Publications by authors named "William Cho"

386 Publications

Prognostic Implication of the mA RNA Methylation Regulators in Rectal Cancer.

Front Genet 2021 3;12:604229. Epub 2021 Jun 3.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.

N6-methyladenosine (mA) is a very common and abundant RNA modifications occurring in nearly all types of RNAs. Although the dysregulated expression of mA regulators is implicated in cancer progression, our understanding of the prognostic value of the mA regulators in rectal cancer is still quite limited. In this study, we analyzed the RNA expression levels of the 17 mA regulator genes of 95 rectal cancer and 10 normal rectal samples from the The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) dataset. Lasso regression analysis was conducted to build a prognostic model and calculate the risk score. The rectal cancer patients were then devided into the high-risk and low-risk groups according to the mean risk score. The prognostic value of the identified model was separately evaluated in the TCGA-READ and GSE87211 datasets. GSEA was conducted to analyze the functional difference of high-risk and low-risk rectal cancer patients. Our analysis revealed that rectal cancer patients with lower expression of YTHDC2 and METTL14 had a remarkable worse overall survival ( < 0.05). The prognostic value of the model was validated in GSE87211 datasets, with AUC = 0.612 for OS and AUC = 0.651 for RFS. Furthermore, the mA modification-based risk score system is associated with activation of distinct signaling pathways, such as DNA repair, epithelial-mesenchymal transition, GM checkpoint and the MYC pathway, that may contribute to the progression of rectal cancer. In conclusion, our findings demonstrated that the mA RNA methylation regulators, specifically YTHDC2 and METTL14, were significantly down-regulated and might be potential prognostic biomarkers in rectal cancer.
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http://dx.doi.org/10.3389/fgene.2021.604229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209494PMC
June 2021

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies.

Front Oncol 2021 25;11:635007. Epub 2021 May 25.

Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong.

Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.
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http://dx.doi.org/10.3389/fonc.2021.635007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185359PMC
May 2021

An overview of rational design of mRNA-based therapeutics and vaccines.

Expert Opin Drug Discov 2021 May 31. Epub 2021 May 31.

Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China.

Introduction: Messenger RNA (mRNA)-based therapeutics and vaccines have emerged as a disruptive new drug class for various applications, including regenerative medicine, cancer treatment, and prophylactic and therapeutic vaccinations.

Areas Covered: This review provides an update about the rational structure-based design of various formats of mRNA-based therapeutics. The authors discuss the recent advances in the mRNA modifications that have been used to enhance stability, promote translation efficiency and regulate immunogenicity for specific applications.

Expert Opinion: Extensive research efforts have been made to optimize mRNA constructs and preparation procedures to unleash the full potential of mRNA-based therapeutics and vaccines. Sequence optimization (untranslated region and codon usage), chemical engineering of nucleotides and modified 5'cap, and optimization of transcription and mRNA purification protocols have overcome the major obstacles (instability, delivery, immunogenicity and safety) hindering the clinical applications of mRNA therapeutics and vaccines. The optimized design parameters should not be applied as default to different biological systems, but rather individually optimized for each mRNA sequence and intended application. Further advancement in the mRNA design and delivery technologies for achieving cell type- and organ site-specificity will broaden the scope and usefulness of this new class of drugs.
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http://dx.doi.org/10.1080/17460441.2021.1935859DOI Listing
May 2021

A Novel CAR Expressing NK Cell Targeting CD25 With the Prospect of Overcoming Immune Escape Mechanism in Cancers.

Front Oncol 2021 14;11:649710. Epub 2021 May 14.

Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

For many years, high-affinity subunit of IL-2 receptor (CD25) has been considered as a promising therapeutic target for different pathologic conditions like allograft rejection, autoimmunity, and cancers. Although CD25 is transiently expressed by newly-activated T cells, it is the hallmark of regulatory T (Treg) cells which are the most important immunosuppressive elements in tumor microenvironment. Thus, Tregs can be considered as a potential target for chimeric antigen receptor (CAR)-based therapeutic approaches. On the other hand, due to some profound adverse effects pertaining to the use of CAR T cells, CAR NK cells have caught researchers' attention as a safer choice. Based on these, the aim of this study was to design and develop a CAR NK cell against CD25 as the most prominent biomarker of Tregs with the prospect of overcoming immune escape mechanism in solid and liquid cancers. In the current study, an anti-CD25 CAR was designed and evaluated by comprehensive analyses. Then, using lentiviral transduction system, NK-92 cell line was engineered to express this anti-CD25 CAR construct. functional analyses of anti-CD25 CAR for its reactivity against CD25 antigen as well as for cytotoxicity and cytokine production assays against CD25 bearing Jurkat cell line were done. analyses demonstrated that the anti-CD25 CAR transcript and scFv protein structures were stable and had proper interaction with the target. Also, analyses showed that the anti-CD25 CAR-engineered NK-92 cells were able to specifically detect and lyse target cells with an appropriate cytokine production and cytotoxic activity. To conclude, the results showed that this novel CAR NK cell is functional and warrant further investigations.
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http://dx.doi.org/10.3389/fonc.2021.649710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160382PMC
May 2021

