Publications by authors named "Qiushi Chen"

60 Publications

Multi-platform omics analysis reveals molecular signature for COVID-19 pathogenesis, prognosis and drug target discovery.

Signal Transduct Target Ther 2021 Apr 15;6(1):155. Epub 2021 Apr 15.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.
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http://dx.doi.org/10.1038/s41392-021-00508-4DOI Listing
April 2021

Knowledge about Coronavirus Disease 2019 among adults in China: A cross-sectional online survey.

J Med Internet Res 2021 Apr 11. Epub 2021 Apr 11.

Heidelberg Institute of Global Health, Heidelberg University, INF 130.3, Heidelberg, Germany, Heidelberg, DE.

Background: A detailed understanding of the public's knowledge and perceptions of coronavirus disease 2019 (COVID-19) could inform governments' public health actions in response to the pandemic.

Objective: The aim of this study was to determine the knowledge and perceptions of COVID-19 among adults in China, and its variation among provinces and by sociodemographic characteristics.

Methods: Between 8 May 2020 and 8 June 2020, we conducted a cross-sectional online survey among adults in China who were registered with the private survey company KuRunData. We set a target sample size of 10,000 adults, aiming to sample 300-360 adults from each province in China. Participants were asked 25 questions that tested their knowledge about COVID-19, including measures to prevent infection, common symptoms, and recommended care-seeking behavior. We disaggregated responses by age, sex, education, province, household income, rural-urban residency, and whether or not a participant had a family member, friend, or acquaintance who they know to have been infected with SARS-CoV-2. All analyses used survey sampling weights.

Results: 5,079 men and 4,921 women completed the questionnaire and were included in the analysis. Out of 25 knowledge questions, participants answered a mean and median of 21.4 (95% CI: 21.3-21.4) and 22 (IQR: 20 - 23) questions correctly, respectively. 83.4% (95% CI: 82.7%-84.1%) of participants answered four-fifths or more of the questions correctly. For at least one of four ineffective prevention measures (using a hand dryer, regular nasal irrigation, gargling mouthwash, and taking antibiotics), 68.9% (95% CI: 68.0%-69.8%) of participants answered that it was an effective method to prevent a SARS-CoV-2 infection. While knowledge overall was similar across provinces, the percent of participants who answered the question on recommended care-seeking behavior correctly varied from 47.0% (95% CI: 41.4%-52.7%) in Tibet to 87.5% (95% CI: 84.1%-91.0%) in Beijing. Within provinces, participants who were male, middle-aged, residing in urban areas, and had higher household income tended to answer a higher proportion of the knowledge questions correctly.

Conclusions: This online study of individuals across China suggests that the majority of the population has good knowledge of COVID-19. However, a significant proportion still holds misconceptions or incorrect beliefs about prevention methods and recommended healthcare-seeking behaviors, especially in rural areas and some less wealthy provinces in Western China. This study can inform the development of tailored public health policies and promotion campaigns by identifying knowledge areas for which misconceptions are comparatively common and provinces that have relatively low knowledge.

Clinicaltrial:
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http://dx.doi.org/10.2196/26940DOI Listing
April 2021

Curbing the COVID-19 pandemic with facility-based isolation of mild cases: a mathematical modeling study.

J Travel Med 2021 02;28(2)

Heidelberg Institute of Global Health, Faculty of Medicine and University Hospital, Heidelberg University, Heidelberg, Germany, 69120.

Background: In many countries, patients with mild coronavirus disease 2019 (COVID-19) are told to self-isolate at home, but imperfect compliance and shared living space with uninfected people limit the effectiveness of home-based isolation. We examine the impact of facility-based isolation compared to self-isolation at home on the continuing epidemic in the USA.

Methods: We developed a compartment model to simulate the dynamic transmission of COVID-19 and calibrated it to key epidemic measures in the USA from March to September 2020. We simulated facility-based isolation strategies with various capacities and starting times under different diagnosis rates. Our primary model outcomes are new infections and deaths over 2 months from October 2020 onwards. In addition to national-level estimations, we explored the effects of facility-based isolation under different epidemic burdens in major US Census Regions. We performed sensitivity analyses by varying key model assumptions and parameters.

Results: We find that facility-based isolation with moderate capacity of 5 beds per 10 000 total population could avert 4.17 (95% credible interval 1.65-7.11) million new infections and 16 000 (8000-23 000) deaths in 2 months compared with home-based isolation. These results are equivalent to relative reductions of 57% (44-61%) in new infections and 37% (27-40%) in deaths. Facility-based isolation with high capacity of 10 beds per 10 000 population could achieve reductions of 76% (62-84%) in new infections and 52% (37-64%) in deaths when supported by expanded testing with an additional 20% daily diagnosis rate. Delays in implementation would substantially reduce the impact of facility-based isolation. The effective capacity and the impact of facility-based isolation varied by epidemic stage across regions.

Conclusion: Timely facility-based isolation for mild COVID-19 cases could substantially reduce the number of new infections and effectively curb the continuing epidemic in the USA. Local epidemic burdens should determine the scale of facility-based isolation strategies.
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http://dx.doi.org/10.1093/jtm/taaa226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799023PMC
February 2021

ppGalNAc-T4-catalyzed O-Glycosylation of TGF-β type Ⅱ receptor regulates breast cancer cells metastasis potential.

J Biol Chem 2020 Dec 3;296:100119. Epub 2020 Dec 3.

School of Life Science & Pharmacy, Dalian University of Technology, Panjin, China. Electronic address:

