Publications by authors named "Vincent Chow"

280 Publications

Outcomes of 1,098 Patients Following Transcatheter Aortic Valve Implantation: A Statewide Population-Linkage Cohort Study.

Heart Lung Circ 2021 Mar 12. Epub 2021 Mar 12.

Department of Cardiology, Concord Hospital, The University of Sydney, Sydney, NSW, Australia. Electronic address:

Background: The increasing implementation of transcatheter aortic valve implantation (TAVI) in Australia warrants real-world data on the prevalence and outcomes of these patients. The aim of this study is to describe trends in case-volumes of TAVI in New South Wales (NSW), Australia and associated mortality outcomes.

Methods: From the Centre of Health Record Linkage registry, all NSW residents who underwent TAVI between 5 June 2013 and 30 June 2018 were identified. Cause-specific mortality was tracked from the statewide death registry. Temporal trends in case-volumes between 2013 and 2018 were assessed by linear regression. Binary logistic regression was used to compare differences in in-hospital and 30-day mortality, while Cox proportional hazards regression was used to compare mortality beyond 30 days.

Results: Case-volumes increased from 30 in 2013 to 345 by 2017. The cohort comprised 1,098 persons (mean[±SD] age: 83.3±7.7 yrs). Cumulative in-hospital, 180-day and at end-of-study (mean: 1.8±1.2 yrs) all-cause mortality were 1.3% (n=14), 4.9% (n=54) and 20.3% (n=224) respectively. Heart failure (14.3%, n=2), myocardial infarction (14.3%, n=2), and sepsis (14.3%, n=2) were the primary causes of in-hospital death. Post-discharge, sepsis (25.2%, n=53) was the main cause-specific death, while combined cardiovascular deaths accounted for 46% (n=97), mostly from heart failure (n=35). Heart failure, chronic kidney disease, and requirement for ventilation post-TAVI were independent predictors of in-hospital death and at 180 days. TAVI procedure in low-volume public centres was a predictor of mortality at 180 days.

Conclusion: The number of TAVI procedures increased 10-fold between 2013 and 2017 state-wide, with mortality rates comparable to international cohorts at short and medium-term follow-up. Pre-existing comorbidities and site-specific caseloads may be important determinants of outcome, emphasising the importance of appropriate patient selection and treating centre.
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http://dx.doi.org/10.1016/j.hlc.2021.02.007DOI Listing
March 2021

Contact-Free Co-Culture Model for the Study of Innate Immune Cell Activation During Respiratory Virus Infection.

J Vis Exp 2021 02 28(168). Epub 2021 Feb 28.

Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore; NUHS Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore;

The early interactions between the nasal epithelial layer and the innate immune cells during viral infections remains an under-explored area. The significance of innate immunity signaling in viral infections has increased substantially as patients with respiratory infections who exhibit high innate T cell activation show a better disease outcome. Hence, dissecting these early innate immune interactions allows the elucidation of the processes that govern them and may facilitate the development of potential therapeutic targets and strategies for dampening or even preventing early progression of viral infections. This protocol details a versatile model that can be used to study early crosstalk, interactions, and activation of innate immune cells from factors secreted by virally infected airway epithelial cells. Using an H3N2 influenza virus (A/Aichi/2/1968) as the representative virus model, innate cell activation of co-cultured peripheral blood mononuclear cells (PBMCs) has been analyzed using flow cytometry to investigate the subsets of cells that are activated by the soluble factors released from the epithelium in response to the viral infection. The results demonstrate the gating strategy for differentiating the subsets of cells and reveal the clear differences between the activated populations of PBMCs and their crosstalk with the control and infected epithelium. The activated subsets can then be further analyzed to determine their functions as well as molecular changes specific to the cells. Findings from such a crosstalk investigation may uncover factors that are important for the activation of vital innate cell populations, which are beneficial in controlling and suppressing the progression of viral infection. Furthermore, these factors can be universally applied to different viral diseases, especially to newly emerging viruses, to dampen the impact of such viruses when they first circulate in naïve human populations.
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http://dx.doi.org/10.3791/62115DOI Listing
February 2021

Use of nonclinical toxicity studies to support biosimilar antibody development.

Regul Toxicol Pharmacol 2021 Mar 1;122:104912. Epub 2021 Mar 1.

Amgen Inc., One Amgen Drive, Thousand Oaks, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.yrtph.2021.104912DOI Listing
March 2021

Trends in Acute Pulmonary Embolism Admission Rates and Mortality Outcomes in Australia, 2002-2003 to 2017-2018: A Retrospective Cohort Study.

Thromb Haemost 2021 Feb 28. Epub 2021 Feb 28.

Department of Cardiology, Concord Hospital, The University of Sydney, Concord, NSW, Australia.

Background:  Contemporary Australian epidemiological data on acute pulmonary embolism (PE) are lacking.

Objectives:  To determine the admission rates of acute PE in Australia, and to assess the temporal trends in short- and medium-term mortality following acute PE.

Methods:  Retrospective population-linkage study of all New South Wales residents admitted with a primary diagnosis of PE between January 1, 2002 and December 31, 2018 using data from the Centre for Health Record Linkage databases. Main outcome measures included temporal trends in total PE admissions and all-cause mortality at prespecified time points up to 1 year, stratified by gender.

Results:  There were 61,607 total PE admissions between 2002 and 2018 (mean ± standard deviation: 3,624 ± 429 admissions per annum; 50.42 ± 3.70 admissions per 100,000 persons per annum). The mean admission rate per annum was higher for females than for males (54.85 ± 3.65 vs. 44.91 ± 4.34 admissions per 100,000 persons per annum, respectively) and remained relatively stable for both genders throughout the study period. The main study cohort, limited to index PE admission only, comprised 46,382 persons (mean age: 64.6 ± 17.3 years; 44.4% males). The cumulative in-hospital, 30-day, 3-month, and 1-year mortality rates were 3.7, 5.6, 9.6, and 16.8%, respectively. When compared with 2002 as the reference year, there was a significant reduction in in-hospital (odds ratio [OR] = 0.34; 95% confidence interval [CI] = 0.25-0.46), 30-day (OR = 0.58, 95% CI = 0.46-0.73), and 1-year (hazard ratio = 0.74, 95% CI = 0.66-0.84) (all  < 0.001) mortality risk by 2017 after adjusting for age, gender, and relevant confounders. The survival improvements were seen in both genders and were greater for females than for males.

Conclusion:  Mortality following PE has improved with reductions observed in both short- and medium-term follow-ups between 2002 and 2018 with greater reductions in females despite their higher admission rates over time.
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http://dx.doi.org/10.1055/s-0041-1725932DOI Listing
February 2021

Design and Multicenter Clinical Validation of a 3-Dimensionally Printed Nasopharyngeal Swab for SARS-CoV-2 Testing.