Editorial: Going the Distance: Enabling 3D Cell Culture Systems for Biomedical Research and Drug Treatment.

Front Mol Biosci 2021 10;8:685095. Epub 2021 May 10.

Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, China.

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http://dx.doi.org/10.3389/fmolb.2021.685095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141622PMC
May 2021

Integrin α4β1/VCAM-1 Interaction Evokes Dynamic Cell Aggregation Between Immune Cells and Human Lung Microvascular Endothelial Cells at Infectious Hemolysis.

Front Pharmacol 2021 20;12:653143. Epub 2021 Apr 20.

Department of Hepatopathy, Hunan Children's Hospital, Changsha, China.

Bacterial and viral infection is a common cause of pneumonia, respiratory failure, and even acute respiratory distress syndrome. Increasing evidence indicates that red blood cells (RBCs) may contribute to immune response and inflammation. However, the precise molecular mechanisms that link RBC and hemolysis to the development and progression of inflammatory pathologies are not entirely understood. In this study, we used bacterial endotoxin, lipopolysaccharide (LPS), to mimic an infectious hemolysis and found that RBCs dynamically regulated cell aggregation between immune cells and human lung microvascular endothelial cells (HLMVEC). When RBCs were treated with LPS, integrin α4β1 was increased and was accompanied by cytokines and chemokines release (TNF-α, IL-1β, IL-6, IL-8, IFN-γ, CXCL12, CCL5, CCL7 and CCL4). Upon α4β1 elevation, RBCs not only facilitated mature monocyte derived dendritic cell (mo-DCs) adhesion but also promoted HLMVEC aggregation. Furthermore, co-culture of the supernatant of LPS pre-treated RBCs with mo-DCs could promote naïve CD4 T cell proliferation. Notably, the filtered culture from LPS-lysed RBCs further promoted mo-DCs migration in a concentration dependent manner. From a therapeutic perspective, cyclic peptide inhibitor of integrin α4β1 combined with methylprednisolone (α4β1/Methrol) remarkably blocked RBCs aggregation to mo-DCs, HLMVEC, or mo-DCs and HLMVEC mixture. Moreover, α4β1/Methrol dramatically reduced mo-DCs migration up-regulated glucocorticoid-induced leucine zipper in mo-DCs, and ultimately reversed immune cell dysfunction induced by hemolysis. Taken together, these results indicate that integrin α4β1 on RBCs could mediate cell-cell interaction for adaptive immunity through influencing cell adhesion, migration, and T cell proliferation.
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http://dx.doi.org/10.3389/fphar.2021.653143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093802PMC
April 2021

The Adjunctive Effect of Acupuncture for Advanced Cancer Patients in a Collaborative Model of Palliative Care: Study Protocol for a 3-Arm Randomized Trial.

Integr Cancer Ther 2021 Jan-Dec;20:15347354211012749

The University of Hong Kong, Hong Kong, China.

Background: Cancer is the second leading cause of death before the age of 70. Improved cancer survival has put increasing demands on cancer care. Palliative care is the specialized multi-disciplinary care providing relief from the pain, symptoms, and stress of serious illness. The study aims to evaluate the adjunctive effect of acupuncture for advanced cancer patients in a collaborative model of palliative care.

Methods/design: This is a single-blinded, randomized, sham-controlled trial. One hundred twenty advanced cancer patients undergoing palliative care will be randomized in a ratio of 2:1:1 to manual acupuncture plus standard care group (ASC), sham acupuncture plus standard care group (SSC), and standard care group (SC). Patients in ASC and SSC will receive 9 sessions of acupuncture or sham acupuncture for 3 weeks, and will be followed up for 2 months. The primary measure is the change from baseline score of the Edmonton Symptom Assessment System at 3 weeks. The secondary measures include the Brief Fatigue Inventory, Hospital Anxiety and Depression Scale, Insomnia Severity Index, Numeric Rating Scale, and European Organization for Research and Treatment of Cancer Quality of Life 15 items Questionnaire for Palliative Care.

