Publications by authors named "Xiangyi Wang"

20 Publications

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Corrigendum to 'Silencing KIF18B enhances radiosensitivity: Identification of a promising therapeutic target in sarcoma' [EBioMedicine 61 (2020) 103,056].

EBioMedicine 2021 Nov 22;74:103710. Epub 2021 Nov 22.

Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, PR China; Liaoning Key Laboratory of molecular targeted anti-tumor drug development and evaluation, Liaoning Cancer immune peptide drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang 110122, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2021.103710DOI Listing
November 2021

Hypoxia-related prognostic model in bladder urothelial reflects immune cell infiltration.

Am J Cancer Res 2021 15;11(10):5076-5093. Epub 2021 Oct 15.

Department of Pharmacology, School of Pharmacy, China Medical University Shenyang 110122, Liaoning, China.

Hypoxia is a common feature of tumor microenvironment (TME). This study aims to establish the genetic features related to hypoxia in Bladder urothelial carcinoma (BLCA) and investigate the potential correlation with hypoxia in the TME and immune cells. We established a BLCA outcome model using the hypoxia-related genes from The Cancer Genome Atlas using regression analysis and verified the model using the Gene Expression Omnibus GSE32894 cohort. We measured the effect of each gene in the hypoxia-related risk model using the Human Protein Atlas website. The predictive abilities were compared using the area under the receiver operating characteristic curves. Gene Set Enrichment Analysis was utilized for indicating enrichment pathways. We analyzed immune cell infiltration between risk groups using the CIBERSORT method. The indicators related to immune status between the two groups were also analyzed. The findings indicated that the high-risk group had better outcomes than the low-risk group in the training and validation sets. Each gene in the model affected the survival of BLCA patients. Our hypoxia-related risk model had better performance compared to other hypoxia-related markers (HIF-1α and GLUT-1). The high-risk group was enriched in immune-related pathways. The expression of chemokines and immune cell markers differed significantly between risk groups. Immune checkpoints were more highly expressed in the high-risk group. These findings suggest that the hypoxia-related risk model predicts patients' outcomes and immune status in BLCA risk groups. Our findings may contribute to the treatment of BLCA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569353PMC
October 2021

Oligomerization-driven MLKL ubiquitylation antagonizes necroptosis.

EMBO J 2021 Dec 26;40(23):e103718. Epub 2021 Oct 26.

The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase-independent form of programmed cell death called necroptosis. Receptor-interacting serine/threonine protein kinase 3 (RIPK3) phosphorylates MLKL, triggering MLKL oligomerization, membrane translocation and membrane disruption. MLKL also undergoes ubiquitylation during necroptosis, yet neither the mechanism nor the significance of this event has been demonstrated. Here, we show that necroptosis-specific multi-mono-ubiquitylation of MLKL occurs following its activation and oligomerization. Ubiquitylated MLKL accumulates in a digitonin-insoluble cell fraction comprising organellar and plasma membranes and protein aggregates. Appearance of this ubiquitylated MLKL form can be reduced by expression of a plasma membrane-located deubiquitylating enzyme. Oligomerization-induced MLKL ubiquitylation occurs on at least four separate lysine residues and correlates with its proteasome- and lysosome-dependent turnover. Using a MLKL-DUB fusion strategy, we show that constitutive removal of ubiquitin from MLKL licences MLKL auto-activation independent of necroptosis signalling in mouse and human cells. Therefore, in addition to the role of ubiquitylation in the kinetic regulation of MLKL-induced death following an exogenous necroptotic stimulus, it also contributes to restraining basal levels of activated MLKL to avoid unwanted cell death.
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http://dx.doi.org/10.15252/embj.2019103718DOI Listing
December 2021

Advanced applications of mass spectrometry imaging technology in quality control and safety assessments of traditional Chinese medicines.

J Ethnopharmacol 2021 Oct 19;284:114760. Epub 2021 Oct 19.

New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Beijing Union-Genius Pharmaceutical Technology Development Co., Ltd., Beijing 100176, China; NMPA Key Laboratory for Safety Research and Evaluation of Innovative Drug, Beijing 100050, China. Electronic address:

Ethnopharmacological Relevance: Traditional Chinese medicines (TCMs) have made great contributions to the prevention and treatment of human diseases in China, and especially in cases of COVID-19. However, due to quality problems, the lack of standards, and the diversity of dosage forms, adverse reactions to TCMs often occur. Moreover, the composition of TCMs makes them extremely challenging to extract and isolate, complicating studies of toxicity mechanisms.

Aim Of The Review: The aim of this paper is therefore to summarize the advanced applications of mass spectrometry imaging (MSI) technology in the quality control, safety evaluations, and determination of toxicity mechanisms of TCMs.