JAMA Otolaryngol Head Neck Surg 2021 Feb 18. Epub 2021 Feb 18.

Division of Infectious Diseases, Department of Medicine, National University Hospital, Singapore.

Importance: Three-dimensionally printed nasopharyngeal swabs (3DP swabs) have been used to mitigate swab shortages during the coronavirus disease 2019 (COVID-19) pandemic. Clinical validation for diagnostic accuracy and consistency, as well as patient acceptability, is crucial to evaluate the swab's performance.

Objective: To determine the accuracy and acceptability of the 3DP swab for identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Design, Setting, And Participants: A diagnostic study was conducted from May to July 2020 at 2 tertiary care centers in Singapore with different reference swabs (FLOQSwab [COPAN Diagnostics] or Dacron swab [Deltalab]) and swab processing techniques (wet or dry) to evaluate the performance of the 3DP swab compared with traditional, standard-of-care nasopharyngeal swabs used in health care institutions. The participants were patients with COVID-19 in the first 2 weeks of illness and controls with acute respiratory illness with negative test results for SARS-CoV-2. Paired nasopharyngeal swabs were obtained from the same nostril and tested for SARS-CoV-2 by reverse-transcriptase polymerase chain reaction. The sequence of swabs was randomized based on odd and even participant numbers.

Main Outcomes And Measures: Primary outcome measures were overall agreement (OA), positive percentage agreement (PPA), and negative percentage agreement of the 3DP swab compared with reference swabs. Secondary outcome measures were the correlation of cycle threshold (Ct) values of both swabs.

Results: The mean (SD) age of participants was 45.4 (13.1) years, and most participants were men (87 of 89 [97.8%]), in keeping with the epidemiology of the COVID-19 pandemic in Singapore. A total of 79 patients with COVID-19 and 10 controls were recruited. Among the patients with COVID-19, the overall agreement and PPA of the 3DP swab was 91.1% and 93.5%, respectively, compared with reference swabs. The PPA was 100% for patients with COVID-19 who were tested within the first week of illness. All controls tested negative. The reverse-transcriptase polymerase chain reaction Ct values for the ORF1ab and E-gene targets showed a strong correlation (intraclass correlations coefficient, 0.869-0.920) between the 3DP and reference swab on independent testing at each institution despite differences in sample processing. Discordant results for both gene targets were observed only at high Ct values.

Conclusions And Relevance: In this diagnostic study of 79 patients with COVID-19 and 10 controls, the 3DP swab performed accurately and consistently across health care institutions and could help mitigate strained resources in the escalating COVID-19 pandemic.
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http://dx.doi.org/10.1001/jamaoto.2020.5680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893548PMC
February 2021

Administration of a CXC Chemokine Receptor 2 (CXCR2) Antagonist, SCH527123, Together with Oseltamivir Suppresses NETosis and Protects Mice from Lethal Influenza and Piglets from Swine-Influenza Infection.

Am J Pathol 2021 04 14;191(4):669-685. Epub 2021 Jan 14.

Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma. Electronic address:

Excessive neutrophil influx, their released neutrophil extracellular traps (NETs), and extracellular histones are associated with disease severity in influenza-infected patients. Neutrophil chemokine receptor CXC chemokine receptor 2 (CXCR2) is a critical target for suppressing neutrophilic inflammation. Herein, temporal dynamics of neutrophil activity and NETosis were investigated to determine the optimal timing of treatment with the CXCR2 antagonist, SCH527123 (2-hydroxy-N,N-dimethyl-3-[2-([(R)-1-(5-methyl-furan-2-yl)-propyl]amino)-3,4-dioxo-cyclobut-1-enylamino]-benzamide), and its efficacy together with antiviral agent, oseltamivir, was tested in murine and piglet influenza-pneumonia models. SCH527123 plus oseltamivir markedly improved survival of mice infected with lethal influenza, and diminished lung pathology in swine-influenza-infected piglets. Mechanistically, addition of SCH527123 in the combination treatment attenuated neutrophil influx, NETosis, in both mice and piglets. Furthermore, neutrophils isolated from influenza-infected mice showed greater susceptibility to NETotic death when stimulated with a CXCR2 ligand, IL-8. In addition, CXCR2 stimulation induced nuclear translocation of neutrophil elastase, and enhanced citrullination of histones that triggers chromatin decondensation during NET formation. Studies on temporal dynamics of neutrophils and NETs during influenza thus provide important insights into the optimal timing of CXCR2 antagonist treatment for attenuating neutrophil-mediated lung pathology. These findings reveal that pharmacologic treatment with CXCR2 antagonist together with an antiviral agent could significantly ameliorate morbidity and mortality in virulent and sublethal influenza infections.
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http://dx.doi.org/10.1016/j.ajpath.2020.12.013DOI Listing
April 2021

Clinical Diagnostic Study of a Novel Injection Molded Swab for SARS-Cov-2 Testing.

Infect Dis Ther 2021 Jan 11. Epub 2021 Jan 11.

Division of Infectious Diseases, Department of Medicine, National University Hospital, Singapore, Singapore.

Introduction: The gold standard for COVID-19 diagnosis is currently a real-time reverse transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2. This is most commonly performed on respiratory secretions obtained via a nasopharyngeal swab. Due to supply chain limitations and high demand worldwide because of the COVID-19 pandemic, access to commercial nasopharyngeal swabs has not been assured. 3D printing methods have been used to meet the shortfall. For longer-term considerations, 3D printing may not compare well with injection molding as a production method due to the challenging scalability and greater production costs of 3D printing.

Methods: To secure sufficient nasopharyngeal swab availability for our national healthcare system, we designed a novel injection molded nasopharyngeal swab (the IM2 swab). We performed a clinical diagnostic study comparing the IM2 swab to the Copan FLOQSwab. Forty patients with a known diagnosis of COVID-19 and 10 healthy controls were recruited. Paired nasopharyngeal swabs were obtained from the same nostril of each participant and tested for SARS-CoV-2 by RT-PCR.

Results: When compared to the Copan FLOQswab, results from the IM2 swab displayed excellent overall agreement and positive percent agreement of 96.0% and 94.9%, respectively. There was no significant difference in mean RT-PCR cycle threshold values for the ORF1ab (28.05 vs. 28.03, p = 0.97) and E-gene (29.72 vs. 29.37, p = 0.64) targets, respectively. We did not observe any significant adverse events and there was no significant difference in patient-reported pain.

Conclusion: In summary, the IM2 nasopharyngeal swab is a clinically safe, highly accurate option to commercial nasopharyngeal swabs.
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http://dx.doi.org/10.1007/s40121-020-00391-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799401PMC
January 2021

Host Antiviral Response Suppresses Ciliogenesis and Motile Ciliary Functions in the Nasal Epithelium.