Discussion: The finding of this trial will provide high-quality evidence on the adjunctive effect of acupuncture to standard care on advanced cancer patients undergoing palliative care.

Trial Registration: Clinicaltrials.gov, NCT04398875 (https://www.clinicaltrials.gov/ct2/show/NCT04398875), Registered on 21 May 2020.
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http://dx.doi.org/10.1177/15347354211012749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113363PMC
May 2021

Performance comparison of the Cobas® Liat® and Cepheid® GeneXpert® systems on SARS-CoV-2 detection in nasopharyngeal swab and posterior oropharyngeal saliva.

Expert Rev Mol Diagn 2021 05 28;21(5):515-518. Epub 2021 Apr 28.

Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong Special Administrative Region.

: Nucleic acid amplification tests (NAATs) based methods such as real-time reverse transcription polymerase-chain reaction (real-time RT-PCR) are the gold standard for diagnosis of current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The cobas® Liat® and cepheid® GeneXpert® systems are two rapid real-time RT-PCR platforms offering rapid, specimen-to-answer detection of SARS-CoV-2.: In this study, we compared the performance of these two systems on SARS-CoV-2 detection in 9 nasopharyngeal swab (NPS) and 70 posterior oropharyngeal saliva specimens collected from 79 patients suspected of SARS-CoV-2 infection between August 2020 and March 2021.: The Positive Percent Agreement (PPA), Negative Percent Agreement (NPA) and overall Percent Agreement (OPA) between cepheid® Xpress SARS-CoV-2 assay and cobas® Liat® SARS-CoV-2 & Influenza A/B assay were found to be 100%. We demonstrated an excellent overall test concordance of the Liat® SARS-CoV-2 & Influenza A/B assay and Xpress SARS-CoV-2 assay. The small sample size of SARS-CoV-2 positive and weak-positive specimens is the inherent limitation of this study.: The performance of the cobas® Liat® SARS-CoV-2 & Influenza A/B assay is equivalent to the cepheid® Xpress SARS-CoV-2 assay for SARS-CoV-2 detection using NPS and posterior oropharyngeal saliva.
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http://dx.doi.org/10.1080/14737159.2021.1919513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095157PMC
May 2021

Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling.

Nat Commun 2021 04 14;12(1):2242. Epub 2021 Apr 14.

Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong.

Breast cancer is a heterogeneous disease, affecting over 3.5 million women worldwide, yet the functional role of cis-regulatory elements including super-enhancers in different breast cancer subtypes remains poorly characterized. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.
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http://dx.doi.org/10.1038/s41467-021-22445-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046763PMC
April 2021

Long Non-Coding RNAs in Multidrug Resistance of Glioblastoma.

Genes (Basel) 2021 Mar 23;12(3). Epub 2021 Mar 23.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran.

Glioblastoma, also known as glioblastoma multiforme, is the most aggressive brain tumor in adults. Despite the huge advance in developing novel therapeutic strategies for patients with glioblastoma, the appearance of multidrug resistance (MDR) against the common chemotherapeutic agents, including temozolomide, is considered as one of the important causes for the failure of glioblastoma treatment. On the other hand, recent studies have demonstrated the critical roles of long non-coding RNAs (lncRNAs), particularly in the development of MDR in glioblastoma. Therefore, this article aimed to review lncRNA's contribution to the regulation of MDR and elucidate the underlying mechanisms in glioblastoma, which will open up new lines of inquiry in the treatment of glioblastoma.
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http://dx.doi.org/10.3390/genes12030455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004794PMC
March 2021

MiR-142-3p targets HMGA2 and suppresses breast cancer malignancy.

Life Sci 2021 Jul 27;276:119431. Epub 2021 Mar 27.

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

MicroRNAs (miRNAs) have the ability to regulate gene expression programs in cells. Hence, altered expression of miRNAs significantly contributes to breast cancer development and progression. Here, we demonstrate that the miRNA miR-142-3p directly targets the 3' untranslated region of HMGA2, which encodes an onco-embryonic protein that is overexpressed in most cancers, including breast cancer. Down regulation of miR-142-3p predicting poor patient survival in grade 3 breast cancer (P-value = 0.045). MiR-142-3p downregulates HMGA2 mRNA and protein levels. Higher miR-142-3p and lower HMGA2 expressed are found in breast cancer versus normal breast tissue (P-value<0.05), and their levels inversely correlate in breast cancers (P-value = 1.46 × 10). We demonstrate that miR-142-3p induces apoptosis and G2/M cell cycle arrest in breast cancer cells. In addition, it inhibits breast cancer stem cell properties and decreases SOX2, NANOG, ALDH and c-Myc expression. MiR-142-3p also decreases cell proliferation through inhibition of the ERK/AKT/STAT3 signaling pathways. Finally, pathway analyses of patient samples suggest that these mechanisms also acting in the tumors of breast cancer patients. Thus, our work identifies HMGA2 as a direct miR-142-3p target and indicates that miR-142-3p is an important suppressor of breast cancer oncogenesis. This identifies miR-142-3p may candidate as a therapeutic molecule for breast cancer treatment.
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http://dx.doi.org/10.1016/j.lfs.2021.119431DOI Listing
July 2021

