Miracle-dz/UniFAR-FTUs huggingface dataset:
Mepolizumab as the first targeted treatment for eosinophilic granulomatosis with polyangiitis: a review of current evidence and potential place in therapy

: Mepolizumab is an anti-interleukin-5 (IL-5) humanized monoclonal antibody that binds to free IL-5. It induces bone marrow eosinophil maturation arrest and decreases eosinophil progenitors and subsequent maturation in the blood and bronchial mucosa. Its use has been extensively studied in severe eosinophilic asthma at a dose of 100 mg subcutaneously (SC) every 4 weeks and, more recently, in other hypereosinophilic syndromes. Eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophilic vasculitis that may involve multiple organs. Characteristic clinical manifestations are asthma, sinusitis, transient pulmonary infiltrates and neuropathy. Among the numerous pathways involved in the pathogenesis of EGPA, the Th-2 phenotype has a main role, as suggested by the prominence of the asthmatic component, in triggering the release of key cytokines for the activation, maturation and survival of eosinophils. In particular, IL-5 is highly increased in active EGPA and its inhibition can represent a potential therapeutic target. In this scenario, mepolizumab may play a therapeutic role. After some positive preliminary observations on the use of mepolizumab in small case series of EGPA patients with refractory or relapsing disease despite standard of care treatment, a randomized controlled trial was published in 2017. Mepolizumab at a dose of 300 mg administered by SC injection every 4 weeks proved effective in prolonging the period of remission of the disease, allowing for reduced steroid use. The positive results of this study, which met both of the primary end-points, led to the approval in the USA of mepolizumab in adult patients with EGPA by the Food and Drug Administration in 2017. Therefore, mepolizumab can be officially considered as an add-on therapy with steroid-sparing effect in cases of relapsing or refractory EGPA. However, the most appropriate dose and duration of therapy still need to be determined. Future studies on larger multinational populations with prolonged follow-up are warranted.
INVITED EDITORIAL COMMENT

1. Mark Kritzman 1. is the CEO of Windham Capital Management in Boston, MA, and a senior lecturer at MIT Sloan School of Management in Cambridge, MA . (kritzman{at}mit.edu) As is true with most scientific fields, the state of research in finance ebbs and flows. Although some may argue this
Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub

Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation. TLR4/MD2 activation leads only to formation of TLR4/MD2 heterotetramers, but not oligomers, suggesting a stoichiometric mismatch between activated receptors and MyDDosomes. The strength of TLR4 signalling depends not only on the number and size of MyDDosomes formed but also how quickly these structures assemble. Activated TLR4, therefore, acts transiently nucleating assembly of MyDDosomes, a process that is uncoupled from receptor activation. These data explain how the oncogenic mutation of MyD88 (L265P) assembles MyDDosomes in the absence of receptor activation to cause constitutive activation of pro-survival NF-κB signalling.
A First-in-Human Dose Finding Study of Camrelizumab in Patients with Advanced or Metastatic Cancer in Australia

Purpose: Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety pro ﬁ les for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population. Methods: Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks. Results: Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity pro ﬁ le of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK pro ﬁ le showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3 – 28.9). Conclusion: Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia.
Cost Effective, Reliable and Secure Workflow Deployment over Federated Clouds

The significant growth in cloud computing has led to increasing number of cloud providers, each offering their service under different conditions – one might be more secure whilst another might be less expensive or more reliable. At the same time user applications have become more and more complex. Often, they consist of a diverse collection of software components, and need to handle variable workloads, which poses different requirements on the infrastructure. Therefore, many organisations are considering using a combination of different clouds to satisfy these needs. It raises, however, a non-trivial issue of how to select the best combination of clouds to meet the application requirements. This paper presents a novel algorithm to deploy workflow applications on federated clouds. First, we introduce an entropy-based method to quantify the most reliable workflow deployments. Second, we apply an extension of the Bell-LaPadula Multi-Level security model to address application security requirements. Finally, we optimise deployment in terms of its entropy and also its monetary cost, taking into account the cost of computing power, data storage and inter-cloud communication. We implemented our new approach and compared it against two existing scheduling algorithms: Extended Dynamic Constraint Algorithm (EDCA) and Extended Biobjective dynamic level scheduling (EBDLS). We show that our algorithm can find deployments that are of equivalent reliability but are less expensive and meet security requirements. We have validated our solution through a set of realistic scientific workflows, using well-known cloud simulation tools (WorkflowSim and DynamicCloudSim) and a realistic cloud based data analysis system (e-Science Central).
Edinburgh Research Explorer Efficacy and safety of single 40 mg/kg oral praziquantel in the treatment of schistosomiasis in preschool-age versus school-age children