GalNAc-type O-glycosylation, initially catalyzed by polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts), is one of the most abundant and complex posttranslational modifications of proteins. Emerging evidence has proven that aberrant ppGalNAc-Ts are involved in malignant tumor transformation. However, the exact molecular functions of ppGalNAc-Ts are still unclear. Here, the role of one isoform, ppGalNAc-T4, in breast cancer cell lines was investigated. The expression of ppGalNAc-T4 was found to be negatively associated with migration of breast cancer cells. Loss-of-function studies revealed that ppGalNAc-T4 attenuated the migration and invasion of breast cancer cells by inhibiting the epithelial-mesenchymal transition (EMT) process. Correspondingly, transforming growth factor beta (TGF-β) signaling, which is the upstream pathway of EMT, was impaired by ppGalNAc-T4 expression. ppGalNAc-T4 knockout decreased O-GalNAc modification of TGF-β type Ⅰ and Ⅱ receptor (TβR Ⅰ and Ⅱ) and led to the elevation of TGF-β receptor dimerization and activity. Importantly, a peptide from TβR Ⅱ was identified as a naked peptide substrate of ppGalNAc-T4 with a higher affinity than ppGalNAc-T2. Further, Ser31, corresponding to the extracellular domain of TβR Ⅱ, was identified as the O-GalNAcylation site upon in vitro glycosylation by ppGalNAc-T4. The O-GalNAc-deficient S31 A mutation enhanced TGF-β signaling activity and EMT in breast cancer cells. Together, these results identified a novel mechanism of ppGalNAc-T4-catalyzed TGF-β receptors O-GalNAcylation that suppresses breast cancer cell migration and invasion via the EMT process. Targeting ppGalNAc-T4 may be a potential therapeutic strategy for breast cancer treatment.
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http://dx.doi.org/10.1074/jbc.RA120.016345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948473PMC
December 2020

Proteomic profiling and genome-wide mapping of O-GlcNAc chromatin-associated proteins reveal an O-GlcNAc-regulated genotoxic stress response.

Nat Commun 2020 11 19;11(1):5898. Epub 2020 Nov 19.

School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.

O-GlcNAc modification plays critical roles in regulating the stress response program and cellular homeostasis. However, systematic and multi-omics studies on the O-GlcNAc regulated mechanism have been limited. Here, comprehensive data are obtained by a chemical reporter-based method to survey O-GlcNAc function in human breast cancer cells stimulated with the genotoxic agent adriamycin. We identify 875 genotoxic stress-induced O-GlcNAc chromatin-associated proteins (OCPs), including 88 O-GlcNAc chromatin-associated transcription factors and cofactors (OCTFs), subsequently map their genomic loci, and construct a comprehensive transcriptional reprogramming network. Notably, genotoxicity-induced O-GlcNAc enhances the genome-wide interactions of OCPs with chromatin. The dynamic binding switch of hundreds of OCPs from enhancers to promoters is identified as a crucial feature in the specific transcriptional activation of genes involved in the adaptation of cancer cells to genotoxic stress. The OCTF nuclear factor erythroid 2-related factor-1 (NRF1) is found to be a key response regulator in O-GlcNAc-modulated cellular homeostasis. These results provide a valuable clue suggesting that OCPs act as stress sensors by regulating the expression of various genes to protect cancer cells from genotoxic stress.
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http://dx.doi.org/10.1038/s41467-020-19579-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678849PMC
November 2020

Assessment of Incidence of and Surveillance Burden for Hepatocellular Carcinoma Among Patients With Hepatitis C in the Era of Direct-Acting Antiviral Agents.

JAMA Netw Open 2020 11 2;3(11):e2021173. Epub 2020 Nov 2.

Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School, Boston.

Importance: In the US, hepatocellular carcinoma (HCC), primarily associated with hepatitis C virus (HCV) infection, is the fastest rising cause of cancer-related death. Wider use of highly effective direct-acting antiviral agents (DAAs) substantially reduces the burden of chronic HCV infection, but the subsequent impacts with HCV-associated HCC remain unknown.

Objective: To assess projected changes in the incidence rate of and surveillance burden for HCC in the era of DAA treatment for HCV.

Design, Setting, And Participants: This decision analytical model study was performed from January 2019 to February 2020, using an individual-level state-transition simulation model to simulate disease progression, screening, and different waves of antiviral treatments for HCV in the US from 2012 to 2040.

Interventions: Current clinical management for chronic HCV infection.

Main Outcomes And Measures: Model outcomes were projected temporal trends and age distribution of incident HCC cases and candidates for HCC surveillance among patients with viremia and patients with virologically cured HCV.

Results: The simulation model projected that the annual incidence of HCC among patients with viremia and patients with virologically cured HCV will continue increasing to 24 000 (95% uncertainty interval [UI], 18 000-31 000) cases until 2021. In patients with virologically cured HCV, incident HCC cases are projected to increase from 1000 (95% UI, 500-2100) in 2012 to the peak of 7000 (95% UI, 5000-9600) in 2031 with a subsequent decrease to 6000 (95% UI, 4300-8300) by 2040. The proportion of incident HCC cases that occur in individuals with virologically cured HCV is estimated to increase from 5.3% in 2012 to 45.8% in 2040. The number of candidates for HCC surveillance in the population with virologically cured HCV is projected to increase from 106 000 (95% UI, 70 000-178 000) in 2012 to the peak of 649 000 (95% UI, 512 000-824 000) in 2030 and decrease to 539 000 (95% UI, 421 000-687 000) by 2040, while the proportion of all candidates for surveillance who are virologically cured is estimated to increase from 8.5% to 64.6% during the same period. The average age of HCC incidence and surveillance candidates is estimated to increase from 55 in 2012 to 72 and 71, respectively, by 2040.

Conclusions And Relevance: The results of this study suggest that the burden of HCC will shift from patients with viremia to patients with virologically cured HCV, and to older populations. Appropriate management may be warranted for early detection of HCC in patients who may no longer be receiving specialty care for liver conditions.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.21173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675109PMC
November 2020

Buying Time for an Effective Epidemic Response: The Impact of a Public Holiday for Outbreak Control on COVID-19 Epidemic Spread.

Engineering (Beijing) 2020 Oct 20;6(10):1108-1114. Epub 2020 Sep 20.

Heidelberg Institute of Global Health (HIGH), Faculty of Medicine and University Hospital, Heidelberg University, Heidelberg 69117, Germany.

