Publications by authors named "William C Cho"

316 Publications

Early Detection and Investigation of Extracellular Vesicles Biomarkers in Breast Cancer.

Front Mol Biosci 2021 8;8:732900. Epub 2021 Nov 8.

Biosciences Laboratory, IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy.

Breast cancer (BC) is the most commonly diagnosed malignant tumor in women worldwide, and the leading cause of cancer death in the female population. The percentage of patients experiencing poor prognosis along with the risk of developing metastasis remains high, also affecting the resistance to current main therapies. Cancer progression and metastatic development are no longer due entirely to their intrinsic characteristics, but also regulated by signals derived from cells of the tumor microenvironment. Extracellular vesicles (EVs) packed with DNA, RNA, and proteins, are the most attractive targets for both diagnostic and therapeutic applications, and represent a decisive challenge as liquid biopsy-based markers. Here we performed a study based on a multiplexed phenotyping flow cytometric approach to characterize BC-derived EVs from BC patients and cell lines, through the detection of multiple antigens. Our data reveal the expression of EVs-related biomarkers derived from BC patient plasma and cell line supernatants, suggesting that EVs could be exploited for characterizing and monitoring disease progression.
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http://dx.doi.org/10.3389/fmolb.2021.732900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606536PMC
November 2021

Editorial: Recent Advances in In Vitro and In Vivo Multi-Omics Analyses of Extracellular Vesicles: Therapeutic Targets and Biomarkers.

Front Mol Biosci 2021 27;8:784436. Epub 2021 Oct 27.

Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia.

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http://dx.doi.org/10.3389/fmolb.2021.784436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578700PMC
October 2021

Quercetin Impact in Pancreatic Cancer: An Overview on Its Therapeutic Effects.

Oxid Med Cell Longev 2021 3;2021:4393266. Epub 2021 Nov 3.

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

Pancreatic cancer (PC) is a lethal malignancy cancer, and its mortality rates have been increasing worldwide. Diagnosis of this cancer is complicated, as it does not often present symptoms, and most patients present an irremediable tumor having a 5-year survival rate after diagnosis. Regarding treatment, many concerns have also been raised, as most tumors are found at advanced stages. At present, anticancer compounds-rich foods have been utilized to control PC. Among such bioactive molecules, flavonoid compounds have shown excellent anticancer abilities, such as quercetin, which has been used as an adjunctive or alternative drug to PC treatment by inhibitory or stimulatory biological mechanisms including autophagy, apoptosis, cell growth reduction or inhibition, EMT, oxidative stress, and enhancing sensitivity to chemotherapy agents. The recognition that this natural product has beneficial effects on cancer treatment has boosted the researchers' interest towards more extensive studies to use herbal medicine for anticancer purposes. In addition, due to the expensive cost and high rate of side effects of anticancer drugs, attempts have been made to use quercetin but also other flavonoids for preventing and treating PC. Based on related studies, it has been found that the quercetin compound has significant effect on cancerous cell lines as well as animal models. Therefore, it can be used as a supplementary drug to treat a variety of cancers, particularly pancreatic cancer. This review is aimed at discussing the therapeutic effects of quercetin by targeting the molecular signaling pathway and identifying antigrowth, cell proliferation, antioxidative stress, EMT, induction of apoptotic, and autophagic features.
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http://dx.doi.org/10.1155/2021/4393266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580629PMC
November 2021

Roles of Therapeutic Bioactive Compounds in Hepatocellular Carcinoma.

Oxid Med Cell Longev 2021 31;2021:9068850. Epub 2021 Oct 31.

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

Hepatocellular carcinoma (HCC) is due to poor prognosis and lack of availability of effective treatment. Novel therapeutic strategies will be the fine tuning of intracellular ROS signaling to effectively deprive cells of ROS-induced tumor-promoting events. This review discusses the generation of ROS, the major signaling their modulation in therapeutics. We explore some of the major pathways involved in HCC, which include the VEGF, MAPK/ERK, mTOR, FGF, and Ser/Thr kinase pathways. In this review, we study cornerstone on natural bioactive compounds with their effect on hepatocarcinomas. Furthermore, we focus on oxidative stress and FDA-approved signaling pathway inhibitors, along with chemotherapy and radiotherapy enhancers which with early evidence of success. While more in vivo testing is required to confirm the findings presented here, our findings will aid future nonclinical, preclinical, and clinical studies with these compounds, as well as inspire medicinal chemistry scientists to conduct appropriate research on this promising natural compound and their derivatives.
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http://dx.doi.org/10.1155/2021/9068850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572616PMC
October 2021

TCOF1 upregulation in triple-negative breast cancer promotes stemness and tumour growth and correlates with poor prognosis.