Clinical application of circulating tumor DNA in breast cancer.

J Cancer Res Clin Oncol 2021 May 24;147(5):1431-1442. Epub 2021 Mar 24.

Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China.

Background: The recent advancement in massively parallel sequencing technologies has empowered liquid biopsies, in particular circulating tumor DNA (ctDNA) analysis, to be the new paradigm in personalized cancer management. Plasma ctDNA detection overcomes the current limitations in tumor tissue procurement and serves as a convenient and non-invasive method to capture tumor heterogeneity and genetic evolution along patients' cancer journey. In breast cancer, the current clinical application of ctDNA includes real-time monitoring of tumor response, detection of drug-resistant clones, assessing dynamic variations in tumor mutational landscape, identifying actionable mutations, detecting minimal residual disease and screening of early tumor.

Purpose: This review aims to summarize the current clinical evidence of ctDNA application in the management of breast cancer.
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http://dx.doi.org/10.1007/s00432-021-03588-5DOI Listing
May 2021

Evaluation of Acetogenins as Potential Anti-SARS-CoV-2 Agents Through Computational Approaches.

Front Chem 2020 27;8:624716. Epub 2021 Jan 27.

Laboratorio Virtual NANOCOSMOS, Departamento de Medio Ambiente y Energía, Centro de Investigación en Materiales Avanzados, Chihuahua, Mexico.

, a tropical plant which has been extensively used in ethnomedicine to treat a wide range of diseases, from malaria to cancer. Interestingly, this plant has been reported to demonstrate significant antiviral properties against the human immunodeficiency virus, herpes simplex virus, human papilloma virus, hepatitis C virus and dengue virus. Additionally, the bioactive compounds responsible for antiviral efficacy have also shown to be selectively cytotoxic while inhibiting tumorigenic cell growth without affecting the normal cell growth. Annonaceous Acetogenins are a class of bioactive compounds exclusive to the Annonaceae family at which the plant belongs. In the current study, we have created a library of Acetogenins unique to the plant, comprising of Annomuricin A, Annomuricin B, Annomuricin C, Muricatocin C, Muricatacin, -Annonacin, Annonacin-10-one, -Goniothalamicin, Arianacin and Javoricin, for and theoretical evaluations against the SARS-CoV-2 spike protein in an attempt toward promotion of plant based drug development for the current pandemic of coronavirus disease 2019 (COVID-19). We found that all the Acetogenins showing spike protein significantly docking with good binding affinities. Moreover, we envision Acetogenins can be further studied by and models to identify potential anti-SARS-CoV-2 agents.
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http://dx.doi.org/10.3389/fchem.2020.624716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958878PMC
January 2021

The Emerging Role of Exosomes in Oral Squamous Cell Carcinoma.

Front Cell Dev Biol 2021 22;9:628103. Epub 2021 Feb 22.

Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, China.

Oral cancer constitutes approximately 2% of all cancers, while the most common type, oral squamous cell carcinoma (OSCC) represents 90% of oral cancers. Although the treatment of OSCC has improved recently, it still has a high rate of local recurrence and poor prognosis, with a 5-year survival rate of only 50%. Advanced stage OSCC tends to metastasize to lymph nodes. Thus, exploring new therapeutic strategies for OSCC is therefore an urgent priority. Exosomes, the small membrane vesicles derived from endosomes, have been detected in a wide array of bodily fluids. Exosomes contain a diversity of proteins, mRNAs, and non-coding RNAs, including microRNAs, long non-coding RNAs, piRNAs, circular RNAs, tsRNAs, and ribosomal RNAs, which are delivered to neighboring cells or even transported to distant sites. Exosomes have been associated with the tumorigenesis of OSCC, promote the proliferation, colonization, and metastasis of OSCC by transferring their contents to the target cells. Furthermore, exosomes are involved in the regulation of the tumor microenvironment to transform conditions favoring cancer progression . In this review, we summarize the crucial role of exosomes in the tumorigenesis and progression of OSCC and discuss the potential clinical application of exosomes in OSCC treatment.
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http://dx.doi.org/10.3389/fcell.2021.628103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951141PMC
February 2021

Identification of Different Extracellular Vesicles in the Hydatid Fluid of and Immunomodulatory Effects of 110 K EVs on Sheep PBMCs.

