Publications by authors named "Yibo Gao"

97 Publications

GDF-8 stimulates trophoblast cell invasion by inducing ALK5-SMAD2/3-mediated MMP2 expression.

Reproduction 2021 Aug 1. Epub 2021 Aug 1.

Y Sun, Center for Reproductive Medicine, Zhengzhou University First Affiliated Hospital, Zhengzhou, China.

Matrix metalloproteinases (MMPs) play a pivotal role in the regulation of cell invasion. Placental trophoblast cell invasion is a precisely regulated event. Dysregulation of MMPs has been linked to various placental diseases. Growth differentiation factor-8 (GDF-8), also known as myostatin, is a member of the transforming growth factor-beta (TGF-β) superfamily. GDF-8 and its putative receptors are expressed in human extravillous cytotrophoblast cells (EVTs). Although the pro-invasive effect of GDF-8 in human EVT cells has been recently reported, the underlying molecular mechanism remains largely unknown. In this study, we investigate the effects of GDF-8 on the expression of the two most important MMPs, MMP2 and MMP9, in the HTR-8/SVneo human EVT cell line. Our results show that GDF-8 significantly upregulates the expression of MMP2. The expression of MMP9 is not affected by GDF-8. Using a siRNA-mediated knockdown approach, we reveal that the stimulatory effect of GDF-8 on MMP2 expression is mediated by the ALK5-SMAD2/3 signaling pathway. Additionally, the knockdown of MMP2 attenuates the GDF-8-induced cell invasiveness. These findings deepen our understanding of the biological roles of GDF-8 in the regulation of human trophoblast cell invasion.
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http://dx.doi.org/10.1530/REP-21-0197DOI Listing
August 2021

Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis.

Lancet Oncol 2021 09 13;22(9):1265-1274. Epub 2021 Aug 13.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: Numerous ongoing trials are testing anti-PD-1-based or anti-PD-L1-based cancer treatment combinations. Understanding the toxicity profiles of treatment-related adverse events is essential. The aim of this study was to comprehensively investigate the incidences and profiles of treatment-related adverse events across different combination therapies.

Methods: We did a systematic review and meta-analysis comparing different chemotherapy, targeted therapy, immunotherapy, and radiotherapy combinations with PD-1 or PD-L1 inhibitors. We searched Pubmed, Embase, and Cochrane databases for articles published in English between Jan 1, 2000, and May 21, 2020, investigating globally approved PD-1 or PD-L1 inhibitor-based combination therapies. Only prospective trials reporting overall incidence or tabulated data of treatment-related adverse events were included. Trials investigating sequential therapies, comprising three or more classes of therapies, and enrolling less than ten patients were excluded. The primary outcomes were overall incidences and profiles for all-grade and grade 3 or higher treatment-related adverse events by random-effect models. Heterogeneity between studies was assessed with I statistics. The summary measures for main outcomes are incidences (95% CI). The 95% CI were calculated together with the incidence through a random-effects model with a logit transformation. The protocol is registered with PROSPERO (CRD42020189617).

Findings: We identified 2540 records, of which 161 studies (17 197 patients) met the inclusion criteria. The overall incidence of treatment-related adverse events in the chemotherapy combination was 97·7% (95% CI 96·4-98·5; I=75%) for all-grade adverse events and 68·3% (60·7-75·0; I=93%) for grade 3 or higher adverse events; in the targeted therapy combination was 94·5% (90·7-96·8; I=86%) for all-grade adverse events and 47·3% (37·3-57·5; I=93%) for grade 3 or higher adverse events; in the immunotherapy combination was 86·8% (80·9-91·1; I=94%) for all-grade adverse events and 35·9% (29·5-42·9; I=92%) for grade 3 or higher adverse events; and in the radiotherapy combination was 89·4% (69·0-96·9; I=74%) for all-grade adverse events and 12·4% (4·4-30·6; I=73%) for grade 3 or higher adverse events. For these four combination therapies, the most common all-grade adverse events were anaemia (45.4% [95% CI 32·4-59·1]), fatigue (34·3% [27·5-41·9]), fatigue (26·4% [19·2-35·2]), and dysphagia (30·0% [18·7-44·5]), respectively, and the most common grade 3 or higher adverse events were neutropenia (19·6% [13·5-27·7]), hypertension (9·3% [5·7-14·9]), lipase increased (7·2% [5·2-9·9]), and lymphopenia (10·3% [4·5-21·8]). All included randomised controlled trials had a low risk of bias.

Interpretation: Our study provides comprehensive data on treatment-related adverse events of different PD-1 or PD-L1 inhibitor-based combination therapies. Our results provide an essential reference of toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies for clinicians in routine practice of cancer care.

Funding: National Key Research and Development Programme, National Natural Science Foundation of China key program, National Natural Science Foundation of China general program, Chinese Academy of Medical Sciences Initiative for Innovative Medicine, Beijing Municipal Science and Technology Commission, Non-profit Central Research Institute Fund.
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http://dx.doi.org/10.1016/S1470-2045(21)00333-8DOI Listing
September 2021

Amphiregulin stimulates human chorionic gonadotropin expression by inducing ERK1/2-mediated ID3 expression in trophoblast cells.

Placenta 2021 Sep 23;112:73-80. Epub 2021 Jul 23.

Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address:

Introduction: The human chorionic gonadotropin (hCG) is a dimer consisting of an α subunit and a β subunit which is encoded by the CGB gene and is unique to hCG. hCG is a hormone mainly synthesized by syncytiotrophoblast cells in the placenta, plays a critical role in stimulating progesterone production that is necessary for maintaining normal pregnancy in the early stage. Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase family which has been shown to regulate various physiological and pathological events. In human chorionic villi and amniotic fluid, amphiregulin (AREG) is reported to be the most abundant EGFR ligand and can stimulate hCG expression. However, the underlying mechanism remains unknown.

Methods: We use BeWo cells, the commonly used cell model for the hCG production of trophoblast cells, as an in vitro model. The effects of AREG on CGB expression and hCG secretion as well as the underlying mechanisms were explored by a series of in vitro experiments.

Results: We show that treatment with AREG stimulates CGB expression and hCG secretion. Using pharmacological inhibitors, we show that the stimulatory effects of AREG on CGB expression and hCG secretion are mediated by the EGFR-activated ERK1/2 signaling pathways. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) is upregulated by AREG. Knockdown of ID3 attenuates the AREG-induced upregulation of CGB expression and hCG secretion.