Br J Cancer 2021 Oct 30. Epub 2021 Oct 30.

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

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. By performing multiomic profiling, we recently uncovered super-enhancer heterogeneity between breast cancer subtypes. Our data also revealed TCOF1 as a putative TNBC-specific super-enhancer-regulated gene. TCOF1 plays a critical role in craniofacial development but its function in cancer remains unclear.

Methods: Overall survival and multivariant Cox regression analyses were conducted using the METABRIC data set. The effect of TCOF1 knockout on TNBC growth and stemness was evaluated by in vitro and in vivo assays. RNA-seq and rescue experiments were performed to explore the underlying mechanisms.

Results: TCOF1 is frequently upregulated in TNBC and its elevated expression correlates with shorter overall survival. TCOF1 depletion significantly inhibits the growth and stemness of basal-like TNBC, but not of mesenchymal-like cells, highlighting the distinct molecular dependency in different TNBC subgroups. RNA-seq uncovers several stem cell molecules regulated by TCOF1. We further demonstrate that KIT is a downstream effector of TCOF1 in mediating TNBC stemness. TCOF1 expression in TNBC is regulated by the predicted super-enhancer.

Conclusions: TCOF1 depletion potently attenuates the growth and stemness of basal-like TNBC. Expression of TCOF1 may serve as a TNBC prognostic marker and a therapeutic target.
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http://dx.doi.org/10.1038/s41416-021-01596-3DOI Listing
October 2021

Paving Luteolin Therapeutic Potentialities and Agro-Food-Pharma Applications: Emphasis on Pharmacological Effects and Bioavailability Traits.

Oxid Med Cell Longev 2021 20;2021:1987588. Epub 2021 Sep 20.

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

Luteolin is a naturally occurring secondary metabolite belonging to the class of flavones. As many other natural flavonoids, it is often found in combination with glycosides in many fruits, vegetables, and plants, contributing to their biological and pharmacological value. Many preclinical studies report that luteolin present excellent antioxidant, anticancer, antimicrobial, neuroprotective, cardioprotective, antiviral, and anti-inflammatory effects, and as a consequence, various clinical trials have been designed to investigate the therapeutic potential of luteolin in humans. However, luteolin has a very limited bioavailability, which consequently affects its biological properties and efficacy. Several drug delivery strategies have been developed to raise its bioavailability, with nanoformulations and lipid carriers, such as liposomes, being the most intensively explored. Pharmacological potential of luteolin in various disorders has also been underlined, but to some of them, the exact mechanism is still poorly understood. Given the great potential of this natural antioxidant in health, this review is aimed at providing an extensive overview on the pharmacological action of luteolin and at stressing the main features related to its bioavailability, absorption, and metabolism, while essential steps determine its absolute health benefits and safety profiles. In addition, despite the scarcity of studies on luteolin bioavailability, the different drug delivery formulations developed to increase its bioavailability are also listed here.
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http://dx.doi.org/10.1155/2021/1987588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478534PMC
September 2021

Nano-Derived Therapeutic Formulations with Curcumin in Inflammation-Related Diseases.

Oxid Med Cell Longev 2021 15;2021:3149223. Epub 2021 Sep 15.

