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Superior antibody and membrane protein‑specific T‑cell responses to CoronaVac by intradermal versus intramuscular routes in adolescents

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World Journal of Pediatrics 2024年第4期20卷 353-370页

作者： Jaime S.Rosa Duque Samuel M.S.Cheng Carolyn A.Cohen Daniel Leung Xiwei Wang Xiaofeng Mu yuet Chung Tsun Ming lau Manni Wang Wenyue Zhang Yanmei Zhang Howard H.W.Wong Leo C.H.Tsang Sara Chaothai Tsz Chun Kwan John K.C.Li Karl C.K.Chan Leo L.H.Luk Jenson C.H.Ho Wing Yan Li Amos M.T.Lee Jennifer H.Y.Lam Sau Man Chan Wilfred H.S.Wong Issan Y.S.Tam Masashi Mori Sophie A.Valkenburg Malik Peiris Wenwei Tu yu lung lau Department of Paediatrics and Adolescent Medicine The University of Hong KongHong KongChina School of Public Health The University of Hong KongHong KongChina HKU‑Pasteur Research Pole School of Public HealthThe University of Hong KongHong KongChina Research Institute for Bioresources and Biotechnology Ishikawa Prefectural UniversityNonoichiJapan Department of Microbiology and Immunology Peter Doherty Institute for Infectionand ImmunityUniversity of MelbourneMelbourneVICAustralia Center for Immunology and Infection C2i Hong KongChina

Background Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is necessary.Fractional dosing by intradermal(ID)administration has been shown to be equally immunogenic as intramuscular(IM)administration for several vaccines,but the immunogenicity of ID inactivated whole severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)at the full dose is unknown.This study(NCT04800133)investigated the superiority of antibody and T-cell responses of full-dose CoronaVac by ID over IM administration in adolescents.Methods Participants aged 11–17 years received two doses of IM or ID vaccine,followed by the 3rd dose 13–42 days later.Humoral and cellular immunogenicity outcomes were measured post-dose 2(IM-CC versus ID-CC)and post-dose 3(IMCCC versus ID-CCC).Doses 2 and 3 were administered to 173 and 104 adolescents,respectively.Results Spike protein(S)immunoglobulin G(IgG),S-receptor-binding domain(RBD)IgG,S IgG Fcγreceptor IIIa(FcγRIIIa)-binding,SNM[sum of individual(S),nucleocapsid protein(N),and membrane protein(M)peptide pool]-specific interleukin-2(IL-2)+CD4+,SNM-specific IL-2+CD8+,S-specific IL-2+CD8+,N-specific IL-2+CD4+,N-specific IL-2+CD8+and M-specific IL-2+CD4+responses fulfilled the superior and non-inferior criteria for ID-CC compared to IM-CC,whereas IgG avidity was inferior.For ID-CCC,S-RBD IgG,surrogate virus neutralisation test,90%plaque reduction neutralisation titre(PRNT90),PRNT50,S IgG avidity,S IgG FcγRIIIa-binding,M-specific IL-2+CD4+,interferon-γ+CD8+and IL-2+CD8+responses were superior and non-inferior to IM-CCC.The estimated vaccine efficacies were 49%,52%,66%and 79%for IM-CC,ID-CC,IM-CCC and ID-CCC,respectively.The ID groups reported more local,mild adverse reactions.Conclusion This is the first study to demonstrate superior antibody and M-specific T-cell responses by ID inactivated SARSCoV-2 vaccination and serves as the basis for future research to improve the immunogenicity of inactivated vaccines.

关键词： CoronaVac Coronavirus disease 2019 Immunity Intradermal Vaccine

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Bile acids,gut microbiota,and therapeutic insights in hepatocellular carcinoma

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Cancer Biology & Medicine 2024年第2期21卷 144-162页

作者： Yang Song Harry CH lau Xiang Zhang Jun yu Institute of Digestive Disease and Department of Medicine and Therapeutics State Key Laboratory of Digestive DiseaseLi Ka Shing Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong KongChina Department of Gastroenterology Zhongshan Hospital Xiamen UniversityXiamen 361004China