Front Immunol 2021 23;12:602717. Epub 2021 Feb 23.

State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.

Echinococcosis, mainly caused by , is one of the 17 neglected tropical diseases. Extracellular vesicles (EVs) play an essential role in the host-parasite interplay. However, the EVs in the hydatid fluid (HF) of are not fully characterized. Herein, three different types of HF EVs, designated as 2 K, 10 K, and 110 K EVs based on the centrifugal force used, were morphologically identified. A total of 97, 80, and 581 proteins were identified in 2 K, 10 K, and 110 K EVs, respectively, 39 of which were commonly shared. Moreover, 11, 8, and 25 miRNAs were detected, respectively, and all of the 7 selected miRNAs were validated by qPCR to be significantly lower abundant than that in protoscoleces. It was further deemed that 110 K EVs were internalized by sheep peripheral blood mononuclear cells (PBMCs) in a time-dependent manner and thus induced interleukin (IL)-10, tumor necrosis factor-α (TNF-α), and IRF5 were significantly upregulated and IL-1β, IL-17, and CD14 were significantly downregulated ( < 0.05). These data demonstrate the physical discrepancy of three HF EVs and an immunomodulatory effect of 110 K EVs on sheep PMBCs, suggesting a role in immune responses during infection.
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http://dx.doi.org/10.3389/fimmu.2021.602717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940240PMC
June 2021

Gut bacteria formation and influencing factors.

FEMS Microbiol Ecol 2021 03;97(4)

State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, CAAS, 1 Xujiaping, Chengguan District, Lanzhou 730046, China.

The gut microbiota plays an important role in human health. In modern life, with the improvement of living conditions, the intake of high-sugar and high-fat diets as well as the large-scale use of antibacterial drugs have an extensive impact on the gut microbiota, even leading to gut microbiota-orchestrating disorders. This review discusses the effects of various factors, including geographic location, age, diet, antibacterial drugs, psychological situation and exercise on gut bacteria, which helps us profoundly to understand the significance of gut bacteria to human health and to find effective solutions to prevent or treat related diseases.
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http://dx.doi.org/10.1093/femsec/fiab043DOI Listing
March 2021

Proteomic profiling in extracellular vesicles for cancer detection and monitoring.

Proteomics 2021 Mar 4:e2000094. Epub 2021 Mar 4.

Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China.

Extracellular vesicles (EVs) are nanometer-size lipid vesicles released by cells, which play essential biological functions in intercellular communication. Increasing evidence indicates that EVs participate in cancer development, including invasion, migration, metastasis, and cancer immune modulation. One of the key mechanisms is that EVs affect different cells in the tumor microenvironment through surface-anchor proteins and protein cargos. Moreover, proteins specifically expressed in tumor-derived EVs can be applied in cancer diagnosis and monitoring. Besides, the EV proteome also helps to understand drug resistance in cancers and to guide clinical medication. With the development of mass spectrometry and array-based multi-protein detection, the research of EV proteomics has entered a new era. The high-throughput parallel proteomic profiling based on these new platforms allows us to study the impact of EV proteome on cancer progression more comprehensively and to describe the proteomic landscape in cancers with more details. In this article, we review the role and function of different types of EVs in cancer progression. More importantly, we summarize the proteomic profiling of EVs based on different methods and the application of EV proteome in cancer detection and monitoring.
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http://dx.doi.org/10.1002/pmic.202000094DOI Listing
March 2021

EGFR mutation-guided use of afatinib, erlotinib and gefitinib for advanced non-small-cell lung cancer in Hong Kong - A cost-effectiveness analysis.

PLoS One 2021 1;16(3):e0247860. Epub 2021 Mar 1.

Oncology Center, Hong Kong Adventist Hospital, Hong Kong SAR, China.

Introduction: Tyrosine kinase inhibitors (TKIs) therapy targets at epidermal growth factor receptor (EGFR) gene mutations in non-small-cell lung cancer (NSCLC). We aimed to compare the EGFR mutation-guided target therapy versus empirical chemotherapy for first-line treatment of advanced NSCLC in the public healthcare setting of Hong Kong.