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

Due to its vast therapeutic potential, the plant-derived polyphenol curcumin is utilized in an ever-growing number of health-related applications. Here, we report the extraction methodologies, therapeutic properties, advantages and disadvantages linked to curcumin employment, and the new strategies addressed to improve its effectiveness by employing advanced nanocarriers. The emerging nanotechnology applications used to enhance CUR bioavailability and its targeted delivery in specific pathological conditions are collected and discussed. In particular, new aspects concerning the main strategic nanocarriers employed for treating inflammation and oxidative stress-related diseases are reported and discussed, with specific emphasis on those topically employed in conditions such as wounds, arthritis, or psoriasis and others used in pathologies such as bowel (colitis), neurodegenerative (Alzheimer's or dementia), cardiovascular (atherosclerosis), and lung (asthma and chronic obstructive pulmonary disease) diseases. A brief overview of the relevant clinical trials is also included. We believe the review can provide the readers with an overview of the nanostrategies currently employed to improve CUR therapeutic applications in the highlighted pathological conditions.
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http://dx.doi.org/10.1155/2021/3149223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470924PMC
September 2021

From Anti-PD-1/PD-L1 to CTLA-4 and to MUC1-Is the Better Response to Treatment in Smokers of Cancer Patients Drug Specific?

J Pers Med 2021 Sep 13;11(9). Epub 2021 Sep 13.

Beijing Cancer Hospital and Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China.

Whether smokers respond to anti-cancer drugs differently than non-smokers remains controversial. The objective of this study is to explore whether the better response of the smokers is specific to therapy of anti-PD-1/PD-L1, anti-checkpoint inhibitor, individual drugs on the cell surface, or lung cancer. Our results showed that among all non-small cell lung cancer (NSCLC) patients, when the data from anti-PD-1/PD-L1, anti-CTLA-4, and anti-MUC1 drugs are combined, the mean hazard ratios (HR) of smokers and non-smokers were 0.751 and 1.016, respectively. A meta-analysis with a fixed effect (FE) model indicated that the smokers have an HR value of 0.023 lower than that of the non-smokers. A stratified subgroup meta-analysis indicated that when treated with anti-CTLA-4 drugs, smokers had reduced HR values of 0.152 and 0.165 on average and FE model meta-analysis, respectively. When treated with an anti-MUC1 drug, smokers had reduced HR values of 1.563 and 0.645, on average and FE model meta-analysis, respectively. When treated with a combination of nivolumab and ipilimumab drugs, smokers had, on average, reduced HR and FE model meta-analysis values (0.257 and 0.141), respectively. Smoking is a clinical response predictor for anti-PD/PD-L1 monotherapy or first-line treatment in lung, urothelial carcinoma, and head and neck cancer. Smokers treated with other drugs have shown worse responses in comparison to non-smokers. These data suggest that, along with the progress in the development of new drugs for cancer, drugs acting on specific genotypes of smokers likely will arise.
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http://dx.doi.org/10.3390/jpm11090914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471889PMC
September 2021

Therapeutic Potential of Isoflavones with an Emphasis on Daidzein.

Oxid Med Cell Longev 2021 9;2021:6331630. Epub 2021 Sep 9.

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

Daidzein is a phytoestrogen isoflavone found in soybeans and other legumes. The chemical composition of daidzein is analogous to mammalian estrogens, and it could be useful with a dual-directional purpose by substituting/hindering with estrogen and estrogen receptor (ER) complex. Hence, daidzein puts forth shielding effects against a great number of diseases, especially those associated with the control of estrogen, such as breast cancer, diabetes, osteoporosis, and cardiovascular disease. However, daidzein also has other ER-independent biological activities, such as oxidative damage reduction acting as an antioxidant, immune regulator as an anti-inflammatory agent, and apoptosis regulation, directly linked to its potential anticancer effects. In this sense, the present review is aimed at providing a deepen analysis of daidzein pharmacodynamics and its implications in human health, from its best-known effects alleviating postmenopausal symptoms to its potential anticancer and antiaging properties.
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http://dx.doi.org/10.1155/2021/6331630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448605PMC
September 2021

spp.: A Review on Phytochemical Composition, Biological Activity, and Health-Promoting Effects.

Oxid Med Cell Longev 2021 7;2021:4014867. Epub 2021 Sep 7.

