Publications by authors named "Huanyu Wang"

94 Publications

Wuxiang Virus Is a Virus Circulated Naturally in Wuxiang County, China.

Vector Borne Zoonotic Dis 2021 Apr 17;21(4):289-300. Epub 2021 Feb 17.

State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Wuxiang virus was isolated from sandfly specimens collected in Wuxiang County, Shanxi Province, China in 2018, representing the first reported isolation of sandfly-borne virus from sandflies collected in a natural environment in China. The local sandfly density, seasonal fluctuations, and temporal and spatial distributions of the virus in Wuxiang County remain unclear. Four fixed sandfly collection sites were set up in Wuxiang County and sandfly specimens were collected continuously from June to August 2019. All sandfly specimens were subjected to viral isolation and molecular biological analysis. The data on sandfly specimens collected in Wuxiang County from June to August 2019 showed a significant difference in the density of sandflies between June 26 and August 16 ( < 0.05). No statistical difference was found in sandfly density among collection sites ( > 0.05). A total of 33 virus isolates causing cytopathic effects in mammalian (BHK-21) cells were obtained from 7466 sandflies (91 pools) collected from June to August 2019. The results of molecular genetic evolution analysis of the nucleotide sequence of these isolates showed that the L and S genes (encoding NS and N proteins) of the 33 viruses isolated in 2019 are in the same evolutionary branch as the previously isolated Wuxiang virus. No significant difference was found in the virus isolation rate (the pool isolation rate of virus) among sandflies collected at different times from June to August ( > 0.05). The virus isolation rate of sandflies collected at different collection sites showed a statistically significant difference ( < 0.05). The results of this study suggest that the Wuxiang virus is a stable viral population in local sandflies. Strengthened research into Wuxiang virus infection of humans and animals and clarification of the public health hazards posed by Wuxiang virus to both humans and animals are urgently needed.
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http://dx.doi.org/10.1089/vbz.2020.2702DOI Listing
April 2021

B7-H3 Chimeric Antigen Receptor Redirected T Cells Target Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma.

Cancers (Basel) 2020 Dec 17;12(12). Epub 2020 Dec 17.

Sheng Yushou Center of Cell Biology and Immunology, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200032, China.

Potent CAR-T therapies that target appropriate antigens can benefit the treatment of anaplastic lymphoma kinase-positive (ALK) anaplastic large cell lymphoma (ALCL), which is the most common subtype of T cell lymphoma. In this study, we observed overexpression of B7-H3 in ALCL cell lines derived from clinical samples and differential expression of B7-H3 in an ALK-induced T cell transformation model. A B7-H3-redirected CAR based on scFv from mAb 376.96 was developed. B7-H3 CAR-T cells showed strong cytotoxicity and cytokine secretion against target ALCL cells (SUP-M2, SU-DHL-1, and Karpas 299) in vitro. Furthermore, the B7-H3 CAR-T cells exhibited proliferative capacity and a memory phenotype upon repeated antigen stimulation. We demonstrated that B7-H3 CAR-T cells could promptly eradicate ALCL in murine xenografts. Taken together, B7-H3 is a novel and promising target in ALCLs and B7-H3 CAR-T may be a viable treatment option for ALCL.
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http://dx.doi.org/10.3390/cancers12123815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766167PMC
December 2020

Emergence of Japanese encephalitis among adults 40 years of age or older in northern China: Epidemiological and clinical characteristics.

Transbound Emerg Dis 2020 Dec 7. Epub 2020 Dec 7.

Department of Viral Encephalitis, NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Japanese encephalitis (JE) is a vector-borne vaccine preventable infectious disease for which vaccine provides direct protection. China introduced nationwide JE vaccination of young children in 2007, rapidly achieving high coverage. In 2018, 1,800 JE cases were reported in China, with morbidity and mortality rates of 0.13/100,000 and 0.0097/100,000. Nationally, 64% of cases were among adults aged 40 years or older, and in northern China, 82% were among adults, mainly in outbreaks. Severity varied little by age grouping. Compared with the previous 10 years, the proportion and absolute number of cases among adults increased, indicating possible emergence of adult JE in China as childhood JE decreased. We describe JE epidemiology and clinical features nationally and in areas with low endemicity after more than 10 years of routine childhood JE vaccination. Determining population JE seroprevalence should be a priority; vaccination campaigns among adults in high risk areas should be considered.
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http://dx.doi.org/10.1111/tbed.13945DOI Listing
December 2020

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies.

Front Oncol 2020 29;10:572722. Epub 2020 Sep 29.

Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies with an extremely poor prognosis. Energy metabolism reprogramming, an emerging hallmark of cancer, has been implicated in the tumorigenesis and development of pancreatic cancer. In addition to well-elaborated enhanced glycolysis, investigating the role of reprogramming of amino acid metabolism has sparked great interests in recent years. The rewiring amino acid metabolism orchestrated by genetic alterations contributes to pancreatic cancer malignant characteristics including cell proliferation, invasion, metastasis, angiogenesis and redox balance. In the unique hypoperfused and nutrient-deficient tumor microenvironment (TME), the interactions between cancer cells and stromal components and salvaging processes including autophagy and macropinocytosis play critical roles in fulfilling the metabolic requirements and supporting growth of PDAC. In this review, we elucidate the recent advances in the amino acid metabolism reprogramming in pancreatic cancer and the mechanisms of amino acid metabolism regulating PDAC progression, which will provide opportunities to develop promising therapeutic strategies.
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http://dx.doi.org/10.3389/fonc.2020.572722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550743PMC
September 2020

Osteomyelitis Due to Mycobacterium goodii in an Adolescent, United States.