Materials And Methods: Relevant studies from the literature have been collected from scientific databases, such as "PubMed", "Scifinder", "Elsevier", "Google Scholar" using the keywords "MSI", "traditional Chinese medicines", "quality control", "metabolomics", and "mechanism".

Results: MSI is a new analytical imaging technology that can detect and image the metabolic changes of multiple components of TCMs in plants and animals in a high throughput manner. Compared to other chemical analysis methods, such as liquid chromatography-mass spectrometry (LC-MS), this method does not require the complex extraction and separation of TCMs, and is fast, has high sensitivity, is label-free, and can be performed in high-throughput. Combined with chemometrics methods, MSI can be quickly and easily used for quality screening of TCMs. In addition, this technology can be used to further focus on potential biomarkers and explore the therapeutic/toxic mechanisms of TCMs.

Conclusions: As a new type of analysis method, MSI has unique advantages to metabolic analysis, quality control, and mechanisms of action explorations of TCMs, and contributes to the establishment of quality standards to explore the safety and toxicology of TCMs.
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http://dx.doi.org/10.1016/j.jep.2021.114760DOI Listing
October 2021

Mannose-modified liposome designed for epitope peptide drug delivery in cancer immunotherapy.

Int Immunopharmacol 2021 Oct 12;101(Pt A):108148. Epub 2021 Oct 12.

School of Pharmacy, China Medical University, Shenyang 110122, China. Electronic address:

Background: Based on the interaction between cytotoxic T lymphocyte (CTL) dominant epitopes and dendritic cells (DCs), CD8T cells are specifically activated into CTL cells. Targeted killing is a type of tumor vaccine for immunotherapy with great development potential. However, because of the disadvantages of poor stability in vivo and low uptake rate of DCs caused by single use of dominant epitope peptide drugs, its use is limited. Here, we investigated the antitumor potential of M-YL/LA-Lipo, a novel liposome drug delivery system.

Methods: We assembled mannose on the surface of liposome, which has a highly targeted effect on the mannose receptor on the surface of DCs. The dominant epitope peptide drugs were encapsulated into the liposome using membrane hydration method, and the encapsulation rate, release rate, in vitro stability, and microstructure were characterized using ultrafiltration method, dialysis method, and negative staining transmission electron microscopy. In addition, its targeting ability was verified by in vitro interaction with DCs, and its anticancer effect was verified by animal experiments.

Results: We have successfully prepared a liposome drug delivery system with stable physical and chemical properties. Moreover, we demonstrated that it was highly uptaken by DCs and promoted DC maturation in vitro. Furthermore, in vivo animal experiments indicated that M-YL/LA-Lipo specific CTL significantly inhibited the hematogenous spread of lung metastasis of triple negative breast cancer.

Conclusions: we successfully constructed a new polypeptide liposome drug delivery system by avoiding the disadvantages of single use of dominant epitope peptide drugs and accurate targeted therapy for tumors.
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http://dx.doi.org/10.1016/j.intimp.2021.108148DOI Listing
October 2021

Sub-Nanometer Thick Wafer-Size NiO Films with Room-Temperature Ferromagnetic Behavior.

Angew Chem Int Ed Engl 2021 Nov 18;60(47):25020-25027. Epub 2021 Oct 18.

College of Energy, Key Lab of Advanced Optical Manufacturing Technologies of Jiangsu Province & Key Lab of Modern Optical Technologies of Education Ministry of China, Soochow University, Suzhou, 215123, China.

Adding ferromagnetism into semiconductors attracts much attentions due to its potential usage of magnetic spins in novel devices, such as spin field-effect transistors. However, it remains challenging to stabilize their ferromagnetism above room temperature. Here we introduce an atomic chemical-solution strategy to grow wafer-size NiO thin films with controllable thickness down to sub-nanometer scale (0.92 nm) for the first time. Surface lattice defects break the magnetic symmetry of NiO and produce surface ferromagnetic behaviors. Our sub-nanometric NiO thin film exhibits the highest reported room-temperature ferromagnetic behavior with a saturation magnetization of 157 emu/cc and coercivity of 418 Oe. Attributed to wafer size, the easily-transferred NiO thin film is further verified in a magnetoresistance device. Our work provides a sub-nanometric platform to produce wafer-size ferromagnetic NiO thin films as atomic layer magnetic units in future transparent magnetoelectric devices.
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http://dx.doi.org/10.1002/anie.202110185DOI Listing
November 2021

Immobilized Precursor Particle Driven Growth of Centimeter-Sized MoTe Monolayer.