Background Better knowledge of the efficacy and safety of single-dose 40 mg/kg oral praziquantel in pre-school-age children is required, should preventive chemotherapy programs for schistosomiasis be expanded to include this age group. We analyzed individual participant-level data from 16 studies (13 single-arm or cohort studies and three randomized trials), amounting to 683 preschool-age children (aged < 6 years) and 2,010 school-age children (aged 6–14 years). Children had a documented Schistosoma mansoni or S . haematobium infection, were treated with single 40 mg/kg oral praziquantel, and assessed between 21 and 60 days post-treatment. Efficacy was expressed as
Familial erythrocytosis: molecular links to red blood cell control

Familial or hereditary erythrocytosis is a rare disorder of red cell production that can be inherited in either an autosomal dominant or recessive fashion. In this perspective article, Drs. Percy and Lee illustrate how identification of molecular lesions as the basis of erythrocytosis has provided a compelling correlation with, and indeed, physiological validation of proteins implicated in the pathway that senses oxygen and signals to erythropoiesis. Very interestingly, they show that all of the major elements in the oxygen sensing pathway have now been accounted for in the current OMIM classification of familial erythrocytoses. See related articles on pages 1068 and 1072.
association between respiratory impedance measured by forced oscillation technique and exacerbations in patients with COPD

Background: It is well known that increased airflow limitation as measured by spirometry is associated with the risk of exacerbation in patients with COPD. The forced oscillation technique (FOT) is a noninvasive method used to assess respiratory impedance (resistance and reactance) with minimal patient cooperation required. The clinical utility of the FOT in assessing the risk of exacerbations of COPD is yet to be determined. We examined the relationship between respiratory impedance as measured by FOT and exacerbations in patients with COPD. Materials and methods: Among 310 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stages I–IV) who presented at the outpatient clinic of the Showa University Hospital from September 2014 through January 2015, 119 were collected and assigned into 2 groups according to their history of exacerbation: exacerbators and nonexacerbators. Respiratory resistance components and respiratory reactance components, as measured by FOT, were compared between the two groups. Results: Exacerbators were significantly older and had a higher white blood cell count than nonexacerbators. Resistance at 20 Hz, reactance at 5 Hz (X5), resonant frequency (Fres), and area of low reactance (ALX) differed significantly between the two groups. In addition, among patients with stage II COPD, there were significant differences in X5, Fres, and ALX between the two groups despite no significant differences in respiratory function as assessed by spirometry. Finally, receiver operating characteristic curve analysis revealed that the reactance components rather than the resistance components were associated with the risk of exacerbation. Conclusion: There were significant differences in respiratory impedance between exacerbators and nonexacerbators in patients with moderate COPD. FOT is a promising tool for assessing future exacerbations in patients with COPD.
Wavelet-based analysis of ground deformation coupling satellite acquisitions (Sentinel-1, SMOS) and data from shallow and deep wells in Southwestern France

Acquisitions of the Sentinel-1 satellite are processed and comprehensively analyzed to investigate the ground displacement during a 3-year period above a gas storage site in Southwestern France. Despite quite low vertical displacements (between 4 and 8 mm) compared to the noise level, the local displacements reflects the variations due to charge and discharge during summer and winter periods, respectively. A simplified mechanical model can explain these displacements at both storage sites (Lussagnet and Izaute). However, these lowmagnitude ground movements may be also controlled by natural factors, like the temperature or the surface soil moisture (SSM). Using an additive decomposition, we show first that the temperature is only a second order triggering factor compared to the reservoir pressure. Using a wavelet-based analysis, we show there is an uplift in the Lussagnet zone that contrasts both in phase and period with the seasonal deformation due to the gas exploitation and that is linked to the SSM measured by the SMOS satellite. This other displacement is consistent with the water infiltration in the unsaturated zone followed by the expansion of a clay layer. This work provides therefore new insights on the ground deformation using a three-year integrated monitoring of a gas storage site.
COMMENTARY Glucocorticoid-Remediable Aldosteronism