Emerg Infect Dis 2020 11;26(11):2781-2783

Osteomyelitis is a rare clinical manifestation of infection with nontuberculous mycobacteria (NTM). We report an adolescent with femoral osteomyelitis associated with prosthetic material due to an emerging pathogen, Mycobacterium goodii. Application of secA1 and 16S ribosomal RNA gene sequencing reliably determined the NTM species, enabling targeted antimicrobial therapy.
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http://dx.doi.org/10.3201/eid2611.200206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588509PMC
November 2020

Year-Round, Routine Testing of Multiple Body Site Specimens for Human Parechovirus in Young Febrile Infants.

J Pediatr 2021 Feb 9;229:216-222.e2. Epub 2020 Oct 9.

Division of Infectious Diseases, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH.

Objectives: To test our hypothesis that routine year-round testing of specimens from multiple body sites and genotyping of detected virus would describe seasonal changes, increase diagnostic yield, and provide a better definition of clinical manifestations of human parechovirus (PeV-A) infections in young febrile infants.

Study Design: PeV-A reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was incorporated in routine evaluation of infants aged ≤60 days hospitalized at Nationwide Children's Hospital for fever and/or suspected sepsis-like syndrome beginning in July 2013. We reviewed electronic medical records of infants who tested positive for PeV-A between July 2013 and September 2016. Genotyping was performed with specific type 3 RT-PCR and sequencing.

Results: Of 1475 infants evaluated, 130 (9%) tested positive for PeV-A in 1 or more sites: 100 (77%) in blood, 84 (65%) in a nonsterile site, and 53 (41%) in cerebrospinal fluid (CSF). Five infants (4%) were CSF-only positive, 31 (24%) were blood-only positive, and 20 (15%) were nonsterile site-only positive. PeV-A3 was the most common type (85%) and the only type detected in CSF. Although the majority (79%) of infections were diagnosed between July and December, PeV-A was detected year-round. The median age at detection was 29 days. Fever (96%), fussiness (75%), and lymphopenia (56%) were common. Among infants with PeV-A-positive CSF, 77% had no CSF pleocytosis. The median duration of hospitalization was 41 hours. Four infants had bacterial coinfections diagnosed within 24 hours of admission; 40 infants had viral coinfections.

Conclusions: Although most frequent in summer and fall, PeV-A infections were encountered in every calendar month within the 3-year period of study. More than one-half of patients had PeV-A detected at more than 1 body site. Coinfections were common. PeV-A3 was the most common type identified and the only type detected in the CSF.
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http://dx.doi.org/10.1016/j.jpeds.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546655PMC
February 2021

Severe SARS-CoV-2 disease in the context of a NF-κB2 loss-of-function pathogenic variant.

J Allergy Clin Immunol 2021 Feb 30;147(2):532-544.e1. Epub 2020 Sep 30.

Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio; Center for Vaccines and Immunity, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio; Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged recently and has created a global pandemic. Symptomatic SARS-CoV-2 infection, termed coronavirus disease 2019 (COVID-19), has been associated with a host of symptoms affecting numerous organ systems, including the lungs, cardiovascular system, kidney, central nervous system, gastrointestinal tract, and skin, among others.

Objective: Although several risk factors have been identified as related to complications from and severity of COVID-19, much about the virus remains unknown. The host immune response appears to affect the outcome of disease. It is not surprising that patients with intrinsic or secondary immune compromise might be particularly susceptible to complications from SARS-CoV-2 infection. Pathogenic loss-of-function or gain-of-function heterozygous variants in nuclear factor-κB2 have been reported to be associated with either a combined immunodeficiency or common variable immunodeficiency phenotype.

Methods: We evaluated the functional consequence and immunologic phenotype of a novel NFKB2 loss of function variant in a 17-year-old male patient and describe the clinical management of SARS-CoV-2 infection in this context.

Results: This patient required a 2-week hospitalization for SARS-CoV-2 infection, including 7 days of mechanical ventilation. We used biologic therapies to avert potentially fatal acute respiratory distress syndrome and treat hyperinflammatory responses. The patient had an immunologic phenotype of B-cell dysregulation with decreased switched memory B cells. Despite the underlying immune dysfunction, he recovered from the infection with intense management.

Conclusions: This clinical case exemplifies some of the practical challenges in management of patients with SARS-CoV-2 infection, especially in the context of underlying immune dysregulation.
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http://dx.doi.org/10.1016/j.jaci.2020.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525247PMC
February 2021

Emerging Sand Fly-Borne Phlebovirus in China.