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

Cyperaceae are a plant family of grass-like monocots, comprising 5600 species with a cosmopolitan distribution in temperate and tropical regions. Phytochemically, is one of the most promising health supplementing genera of the Cyperaceae family, housing ≈950 species, with L. being the most reported species in pharmacological studies. The traditional uses of spp. have been reported against various diseases, , gastrointestinal and respiratory affections, blood disorders, menstrual irregularities, and inflammatory diseases. spp. are known to contain a plethora of bioactive compounds such as -cyperone, -corymbolol, -pinene, caryophyllene oxide, cyperotundone, germacrene D, mustakone, and zierone, which impart pharmacological properties to its extract. Therefore, sp. extracts were preclinically studied and reported to possess antioxidant, anti-inflammatory, antimicrobial, anticancer, neuroprotective, antidepressive, antiarthritic, antiobesity, vasodilator, spasmolytic, bronchodilator, and estrogenic biofunctionalities. Nonetheless, conclusive evidence is still sparse regarding its clinical applications on human diseases. Further studies focused on toxicity data and risk assessment are needed to elucidate its safe and effective application. Moreover, detailed structure-activity studies also need time to explore the candidature of -derived phytochemicals as upcoming drugs in pharmaceuticals.
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http://dx.doi.org/10.1155/2021/4014867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443348PMC
September 2021

Natural Coumarins: Exploring the Pharmacological Complexity and Underlying Molecular Mechanisms.

Oxid Med Cell Longev 2021 23;2021:6492346. Epub 2021 Aug 23.

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

Coumarins belong to the benzopyrone family commonly found in many medicinal plants. Natural coumarins demonstrated a wide spectrum of pharmacological activities, including anti-inflammatory, anticoagulant, anticancer, antibacterial, antimalarial, casein kinase-2 (CK2) inhibitory, antifungal, antiviral, Alzheimer's disease inhibition, neuroprotective, anticonvulsant, phytoalexins, ulcerogenic, and antihypertensive. There are very few studies on the bioavailability of coumarins; therefore, further investigations are necessitated to study the bioavailability of different coumarins which already showed good biological activities in previous studies. On the evidence of varied pharmacological properties, the present work presents an overall review of the derivation, availability, and biological capacities of coumarins with further consideration of the essential mode of their therapeutic actions. In conclusion, a wide variety of coumarins are available, and their pharmacological activities are of current interest thanks to their synthetic accessibility and riches in medicinal plants. Coumarins perform the valuable function as therapeutic agents in a range of medical fields.
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http://dx.doi.org/10.1155/2021/6492346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440074PMC
August 2021

(Retz.) Sw.: Ethnomedicinal, Phytochemical, and Pharmacological Overview of the Himalayan Ferns.

Oxid Med Cell Longev 2021 2;2021:1917890. Epub 2021 Sep 2.

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

The genus (family: Athyriaceae) comprises approximately 350 species of pteridophytes (Retz.) Sw. is an important member of this genus and commonly known as a wild vegetable in the Himalayan and sub-Himalayan communities. According to the literature analysis, was traditionally used for the prevention or treatment of several diseases such as diabetes, smallpox, asthma, diarrhea, rheumatism, dysentery, headache, fever, wounds, pain, measles, hypertension, constipation, oligospermia, bone fracture, and glandular swellings. Various extracts of were evaluated to elucidate their phytochemical and pharmacological activities. A wide array of pharmacological properties such as antioxidant, antimicrobial, antidiabetic, immunomodulatory, CNS stimulant, and antianaphylactic activities have been recognized in different parts of . The review covers a systematic examination of pharmacognosy, phytochemistry, and pharmacological applications of , but scientifically, it is not fully assessed regarding complete therapeutic effects, toxicity, and safety in the human body. The published literature on and its therapeutic properties were collected from different search engines including Wiley online, PubMed, Springer Link, Scopus, Science Direct, Web of Science, Google Scholar, and ACS publications by using specific terms such as " bioactive compounds, biological activities and health benefits" from 1984 to 2021 (March). Therefore, further studies are required to identify the detailed action mechanism of , and also, more studies should focus on conservation, cultivation, and sustainable utilization of the species.
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http://dx.doi.org/10.1155/2021/1917890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433033PMC
September 2021

Colorectal cancer cell-derived extracellular vesicles transfer miR-221-3p to promote endothelial cell angiogenesis via targeting suppressor of cytokine signaling 3.

Life Sci 2021 Nov 8;285:119937. Epub 2021 Sep 8.