Front Cell Dev Biol 2020 21;8:581340. Epub 2020 Dec 21.

Department of Otolaryngology, Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Background: Respiratory viral infections are one of the main drivers of development and exacerbation for chronic airway inflammatory diseases. Increased viral susceptibility and impaired mucociliary clearance are often associated with chronic airway inflammatory diseases and served as risk factors of exacerbations. However, the links between viral susceptibility, viral clearance, and impaired mucociliary functions are unclear. Therefore, the objective of this study is to provide the insights into the effects of improper clearance of respiratory viruses from the epithelium following infection, and their resulting persistent activation of antiviral response, on mucociliary functions.

Methods: In order to investigate the effects of persistent antiviral responses triggered by viral components from improper clearance on cilia formation and function, we established an air-liquid interface (ALI) culture of human nasal epithelial cells (hNECs) and used Poly(I:C) as a surrogate of viral components to simulate their effects toward re-epithelization and mucociliary functions of the nasal epithelium following damages from a viral infection.

Results: Through previous and current viral infection expression data, we found that respiratory viral infection of hNECs downregulated motile cilia gene expression. We then further tested the effects of antiviral response activation on the differentiation of hNECs using Poly(I:C) stimulation on differentiating human nasal epithelial stem/progenitor cells (hNESPCs). Using this model, we observed reduced ciliated cell differentiation compared to goblet cells, reduced protein and mRNA in ciliogenesis-associated markers, and increased mis-assembly and mis-localization of ciliary protein DNAH5 following treatment with 25 μg/ml Poly(I:C) in differentiating hNECs. Additionally, the cilia length and ciliary beat frequency (CBF) were also decreased, which suggest impairment of ciliary function as well.

Conclusion: Our results suggest that the impairments of ciliogenesis and ciliary function in hNECs may be triggered by specific expression of host antiviral response genes during re-epithelization of the nasal epithelium following viral infection. This event may in turn drive the development and exacerbation of chronic airway inflammatory diseases.
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http://dx.doi.org/10.3389/fcell.2020.581340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779769PMC
December 2020

Effectiveness of a Mobile-Based Influenza-Like Illness Surveillance System (FluMob) Among Health Care Workers: Longitudinal Study.

JMIR Mhealth Uhealth 2020 12 7;8(12):e19712. Epub 2020 Dec 7.

National Centre for Infectious Diseases, Singapore, Singapore.

Background: Existing studies have suggested that internet-based participatory surveillance systems are a valid sentinel for influenza-like illness (ILI) surveillance. However, there is limited scientific knowledge on the effectiveness of mobile-based ILI surveillance systems. Previous studies also adopted a passive surveillance approach and have not fully investigated the effectiveness of the systems and their determinants.

Objective: The aim of this study was to assess the efficiency of a mobile-based surveillance system of ILI, termed FluMob, among health care workers using a targeted surveillance approach. Specifically, this study evaluated the effectiveness of the system for ILI surveillance pertaining to its participation engagement and surveillance power. In addition, we aimed to identify the factors that can moderate the effectiveness of the system.

Methods: The FluMob system was launched in two large hospitals in Singapore from April 2016 to March 2018. A total of 690 clinical and nonclinical hospital staff participated in the study for 18 months and were prompted via app notifications to submit a survey listing 18 acute respiratory symptoms (eg, fever, cough, sore throat) on a weekly basis. There was a period of study disruption due to maintenance of the system and the end of the participation incentive between May and July of 2017.

Results: On average, the individual submission rate was 41.4% (SD 24.3%), with a rate of 51.8% (SD 26.4%) before the study disruption and of 21.5% (SD 30.6%) after the disruption. Multivariable regression analysis showed that the adjusted individual submission rates were higher for participants who were older (<30 years, 31.4% vs 31-40 years, 40.2% [P<.001]; 41-50 years, 46.0% [P<.001]; >50 years, 39.9% [P=.01]), ethnic Chinese (Chinese, 44.4% vs non-Chinese, 34.7%; P<.001), and vaccinated against flu in the past year (vaccinated, 44.6% vs nonvaccinated, 34.4%; P<.001). In addition, the weekly ILI incidence was 1.07% on average. The Pearson correlation coefficient between ILI incidence estimated by FluMob and that reported by Singapore Ministry of Health was 0.04 (P=.75) with all data and was 0.38 (P=.006) including only data collected before the study disruption. Health care workers with higher risks of ILI and influenza such as women, non-Chinese, allied health staff, those who had children in their households, not vaccinated against influenza, and reported allergy demonstrated higher surveillance correlations.

Conclusions: Mobile-based ILI surveillance systems among health care workers can be effective. However, proper operation of the mobile system without major disruptions is vital for the engagement of participants and the persistence of surveillance power. Moreover, the effectiveness of the mobile surveillance system can be moderated by participants' characteristics, which highlights the importance of targeted disease surveillance that can reduce the cost of recruitment and engagement.
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http://dx.doi.org/10.2196/19712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752531PMC
December 2020

Outcomes of 16,436 patients requiring isolated aortic valve surgery: A statewide cohort study.

Int J Cardiol 2021 Mar 10;326:55-61. Epub 2020 Nov 10.

Department of Cardiology, Concord Hospital, The University of Sydney, 1 Hospital Road, Concord 2139, NSW, Australia. Electronic address:

Background: Aortic valve surgery (AVS) is the gold standard treatment for symptomatic aortic valve (AV) disease patients. We report the temporal trends in the incidence of patients requiring isolated AVS in an unselected statewide population and their mortality outcomes over 17-years.

Methods: Patients were identified from the New South Wales, Australia, Admitted-Patient-Data-Collection registry between 1-July-2001 and 31-December-2018. Annual case-volumes and survival outcomes, adjusted for age, sex, referral source, endocarditis, concomitant coronary-artery-bypass-grafting, comorbidities including atrial fibrillation, hypertension and Charlson comorbidity index, were compared across calendar years.

Results: The study cohort comprised 16436 patients who underwent isolated AVS (mean age: 72.2 ± 11.3y; 67.5% males). Annual case-volume increased from 768 to 1048 cases between 2002 and 2017 (r = 0.82; p < 0.0001). Surgical AV replacement (SAVR) with mechanical valves declined from 271 to 104 (r = 0.87; p < 0.0001) between 2002 and 2017. In contrast, bioprosthetic SAVR increased from 342 to 729 cases (r = 0.93; p < 0.0001). The 30-day, 6-month, and 1-year mortality rates improved progressively from 4.39%, 7.72%, and 9.19% in 2002, to 1.89%, 3.49%, and 4.68% by 2017. The adjusted odds ratio for 30-day mortality and hazard ratio for 1-year mortality were 0.33 (95% confidence interval [CI] 0.16-0.69, p < 0.01) and 0.09 (95% CI 0.07-0.12, p < 0.01), respectively. Similar improvements in outcomes were observed after implantation of mechanical or bioprosthetic aortic valves. Heart failure and sepsis were the most common cardiovascular-related and noncardiovascular-related causes death.