Rapid responses in the early stage of a new epidemic are crucial in outbreak control. Public holidays for outbreak control could provide a critical time window for a rapid rollout of social distancing and other control measures at a large population scale. The objective of our study was to explore the impact of the timing and duration of outbreak-control holidays on the coronavirus disease 2019 (COVID-19) epidemic spread during the early stage in China. We developed a compartment model to simulate the dynamic transmission of COVID-19 in China starting from January 2020. We projected and compared epidemic trajectories with and without an outbreak-control holiday that started during the Chinese Lunar New Year. We considered multiple scenarios of the outbreak-control holiday with different durations and starting times, and under different assumptions about viral transmission rates. We estimated the delays in days to reach certain thresholds of infections under different scenarios. Our results show that the outbreak-control holiday in China likely stalled the spread of COVID-19 for several days. The base case outbreak-control holiday (21 d for Hubei Province and 10 d for all other provinces) delayed the time to reach 100 000 confirmed infections by 7.54 d. A longer outbreak-control holiday would have had stronger effects. A nationwide outbreak-control holiday of 21 d would have delayed the time to 100 000 confirmed infections by nearly 10 d. Furthermore, we find that outbreak-control holidays that start earlier in the course of a new epidemic are more effective in stalling epidemic spread than later holidays and that additional control measures during the holidays can boost the holiday effect. In conclusion, an outbreak-control holiday can likely effectively delay the transmission of epidemics that spread through social contacts. The temporary delay in the epidemic trajectory buys time, which scientists can use to discover transmission routes and identify effective public health interventions and which governments can use to build physical infrastructure, organize medical supplies, and deploy human resources for long-term epidemic mitigation and control efforts.
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http://dx.doi.org/10.1016/j.eng.2020.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502241PMC
October 2020

Comprehensive profiling of protein lysine acetylation and its overlap with lysine succinylation in the Porphyromonas gingivalis fimbriated strain ATCC 33277.

Mol Oral Microbiol 2020 12 5;35(6):240-250. Epub 2020 Oct 5.

State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.

Porphyromonas gingivalis is a pathogen closely associated with periodontal and systemic infections. Recently, lysine acetylation (Kac) and lysine succinylation (Ksuc) have been identified in bacterial proteins with diverse biological and pathological functions. The Ksuc of P. gingivalis ATCC 33277 has been characterized in our previous work, and here, we report the systematic analysis of Kac and its crosstalk with Ksuc in this bacterium. A combination of the affinity enrichment by the acetyl-lysine antibody with highly sensitive LC-MS/MS was used to identify the lysine-acetylated proteins and sites in P. gingivalis ATCC 33277. A total of 1,112 lysine-acetylated sites matching 438 proteins were identified. These proteins involved in several cellular processes, especially those proteins related to protein biosynthesis and central metabolism had a high tendency to be lysine acetylated. Moreover, lysine sites flanked by tyrosine, phenylalanine, and histidine in the +1 position, as well as residue lysine in position +4 to +5, were the targets of Kac. Additionally, proteins involved in adhesins, gingipains, black pigmentation, and oxidative stress resistance were identified as substrates of Kac. Collectively, these results suggest Kac may play a critical role in the regulation of physiology and virulence of P. gingivalis. Furthermore, we discovered that, Ksuc and Kac were extensively overlapped in P. gingivalis ATCC 33277, especially in proteins related to ribosomes and metabolism. This study provides a significant beginning for further investigating the role of Kac and Ksuc in the pathogenicity of P. gingivalis.
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http://dx.doi.org/10.1111/omi.12312DOI Listing
December 2020

A Novel Method about the Representation and Discrimination of Traffic State.

Sensors (Basel) 2020 Sep 4;20(18). Epub 2020 Sep 4.

Intelligent Transportation Systems Center (ITSC), Wuhan University of Technology, Wuhan 430000, China.

The representation and discrimination of various traffic states play an essential role in solving traffic accidents and congestion as the foundation of traffic state prediction. However, the existing representation of the traffic state usually only considers the road congestion layer and divides the traffic state into congested and unblocked. Representation only at the congestion layer is difficult to reflect the road traffic state comprehensively. Therefore, we select three indicators from the layers of road congestion, road safety, and road stability, respectively, then utilizing K-means to cluster the traffic state. The clustering results can be regarded as a new type for the representation of a traffic state. As a result, the traffic states are divided into four classes, which comprehensively reflects the level of road congestion, safety, and stability. Using the four traffic states obtained from the clustering results as class labels, we applied a multi-layer perceptron (MLP) to classify the different traffic states, and the receiver operating characteristic (ROC) curve is assessed to verify the superiority of the classification results. Finally, a visual display of the real-time traffic state in a city's central area was given.
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http://dx.doi.org/10.3390/s20185039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570472PMC
September 2020

Long noncoding RNA UCA1 from hypoxia-conditioned hMSC-derived exosomes: a novel molecular target for cardioprotection through miR-873-5p/XIAP axis.

Cell Death Dis 2020 08 10;11(8):696. Epub 2020 Aug 10.

Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.

Exosomes (Exo) secreted from mesenchymal stem cells (hMSCs) are protective against myocardial injury. The purpose of the study was to investigate the role and mechanisms by which exosomes promote cardiomyocyte survival and function following myocardial infarction (MI). hMSCs were cultured under hypoxic and normoxic conditions. Hypoxia-conditioned hMSC-derived exosomes (Hypo-Exo) and normoxic-conditioned hMSC-derived exosomes (Nor-Exo) were collected and intramyocardially injected into rats with MI. The therapeutic effects of Hypo-Exo and Nor-Exo were evaluated after 4 weeks. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of candidate long noncoding RNA urothelial carcinoma associated 1 (lncRNA-UCA1) in Nor-Exo and Hypo-Exo. Intramyocardial injection of lncRNA-UCA1-knockdown-Hypo-Exo in a rat model of MI was then performed and the cardiac function was characterized. The target and downstream of the molecular mechanism lncRNA-UCA1 was disclosed by luciferase reporter assays and western blot. Circulating exosomal lncRNA-UCA1 level in AMI patients and healthy volunteers was assessed. We found that (1) hMSC exosomal (from hypoxic and normoxic conditions) cardioprotection in vitro and in vivo correlated with the presence of encapsulated lncRNA-UCA1 in exosomes; (2) lncRNA-UCA1 targeted miR-873 via sponging, reducing the latter's suppressive effects on its target XIAP, and this translated into AMPK phosphorylation and increased level of the antiapoptotic protein BCL2; and (3) plasma derived from patients with AMI contained exosomes enriched with the lncRNA-UCA1, unlike that from normal subjects. This study demonstrates that Hypo-Exo lncRNA-UCA1 plays a cardioprotective role via the miR-873-5p/XIAP axis and circulating exosomal lncRNA-UCA1 may be a promising novel biomarker for the diagnosis of AMI.
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http://dx.doi.org/10.1038/s41419-020-02783-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442657PMC
August 2020

The Essential Functions and Detection of Bisecting GlcNAc in Cell Biology.

Front Chem 2020 3;8:511. Epub 2020 Jul 3.

Clinical Laboratory of BGI Health, BGI-Shenzhen, Shenzhen, China.