Emerg Infect Dis 2020 10;26(10):2435-2438

We isolated 17 viral strains capable of causing cytopathic effects in mammalian cells and death in neonatal mice from sand flies in China. Phylogenetic analysis showed that these strains belonged to the genus Phlebovirus. These findings highlight the need to control this potentially emerging virus to help safeguard public health.
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http://dx.doi.org/10.3201/eid2610.191374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510709PMC
October 2020

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management.

Signal Transduct Target Ther 2020 08 3;5(1):143. Epub 2020 Aug 3.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, 100023, Beijing, PR China.

Digestive cancers are the leading cause of cancer-related death worldwide and have high risks of morbidity and mortality. Histone methylation, which is mediated mainly by lysine methyltransferases, lysine demethylases, and protein arginine methyltransferases, has emerged as an essential mechanism regulating pathological processes in digestive cancers. Under certain conditions, aberrant expression of these modifiers leads to abnormal histone methylation or demethylation in the corresponding cancer-related genes, which contributes to different processes and phenotypes, such as carcinogenesis, proliferation, metabolic reprogramming, epithelial-mesenchymal transition, invasion, and migration, during digestive cancer development. In this review, we focus on the association between histone methylation regulation and the development of digestive cancers, including gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer, as well as on its clinical application prospects, aiming to provide a new perspective on the management of digestive cancers.
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http://dx.doi.org/10.1038/s41392-020-00252-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398912PMC
August 2020

Spinal hemangioblastoma: surgical procedures, outcomes and review of the literature.

Acta Neurol Belg 2020 Jul 7. Epub 2020 Jul 7.

Department of Neurosurgery, Tianjin Huanhu Hospital, 6 Jizhao Road, Tianjin, 300010, China.

Purpose: total removal of spinal hemangioblastomas with satisfactory clinical outcomes remains a challenge. We aimed to evaluate the surgical outcomes of our spinal hemangioblastomas patients, summarize our experiences with this condition and review-related literature.

Methods: records of 18 spinal hemangioblastoma patients who underwent microsurgical resection were analyzed retrospectively. Clinical features, surgical procedures and outcomes were reviewed to assess the prognosis of their spinal hemangioblastomas. The McCormick classification method was used to evaluate spinal function and MR scans used to assess location and features of the tumor pre-surgically, tumor recurrence and syringomyelia status post-surgically.

Results: total resection of 37 tumors was achieved in all 18 cases. Of those patients, two (11%) were accompanied with von Hippel-Lindau (VHL). Of the 37 tumors, 3 (8.1%) were completely intramedullary, 16 (43.2%) intramedullary-extramedullary and 18 (48.6%) primarily extramedullary. Tumors accompanied with syringomyelia were present in 17 (94.4%) patients. Clinical symptoms such as pain were reduced within 48 h after surgery in 16 patients. Post-operative neurological functions improved in all cases at 3 months post-surgery. Over the subsequent 3-18 month follow-up period, pre-operative symptoms improved in all 18 patients and no tumor recurrence was present. Syringomyelia was reduced or absent within 3-6 months.

Conclusions: our results indicated that a complete microscopic resection was effective in eliminating symptoms in these spinal hemangioblastoma patients, who showed a good prognosis after surgery. These improvements in clinical symptoms may be associated with the blood flow changes, but not with reductions and/or eliminations of syrinx after surgery.
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http://dx.doi.org/10.1007/s13760-020-01420-4DOI Listing
July 2020

Recovery and Genetic Characterization of a West Nile Virus Isolate from China.

Virol Sin 2021 Feb 6;36(1):113-121. Epub 2020 Jul 6.

Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, 100071, China.

West Nile virus (WNV) is an important neurotropic flavivirus that is widely distributed globally. WNV strain XJ11129 was first isolated in Xinjiang, China, and its genetic and biological characteristics remain largely unknown. In this study, phylogenetic and sequence analyses revealed that XJ11129 belongs to lineage 1a and shares high genetic identity with the highly pathogenic strain NY99. Then, the full-length genomic cDNA of XJ11129 was amplified and assembled using a modified Gibson assembly (GA) method. The virus (named rXJ11129) was successfully rescued in days following this method. Compared with other wild-type WNV isolates, rXJ11129 exhibited virulence indistinguishable from that of the NY99 strain in vivo. In summary, the genomic and virulence phenotypes of rXJ11129 were characterized in vivo and in vitro, and these data will improve the understanding of the spread and pathogenesis of this reemerging virus.
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http://dx.doi.org/10.1007/s12250-020-00246-xDOI Listing
February 2021

Emergence of Zika Virus in Culex tritaeniorhynchus and Anopheles sinensis Mosquitoes in China.

Virol Sin 2021 Feb 2;36(1):33-42. Epub 2020 Jul 2.

State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.

