Publications by authors named "Chieh-Hsi Wu"

100 Publications

Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil.

medRxiv 2021 Mar 3. Epub 2021 Mar 3.

Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite high levels of previous infection there. Through genome sequencing of viruses sampled in Manaus between November 2020 and January 2021, we identified the emergence and circulation of a novel SARS-CoV-2 variant of concern, lineage P.1, that acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around early November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.4-2.2 times more transmissible and 25-61% more likely to evade protective immunity elicited by previous infection with non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

One-sentence Summary: We report the evolution and emergence of a SARS-CoV-2 lineage of concern associated with rapid transmission in Manaus.
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http://dx.doi.org/10.1101/2021.02.26.21252554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941639PMC
March 2021

Dataset on SARS-CoV-2 non-pharmaceutical interventions in Brazilian municipalities.

Sci Data 2021 03 4;8(1):73. Epub 2021 Mar 4.

Department of Zoology, University of Oxford, Oxford, UK.

Brazil has one of the fastest-growing COVID-19 epidemics worldwide. Non-pharmaceutical interventions (NPIs) have been adopted at the municipal level with asynchronous actions taken across 5,568 municipalities and the Federal District. This paper systematises the fragmented information on NPIs reporting on a novel dataset with survey responses from 4,027 mayors, covering 72.3% of all municipalities in the country. This dataset responds to the urgency to track and share findings on fragmented policies during the COVID-19 pandemic. Quantifying NPIs can help to assess the role of interventions in reducing transmission. We offer spatial and temporal details for a range of measures aimed at implementing social distancing and the dates when these measures were relaxed by local governments.
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http://dx.doi.org/10.1038/s41597-021-00859-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933188PMC
March 2021

Association between coronavirus disease 2019 (COVID-19) and long-term exposure to air pollution: Evidence from the first epidemic wave in China.

Environ Pollut 2021 May 8;276:116682. Epub 2021 Feb 8.

Department of Occupational and Environmental Health Sciences, School of Public Health, Peking University, China. Electronic address:

People with chronic obstructive pulmonary disease, cardiovascular disease, or hypertension have a high risk of developing severe coronavirus disease 2019 (COVID-19) and of COVID-19 mortality. However, the association between long-term exposure to air pollutants, which increases cardiopulmonary damage, and vulnerability to COVID-19 has not yet been fully established. We collected data of confirmed COVID-19 cases during the first wave of the epidemic in mainland China. We fitted a generalized linear model using city-level COVID-19 cases and severe cases as the outcome, and long-term average air pollutant levels as the exposure. Our analysis was adjusted using several variables, including a mobile phone dataset, covering human movement from Wuhan before the travel ban and movements within each city during the period of the emergency response. Other variables included smoking prevalence, climate data, socioeconomic data, education level, and number of hospital beds for 324 cities in China. After adjusting for human mobility and socioeconomic factors, we found an increase of 37.8% (95% confidence interval [CI]: 23.8%-52.0%), 32.3% (95% CI: 22.5%-42.4%), and 14.2% (7.9%-20.5%) in the number of COVID-19 cases for every 10-μg/m increase in long-term exposure to NO, PM, and PM, respectively. However, when stratifying the data according to population size, the association became non-significant. The present results are derived from a large, newly compiled and geocoded repository of population and epidemiological data relevant to COVID-19. The findings suggested that air pollution may be related to population vulnerability to COVID-19 infection, although the extent to which this relationship is confounded by city population density needs further exploration.
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http://dx.doi.org/10.1016/j.envpol.2021.116682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868737PMC
May 2021

Circulating level of microRNA-142-5p is a potential biomarker for predicting in-stent restenosis: a case-control study.

BMC Cardiovasc Disord 2021 Feb 8;21(1):77. Epub 2021 Feb 8.

School of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan.

Background: Patients who receive percutaneous coronary intervention (PCI) have different chances of developing in-stent restenosis (ISR). To date, no predictable biomarker can be applied in the clinic. MicroRNAs (miRNAs or miRs) play critical roles in transcription regulation, and their circulating levels were reported to have potential as clinical biomarkers.

Methods: In total, 93 coronary stent-implanted patients without pregnancy, liver or renal dysfunction, malignancy, hemophilia, or autoimmune diseases were recruited in this clinical study. All recruited participants were divided into an ISR group (n = 45) and a non-ISR group (n = 48) based on their restenotic status as confirmed by cardiologists at the first follow-up visit (6 months after surgery). Blood samples of all participants were harvested to measure circulating levels of miRNA candidates (miR-132, miR-142-5p, miR-15b, miR-24-2, and miR-424) to evaluate whether these circulating miRNAs can be applied as predictive biomarkers of ISR.

Results: Our data indicated that circulating levels of miR-142-5p were significantly higher in the ISR population, and results from the receiver operating characteristic (ROC) curve analysis also demonstrated superior discriminatory ability of miR-142-5p in predicting patients' restenotic status. In addition, circulating levels of miR-15b, miR-24-2, and miR-424 had differential expressions in participants with diabetes, hyperlipidemia, and hypertension, respectively.

Conclusions: The current study revealed that the circulating level of miR-142-5p has potential application as a clinical biomarker for predicting the development of ISR in stent-implanted patients.
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http://dx.doi.org/10.1186/s12872-021-01893-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869494PMC
February 2021

Establishing diagnostic algorithms for SARS-CoV-2 nucleic acid testing in clinical practice.

J Chin Med Assoc 2020 Nov 9. Epub 2020 Nov 9.

Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Background: Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. Our laboratory initially used a two-step molecular assay, first reported by Corman et al., for SARS-CoV-2 identification (the T-CDC method). As rapid and accurate diagnosis of COVID-19 is required to control the spread of this infectious disease, the current study evaluated three commercially available assays, including the TaqPath COVID-19 Combo kit, the cobas® SARS-CoV-2 test and the Rendu 2019-nCoV Assay kit, to establish diagnostic algorithms for clinical laboratories.

Methods: A total of 790 clinical specimens, including nasopharyngeal swabs, throat swabs, sputum, saliva, stool, endotracheal aspirate and serum were obtained from patients who were suspected or already confirmed to have COVID-19 at the Taipei Veterans General Hospital from February to May 2020. These specimens were tested for SARS-CoV-2 using the different assays and the performance variance between the assays was analyzed.

Results: Of the assays we evaluated, the T-CDC method and the TaqPath COVID-19 Combo kit require lots of hands-on practical lab work, while the cobas® SARS-CoV-2 test and the Rendu 2019-nCoV Assay kit are fully automated detection systems. The T-CDC method and the TaqPath COVID-19 Combo kit showed similar detection sensitivity, however, the T-CDC method frequently delivered false positive signals for E and/or RdRP gene detection, thus increasing the risk of reporting false positive results. A manual test-based testing strategy combining the T-CDC method and the TaqPath COVID-19 Combo kit was developed, which demonstrated excellent concordance rates (>99%) with the cobas and Rendu automatic systems. There were a few cases showing discrepant results, which may be due to the varied detection sensitivities as well as targets among the different platforms. Moreover, the concordance rate between the cobas and Rendu assays was 100%.

Conclusion: Based on our evaluation, two SARS-CoV-2 diagnostic algorithms, one focusing on the manual assays and the other on the automatic platforms, were proposed. Our results provide valuable information that allow clinical laboratories to implement optimal diagnostic strategies for SARS-CoV-2 testing based on their clinical needs, such as test volume, turn-around time, and staff/resource limitations.
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http://dx.doi.org/10.1097/JCMA.0000000000000456DOI Listing
November 2020

Sclareol ameliorated ERCC1-mediated cisplatin resistance in A549 human lung adenocarcinoma cells and a murine xenograft tumor model by suppressing AKT-GSK3β-AP1/Snail and JNK-AP1 pathways.

Chem Biol Interact 2020 Dec 24;332:109304. Epub 2020 Oct 24.

School of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan. Electronic address:

Cisplatin-based chemotherapy is a common first-line regimen for treating non-small cell lung cancer (NSCLC). However, drug resistance is still a major problem. The purposes of this study were to evaluate whether sclareol can reverse cisplatin resistance and to investigate its possible mechanisms. A549 cells, the human NSCLC cells with inherent cisplatin resistance, were used to investigate synergistic effect of sclareol with cisplatin in cell proliferation and migration as well as its regulatory mechanisms in expression of excision repair cross-complementation group 1 (ERCC1), a cisplatin resistance-associated molecule. Nude mice bearing subcutaneous A549 tumors were applied to investigate synergistic activity of sclareol in anti-tumor. As comparing to the cisplatin alone group, the treatment of cisplatin combined with sclareol significantly suppressed survival rate and cell migration of A549 cells. Besides, sclareol also exhibited suppression in ERCC1 expression by inhibiting AKT-GSK3β-AP1/Snail and JNK-AP1 pathways. Furthermore, the experimental data from in vivo study also demonstrated that the combination group of cisplatin and sclareol showed the greatest anti-tumor activity, whose effect could be partially attributed to sclareol-mediated decrease in intratumoral level of ERCC1 protein. Accordingly, sclareol has potential as an adjuvant for the treatment in NSCLC patients with cisplatin resistance.
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http://dx.doi.org/10.1016/j.cbi.2020.109304DOI Listing
December 2020

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer.

Cancer Genet 2020 10 21;248-249:1-10. Epub 2020 Aug 21.

Oxford Institute of Radiation Oncology, University of Oxford, United Kingdom.

We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer.

Background: NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights.

Methods: Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms.

Results: 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2-2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086-1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06-1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04-1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particularly enriched in Consensus Molecular Subtype (CMS) 4.

Conclusion: For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study.
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http://dx.doi.org/10.1016/j.cancergen.2020.08.006DOI Listing
October 2020

Epidemiological and clinical characteristics of the COVID-19 epidemic in Brazil.

Nat Hum Behav 2020 08 31;4(8):856-865. Epub 2020 Jul 31.

Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

The first case of COVID-19 was detected in Brazil on 25 February 2020. We report and contextualize epidemiological, demographic and clinical findings for COVID-19 cases during the first 3 months of the epidemic. By 31 May 2020, 514,200 COVID-19 cases, including 29,314 deaths, had been reported in 75.3% (4,196 of 5,570) of municipalities across all five administrative regions of Brazil. The R value for Brazil was estimated at 3.1 (95% Bayesian credible interval = 2.4-5.5), with a higher median but overlapping credible intervals compared with some other seriously affected countries. A positive association between higher per-capita income and COVID-19 diagnosis was identified. Furthermore, the severe acute respiratory infection cases with unknown aetiology were associated with lower per-capita income. Co-circulation of six respiratory viruses was detected but at very low levels. These findings provide a comprehensive description of the ongoing COVID-19 epidemic in Brazil and may help to guide subsequent measures to control virus transmission.
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http://dx.doi.org/10.1038/s41562-020-0928-4DOI Listing
August 2020

Evolution and epidemic spread of SARS-CoV-2 in Brazil.

Science 2020 09 23;369(6508):1255-1260. Epub 2020 Jul 23.

Department of Zoology, University of Oxford, Oxford, UK.