The N-glycans of mammalian glycoproteins vary greatly in structure, and the biological importance of these variations is mostly unknown. It is widely acknowledged that the bisecting N-acetylglucosamine (GlcNAc) structure, a β1,4-linked GlcNAc attached to the core β-mannose residue, represents a special type of N-glycosylated modification, and it has been reported to be involved in various biological processes, such as cell adhesion, fertilization and fetal development, neuritogenesis, and tumor development. In particular, the occurrence of N-glycans with a bisecting GlcNAc modification on proteins has been proven, with many implications for immune biology. Due to the essential functions of bisecting GlcNAc structures, analytical approaches to this modification are highly required. The traditional approach that has been used for bisecting GlcNAc determinations is based on the lectin recognition of erythroagglutinin (PHA-E); however, poor binding specificity hinders the application of this method. With the development of mass spectrometry (MS) with high resolution and improved sensitivity and accuracy, MS-based glycomic analysis has provided precise characterization and quantification for glycosylation modification. In this review, we first provide an overview of the bisecting GlcNAc structure and its biological importance in neurological systems, immune tolerance, immunoglobulin G (IgG), and tumor metastasis and development and then summarize approaches to its determination by MS for performing precise functional studies. This review is valuable for those readers who are interested in the importance of bisecting GlcNAc in cell biology.
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http://dx.doi.org/10.3389/fchem.2020.00511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350706PMC
July 2020

Protective effects of acetylcholine on hypoxia-induced endothelial-to-mesenchymal transition in human cardiac microvascular endothelial cells.

Mol Cell Biochem 2020 Oct 29;473(1-2):101-110. Epub 2020 Jun 29.

The Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 211166, China.

Endothelial-to-mesenchymal transition (EndMT) has been reported as a key factor in myocardial fibrosis. Acetylcholine (ACh), a neurotransmitter of the vagus nerve, has been confirmed to exert cardio-protective properties with unclear mechanisms. In this study, the specific markers of cell injury, EndMT, inflammation, and autophagy were measured. We found that treatment with ACh prevented hypoxia-induced cell viability reduction and apoptosis in human cardiac microvascular endothelial cells (HCMECs). Additionally, our results indicate that pre-treatment with ACh significantly suppresses hypoxia-induced EndMT and NF-κB activation in HCMECs. ACh also reduced hypoxia-inducible factor (HIF)-1ɑ protein levels under hypoxia. Knock down of HIF-1ɑ enhanced the inhibitory effect of ACh on NF-κB activation. The NF-κB-specific small molecule inhibitor BAY 11-7082, prostaglandin E2, and LY294002 prevented hypoxia-induced EndMT. Moreover, our data show that hypoxia triggers autophagy in HCMECs, and ACh significantly upregulates autophagy activity. Pre-treatment of HCMECs with 3-methyladenine or chloroquine partially reversed ACh-induced EndMT inhibition. These results suggest that ACh may confer protection against hypoxia-induced EndMT through the inhibition of NF-κB and the induction of autophagy.
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http://dx.doi.org/10.1007/s11010-020-03811-wDOI Listing
October 2020

The effect of laser sintering on the microstructure, relative density, and cracking of sol-gel-derived silica thin films.

J Am Ceram Soc 2020 Jan 13;103(1):70-81. Epub 2019 Jun 13.

Department of Materials Science and Engineering, Clemson University, Clemson, South Carolina.

Combining sol-gel processing and laser sintering is a promising way for fabricating functional ceramic deposition with high dimensional resolution. In this work, crack-free silica tracks on a silica substrate with a thickness from ~360 nm to ~950 nm, have been obtained by direct exposure to a CO laser beam. At a fixed scanning speed, the density and microstructures of the silica deposition can be precisely controlled by varying the laser output power. The porosity of the laser-sintered silica tracks ranged from close to 0% to ~60%. When the thickness of the silica deposition exceeded the critical thickness (eg, ~2.2 μm before firing), cracks occurred in both laser-sintered and furnace-sintered samples. Cracks propagated along the edge of the laser-sintered track, resulting in the crack-free track. However, for the furnace heat-treated counterpart, the cracks spread randomly. To understand the laser sintering effect, we established a finite element model (FEM) to calculate the temperature profile of the substrate during laser scanning, which agreed well with the one-dimensional analytical model. The FEM model confirmed that laser sintering was the main thermal effect and the calculated temperature profile can be used to predict the microstructure of the laser-sintered tracks. Combining these results, we were able to fabricate, predesigned patterned (Clemson tiger paw) silica films with high density using a galvo scanner.
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http://dx.doi.org/10.1111/jace.16640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316397PMC
January 2020

Down-Regulated Exosomal MicroRNA-221 - 3p Derived From Senescent Mesenchymal Stem Cells Impairs Heart Repair.

Front Cell Dev Biol 2020 5;8:263. Epub 2020 May 5.

Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.

The composition and biological activity of donor cells is largely determined by the exosomes they secrete. In this study, we isolated exosomes from young (Young-Exo) and aged (Age-Exo) mesenchymal stem cells (MSCs) and compared their regeneration activity. Young Exo MSCs were more efficient than Aged-Exo at promoting the formation of endothelial tube, reducing fibrosis, and inhibiting apoptosis of cardiomyocytes ; and improving cardiac structure and function in the hearts of rats following myocardial infarction (MI). MicroRNA sequencing and polymerase chain reaction (PCR) analysis revealed that miR-221-3p was significantly down-regulated in Aged-Exo. The aged MSCs were rejuvenated and their reparative cardiac ability restored when miR-221-3p was overexpressed in Aged-Exo. The protective effect was lost when miR-221-3p expression was knocked down in Young-Exo. These effects of miR-221-3p were achieved through enhancing Akt kinase activity by inhibiting phosphatase and tensin homolog (PTEN). In conclusion, exosomal miR-221-3p secreted from Aged MSCs attenuated the function of angiogenesis and promoted survival of cardiomyocytes. Up-regulation of miR-221-3p in aged MSCs improved their ability of angiogenesis, migration and proliferation, and suppressed apoptosis via the PTEN/Akt pathway.
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http://dx.doi.org/10.3389/fcell.2020.00263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214920PMC
May 2020

Contact- versus noncontact-guided ablation of the right ventricular outflow tract arrhythmias: A propensity score matched analysis.