Hepatocellular carcinoma(HCC)is a prevalent and aggressive liver malignancy.The interplay between bile acids(BAs)and the gut microbiota has emerged as a critical factor in HCC development and progression.Under normal conditions,BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs.The gut microbiota plays a critical role in BA metabolism,and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis.Of note,dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis,thereby leading to liver inflammation and fibrosis,and ultimately contributing to HCC development.Therefore,understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis.In this review,we comprehensively explore the roles and functions of BA metabolism,with a focus on the interactions between BAs and gut microorganisms in HCC.Additionally,therapeutic strategies targeting BA metabolism and the gut microbiota are discussed,including the use of BA agonists/antagonists,probiotic/prebiotic and dietary interventions,fecal microbiota transplantation,and engineered bacteria.In summary,understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

关键词： Bile acid gut microbiota hepatocellular carcinoma therapeutics microbiota modulation

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A Hf-doped dual-phase high-entropy alloy: phase evolution and wear features

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Rare Metals 2024年第1期43卷 324-333页

作者： Hao Ren Rui-Run Chen Xue-Feng Gao Tong Liu Gang Qin yu-lung Chiu Shi-Ping Wu Jing-Jie Guo National Key Laboratory for Precision Hot Processing of Metals School of Materials Science and EngineeringHarbin Institute of TechnologyHarbin 150001China School of Metallurgy and Materials University of BirminghamEdgbastonBirmingham B152TTUK

Initially defined high entropy alloys(HEAs)usually exhibit a single-phase solid-solution structure.However,two and/or more types of phases in HE As possibly induce the desired microstructure features,which contribute to improving the wear properties of HE As.Here,we prepare a series of(AlCoCrFeNi)_(100-x)Hf_(x)(x=0,2,4and 6;at%) HEAs and concern their phase compositions,micro structures and wear properties.Hf leads to the formation of(Ni,Co)_(2)Hf-type Laves phase and tailors the microstructure from a body-centered cubic(BCC) singlephase structure to a hypoeutectic structure.An increased hardness from~HV 512.3 to~HV 734.1 is due to solid-solution strengthening,grain refinement strengthening and precipitated phase strengthening.And a few oxides(Al_(2)O_(3)+Cr_(2)O_(3)) caused by the wear heating contribute to an 85.5% decrease in wear rate of the HEA system from6.71×10^(-5) to 0.97×10^(-5) m^(3)·N^(-1)·m^(-1).In addition,Hf addition changes the wear mechanism from abrasive wear,mild oxidative wear and adhesive wear to oxidative wear and adhesive wear.

关键词： High entropy alloy Laves phase Hardness Wear mechanism

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Introduction of rare-earth element Sc in alloy design to modify wear features of dual-phase high-entropy alloy

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Rare Metals 2024年第2期43卷 817-828页

作者： Hao Ren Rui-Run Chen Xue-Feng Gao Tong Liu Gang Qin yu-lung Chiu Shi-Ping Wu Jing-Jie Guo Guo National Key Laboratory for Precision Hot Processing of Metals School of Materials Science and EngineeringHarbin Institute of TechnologyHarbin150001China School of Metallurgy and Materials University of BirminghamBirminghamB152TTUK

Tailoring the alloy composition,which induces the hard secondary phase to increase hardness and strength to improve the wear features,is a feasible approach for developing wear-resistant metal materials.Here,a group of(AlCoCrFeNi)_(100–x)Sc_(x)(x=0–2.0,at%)high-entropy alloys(HEAs)are designed and the phase compositions and wear behaviors are explored.Sc-doped HEA series contain the primary body-centered cubic(BCC)and eutectic phases,in which the eutectic phase is composed of the alternately grown BCC and Laves phases.Sc addition promotes the diffusion of Ni atoms from BCC phase to form the Sc-rich Laves phase at the grain boundaries.Vickers hardness increases due to solid solution strengthening and second phase strengthening.And the second phase strengthening plays a more significant role relative to solid solution strengthening.Laves phase and the oxides caused by wear heating prevent the direct contact between friction pair and HEAs,thus inducing a decreased wear rate from 6.82×10^(−5) to 3.47×10^(−5)m^(3)·N^(−1)·m^(−1).Moreover,the wear mechanism changes from adhesive wear,abrasive wear and oxidative wear to abrasive wear and oxidative wear.