J Am Chem Soc 2021 Aug 10;143(33):13314-13324. Epub 2021 Aug 10.

College of Energy, Soochow Institute for Energy and Materials Innovations, and Key Laboratory of Advanced Carbon Materials and Wearable Energy Technologies of Jiangsu Province, Soochow University, Suzhou 215123 China.

Molybdenum ditelluride (MoTe) has attracted ever-growing attention in recent years due to its novel characteristics in spintronics and phase-engineering, and an efficient and convenient method to achieve large-area high-quality film is an essential step toward electronic applications. However, the growth of large-area monolayer MoTe is challenging. Here, for the first time, we achieve the growth of a centimeter-sized monoclinic MoTe monolayer and manifest the mechanism of immobilized precursor particle driven growth. Microscopic characterizations reveal an obvious trend of immobilized precursor particles being consumed by the monolayer and continuing to provide a source for the growth of the monolayer. Time-of-flight secondary ion mass spectrometry verifies the attachment of hydroxide ions on the surface of the MoTe monolayer, thereby realizing the inhibition of crystal growth along the [001] zone axis and the continuous growth of the MoTe monolayer. The first-principles DFT calculations prove the mechanism of immobilized precursor particles and the absorption of hydroxide ions on the MoTe monolayer. The as-grown MoTe monolayer exhibits a surface roughness of 0.19 nm and average conductivity of 1.5 × 10 S/m, which prove the smoothness and uniformity of the MoTe monolayer. Temperature-dependent electrical measurements together with the transfer characteristic curves further demonstrate the typical semimetallic properties of monoclinic MoTe. Our research elaborates the microscopic process of immobilized precursor particles to grow large-area MoTe monolayer and provides a new thinking about the growth of many other two-dimensional materials.
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http://dx.doi.org/10.1021/jacs.1c06250DOI Listing
August 2021

Exploring the metabolic characteristics and pharmacokinetic variation of paroxetine in healthy volunteers using a pharmacometabonomic approach.

J Pharm Biomed Anal 2021 Sep 24;204:114224. Epub 2021 Jun 24.

Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, PR China. Electronic address:

The pharmacokinetic parameters of paroxetine vary between individuals, leading to differences in efficacy. The focus of our research was to predict responses to paroxetine using a pharmacometabonomic approach combining metabolic phenotypes and pharmacokinetic parameters. The pharmacokinetics of 12 healthy volunteers treated with paroxetine over two cycles was determined using high-performance liquid chromatography tandem mass spectrometry. Metabolic profiling and phenotyping were performed on the blood samples that remained after pharmacokinetic studies, using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry. Thirty-nine metabolites (p < 0.05) increased or decreased after treatment with paroxetine. Vitamin B6 metabolism; valine, leucine, and isoleucine biosynthesis; phenylalanine metabolism; pantothenate and coenzyme A biosynthesis; tyrosine metabolism; and glyoxylate and dicarboxylate metabolism were likely to be relevant for the effects of paroxetine. The two-stage partial least squares (PLS) strategy was used to screen potential biomarkers and predict the pharmacokinetic parameters of paroxetine. An orthogonal PLS discriminant analysis strategy was then applied to separate the high- and low-value groups based on the screened biomarkers. Pearson correlation test and receiver operating characteristic curve analysis confirmed the key prediction biomarkers. Seven common biomarkers were able to predict both the area under the curve (AUC) and the maximum concentration (C): cortisone, l-tyrosine, phenylpyruvate, l-valine, 2-oxoglutarate, l-lactate, and glycerate. Furthermore, homoprotocatechuate and l-glutamate were unique biomarkers for AUC, and citicoline and fumarate were unique biomarkers for C. The selected biomarkers were able to predict the AUC and C and discriminate good responders from poor responders to paroxetine treatment. This trial was registered with http://www.chinadrugtrials.org.cn/ (no. CTR20171590).
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http://dx.doi.org/10.1016/j.jpba.2021.114224DOI Listing
September 2021

CSE-Derived HS Inhibits Reactive Astrocytes Proliferation and Promotes Neural Functional Recovery after Cerebral Ischemia/Reperfusion Injury in Mice Via Inhibition of RhoA/ROCK Pathway.

ACS Chem Neurosci 2021 07 12;12(14):2580-2590. Epub 2021 Jul 12.

Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.