Conclusion: The volume of AVS has increased progressively over time and has been associated with increased use of bioprosthetic valves and markedly improved 30-day and 1-year survival.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.010DOI Listing
March 2021

Interleukin-13 Alters Tight Junction Proteins Expression Thereby Compromising Barrier Function and Dampens Rhinovirus Induced Immune Responses in Nasal Epithelium.

Front Cell Dev Biol 2020 25;8:572749. Epub 2020 Sep 25.

Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore.

Tight junctions (TJs) are intercellular structures which are essential for epithelial barrier function and play an important role in antimicrobial defense. Epithelium dysfunction and type-2-skewed inflammation are two main pathological phenomena of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the effect of pro-inflammatory type-2 cytokine IL-13 on TJs in CRSwNP is poorly understood. Nasal biopsies of CRSwNP patients and IL-13-matured human nasal epithelial cells (hNECs) were used to analyze epithelial markers and TJ proteins. Epithelium permeability, transepithelial electrical resistance (TEER), expression of TJs were quantified for IL-13-matured hNECs and that with RV infection. The expression of occludin, claudin-3, and ZO-1 were significantly decreased in CRSwNP biopsies and in hNECs after IL-13 treatment. IL-13 treatment increased epithelium permeability, decreased TEER and altered hNECs composition resulting in lesser ciliated cells and mucus over-secretion. Interestingly, claudin-3 is selectively expressed on ciliated cells. While RV infection induced minimal changes to TJs, the IL-13-matured hNECs has reduced capacity for upregulation of λ and but further increased the expression of upon RV infection. These findings suggested that IL-13-mediated dysfunction of TJs and compromised epithelial barrier. IL-13-induced cilia loss conferred lowered viral replication and impaired antiviral responses of nasal epithelium against RV infection.
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http://dx.doi.org/10.3389/fcell.2020.572749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546404PMC
September 2020

Influenza A Virus Nucleoprotein Activates the JNK Stress-Signaling Pathway for Viral Replication by Sequestering Host Filamin A Protein.

Front Microbiol 2020 25;11:581867. Epub 2020 Sep 25.

School of Science, Monash University Malaysia, Subang Jaya, Malaysia.

Influenza A virus (IAV) poses a major threat to global public health and is known to employ various strategies to usurp the host machinery for survival. Due to its fast-evolving nature, IAVs tend to escape the effect of available drugs and vaccines thus, prompting the development of novel antiviral strategies. High-throughput mass spectrometric screen of host-IAV interacting partners revealed host Filamin A (FLNA), an actin-binding protein involved in regulating multiple signaling pathways, as an interaction partner of IAV nucleoprotein (NP). In this study, we found that the IAV NP interrupts host FLNA-TRAF2 interaction by interacting with FLNA thus, resulting in increased levels of free, displaced TRAF2 molecules available for TRAF2-ASK1 mediated JNK pathway activation, a pathway critical to maintaining efficient viral replication. In addition, siRNA-mediated FLNA silencing was found to promote IAV replication (87% increase) while FLNA-overexpression impaired IAV replication (65% decrease). IAV NP was observed to be a crucial viral factor required to attain FLNA mRNA and protein attenuation post-IAV infection for efficient viral replication. Our results reveal FLNA to be a host factor with antiviral potential hitherto unknown to be involved in the IAV replication cycle thus, opening new possibilities of FLNA-NP interaction as a candidate anti-influenza drug development target.
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http://dx.doi.org/10.3389/fmicb.2020.581867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546217PMC
September 2020

Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia.

Science 2020 12 22;370(6521). Epub 2020 Oct 22.

Institute of Medical Biology, Agency of Science, Technological and Research, 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore.

Immune sensor proteins are critical to the function of the human innate immune system. The full repertoire of cognate triggers for human immune sensors is not fully understood. Here, we report that human NACHT, LRR, and PYD domains-containing protein 1 (NLRP1) is activated by 3C proteases (3Cpros) of enteroviruses, such as human rhinovirus (HRV). 3Cpros directly cleave human NLRP1 at a single site between Glu and Gly This cleavage triggers N-glycine-mediated degradation of the autoinhibitory NLRP1 N-terminal fragment via the cullin complex, which liberates the activating C-terminal fragment. Infection of primary human airway epithelial cells by live human HRV triggers NLRP1-dependent inflammasome activation and interleukin-18 secretion. Our findings establish 3Cpros as a pathogen-derived trigger for the human NLRP1 inflammasome and suggest that NLRP1 may contribute to inflammatory diseases of the airway.
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http://dx.doi.org/10.1126/science.aay2002DOI Listing
December 2020

Increased ABCA1 (ATP-Binding Cassette Transporter A1)-Specific Cholesterol Efflux Capacity in Schizophrenia.

Arterioscler Thromb Vasc Biol 2020 11 10;40(11):2728-2737. Epub 2020 Sep 10.

ANZAC Research institute, Concord Repatriation General Hospital and University of Sydney, Australia (M.K., M.A., V.C., W.J., L.K.).

Objective: Patients with schizophrenia have increased long-term mortality attributable to cardiovascular disease and commonly demonstrate features of mixed dyslipidemia with low HDL-C (high-density lipoprotein cholesterol). The removal of cholesterol from cells by HDL via specific ATP-binding cholesterol transporters is a major functional property of HDL, and its measurement as cholesterol efflux capacity (CEC) can predict cardiovascular risk. Whether HDL function is impaired in patients with schizophrenia is unknown. Approach and Results: We measured basal and ABCA1 (ATP-binding cassette transporter A1)- and ABCG1 (ATP-binding cassette transporter G1)-dependent CEC, comparing patients with schizophrenia with age- and sex-matched healthy controls, and related our findings to nuclear magnetic resonance analysis of lipoprotein subclasses. Total plasma cholesterol and LDL-C (low-density lipoprotein cholesterol) were comparable between healthy controls (n=51) and patients (n=120), but patients with schizophrenia had increased total plasma triglyceride, low HDL-C and apo (apolipoprotein) A-I concentrations. Nuclear magnetic resonance analysis indicated a marked (15-fold) increase in large triglyceride-rich lipoprotein particle concentration, increased small dense LDL particles, and fewer large HDL particles. Despite lower HDL-C concentration, basal CEC was 13.7±1.6% higher, ABCA1-specific efflux was 35.9±1.6% higher, and ABCG1 efflux not different, in patients versus controls. In patients with schizophrenia, ABCA1-specific efflux correlated with the abundance of small 7.8 nm HDL particles but not with serum plasminogen or triglyceride levels.