described a new hypokalemic hypertensive syndrome in a father and son in 1966. Thirty years later, the genetic basis of this disorder is completely understood. In that description, aldosterone secretion was solely regulated by ACTH, and the syndrome was reversed by exogenous glucocorticoid therapy. A similar syndrome was subsequently reported by New and Peterson (2) 1 yr later. Glucocorticoid-remediable aldosteronism (GRA), al-ternatively called dexamethasone-suppressible hyperaldosteronism (DSH) or familial hyperaldosteronism type I, a mineralocorticoid-excess state characterized by low PRA, is now a well-established subset of primary aldosteronism. The early literature described patients with GRA as fitting the description of a mineralocorticoid-excess state, in-cluding hypertension, hyporeninemia, and “spontaneous” hypokalemia. However, recent evidence suggests that the full expression of the classic mineralocorticoid such only a
Translating SOD 1 gene silencing towards the clinic : A highly efficacious , off-target free and biomarker-supported strategy for familial ALS

eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/
Aurora A kinase phosphorylates Hec1 to regulate metaphase kinetochore–microtubule dynamics

regarded as the “master regulator” of kinetochore–microtubule attachment, other mitotic kinases likely contribute to Hec1 phosphorylation. In this study, we demonstrate that Aurora A kinase regulates kinetochore–microtubule dynamics of metaphase chromosomes, and we identify Hec1 S69, a previously uncharacterized phosphorylation target site in the Hec1 tail, as a critical Aurora A substrate for this regulation. Additionally, we demonstrate that Aurora A kinase associates with inner centromere protein (INC ENP) during mitosis and that INC ENP is competent to drive accumulation of the kinase to the centromere region of mitotic chromosomes. These findings reveal that both Aurora A and B contribute to kinetochore–microtubule attachment dynamics, and they uncover an unexpected role for Aurora A in late mitosis.
Tolerability in the elderly population of high-dose alpha lipoic acid: a potential antioxidant therapy for the eye

Purpose: Alpha lipoic acid (ALA) is an antioxidant and iron-chelating supplement that has potential benefits for geographic atrophy in dry age-related macular degeneration as well as other eye diseases. The purpose of this study was to determine the tolerability of ALA in the elderly population. Patients and methods: Fifteen subjects, age $ 65 years, took sequential ALA doses of 600, 800, and 1,200 mg. Each dose was taken once daily with a meal for 5 days. After each dose was taken by the subjects for 5 days, the subjects were contacted by phone, a review of systems was performed, and they were asked if they thought they could tolerate taking that dose of ALA for an extended period of time. Results: The 600 mg dose was well tolerated. At the 800 mg dose, one subject had an intolerable flushing sensation. At the 1,200 mg dose, two subjects had intolerable upper gastrointestinal side effects and one subject had an intolerable flushing sensation. Subjects taking gastrointestinal prophylaxis medications had no upper gastrointestinal side effects. Conclusion: High-dose ALA is not completely tolerated by the elderly. These preliminary data suggest that gastrointestinal prophylaxis may improve tolerability. (ClinicalTrials.gov, NCT02613572).
Routes and Roots: Navigating Caribbean and Pacific Island Literatures

"Routes and Roots" is the first comparative study of Caribbean and Pacific Island literatures and the first work to bring indigenous and diaspora literary studies together in a sustained dialogue. Taking the "tidalectic" between land and sea as a dynamic starting point, Elizabeth DeLoughrey foregrounds geography and history in her exploration of how island writers inscribe the complex relation between routes and roots. The first section looks at the sea as history in literatures of the Atlantic middle passage and Pacific Island voyaging, theorizing the transoceanic imaginary. The second section turns to the land to examine indigenous epistemologies in nation-building literatures. Both sections are particularly attentive to the ways in which the metaphors of routes and roots are gendered, exploring how masculine travelers are naturalized through their voyages across feminized lands and seas. This methodology of charting transoceanic migration and landfall helps elucidate how theories and people travel, positioning island cultures in the world historical process. In fact, DeLoughrey demonstrates how these tropical island cultures helped constitute the very metropoles that deemed them peripheral to modernity. Fresh in its ideas, original in its approach, "Routes and Roots" engages broadly with history, anthropology, and feminist, postcolonial, Caribbean, and Pacific literary and cultural studies. It productively traverses diaspora and indigenous studies in a way that will facilitate broader discussion between these often segregated disciplines.
IL-15 Mediates Mitochondrial Activity through a PPAR ?-Dependent-PPAR ?-Independent Mechanism in Skeletal Muscle Cells

Follow this and additional works at: http://digitalcommons.chapman. edu/health_sciences_articles Part of the Biomechanics Commons, Cell Biology Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Anatomy Commons, Medical Cell Biology Commons, Medical Genetics Commons, Musculoskeletal, Neural, and Ocular Physiology Commons, Musculoskeletal System Commons, Other Kinesiology Commons, Other Medical Sciences Commons, Other Medicine and Health Sciences Commons, and the Physiological Processes Commons
Epigenetic epistatic interactions constrain the evolution of gene expression