关键词： High entropy alloy(HEA) Laves phase Hardness Wear mechanism

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Primary Immunodeficiencies:“New” Disease in an Old Country

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Cellular & Molecular Immunology 2009年第6期6卷 397-406页

作者： Pamela P.W.Lee yu-lung lau Department of Paediatrics and Adolescent Medicine The University of Hong KongHKSARChina Department of Paediatrics and Adolescent Medicine Room 1171/F New Clinical BuildingQueen Mary HospitalPokfulamHong KongChina

Primary immunodeficiency disorders(PIDs)are rare inborn errors of the immune system.Patients with PIDs are unique models that exemplify the functional and phenotypic consequences of various immune defects underlying infections,autoimmunity,lymphoproliferation,allergy and cancer.Over 150 PID syndromes were characterized in the past 60 years,with an ever growing list of new entities being discovered.Because of their rarity,multi-center collaboration for pooled data analysis and molecular studies is important to gain meaningful insights into the phenotypic and genetic diversities of PIDs.In this article,we summarize our research findings on PIDs in Chinese population in the past 20 years.Close collaboration among various immunology centers,cross-referrals and systematic data analysis constitute the foundation for research on PIDs.Future directions include establishment of a national PID registry,raising awareness of PIDs and securing sufficient resources for patient care and scientific research.

关键词： primary immunodeficiency disorders immunodeficiencies development research China

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CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD41 regulatory T cells

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Cellular & Molecular Immunology 2010年第1期7卷 44-50页

作者： Jian Zheng Yinping Liu yu-lung lau Wenwei Tu Department of Paediatrics and Adolescent Medicine Li Ka Shing Faculty of MedicineUniversity of Hong KongHong KongChina Joint Research Centre West China Second University HospitalSichuan University and Faculty of MedicineUniversity of Hong KongChengduChina

CD4^(+)regulatory T cells(Tregs)play an important role in maintaining immune tolerance by suppressing pathologic immune responses.,The generation of large numbers of antigen-specific Tregs ex vivo is critical for the development of clinical immunotherapy based on the adoptive transfer of Tregs.Both CD40-activated B cells(CD40-B)and immature dendritic cells(imDCs)have been used as professional antigen-presenting cells(APCs)to generate antigen-specific Tregs.However,the efficiencies of CD40-B and imDCs to generate CD4^(+)Tregs have not been compared directly and the mechanism driving the generation of these Tregs remains largely unknown.In this study,we found that CD40-B exhibited mature phenotypes and were more able to induce and expand CD4^(high)"CD25^(+)Tregs than imDCs.Moreover,Tregs induced by CD40-B had greater suppressive capacity than those induced by imDCs.The generation of CD4^(high)CD25^(+)Tregs by CD40-B and imDCs is cell-cell contact dependent and partially relies on the expression of human leukocyte antigen(HLA)-DR and CD80/86.Differences in CD4^(high)CD25^(+)Treg generation efficiency were largely explained by the production of endogenous IL-2 by CD40-B.Our results suggest that CD40-B is better able to generate large numbers of antigen-specific Tregs than imDCs.Additionally,using CD40-B to generate Tregs may accelerate the clinical use of Treg-based immunotherapy in the treatment of allograft rejection,graft versus host disease(GVHD)and autoimmune diseases.

关键词： B cells immature DC Treg IL-2

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Variable outcome in infantile-onset inflammatory bowel disease in an Asian cohort

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World Journal of Gastroenterology 2016年第48期22卷 10653-10662页

作者： Way Seah Lee Ruey Terng Ng Koon-Wing Chan yu-lung lau Department of Paediatrics University Malaya Medical Center University Malaya Paediatric and Child Health Research Group University Malaya Department of Paediatrics and Adolescent Medicine Queen Mary Hospital LKS Faculty of Medicine The University of Hong Kong