The effect of cystathionine-γ-lyase (CSE)-derived hydrogen sulfide (HS) on the reactive proliferation of astrocytes and neural functional recovery over 30 d after acute cerebral ischemia and reperfusion (I/R) was determined by applying wild-type (WT) and CSE knockout (KO) mice. The changes of glial fibrillary acidic protein (GFAP) expression in hippocampal tissues was tested. Besides, we assessed the changes of mice spatial learning memory ability, neuronal damage, RhoA, Rho kinase 2 (ROCK), and myelin basic protein (MBP) expressions in hippocampal tissues. The results revealed that cerebral I/R resulted in obvious increase of GFAP expression in hippocampal tissues. Besides, we found the neuronal damage, learning, and memory deficits of mice induced by cerebral I/R as well as revealed the upregulation of RhoA and ROCK expressions and reduced MBP expression in hipppcampal tissues of mice following cerebral I/R. Not surprisingly, the GFAP expression and cerebral injury as well as the upregulation of the RhoA/ROCK pathway were more remarkable in CSE KO mice, compared with those in WT mice over 30 d following acute cerebral I/R, which could be blocked by NaHS treatment, a donor of exogenous HS. In addition, the ROCK inhibitor Fasudil also inhibited the reactive proliferation of astrocytes and ameliorated the recovery of neuronal function over 30 d after cerebral I/R. For the purpose of further confirmation of the role of HS on the astrocytes proliferation following cerebral I/R, the immunofluorescence double staining: bromodeoxyuridine (BrdU) and GFAP was evaluated. There was a marked upregulation of BrdU-labeled cells coexpressed with GFAP in hippocampal tissues at 30 d after acute cerebral I/R; however, the increment of astrocytes proliferation could be ameliorated by both NaHS and Fasudil. These findings indicated that CSE-derived HS could inhibit the reactive proliferation of astrocytes and promote the recovery of mice neural functional deficits induced by a cerebral I/R injury via inhibition of the RhoA/ROCK signal pathway.
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http://dx.doi.org/10.1021/acschemneuro.0c00674DOI Listing
July 2021

Recent progress on MHC-I epitope prediction in tumor immunotherapy.

Am J Cancer Res 2021 15;11(6):2401-2416. Epub 2021 Jun 15.

Department of Pharmacology, School of Pharmacy, China Medical University No. 77 Puhe Road, Shenyang North New District, Shenyang, Liaoning, P. R. China.

Tumor immunotherapy has now become one of the most potential therapy for those intractable cancer diseases. The antigens on the cancer cell surfaces are the keys for the immune system to recognize and eliminate them. As reported, the immunogenicity of the tumor antigens could be determined by the binding between the key epitope peptides and MHC molecules. In recent years, the approaches to anticipate the peptides from the candidate epitopes have gradually changed into more efficient methods. Including the improved conventional methods, more diverse methods were coming into view. Here we review the anticipated methods of the tumor associated epitopes that specifically bind with major histocompatibility complex (MHC) class I molecules, and the recent advances and applications of those epitope prediction methods.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263640PMC
June 2021

Peptide-based therapeutic cancer vaccine: Current trends in clinical application.

Cell Prolif 2021 May 22;54(5):e13025. Epub 2021 Mar 22.

Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China.

The peptide-based therapeutic cancer vaccines have attracted enormous attention in recent years as one of the effective treatments of tumour immunotherapy. Most of peptide-based vaccines are based on epitope peptides stimulating CD8 T cells or CD4 T helper cells to target tumour-associated antigens (TAAs) or tumour-specific antigens (TSAs). Some adjuvants and nanomaterials have been exploited to optimize the efficiency of immune response of the epitope peptide to improve its clinical application. At present, numerous peptide-based therapeutic cancer vaccines have been developed and achieved significant clinical benefits. Similarly, the combination of peptide-based vaccines and other therapies has demonstrated a superior efficacy in improving anti-cancer activity. We delve deeper into the choices of targets, design and screening of epitope peptides, clinical efficacy and adverse events of peptide-based vaccines, and strategies combination of peptide-based therapeutic cancer vaccines and other therapies. The review will provide a detailed overview and basis for future clinical application of peptide-based therapeutic cancer vaccines.
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http://dx.doi.org/10.1111/cpr.13025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088465PMC
May 2021

Silencing KIF18B enhances radiosensitivity: identification of a promising therapeutic target in sarcoma.

EBioMedicine 2020 Nov 7;61:103056. Epub 2020 Oct 7.

Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, P. R. China; Liaoning Key Laboratory of molecular targeted anti-tumour drug development and evaluation; Liaoning Cancer immune peptide drug Engineering Technology Research Center; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education; China Medical University, Shenyang, 110122, P. R. China. Electronic address:

Background: Sarcomas are rare heterogeneous tumours, derived from primitive mesenchymal stem cells, with more than 100 distinct subtypes. Radioresistance remains a major clinical challenge for sarcomas, demanding urgent for effective biomarkers of radiosensitivity.

