Shen, Jing Wang, Jeffrey N. Myers, Faye M. Johnson, Curtis R. Pickering
Journal: Clinical Cancer Research (2020)

Abstract Variations in the molecular function of human papillomavirus (HPV) have been associated with outcome in HPV-positive oropharyngeal squamous cell carcinomas (HPV+OPSCC). HPV-mediated carcinogenesis is initiated by the E6 and E7 proteins, which promotes the inhibition of the p53 and pRb proteins by targeting them for degradation by the proteasome system. Considering that the proteasome system is an important mediator of HPV molecular activity, we hypothesize that its activity may be an important modifier of HPV+OPSCC phenotypes. To test this hypothesis, we analyzed the in silico expression of proteasome genes among HPV+ oropharyngeal squamous cell carcinoma cases from The Cancer Genome Atlas (TCGA) and explored the proteasome activity of HPV+ squamous cell carcinoma cell lines in vitro. Higher expression of proteasome genes was significantly associated with worse 5-year overall survival (p=0.0003), lower expression levels of E1^E4 gene (p = 0.032), and more HPV integration (p = 0.028). In vitro analysis indicated that proteasome activity was distinct between E1^E4 negative and E1^E4 positive HPV+ cell lines. Interestingly, E1^E4 negative cell lines, which exhibited higher levels of some proteasome genes, were more sensitive to proteasome inhibition than E1^E4 positive cells. These results indicate that proteasome activity may vary significantly among HPV+ OPSCC cases and may represent an important modulator of tumor phenotypes. Expression of proteasome genes and also proteasome activity was highly correlated with expression of HPV genes and may function as a potential predictive biomarker. Finally, proteasome targeting may represent a potential therapeutic alternative for a subgroup of HPV+ OPSCC patients. Citation Format: Frederico O. Gleber-Netto, Meng Gao, Li Shen, Jing Wang, Jeffrey N. Myers, Faye M. Johnson, Curtis R. Pickering. Variations in the proteasome activity are associated with human papilloma virus (HPV) gene expression and patient survival in HPV+ oropharyngeal tumors [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B14.
Real-World Budget Impact of the Adoption of Insulin Glargine Biosimilars in Primary Care in England (2015–2018)
Authors: Ion Agirrezabal, Eduardo Sánchez-Iriso, Kiran Mandar, Juan M. Cabasés
Journal: Diabetes Care (2020)

BACKGROUND Lantus, the reference insulin glargine used for the treatment of diabetes, lost its patent protection in 2014, opening the market to biosimilar competitors. OBJECTIVE First, to analyze the adoption rates of insulin glargine biosimilars in primary care in England and estimate the savings realized and missed, since an insulin glargine biosimilar was first used, and second, to assess potential variations in adoption rates across Clinical Commissioning Groups (CCGs). RESEARCH DESIGN AND METHODS Data sets capturing information on all insulin glargine items prescribed by all general practitioners up to December 2018 were used. Total costs of insulin glargine and uptake rates of biosimilars were calculated. The real-world budget impact was estimated assuming the cost of reference insulin glargine for all items and comparing the total costs in this scenario with the total costs in the real world. The missed savings were estimated assuming the cost of biosimilars for all insulin glargine items. Choropleth maps were generated to assess potential variations in uptake across CCGs. RESULTS Insulin glargine biosimilars generated savings of £900,000 between October 2015 (time of first prescription) and December 2018. The missed savings amounted to £25.6 million in this period, indicating that only 3.42% of the potential savings were achieved. The analyses demonstrated a large level of variation in the uptake of insulin glargine biosimilars across CCGs, with market shares ranging from 0 to 53.3% (December 2018). CONCLUSIONS These results may encourage decision makers in England to promote the use of best-value treatments in primary care and to reevaluate variation across CCGs.
Imported dengue serotype 1 outbreak in a non-endemic region, China, 2017: A molecular and seroepidemiological study
Authors: Ming-Xiao Yao, Shu-Zhi Wu, Guo-Lin Wang, Xue-Jun Wang, Wen-Juan Fan, Wei-Guo Zhang, Lin-Lin Yang, Da-Peng Sun, Jia-Ye Liu, Ju-Long Wu, Wen-Ji Zhai, Zhi-Qiang Wang, Jia-Te Wei, Xiao Jing, Shu-Jun Ding, Xian-Jun Wang, Mai-Juan Ma
Journal: Journal of Infection (2020)
The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design
Authors: Munyaradzi Dimairo, Philip Pallmann, James Wason, Susan Todd, Thomas Jaki, Steven A Julious, Adrian P Mander, Christopher J Weir, Franz Koenig, Marc K Walton, Jon P Nicholl, Elizabeth Coates, Katie Biggs, Toshimitsu Hamasaki, Michael A Proschan, John A Scott, Yuki Ando, Daniel Hind, Douglas G Altman
Journal: BMJ (2020)