Zika virus (ZIKV) has been isolated from mosquitoes such as Aedes, Mansonia uniformis, and Culex perfuscus; However, the isolation of ZIKV from Anopheles sinensis and Culex tritaeniorhynchus has not yet been reported. In June and July 2018, 22,985 mosquitoes and 57,500 midges were collected in Jiangxi Province in southeastern China. Among them, six strains of ZIKV were isolated from mosquitoes: four from An. sinensis and two from Cx. tritaeniorhynchus. Molecular genetic analysis showed that the ZIKV isolated from An. sinensis and Cx. tritaeniorhynchus belonged to genotype 2 in the Asian evolutionary branch of ZIKV. In addition, the ZIKV strains isolated from An. sinensis and Cx. tritaeniorhynchus had amino acid substitutions identical to ZIKV strains prevalent in South America since 2015. This study is the first to isolate ZIKV from mosquito specimens collected in the wild of Jiangxi Province, China; This is also the first time that ZIKV has been isolated from An. sinensis and Cx. tritaeniorhynchus. Given that An. sinensis and Cx. tritaeniorhynchus have a very wide geographical distribution in China and even in eastern and southern Asia, the isolation of several strains of ZIKV from these two mosquitoes poses new challenges for the prevention and control of ZIKV infection in the mainland of China and countries and regions with the same distribution of mosquitoes.
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http://dx.doi.org/10.1007/s12250-020-00239-wDOI Listing
February 2021

An outbreak of Japanese encephalitis caused by genotype Ib Japanese encephalitis virus in China, 2018: A laboratory and field investigation.

PLoS Negl Trop Dis 2020 05 26;14(5):e0008312. Epub 2020 May 26.

Department of Arbovirus, NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China.

Although Japanese encephalitis virus genotype Ib (JEV GIb) has replaced JEV GIII as the dominant genotype in endemic areas of Asia, no JEV GIb has been isolated from JE cases and natural mosquitoes at the same time in an outbreak of JE. In this study, we conducted virological and molecular biological laboratory tests on JE case samples (serum/cerebrospinal fluid) and locally collected mosquito samples from the 2018 JE outbreak in Ningxia, China. The result of JEV IgM antibody detection showed that 96% (67/70) of the suspected cases were laboratory-confirmed JE cases. Of the mosquitoes collected from local environments, 70% (17400/24900) were Culex tritaeniorhynchus of which 4.6% (16 /348 of the pools tested) were positive for JEV, other mosquitoes were negative. JEVs isolated from both the human cases and C. tritaeniorhynchus specimens belong to JEV GIb and are in the same evolutionary clade according to molecular evolution analyses. JEV GIb was detected simultaneously from specimens of JE cases and mosquito samples collected in nature in this study, suggesting that the JE outbreak that occurred in Ningxia in 2018 was due to infection of JEV GIb.
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http://dx.doi.org/10.1371/journal.pntd.0008312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274457PMC
May 2020

Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity.

Nat Cell Biol 2020 06 4;22(6):716-727. Epub 2020 May 4.

Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3-ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.
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http://dx.doi.org/10.1038/s41556-020-0510-3DOI Listing
June 2020

Metabolism of pancreatic cancer: paving the way to better anticancer strategies.

Mol Cancer 2020 03 2;19(1):50. Epub 2020 Mar 2.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, PR China.

Pancreatic cancer is currently one of the most lethal diseases. In recent years, increasing evidence has shown that reprogrammed metabolism may play a critical role in the carcinogenesis, progression, treatment and prognosis of pancreatic cancer. Affected by internal or external factors, pancreatic cancer cells adopt extensively distinct metabolic processes to meet their demand for growth. Rewired glucose, amino acid and lipid metabolism and metabolic crosstalk within the tumor microenvironment contribute to unlimited pancreatic tumor progression. In addition, the metabolic reprogramming involved in pancreatic cancer resistance is also closely related to chemotherapy, radiotherapy and immunotherapy, and results in a poor prognosis. Reflective of the key role of metabolism, the number of preclinical and clinical trials about metabolism-targeted therapies for pancreatic cancer is increasing. The poor prognosis of pancreatic cancer patients might be largely improved after employing therapies that regulate metabolism. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights for treatments against pancreatic cancer.
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http://dx.doi.org/10.1186/s12943-020-01169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053123PMC
March 2020

Glutamine and asparagine activate mTORC1 independently of Rag GTPases.

J Biol Chem 2020 03 4;295(10):2890-2899. Epub 2020 Feb 4.

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390. Electronic address:

Nutrient sensing by cells is crucial, and when this sensing mechanism is disturbed, human disease can occur. mTOR complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Leucine, arginine, and methionine signal to mTORC1 through the well-characterized Rag GTPase signaling pathway. In contrast, glutamine activates mTORC1 through a Rag GTPase-independent mechanism that requires ADP-ribosylation factor 1 (Arf1). Here, using several biochemical and genetic approaches, we show that eight amino acids filter through the Rag GTPase pathway. Like glutamine, asparagine signals to mTORC1 through Arf1 in the absence of the Rag GTPases. Both the Rag-dependent and Rag-independent pathways required the lysosome and lysosomal function for mTORC1 activation. Our results show that mTORC1 is differentially regulated by amino acids through two distinct pathways.
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http://dx.doi.org/10.1074/jbc.AC119.011578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062167PMC
March 2020

OLR1 Promotes Pancreatic Cancer Metastasis via Increased c-Myc Expression and Transcription of HMGA2.