1 EMBL-CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG) and University Pompeu Fabra (UPF), Barcelona, Spain and 2 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain * Corresponding author. EMBL-CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG) and University Pompeu Fabra (UPF), Dr Aiguader 88, Barcelona 08003, Spain. Tel. : þ 34933160194; Fax: þ 34933160199; E-mail: ben.lehner@crg.eu
Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of fimasartan, amlodipine, and rosuvastatin using partial replicated design in healthy adult subjects

Objective: The aim of this study was to compare the pharmacokinetics (PK) and safety profiles of a fixed-dose combination (FDC) formulation of fimasartan, amlodipine, and rosuvastatin with the co-administration of the two products by using a replicated crossover study design in healthy male subjects. Materials and methods: This was an open-label, randomized, three-sequence, three-period replicated crossover study in healthy male subjects. The replicated crossover design was done because of high coefficient of variation of PK parameter for fimasartan, that is, . 30%. With a 14 days washout period, an FDC tablet containing 60 mg fimasartan, 10 mg amlodipine, and 20 mg rosuvastatin was administered only once, and separate formulations of fimasartan/ amlodipine 60 mg/10 mg FDC tablet and 20 mg rosuvastatin tablet administered twice. Blood samples were collected up to 72 hours following drug administration. The plasma concentrations of fimasartan, amlodipine, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was assessed by evaluating vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results: The geometric mean ratios and 90% confidence intervals (CIs) for the maximum plasma concentration (C max ) and area under the curve from time zero to the last measurable sampling time (AUC t ) were 1.0776 (0.9201–1.2622) and 0.9978 (0.9538–1.0439) for fimasartan, 1.0038 (0.9782–1.0301) and 1.0055 (0.9828–1.0288) for amlodipine, and 1.0006 (0.9290–1.0776) and 0.9986 (0.9532–1.0461) for rosuvastatin, respectively. A total of 22 adverse events (AEs) were reported by 60 subjects; there were no significant differences in the incidence of AEs between the two groups. Conclusion: The 90% CI of the C max of fimasartan was within the widened acceptance limit, ln(0.6984)–ln(1.4319). The 90% CIs of the other PK parameters for drugs were between ln(0.8) and ln(1.25). These results suggest that the FDC formulation is pharmacokinetically bioequiva-lent and has a similar safety profile, to the co-administration of its three constituent drugs.
long noncoding rna XIST promotes proliferation and invasion by targeting mir-141 in papillary thyroid carcinoma

Background: The long noncoding RNA X-inactive specific transcript ( XIST ) was reported to play vital roles in tumor progression. In the present study, we determined the regulatory function of XIST in papillary thyroid carcinoma (PTC). Materials and methods: XIST expression was determined in PTC tissues and cell lines by quantitative real-time polymerase chain reaction (PCR) (qRT-PCR). Cellular proliferation, migration, and invasion were measured using the Cell Counting Kit-8 (CCK-8) assay, wound-healing assay, and transwell invasion assay, respectively. Western blotting was used to determine protein expression. The downstream target miRNAs for XIST were identified by luciferase reporter assay and qRT-PCR. Results: Relative expression of XIST was upregulated in PTC tissues and cell lines. High XIST expression was positively correlated with TNM stage and lymph node metastasis. Function assay demonstrated that knockdown of XIST significantly decreased cell proliferation, migration, and invasion in PTC cells. Moreover, we showed that the effects of XIST on PTC cell progression were mediated by miR-141. Conclusion: Our results demonstrated that XIST functioned as an oncogene in PTC progression by regulating miR-141, suggesting that XIST might be a promising therapeutic target for PTC treatment.
Human Coronavirus NL63 Molecular Epidemiology and Evolutionary Patterns in Rural Coastal Kenya

Kiyuka, PK; Agoti, CN; Munywoki, PK; Njeru, R; Bett, A; Otieno, JR; Otieno, GP; Kamau, E; Clark, TG; van der Hoek, L; +3 more. Kellam, P; Nokes, DJ; Cotten, M; (2018) Human Coronavirus NL63 Molecular Epidemiology and Evolutionary Patterns in Rural Coastal Kenya. The Journal of infectious diseases, 217 (11). 1728-1739-. ISSN 0022-1899 DOI: https://doi.org/10.1093/infdis/jiy098 Downloaded from: http://researchonline.lshtm. ac.uk/id/eprint/4647711/ DOI: https://doi.org/10.1093/infdis/jiy098