Discussion: This study provides important insights into the molecular mechanisms that mediate AREG-induced upregulation of hCG production in human trophoblast cells which may lead to the development of alternative therapeutic approaches for the treatment of placental diseases.
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http://dx.doi.org/10.1016/j.placenta.2021.07.292DOI Listing
September 2021

Author Correction: METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N-methyladenosine-dependent YTHDF binding.

Nat Commun 2021 Jul 20;12(1):4529. Epub 2021 Jul 20.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

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http://dx.doi.org/10.1038/s41467-021-24860-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292537PMC
July 2021

Profiling of 520 Candidate Genes in 50 Surgically Treated Chinese Small Cell Lung Cancer Patients.

Front Oncol 2021 8;11:644434. Epub 2021 Jun 8.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Small cell lung cancer (SCLC) is one of the severe malignancies with high mortality. Surgically resected tumor tissues from 50 Chinese SCLC patients were collected for next-generation sequencing to detect 520 cancer-related genes. The most frequently altered genes were (94.0%), (86.0%), (44.0%), (26.0%) and (24.0%). We detected that and (<0.05) had a significantly higher mutation frequency in Chinese SCLC compared to the Cologne and MSKCC. The single nucleotide variation (SNV) is dominated by C>A (34.1%). We found a significant association between TMB-H (≥10.3muts/Mb) and (=0.023), (=0.010), (=0.050) and (=0.005) gene mutations in Chinese SCLC patients. Immunostaining was performed using the following antibodies: TTF-1, CgA, CD56, Syn, and Ki-67. Correlation analysis between the expression of 6 markers and mutations in signaling pathways showed that Syn and CgA expression were associated with 4 (cGMP-PKG, Chemokine, TGF-β and Phospholipase D) and 2 (cGMP-PKG and Phosphatidylinositol) signaling pathway mutations. Kaplan-Meier curve showed that age<55 years, mutant and high TMB (≥7muts/Mb) were associated with a better prognosis, while the prognosis of patients with mutations in the Ras pathway was significantly improved. High TMB is an important prognostic factor for SCLC patients showed by multivariate analysis. In the combined cohort composed of current and two previous studies, survival analysis showed that SCLC patients with mutant demonstrated better OS (=0.0017). Patients with a high TMB (≥7muts/Mb) have a better prognosis (=0.0053), consistent with our results in the Chinese cohort. We characterized the genomic alterations profile of Chinese SCLC patients and analyzed the correlation between genomic changes and immunohistochemical phenotypes at the signaling pathway level. Our data might provide useful information in the diagnosis and treatment for Chinese SCLC patients.
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http://dx.doi.org/10.3389/fonc.2021.644434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217828PMC
June 2021

METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N-methyladenosine-dependent YTHDF binding.

Nat Commun 2021 06 21;12(1):3803. Epub 2021 Jun 21.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and their adjacent normal tissues and demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in tumour tissues. mA-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the mA modification of APC, which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of β-catenin and β-catenin-mediated cyclin D1, c-Myc, and PKM2 expression, thereby leading to enhanced aerobic glycolysis, ESCC cell proliferation, and tumour formation in mice. In addition, downregulated APC expression correlates with upregulated METTL3 expression in human ESCC specimens and poor prognosis in ESCC patients. Our findings reveal a mechanism by which the Wnt/β-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC.
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http://dx.doi.org/10.1038/s41467-021-23501-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217513PMC
June 2021

Multi-omics profiling of primary small cell carcinoma of the esophagus reveals RB1 disruption and additional molecular subtypes.

Nat Commun 2021 06 18;12(1):3785. Epub 2021 Jun 18.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China.

Primary small cell carcinoma of the esophagus (PSCCE) is a lethal neuroendocrine carcinoma. Previous studies proposed a genetic similarity between PSCCE and esophageal squamous cell carcinoma (ESCC) but provided little evidence for differences in clinical course and neuroendocrine differentiation. We perform whole-exome sequencing, RNA sequencing and immunohistochemistry profiling on 46 PSCCE cases. Integrated analyses enable the discovery of multiple mechanisms of RB1 disruption in 98% (45/46) of cases. The transcriptomic landscape of PSCCE closely resembles small cell lung cancer (SCLC) but differs from ESCC or esophageal adenocarcinoma (EAC). Distinct gene expression patterns regulated by ASCL1 and NEUROD1 define two molecular subtypes, PSCCE-A and PSCCE-N, which are highly similar to SCLC subtypes. A T cell excluded phenotype is widely observed in PSCCE. In conclusion, PSCCE has genomic alterations, transcriptome features and molecular subtyping highly similar to SCLC but distinct from ESCC or EAC. These observations are relevant to oncogenesis mechanisms and therapeutic vulnerability.
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http://dx.doi.org/10.1038/s41467-021-24043-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213753PMC
June 2021

Cholinergic-Induced Specific Oscillations in the Medial Prefrontal Cortex to Reverse Propofol Anesthesia.

Front Neurosci 2021 26;15:664410. Epub 2021 May 26.

Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

General anesthesia is a drug-induced reversible state comprised of altered states of consciousness, amnesia, analgesia, and immobility. The medial frontal cortex (mPFC) has been discovered to modulate the level of consciousness through cholinergic and glutamatergic pathways. The optogenetic tools combined with electrophysiological recording were used to study the neural oscillatory modulation mechanisms in mPFC underlying the loss of consciousness (LOC) and emergence. We found that optogenetic activation of both cholinergic and glutamatergic neurons in the basal forebrain (BF) reversed the hypnotic effect of propofol and accelerated the emergence from propofol-induced unconsciousness. The cholinergic light-activation during propofol anesthesia increased the power in the β (12-20 Hz) and low γ (20-30 Hz) bands. Conversely, glutamatergic activation increased the power at less specific broad (1-150 Hz) bands. The cholinergic-induced alteration to specific power bands after LOC had opposite effects to that of propofol. These results suggested that the cholinergic system might act on more specific cortical neural circuits related to propofol anesthesia.
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http://dx.doi.org/10.3389/fnins.2021.664410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187623PMC
May 2021

Spatial and Temporal Characteristics of Hand-Foot-and-Mouth Disease and Their Influencing Factors in Urumqi, China.