Mol Cancer Res 2020 05 4;18(5):685-697. Epub 2020 Feb 4.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis. However, the mechanisms of metastasis in pancreatic cancer remain unclear. Oxidized low-density lipoprotein receptor 1 (OLR1), a lectin-like scavenger receptor that recognizes several ligands, such as oxidized low-density lipoprotein, was previously reported in cardiovascular and metabolic diseases. The role and mechanism of OLR1 in pancreatic cancer is unclear. In this study, we found that OLR1 expression was significantly higher in pancreatic cancer tissues than that in adjacent normal tissues and closely associated with reduced overall survival. OLR1 promoted proliferation and metastasis of pancreatic cancer cells and . Mechanistically, OLR1 increased HMGA2 transcription by upregulating c-Myc expression to promote the metastasis of pancreatic cancer cells. In addition, patients with pancreatic cancer with high expression of OLR1-c-Myc-HMGA2 axis showed worse prognosis compared with patients with low expression of OLR1-c-Myc-HMGA2 axis. IMPLICATIONS: Our findings suggested that the OLR1-c-Myc-HMGA2 axis promotes metastasis of pancreatic cancer cells and may serve as potential therapeutic targets and prognosis markers for patients with pancreatic cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0718DOI Listing
May 2020

Enterovirus D68 outbreak detection through a syndromic disease epidemiology network.

J Clin Virol 2020 03 16;124:104262. Epub 2020 Jan 16.

Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 64108, United States. Electronic address:

Background: In 2014, enterovirus D68 (EV-D68) was responsible for an outbreak of severe respiratory illness in children, with 1,153 EV-D68 cases reported across 49 states. Despite this, there is no commercial assay for its detection in routine clinical care. BioFire® Syndromic Trends (Trend) is an epidemiological network that collects, in near real-time, deidentified. BioFire test results worldwide, including data from the BioFire® Respiratory Panel (RP).

Objectives: Using the RP version 1.7 (which was not explicitly designed to differentiate EV-D68 from other picornaviruses), we formulate a model, Pathogen Extended Resolution (PER), to distinguish EV-D68 from other human rhinoviruses/enteroviruses (RV/EV) tested for in the panel. Using PER in conjunction with Trend, we survey for historical evidence of EVD68 positivity and demonstrate a method for prospective real-time outbreak monitoring within the network.

Study Design: PER incorporates real-time polymerase chain reaction metrics from the RPRV/EV assays. Six institutions in the United States and Europe contributed to the model creation, providing data from 1,619 samples spanning two years, confirmed by EV-D68 gold-standard molecular methods. We estimate outbreak periods by applying PER to over 600,000 historical Trend RP tests since 2014. Additionally, we used PER as a prospective monitoring tool during the 2018 outbreak.

Results: The final PER algorithm demonstrated an overall sensitivity and specificity of 87.1% and 86.1%, respectively, among the gold-standard dataset. During the 2018 outbreak monitoring period, PER alerted the research network of EV-D68 emergence in July. One of the first sites to experience a significant increase, Nationwide Children's Hospital, confirmed the outbreak and implemented EV-D68 testing at the institution in response. Applying PER to the historical Trend dataset to determine rates among RP tests, we find three potential outbreaks with predicted regional EV-D68 rates as high as 37% in 2014, 16% in 2016, and 29% in 2018.

Conclusions: Using PER within the Trend network was shown to both accurately predict outbreaks of EV-D68 and to provide timely notifications of its circulation to participating clinical laboratories.
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http://dx.doi.org/10.1016/j.jcv.2020.104262DOI Listing
March 2020

Propensity score-matched analysis of clinical outcome after enucleation versus regular pancreatectomy in patients with small non-functional pancreatic neuroendocrine tumors.

Pancreatology 2020 Mar 3;20(2):169-176. Epub 2020 Jan 3.

Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address:

Objectives: The effectiveness of enucleation in treatment for low-grade (G1, G2) small (≤2 cm) non-functional pancreatic neuroendocrine tumors (sNF-pNETs) remains controversial. This study investigated short- and long-term outcome of enucleation comparing with regular pancreatectomy in patients with sNF-pNETs.

Methods: The clinical data of patients with sNF-pNETs who underwent surgery in our hospital from January 2000 to December 2017 were retrospectively collected. Short- and long-term outcomes of two operations were analyzed. The propensity score matching (PSM) was performed to reduce potential selection bias.

Results: A total of 123 patients with sNF-pNETs were enrolled with 62 males, 69 G1, and median age was 56.91 ± 10.04 years old. During the follow-up period (mean 87 ± 58.1 months), 9(7.32%) disease progressed (recurrence or metastasis) and 2 died (1.62%), 5-years OS was 100%, 5-years DFS was 91.4%. Both lymph node metastasis (p = 0.117) and pathological grade (p = 0.050) were not prognostic factors for sNF-pNETs. The propensity score-matched cohort comprised 27 patients with enucleation and 44 patients with regular pancreatectomy. Enucleation was noninferior to regular pancreatectomy in terms of DFS, before or after PSM. The surgical duration (P < 0.01) and blood loss (P < 0.01) significantly decreased in enucleation compared with regular pancreatectomy. The other postoperative complications tended to occur in regular pancreatectomy than in enucleation, but no statistically significant difference (all p > 0.05).