Brazil currently has one of the fastest-growing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemics in the world. Because of limited available data, assessments of the impact of nonpharmaceutical interventions (NPIs) on this virus spread remain challenging. Using a mobility-driven transmission model, we show that NPIs reduced the reproduction number from >3 to 1 to 1.6 in São Paulo and Rio de Janeiro. Sequencing of 427 new genomes and analysis of a geographically representative genomic dataset identified >100 international virus introductions in Brazil. We estimate that most (76%) of the Brazilian strains fell in three clades that were introduced from Europe between 22 February and 11 March 2020. During the early epidemic phase, we found that SARS-CoV-2 spread mostly locally and within state borders. After this period, despite sharp decreases in air travel, we estimated multiple exportations from large urban centers that coincided with a 25% increase in average traveled distances in national flights. This study sheds new light on the epidemic transmission and evolutionary trajectories of SARS-CoV-2 lineages in Brazil and provides evidence that current interventions remain insufficient to keep virus transmission under control in this country.
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http://dx.doi.org/10.1126/science.abd2161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402630PMC
September 2020

Image-based consensus molecular subtype (imCMS) classification of colorectal cancer using deep learning.

Gut 2021 Mar 20;70(3):544-554. Epub 2020 Jul 20.

Department of Oncology, University of Oxford, Oxford, UK

Objective: Complex phenotypes captured on histological slides represent the biological processes at play in individual cancers, but the link to underlying molecular classification has not been clarified or systematised. In colorectal cancer (CRC), histological grading is a poor predictor of disease progression, and consensus molecular subtypes (CMSs) cannot be distinguished without gene expression profiling. We hypothesise that image analysis is a cost-effective tool to associate complex features of tissue organisation with molecular and outcome data and to resolve unclassifiable or heterogeneous cases. In this study, we present an image-based approach to predict CRC CMS from standard H&E sections using deep learning.

Design: Training and evaluation of a neural network were performed using a total of n=1206 tissue sections with comprehensive multi-omic data from three independent datasets (training on FOCUS trial, n=278 patients; test on rectal cancer biopsies, GRAMPIAN cohort, n=144 patients; and The Cancer Genome Atlas (TCGA), n=430 patients). Ground truth CMS calls were ascertained by matching random forest and single sample predictions from CMS classifier.

Results: Image-based CMS (imCMS) accurately classified slides in unseen datasets from TCGA (n=431 slides, AUC)=0.84) and rectal cancer biopsies (n=265 slides, AUC=0.85). imCMS spatially resolved intratumoural heterogeneity and provided secondary calls correlating with bioinformatic prediction from molecular data. imCMS classified samples previously unclassifiable by RNA expression profiling, reproduced the expected correlations with genomic and epigenetic alterations and showed similar prognostic associations as transcriptomic CMS.

Conclusion: This study shows that a prediction of RNA expression classifiers can be made from H&E images, opening the door to simple, cheap and reliable biological stratification within routine workflows.
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http://dx.doi.org/10.1136/gutjnl-2019-319866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873419PMC
March 2021

The effect of human mobility and control measures on the COVID-19 epidemic in China.

medRxiv 2020 Mar 6. Epub 2020 Mar 6.

Network Science Institute, Northeastern University, Boston, United States.

The ongoing COVID-19 outbreak has expanded rapidly throughout China. Major behavioral, clinical, and state interventions are underway currently to mitigate the epidemic and prevent the persistence of the virus in human populations in China and worldwide. It remains unclear how these unprecedented interventions, including travel restrictions, have affected COVID-19 spread in China. We use real-time mobility data from Wuhan and detailed case data including travel history to elucidate the role of case importation on transmission in cities across China and ascertain the impact of control measures. Early on, the spatial distribution of COVID-19 cases in China was well explained by human mobility data. Following the implementation of control measures, this correlation dropped and growth rates became negative in most locations, although shifts in the demographics of reported cases are still indicative of local chains of transmission outside Wuhan. This study shows that the drastic control measures implemented in China have substantially mitigated the spread of COVID-19.
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http://dx.doi.org/10.1101/2020.03.02.20026708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239080PMC
March 2020

An investigation of transmission control measures during the first 50 days of the COVID-19 epidemic in China.

Science 2020 05 31;368(6491):638-642. Epub 2020 Mar 31.

Department of Zoology, University of Oxford, Oxford, UK.

Responding to an outbreak of a novel coronavirus [agent of coronavirus disease 2019 (COVID-19)] in December 2019, China banned travel to and from Wuhan city on 23 January 2020 and implemented a national emergency response. We investigated the spread and control of COVID-19 using a data set that included case reports, human movement, and public health interventions. The Wuhan shutdown was associated with the delayed arrival of COVID-19 in other cities by 2.91 days. Cities that implemented control measures preemptively reported fewer cases on average (13.0) in the first week of their outbreaks compared with cities that started control later (20.6). Suspending intracity public transport, closing entertainment venues, and banning public gatherings were associated with reductions in case incidence. The national emergency response appears to have delayed the growth and limited the size of the COVID-19 epidemic in China, averting hundreds of thousands of cases by 19 February (day 50).
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http://dx.doi.org/10.1126/science.abb6105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164389PMC
May 2020

The effect of human mobility and control measures on the COVID-19 epidemic in China.

Science 2020 05 25;368(6490):493-497. Epub 2020 Mar 25.

Network Science Institute, Northeastern University, Boston, MA, USA.

The ongoing coronavirus disease 2019 (COVID-19) outbreak expanded rapidly throughout China. Major behavioral, clinical, and state interventions were undertaken to mitigate the epidemic and prevent the persistence of the virus in human populations in China and worldwide. It remains unclear how these unprecedented interventions, including travel restrictions, affected COVID-19 spread in China. We used real-time mobility data from Wuhan and detailed case data including travel history to elucidate the role of case importation in transmission in cities across China and to ascertain the impact of control measures. Early on, the spatial distribution of COVID-19 cases in China was explained well by human mobility data. After the implementation of control measures, this correlation dropped and growth rates became negative in most locations, although shifts in the demographics of reported cases were still indicative of local chains of transmission outside of Wuhan. This study shows that the drastic control measures implemented in China substantially mitigated the spread of COVID-19.
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http://dx.doi.org/10.1126/science.abb4218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146642PMC
May 2020

Epidemiological data from the COVID-19 outbreak, real-time case information.