Pacing Clin Electrophysiol 2020 08 11;43(8):822-827. Epub 2020 Jul 11.

Section of Pacing and Electrophysiology, Division of Cardiology, Jiangsu Province Hospital and the First Affiliated Hospital with Nanjing Medical University, Nanjing, China.

Background: There are unique advantages and disadvantages in the choice of contact mapping (CM) versus noncontact mapping (NCM) systems during ablation of right ventricular outflow tract (RVOT) arrhythmias. This study compared acute procedural success and clinical outcomes in matched patients undergoing CM- versus NCM-guided RVOT ablation.

Methods: A total of 167 consecutive patients with idiopathic RVOT ventricular arrhythmias underwent NCM- or CM-guided ablation. Propensity scoring was used to match each patient undergoing NCM-guided ablation to one control patient undergoing CM-guided ablation.

Results: A total of 120 patients were included in this final analysis. If initial ablation was acutely unsuccessful in either group, patients crossed over to the other group. Ablation was acutely successful in 47 of 60 (78.3 %) patients in the NCM group and 55 of 60 (91.7%) in the CM group (P = .002). Thirteen NCM patients required CM and two CM patients crossed over to utilize NCM (P = .002). Procedural duration, fluoroscopy time, and dose in NCM were greater than that in CM (P < .05, respectively). However, procedural complications were not different between two groups. During a mean follow-up of 51 ± 20.6 months, 51 of the 60 NCM patients remained free of arrhythmia, while 48 of the 60 CM patients had no recurrent arrhythmias (P = .47).

Conclusion: Contact mapping, compared to NCM, is the superior initial technique to guide RVOT arrhythmia ablation due to a higher procedural success without the need to switch to alternative mapping techniques and shorter procedural and fluoroscopic times.
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http://dx.doi.org/10.1111/pace.13935DOI Listing
August 2020

Estimating the price at which hepatitis C treatment with direct-acting antivirals would be cost-saving in Japan.

Sci Rep 2020 03 5;10(1):4089. Epub 2020 Mar 5.

Massachusetts General Hospital Institute for Technology Assessment, Boston, MA, USA.

In Japan, 1.5-2 million people are chronically infected with hepatitis C virus (HCV) infection. New direct-acting antiviral agents (DAA) offer an unprecedented opportunity to cure HCV. While the price of HCV treatment decreased recently in most countries, it remains one of the highest in Japan. Our objective was to evaluate the cost-effectiveness of HCV treatment in patients of different age groups and to estimate the price at which DAAs become cost-saving in Japan. A previously developed microsimulation model was adapted to the Japanese population and updated with Japan-specific health utilities and costs. Our model showed that compared with no treatment, the incremental cost-effectiveness ratio (ICER) of DAAs at a price USD 41,046 per treatment was USD 9,080 per quality-adjusted life year (QALY) gained in 60-year-old patients. HCV treatment became cost-effective after 9 years of starting treatment. However, if the price of DAAs is reduced by 55-85% (USD 6,730 to 17,720), HCV treatment would be cost-saving within a 5 to 20-year time horizon, which should serve to increase the uptake of DAA-based HCV treatment. The payers of health care in Japan could examine ways to procure DAAs at a price where they would be cost-saving.
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http://dx.doi.org/10.1038/s41598-020-60986-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058050PMC
March 2020

Glycan biomarkers for Alzheimer disease correlate with T-tau and P-tau in cerebrospinal fluid in subjective cognitive impairment.

FEBS J 2020 Aug 14;287(15):3221-3234. Epub 2020 Jan 14.

Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Solna, Sweden.

Alzheimer disease (AD) is a devastating disease and a global health problem, and current treatments are only symptomatic. A wealth of clinical studies support that the disease starts to develop decades before the first symptoms appear, emphasizing the importance of studying early changes for improving early diagnosis and guiding toward novel treatment strategies. Protein glycosylation is altered in AD but it remains to be clarified why these alterations occur and how they affect the disease development. Here, we used a glycomics approach to search for alterations in protein glycosylation in cerebrospinal fluid (CSF) in AD compared with nondemented controls. Using both matrix-assisted laser desorption ionization-time of flight and liquid chromatography-electrospray mass spectrometry, we observed an increase in N-glycans carrying bisecting N-acetylglucosamine in AD. Based on those findings, we designed an enzyme-linked multiwell plate assay to quantify N-glycans binding to the lectin Phaseolus vulgaris Erythroagglutinin (PHA-E), which is specific for N-glycans containing bisecting N-acetylglucosamine. Using this assay, we found a similar increase in CSF in AD compared with controls. Further analysis of CSF from 242 patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or AD dementia revealed significantly increased binding to PHA-E in MCI and AD compared to SCI. Interestingly, PHA-E binding correlated with CSF levels of phosphorylated tau and total tau and this correlation was most prominent in the SCI group (R = 0.53-0.54). This study supports a link between N-glycosylation, neurodegeneration, and tau pathology in AD and suggests that glycan biomarkers have potential to identify SCI cases at risk of developing AD.
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http://dx.doi.org/10.1111/febs.15197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496940PMC
August 2020

Bipolar catheter ablation in ventricular myocardium.

Pacing Clin Electrophysiol 2020 01 23;43(1):54-61. Epub 2019 Dec 23.

Department of Cardiology, National University Heart Centre, Singapore.

Background: Recurrence rates after catheter radiofrequency ablation (RFA) for arrhythmias arising from deep myocardial substrates can exceed 40%. Failure of RFA is in part due to the inability of widely used unipolar ablation (UA) to create transmural lesions capable of disrupting the critical components of the arrhythmia circuit. A radiofrequency generator was custom-made to deliver bipolar ablation (BA) to test the hypothesis that BA is more effective compared to UA in achieving transmurality and to determine the optimal configuration for ventricular BA.

Methods: Sequential UA and BA were created in porcine ventricular septal and free wall preparations using irrigated, contact-force sensing ablation catheters, orientated perpendicularly to the myocardium. Return catheters, durations of ablation, irrigating fluids, and power settings were varied to determine the optimal configuration for BA. Lesion characteristics, transmurality, and occurrence of steam pops were analyzed.

Results: In both ventricular septal and free wall models, BA resulted in significantly more transmural lesions while causing less steam pops (P < .01). BA lesions were deeper, narrower but larger in volume. Use of 8 mm ground catheters in the epicardium resulted in overheating during BA with temperatures exceeding 95°C, limiting power delivery. Increasing duration and powers of BA resulted in progressively larger lesions and increased transmurality (all P < .01), and 0.45% saline as the irrigation did not enhance BA.