Conclusion: Enucleation seems to be an effective option for the treatment of sNF-pNETs with a lower total rate of postoperative complications and similar long-term prognosis, compared with regular pancreatectomy.
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http://dx.doi.org/10.1016/j.pan.2019.12.007DOI Listing
March 2020

Epidemiology of tick-borne encephalitis in China, 2007- 2018.

PLoS One 2019 26;14(12):e0226712. Epub 2019 Dec 26.

Department of Viral Encephalitis, NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Tick-borne encephalitis (TBE) is endemic to Europe and some Asian countries and is prevalent in northeast China. We analyzed the epidemiology of TBE in China from 2007 to 2018. A total of 3,364 TBE cases were reported in mainland China from 2007 to 2018, for an annual incidence of 0.09 to 0.44/100,000. Among the TBE cases, 89.92% were reported in forest areas (41.94% in DaXingAnLing, 8.70% in XiaoXingAnLing, and 39.21% in ChangBaiShan) in northeast China. The TBE cases were primarily male with a proportion of 67.15% (2,259/3,364 cases) and in 40-49-year age group with a proportion of 31.89% (1,073/3,364 cases). The epidemiology of TBE differed slightly among the three forest regions. Domestic workers and forestry workers accounted for the most of the TBE cases in DaXingAnLing, and domestic workers and farmers in XiaoXingAnLing and ChangBaiShan, respectively. The TBE cases mainly occurred from April to August with a peak in June. The TBE laboratory confirmed rate in DaXingAnLing (84.14%, 1,189/1,413 cases) was highest, compared with XiaoXingAnLing and ChangBaiShan (13.99% and 11.37%, respectively). Moreover, the hospital with the highest laboratory confirmed rate (88.01%, 1,336/1,518 cases) was Inner Mongolia Forestry General Hospital of DaXingAnling region. Systematic enhanced TBE surveillance and a vaccination program are needed to improve the laboratory confirmed rate and reduce the incidence of TBE in northeast China.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226712PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932775PMC
April 2020

Identification and genetic analysis of a totivirus isolated from the Culex tritaeniorhynchus in northern China.

Arch Microbiol 2020 May 16;202(4):807-813. Epub 2019 Dec 16.

NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, People's Republic of China.

Totiviridae, a viral family of double-stranded RNA (dsRNA) viruses, contain a single dsRNA genome 4.6-7.0 kb in length. Totiviridae were initially only known to infect fungi and other eukaryotes as well as plants, but an increase in totiviruses has been detected in insects, mosquitoes, and bats. Here, we describe the isolation and characterization of a strain belonging to the family Totiviridae isolated from Culex tritaeniorhynchus in Kenli, China, in 2016. We isolated a totivirus from field-collected mosquitoes in China by cell culture in Aedes albopictus C6/36 cells, identified the virus by morphological observation and complete genome sequencing, and characterized it by phylogenetic analysis. Transmission electron microscopy identified icosahedral, non-enveloped virus particles with a mean diameter of 35-40 nm. The genome was 7612 bp in length, including two open reading frames (ORFs). ORF1 (5058 nt) encodes the capsid protein, while ORF2 (2216 nt) encodes the viral RNA-dependent RNA polymerase (RdRp). Nucleotide and amino acid homology analysis of isolate showed higher levels of sequence identity with isolate CTV_NJ2 (China, 2010) with 94.87% nucleic acid identity and 97.32% amino acid identity. The isolate was designated C. tritaeniorhynchus totivirus KL (CTV-KL). This is the first identification of a totivirus in a C. tritaeniorhynchus in northern China. Analysis of the virus's morphology, characteristic and genome organization will further enrich our understanding of the molecular and biological characteristics of dsRNA Totiviridae viruses.
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http://dx.doi.org/10.1007/s00203-019-01788-9DOI Listing
May 2020

Characterization of viromes within mosquito species in China.

Sci China Life Sci 2020 Jul 10;63(7):1089-1092. Epub 2019 Dec 10.

NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.

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http://dx.doi.org/10.1007/s11427-019-1583-9DOI Listing
July 2020

Molecular and Clinical Comparison of Enterovirus D68 Outbreaks among Hospitalized Children, Ohio, USA, 2014 and 2018.

Emerg Infect Dis 2019 11 17;25(11):2055-2063. Epub 2019 Nov 17.

Enterovirus D68 (EV-D68) causes respiratory tract infections and neurologic manifestations. We compared the clinical manifestations from 2 EV-D68 outbreaks in 2014 and 2018 and a low-activity period in 2016 among hospitalized children in central Ohio, USA, and used PCR and sequencing to enable phylogenetic comparisons. During both outbreak periods, infected children had respiratory manifestations that led to an increase in hospital admissions for asthma. The 2018 EV-D68 outbreak appeared to be milder in terms of respiratory illness, as shown by lower rates of pediatric intensive care unit admission. However, the frequency of severe neurologic manifestations was higher in 2018 than in 2014. During the same period in 2016, we noted neither an increase in EV-D68 nor a significant increase in asthma-related admissions. Phylogenetic analyses showed that EV-D68 isolates from 2018 clustered differently within clade B than did isolates from 2014 and are perhaps associated with a different EV-D68 subclade.
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http://dx.doi.org/10.3201/eid2511.190973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810223PMC
November 2019

The enhancement of glycolysis regulates pancreatic cancer metastasis.