Sci Data 2020 03 24;7(1):106. Epub 2020 Mar 24.

Department of Zoology, University of Oxford, Oxford, United Kingdom.

Cases of a novel coronavirus were first reported in Wuhan, Hubei province, China, in December 2019 and have since spread across the world. Epidemiological studies have indicated human-to-human transmission in China and elsewhere. To aid the analysis and tracking of the COVID-19 epidemic we collected and curated individual-level data from national, provincial, and municipal health reports, as well as additional information from online reports. All data are geo-coded and, where available, include symptoms, key dates (date of onset, admission, and confirmation), and travel history. The generation of detailed, real-time, and robust data for emerging disease outbreaks is important and can help to generate robust evidence that will support and inform public health decision making.
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http://dx.doi.org/10.1038/s41597-020-0448-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093412PMC
March 2020

Oxidative stress-induced cellular senescence desensitizes cell growth and migration of vascular smooth muscle cells through down-regulation of platelet-derived growth factor receptor-beta.

Aging (Albany NY) 2019 10 3;11(19):8085-8102. Epub 2019 Oct 3.

School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.

The relationship between aging and restenosis are unclear. The purposes of this study were to investigate the possible pathological role and mechanism of aging on formation of restenosis. Our data indicated that cell proliferation and migration of the oxidative stress-induced senescent vascular smooth muscle cells were obviously desensitized to stimulation by platelet-derived growth factor (PDGF)-BB, which may have been caused by suppression of promoter activity, transcription, translation, and activation levels of PDGF receptor (PDGFR)-β. The analyzed data obtained from the binding array of transcription factors (TFs) showed that binding levels of eighteen TFs on the PDGFR-β promoter region (-523 to -1) were significantly lower in senescent cells compared to those of non-senescent cells. Among these TFs, the bioinformatics prediction suggested that the putative binding sites of ten TFs were found in this promoter region. Of these, transcriptional levels of seven TFs were markedly reduced in senescent cells. The clinical data showed that the proportion of restenosis was relatively lower in the older group than that in the younger group. Our study results suggested that a PDGFR-β-mediated pathway was suppressed in aging cells, and our clinical data showed that age and the vascular status were slightly negatively correlated in overall participants.
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http://dx.doi.org/10.18632/aging.102270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814625PMC
October 2019

Emergence of the Asian lineage of Zika virus in Angola: an outbreak investigation.

Lancet Infect Dis 2019 10;19(10):1138-1147

Department of Zoology, University of Oxford, Oxford, UK. Electronic address:

Background: Zika virus infections and suspected microcephaly cases have been reported in Angola since late 2016, but no data are available about the origins, epidemiology, and diversity of the virus. We aimed to investigate the emergence and circulation of Zika virus in Angola.

Methods: Diagnostic samples collected by the Angolan Ministry of Health as part of routine arboviral surveillance were tested by real-time reverse transcription PCR by the Instituto Nacional de Investigação em Saúde (Ministry of Health, Luanda, Angola). To identify further samples positive for Zika virus and appropriate for genomic sequencing, we also tested samples from a 2017 study of people with HIV in Luanda. Portable sequencing was used to generate Angolan Zika virus genome sequences from three people positive for Zika virus infection by real-time reverse transcription PCR, including one neonate with microcephaly. Genetic and mobility data were analysed to investigate the date of introduction and geographical origin of Zika virus in Angola. Brain CT and MRI, and serological assays were done on a child with microcephaly to confirm microcephaly and assess previous Zika virus infection.

Findings: Serum samples from 54 people with suspected acute Zika virus infection, 76 infants with suspected microcephaly, 24 mothers of infants with suspected microcephaly, 336 patients with suspected dengue virus or chikungunya virus infection, and 349 samples from the HIV study were tested by real-time reverse transcription PCR. Four cases identified between December, 2016, and June, 2017, tested positive for Zika virus. Analyses of viral genomic and human mobility data suggest that Zika virus was probably introduced to Angola from Brazil between July, 2015, and June, 2016. This introduction probably initiated local circulation of Zika virus in Angola that continued until at least June, 2017. The infant with microcephaly in whom CT and MRI were done had brain abnormalities consistent with congenital Zika syndrome and serological evidence for Zika virus infection.

Interpretation: Our analyses show that autochthonous transmission of the Asian lineage of Zika virus has taken place in Africa. Zika virus surveillance and surveillance of associated cases of microcephaly throughout the continent is crucial.

Funding: Royal Society, Wellcome Trust, Global Challenges Research Fund (UK Research and Innovation), Africa Oxford, John Fell Fund, Oxford Martin School, European Research Council, Departamento de Ciência e Tecnologia/Ministério da Saúde/National Council for Scientific and Technological Development, and Ministério da Educação/Coordenação de Aperfeicoamento de Pessoal de Nível Superior.
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http://dx.doi.org/10.1016/S1473-3099(19)30293-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892302PMC
October 2019

BEAST 2.5: An advanced software platform for Bayesian evolutionary analysis.

PLoS Comput Biol 2019 04 8;15(4):e1006650. Epub 2019 Apr 8.

Centre of Computational Evolution, University of Auckland, Auckland, New Zealand.