Conclusion: BA created larger lesions with increased chances of transmurality but at lower risks of steam pops. Use of an irrigated catheter as the return electrode and 30 W of BA delivered over 120 seconds provides the optimal balance between creating deep, transmural lesions and avoiding steam pops.
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http://dx.doi.org/10.1111/pace.13844DOI Listing
January 2020

Changes in hepatitis C burden and treatment trends in Europe during the era of direct-acting antivirals: a modelling study.

BMJ Open 2019 06 11;9(6):e026726. Epub 2019 Jun 11.

Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objectives: Oral direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have dramatically changed the treatment paradigm. Our aim was to project temporal trends in HCV diagnosis, treatment and disease burden in France, Germany, Italy, Spain and the UK.

Design: A mathematical simulation model of natural history of HCV infection.

Participants: HCV-infected patients defined based on country-specific age, fibrosis and genotype distributions.

Interventions: HCV screening practice and availability of different waves of DAA treatment in each country.

Outcome Measures: Temporal trends in the number of patients who achieve sustained virological response (SVR), fail treatment (by drug regimen) and develop advanced sequelae from 2014 to 2030 in each country.

Results: We projected that 1 324 000 individuals would receive treatment from 2014 to 2030 in the five European countries and 12 000-37 000 of them would fail to achieve SVR. By 2021, the number of individuals cured of HCV would supersede the number of actively infected individuals in France, Germany, Spain and the UK. Under status quo, the diagnosis rate would reach between 65% and 75% and treatment coverage between 65% and 74% by 2030 in these countries. The number of patients who fail treatment would decrease over time, with the majority of those who fail treatment having been exposed to non-structural protein 5A inhibitors.

Conclusions: In the era of DAAs, the number of people with HCV who achieved a cure will exceed the number of viraemic patients, but many patients will remain undiagnosed, untreated, fail multiple treatments and develop advanced sequelae. Scaling-up screening and treatment capacity, and timely and effective retreatment are needed to avail the full benefits of DAAs and to meet HCV elimination targets set by WHO.
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http://dx.doi.org/10.1136/bmjopen-2018-026726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576109PMC
June 2019

The impact of direct-acting anti-virals on the hepatitis C care cascade: identifying progress and gaps towards hepatitis C elimination in the United States.

Aliment Pharmacol Ther 2019 07 22;50(1):66-74. Epub 2019 May 22.

Michael E. DeBakey Veterans Affairs Medical Center, and Baylor College of Medicine, Houston, Texas.

Background: The hepatitis C virus (HCV) care cascade has changed dramatically following the introduction of direct-acting anti-virals (DAAs). Up-to-date estimates of the cascade are needed to monitor progress, identify key gaps and inform policy.

Aim: To estimate the current and future HCV care cascade in the United States, nationally and in select subpopulations of interest.

Methods: We used a previously validated mathematical model to simulate the landscape of HCV in the United States from 2011 onwards, accounting for HCV screening policy updates, newer HCV treatments and rising HCV incidence.

Results: By the end of 2018, of 4.29 million HCV persons alive, 2.71 million (63%) were actively viremic, 2.24 million (52%) aware and 1.58 million (37%) cured. By 2030, under the status quo, of 3.65 million HCV persons alive, 1.88 million (51%) would be viremic, 2.25 million (62%) aware and 1.77 million (49%) cured. The HCV care cascade in 2018 differed substantially by subpopulation: of 1.34 million incarcerated HCV persons, 96% were viremic, 36% aware and 4% cured; of 0.87 million HCV persons in Medicare, 31% were viremic, 72% aware and 69% cured; and of 0.37 million HCV persons in Medicaid, 49% were viremic, 54% aware and 51% cured. Implementing universal screening, providing unrestricted treatment and controlling HCV incidence were factors found to have the largest effect on improving the HCV care cascade.

Conclusions: Since the launch of DAAs, the HCV care cascade has shifted towards higher awareness and treatment rates; however, additional interventions are needed to move towards HCV elimination.
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http://dx.doi.org/10.1111/apt.15291DOI Listing
July 2019

Assessment of the Feasibility and Cost of Hepatitis C Elimination in Pakistan.

JAMA Netw Open 2019 05 3;2(5):e193613. Epub 2019 May 3.

Houston Veterans Affairs Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.

Importance: Chronic hepatitis C virus (HCV) infection is a global health problem. The World Health Assembly recently pledged to eliminate HCV by 2030. However, in Pakistan, a country with one of the highest prevalence rates, the feasibility and cost of HCV elimination are not known.

Objectives: To investigate whether and under what conditions HCV elimination is feasible in Pakistan and to estimate the cost of such elimination.

Design, Setting, And Participants: This decision analytical model study used a microsimulation model of the HCV epidemic in Pakistan from 2015 to 2030. Using Pakistan-specific variables, the model simulated the landscape of HCV in Pakistan and evaluated the minimum required screening and treatment rates needed to eliminate HCV in Pakistan. The study used simulated individuals chronically infected with HCV from 2015 to 2030. The analysis was performed in 2018.

Interventions: The status quo and 7 scenarios that can lead to HCV elimination in Pakistan by 2030, which were defined by different combinations of tests for screening, detection of viremia before treatment, and confirmation of treatment response.

Main Outcomes And Measures: Temporal trends in HCV infection prevalence, mortality, and disability-adjusted life-years and total cost of HCV infection care under the status quo and scenarios that can eliminate HCV by 2030.

Results: Under the status quo, from 2015 to 2030, 1.44 million people are projected to die of HCV infection; 48% of deaths would be among people younger than 50 years. To achieve HCV elimination in Pakistan, HCV testing would need to be scaled up to at least 25 million people to diagnose 900 000 persons and treatment to 700 000 people per year. Compared with the status quo, the elimination scenario would avert 323 000 liver-related deaths and 13.0 million HCV-associated disability-adjusted life-years from 2015 to 2030. The elimination scenario was associated with cost savings of $2.6 billion from 2018 to 2030 with use of a point-of-care test for population-wide antibody screening and detection of viremia and treatment response.