Int J Environ Res Public Health 2021 05 5;18(9). Epub 2021 May 5.

College of Resources and Environmental Sciences, Xinjiang University, Urumqi 830046, China.

Hand, foot, and mouth disease (HFMD) remains a serious health threat to young children. Urumqi is one of the most severely affected cities in northwestern China. This study aims to identify the spatiotemporal distribution characteristics of HFMD, and explore the relationships between driving factors and HFMD in Urumqi, Xinjiang.

Methods: HFMD surveillance data from 2014 to 2018 were obtained from the China Center for Disease Control and Prevention. The center of gravity and geographical detector model were used to analyze the spatiotemporal distribution characteristics of HFMD and identify the association between these characteristics and socioeconomic and meteorological factors.

Results: A total of 10,725 HFMD cases were reported in Urumqi during the study period. Spatially, the morbidity number of HFMD differed regionally and the density was higher in urban districts than in rural districts. Overall, the development of HFMD in Urumqi expanded toward the southeast. Temporally, we observed that the risk of HFMD peaked from June to July. Furthermore, socioeconomic and meteorological factors, including population density, road density, GDP, temperature and precipitation were significantly associated with the occurrence of HFMD.

Conclusions: HFMD cases occurred in spatiotemporal clusters. Our findings showed strong associations between HFMD and socioeconomic and meteorological factors. We comprehensively considered the spatiotemporal distribution characteristics and influencing factors of HFMD, and proposed some intervention strategies that may assist in predicting the morbidity number of HFMD.
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http://dx.doi.org/10.3390/ijerph18094919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124546PMC
May 2021

Intensity modulated radiation therapy may improve survival for tracheal-bronchial adenoid cystic carcinoma: A retrospective study of 133 cases.

Lung Cancer 2021 07 8;157:116-123. Epub 2021 May 8.

Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Radiation Oncology, National Cancer Center/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China. Electronic address:

Purposes: This study aimed to evaluate the role of radiotherapy (RT) and intensity modulated radiation therapy (IMRT) in adjuvant and definitive settings of tracheal-bronchial adenoid cystic carcinoma (TACC) treatment.

Materials/methods: TACC patients (n = 133) treated with surgery and/or RT curatively in our institution between January 1, 1984 and December 31, 2017 were analyzed retrospectively.

Results: Among the 116 patients undergoing surgery, 50 (43.1 %) achieved complete resections and 66 (56.9 %) had positive surgical margins. For patients with positive margins, overall adjuvant RT was correlated with no significantly improved OS (10-year: 58.0 % vs. 47.9 %; P =  0.340) and a slight LRFS benefit (5-year: 81.9 % vs.75.6 %; P =  0.056), but adjuvant IMRT showed significant superiority in both OS (10-year: 82.9 % vs. 47.9 %; P =  0.031) and LRFS (5-year: 100.0 % vs. 75.6 %; P =  0.001) in comparison with no postoperative RT. Multivariate analysis also identified adjuvant IMRT as a significant favorable factor with OS (HR = 0.186, 95 %CI: 0.039-0.883; P =  0.034). For 17 patients receiving definitive RT, IMRT achieved promising 5-year OS of 88.9 % and LRFS of 64.3 %, yet no significant difference from non-IMRT group was reached (P = 0.447 and 0.706). Different therapies presented no significantly different impact on DMFS, whilst DMFS explained more of the OS variances (P < 0.001, R = 0.480) than LRFS (P < 0.001, R = 0.323).

Conclusion: IMRT could confer greatly improved OS and LRFS in postoperative setting for TACC patients with positive surgical margins. IMRT was also a good therapeutic option for definitive TACC with promising survival and local control.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.006DOI Listing
July 2021

MiRACLe: an individual-specific approach to improve microRNA-target prediction based on a random contact model.

Brief Bioinform 2021 May;22(3)

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Deciphering microRNA (miRNA) targets is important for understanding the function of miRNAs as well as miRNA-based diagnostics and therapeutics. Given the highly cell-specific nature of miRNA regulation, recent computational approaches typically exploit expression data to identify the most physiologically relevant target messenger RNAs (mRNAs). Although effective, those methods usually require a large sample size to infer miRNA-mRNA interactions, thus limiting their applications in personalized medicine. In this study, we developed a novel miRNA target prediction algorithm called miRACLe (miRNA Analysis by a Contact modeL). It integrates sequence characteristics and RNA expression profiles into a random contact model, and determines the target preferences by relative probability of effective contacts in an individual-specific manner. Evaluation by a variety of measures shows that fitting TargetScan, a frequently used prediction tool, into the framework of miRACLe can improve its predictive power with a significant margin and consistently outperform other state-of-the-art methods in prediction accuracy, regulatory potential and biological relevance. Notably, the superiority of miRACLe is robust to various biological contexts, types of expression data and validation datasets, and the computation process is fast and efficient. Additionally, we show that the model can be readily applied to other sequence-based algorithms to improve their predictive power, such as DIANA-microT-CDS, miRanda-mirSVR and MirTarget4. MiRACLe is publicly available at https://github.com/PANWANG2014/miRACLe.
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http://dx.doi.org/10.1093/bib/bbaa117DOI Listing
May 2021

Safety and Efficacy of Neoadjuvant Immune Checkpoint Inhibitor Therapy in Patients with Resectable Non-small-Cell Lung Cancer: A Systematic Review.

Target Oncol 2021 07 13;16(4):425-434. Epub 2021 May 13.

Thoracic Surgery Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan Nanli No 17, Beijing, 100021, People's Republic of China.

Background: Non-small-cell lung cancer (NSCLC) accounts for most new diagnoses of lung cancer, with high morbidity and mortality worldwide. Immune checkpoint inhibitor (ICI) therapy has transformed the treatment of metastatic and advanced NSCLC. For resectable NSCLC, while surgery is the cornerstone of standard treatment, a number of clinical trials of neoadjuvant immunotherapy have been conducted.

Objective: To perform a systematic review on the safety and efficacy of neoadjuvant ICI therapy in patients with resectable NSCLC.

Methods: This systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We undertook a comprehensive literature search of PubMed, Embase, Cochrane Library, and abstracts and posters from annual meetings of the major oncology societies, American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), American Association for Cancer Research (AACR) up until 29 April 2021.