Elaboration of Bayesian phylogenetic inference methods has continued at pace in recent years with major new advances in nearly all aspects of the joint modelling of evolutionary data. It is increasingly appreciated that some evolutionary questions can only be adequately answered by combining evidence from multiple independent sources of data, including genome sequences, sampling dates, phenotypic data, radiocarbon dates, fossil occurrences, and biogeographic range information among others. Including all relevant data into a single joint model is very challenging both conceptually and computationally. Advanced computational software packages that allow robust development of compatible (sub-)models which can be composed into a full model hierarchy have played a key role in these developments. Developing such software frameworks is increasingly a major scientific activity in its own right, and comes with specific challenges, from practical software design, development and engineering challenges to statistical and conceptual modelling challenges. BEAST 2 is one such computational software platform, and was first announced over 4 years ago. Here we describe a series of major new developments in the BEAST 2 core platform and model hierarchy that have occurred since the first release of the software, culminating in the recent 2.5 release.
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http://dx.doi.org/10.1371/journal.pcbi.1006650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472827PMC
April 2019

High-Resolution Evolutionary Analysis of Within-Host Hepatitis C Virus Infection.

J Infect Dis 2019 05;219(11):1722-1729

Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, United Kingdom.

Background: Despite recent breakthroughs in treatment of hepatitis C virus (HCV) infection, we have limited understanding of how virus diversity generated within individuals impacts the evolution and spread of HCV variants at the population scale. Addressing this gap is important for identifying the main sources of disease transmission and evaluating the risk of drug-resistance mutations emerging and disseminating in a population.

Methods: We have undertaken a high-resolution analysis of HCV within-host evolution from 4 individuals coinfected with human immunodeficiency virus 1 (HIV-1). We used long-read, deep-sequenced data of full-length HCV envelope glycoprotein, longitudinally sampled from acute to chronic HCV infection to investigate the underlying viral population and evolutionary dynamics.

Results: We found statistical support for population structure maintaining the within-host HCV genetic diversity in 3 out of 4 individuals. We also report the first population genetic estimate of the within-host recombination rate for HCV (0.28 × 10-7 recombination/site/year), which is considerably lower than that estimated for HIV-1 and the overall nucleotide substitution rate estimated during HCV infection.

Conclusions: Our findings indicate that population structure and strong genetic linkage shapes within-host HCV evolutionary dynamics. These results will guide the future investigation of potential HCV drug resistance adaptation during infection, and at the population scale.
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http://dx.doi.org/10.1093/infdis/jiy747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500553PMC
May 2019

Evolution of HIV-1 within untreated individuals and at the population scale in Uganda.

PLoS Pathog 2018 07 27;14(7):e1007167. Epub 2018 Jul 27.

Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

HIV-1 undergoes multiple rounds of error-prone replication between transmission events, resulting in diverse viral populations within and among individuals. In addition, the virus experiences different selective pressures at multiple levels: during the course of infection, at transmission, and among individuals. Disentangling how these evolutionary forces shape the evolution of the virus at the population scale is important for understanding pathogenesis, how drug- and immune-escape variants are likely to spread in populations, and the development of preventive vaccines. To address this, we deep-sequenced two regions of the HIV-1 genome (p24 and gp41) from 34 longitudinally-sampled untreated individuals from Rakai District in Uganda, infected with subtypes A, D, and inter-subtype recombinants. This dataset substantially increases the availability of HIV-1 sequence data that spans multiple years of untreated infection, in particular for different geographical regions and viral subtypes. In line with previous studies, we estimated an approximately five-fold faster rate of evolution at the within-host compared to the population scale for both synonymous and nonsynonymous substitutions, and for all subtypes. We determined the extent to which this mismatch in evolutionary rates can be explained by the evolution of the virus towards population-level consensus, or the transmission of viruses similar to those that establish infection within individuals. Our findings indicate that both processes are likely to be important.
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http://dx.doi.org/10.1371/journal.ppat.1007167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082572PMC
July 2018

Genomic Epidemiology Reconstructs the Introduction and Spread of Zika Virus in Central America and Mexico.

Cell Host Microbe 2018 06 24;23(6):855-864.e7. Epub 2018 May 24.

Department of Zoology, University of Oxford, Oxford, UK. Electronic address:

The Zika virus (ZIKV) epidemic in the Americas established ZIKV as a major public health threat and uncovered its association with severe diseases, including microcephaly. However, genetic epidemiology in some at-risk regions, particularly Central America and Mexico, remains limited. We report 61 ZIKV genomes from this region, generated using metagenomic sequencing with ZIKV-specific enrichment, and combine phylogenetic, epidemiological, and environmental data to reconstruct ZIKV transmission. These analyses revealed multiple independent ZIKV introductions to Central America and Mexico. One introduction, likely from Brazil via Honduras, led to most infections and the undetected spread of ZIKV through the region from late 2014. Multiple lines of evidence indicate biannual peaks of ZIKV transmission in the region, likely driven by varying local environmental conditions for mosquito vectors and herd immunity. The spatial and temporal heterogeneity of ZIKV transmission in Central America and Mexico challenges arbovirus surveillance and disease control measures.
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http://dx.doi.org/10.1016/j.chom.2018.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006413PMC
June 2018

Suppression of Cell Growth, Migration and Drug Resistance by Ethanolic Extract of Antrodia cinnamomea in Human Lung Cancer A549 Cells and C57BL/6J Allograft Tumor Model.

Int J Mol Sci 2018 Mar 9;19(3). Epub 2018 Mar 9.

School of Pharmacy, China Medical University, Taichung 40402, Taiwan.