AIM Infantile-onset inflammatory bowel disease(IO-IBD) with the onset of disease before 12 mo of age, is a different disease entity from childhood IBD. We aimed to describe the clinical features, outcome and role of mutation in interleukin-10(IL-10) and interleukin-10 receptors(IL-10R) in Asian children with IO-IBD. METHODS All cases of IO-IBD, defined as onset of disease before 12 mo of age, seen at University Malaya Medical Center, Malaysia were reviewed. We performed mutational analysis for IL10 and IL10 R genes in patients with presenting clinical features of Crohn's disease(CD).RESULTS Six [13%; CD = 3, ulcerative colitis(UC) = 2, IBDunclassified(IBD-U) = 1] of the 48 children(CD = 25; UC = 23) with IBD have IO-IBD. At final review [median(range) duration of follow-up: 6.5(3.0-20) years], three patients were in remission without immunosuppression [one each for post-colostomy(IBD-U), after standard immunosuppression(CD), and after total colectomy(UC)]. Three patients were on immunosuppression:one(UC) was in remission while two(both CD) had persistent disease. As compared with later-onset disease, IO-IBD were more likely to present with bloody diarrhea(100% vs 55%, P = 0.039) but were similar in terms of an associated autoimmune liver disease(0% vs 19%, P = 0.31), requiring biologics therapy(50% vs 36%, P = 0.40), surgery(50% vs 29%, P = 0.27), or achieving remission(50% vs 64%, P = 0.40). No mutations in either IL10 or IL10 R in the three patients with CD and the only patient with IBD-U were identified.CONCLUSION The clinical features of IO-IBD in this Asian cohort of children who were negative for IL-10 or IL-10 R mutations were variable. As compared to childhood IBD with onset of disease after 12 mo of age, IO-IBD achieved remission at a similar rate.

关键词： Infantile-onset inflammatory bowel disease Pediatric

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Avian influenza virus directly infects human natural killer cells and inhibits cell activity

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Virologica Sinica 2017年第2期32卷 122-129页

作者： Huawei Mao Yinping Liu Sin Fun Sia JS Malik Peiris yu-lung lau Wenwei Tu Department of Paediatrics The University of Hong Kong - Shenzhen Hospital Shenzhen 518000 China Department of Paediatrics & Adolescent Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China Department of Microbiology The University of Hong Kong Hong Kong SAR China Shenzhen Engineering Laboratory of PID Diagnosis & Therapy Technology Shenzhen 518000 China

Natural killer(NK) cell is a key component of innate immunity and plays an important role in host defense against virus infection by directly destroying infected cells. Influenza is a respiratory disease transmitted in the early phase of virus infection. Evasion of host innate immunity including NK cells is critical for the virus to expand and establish a successful acute infection. Previously,we showed that human influenza H1N1 virus infects NK cells and induces cell apoptosis, as well as inhibits NK cell activity. In this study, we further demonstrated that avian influenza virus also directly targeted NK cells as an immunoevasion strategy. The avian virus infected human NK cells and induced cell apoptosis. In addition, avian influenza virion and HA protein inhibited NK cell cytotoxicity. This novel strategy has obvious advantages for avian influenza virus, allowing the virus sufficient time to expand and subsequent spread before the onset of the specific immune response. Our findings provide an important clue for the immunopathogenesis of avian influenza,and also suggest that direct targeting NK cells may be a common strategy used by both human and avian influenza viruses to evade NK cell immunity.

关键词：生来的杀手(NK ) 房间鸟的流行性感冒病毒(AIV ) immunoevasion 方向感染抑制 cytotoxicity

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Immunoregulatory and Anti-cancer Activities of Combination Treatment of Novel Four-Herb Formula and Doxorubicin in 4T1-Breast Cancer Bearing Mice

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Chinese Journal of Integrative Medicine 2024年第4期30卷 311-321页

作者： Lea Ling-yu Kan Ben Chung-Lap Chan Grace Gar-Lee yue LI Pei-ting Sharon Sze-Man Hon HUANG Dan-qi Miranda Sin-Man Tsang Clara Bik-San lau Ping-Chung Leung Chun-Kwok Wong Institute of Chinese Medicine The Chinese University of Hong KongHong Kong SARChina State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong KongHong KongChina Department of Chemical Pathology The Chinese University of Hong KongHong Kong SARChina China-Australia International Research Centre for Chinese Medicine School of Health and Biomedical SciencesSTEM CollegeRMIT UniversityBundooraVictoriaAustralia Li Dak Sum Yip Yio Chin R&D Centre for Chinese Medicine The Chinese University of Hong Kong SARHong KongChina