Methods: The radiosensitive gene Kinesin family member 18B (KIF18B) was mined through bioinformatics with integrating of 15 Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) database. We used radiotherapy-sh-KIF18B combination to observe the anti-tumour effect in sarcoma cells and subcutaneous or orthotopic xenograft models. The KIF18B-sensitive drug T0901317 (T09) was further mined to act as radiosensitizer using the Genomics of Drug Sensitivity in Cancer (GDSC) database.

Findings: KIF18B mRNA was significantly up-regulated in most of the subtypes of bone and soft tissue sarcoma. Multivariate Cox regression analysis showed that KIF18B high expression was an independent risk factor for prognosis in sarcoma patients with radiotherapy. Silencing KIF18B or using T09 significantly improved the radiosensitivity of sarcoma cells, delayed tumour growth in subcutaneous and orthotopic xenograft model, and elongated mice survival time. Furthermore, we predicted that T09 might bind to the structural region of KIF18B to exert radiosensitization.

Interpretation: These results indicated that sarcomas with low expression of KIF18B may benefit from radiotherapy. Moreover, the radiosensitivity of sarcomas with overexpressed KIF18B could be effectively improved by silencing KIF18B or using T09, which may provide promising strategies for radiotherapy treatment of sarcoma.

Fundings: A full list of funding can be found in the Funding Sources section.
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http://dx.doi.org/10.1016/j.ebiom.2020.103056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648128PMC
November 2020

Identifying Microbe-Disease Association Based on a Novel Back-Propagation Neural Network Model.

IEEE/ACM Trans Comput Biol Bioinform 2020 Apr 13. Epub 2020 Apr 13.

Over the years, numerous evidences have demonstrated that microbes living in the human body are closely related to human life activities and human diseases. However, traditional biological experiments are time-consuming and expensive, so it has become a research topic in bioinformatics to predict potential microbe-disease associations by adopting computational methods. In this study, a novel calculative method called BPNNHMDA is proposed to identify potential microbe-disease associations. In BPNNHMDA, a novel neural network model is first designed to infer potential microbe-disease associations, its input signal is a matrix of known microbe-disease associations, and its output signal is matrix of potential microbe-disease associations probabilities. And moreover, a new activation function is designed based on the hyperbolic tangent function, and its initial connection weights are optimized by adopting GIP similarity for microbes, which can improve the training speed of BPNNHMDA efficiently. Finally, in order to verify the performance of our prediction model, Leave-One-Out Cross Validation and k-Fold Cross Validation are implemented on BPNNHMDA respectively. Simulation results illustrate that BPNNHMDA can achieve reliable AUCs of 0.9242, 0.9127 ± 0.0009 and 0.8955 ± 0.0018 in LOOCV, 5-Fold CV and 2-Fold CV separately, which are superior to previous state-of-the-art methods. Furthermore, case studies demonstrate that BPNNHMDA has excellent prediction ability in practical applications as well.
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http://dx.doi.org/10.1109/TCBB.2020.2986459DOI Listing
April 2020

Implications of driver genes associated with a high tumor mutation burden identified using next-generation sequencing on immunotherapy in hepatocellular carcinoma.

Oncol Lett 2020 Apr 5;19(4):2739-2748. Epub 2020 Feb 5.

Department of Oncology, Peking University International Hospital, Beijing 102206, P.R. China.

Immune checkpoint blockade (ICB) therapy is a treatment strategy for hepatocellular carcinoma (HCC); however, its clinical efficacy is limited to a select subset of patients. Next-generation sequencing has identified the value of tumor mutation burden (TMB) as a predictor for ICB efficacy in multiple types of tumor, including HCC. Specific driver gene mutations may be indicative of a high TMB (TMB-H) and analysis of such mutations may provide novel insights into the underlying mechanisms of TMB-H and potential therapeutic strategies. In the present study, a hybridization-capture method was used to target 1.45 Mb of the genomic sequence (coding sequence, 1 Mb), analyzing the somatic mutation landscape of 81 HCC tumor samples. Mutations in five genes were significantly associated with TMB-H, including mutations in tumor protein 53 (TP53), Catenin1 (CTNNB1), AT-rich interactive domain-containing protein 1A (ARID1A), myeloid/lymphoid or mixed-lineage leukemia (MLL) and nuclear receptor co-repressor 1 (NCOR1). Further analysis using The Cancer Genome Atlas Liver Hepatocellular Carcinoma database showed that TP53, CTNNB1 and MLL mutations were positively correlated with TMB-H. Meanwhile, mutations in ARID1A, TP53 and MLL were associated with poor overall survival of patients with HCC. Overall, TMB-H and associated driver gene mutations may have potential as predictive biomarkers of ICB therapy efficacy for treatment of patients with HCC.
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http://dx.doi.org/10.3892/ol.2020.11372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068659PMC
April 2020

CDK6 inhibits lymphoid cell infiltration and represents a prognostic marker in HPV+ squamous cell carcinoma of head and neck.