Abstract Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised. This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process. The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text. The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits.
SAT0525 EFFICACY AND SAFETY OF MZR FOR IgG4-RELATED DISEASE.
Authors: S. Kawaai, S. Fukui, T. Nakai, G. Kidoguchi, H. Ozawa, Y. Ikeda, A. Koido, Y. Ohara, H. Shimizu, H. Tamaki, K. Yamaguchi, M. Okada
Journal: Annals of the Rheumatic Diseases (2020)

Background: IgG4-Related Disease (IgG4RD) is known to cause multiple organ lesions with infiltration of IgG4-positive plasma cells, and patients often have relapses with tapering treatments despite an initial good response to glucocorticoids therapy. Mizoribine (MZR) is an immunosuppressant working as an inhibitor of purine synthesis, which mechanism of action is similar to mycophenolate mofetil. Data regarding the efficacy and safety of MZR on IgG4RD is limited although some previous case reports 1 showed effectiveness for IgG4RD. Objectives: This study aims to assess the efficacy and safety of MZR in patients with IgG4RD. Methods: We retrospectively reviewed charts of IgG4RD patients who used MZR between January 2004 and December 2019 at Immuno-Rheumatology Center in St. Luke’s International Hospital, Tokyo, Japan. We investigated basic demographics, involved organs, results of blood tests including IgG and IgG4 titer, and medications used including glucocorticoid and other immunosuppressants (IS). We followed IgG4 titer, dose of glucocorticoid, flare of disease and retention of MZR at the beginning, 6 and 12months after starting MZR. We compared changes in PSL (prednisolone) doses and IgG4 titers over time using Friedman test with Bonferroni correction. We also checked adverse events during follow up. Results: Twenty-two patients with IgG4RD who used MZR were included. Median age was 62 years old, and 15 (68.2%) patients are male. Lacrimal and salivary glands, pancreatitis and retroperitoneal fibrosis were common lesions. All patients were initially treated with glucocorticoids. Flare was observed in 5 (22.7 %) patients before initiation of MZR. The number of patients who continued MZR without flare are 19 (86.4 %) at 6 months, and 14 (73.7 %) at 12 months. IgG4 titer significantly declined at 6 and 12 months from baseline although significant consecutive decrease in PSL dose (Figure 1, 2). Liver dysfunctions are commonest adverse events (n=16, 72.7%) but mild (grade1; n=15, 68.2%) and most cases are apparently due to other reasons. Serious infection (SI) occurred in 3 (13.6%) patients in total follow up, however no SI were observed during 1 year after MZR treatment. Conclusion: MZR can be safely used in patients of IgG4RD with high retention rate, and seemed to have steroid-sparing effect. Prospective comparative studies are needed. References: [1]Nanke Y, Kobashigawa T, Yago T, Kamatani N, Kotake S. A case of Mikulicz’s disease, IgG4-related plasmacytic syndrome, successfully treated by corticosteroid and mizoribine, and then by mizoribine alone. Intern Med 49: 1449-1453, 2010. Table 1. Patient characteristics Table 2. Disease and treatment status before and after initiation of MZR Figure 1. Serum IgG4 level changes Figure 2. Changes in the PSL dose over time Disclosure of Interests: None declared
A decade of advances in transposon-insertion sequencing
Authors: Amy K. Cain, Lars Barquist, Andrew L. Goodman, Ian T. Paulsen, Julian Parkhill, Tim van Opijnen
Journal: Nature Reviews Genetics (2020)

It has been 10 years since the introduction of modern transposon-insertion sequencing (TIS) methods, which combine genome-wide transposon mutagenesis with high-throughput sequencing to estimate the fitness contribution or essentiality of each genetic component in a bacterial genome. Four TIS variations were published in 2009: transposon sequencing (Tn-Seq), transposon-directed insertion site sequencing (TraDIS), insertion sequencing (INSeq) and high-throughput insertion tracking by deep sequencing (HITS). TIS has since become an important tool for molecular microbiologists, being one of the few genome-wide techniques that directly links phenotype to genotype and ultimately can assign gene function. In this Review, we discuss the recent applications of TIS to answer overarching biological questions. We explore emerging and multidisciplinary methods that build on TIS, with an eye towards future applications. In this Review, several experts discuss progress in the decade since the development of transposon-based approaches for bacterial genetic screens. They describe how advances in both experimental technologies and analytical strategies are resulting in insights into diverse biological processes.
Response to: ‘COVID-19 in patients with rheumatological diseases treated with Anti-TNF’ by Brito et al and ‘Clinical characteristics and outcomes of patients with COVID-19 and rheumatic disease in China ‘hot spot’ versus in US ‘hot spot’: similarities and differences’ by Zhao et al
Authors: Kristin M D’Silva, Naomi Serling-Boyd, Rachel Wallwork, Tiffany Hsu, Jeffrey A Sparks, Zachary Scott Wallace
Journal: Annals of the Rheumatic Diseases (2020)