Methods: A Markov model was designed to simulate outcomes of a hypothetical cohort of advanced (stage IIIB/IV) NSCLC adult patients with un-tested EGFR-sensitizing mutation status. Four treatment strategies were evaluated: Empirical first-line chemotherapy with cisplatin-pemetrexed (empirical chemotherapy group), and EGFR mutation-guided use of a TKI (afatinib, erlotinib, and gefitinib). Model outcome measures were direct medical cost, progression-free survival, overall survival, and quality-adjusted life-years (QALYs). Incremental cost per QALY gained (ICER) was estimated. Sensitivity analyses were performed to examine robustness of model results.

Results: Empirical chemotherapy and EGFR mutation-guided gefitinib gained lower QALYs at higher costs than the erlotinib group. Comparing with EGFR mutation-guided erlotinib, the afatinib strategy gained additional QALYs with ICER (540,633 USD/QALY). In 10,000 Monte Carlo simulations for probabilistic sensitivity analysis, EGFR mutation-guided afatinib, erlotinib, gefitinib and empirical chemotherapy were preferred strategy in 0%, 98%, 0% and 2% of time at willingness-to-pay (WTP) 47,812 USD/QALY (1x gross domestic product (GDP) per capita), and in 30%, 68%, 2% and 0% of time at WTP 143,436 USD/QALY (3x GDP per capita), respectively.

Conclusions: EGFR mutation-guided erlotinib appears to be the cost-effective strategy from the perspective of Hong Kong public healthcare provider over a broad range of WTP.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247860PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920377PMC
March 2021

Covalent conjugation of extracellular vesicles with peptides and nanobodies for targeted therapeutic delivery.

J Extracell Vesicles 2021 Feb 16;10(4):e12057. Epub 2021 Feb 16.

Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore.

Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, existing methods to engineer target-specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody facilitates their accumulation in EGFR-positive cancer cells, both and . Systemic delivery of paclitaxel by EGFR-targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR-positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
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http://dx.doi.org/10.1002/jev2.12057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886705PMC
February 2021

Effect of N6-Methyladenosine Regulators on Progression and Prognosis of Triple-Negative Breast Cancer.

Front Genet 2020 28;11:580036. Epub 2021 Jan 28.

Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.

The N6-methyladenosine (mA) modification plays a critical role in cancer development. Little is known about the mA modification in triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Thus, the prognostic value of mA RNA methylation in TNBC deserves exploration. The expression levels of the 13 mA methylation regulators were compared between the 98 TNBC tumor samples and normal tissue samples based on the transcriptome profiles from The Cancer Genome Atlas (TCGA). The association between the mA regulators and patients' overall survival was assessed by Kaplan-Meier survival analysis and Cox regression analysis. Lasso regression analysis was conducted to construct a prognostic model based on the mA methylation system. The prognostic performance of the identified model was validated in GSE88847 and GSE135565 datasets. A nomogram combining the TNM stage and the mA prognostic model was further constructed for the survival prediction of TNBC patients. The mA regulator genes were remarkably dysregulated in TNBC tumor tissues, with , and significantly up-regulated and , and significantly down-regulated ( < 0.01). The expression level of was an independent unfavorable prognostic factor ( = 3.327, = 0.006), while ( = 0.425, = 0.009) was an independent favorable prognostic factor for TNBC patients. A prognostic model consisting of and was therefore proposed displaying higher accuracy of risk prediction when combined with TNM stage with an AUC of 0.791. The prognostic value of the identified signature remained consistent within the two external validation datasets. The mA methylation regulators were significantly dysregulated in TNBC tissues and could constitute a novel prognostic signature for the survival prediction of TNBC patients.
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http://dx.doi.org/10.3389/fgene.2020.580036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877483PMC
January 2021

MicroRNAs and Natural Compounds Mediated Regulation of TGF Signaling in Prostate Cancer.

Front Pharmacol 2020 27;11:613464. Epub 2021 Jan 27.

Branch in Sandomierz, Jan Kochanowski University in Kielce, Sandomierz, Poland.