The purpose of this study was to investigate the inhibitory activities of ethanolic extracts from (EEAC) on lung cancer. Cell proliferation and cell cycle distribution were analyzed using (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay and flow cytometry, respectively. Wound-healing assay, Western blotting, and a murine tumor model were separately used to examine cell migration, protein expression, and tumor repression. Our results showed that EEAC induced cell cycle arrest at the G0/G1 phase resulting decreased cell viability in A549 cells. Moreover, EEAC up-regulated the growth-suppressing proteins, adenosine 5'-monophosphate-activated protein kinase (AMPK), p21 and p27, but down-regulated the growth-promoting proteins, protein kinase B (Akt), mammalian tarfet of rapamycin (mTOR), extracellular signal-regulating kinase 1/2 (ERK1/2), retinoblastoma protein (Rb), cyclin E, and cyclin D1. EEAC also inhibited A549 cell migration and reduced expression of gelatinases. In addition, our data showed that tumor growth was suppressed after treatment with EEAC in a murine allograft tumor model. Some bioactive compounds from EEAC, such as cordycepin and zhankuic acid A, were demonstrated to reduce the protein expressions of matrix metalloproteinase (MMP)-9 and cyclin D1 in A549 cells. Furthermore, EEAC enhanced chemosensitivity of A549 to paclitaxel by reducing the protein levels of caveolin-1. Our data suggests that EEAC has the potential to be an adjuvant medicine for the treatment of lung cancer.
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http://dx.doi.org/10.3390/ijms19030791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877652PMC
March 2018

Severe infections emerge from commensal bacteria by adaptive evolution.

Elife 2017 12 19;6. Epub 2017 Dec 19.

Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, Oxford, United Kingdom.

Bacteria responsible for the greatest global mortality colonize the human microbiota far more frequently than they cause severe infections. Whether mutation and selection among commensal bacteria are associated with infection is unknown. We investigated de novo mutation in 1163 genomes from 105 infected patients with nose colonization. We report that 72% of infections emerged from the nose, with infecting and nose-colonizing bacteria showing parallel adaptive differences. We found 2.8-to-3.6-fold adaptive enrichments of protein-altering variants in genes responding to , which regulates surface antigens and toxin production; , which regulates quorum-sensing, toxin production and abscess formation; and host-derived antimicrobial peptides. Adaptive mutations in pathogenesis-associated genes were 3.1-fold enriched in infecting but not nose-colonizing bacteria. None of these signatures were observed in healthy carriers nor at the species-level, suggesting infection-associated, short-term, within-host selection pressures. Our results show that signatures of spontaneous adaptive evolution are specifically associated with infection, raising new possibilities for diagnosis and treatment.
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http://dx.doi.org/10.7554/eLife.30637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736351PMC
December 2017

Suppressive activities and mechanisms of ugonin J on vascular smooth muscle cells and balloon angioplasty-induced neointimal hyperplasia.

Phytother Res 2018 Feb 18;32(2):312-320. Epub 2017 Dec 18.

School of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan.

Neointimal hyperplasia (or restenosis) is primarily attributed to excessive proliferation and migration of vascular smooth muscle cells (VSMCs). In this study, we investigated the inhibitory effects and mechanisms of ugonin J on VSMC proliferation and migration as well as neointimal formation. Cell viability and the cell-cycle distribution were, respectively, analyzed using an MTT assay and flow cytometry. Cell migration was examined using a wound-healing analysis and a transwell assay. Protein expressions and gelatinase activities were, respectively, measured using Western blot and gelatin zymography. Balloon angioplasty-induced neointimal formation was induced in a rat carotid artery model and then examined using immunohistochemical staining. Ugonin J induced cell-cycle arrest at the G /G phase and apoptosis to inhibit VSMC growth. Ugonin J also exhibited marked suppressive activity on VSMC migration. Ugonin J significantly reduced activations of focal adhesion kinase, phosphoinositide 3-kinase, v-akt murine thymoma viral oncogene homolog 1, and extracellular signal-regulated kinase 1/2 proteins. Moreover, ugonin J obviously reduced expressions and activity levels of matrix metalloproteinase-2 and matrix metalloproteinase-9. In vivo data indicated that ugonin J prevented balloon angioplasty-induced neointimal hyperplasia. Our study suggested that ugonin J has the potential for application in the prevention of balloon injury-induced neointimal formation.
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http://dx.doi.org/10.1002/ptr.5979DOI Listing
February 2018

Genomic and epidemiological characterisation of a dengue virus outbreak among blood donors in Brazil.

Sci Rep 2017 11 9;7(1):15216. Epub 2017 Nov 9.

Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.

Outbreaks caused by Dengue, Zika and Chikungunya viruses can spread rapidly in immunologically naïve populations. By analysing 92 newly generated viral genome sequences from blood donors and recipients, we assess the dynamics of dengue virus serotype 4 during the 2012 outbreak in Rio de Janeiro. Phylogenetic analysis indicates that the outbreak was caused by genotype II, although two isolates of genotype I were also detected for the first time in Rio de Janeiro. Evolutionary analysis and modelling estimates are congruent, indicating a reproduction number above 1 between January and June, and at least two thirds of infections being unnoticed. Modelling analysis suggests that viral transmission started in early January, which is consistent with multiple introductions, most likely from the northern states of Brazil, and with an increase in within-country air travel to Rio de Janeiro. The combination of genetic and epidemiological data from blood donor banks may be useful to anticipate epidemic spread of arboviruses.
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http://dx.doi.org/10.1038/s41598-017-15152-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680240PMC
November 2017

Evolutionary dynamics of language systems.

Proc Natl Acad Sci U S A 2017 10 4;114(42):E8822-E8829. Epub 2017 Oct 4.

Department of Linguistic and Cultural Evolution, Max Planck Institute for the Science of Human History, 07745 Jena, Germany.