Chin J Cancer Res 2019 Dec;31(6):901-909

Department of Medical Oncology, Peking University International Hospital, Beijing 102206, China.

Objective: We investigated the correlations between cyclin-dependent kinase 4/6 (CDK4/6) levels and human papillomavirus (HPV) infection state in head and neck squamous cell cancer (HNSCC). The aim was to explore the potential value of CDK4/6 inhibitors in the treatment of HNSCC.

Methods: Multiomic sequencing data for HNSCC were obtained from The Cancer Genome Atlas (TCGA), and the mRNA levels and copy number variations (CNVs) of CDK4 and CDK6 were strictly analyzed. Overall survival (OS) curves were produced using the Kaplan-Meier method, and survival differences between groups were assessed by the log-rank test. Next, gene set enrichment analysis (GSEA) was applied to interrogate CDK4/6-associated molecular pathways in HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC. Last, lymphoid cell infiltrates in each type of HNSCC were explored, and the correlations between CDK4/6 expression and lymphoid infiltrates were explored by Tumor Immune Estimation Resource (TIMER) analysis.

Results: Overexpression of either CDK6 or CDK4 was not a relevant factor for OS in HPV- HNSCC (CDK6: top 40%. bottom 40%, P=0.885; CDK4: top 40% . bottom 40%, P=0.267). In HPV+ HNSCC, CDK6 but not CDK4 was a relevant factor for OS (CDK6: top 40% . bottom 40%, P=0.002; CDK4: top 40% . bottom 40%, P=0.452). GSEA found that overexpressed CDK6 in HPV+ HNSCC inhibited pathways involved in the tumor immune response, suggesting its roles in antitumor immunity. TIMER analysis results revealed that CDK6 but not CDK4 accumulation was negatively correlated with the number of tumor-infiltrating lymphocytes specific for HPV+ HNSCC, which led to tumor response suppression.

Conclusions: CDK6, but not CDK4, is a poor prognostic marker specific in HPV+ HNSCC patients. Overexpressed CDK6 might stimulate tumor progression by suppressing lymphocytes infiltration independent of its kinase activity. Only abrogating its kinase activity using current CDK4/6 inhibitors was not enough to block its tumor promotion function.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2019.06.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955169PMC
December 2019

Clinical Characteristics and Prognosis of Gastrointestinal Metastases in Solid Tumor Patients: A Retrospective Study and Review of Literatures.

Anal Cell Pathol (Amst) 2019 20;2019:4508756. Epub 2019 Dec 20.

Department of Oncology, Peking University International Hospital, Life Park of Zhongguancun, Changping District, Beijing, China 102206.

Background: According to the literature and our experience, patients with gastrointestinal metastases are relatively rare. Numerous case reports and literature reviews have been reported. We present one of the larger case series of gastrointestinal metastases.

Objectives: To explore the clinical characteristics and prognosis of patients with gastrointestinal tract metastases, which are rare metastatic sites.

Methods: Patients with gastrointestinal metastases in the setting of stage IV primary carcinomas treated at Beijing Ditan Hospital and Peking University International Hospital from November 1992 to August 2017 were included in this study. The diagnosis of gastrointestinal tract metastases was based on histopathology.

Results: 30 patients (median age 56 years, 56.7% female) were included. The most common primary carcinomas associated with gastrointestinal metastases were breast (11 patients, 36.7%), stomach (9 patients, 30.0%), and lung (4 patients, 13.3%) cancer. The major pathological types were adenocarcinoma (16 patients, 53.3%) and ductal carcinoma (9 patients, 30.0%). Ten patients (33.3%) underwent local gastrointestinal treatment, and 20 patients (66.7%) underwent nonlocal treatment (involving chemotherapy alone or best supportive care). For breast cancer patients and gastric cancer patients who underwent local therapy, a significant survival advantage was observed ( = 0.001 and = 0.012, respectively). The presence of other common metastases was identified as an independent poor prognostic factor through multivariate analysis with a HR (hazard ratio) of survival of 0.182 (95% confidence interval (CI) 0.11-0.523, = 0.031).

Conclusion: Gastrointestinal metastases are most frequently from breast invasive ductal carcinoma. The presentation of other common metastases with gastrointestinal metastasis indicates poor prognosis, and selected patients may benefit from surgical intervention.
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http://dx.doi.org/10.1155/2019/4508756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939450PMC
August 2020

Using Pre-Treatment Neutrophil-to-Lymphocyte Ratio to Predict the Prognosis of Young Patients with Hepatocellular Carcinoma Implemented Minimally Invasive Treatment.