Conclusions: Patients with schizophrenia have increased concentrations of atherogenic apoB-containing lipoproteins, decreased concentrations of large HDL particles, but enhanced ABCA1-mediated CEC. In this population, preventative strategies should focus on reducing atherogenic lipoproteins rather than increasing CEC.
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http://dx.doi.org/10.1161/ATVBAHA.120.314847DOI Listing
November 2020

Self-monitoring for recurrence of secondary atrial fibrillation following non-cardiac surgery or acute illness: A pilot study.

Int J Cardiol Heart Vasc 2020 Aug 29;29:100566. Epub 2020 Jun 29.

Heart Research Institute, Sydney, Australia.

Background: Atrial fibrillation (AF) secondary to non-cardiac surgery and medical illness is common and, although often transient, is associated with an increased risk of stroke and mortality. This pilot study tested the feasibility of self-monitoring to detect recurrent AF in this setting and the frequency with which it occurred.

Methods: Patients with new secondary AF after non-cardiac surgery or medical illness that reverted to sinus rhythm before discharge were recruited in three tertiary hospitals in Australia. Participants performed self-monitoring for AF recurrence using a Handheld single-lead ECG device 3-4 times/day for 4-weeks.

Results: From 16,454 admissions, 224 (1.4%) secondary AF cases were identified. Of these, 94 were eligible, and 29 agreed to participate in self-monitoring (66% male; median age 67 years). Self-monitoring was feasible and acceptable to participants in this setting. Self-monitoring identified AF recurrence in 10 participants (34%; 95% CI, 18% -54%), with recurrence occurring ≤ 9 days following discharge in 9/10 participants. Only 4 participants (40%) reported associated palpitations with recurrence. Six participants (60%) with recurrence had a CHADS-VA score ≥ 2, suggesting a potential indication for oral anticoagulation.

Conclusions: Approximately 1 in 3 patients with transient secondary AF will have recurrent AF within nine days of discharge. These recurrent episodes are often asymptomatic but can be detected promptly using patient self-monitoring, which was feasible and acceptable. Future research is warranted to further investigate the incidence of secondary AF, the rate of recurrence after discharge and its prognosis, and whether use of oral anticoagulation can reduce stroke in this setting.
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http://dx.doi.org/10.1016/j.ijcha.2020.100566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452573PMC
August 2020

Deep learning method for localization and segmentation of abdominal CT.

Comput Med Imaging Graph 2020 Oct 14;85:101776. Epub 2020 Aug 14.

School of Engineering Science, Simon Fraser University, Canada.

Computed Tomography (CT) imaging is widely used for studying body composition, i.e., the proportion of muscle and fat tissues with applications in areas such as nutrition or chemotherapy dose design. In particular, axial CT slices from the 3rd lumbar (L3) vertebral location are commonly used for body composition analysis. However, selection of the third lumbar vertebral slice and the segmentation of muscle/fat in the slice is a tedious operation if performed manually. The objective of this study is to automatically find the middle axial slice at L3 level from a full or partial body CT scan volume and segment the skeletal muscle (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and intermuscular adipose tissue (IMAT) on that slice. The proposed algorithm includes an L3 axial slice localization network followed by a muscle-fat segmentation network. The localization network is a fully convolutional classifier trained on more than 12,000 images. The segmentation network is a convolutional neural network with an encoder-decoder architecture. Three datasets with CT images taken for patients with different types of cancers are used for training and validation of the networks. The mean slice error of 0.87±2.54 was achieved for L3 slice localization on 1748 CT scan volumes. The performance of five class tissue segmentation network evaluated on two datasets with 1327 and 1202 test samples. The mean Jaccard score of 97% was achieved for SM and VAT tissue segmentation on 1327 images. The mean Jaccard scores of 98% and 83% are corresponding to SAT and IMAT tissue segmentation on the same dataset. The localization and segmentation network performance indicates the potential for fully automated body composition analysis with high accuracy.
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http://dx.doi.org/10.1016/j.compmedimag.2020.101776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803471PMC
October 2020

Monoclonal antibodies for the S2 subunit of spike of SARS-CoV-1 cross-react with the newly-emerged SARS-CoV-2.

Euro Surveill 2020 07;25(28)

Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore.

BackgroundA novel coronavirus, SARS-CoV-2, which emerged at the end of 2019 and causes COVID-19, has resulted in worldwide human infections. While genetically distinct, SARS-CoV-1, the aetiological agent responsible for an outbreak of severe acute respiratory syndrome (SARS) in 2002-2003, utilises the same host cell receptor as SARS-CoV-2 for entry: angiotensin-converting enzyme 2 (ACE2). Parts of the SARS-CoV-1 spike glycoprotein (S protein), which interacts with ACE2, appear conserved in SARS-CoV-2.AimThe cross-reactivity with SARS-CoV-2 of monoclonal antibodies (mAbs) previously generated against the S protein of SARS-CoV-1 was assessed.MethodsThe SARS-CoV-2 S protein sequence was aligned to those of SARS-CoV-1, Middle East respiratory syndrome (MERS) and common-cold coronaviruses. Abilities of mAbs generated against SARS-CoV-1 S protein to bind SARS-CoV-2 or its S protein were tested with SARS-CoV-2 infected cells as well as cells expressing either the full length protein or a fragment of its S2 subunit. Quantitative ELISA was also performed to compare binding of mAbs to recombinant S protein.ResultsAn immunogenic domain in the S2 subunit of SARS-CoV-1 S protein is highly conserved in SARS-CoV-2 but not in MERS and human common-cold coronaviruses. Four murine mAbs raised against this immunogenic fragment could recognise SARS-CoV-2 S protein expressed in mammalian cell lines. In particular, mAb 1A9 was demonstrated to detect S protein in SARS-CoV-2-infected cells and is suitable for use in a sandwich ELISA format.ConclusionThe cross-reactive mAbs may serve as useful tools for SARS-CoV-2 research and for the development of diagnostic assays for COVID-19.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.28.2000291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376845PMC
July 2020

A Randomized, Double-Blind Study Comparing Pharmacokinetics and Pharmacodynamics of Proposed Biosimilar ABP 798 With Rituximab Reference Product in Subjects With Moderate to Severe Rheumatoid Arthritis.

Clin Pharmacol Drug Dev 2020 11 5;9(8):1003-1014. Epub 2020 Jul 5.

Metroplex Clinical Research Center, Dallas, Texas, USA.