Understanding how and why language subsystems differ in their evolutionary dynamics is a fundamental question for historical and comparative linguistics. One key dynamic is the rate of language change. While it is commonly thought that the rapid rate of change hampers the reconstruction of deep language relationships beyond 6,000-10,000 y, there are suggestions that grammatical structures might retain more signal over time than other subsystems, such as basic vocabulary. In this study, we use a Dirichlet process mixture model to infer the rates of change in lexical and grammatical data from 81 Austronesian languages. We show that, on average, most grammatical features actually change faster than items of basic vocabulary. The grammatical data show less schismogenesis, higher rates of homoplasy, and more bursts of contact-induced change than the basic vocabulary data. However, there is a core of grammatical and lexical features that are highly stable. These findings suggest that different subsystems of language have differing dynamics and that careful, nuanced models of language change will be needed to extract deeper signal from the noise of parallel evolution, areal readaptation, and contact.
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http://dx.doi.org/10.1073/pnas.1700388114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651730PMC
October 2017

Toxicological effects of NCKU-21, a phenanthrene derivative, on cell growth and migration of A549 and CL1-5 human lung adenocarcinoma cells.

PLoS One 2017 25;12(9):e0185021. Epub 2017 Sep 25.

School of Pharmacy, Taipei Medical University, Taipei, Taiwan.

Background: Chemotherapy insensitivity continues to pose significant challenges for treating non-small cell lung cancer (NSCLC). The purposes of this study were to investigate whether 3,6-dimethoxy-1,4,5,8-phenanthrenetetraone (NCKU-21) has potential activity to induce effective toxicological effects in different ethnic NSCLC cell lines, A549 and CL1-5 cells, and to examine its anticancer mechanisms.

Methods: Mitochondrial metabolic activity and the cell-cycle distribution were analyzed using an MTT assay and flow cytometry in NCKU-21-treated cells. NCKU-21-induced cell apoptosis was verified by Annexin V-FITC/propidium iodide (PI) double-staining and measurement of caspase-3 activity. Western blotting and wound-healing assays were applied to respectively evaluate regulation of signaling pathways and cell migration by NCKU-21. Molecular interactions between target proteins and NCKU-21 were predicted and performed by molecular docking. A colorimetric screening assay kit was used to evaluate potential regulation of matrix metalloproteinase-9 (MMP-9) activity by NCKU-21.

Results: Results indicated that NCKU-21 markedly induced cytotoxic effects that reduced cell viability via cell apoptosis in tested NSCLC cells. Activation of AMP-activated protein kinase (AMPK) and p53 protein expression also increased in both NSCLC cell lines stimulated with NCKU-21. However, repression of PI3K-AKT activation by NCKU-21 was found in CL1-5 cells but not in A549 cells. In addition, increases in phosphatidylserine externalization and caspase-3 activity also confirmed the apoptotic effect of NCKU-21 in both NSCLC cell lines. Moreover, cell migration and translational levels of the gelatinases, MMP-2 and MMP-9, were obviously reduced in both NSCLC cell lines after incubation with NCKU-21. Experimental data obtained from molecular docking suggested that NCKU-21 can bind to the catalytic pocket of MMP-9. However, the in vitro enzyme activity assay indicated that NCKU-21 has the potential to increase MMP-9 activity.

Conclusions: Our results suggest that NCKU-21 can effectively reduce cell migration and induce apoptosis in A549 and CL1-5 cells, the toxicological effects of which may be partly modulated through PI3K-AKT inhibition, AMPK activation, an increase in the p53 protein, and gelatinase inhibition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612657PMC
October 2017

Pharmacokinetics and tissue distribution of five major triterpenoids after oral administration of Rhizoma Alismatis extract to rats using ultra high-performance liquid chromatography-tandem mass spectrometry.

J Pharm Biomed Anal 2017 Nov 6;146:314-323. Epub 2017 Sep 6.

College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Centre of Biomedical Research & Development, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. Electronic address:

Rhizoma Alismatis (RA) was wildly used for treatment of dysuria, pyelonephritis, hyperlipidemia, enteritis diarrhea, diabetes, inflammation, and cancer. Triterpenoids are the major active components of RA, and its extract is mainly composed of alisol A (ALA), alisol B (ALB), alisol C 23-acetate (ALC-23A), alisol A 24-acetate (ALA-24A), and alisol B 23-acetate (ALB-23A). In this study, a simple, reliable, and sensitive ultra high-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-MS/MS) method was created and validated for the quantification of the five major triterpenoids in rat plasma and various tissues biosamples (including intestine, stomach, liver, kidney, fat, muscle, brain, heart, lung, spleen, and testes). The plasma and tissues biosamples were pretreated by direct precipitation deproteinization method with acetonitrile. 17α-Hydroxyprogesterone was used as internal standard (IS). The chromatography was performed on a Phenomenex C8 column (30×2.00mm, 1.8μm) at room temperature with gradient elution. Compounds were quantified by selected multi-reactions monitoring (SRM) scanning with positive electric spray ionization mode. The linearity of detection for each triterpene was respectively from 1 to 1000ng/mL for ALC-23A and ALA, from 4 to 4000ng/mL for ALA-24A, from 10 to 10,000ng/mL for ALB, and from 2 to 2000ng/mL for ALB-23B (r>0.99) with low quantification limits of 1-10ng/mL for all analytes. All of the other validation parameters were also in an acceptable range. The validated UHPLC-MS/MS method subsequently applied for the pharmacokinetic and tissue distribution studies of RA extract. After orally given 100mg/kg of RA extract, ALA was the most exposed component, followed by ALB and ALA-24A. Whereas significant gender difference was observed for ALB, ALA, and ALA-24A between female and male rats. The AUC of ALA, ALB, and ALA-24A in female rats were approximately 2-5 fold larger than that in male rats. These triterpenoids also displayed approximately 1.5-2 times longer half-life (t) in female rats. Appearant K, V and C of ALA, ALB, and ALA-24A were calculated by substrate depletion approach, rat P450 CYP3A2 plays an important role in the metabolism of ALA, ALB, and ALA-24A, which is an important factor leading to the different exprosures of ALA, ALB, and ALA-24A between the male rats and the female rats. Furthermore, results from tissue distribution in male rats showed that the main tissue depots of five triterpenoids were the stomach/intestine, followed by the liver, brain, and fat. However, ALA was still measured in the kidney after a long elimination time. ALB and ALB-23B exhibited lower elimination rate in the testis. These results provide a fundamental support for further pharmacological development and clinical safety application of RA.
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http://dx.doi.org/10.1016/j.jpba.2017.09.009DOI Listing
November 2017