J Adolesc Young Adult Oncol 2020 02 17;9(1):85-89. Epub 2019 Oct 17.

Department of Oncology, Capital Medical University Affiliated Beijing Ditan Hospital, Beijing, China.

Neutrophil-to-lymphocyte ratio (NLR) is considered as a prognostic factor in some patients with hepatocellular carcinoma (HCC). This factor has not been extensively examined in young HCC patients. The objective of this study is to assess whether pre-treatment NLR could predict the survival in young HCC patients implemented minimally invasive treatment. Young HCC patients treated by transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) at our institutes from 2008 to 2017 were retrospectively reviewed. The best cutoff value of NLR was determined with time-dependent receiver operating characteristic curve analysis. The associations between overall survival and various potential risk factors, including tumor size, vascular invasion, hepatitis B virus infection, Child-Pugh scores, Barcelona Clinic Liver Cancer (BCLC) stage, aspartate aminotransferase (AST), and NLR, were analyzed. Data were collected from 47 HCC patients who were <45 years old (range 30-44). In univariate analysis, vascular invasion ( = 0.001), tumor maximum diameter ( = 0.000), BCLC stage ( = 0.001), HBsAg positive  = 0.025), AST ≥2 × upper limits of normal (ULN) ( = 0.027), and NLR ≥3.09 ( = 0.027) were predictors for poor survival in young HCC patients treated by TACE combined with RFA. The multivariate Cox proportional hazard model analysis showed that except NLR (hazard ratio [HR] = 0.720, 95% CI 0.287-1.808,  = 0.485), tumor maximum diameter ≥5 cm (HR = 0.444, 95% CI 0.199-0.991,  = 0.047) and AST ≥2 × ULN (HR = 4.578, 95% CI 1.544-13.575,  = 0.006) were independent indicators for poor prognosis. Pre-treatment NLR ≥3.09 is related to poor prognosis of young HCC patients implemented minimally invasive treatment. However, it is not an independent indicator for prognosis.
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http://dx.doi.org/10.1089/jayao.2019.0046DOI Listing
February 2020

Agro-ecological suitability assessment of Chinese Medicinal Yam under future climate change.

Environ Geochem Health 2020 Mar 15;42(3):987-1000. Epub 2019 Oct 15.

Shanghai Institute of Technology, Shanghai, 201418, China.

Chinese Medicinal Yam (CMY) has been prescribed as medicinal food for thousand years in China by Traditional Chinese Medicine (TCM) practitioners. Its medical benefits include nourishing the stomach and spleen to improve digestion, replenishing lung and kidney, etc., according to the TCM literature. As living standard rises and public health awareness improves in recent years, the potential medicinal benefits of CMY have attracted increasing attention in China. It has been found that the observed climate change in last several decades, together with the change in economic structure, has driven significant shift in the pattern of the traditional CMY planting areas. To identify suitable planting area for CMY in the near future is critical for ensuring the quality and supply quantity of CMY, guiding the layout of CMY industry, and safeguarding the sustainable development of CMY resources for public health. In this study, we first collect 30-year records of CMY varieties and their corresponding phenology and agro-meteorological observations. We then consolidate these data and use them to enrich and update the eco-physiological parameters of CMY in the agro-ecological zone (AEZ) model. The updated CMY varieties and AEZ model are validated using the historical planting area and production under observed climate conditions. After the successful validation, we use the updated AEZ model to simulate the potential yield of CMY and identify the suitable planting regions under future climate projections in China. This study shows that regions with high ecological similarity to the genuine and core producing areas of CMY mainly distribute in eastern Henan, southeastern Hebei, and western Shandong. The climate suitability of these areas will be improved due to global warming in the next 50 years, and therefore, they will continue to be the most suitable CMY planting regions.
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http://dx.doi.org/10.1007/s10653-019-00437-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188720PMC
March 2020

Cytoplasmic expression of estrogen receptor β may predict poor outcome of EGFR-TKI therapy in metastatic lung adenocarcinoma.

Oncol Lett 2018 Aug 8;16(2):2382-2390. Epub 2018 Jun 8.

Department of Oncology, Peking University International Hospital, Beijing 102206, P.R. China.