ABP 798 is a proposed biosimilar to rituximab reference product (RP), an anti-CD20 monoclonal antibody. Pharmacokinetics (PK), pharmacodynamics (PD), and safety results from the comparative clinical study that evaluated the PK, PD, safety, efficacy, and immunogenicity of ABP 798 versus rituximab RP are presented here. Subjects with moderate to severe rheumatoid arthritis (RA) received 2 doses of ABP 798, United States-sourced RP (rituximab US) or European Union-sourced RP (rituximab EU), each consisting of two 1000-mg infusions 2 weeks apart. For the second dose (week 24), ABP 798- and rituximab EU-treated subjects received the same treatment; rituximab US-treated subjects transitioned to ABP 798. End points included area under the serum concentration-time curve from time 0 extrapolated to infinity and maximum observed serum concentration following the second infusion of the first dose (PK) and percentage of subjects with complete CD19+ cell depletion days 1-33 (PD). Primary analysis established PK similarity between ABP 798 and rituximab RP based on 90% confidence intervals of the adjusted geometric mean ratios being within a prespecified equivalence margin of 0.8 and 1.25. Complete CD19+ B-cell depletion on day 3 among groups confirmed PD similarity. These findings demonstrated PK/PD similarity between ABP 798 and rituximab RP in subjects with moderate to severe RA.
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http://dx.doi.org/10.1002/cpdd.845DOI Listing
November 2020

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19.

Front Pharmacol 2020 5;11:870. Epub 2020 Jun 5.

Department of Microbiology, Immunology and Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States.

There is an urgent need for new therapeutic strategies to contain the spread of the novel coronavirus disease 2019 (COVID-19) and to curtail its most severe complications. Severely ill patients experience pathologic manifestations of acute respiratory distress syndrome (ARDS), and clinical reports demonstrate striking neutrophilia, elevated levels of multiple cytokines, and an exaggerated inflammatory response in fatal COVID-19. Mechanical respirator devices are the most widely applied therapy for ARDS in COVID-19, yet mechanical ventilation achieves strikingly poor survival. Many patients, who recover, experience impaired cognition or physical disability. In this review, we argue the need to develop therapies aimed at inhibiting neutrophil recruitment, activation, degranulation, and neutrophil extracellular trap (NET) release. Moreover, we suggest that currently available pharmacologic approaches should be tested as treatments for ARDS in COVID-19. In our view, targeting host-mediated immunopathology holds promise to alleviate progressive pathologic complications of ARDS and reduce morbidities and mortalities in severely ill patients with COVID-19.
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http://dx.doi.org/10.3389/fphar.2020.00870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291833PMC
June 2020

Production of Neutrophil Extracellular Traps Contributes to the Pathogenesis of tularemia.

Front Immunol 2020 24;11:679. Epub 2020 Apr 24.

College of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma, OK, United States.

() is a highly virulent, intracellular Gram-negative bacterial pathogen. Acute infection by aerosol route causes pneumonic tularemia, characterized by nodular hemorrhagic lesions, neutrophil-predominant influx, necrotic debris, fibrin deposition, and severe alveolitis. suppresses activity of neutrophils by impairing their respiratory burst and phagocytic activity. However, the fate of the massive numbers of neutrophils recruited to the infection site is unclear. Here, we show that infection resulted in prominent induction of neutrophil extracellular traps (NETs) within damaged lungs of mice infected with the live attenuated vaccine strain of (-LVS), as well as in the lungs of domestic cats and rabbits naturally infected with . Further, -LVS infection increased lung myeloperoxidase (MPO) activity, which mediates histone protein degradation during NETosis and anchors chromatin scaffolds in NETs. In addition, infection also induced expression of peptidylarginine deiminase 4, an enzyme that causes citrullination of histones during formation of NETs. The released NETs were found largely attached to the alveolar epithelium, and disrupted the thin alveolar epithelial barrier. Furthermore, infection induced a concentration-dependent release of NETs from neutrophils Pharmacological blocking of MPO reduced -induced NETs release, whereas addition of HO (a substrate of MPO) significantly augmented NETs release, thus indicating a critical role of MPO in induced NETs. Although immunofluorescence and electron microscopy revealed that NETs could efficiently trap bacteria, NETs failed to exert bactericidal effects. Taken together, these findings suggest that NETs exacerbate tissue damage in pulmonary infection, and that targeting NETosis may offer novel therapeutic interventions in alleviating -induced tissue damage.
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http://dx.doi.org/10.3389/fimmu.2020.00679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193117PMC
April 2021

Evaluation of automated computed tomography segmentation to assess body composition and mortality associations in cancer patients.

J Cachexia Sarcopenia Muscle 2020 10 20;11(5):1258-1269. Epub 2020 Apr 20.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Background: Body composition from computed tomography (CT) scans is associated with cancer outcomes including surgical complications, chemotoxicity, and survival. Most studies manually segment CT scans, but Automatic Body composition Analyser using Computed tomography image Segmentation (ABACS) software automatically segments muscle and adipose tissues to speed analysis. Here, we externally evaluate ABACS in an independent dataset.

Methods: Among patients with non-metastatic colorectal (n = 3102) and breast (n = 2888) cancer diagnosed from 2005 to 2013 at Kaiser Permanente, expert raters annotated tissue areas at the third lumbar vertebra (L3). To compare ABACS segmentation results to manual analysis, we quantified the proportion of pixel-level image overlap using Jaccard scores and agreement between methods using intra-class correlation coefficients for continuous tissue areas. We examined performance overall and among subgroups defined by patient and imaging characteristics. To compare the strength of the mortality associations obtained from ABACS's segmentations to manual analysis, we computed Cox proportional hazards ratios (HRs) and 95% confidence intervals (95% CI) by tertile of tissue area.

Results: Mean ± SD age was 63 ± 11 years for colorectal cancer patients and 56 ± 12 for breast cancer patients. There was strong agreement between manual and automatic segmentations overall and within subgroups of age, sex, body mass index, and cancer stage: average Jaccard scores and intra-class correlation coefficients exceeded 90% for all tissues. ABACS underestimated muscle and visceral and subcutaneous adipose tissue areas by 1-2% versus manual analysis: mean differences were small at -2.35, -1.97 and -2.38 cm , respectively. ABACS's performance was lowest for the <2% of patients who were underweight or had anatomic abnormalities. ABACS and manual analysis produced similar associations with mortality; comparing the lowest to highest tertile of skeletal muscle from ABACS versus manual analysis, the HRs were 1.23 (95% CI: 1.00-1.52) versus 1.38 (95% CI: 1.11-1.70) for colorectal cancer patients and 1.30 (95% CI: 1.01-1.66) versus 1.29 (95% CI: 1.00-1.65) for breast cancer patients.