Results: A total of 399 patients were identified from six articles and four meeting abstracts. 229, 140, and 30 patients received anti-programmed cell death ligand 1 therapy (anti-PD-L1, atezolizumab and durvalumab), anti-programmed cell death 1 therapy (anti-PD-1, nivolumab, pembrolizumab, sintilimab), and anti-PD-1/anti-CTLA-4 combination therapy (nivolumab and ipilimumab), respectively. 255 patients received only ICI therapy before surgery, and 144 patients received ICI and chemotherapy. While ICI therapy was generally well tolerated, grade 3 or higher immune-related adverse events were observed in 13 of 144 patients (9.0%) in the five studies that reported such adverse events data. Patients displayed an overall mean surgical resection rate of 87.5% (349/399, range, 66.7-100%), a surgical delay rate of 1.4%, and an incidence of surgical complications of 21%. On average, 45.6% (159/349), (range 17-83%) of patients exhibited major pathological response (MPR), while 76/349 (21.8%) patients achieved pathological complete response (pCR). In the studies with patients undergoing ICI and chemotherapy, the MPR rate was 66.7% and pCR rate was 35.4%.

Conclusions: ICI neoadjuvant therapy may be a safe and efficacious treatment option in patients with resectable NSCLC. Combined with chemotherapy, ICI appears to be more efficacious, but displays more adverse events. More ongoing clinical trials will shed further light on the safety and efficacy of ICI neoadjuvant therapy in patients with resectable NSCLC.
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http://dx.doi.org/10.1007/s11523-021-00818-1DOI Listing
July 2021

WNT/β-catenin-suppressed FTO expression increases mA of c-Myc mRNA to promote tumor cell glycolysis and tumorigenesis.

Cell Death Dis 2021 05 8;12(5):462. Epub 2021 May 8.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China.

FTO removes the N6-methyladenosine (mA) modification from genes and plays a critical role in cancer development. However, the mechanisms underlying the regulation of FTO and its subsequent impact on the regulation of the epitranscriptome remain to be further elucidated. Here, we demonstrate that FTO expression is downregulated and inversely correlated with poor survival of lung adenocarcinoma patients. Mechanistically, Wnt signaling induces the binding of EZH2 to β-catenin. This protein complex binds to the LEF/TCF-binding elements at the promoter region of FTO, where EZH2 enhances H3K27me3 and inhibits FTO expression. Downregulated FTO expression substantially enhances the mA levels in the mRNAs of a large number of genes in critical pathways, particularly metabolic pathway genes, such as MYC. Enhanced mA levels on MYC mRNA recruit YTHDF1 binding, which promotes MYC mRNA translation and a subsequent increase in glycolysis and proliferation of tumor cells and tumorigenesis. Our findings uncovered a critical mechanism of epitranscriptome regulation by Wnt/β-catenin-mediated FTO downregulation and underscored the role of mA modifications of MYC mRNA in regulating tumor cell glycolysis and growth.
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http://dx.doi.org/10.1038/s41419-021-03739-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106678PMC
May 2021

Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma.

Front Oncol 2021 26;11:561247. Epub 2021 Mar 26.

Zhejiang Provincial Key Laboratory of Pancreatic Disease of the First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Metabolic enzymes can perform non-metabolic functions and play critical roles in the regulation of a variety of important cellular activities. Phosphoenolpyruvate carboxykinase 1 (PCK1), a gluconeogenesis enzyme, was recently identified as an AKT-regulated protein kinase that phosphorylates INSIG1/2 to promote nuclear SREBP1-dependent lipogenesis. However, the relationship of this regulation with the progression of non-small-cell lung carcinoma (NSCLC) is unclear. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces AKT-dependent PCK1 pS90, PCK1-mediated INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 accumulation in NSCLC cells. In addition, the expression levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are higher in 451 analyzed human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other in the tumor specimens. Furthermore, the expression levels of PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are associated with TNM stage and progression in NSCLC. Importantly, levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 are positively correlated with poor prognosis in NSCLC patients, and the combined expression value of the PCK1 and INSIG1/2 phosphorylation has a better prognostic value than that of each individual protein phosphorylation value and is an independent prognostic marker for NSCLC. These findings reveal the role of PCK1-mediated nuclear SREBP1 activation in NSCLC progression and highlight the potential to target the protein kinase activity of PCK1 for the diagnosis and treatment of human NSCLC.
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http://dx.doi.org/10.3389/fonc.2021.561247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033018PMC
March 2021

Comprehensive Analysis of Ferroptosis Regulators in Lung Adenocarcinomas Identifies Prognostic and Immunotherapy-Related Biomarkers.

Front Mol Biosci 2021 12;8:587436. Epub 2021 Mar 12.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Ferroptosis is a newly discovered type of programmed cell death that differs from canonical apoptosis. However, the potential role of ferroptosis in lung adenocarcinoma (LUAD) has not been elaborated. In total, 1,328 samples from databases and 36 ferroptosis regulators were included in this study. By combining random survival forest and principal component analysis algorithms, a robust prognostic ferroptosis-related risk score (FRRS) was constructed, and the performance was validated in three independent datasets. Based on the median risk score, two subgroups were identified. Then, comparisons, including of mutational profiles, functional enrichment analyses and immune components, were conducted between subgroups. An immunotherapy cohort was applied to explore potential therapeutic-related biomarkers. Finally, the clinical utility of FRRS was validated in a proteomic cohort. In the TCGA-LUAD cohort, FRRS was calculated using the expression of 11 selected genes, and patients with high FRRS had a significantly ( < 0.001) worse prognosis than those with low FRRS. Multivariate regression suggested that FRRS was an independent prognostic factor. Functional enrichment analysis indicated that FRRS was mainly involved in cell cycle, metabolic and immune-related pathways. Furthermore, FRRS was shown to be significantly ( < 0.001) associated with the abundance of CD8 T cells and tumor mutation burden (TMB). The combination of TMB and FANCD2 expression, the main contributor to FRRS, substantially increased the precision of predicting the therapeutic response. In conclusion, the present study revealed the potential role of ferroptosis regulators in LUAD and identified ferroptosis-related biomarkers for prognostic and immunotherapeutic predictions.
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http://dx.doi.org/10.3389/fmolb.2021.587436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994623PMC
March 2021

Point-of-care testing detection methods for COVID-19.