Monoamine oxidase A is highly expressed in classical Hodgkin lymphoma.

J Pathol 2017 10 5;243(2):220-229. Epub 2017 Sep 5.

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.

Monoamine oxidase A (MAOA) is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines and produces H O . It facilitates the progression of gliomas and prostate cancer, but its expression and functional relevance have not been studied in lymphoma. Here, we evaluated MAOA in 427 cases of Hodgkin and non-Hodgkin lymphoma and in a spectrum of reactive lymphoid tissues by immunohistochemistry on formalin-fixed, paraffin-embedded specimens. MAOA was expressed by Hodgkin Reed-Sternberg (HRS) cells in the majority of classical Hodgkin lymphomas (cHLs) (181/241; 75%), with 34.8% showing strong expression. Weak MAOA was also noted in a minority of primary mediastinal large B-cell lymphomas (8/47; 17%) and in a mediastinal gray-zone lymphoma. In contrast, no MAOA was found in non-neoplastic lymphoid tissues, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL; 0/8) or any other non-Hodgkin lymphomas studied (0/123). MAOA was more common in Epstein-Barr virus (EBV)-negative compared to EBV-positive cHL (p < 0.0001) and was especially prevalent in the EBV-negative nodular sclerosing subtype. Similar to primary human lymphoma specimens, most cHL-derived cell lines displayed MAOA activity, whereas non-Hodgkin-lymphoma-derived cell lines did not. The MAOA inhibitor clorgyline reduced the growth of L1236 cells and U-HO1 cells, and shRNA knockdown of MAOA reduced the growth of L1236 cells. Conversely, ectopic overexpression of MAOA increased the growth of MAOA-negative HDLM2 cells. Combined treatment with clorgyline and ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was more effective in reducing cell growth than either regimen alone. In summary, MAOA is highly expressed in cHL and may reflect the distinct biology of this lymphoma. Further studies on the potential utility of MAOA as a diagnostic marker and therapeutic target are warranted. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605421PMC
October 2017

Activation of IGF-I Survival Signaling and Its Compensative Inhibition of the Cardiac Apoptosis on Carotid Arteries Balloon-Injured Rat Hearts.

Chin J Physiol 2017 Jun;60(3):166-173

Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan.

In this study, a rat carotid balloon injury-animal model was used to elucidate the temporal relation of hypertrophy in the progression of cardiac damage and the role of insulin-like growth factor (IGF)-I survival pathway on course of the cardiac damage. Rats were subjected to carotid balloon-injury and examined at different time points. We further studied the heart-weight/body-weight-ratio, histology and protein expression to understand the pathological events associated with percutaneous transluminal coronary angioplasty (PTCA) induced damages. Protein expression analysis showed increased levels of IGF-I signaling pathway and mitogen-activated protein kinase (MAPK) signaling pathway after 2 h and after 2 d of carotid balloon injury. On the other hand, apoptosis signaling pathways were enhanced after 14 d of carotid balloon injury. According to the results, rat carotid balloon injury significantly induced IGF-I survival signaling and compensated hypertrophy pathway during the initial period of injury however after 14 d the proteins involved in apoptotic cell death were elevated and the proteins of the survival pathway and compensatory hypertrophy were significantly reduced.
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http://dx.doi.org/10.4077/CJP.2017.BAF455DOI Listing
June 2017

SCOTTI: Efficient Reconstruction of Transmission within Outbreaks with the Structured Coalescent.

PLoS Comput Biol 2016 Sep 28;12(9):e1005130. Epub 2016 Sep 28.

Institute for Emerging Infections, Oxford Martin School, University of Oxford, Oxford, United Kingdom.

Exploiting pathogen genomes to reconstruct transmission represents a powerful tool in the fight against infectious disease. However, their interpretation rests on a number of simplifying assumptions that regularly ignore important complexities of real data, in particular within-host evolution and non-sampled patients. Here we propose a new approach to transmission inference called SCOTTI (Structured COalescent Transmission Tree Inference). This method is based on a statistical framework that models each host as a distinct population, and transmissions between hosts as migration events. Our computationally efficient implementation of this model enables the inference of host-to-host transmission while accommodating within-host evolution and non-sampled hosts. SCOTTI is distributed as an open source package for the phylogenetic software BEAST2. We show that SCOTTI can generally infer transmission events even in the presence of considerable within-host variation, can account for the uncertainty associated with the possible presence of non-sampled hosts, and can efficiently use data from multiple samples of the same host, although there is some reduction in accuracy when samples are collected very close to the infection time. We illustrate the features of our approach by investigating transmission from genetic and epidemiological data in a Foot and Mouth Disease Virus (FMDV) veterinary outbreak in England and a Klebsiella pneumoniae outbreak in a Nepali neonatal unit. Transmission histories inferred with SCOTTI will be important in devising effective measures to prevent and halt transmission.
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http://dx.doi.org/10.1371/journal.pcbi.1005130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040440PMC
September 2016