Conclusions: In the first study to externally evaluate a commercially available software to assess body composition, automated segmentation of muscle and adipose tissues using ABACS was similar to manual analysis and associated with mortality after non-metastatic cancer. Automated methods will accelerate body composition research and, eventually, facilitate integration of body composition measures into clinical care.
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http://dx.doi.org/10.1002/jcsm.12573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567141PMC
October 2020

A randomized, double-blind, single-dose, three-arm, parallel group study to determine pharmacokinetic similarity of ABP 959 and eculizumab (Soliris ) in healthy male subjects.

Eur J Haematol 2020 Jul 27;105(1):66-74. Epub 2020 Apr 27.

Amgen Inc., Thousand Oaks, CA, USA.

Objectives: ABP 959 is a proposed biosimilar to eculizumab, a monoclonal antibody targeting the human C5 complement protein. The objective of this randomized, double-blind, three-arm, study was to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity of ABP 959 relative to the eculizumab reference product (RP) in healthy adult male subjects.

Methods: Eligible subjects aged 18-45 years were randomized to receive a 300-mg IV infusion of ABP 959, or FDA-licensed eculizumab (eculizumab US), or EU-authorized eculizumab (eculizumab EU). Primary PK endpoint was area under the total serum concentration-time curve from 0 to infinity (AUC ); primary PD endpoint was area between the effect curve (ABEC) of CH50-time data.

Results: The geometric mean of PK and PD parameters were similar between ABP 959 versus eculizumab US and eculizumab EU; PK and PD similarity was established based on 90% confidence intervals of the geometric mean ratio being within prespecified equivalence margin of 0.8 and 1.25. The incidence of treatment-emergent adverse events was similar across groups. The incidence of binding anti-drug antibodies was similar across treatments; no subjects developed neutralizing antibodies.

Conclusions: This study demonstrated PK and PD similarity of ABP 959 to eculizumab RP; safety and immunogenicity profiles were also similar.
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http://dx.doi.org/10.1111/ejh.13411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384155PMC
July 2020

Respiratory Viral Infections in Exacerbation of Chronic Airway Inflammatory Diseases: Novel Mechanisms and Insights From the Upper Airway Epithelium.

Front Cell Dev Biol 2020 25;8:99. Epub 2020 Feb 25.

Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.
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http://dx.doi.org/10.3389/fcell.2020.00099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052386PMC
February 2020

Right ventricular speckle tracking strain echocardiography in patients with acute pulmonary embolism.

Int J Cardiovasc Imaging 2020 May 12;36(5):865-872. Epub 2020 Feb 12.

Department of Cardiology, Westmead Hospital, Wentworthville, PO BOX 533, Sydney, NSW, 2145, Australia.

Right atrial (RA) and right ventricular (RV) parameters assessed by traditional echocardiography lack sensitivity to identify pulmonary embolism (PE). We sought to determine if alterations in RV free wall longitudinal strain (FWS) would be present in PE patients and improve evaluation. This retrospective study comprised of 84 consecutive PE patients from 2 centres, with adequate transthoracic echocardiography (TTE) images for RV FWS analysis. PE patients were compared to 66 healthy controls. Compared to controls, PE patients had increased RV parasternal long-axis diameter (RVPLAX) (33.4 ± 5.8 mm vs 39.9 ± 4.1 mm) and RA area (17.4 ± 5.6 cm vs 14.5 ± 3.1 cm) (p < 0.001 for both). RV function was reduced in PE patients (RV fractional area change 31.1 ± 13.2% vs 41.7 ± 9.1%, TAPSE 17.0 ± 4.5 vs 21.3 ± 2.2 mm; p < 0.001 for both). RV FWS was reduced in PE patients (-14.4 ± 7.2% vs - 26.0 ± 4.4%, p < 0.001). RV FWS was the best discriminator for PE (AUC 0.912). In comparative multiple logistic regression models for PE, the model which included traditional measures of RV size and function and RV FWS, produced a powerful classifier (AUC 0.966, SE 0.013) with significantly better performance (p < 0.022) than the model without RV FWS (AUC 0.921, SE 0.024). RV FWS is a discriminator of PE patients; addition of RV FWS to existing parameters of RV size and function, significantly improves sensitivity and specificity for diagnosis of PE, and may play a role in diagnosis and guiding therapy. Validation in other PE groups is required to confirm these observations and its prognostic value needs evaluation.
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http://dx.doi.org/10.1007/s10554-020-01779-8DOI Listing
May 2020

Functional and Nonclinical Similarity of ABP 980, a Biosimilar of Trastuzumab.

Pharm Res 2019 Nov 6;36(12):177. Epub 2019 Nov 6.

Amgen Inc, One Amgen Center Drive, Thousand Oaks, California, 91320, USA.

Purpose: The in vitro and in vivo pharmacologic assessment of ABP 980 similarity to its reference product is intended to compare the activity of ABP 980 and trastuzumab and support the overall conclusion of similarity based on a comprehensive analytical and functional evaluation.

Methods: This work complements the primary assessment of functional similarity with additional in vitro assays, binding studies, and non-clinical studies including human epidermal growth factor receptor-2 (HER2) kinetic binding, HER2 signaling, HER2 internalization, synergy with docetaxel chemotherapy, FcγR kinetic binding, primary natural killer and monocyte cell binding, antibody-dependent cellular phagocytosis activity, in vivo xenograft studies, and toxicokinetic parameters.

Results: The results contribute to the totality of evidence with respect to functional similarity and support that ABP 980 is similar to trastuzumab in all primary and secondary mechanisms of action.

Conclusions: These results also support the scientific justification of extrapolation to all approved indications of trastuzumab given the established functional similarity of the two products and the same mechanisms of action across all conditions of use.
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http://dx.doi.org/10.1007/s11095-019-2702-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834741PMC
November 2019

Molecular insights into evolution, mutations and receptor-binding specificity of influenza A and B viruses from outpatients and hospitalized patients in Singapore.

Int J Infect Dis 2020 Jan 25;90:84-96. Epub 2019 Oct 25.

Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Background: This study compared the genomes of influenza viruses that caused mild infections among outpatients and severe infections among hospitalized patients in Singapore, and characterized their molecular evolution and receptor-binding specificity.

Methods: The complete genomes of influenza A/H1N1, A/H3N2 and B viruses that caused mild infections among outpatients and severe infections among inpatients in Singapore during 2012-2015 were sequenced and characterized. Using various bioinformatics approaches, we elucidated their evolutionary, mutational and structural patterns against the background of global and vaccine strains.