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

Background: Secreted microRNAs (miRNAs) can serve as promising diagnostic markers for colorectal cancer (CRC). Herein, we evaluated the potential clinical significance of a signature of four circulating serum-derived miRNAs in CRC. We also demonstrated that extracellular vesicles (EVs) containing miR-221-3p could facilitate endothelial cell angiogenesis.

Methods: The expressions of four circulating serum-derived miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) were measured by real-time quantitative PCR, and their associations with lymph node metastasis were determined in CRC patients. Receiver operating characteristic curve analysis was used to determine their diagnostic accuracy. EVs were isolated and characterized from the conditioned media of human CRC cells (HCT116 and Caco2). Cell proliferation, transwell migration, and tube formation assays were performed to investigate the pro-angiogenic effect of miR-221-3p transferred by CRC-EVs into the endothelial cells. In silico analysis was used to show the regulatory functions of miR-221-3p on SOCS3, validated by luciferase and Western blotting assays.

Results: The expression levels of serum-derived miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p were significantly higher in CRC than in healthy individuals. The expression of miR-19a-3p, miR-203-3p, and miR-221-3p were positively correlated with the lymph node metastasis status. Moreover, SOCS3 was identified as a direct target of miR-221-3p and the secreted miR-221-3p shuttled by CRC-EVs regulated STAT3/VEGFR-2 signaling axis by targeting SOCS3 in endothelial cells. CRC-EVs promoted endothelial cell proliferation, migration, and the formation of vessel-like structures. The proangiogenic effect of CRC-EVs on the cells was recapitulated by miR-221-3p overexpression, showing the importance of EVs-derived miR-221-3p in promoting endothelial cell angiogenesis.

Conclusion: We introduced a signature of four-circulating miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) as a novel diagnostic biomarker for CRC. Besides, we revealed that miR-221-3p induces endothelial cell angiogenesis in vitro by targeting SOCS3.
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http://dx.doi.org/10.1016/j.lfs.2021.119937DOI Listing
November 2021

Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics.

Authors:
William C S Cho

Int J Mol Sci 2021 Sep 3;22(17). Epub 2021 Sep 3.

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

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http://dx.doi.org/10.3390/ijms22179586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430677PMC
September 2021

Paving Plant-Food-Derived Bioactives as Effective Therapeutic Agents in Autism Spectrum Disorder.

Oxid Med Cell Longev 2021 21;2021:1131280. Epub 2021 Aug 21.

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

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, where social and communication deficits and repetitive behaviors are present. Plant-derived bioactives have shown promising results in the treatment of autism. In this sense, this review is aimed at providing a careful view on the use of plant-derived bioactive molecules for the treatment of autism. Among the plethora of bioactives, curcumin, luteolin, and resveratrol have revealed excellent neuroprotective effects and can be effectively used in the treatment of neuropsychological disorders. However, the number of clinical trials is limited, and none of them have been approved for the treatment of autism or autism-related disorder. Further clinical studies are needed to effectively assess the real potential of such bioactive molecules.
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http://dx.doi.org/10.1155/2021/1131280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405324PMC
August 2021

Phenolic Bioactives as Antiplatelet Aggregation Factors: The Pivotal Ingredients in Maintaining Cardiovascular Health.

Oxid Med Cell Longev 2021 17;2021:2195902. Epub 2021 Aug 17.

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

Cardiovascular diseases (CVD) are one of the main causes of mortality in the world. The development of these diseases has a specific factor-alteration in blood platelet activation. It has been shown that phenolic compounds have antiplatelet aggregation abilities and a positive impact in the management of CVD, exerting prominent antioxidant, anti-inflammatory, antitumor, cardioprotective, antihyperglycemic, and antimicrobial effects. Thus, this review is intended to address the antiplatelet activity of phenolic compounds with special emphasis in preventing CVD, along with the mechanisms of action through which they are able to prevent and treat CVD. and studies have shown beneficial effects of phenolic compound-rich plant extracts and isolated compounds against CVD, despite that the scientific literature available on the antiplatelet aggregation ability of phenolic compounds is scarce. Thus, despite the current advances, further studies are needed to confirm the cardioprotective potential of phenolic compounds towards their use alone or in combination with conventional drugs for effective therapeutic interventions.
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http://dx.doi.org/10.1155/2021/2195902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384526PMC
August 2021

Echinococcus multilocularis infection induces UBE2N suppression via exosomal emu-miR-4989.