There is growing evidence that estrogen receptors (ER) are expressed in lung cancer cells, and are able to interact with the epidermal growth factor receptor (EGFR) signaling pathway. However, data on the association between cytoplasmic ER expression and the response to EGFR-tyrosine kinase inhibitors (TKI) treatment are limited. The aim of the present study was to investigate the associations between ERα/ERβ expression and EGFR mutational status and response to TKI treatment in metastatic lung adenocarcinoma. A retrospective study of 126 consecutive patients with lung adenocarcinoma who were diagnosed with stage IV disease and had received EGFR-TKI treatment was conducted. ER expression was detected by immunohistochemistry. EGFR and GTPase KRas (KRAS) mutational statuses were evaluated by denaturing high performance liquid chromatography and PCR-restriction fragment length polymorphism, respectively. In the overall cohort of 126 lung adenocarcinoma samples analyzed, ERα expression in the nucleus of tumor cells was identified in 17 (18.9%) patients, whereas ERβ expression was identified in the nucleus (22/126, 17.5%) and cytoplasm (17/126, 13.5%). The nuclear expression of ERβ was positively associated with the degree of tumor differentiation (P=0.010). EGFR-sensitizing mutations were significantly associated with improved objective response rates (ORR), disease control rates (DCR), median progression-free survival (mPFS) and median overall survival (mOS) (P<0.001; P<0.001; P=0.003; and P=0.026, respectively). Patients with cytoplasmic ERβ expression exhibited non-significant poorer ORR, DCR, mPFS and mOS compared with patients without cytoplasmic ERβ expression (P=0.082; P=0.106; P=0.084; and P=0.119, respectively). However, the significant decrease of ORR, DCR and mPFS was observed in patients with coexisting cytoplasmic ERβ expression and EGFR-sensitizing mutations (P=0.030; P=0.009; and P=0.018, respectively) in comparison with the subgroup with EGFR sensitizing mutations but negative expression of cytoplasmic ERβ. A trend towards shorter mOS was also observed in patients with coexisting cytoplasmic ERβ expression and EGFR-sensitizing mutations (P=0.071). No KRAS mutations were identified in patients with cytoplasmic ERβ expression. Subsequent to adjusting for sex, smoking status and EGFR mutation status, the Cox repression analysis indicated that cytoplasmic expression of ERβ was a negative independent predictor for mPFS in the whole patient cohort (HR=1.870; 95% confidence interval 1.058-3.305; P=0.031). Cytoplasmic ERβ expression was negatively correlated with the efficacy of EGFR-TKI treatment for metastatic lung adenocarcinoma, particularly for patients with coexisting cytoplasmic ERβ expression and EGFR-sensitizing mutations. Cytoplasmic ERβ may be a promising marker to predict the outcome of EGFR-TKI treatment.
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http://dx.doi.org/10.3892/ol.2018.8936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036564PMC
August 2018

Clinical characteristics of hepatocellular carcinoma patients with normal serum alpha-fetoprotein level: A study of 112 consecutive cases.

Asia Pac J Clin Oncol 2018 Oct 26;14(5):e336-e340. Epub 2017 Oct 26.

Department of Oncology, Peking University International Hospital, Beijing, China.

Background: Serum alpha-fetoprotein (AFP) level is normal in 30-40% of hepatocellular carcinoma (HCC) patients, and knowledge on its characteristics and clinical outcome is limited. The purpose of this observational study was to determine the clinical presentation, biological behavior and outcome of HCC patients with normal AFP level.

Methods: Data of 112 consecutive HCC patients with normal AFP level were analyzed retrospectively. Statistical analysis including survival and factors associated with serum AFP level were performed by Kaplan-Meier method and t-test, respectively.

Results: Hepatitis B virus infection exited in 83.0% of all 112 HCC patients with normal AFP level. During a mean 52 ± 20 months (range 5-85 months) follow-up, the 1-, 2-, 3-year overall survival (OS) rate was 97.2%, 85.3% and 81.7%, respectively. The OS rates at 3 years stratified by stages at diagnosis were 100%, 96.2%, 85.7%, 11.1% and 0%, respectively for Barcelona Clinic Liver Cancer (BCLC) stage 0-D diseases. Significant difference in OS was observed among patients with BCLC stage 0-D diseases, P < 0.05. Using 8.78 ng/mL as the cut off value, serum AFP level elevated beyond normal figure during follow-up (AFP conversion) in 16 patients, which related with deterioration of liver function, quantitative changes of T helper cell subsets, rapid tumor progression and shorter survival. Patients with sustained normal AFP level had better survival than patients with AFP conversion, P < 0.05. There was significant difference between the time of diagnosis with HCC to serum AFP level elevation and the time of AFP elevation to death, P < 0.05.

Conclusion: Prognosis of HCC patients with normal AFP level was relatively optimal. Serum AFP level elevation during follow-up was significantly associated with clinical outcome in terms of OS.
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http://dx.doi.org/10.1111/ajco.12816DOI Listing
October 2018
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