Aging is associated with reduced IL-2 production and T cell proliferation. Vitamin E supplementation, in aged animals and humans, increases cell division and IL-2 production by naive T cells. The immune synapse forms at the site of contact between a T cell and an APC and participates in T cell activation. We evaluated whether vitamin E affects the redistribution of signaling proteins to the immune synapse. Purified CD4<sup>+</sup> T cells, from the spleens of young and old mice, were treated with vitamin E before stimulation with a surrogate APC expressing anti-CD3. Using confocal fluorescent microscopy, we observed that CD4<sup>+</sup> T cells from old mice were significantly less likely to recruit signaling proteins to the immune synapse than cells from young mice. Vitamin E increased the percentage of old CD4<sup>+</sup> T cells capable of forming an effective immune synapse. Similar results were found following in vivo supplementation with vitamin E. When compared with memory cells, naive T cells from aged mice were more defective in immune synapse formation and were more responsive to vitamin E supplementation. These data show, for the first time, that vitamin E significantly improves age-related early T cell signaling events in naive CD4<sup>+</sup> T cells.
AB0442 RISK FACTORS ASSOCIATED WITH THROMBOTIC EVENTS IN KOREAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: D. J. Park, S. E. Choi, H. Xu, J. H. Kang, S. S. Lee
Journal: Annals of the Rheumatic Diseases (2020)

Background: Objectives: Up to 30~40% of all patients with systemic lupus erythematosus (SLE) experience thrombosis, presenting as stroke and myocardial infarction, and these thrombotic events cause substantial morbidity and mortality in SLE. We explored the risk factors associated with the occurrence of thrombotic events in SLE patients. Methods: This study enrolled 259 SLE patients (mean age, 34.0 ± 13.7; 239 females) with available clinical data at the time of SLE onset from the lupus cohort at Chonnam National University Hospital. Sociodemographic, clinical, and laboratory data, and history of concomitant diseases were obtained. Thrombotic events were defined as the presence of arterial or venous thrombosis. The multivariable Cox’s model was performed to investigate the possible risk factors for thrombotic events. Results: During a mean follow-up of 103.3 months (SD, 53.4), 27 patients (10.4%) developed thrombotic events: stroke in 15 patients, venous thrombosis in five patients, myocardial infarction in four patients, and angina in three patients. In the multivariable Cox’s regression analysis, hypertension (hazard ratio [HR], 16.946; P=0.031), antiphospholipid syndrome (APS) (HR, 18.348; P=0.001), cumulative prednisolone &gt;5 mg/day (HR, 14.374; P&lt;0.001), use of ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB) (HR, 0.110; P=0.004), and Systemic Lupus International Collaborating Clinics Group (SLICC) damage index (HR, 1.972; P=0.004) were significant predictors of the development of thrombotic events in patients with SLE. Conclusion: Patients with SLE showed significant thrombotic events during the course of their disease. Risk factors associated with thrombotic complications were higher cumulative dose of prednisolone, diagnosis of APS, and higher SLICC damage index. On the other hand, the use of ACEi or ARBs was associated with a reduced risk of thrombotic complications in patients with SLE. Our results support the need for increased monitoring of thrombotic complications in SLE patients. Disclosure of Interests: : None declared
Abstract 11949: Non-invasive Cardiac System (NICaS) Derived Resting and Exercise-augmented Hemodynamic Parameters From Patients With Fontan Circulation
Authors: Pedram Hassan-Tash, Gurkirat Chana, David Kent, C Nolan Turnbull, Meaghan Rempel-Ewharekuko, Nicole Johnston, Brett Hiebert, Robin Ducas, James W Tam, Todd Duhamel, Ashish H Shah
Journal: Circulation (2019)

Introduction: Patients born with anatomical or functional single ventricle are treated with establishment of Fontan circulation, characterized by passive filling of pulmonary circulation. Patients ...
Targeting<i>MET</i>Dysregulation in Cancer
Authors: Gonzalo Recondo, Jianwei Che, Pasi A. Jänne, Mark M. Awad
Journal: Cancer Discovery (2020)

Abstract Aberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET gene amplification, mutation, rearrangement, and overexpression. Improvements in biomarker discovery and testing have more recently enabled the selection of patients with MET-dependent cancers for treatment with potent, specific, and novel MET-targeting therapies. We review the known oncologic processes that activate MET, discuss therapeutic strategies for MET-dependent malignancies, and highlight emerging challenges in acquired drug resistance in these cancers. Significance: Increasing evidence supports the use of MET-targeting therapies in biomarker-selected cancers that harbor molecular alterations in MET. Diverse mechanisms of resistance to MET inhibitors will require the development of novel strategies to delay and overcome drug resistance.
Diagnostic Classification for Human Autism and Obsessive-Compulsive Disorder Based on Machine Learning From a Primate Genetic Model
Authors: Yafeng Zhan, Jianze Wei, Jian Liang, Xiu Xu, Ran He, Trevor W. Robbins, Zheng Wang
Journal: American Journal of Psychiatry (2020)