Lab Chip 2021 05;21(9):1634-1660

Department of Physics, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

COVID-19 is an acute respiratory disease caused by SARS-CoV-2, which has high transmissibility. People infected with SARS-CoV-2 can develop symptoms including cough, fever, pneumonia and other complications, which in severe cases could lead to death. In addition, a proportion of people infected with SARS-CoV-2 may be asymptomatic. At present, the primary diagnostic method for COVID-19 is reverse transcription-polymerase chain reaction (RT-PCR), which tests patient samples including nasopharyngeal swabs, sputum and other lower respiratory tract secretions. Other detection methods, e.g., isothermal nucleic acid amplification, CRISPR, immunochromatography, enzyme-linked immunosorbent assay (ELISA) and electrochemical sensors are also in use. As the current testing methods are mostly performed at central hospitals and third-party testing centres, the testing systems used mostly employ large, high-throughput, automated equipment. Given the current situation of the epidemic, point-of-care testing (POCT) is advantageous in terms of its ease of use, greater approachability on the user's end, more timely detection, and comparable accuracy and sensitivity, which could reduce the testing load on central hospitals. POCT is thus conducive to daily epidemic control and achieving early detection and treatment. This paper summarises the latest research advances in POCT-based SARS-CoV-2 detection methods, compares three categories of commercially available products, i.e., nucleic acid tests, immunoassays and novel sensors, and proposes the expectations for the development of POCT-based SARS-CoV-2 detection including greater accessibility, higher sensitivity and lower costs.
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http://dx.doi.org/10.1039/d0lc01156hDOI Listing
May 2021

Construction and Comprehensive Analyses of a METTL5-Associated Prognostic Signature With Immune Implication in Lung Adenocarcinomas.

Front Genet 2020 19;11:617174. Epub 2021 Feb 19.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

For lung adenocarcinoma (LUAD), patients of different stages have strong heterogeneity, and their overall prognosis varies greatly. Thus, exploration of novel biomarkers to better clarify the characteristics of LUAD is urgent. Multi-omics information of LUAD patients were collected form TCGA. Three independent LUAD cohorts were obtained from gene expression omnibus (GEO). A multi-omics correlation analysis of was performed in TCGA dataset. To build a -associated prognostic score (MAPS). Spathial and random forest methods were first applied for feature selection. Then, LASSO was implemented to develop the model in TCGA cohort. The prognostic value of MAPS was validated in three independent GEO datasets. Finally, functional annotation was conducted using gene set enrichment analysis (GSEA) and the abundances of infiltrated immune cells were estimated by ImmuCellAI algorithm. A total of 901 LUAD patients were included. The expression of in LUAD was significantly higher than that in normal lung tissue. And high expression of indicated poor prognosis in all different stages ( < 0.001, HR = 1.81). Five genes (, and ) were used to construct MAPS and MAPS was significantly correlated with poor prognosis ( < 0.001, HR = 2.15). Furthermore, multivariate Cox regression analysis suggested MAPS as an independent prognostic factor. Functional enrichment revealed significant association between MAPS and several immune components and pathways. This study provides insights into the potential significance of in LUAD and MAPS can serve as a promising biomarker for LUAD.
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http://dx.doi.org/10.3389/fgene.2020.617174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933593PMC
February 2021

Spatial and Temporal Characteristics of Hand-Foot-and-Mouth Disease and Its Response to Climate Factors in the Ili River Valley Region of China.

Int J Environ Res Public Health 2021 02 17;18(4). Epub 2021 Feb 17.

College of Resources and Environmental Sciences, Xinjiang University, Urumqi 830046, China.

Background: As the global climate changes, the number of cases of hand-foot-and-mouth disease (HFMD) is increasing year by year. This study comprehensively considers the association of time and space by analyzing the temporal and spatial distribution changes of HFMD in the Ili River Valley in terms of what climate factors could affect HFMD and in what way.

Methods: HFMD cases were obtained from the National Public Health Science Data Center from 2013 to 2018. Monthly climate data, including average temperature (MAT), average relative humidity (MARH), average wind speed (MAWS), cumulative precipitation (MCP), and average air pressure (MAAP), were obtained from the National Meteorological Information Center. The temporal and spatial distribution characteristics of HFMD from 2013 to 2018 were obtained using kernel density estimation (KDE) and spatiotemporal scan statistics. A regression model of the incidence of HFMD and climate factors was established based on a geographically and temporally weighted regression (GTWR) model and a generalized additive model (GAM).

Results: The KDE results show that the highest density was from north to south of the central region, gradually spreading to the whole region throughout the study period. Spatiotemporal cluster analysis revealed that clusters were distributed along the Ili and Gongnaisi river basins. The fitted curves of MAT and MARH were an inverted V-shape from February to August, and the fitted curves of MAAP and MAWS showed a U-shaped change and negative correlation from February to May. Among the individual climate factors, MCP coefficient values varied the most while MAWS values varied less from place to place. There was a partial similarity in the spatial distribution of coefficients for MARH and MAT, as evidenced by a significant degree of fit performance in the whole region. MCP showed a significant positive correlation in the range of 15-35 mm, and MAAP showed a positive correlation in the range of 925-945 hPa. HFMD incidence increased with MAT in the range of 15-23 °C, and the effective value of MAWS was in the range of 1.3-1.7 m/s, which was positively correlated with incidences of HFMD.

Conclusions: HFMD incidence and climate factors were found to be spatiotemporally associated, and climate factors are mostly non-linearly associated with HFMD incidence.
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http://dx.doi.org/10.3390/ijerph18041954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923010PMC
February 2021

TGF-β1 stimulates aromatase expression and estradiol production through SMAD2 and ERK1/2 signaling pathways in human granulosa-lutein cells.

J Cell Physiol 2021 Sep 29;236(9):6619-6629. Epub 2021 Jan 29.