Prostate cancer (PCa) is with rising incidence in male population globally. It is a complex anomaly orchestrated by a plethora of cellular processes. Transforming growth factor-beta (TGF-β) signaling is one of the key signaling pathways involved in the tumorigenesis of PCa. TGF-β signaling has a dual role in the PCa, making it difficult to find a suitable therapeutic option. MicroRNAs (miRNAs) mediated regulation of TGF-β signaling is responsible for the TGF- paradox. These are small molecules that modulate the expression of target genes and regulate cancer progression. Thus, miRNAs interaction with different signaling cascades is of great attention for devising new diagnostic and therapeutic options for PCa. Natural compounds have been extensively studied due to their high efficacy and low cytotoxicity. Here, we discuss the involvement of TGF- signaling in PCa with the interplay between miRNAs and TGF-β signaling and also review the role of natural compounds for the development of new therapeutics for PCa.
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http://dx.doi.org/10.3389/fphar.2020.613464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873640PMC
January 2021

Vacuolin-1 inhibits endosomal trafficking and metastasis via CapZβ.

Oncogene 2021 Mar 9;40(10):1775-1791. Epub 2021 Feb 9.

City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zβ (CapZβ) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZβ to inhibit endosomal trafficking and metastasis.
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http://dx.doi.org/10.1038/s41388-021-01662-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946642PMC
March 2021

The oncogenic and tumor suppressive roles of RNA-binding proteins in human cancers.

J Cell Physiol 2021 Sep 8;236(9):6200-6224. Epub 2021 Feb 8.

Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

Posttranscriptional regulation is a mechanism for the cells to control gene regulation at the RNA level. In this process, RNA-binding proteins (RBPs) play central roles and orchestrate the function of RNA molecules in multiple steps. Accumulating evidence has shown that the aberrant regulation of RBPs makes  contributions to the initiation and progression of tumorigenesis via numerous mechanisms such as genetic changes, epigenetic alterations, and noncoding RNA-mediated regulations. In this article, we review the effects caused by RBPs and their functional diversity in the malignant transformation of cancer cells that occurs through the involvement of these proteins in various stages of RNA regulation including alternative splicing, stability, polyadenylation, localization, and translation. Besides this, we review the various interactions between RBPs and other crucial posttranscriptional regulators such as microRNAs and long noncoding RNAs in the pathogenesis of cancer. Finally, we discuss the potential approaches for targeting RBPs in human cancers.
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http://dx.doi.org/10.1002/jcp.30311DOI Listing
September 2021

Computational study for suppression of CD25/IL-2 interaction.

Biol Chem 2021 01 19;402(2):167-178. Epub 2020 Nov 19.

Department of Clinical Oncology, Queen Elizabeth Hospital, HKSAR, China.

Cancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which designed small interfering RNAs (siRNAs), designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further and studies.
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http://dx.doi.org/10.1515/hsz-2020-0326DOI Listing
January 2021

Flavonoids Overcome Drug Resistance to Cancer Chemotherapy by Epigenetically Modulating Multiple Mechanisms.

Curr Cancer Drug Targets 2021 ;21(4):289-305

Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China.

Drug resistance is the major reason accounting for the treatment failure in cancer chemotherapy. Dysregulation of the epigenetic machineries is known to induce chemoresistance. It was reported that numerous genes encoding the key mediators in cancer proliferation, apoptosis, DNA repair, and drug efflux are dysregulated in resistant cancer cells by aberrant DNA methylation. The imbalance of various enzymes catalyzing histone post-translational modifications is also known to alter chromatin configuration and regulate multiple drug resistance genes. Alteration in miRNA signature in cancer cells also gives rise to chemoresistance. Flavonoids are a large group of naturally occurring polyphenolic compounds ubiquitously found in plants, fruits, vegetables and traditional herbs. There has been increasing research interest in the health-promoting effects of flavonoids. Flavonoids were shown to directly kill or re-sensitize resistant cancer cells to conventional anticancer drugs by epigenetic mechanisms. In this review, we summarize the current findings of the circumvention of drug resistance by flavonoids through correcting the aberrant epigenetic regulation of multiple resistance mechanisms. More investigations including the evaluation of synergistic anticancer activity, dosing sequence effect, toxicity in normal cells, and animal studies, are warranted to establish the full potential of the combination of flavonoids with conventional chemotherapeutic drugs in the treatment of cancer with drug resistance.
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http://dx.doi.org/10.2174/1568009621666210203111220DOI Listing
January 2021

Lithium from breast-milk inhibits thyroid iodine uptake and hormone production, which are remedied by maternal iodine supplementation.

Bipolar Disord 2021 Jan 28. Epub 2021 Jan 28.

Department of Physics, City University of Hong Kong, Hong Kong SAR, China.

Background: Lithium is especially taken as a maintenance medication for Bipolar Disorder. In women with bipolar disorder, lithium is often effective during postpartum period, but breast-feeding for medicated mothers is controversial because of harmful effects for her child. At present, the biological mechanisms of lithium are not well-understood, affecting its usage and overall health implications.