Objective To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula(4HF)and doxorubicin in triple-negative breast cancer(TNBC).Methods Murine-derived triple-negative mammary carcinoma cell line,4T1 cells,was cultured and inoculated into mouse mammary glands.Sixty-six mice were randomly assigned into 6 groups(n=11 in ench):naive,control,LD 4HF(low dose 4HF),HD 4HF(high dose 4HF),LD 4HF+D(low dose and doxorubicin),and D(doxorubicin).Apart from the naive group,each mouse received subcutaneous inoculation with 5×10^(5)4T1 cells resuspended in 100µL of normal saline in the mammary fat pads.Starting from the day of tumor cell inoculation,tumors were grown for 6 days.The LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF,respectively.The LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin(5 mg/kg).The D group received weekly intraperitoneal injections of doxorubicin(5 mg/kg).The treatment naive mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a week.The control group received daily oral gavage of 0.2 mL double-distilled water.The treatment period was 30 days.At the end of treatment,mice organs were harvested to analyze immunological activities via immunophenotyping,gene and multiplex analysis,histological staining,and gut microbiota analysis.Results Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens(P<0.05),altered the hypoxia and overall immune lymphocyte landscape,and manipulated gut microbiota to favor the anti-tumor immunological activities.Moreover,immunosuppressive genes,cytokines,and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated(P<0.05).4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response(P<

关键词： adjunctivetherapy breast cancer cytokines Chinese medicine tumor microenvironment

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Multifunctional catalytic sites regulation of atomic-scale iridium on orthorhombic-CoSe_(2)for high efficiency dual-functional alkaline hydrogen evolution and organic degradation

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Journal of Energy Chemistry 2024年第5期92卷 271-281页

作者： Jingjing Huang Chenglin Zhong Yanjie Xia Jia Liu Guizhen Li Chao Yang Jiahong Wang Qian Wang Zhenbao Zhang Feng Yan Jianghua Wu yu Deng Zhenjiang Zhou Xingchen He Paul K.Chu Woon-Ming lau Xue-Feng yu College of Chemistry and Chemical Engineering Linyi UniversityLinyi 276005ShandongChina Shenzhen Engineering Center for the Fabrication of Two-Dimensional Atomic Crystals Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055GuangdongChina National Laboratory of Solid State Microstructures Jiangsu Key Laboratory of Artificial Functional MaterialsCollege of Engineering and Applied Sciences and Collaborative Innovation Center of Advanced MicrostructuresNanjing UniversityNanjing 210093JiangsuChina College of Biosystems Engineering and Food Science Zhejiang UniversityHangzhou 310058ZhejiangChina Department of Physics Department of Materials Science and EngineeringDepartment of Biomedical EngineeringCity University of Hong KongTat Chee AvenueKowloonHong KongChina

The earth-abundant and high-performance catalysts are crucial for commercial implementation of hydrogen evolution reaction(HER).Herein,a multifunctional site strategy to construct excellent HER catalysts by incorporating iridium(Ir)ions on the atomic scale into orthorhombic-CoSe2(Ir-CoSe_(2))was reported.Outstanding hydrogen evolution activity in alkaline media such as a low overpotential of 48.7 mV at a current density of 10 mA cm^(-2)and better performance than commercial Pt/C catalysts at high current densities were found in the Ir-CoSe_(2) samples.In the experiments and theoretical calculations,it was revealed that Ir enabled CoSe_(2)to form multifunctional sites to synergistically catalyze alkaline HER by promoting the adsorption and dissociation of H_(2)O(Ir sites)and optimizing the binding energy for H^(*)on Co sites.It was noticeable that the electrolytic system comprising the Ir-CoSe_(2)electrode not only produced hydrogen efficiently via HER,but also degraded organic pollutants(Methylene blue).The cell voltage of the dual-function electrolytic system was 1.58 V at the benchmark current density of 50 mA cm^(-2),which was significantly lower than the conventional water splitting voltage.It was indicated that this method was a novel strategy for designing advanced HER electrocatalysts by constructing multifunctional catalytic sites for hydrogen production and organic degradation.

关键词： Orthorhombic-CoSe_(2) Multifunctional sites design Hydrogen evolution reaction Synergistically catalyze Methylene blue oxidation

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