Henan Key Laboratory of Reproduction and Genetics, Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

Estradiol (E2), one of the main steroid hormones secreted by the ovaries, plays an important role in maintaining normal female reproductive function. Ovarian granulosa cells are the main source of E2 production because these cells express aromatase, which is encoded by the CYP19A1 gene and catalyzes the final step in E2 biosynthesis from androgens. Transforming growth factor-beta 1 (TGF-β1) and its receptors are expressed in human granulosa cells, and TGF-β1 expression can be detected in human follicular fluid. To date, TGF-β1 has been shown to regulate various ovarian functions. However, whether aromatase can be regulated by TGF-β1 in human granulosa cells has not been determined. In the present study, we demonstrate that TGF-β1 stimulates aromatase expression in primary human granulosa-lutein cells and in the human ovarian granulose-like tumor cell line, KGN. We used pharmacological inhibitors and small interfering RNA-mediated knockdown approaches to reveal that the SMAD2 and ERK1/2 signaling pathways are involved in TGF-β1-induced aromatase expression and E2 production. These results not only provide important insights into the molecular mechanisms that mediate TGF-β1-induced aromatase expression and E2 production in human granulosa cells but also increase the understanding of the normal physiological roles of TGF-β1 in the ovary.
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http://dx.doi.org/10.1002/jcp.30305DOI Listing
September 2021

Monoacylglycerol Lipase Knockdown Inhibits Cell Proliferation and Metastasis in Lung Adenocarcinoma.

Front Oncol 2020 9;10:559568. Epub 2020 Dec 9.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abnormal metabolism is one of the hallmarks of cancer cells. Monoacylglycerol lipase (MGLL), a key enzyme in lipid metabolism, has emerged as an important regulator of tumor progression. In this study, we aimed to characterize the role of MGLL in the development of lung adenocarcinoma (LUAD). To this end, we used tissue microarrays to evaluate the expression of MGLL in LUAD tissue and assessed whether the levels of this protein are correlated with clinicopathological characteristics of LUAD. We found that the expression of MGLL is higher in LUAD samples than that in adjacent non-tumor tissues. In addition, elevated MGLL expression was found to be associated with advanced tumor progression and poor prognosis in LUAD patients. Functional studies further demonstrated that stable short hairpin RNA (shRNA)-mediated knockdown of MGLL inhibits tumor proliferation and metastasis, both and , and mechanistically, our data indicate that MGLL regulates Cyclin D1 and Cyclin B1 in LUAD cells. Moreover, we found that knockdown of MGLL suppresses the expression of matrix metalloproteinase 14 (MMP14) in A549 and H322 cells, and in clinical samples, expression of MMP14 is significantly correlated with MGLL expression. Taken together, our results indicate that MGLL plays an oncogenic role in LUAD progression and metastasis and may serve as a potential biomarker for disease prognosis and as a target for the development of personalized therapies.
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http://dx.doi.org/10.3389/fonc.2020.559568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756122PMC
December 2020

pH-dependent rearrangement determines the iron-activation and antitumor activity of artemisinins.

Free Radic Biol Med 2021 02 25;163:234-242. Epub 2020 Dec 25.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address:

The action mechanisms of artemisinins remains elusive for decades, and one long-standing question is whether the indispensable peroxide group is activated by iron or heme. Although heme usually reacts faster with artemisinins than iron does, we have found that rearrangement of dihydroartemisinin (DHA) into monoketo-aldehyde-peroxyhemiacetal (MKA) under physiological conditions can significantly enhance its reaction towards iron. The rearrangement is pH-dependent and the derived MKA is identified by LC-MS in the cellular metabolites of DHA in cancer cells. MKA reacts quickly with ferrous irons to afford reactive carbon-centered radicals and can inhibit enzyme activities in vitro. Moreover, MKA oxidizes ferrous irons to ferric irons, which may explain the effect of DHA on decreasing cellular labile iron pool (LIP). Both addition of exogenous iron and increase in LIP via triggering ferroptosis can enhance the cytotoxicity of DHA against cancer cells. While artesunate (ATS) can also decompose to MKA after hydrolyzing into DHA, the other artemisinins of lower antitumor activity, e.g. artemisinin (ART), artemether (ATM) and arteether (ATE), exhibit negligible hydrolysis and rearrangement under the same conditions. Our study reveals the vital role of molecular rearrangement to the activation and activity of artemisinins and provides a new strategy for designing antitumor molecules containing endoperoxide group.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.12.024DOI Listing
February 2021

Prognostic immunohistochemical markers for small cell lung cancer: A review.

Pathol Res Pract 2021 Jan 4;217:153311. Epub 2020 Dec 4.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, PR China. Electronic address:

Background: Small Cell Lung Cancer (SCLC) is one of the most aggressive thoracic malignancies and has been very challenging in developing personalized medicine. While immunohistochemistry (IHC) markers have established role in pathology diagnosis of SCLC, it is particularly important to apply early and simple methods to effectively determine the prognosis. This study aimed to review and identify prognostic protein markers that have potential to be incorporated into clinical care for SCLC.

Methods: we systematically reviewed PubMed, Embase, Web of Science and Cochrane Library until October 19th, 2019 that reported prognostic IHC markers in SCLC. In this review, we focused on markers evaluated in at least two independent studies to compile the most forthcoming prognostic markers.

Results: According to their function in the tumor, including proliferation-related markers, growth suppression-related markers, invasion- and metastasis-related markers, apoptosis-related markers, angiogenesis-related markers, immune regulation-related markers. Extensive reports into informative tables based on sufficiencies of evidence were summarized as some easy-to-use literature reservoirs for further referring.

Conclusions: Strong evidence supports that the 24 emerging markers or their combinations may be useful in predicting prognosis, helping personalized therapy decision-making for SCLC patients.
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http://dx.doi.org/10.1016/j.prp.2020.153311DOI Listing
January 2021

Association of phosphoenolpyruvate carboxykinase 1 protein kinase activity-dependent sterol regulatory element-binding protein 1 activation with prognosis of oesophageal carcinoma.

Eur J Cancer 2021 01 2;142:123-131. Epub 2020 Dec 2.

Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of the First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310029, China. Electronic address:

Background: Metabolic enzymes have non-canonical functions and play vital roles in the regulation of various cellular activities. Phosphoenolpyruvate carboxykinase 1 (PCK1), a gluconeogenic enzyme, was recently identified as an AKT-dependent protein kinase and promoted sterol regulatory element-binding protein 1 (SREBP1)-dependent lipogenesis. However, association of this protein kinase activity of PCK1 with progression of oesophageal squamous cell carcinoma (ESCC) is unclear.

Methods: We examined 200 ESCC patient samples and prognosis using immunohistochemistry, multivariate Cox regression and Kaplan-Meier Plot analyses.