Cell Mol Life Sci 2020 Jan 20;77(2):305-321. Epub 2019 Aug 20.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China.

Pancreatic ductal adenocarcinoma is prone to distant metastasis and is expected to become the second leading cause of cancer-related death. In an extremely nutrient-deficient and hypoxic environment resulting from uncontrolled growth, vascular disturbances and desmoplastic reactions, pancreatic cancer cells utilize "metabolic reprogramming" to satisfy their energy demand and support malignant behaviors such as metastasis. Notably, pancreatic cancer cells show extensive enhancement of glycolysis, including glycolytic enzyme overexpression and increased lactate production, and this is caused by mitochondrial dysfunction, cancer driver genes, specific transcription factors, a hypoxic tumor microenvironment and stromal cells, such as cancer-associated fibroblasts and tumor-associated macrophages. The metabolic switch from oxidative phosphorylation to glycolysis in pancreatic cancer cells regulates the invasion-metastasis cascade by promoting epithelial-mesenchymal transition, tumor angiogenesis and the metastatic colonization of distant organs. In addition to aerobic glycolysis, oxidative phosphorylation also plays a critical role in pancreatic cancer metastasis in ways that remain unclear. In this review, we expound on the intracellular and extracellular causes of the enhancement of glycolysis in pancreatic cancer and the strong association between glycolysis and cancer metastasis, which we expect will yield new therapeutic approaches targeting cancer metabolism.
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http://dx.doi.org/10.1007/s00018-019-03278-zDOI Listing
January 2020

Overexpression of human MX2 gene suppresses cell proliferation, migration, and invasion via ERK/P38/NF-κB pathway in glioblastoma cells.

J Cell Biochem 2019 11 2;120(11):18762-18770. Epub 2019 Jul 2.

Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.

In human, there are two myxovirus resistance genes-MX1 and MX2, which respectively encode MXA and MXB protein. For MXB, it was traditionally deemed to work in the progression of cell cycle and adjustment of nuclear import. Thus, we speculated that it might play important roles in tumor progression. The purpose of this study was to preliminarily explore the underlying functions and mechanism of the MX2 gene on glioblastoma multiforme. Quantitative reverse transcription polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT), and transwell experiments were to detect the relative MX2 mRNA level and its biological functions on glioma cells, respectively. The data displayed that MX2 was obviously downregulated both in glioblastoma (GBM) and GBM cell lines, meanwhile, its overexpression could markedly reduce cell proliferation, migration, and invasion of glioma cells, implying that it was related with glioblastoma progression. In addition, the overall survival of patient with glioblastoma had a negative correlation with the MX2 expression. Then, Western blot indicated the potential mechanism of MX2 in glioblastoma. We found that MX2 overexpression could decrease the relative levels of phosphorylated-ERK1/2 (p-ERK1/2), p-p38, and nuclear factor-κB (NF-κB), while have no effects on extracellular signal-regulated kinase (ERK), p38, and lamin B1. Moreover, the influences of MX2 overexpression on cell proliferation, migration, and invasion could be weakened by the three inhibitors (PD98059, SB203580, and (pyridin-2-ylmethyl) dithiocarbamate [PDTC]). These results implied that MX2 might suppress the proliferation and metastasis of glioma cells by manipulating the ERK/P38/NF-κB signaling pathway. In conclusion, MX2 is potential to be a new marker used for glioblastoma prognosis or a new target for glioblastoma treatments.
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http://dx.doi.org/10.1002/jcb.29189DOI Listing
November 2019

GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor.

Elife 2019 05 21;8. Epub 2019 May 21.

Department of Pharmacology, University of California, San Diego, La Jolla, United States.

The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth, metabolism, and autophagy. Extensive research has focused on pathways that activate mTORC1 like growth factors and amino acids; however, much less is known about signaling cues that directly inhibit mTORC1 activity. Here, we report that G-protein coupled receptors (GPCRs) paired to Gα proteins increase cyclic adenosine 3'5' monophosphate (cAMP) to activate protein kinase A (PKA) and inhibit mTORC1. Mechanistically, PKA phosphorylates the mTORC1 component Raptor on Ser 791, leading to decreased mTORC1 activity. Consistently, in cells where Raptor Ser 791 is mutated to Ala, mTORC1 activity is partially rescued even after PKA activation. Gα-coupled GPCRs stimulation leads to inhibition of mTORC1 in multiple cell lines and mouse tissues. Our results uncover a signaling pathway that directly inhibits mTORC1, and suggest that GPCRs paired to Gα proteins may be potential therapeutic targets for human diseases with hyperactivated mTORC1.
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http://dx.doi.org/10.7554/eLife.43038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529218PMC
May 2019

Integrated analysis of gene expression and methylation profiles of novel pancreatic cancer cell lines with highly metastatic activity.

Sci China Life Sci 2019 Jun 13;62(6):791-806. Epub 2019 Mar 13.

Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.

Pancreatic cancer is one of the most lethal human malignancies, partly because of its propensity for metastasis. However, highly metastatic human pancreatic cancer cell lines suitable for studies of metastasis are currently lacking. Here we established two highly metastatic human pancreatic cancer cell lines, MIA PaCa-2 In8 and Panc-1 In8, by Matrigel induction assay. The cell lines were further characterized both in vitro and in vivo. MIA PaCa-2 In8 and Panc-1 In8 cells demonstrated increased migration and invasion compared with their respective parental cells. Following injection into nude mice, MIA PaCa-2 In8 and Panc-1 In8 cells resulted in more pulmonary metastases compared with the parental cells. Furthermore, analyses of mRNA, long non-coding RNA, micro RNA, and methylation profiling revealed that these factors were aberrantly regulated in the highly metastatic cells, indicating that they probably affected metastasis. We thus established and characterized two highly metastatic human pancreatic cell lines that could be used as valuable tools for future investigations into the pathogenesis, metastasis, and potential treatment of human pancreatic cancer.
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http://dx.doi.org/10.1007/s11427-018-9495-2DOI Listing
June 2019

Staphylococcus aureus and methicillin resistance detection directly from pediatric samples using PCR assays with differential cycle threshold values for corroboration of methicillin resistance.

J Microbiol Methods 2019 04 28;159:167-173. Epub 2019 Feb 28.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, United States of America. Electronic address:

Staphylococcus aureus is a major human pathogen, causing a variety of nosocomial and community-acquired infections. While S. aureus usually grows well, there are situations where it cannot be isolated in culture, such as patients who have received prior antimicrobial therapy. There are commercially available tests for molecular identification of S. aureus and methicillin resistance; however, they often have limited utility due to restrictive specimen requirements, lack of data in pediatric populations and issues with specificity for methicillin resistance detections. Our objective was to evaluate the performance of laboratory-developed PCR assays that detect S. aureus and methicillin resistance directly from various specimen types. We developed two real-time PCR assays: 1) a singleplex assay targeting the nucA gene and 2) a multiplex PCR assay (mecA/SCC-orf PCRs) that detects the mecA gene and the conjunction region where SCCmec elements insert into the genome. A total of 538 pediatric specimens, including specimens from the lower respiratory tract (n = 149), abscess/wounds (n = 245), tissue and body fluids (n = 144), were tested and the results compared with culture and susceptibility testing. The nucA PCR is sensitive and specific for detection of S. aureus when compared with culture with an overall agreement of 93.1% and sensitivity and specificity of 93.5% and 93.0%, respectively. Among those culture-confirmed and nucA PCR positive specimens (n = 145), concordance between mecA/SCC-orf PCRs, using cycle threshold values for corroboration, and conventional methods was 98.6% and the sensitivity and specificity were 97.3% and 100%, respectively. The assays' performance suggests they are rapid, reliable tools to detect and differentiate between methicillin susceptible and methicillin resistant S. aureus in our pediatric patient population providing diagnostic impact when used in conjunction with culture.
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http://dx.doi.org/10.1016/j.mimet.2019.01.009DOI Listing
April 2019

Isolation and Genome Phylogenetic Analysis of Arthropod-Borne Viruses, Including Akabane Virus, from Mosquitoes Collected in Hunan Province, China.

Vector Borne Zoonotic Dis 2019 01 11;19(1):62-72. Epub 2018 Dec 11.

1 State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

This study investigated the abundance of mosquitoes and circulation of mosquito-borne arboviruses from 16 villages in 8 cities of Hunan Province, China, in July-August of 2010 and in August of 2011. In total, 16,076 mosquitoes consisting of seven species from four genera were collected by ultraviolet-light trap. Culex quinquefasciatus was the most common species, accounting for 50.63% (8140/16,076) of the total. Anopheles sinensis (24.26%, 3900/16,076) made up the second most common species, followed by Culex tritaeniorhynchus (9.76%, 1569/16,076). The proportions of Culex pipiens pallens, Armigeres subalbatus, and Culex modestus were 6.7%, 5.2%, and 3.31%, respectively. Fourteen Aedes albopictus were detected. The mosquitoes were identified by morphologic characteristics and frozen in liquid nitrogen. The mosquitoes were pooled, triturated, and centrifuged. The clarified supernatant was used to inoculate monolayers of C6/36 and baby hamster kidney-21 cells. We obtained six virus isolates that caused cytopathic effects. Phylogenetic analysis revealed that two isolates were Akabane virus (AKAV, from A. sinensis and C. quinquefasciatus), two isolates were Japanese encephalitis virus (from C. pipiens pallens and C. quinquefasciatus), and two isolates were Tibet orbivirus (from C. quinquefasciatus and C. tritaeniorhynchus). This is the first report of AKAV isolated from A. sinensis and C. quinquefasciatus in nature in China. The detection of AKAV in these species confirms circulation of AKAV in Hunan province and suggests potential challenges to the prevention and control of arthropod-borne animal viruses in mainland China.
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http://dx.doi.org/10.1089/vbz.2018.2267DOI Listing
January 2019