Acta Trop 2021 Nov 10;223:106087. Epub 2021 Aug 10.

State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, CAAS, Lanzhou 730046, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China. Electronic address:

Echinococcus multilocularis metacestodes mainly reside in liver in humans and animals, and cause serious damages. UBE2N was herein shown to be downregulated in response to the infection. UBE2N was further shown to be predominantly expressed in the hepatocytes, which was also significantly downregulated during the infection. UBE2N was a target of emu-miR-4989, which was loaded into the exosomes secreted by parasites. These emu-miR-4989-encapsulating exosomes were internalized by hepatocytes, and induced a significant decrease of relative luciferase activity in the cells transfected with the construct containing a wild type of UBE2N 3'-UTR compared to the control (p < 0.05). These results demonstrate that emu-miR-4989 is involved in the UBE2N inhibition in the hepatocytes during E. multilocularis through exosomes.
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http://dx.doi.org/10.1016/j.actatropica.2021.106087DOI Listing
November 2021

Quercetin as a Novel Therapeutic Approach for Lymphoma.

Oxid Med Cell Longev 2021 2;2021:3157867. Epub 2021 Aug 2.

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

Lymphoma is a name for malignant diseases of the lymphatic system including Hodgkin's lymphoma and non-Hodgkin's lymphoma. Although several approaches are used for the treatment of these diseases, some of them are not successful and have serious adverse effects. Therefore, other effective treatment methods might be interesting. Studies have indicated that plant ingredients play a key role in treating several diseases. Some plants have already shown a potential therapeutic effect on many malignant diseases. Quercetin is a flavonoid found in different plants and could be useful in the treatment of different malignant diseases. Quercetin has its antimalignant effects through targeting main survival pathways activated in tumor cells. / experimental studies have demonstrated that quercetin possesses a cytotoxic effect on lymphoid cancer cells. Regardless of the optimum results that have been obtained from both / studies, few clinical studies have analyzed the antitumor effects of quercetin in lymphoid cancers. Thus, it seems that more clinical studies should introduce quercetin as a therapeutic, alone or in combination with other chemotherapy agents. Here, in this study, we reviewed the anticancer effects of quercetin and highlighted the potential therapeutic effects of quercetin in various types of lymphoma.
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http://dx.doi.org/10.1155/2021/3157867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352693PMC
August 2021

Genus : Therapeutic Potentialities and Agro-Food-Pharma Applications.

Oxid Med Cell Longev 2021 16;2021:3095514. Epub 2021 Jul 16.

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

The genus (Adoxaceae, Dipsacales) is of scientific interest due to the chemical components and diverse biological activities found across species of the genus, which includes more than 230 species of evergreen, semievergreen, or deciduous shrubs and small trees. Although frequently used as an ornament, the species show biological properties with health-promoting effects. Fruits, flowers, and barks of certain species are used for pharmaceutical purposes or as cooking ingredients, hence containing biochemical compounds with health-promoting activity such are carotenoids, polyphenols, and flavonoids. However, its taxonomical determination is difficult, due to its wide distribution and frequent hybridizations; therefore, an objective classification would allow us to understand its biological activity based on its phytochemical components. More than sixty phytochemical compounds have been reported, where vibsanin-type diterpenes and their derivatives are the most prevalent. Leaves and twigs of contain the largest number of phytochemicals among the genus. Through preclinical evidence, this study provides insight regarding antioxidant, antibacterial, anti-inflammatory, cytotoxic, and anticancer activities of genus .
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http://dx.doi.org/10.1155/2021/3095514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310452PMC
July 2021

spp.: A Comprehensive Review on Bioactivities and Health-Enhancing Effects and Their Potential for the Formulation of Functional Foods and Pharmaceutical Drugs.

Oxid Med Cell Longev 2021 27;2021:5900422. Epub 2021 Jun 27.