Results: We show that the expression levels of AKT pS473, AKT-regulated PCK1 pS90, PCK1-mediated INSIG1 pS207/INSIG2 pS151 and nuclear SREBP1 were higher in analysed 200 human ESCC specimens than in their adjacent non-tumour tissues; the expression levels of these proteins were significantly and positively correlated with each other in tumour specimens. In addition, the expression levels of PCK1 pS90, INSIG1 pS207/INSIG2 pS151 and SREBP1 were associated with the tumour, node and metastasis stage and progression in ESCC. Importantly, levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 or nuclear SREBP1 were positively correlated with poor prognosis in patients with ESCC, and the combined expression values of PCK1 pS90, INSIG1 pS207/INSIG2 pS151 and nuclear SREBP1 had a better prognostic value than that of each individual protein expression value and was an independent prognostic marker for ESCC.

Conclusion: These findings reveal the role of PCK1 protein kinase activity-dependent SREBP1 activation in ESCC progression. The regulation of SREBP1 by AKT activation-dependent PCK1 protein kinase activity may provide the potential for the diagnosis and treatment of human ESCC.
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http://dx.doi.org/10.1016/j.ejca.2020.09.040DOI Listing
January 2021

A Novel Approach for Atrial Fibrillation Signal Identification Based on Temporal Attention Mechanism.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:316-319

Atrial fibrillation (AF) is a common heart rhythm which occurs when the upper chambers of the heart beat irregularly. With the rapid development of the deep learning algorithm, the Convolutional Neural Networks (CNN) is widely investigated for the ECG classification task. However, for AF detection, the performance of CNN is greatly limited due to the lack of consideration for temporal characteristic of the ECG signal. In order to improve the discriminative ability of CNN, we introduce the attention mechanism to help the network concentrate on the informative parts and obtain the temporal features of the signals. Inspired by this idea, we propose a temporal attention block (TA-block) and a temporal attention convolutional neural network (TACNN) for the AF detection tasks. The TA-block can adaptively learn the temporal features of the signal and generate the attention weights to enhance informative features. With a stack architecture of TA-blocks, the TA-CNN obtains better performance as a result of paying more attention to the informative parts of the signal. We validate our approach on the single lead ECG classification dataset of The PhysioNet Computing in Cardiology Challenge 2017. The experimental results indicate that the proposed framework outperform state-of-the-arts classification networks.Clinical Relevance-The proposed algorithm can be potentially applied to the portable cardiovascular monitoring devices reducing the danger of AF.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175823DOI Listing
July 2020

Integrated molecular characterization reveals potential therapeutic strategies for pulmonary sarcomatoid carcinoma.

Nat Commun 2020 09 28;11(1):4878. Epub 2020 Sep 28.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here, we perform multi-omics analysis of 56 PSC samples, 14 of which are microdissected to analyze intratumoral heterogeneity. We report the mutational landscape of PSC. The epithelial and sarcomatoid components share numerous genomic alterations, indicating a common progenitor. We find that epithelial-mesenchymal transition (EMT) plays important roles in the carcinogenesis of PSC. The pan-cancer analysis reveals high tumor mutation burden and leukocyte fraction of PSC. Integrated molecular classification shows three subgroups with distinct biology, prognosis and potential therapeutic strategies. Actionable mutations are enriched in C1 and C2, patients in C3 have a significantly longer overall survival, and C1 and C2 exhibit T-cell inflamed microenvironments. The three subgroups show molecular similarities to specific subtypes of conventional lung cancer. In conclusion, our study reveals the molecular characteristics and provides entry points for the treatment of PSC.
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http://dx.doi.org/10.1038/s41467-020-18702-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522294PMC
September 2020

Improving confirmed nanometric sulfur bioproduction using engineered Thioalkalivibrio versutus.

Bioresour Technol 2020 Dec 14;317:124018. Epub 2020 Aug 14.

Key Laboratory of Green Process and Engineering, State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences (CAS), Beijing 100190, China; College of Chemical Engineering, University of Chinese Academy of Sciences, 19 A Yuquan Road, Beijing 100049, China. Electronic address:

Complicated production procedures and superior characteristics of nano-sized sulfur elevate its price to 25-40 fold higher than micrograde kind. Also, natural gas hydrogen sulfide levels are restricted because of its toxic environmental consequences. Thioalkalivibrio versutus is a polyextremophilic industrial autotroph with high natural gas desulfurization capability. Here, nanometric (>50 nm) sulfur bioproduction using T. versutus while desulfurizing natural gas was validated. Also, this production was enhanced by 166.7% via lowering sulfate production by 55.1%. A specially-developed CRISPR system, with 42% editing efficiency, simplified the genome editing workflow scheme for this challenging bacterium. In parallel, sulfur metabolism was uncovered using proteins mining and transcriptome studies for defining sulfate-producing key genes (heterodisulfide reductase-like complex, sulfur dioxygenase, sulfite dehydrogenase and sulfite oxidase). This study provided cost-effective nanometric sulfur production and improved this production using a novel CRISPR strategy, which could be suitable for industrial polyextremophiles, after uncovering sulfur pathways in T. versutus.
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http://dx.doi.org/10.1016/j.biortech.2020.124018DOI Listing
December 2020

Prognostic value of tumor-infiltrating lymphocytes in esophageal cancer: an updated meta-analysis of 30 studies with 5,122 patients.

Ann Transl Med 2020 Jul;8(13):822

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: The prognostic role of tumor-infiltrating lymphocytes (TILs) in esophageal cancer (EC) patients is controversial; therefore, we performed a meta-analysis to obtain a consensus.

Methods: The PubMed, PubMed Central, Embase, Cochrane Library, and Web of Science databases were searched. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using fixed effect or random effect models depending on the heterogeneity.

Results: A total of 30 articles comprising 5,122 patients were included in this meta-analysis. High levels of generalized TIL infiltration were associated with better overall survival (OS) (HR =0.67, 95% CI: 0.47-0.95, P=0.02) in EC patients. High CD8+ T-cell infiltration and high CD4+ T-cell infiltration were associated with better OS (HR =0.68, 95% CI: 0.60-0.78, P<0.001; HR =0.70, 95% CI: 0.57-0.85, P<0.001, respectively). However, the pooled results showed that neither CD3+ nor FOXP3+ T-cell infiltration were associated with patient survival (P>0.05). Moreover, for esophageal squamous cell carcinoma (ESCC), high CD8+ T lymphocyte infiltration in the TN (Tumor nest) or TS (Tumor stroma) significantly predicted better OS (pooled HR =0.70, 95% CI: 0.57-0.85; P=0.001; pooled HR =0.77, 95% CI: 0.65-0.91; P=0.003).