Results: The phylogenetic trees of the 8 gene segments revealed that the outpatient and inpatient strains overlapped with representative global and vaccine strains. We observed a cluster of inpatients with A/H3N2 strains that were closely related to vaccine strain A/Texas/50/2012(H3N2). Several protein sites could accurately discriminate between outpatient versus inpatient strains, with site 221 in neuraminidase (NA) achieving the highest accuracy for A/H3N2. Interestingly, amino acid residues of inpatient but not outpatient isolates at those sites generally matched the corresponding residues in vaccine strains, except at site 145 of hemagglutinin (HA). This would be especially relevant for future surveillance of A/H3N2 strains in relation to their antigenicity and virulence. Furthermore, we observed a trend in which the HA proteins of influenza A/H3N2 and A/H1N1 exhibited enhanced ability to bind both avian and human host cell receptors. In contrast, the binding ability to each receptor was relatively stable for the HA of influenza B.

Conclusions: Overall, our findings extend our understanding of the molecular and structural evolution of influenza virus strains in Singapore within the global context of these dynamic viruses.
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http://dx.doi.org/10.1016/j.ijid.2019.10.024DOI Listing
January 2020

Reverse Genetic Analysis of Adaptive Mutations within the Capsid Proteins of Enterovirus 71 (EV-A71) Strains Necessary for Infection of CHO-K1 Cells.

Virol Sin 2020 Feb 21;35(1):110-114. Epub 2019 Oct 21.

Temasek Lifesciences Laboratory, 1 Research Link, National University of Singapore, Singapore, 117604, Singapore.

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http://dx.doi.org/10.1007/s12250-019-00167-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035393PMC
February 2020

Pharmacokinetic Similarity of ABP 710, a Proposed Biosimilar to Infliximab: Results From a Randomized, Single-Blind, Single-Dose, Parallel-Group Study in Healthy Subjects.

Clin Pharmacol Drug Dev 2020 02 19;9(2):246-255. Epub 2019 Oct 19.

Biosimilars, Amgen Inc., Thousand Oaks, California, USA.

This was a randomized, single-blind, single-dose, 3-arm parallel-group study. Healthy subjects were randomized to receive ABP 710 (n = 50) or infliximab reference product (RP) sourced from the United States (infliximab US; n = 50) or the European Union (infliximab EU; n = 50) 5 mg/kg intravenously over 2 hours. The primary endpoint was area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC ) for the comparison of ABP 710 to infliximab US and infliximab EU. Secondary endpoints included safety, tolerability, and immunogenicity. AUC was similar across the 3 groups, showing similarity of ABP 710 to infliximab RP as well as similarity of infliximab US with infliximab EU. Geometric mean ratio of AUC was 0.89 between ABP 710 and infliximab US, 1.00 between ABP 710 and infliximab EU, and 1.11 between infliximab US and infliximab EU. All 90% confidence intervals of the geometric mean ratios were fully contained within the prespecified standard pharmacokinetic equivalence criteria range of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and reported for 83.7%, 86.0%, and 83.7% of subjects in the ABP 710, infliximab US, and infliximab EU treatment groups, respectively; incidence of antidrug antibody rates observed across the 3 groups were similar. Results of this study demonstrated pharmacokinetic similarity of ABP 710 with infliximab RP following a single 5-mg/kg intravenous injection. The safety and tolerability of ABP 710 and infliximab RP were comparable. These results add to the totality of evidence providing further support that the proposed biosimilar ABP 710 is similar to infliximab RP. (Trial ID: ACTRN12614000903684.).
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http://dx.doi.org/10.1002/cpdd.738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027815PMC
February 2020

RNA Sequencing of H3N2 Influenza Virus-Infected Human Nasal Epithelial Cells from Multiple Subjects Reveals Molecular Pathways Associated with Tissue Injury and Complications.

Cells 2019 08 27;8(9). Epub 2019 Aug 27.

Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

The human nasal epithelium is the primary site of exposure to influenza virus, the initiator of host responses to influenza and the resultant pathologies. Influenza virus may cause serious respiratory infection resulting in major complications, as well as severe impairment of the airways. Here, we elucidated the global transcriptomic changes during H3N2 infection of human nasal epithelial cells from multiple individuals. Using RNA sequencing, we characterized the differentially-expressed genes and pathways associated with changes occurring at the nasal epithelium following infection. We used in vitro differentiated human nasal epithelial cell culture model derived from seven different donors who had no concurrent history of viral infections. Statistical analysis highlighted strong transcriptomic signatures significantly associated with 24 and 48 h after infection, but not at the earlier 8-h time point. In particular, we found that the influenza infection induced in the nasal epithelium early and altered responses in interferon gamma signaling, B-cell signaling, apoptosis, necrosis, smooth muscle proliferation, and metabolic alterations. These molecular events initiated at the infected nasal epithelium may potentially adversely impact the airway, and thus the genes we identified could serve as potential diagnostic biomarkers or therapeutic targets for influenza infection and associated disease management.
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http://dx.doi.org/10.3390/cells8090986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770044PMC
August 2019

Insights into Early Recovery from Influenza Pneumonia by Spatial and Temporal Quantification of Putative Lung Regenerating Cells and by Lung Proteomics.

Cells 2019 08 26;8(9). Epub 2019 Aug 26.

Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore.

During influenza pneumonia, the alveolar epithelial cells of the lungs are targeted by the influenza virus. The distal airway stem cells (DASCs) and proliferating alveolar type II (AT2) cells are reported to be putative lung repair cells. However, their relative spatial and temporal distribution is still unknown during influenza-induced acute lung injury. Here, we investigated the distribution of these cells, and concurrently performed global proteomic analysis of the infected lungs to elucidate and link the cellular and molecular events during influenza pneumonia recovery. BALB/c mice were infected with a sub-lethal dose of influenza H1N1 virus. From 5 to 25 days post-infection (dpi), mouse lungs were subjected to histopathologic and immunofluorescence analysis to probe for global distribution of lung repair cells (using P63 and KRT5 markers for DASCs; SPC and PCNA markers for AT2 cells). At 7 and 15 dpi, infected mouse lungs were also subjected to protein mass spectrometry for relative protein quantification. DASCs appeared only in the damaged area of the lung from 7 dpi onwards, reaching a peak at 21 dpi, and persisted until 25 dpi. However, no differentiation of DASCs to AT2 cells was observed by 25 dpi. In contrast, AT2 cells began proliferating from 7 dpi to replenish their population, especially within the boundary area between damaged and undamaged areas of the infected lungs. Mass spectrometry and gene ontology analysis revealed prominent innate immune responses at 7 dpi, which shifted towards adaptive immune responses by 15 dpi. Hence, proliferating AT2 cells but not DASCs contribute to AT2 cell regeneration following transition from innate to adaptive immune responses during the early phase of recovery from influenza pneumonia up to 25 dpi.
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http://dx.doi.org/10.3390/cells8090975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769472PMC
August 2019