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

The genus includes four species widely distributed in warm temperate to subtropical regions from the Mediterranean to Mongolia as well as certain regions in America. Among these species, L., distributed from the Mediterranean region to Central Asia, has been studied and its phytochemical profile, traditional folk use, and application in pharmacological and clinical trials are well known. The review is aimed at presenting an insight into the botanical features and geographical distribution of spp. along with traditional folk uses. This manuscript also reviews the phytochemical profile of spp. and its correlation with biological activities evidenced by the and investigations. Moreover, this review gives us an understanding of the bioactive compounds from as health promoters followed by the safety and adverse effects on human health. In relation to their multipurpose therapeutic properties, various parts of this plant such as seeds, bark, and roots present bioactive compounds promoting health benefits. An updated search (until December 2020) was carried out in databases such as PubMed and ScienceDirect. Chemical studies have presented beta-carboline alkaloids as the most active constituents, with harmalol, harmaline, and harmine being the latest and most studied among these naturally occurring alkaloids. The spp. extracts have shown neuroprotective, anticancer, antimicrobial, and antiviral effects. The extracts are also found effective in improving respiratory disorders (asthma and cough conditions), dermatoses, and knee osteoarthritis. Bioactivities and health-enhancing effects of spp. make it a potential candidate for the formulation of functional foods and pharmaceutical drugs. Nevertheless, adverse effects of this plant have also been described, and therefore new bioproducts need to be studied in depth. In fact, the design of new formulations and nanoformulations to control the release of active compounds will be necessary to achieve successful pharmacological and therapeutic treatments.
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http://dx.doi.org/10.1155/2021/5900422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260309PMC
June 2021

The Therapeutic Potential of Wogonin Observed in Preclinical Studies.

Evid Based Complement Alternat Med 2021 15;2021:9935451. Epub 2021 Jun 15.

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

Wogonin is a flavonoid found in different plants such as roots of Georgi distributed mainly in Asia and Europe. Dried root extracts of with high content of wogonin, popularly known as "Huang-Qin" or Chinese or baical skullcap, have been used for long time in traditional Chinese medicine. Several health benefits are attributed to wogonin and derivatives showing anti-inflammatory, antiviral, anticancer, and antioxidant effects and more recently antineurodegenerative properties. Preclinical pharmacological activities of wogonin against diverse types of cancer such as breast, colorectal, and human gastric cancer will be presented in this review. In addition, studies on oxidative stress and bioavailability of wogonin will be discussed together with antineurodegenerative potential with special focus on Alzheimer's disease. Outcomes extracted from the last preclinical studies related to therapeutic applications of wogonin will be commented and updated in this review. The scientific evidence collected in this review aims to encourage transfer of the preclinical evidence of wogonin to new clinical studies.
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http://dx.doi.org/10.1155/2021/9935451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221866PMC
June 2021

Regulation of Hippo, TGFβ/SMAD, Wnt/-Catenin, JAK/STAT, and NOTCH by Long Non-Coding RNAs in Pancreatic Cancer.

Front Oncol 2021 9;11:657965. Epub 2021 Jun 9.

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

Rapidly evolving and ever-increasing knowledge of the molecular pathophysiology of pancreatic cancer has leveraged our understanding altogether to a next level. Compared to the exciting ground-breaking discoveries related to underlying mechanisms of pancreatic cancer onset and progression, however, there had been relatively few advances in the therapeutic options available for the treatment. Since the discovery of the DNA structure as a helix which replicates semi-conservatively to pass the genetic material to the progeny, there has been conceptual refinement and continuous addition of missing pieces to complete the landscape of central dogma. Starting from transcription to translation, modern era has witnessed non-coding RNA discovery and central role of these versatile regulators in onset and progression of pancreatic cancer. Long non-coding RNAs (lncRNAs) have been shown to act as competitive endogenous RNAs through sequestration and competitive binding to myriad of microRNAs in different cancers. In this article, we set spotlight on emerging evidence of regulation of different signaling pathways (Hippo, TGFβ/SMAD, Wnt/-Catenin, JAK/STAT and NOTCH) by lncRNAs. Conceptual refinements have enabled us to understand how lncRNAs play central role in post-translational modifications of various proteins and how lncRNAs work with epigenetic-associated machinery to transcriptionally regulate gene network in pancreatic cancer.
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http://dx.doi.org/10.3389/fonc.2021.657965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220219PMC
June 2021

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 Nov 19;16(11):1307-1317. Epub 2021 Jul 19.

Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, 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
November 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

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

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
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