Conclusions: High levels of generalized TILs, high CD8+ T-cell infiltration and high CD4+ T-cell infiltration have the potential to serve as prognostic markers in EC patients. Moreover, high CD8+ TIL in TNs or TS can predict better OS in ESCC patients.
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http://dx.doi.org/10.21037/atm-20-151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396260PMC
July 2020

Development and validation of an immune-related prognostic signature in lung adenocarcinoma.

Cancer Med 2020 08 26;9(16):5960-5975. Epub 2020 Jun 26.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, China.

Background: Lung adenocarcinomas (LUAD) is the most common histological subtype of lung cancers. Tumor immune microenvironment (TIME) is involved in tumorigeneses, progressions, and metastases. This study is aimed to develop a robust immune-related signature of LUAD.

Methods: A total of 1774 LUAD cases sourced from public databases were included in this study. Immune scores were calculated through ESTIMATE algorithm and weighted gene co-expression network analysis (WGCNA) was applied to identify immune-related genes. Stability selections and Lasso COX regressions were implemented to construct prognostic signatures. Validations and comparisons with other immune-related signatures were conducted in independent Gene Expression Omnibus (GEO) cohorts. Abundant infiltrated immune cells and pathway enrichment analyses were carried out, respectively, through ImmuCellAI and gene set enrichment analysis (GSEA).

Results: In Cancer Genome Atlas (TCGA) LUAD cohorts, immune scores of higher levels were significantly associated with better prognoses (P < .05). Yellow (n = 270) and Blue (n = 764) colored genes were selected as immune-related genes, and after univariate Cox regression analysis (P < .005), a total of 133 genes were screened out for subsequent model constructions. A four-gene signature (ARNTL2, ECT2, PPIA, and TUBA4A) named IPSLUAD was developed through stability selection and Lasso COX regression. It was suggested by multivariate and subgroup analyses that IPSLUAD was an independent prognostic factor. It was suggested by Kaplan-Meier survival analysis that eight out of nine patients in high-risk groups had significantly worse prognoses in validation data sets (P < .05). IPSLUAD outperformed other signatures in two independent cohorts.

Conclusions: A robust immune-related prognostic signature with great performances in multiple LUAD cohorts was developed in this study.
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http://dx.doi.org/10.1002/cam4.3240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433810PMC
August 2020

Synergistic Optimization toward the Sensitivity and Linearity of Flexible Pressure Sensor via Double Conductive Layer and Porous Microdome Array.

ACS Appl Mater Interfaces 2020 Jul 23;12(27):31021-31035. Epub 2020 Jun 23.

Joint Key Laboratory of the Ministry of Education, Institute of Applied Physics and Materials Engineering, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China.

Recently, wearable pressure sensors have attracted considerable interest in various fields such as healthcare monitoring, intelligent robots, etc. Although artificial structures or conductive materials have been well developed, the trade-off between sensitivity and linearity of pressure sensors is yet to be fully resolved by a traditional approach. Herein, from theoretical analysis to experimental design, we present the novel CPDMS/AgNWs double conductive layer (DCL) to synergistically optimize the sensitivity and linearity of piezoresistive pressure sensors. The facilely fabricated solid microdome array (SDA) is first employed as the elastomer to clarify the unrevealed working mechanism of DCL. Attributed to the synergistic effect of DCL, the DCL/SDA based sensor exhibits ultrahigh sensitivity (up to 3788.29 kPa) in an obviously broadened linearity range (0-6 kPa). We also demonstrated that the synergistic effect of DCL can be regulated with use of porous microdome array (PDA) to further optimize the sensing property. The linearity range can be improved up to 70 kPa while preserving the high sensitivity of 924.37 kPa based on the interlocked PDA structure (IPDA), which is rarely reported in previous studies. The optimized sensitivity and linearity allow the competitive DCL/IPDA based sensor as a reliable platform to monitor kinds of physiological signals covering from low pressures (e.g., artery pulses), medium pressures (e.g., muscle expansions), to high pressures (e.g., body motions). We believe that the methodology along with the robust sensor can be of great potential for reliable healthcare monitoring and wearable electronic applications in the future.
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http://dx.doi.org/10.1021/acsami.0c08910DOI Listing
July 2020

The key iron assimilation genes ClFTR1, ClNPS6 were crucial for virulence of Curvularia lunata via initiating its appressorium formation and virulence factors.

Environ Microbiol 2021 02 25;23(2):613-627. Epub 2020 Jun 25.

College of Plant Protection, Shenyang Agricultural University, Shenyang, 110161, China.

Iron is virtually an essential nutrient for all organisms, to understand how iron contributes to virulence of plant pathogenic fungi, we identified ClFTR1 and ClNPS6 in maize pathogen Curvularia lunata (Cochliobolus lunatus) in this study. Disruption of ClNPS6 significantly impaired siderophore biosynthesis. ClFTR1 and ClNPS6 did mediate oxidative stress but had no significant impact on vegetative growth, conidiation, cell wall integrity and sexual reproduction. Conidial germination delayed and appressoria formation reduced in ΔClftr1 comparing with wild type (WT) CX-3. Genes responsible for conidial germination, appressoria formation, non-host selective toxin biosynthesis and cell wall degrading enzymes were also downregulated in the transcriptome of ΔClftr1 and ΔClnps6 compared with WT. The conidial development, toxin biosynthesis and polygalacturonase activity were impaired in the mutant strains with ClFTR1 and ClNPS6 deletion during their infection to maize. ClFTR1 and ClNPS6 were upregulated expression at 12-24 and 48-120 hpi in WT respectively. ClFTR1 positively regulated conidial germination, appressoria formation in the biotrophy-specific phase. ClNPS6 positively regulates non-host selective toxin biosynthesis and cell wall degrading enzyme activity in the necrotrophy-specific phase. Our results indicated that ClFTR1 and ClNPS6 were key genes of pathogen known to conidia development and virulence factors.
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http://dx.doi.org/10.1111/1462-2920.15101DOI Listing
February 2021
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