Conclusions And Relevance: Substantial scale-up of HCV testing and treatment may be essential to eliminate HCV infection in Pakistan, and such a strategy may be associated with cost savings in the near future. Although HCV elimination in Pakistan may be ambitious, strategic planning and strong support from the government may aid in its elimination.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.3613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512462PMC
May 2019

Performance Bound for Joint Multiple Parameter Target Estimation in Sparse Stepped-Frequency Radar: A Comparison Analysis.

Sensors (Basel) 2019 Apr 29;19(9). Epub 2019 Apr 29.

Department of Electronic and Information Engineering, Harbin Institute of Technology, Harbin 150001, China.

A performance bound-Cramér-Rao lower bound (CRLB) for target estimation and detection in sparse stepped frequency radars is presented. The vector formulation of this CRLB is used to obtain a lower bound on the estimation error. The estimation performance can be transformed into different types of CRLB structures. Therefore, the expressions of bounds under three equivalent models are derived separately: time delay and Doppler stretch estimator, joint multiple parameter estimator, and sparse-based estimator. The variables to be estimated include the variances of unknown noise, range, velocity, and the real and imaginary parts of the amplitude. A general performance expression is proposed by considering the echo of the target in the line-of-sight. When the relationship between CRLB and various parameters are discussed in detail, the specific effect of waveform parameters on a single CRLB is compared and analyzed. Numerical simulations demonstrated that the resulting CRLB exhibits considerable theoretical and practical significance for the selection of optimal waveform parameters.
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http://dx.doi.org/10.3390/s19092002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540301PMC
April 2019

Identification of the O-GalNAcylation site(s) on FOXA1 catalyzed by ppGalNAc-T2 enzyme in vitro.

Biochem Biophys Res Commun 2019 06 25;514(1):157-165. Epub 2019 Apr 25.

School of Life Science & Medicine, Dalian University of Technology, Panjin, China. Electronic address:

FOXA1 functions as a pioneer factor of transcriptional regulation that binds to specific sites in the chromatin and recruits other transcription factors, promoting the initiation of gene transcription and mediating the regulation of downstream target gene expression. FOXA1 was reported to facilitate or reprogram ERα binding, thus playing a key function in breast cancer progression. Our previous results indicated that the O-linked N-acetylgalactosamine (O-GalNAc) modification of FOXA1 plays a potentially significant role in the ERα transcription network. However, further investigations are needed to identify the specific mechanism of modification and the specific glycosylation sites on FOXA1. In this study, we first suggested that FOXA1 could be O-GalNAcylated by ppGalNAc-T2 in vitro. By dividing and expressing recombinant FOXA1 as three segments, two O-GalNAcylation sites were found on FOXA1, both located at the C-terminal of the protein. Then, synthesized peptides, including the predicted O-GalNAc sites in the C-terminus of FOXA1, were used in a vitro reaction, and peptides mutated at the predicted O-GalNAc sites were employed as controls. Through an ESI-MS assay, S354 and S355 were identified as probable O-GalNAcylation sites on FOXA1. Additionally, we performed ESI-ETD-MS/MS analysis of the full-length O-GalNAcylated FOXA1 protein and identified S355 as the O-GalNAc modification site on FOXA1, consistent with the peptide reaction. In conclusion, our results demonstrated that FOXA1 can be O-GalNAcylated by ppGalNAc-T2 at S355 in vitro. These results will provide new insights for studying the role of O-GalNAcylation in the development of breast cancer.
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http://dx.doi.org/10.1016/j.bbrc.2019.04.146DOI Listing
June 2019

Prevention of Prescription Opioid Misuse and Projected Overdose Deaths in the United States.

JAMA Netw Open 2019 02 1;2(2):e187621. Epub 2019 Feb 1.

Institute for Technology Assessment, Department of Radiology, Massachusetts General Hospital, Boston.

Importance: Deaths due to opioid overdose have tripled in the last decade. Efforts to curb this trend have focused on restricting the prescription opioid supply; however, the near-term effects of such efforts are unknown.

Objective: To project effects of interventions to lower prescription opioid misuse on opioid overdose deaths from 2016 to 2025.

Design, Setting, And Participants: This system dynamics (mathematical) model of the US opioid epidemic projected outcomes of simulated individuals who engage in nonmedical prescription or illicit opioid use from 2016 to 2025. The analysis was performed in 2018 by retrospectively calibrating the model from 2002 to 2015 data from the National Survey on Drug Use and Health and the Centers for Disease Control and Prevention.

Interventions: Comparison of interventions that would lower the incidence of prescription opioid misuse from 2016 to 2025 based on historical trends (a 7.5% reduction per year) and 50% faster than historical trends (an 11.3% reduction per year), vs a circumstance in which the incidence of misuse remained constant after 2015.

Main Outcomes And Measures: Opioid overdose deaths from prescription and illicit opioids from 2016 to 2025 under each intervention.

Results: Under the status quo, the annual number of opioid overdose deaths is projected to increase from 33 100 in 2015 to 81 700 (95% uncertainty interval [UI], 63 600-101 700) in 2025 (a 147% increase from 2015). From 2016 to 2025, 700 400 (95% UI, 590 200-817 100) individuals in the United States are projected to die from opioid overdose, with 80% of the deaths attributable to illicit opioids. The number of individuals using illicit opioids is projected to increase by 61%-from 0.93 million (95% UI, 0.83-1.03 million) in 2015 to 1.50 million (95% UI, 0.98-2.22 million) by 2025. Across all interventions tested, further lowering the incidence of prescription opioid misuse from 2015 levels is projected to decrease overdose deaths by only 3.0% to 5.3%.

Conclusions And Relevance: This study's findings suggest that interventions targeting prescription opioid misuse such as prescription monitoring programs may have a modest effect, at best, on the number of opioid overdose deaths in the near future. Additional policy interventions are urgently needed to change the course of the epidemic.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.7621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415966PMC
February 2019

Assessing the Effectiveness of Treatment Sequences for Older Patients With High-risk Follicular Lymphoma With a Multistate Model.

Clin Lymphoma Myeloma Leuk 2019 05 3;19(5):300-309.e5. Epub 2019 Jan 3.

Winship Cancer Institute of Emory University, Atlanta, GA.

Background: Disease progression within < 2 years of initial chemoimmunotherapy and patient age > 60 years have been associated with poor overall survival (OS) in follicular lymphoma (FL). No standard treatment exists for these high-risk patients, and the effectiveness of sequential therapies remains unclear.