Procedure: We developed a rat lithium and breast-feeding model at human therapeutic levels to study the effects of lithium exposure through breast-milk on pups' thyroid function. Novel laser analytical spectroscopy, along with traditional blood and immunohistochemical tests, were applied to further investigate the mechanisms behind the thyroid dysfunction. Maternal iodine supplementation was evaluated as a therapeutic method to address the pups' thyroid dysfunction.

Results: Pups exposed to lithium via breastmilk, even with the dam on a sub-therapeutic level, experienced weight gain, reduced blood thyroxine (T ), and elevated blood urea nitrogen, indicating effects on thyroid and kidney function. We show that lithium inhibited iodine uptake by thyroid follicles, initiating a mechanism that reduced iodination of tyrosine, thyroglobulin cleavage, and thyroid hormone production. Importantly, infant thyroid function can be significantly improved by administering supplementary iodine to the medicated dam's diet during breast-feeding.

Conclusion: These results elucidate the mechanisms of lithium in thyroid function, provide valuable information on use postpartum, and suggest a clinically applicable remedy to side-effects. The results are particularly important for patients (and their infants) who respond well to lithium and need, or choose, to breast-feed.
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http://dx.doi.org/10.1111/bdi.13047DOI Listing
January 2021

microRNA-21: a key modulator in oncogenic viral infections.

RNA Biol 2021 05 22;18(5):809-817. Epub 2021 Mar 22.

State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China.

Oncogenic viruses are associated with approximately 15% of human cancers. In viral infections, microRNAs play an important role in host-pathogen interactions. miR-21 is a highly conserved non-coding RNA that not only regulates the development of oncogenic viral diseases, but also responds to the regulation of intracellular signal pathways. Oncogenic viruses, including HBV, HCV, HPV, and EBV, co-evolve with their hosts and cause persistent infections. The upregulation of host miR-21 manipulates key cellular pathways to evade host immune responses and then promote viral replication. Thus, a better understanding of the role of miR-21 in viral infections may help us to develop effective genetically-engineered oncolytic virus-based therapies against cancer.
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http://dx.doi.org/10.1080/15476286.2021.1880756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078529PMC
May 2021

A GLP-1 analog lowers ER stress and enhances protein folding to ameliorate homocysteine-induced endothelial dysfunction.

Acta Pharmacol Sin 2021 Jan 25. Epub 2021 Jan 25.

School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong SAR, China.

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases and increases mortality in type 2 diabetic patients. HHcy induces endoplasmic reticulum (ER) stress and oxidative stress to impair endothelial function. The glucagon-like peptide 1 (GLP-1) analog exendin-4 attenuates endothelial ER stress, but the detailed vasoprotective mechanism remains elusive. The present study investigated the beneficial effects of exendin-4 against HHcy-induced endothelial dysfunction. Exendin-4 pretreatment reversed homocysteine-induced impairment of endothelium-dependent relaxations in C57BL/6 mouse aortae ex vivo. Four weeks subcutaneous injection of exendin-4 restored the impaired endothelial function in both aortae and mesenteric arteries isolated from mice with diet-induced HHcy. Exendin-4 treatment lowered superoxide anion accumulation in the mouse aortae both ex vivo and in vivo. Exendin-4 decreased the expression of ER stress markers (e.g., ATF4, spliced XBP1, and phosphorylated eIF2α) in human umbilical vein endothelial cells (HUVECs), and this change was reversed by cotreatment with compound C (CC) (AMPK inhibitor). Exendin-4 induced phosphorylation of AMPK and endothelial nitric oxide synthase in HUVECs and arteries. Exendin-4 increased the expression of endoplasmic reticulum oxidoreductase (ERO1α), an important ER chaperone in endothelial cells, and this effect was mediated by AMPK activation. Experiments using siRNA-mediated knockdown or adenoviral overexpression revealed that ERO1α mediated the inhibitory effects of exendin-4 on ER stress and superoxide anion production, thus ameliorating HHcy-induced endothelial dysfunction. The present results demonstrate that exendin-4 reduces HHcy-induced ER stress and improves endothelial function through AMPK-dependent ERO1α upregulation in endothelial cells and arteries. AMPK activation promotes the protein folding machinery in endothelial cells to suppress ER stress.
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http://dx.doi.org/10.1038/s41401-020-00589-xDOI Listing
January 2021

Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer.

Front Oncol 2020 7;10:607607. Epub 2021 Jan 7.

Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.
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http://dx.doi.org/10.3389/fonc.2020.607607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817854PMC
January 2021