Psychiatric disorders commonly comprise comorbid symptoms, such as autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD), raising controversies over accurate diagnosis and overlap of their neural underpinnings. The authors used noninvasive neuroimaging in humans and nonhuman primates to identify neural markers associated with DSM-5 diagnoses and quantitative measures of symptom severity.Resting-state functional connectivity data obtained from both wild-type and methyl-CpG binding protein 2 (MECP2) transgenic monkeys were used to construct monkey-derived classifiers for diagnostic classification in four human data sets (ASD: Autism Brain Imaging Data Exchange [ABIDE-I], N=1,112; ABIDE-II, N=1,114; ADHD-200 sample: N=776; OCD local institutional database: N=186). Stepwise linear regression models were applied to examine associations between functional connections of monkey-derived classifiers and dimensional symptom severity of psychiatric disorders.Nine core regions prominently distributed in frontal and temporal cortices were identified in monkeys and used as seeds to construct the monkey-derived classifier that informed diagnostic classification in human autism. This same set of core regions was useful for diagnostic classification in the OCD cohort but not the ADHD cohort. Models based on functional connections of the right ventrolateral prefrontal cortex with the left thalamus and right prefrontal polar cortex predicted communication scores of ASD patients and compulsivity scores of OCD patients, respectively.The identified core regions may serve as a basis for building markers for ASD and OCD diagnoses, as well as measures of symptom severity. These findings may inform future development of machine-learning models for psychiatric disorders and may improve the accuracy and speed of clinical assessments.
AB0796 PSORIATIC ONYCHOPATHY: MORE THAN MEETS THE EYE
Authors: I. Mahmoud, S. Rahmouni, A. Ben Tekaya, S. Bouden, R. Tekaya, O. Saidane, L. Abdelmoula
Journal: Annals of the Rheumatic Diseases (2020)

Background: Psoriatic onychopathy is an independent predictor of the onset of psoriatic arthritis (PsA). Assessment of nail disease is difficult given the limited utility of clinical assessment tools for the nail. Recently, ultrasound (US) proved to be informative in the assessment of nail involvement. Objectives: We aimed to describe morphologic ultrasonographic nail disease changes and to look for correlations between these features and the characteristics of the PsA. Methods: The study included patients who met the CASPAR criteria for PsA. An US scan of patient’s nails was performed in order to study the nail, matrix and skin thickness. Results: We included 33 patients with PsA with a mean age of 51.2±12.5 years. The mean DAPSA was 22.8± 19.7 (remission:9 patients, low activity: 5 patients, moderate activity: 11 patients and high activity: 8 patients). Twenty-nine patients had a personal history of skin psoriasis, present in 64 % of the patients the day of the examination with a mean PASI of 2.76 ±3.9. Eleven patients (33.4%) presented with psoriatic onychopathy (45 fingernails) with a mean mNAPSI of 14.1± 16. The most common patterns of nail involvement were: Oil-drop patches (5 fingernails), pitting (4 fingernails), onycholysis (3 fingernails), crumbling (3 fingernails), subungual hyperkeratosis (2 fingernails), leukonychia (2 fingernails), paronychia (2 fingernails), splinter hemorrhages (1 fingernail). We scanned 330 fingernails. The US study revealed dystrophy in 75 nails (22.7%) of the nails, in 17 patients (51.5%): Undulations or pitting (n=47), followed by disappearance of the anechoic space (n=38) and anechoic ventral nail plate (n=18). The mean thickness of skin, nail plate and nail matrix region were 2.25±0.32 mm, 0.38±0.07 mm and 1.89±0.33, respectively. We found a positive correlation between nail plate thickness and both skin and nail matrix region thickness (r=0.561, p=0.001 and r=0.523, p=0.002). Skin, nail and nail matrix thickness were significantly higher in men and in smokers. Manual workers did not have greater skin, nail plate nor nail matrix thickness. There were no correlations between disease activity evaluated by the ASDAS-CRP, DAS28, PASI, ESR or by CRP and any of the US parameters. In contrast, there was a significant negative correlation between psoriatic disease duration and nail plate thickness (r=-0.372, p=0,036). Conclusion: Ultrasound offers an appropriate alternative for the evaluation of the nail unit. In our study it was able to detect subclinical involvement of the nail in 30 fingernails and in two patients. Disclosure of Interests: None declared