Patients And Methods: We studied the course of FL with first-, second-, and third-line treatment. Using large population-based data, we identified 5234 patients with FL diagnosed in 2000 to 2009. Of these patients, 71% had received second-line therapy < 2 years, and 29% had received no therapy after first-line therapy, with a median OS of < 3 years. Treatment included rituximab, R-CVP (rituximab, cyclophosphamide, vincristine), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine), R-Other (other rituximab-containing), and other regimens. The Aalen-Johansen estimator and Cox proportional hazards models were used to quantify the outcomes and assess the effects of the clinical and sociodemographic factors.

Results: R-CHOP demonstrated the most favorable 5-year OS among first- (71%), second- (55%), and third-line (61%) therapies. First-line R-CHOP improved OS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.50-0.64) and reduced the mortality risks after first-line (HR, 0.60; 95% CI, 0.47-0.77), second-line (HR, 0.40; 95% CI, 0.29-0.53), and third-line (HR, 0.63; 95% CI, 0.53-0.76) treatments. B-symptoms, being married, and histologic grade 1/2 were associated with the use of earlier second-line therapy. Early progression from second- to third-line therapy was associated with poor OS. The repeated use of R-CHOP or R-CVP as first- and second-line treatment yielded high 2-year mortality rates (R-CHOP + R-CHOP, 17.3%; R-CVP + R-CVP, 21.1%).

Conclusion: Our multistate approach assessed the effect of sequential therapy on the immediate and subsequent treatment-line outcomes. We found that R-CHOP in any line improved OS for patients with high-risk FL.
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http://dx.doi.org/10.1016/j.clml.2018.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555660PMC
May 2019

Microsimulation Modeling in Oncology.

JCO Clin Cancer Inform 2018 12;2:1-11

Çağlar Çağlayan and Turgay Ayer, Georgia Institute of Technology; Hiromi Terawaki and Christopher R. Flowers, Emory University; Ashish Rai, American Cancer Society, Atlanta GA; and Qiushi Chen, Massachusetts General Hospital, Boston MA.

Purpose: Microsimulation is a modeling technique that uses a sample size of individual units (microunits), each with a unique set of attributes, and allows for the simulation of downstream events on the basis of predefined states and transition probabilities between those states over time. In this article, we describe the history of the role of microsimulation in medicine and its potential applications in oncology as useful tools for population risk stratification and treatment strategy design for precision medicine.

Methods: We conducted a comprehensive and methodical search of the literature using electronic databases-Medline, Embase, and Cochrane-for works published between 1985 and 2016. A medical subject heading search strategy was constructed for Medline searches by using a combination of relevant search terms, such as "microsimulation model medicine," "multistate modeling cancer," and "oncology."

Results: Microsimulation modeling is particularly useful for the study of optimal intervention strategies when randomized control trials may not be feasible, ethical, or practical. Microsimulation models can retain memory of prior behaviors and states. As such, it allows an explicit representation and understanding of how various processes propagate over time and affect the final outcomes for an individual or in a population.

Conclusion: A well-calibrated microsimulation model can be used to predict the outcome of the event of interest for a new individual or subpopulations, assess the effectiveness and cost effectiveness of alternative interventions, and project the future disease burden of oncologic diseases. In the growing field of oncology research, a microsimulation model can serve as a valuable tool among the various facets of methodology available.
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http://dx.doi.org/10.1200/CCI.17.00029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386553PMC
December 2018

Hep C Calculator: an online tool for cost-effectiveness analysis of DAAs.

Lancet Gastroenterol Hepatol 2018 12;3(12):819

Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

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http://dx.doi.org/10.1016/S2468-1253(18)30281-4DOI Listing
December 2018

A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in Leukemia.

Cancer Res 2018 12 22;78(24):6762-6770. Epub 2018 Oct 22.

Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon.

: Mutations in the colony-stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as acute myeloid leukemia. Here, we studied the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions were potently oncogenic and activated the receptor independently of its ligand GCSF. These mutations activated the JAK-STAT signaling pathway and conferred sensitivity to JAK inhibitors. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. N610 was also the primary site of sialylation of the receptor. Membrane-proximal N-linked glycosylation was critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Kinase inhibitors blocked growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation. SIGNIFICANCE: This study reveals the critical importance of membrane-proximal N-linked glycosylation of CSF3R for the maintenance of ligand dependency in leukemia.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295230PMC
December 2018

CRISPR/Cas9 gene editing for the creation of an MGAT1-deficient CHO cell line to control HIV-1 vaccine glycosylation.

PLoS Biol 2018 08 29;16(8):e2005817. Epub 2018 Aug 29.

Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California, United States of America.

Over the last decade, multiple broadly neutralizing monoclonal antibodies (bN-mAbs) to the HIV-1 envelope protein (Env) gp120 have been described. Many of these recognize epitopes consisting of both amino acid and glycan residues. Moreover, the glycans required for binding of these bN-mAbs are early intermediates in the N-linked glycosylation pathway. This type of glycosylation substantially alters the mass and net charge of Envs compared to molecules with the same amino acid sequence but possessing mature, complex (sialic acid-containing) carbohydrates. Since cell lines suitable for biopharmaceutical production that limit N-linked glycosylation to mannose-5 (Man5) or earlier intermediates are not readily available, the production of vaccine immunogens displaying these glycan-dependent epitopes has been challenging. Here, we report the development of a stable suspension-adapted Chinese hamster ovary (CHO) cell line that limits glycosylation to Man5 and earlier intermediates. This cell line was created using the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing system and contains a mutation that inactivates the gene encoding Mannosyl (Alpha-1,3-)-Glycoprotein Beta-1,2-N-Acetylglucosaminyltransferase (MGAT1). Monomeric gp120s produced in the MGAT1- CHO cell line exhibit improved binding to prototypic glycan-dependent bN-mAbs directed to the V1/V2 domain (e.g., PG9) and the V3 stem (e.g., PGT128 and 10-1074) while preserving the structure of the important glycan-independent epitopes (e.g., VRC01). The ability of the MGAT1- CHO cell line to limit glycosylation to early intermediates in the N-linked glycosylation pathway without impairing the doubling time or ability to grow at high cell densities suggests that it will be a useful substrate for the biopharmaceutical production of HIV-1 vaccine immunogens.
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http://dx.doi.org/10.1371/journal.pbio.2005817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133382PMC
August 2018