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Single-cell approaches to investigate B cells and antibodies in autoimmune neurological disorders

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Cellular & Molecular Immunology 2021年第2期18卷 294-306页

作者： Alicia Zou Sudarshini Ramanathan Russell C.Dale Fabienne Brilot Brain Autoimmunity Group Kids Neuroscience CentreKids Research at the Children’s Hospital at WestmeadSydneyNSWAustralia Discipline of Child and Adolescent health Faculty of Medicine and HealthThe University of SydneySydneyNSWAustralia Brain and Mind Centre The University of SydneySydneyNSWAustralia School of medical Sciences Discipline of Applied Medical ScienceFaculty of Medicine and HealthThe University of SydneySydneyNSWAustralia

Autoimmune neurological disorders,including neuromyelitis optica spectrum disorder,anti-N-methyl-D-aspartate receptor encephalitis,anti-MOG antibody-associated disorders,and myasthenia gravis,are clearly defined by the presence of autoantibodies against neurological *** these autoantibodies have been heavily studied for their biological activities,given the heterogeneity of polyclonal patient samples,the characteristics of a single antibody cannot be definitively *** review details the findings of polyclonal serum and CSF studies and then explores the advances made by single-cell technologies to the field of antibody-mediated neurological ***-resolution single-cell methods have revealed abnormalities in the tolerance mechanisms of several disorders and provided further insight into the B cells responsible for autoantibody ***,several factors,including epitope specificity and binding affinity,finely regulate the pathogenic potential of an autoantibody,and a deeper appreciation of these factors may progress the development of targeted immunotherapies for *** options.

关键词： B cells Recombinant antibodies Autoimmunity Central nervous system Neurological disorders Monoclonal Single cell Sequencing Pathogenicity Epitope Affinity B cell tolerance

From signalling pathways to targeted therapies: unravelling glioblastoma’s secrets and harnessing two decades of progress

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5270-5302页

作者： Brittany Dewdney Misty RJenkins Sarah ABest Saskia Freytag Krishneel Prasad Jeff Holst Raelene Endersby Terrance GJohns Cancer Centre Telethon Kids InstituteNedlandsWA6009Australia Centre For Child health research University of Western AustraliaPerthWA6009Australia Immunology Division The Walter and Eliza Hall Institute of Medical ResearchMelbourne3052Australia Department of medical Biology University of MelbourneMelbourne3010Australia Personalised Oncology Division The Walter and Eliza Hall Institute of Medical ResearchMelbourne3052Australia School of Biomedical Sciences University of New South WalesSydney2052Australia

Glioblastoma,a rare,and highly lethal form of brain cancer,poses significant challenges in terms of therapeutic resistance,and poor survival rates for both adult and paediatric patients *** advancements in brain cancer research driven by a technological revolution,translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet *** review emphasises the intricate role of receptor tyrosine kinase signalling pathways,epigenetic mechanisms,and metabolic functions in glioblastoma tumourigenesis and therapeutic *** also discuss the extensive efforts over the past two decades that have explored targeted therapies against these *** therapeutic approaches,such as antibody-toxin conjugates or CAR T cell therapies,offer potential by specifically targeting proteins on the glioblastoma cell *** strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical ***,gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine *** these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.

关键词： glioblastoma therapies targeted

VPOT:A Customizable Variant Prioritization Ordering Tool for Annotated Variants

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Genomics, Proteomics & Bioinformatics 2019年第5期17卷 540-545页

作者： Eddie Ip Gavin Chapman David Winlaw Sally LDunwoodie Eleni Giannoulatou Victor Chang Cardiac research Institute Sydney 2010Australia St Vincent’s Clinical School University of New South WalesSydney 2052Australia Heart Centre for Children The Children’s Hospital at WestmeadSydney 2145Australia Sydney medical School University of SydneySydney 2050Australia School of Biotechnology and Biomolecular Sciences University of New South WalesSydney 2033Australia

Next-generation sequencing(NGS) technologies generate thousands to millions of genetic variants per *** of potential disease-causal variants is labor intensive as it relies on filtering using various annotation metrics and consideration of multiple pathogenicity prediction *** have developed VPOT(variant prioritization ordering tool),a python-based command line tool that allows researchers to create a single fully customizable pathogenicity ranking score from any number of annotation values,each with a user-defined *** use of VPOT can be informative when analyzing entire cohorts,as variants in a cohort can be *** also provides additional functions to allow variant filtering based on a candidate gene list or by affected status in a family *** outperforms similar tools in terms of efficacy,flexibility,scalability,and computational *** is freely available for public use at Git Hub(https://***/VCCRI/VPOT/).Documentation for installation along with a user tutorial,a default parameter file,and test data are provided.

关键词： Next-generation sequencing Pathogenicity predictions Variant prioritization Customizable ranking Genomic annotation

The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34 ＋ stem cells in the presence of fins-like tyrosine kinase 3 ligand and thrombopoietin

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Cellular & Molecular Immunology 2012年第6期9卷 446-454页

作者： AI Proietto D Mittag AW Roberts N Sprigg L Wu Molecular Immunology Division The Walter and Eliza Hall Institute of Medical Research Parkville Vic. Australia Autoimmunity and Transplantation Division The Walter and Eliza Hall Institute of Medical Research Parkville Vic. Australia Transfusion research Australian Red Cross Blood Services West Melbourne Vic. 3003 Australia Cancer and Haematology Division The Walter and Eliza Hall Institute of Medical Research Parkville Vic. Australia Tsinghua U niversity-Peking University Joint Center for Life Sciences Tsinghua University School of Medicine Beijing China

Dendritic cells （DCs） are immune cells specialized to capture, process and present antigen to T cells in order to initiate an appropriate adaptive immune response. The study of mouse DC has revealed a heterogeneous population of cells that differ in their development, surface phenotype and function. The study of human blood and spleen has shown the presence of two subsets of conventional DC including the CDlb/c＋ and CD141＋CLEC9A＋ conventional DC （cDC） and a plasmacytoid DC （pDC） that is CD304＋CD123＋. Studies on these subpopulations have revealed phenotypic and functional differences that are similar to those described in the mouse. In this study, the three DC subsets have been generated in vitrofrom human CD34＋ precursors in the presence of fins-like tyrosine kinase 3 ligand （FIt3L） and thrombopoietin （TPO）. The DC subsets so generated, including the CDlb/c＋ and CLEC9A＋ cDCs and CD123 ＋ pDCs, were largely similar to their blood and spleen counterparts with respect to surface phenotype, toll-like receptor and transcription factor expression, capacity to stimulate T cells, cytokine secretion and cross-presentation of antigens. This system may be utilized to study aspects of DC development and function not possible in vivo.

关键词： dendritic cells fms-like tyrosine kinase 3 ligand thrombopoietin

The VEGF signaling pathway in cancer: the road ahead

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Chinese Journal of Cancer 2013年第6期32卷 297-302页

作者： Steven A. Stacker Marc G. Achen Tumour Angiogenesis Program Peter MacCallum Cancer Centre St. Andrews Place Sir Peter MacCallum Department of Oncology University of Melbourne

The vascular endothelial growth factor (VEGF) family of soluble protein growth factors consists of key mediators of angiogenesis and lymphangiogenesis in the context of tumor biology. The members of the family, VEGF-A (also known as VEGF), VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF), play important roles in vascular biology in both normal physiology and pathology. The generation of a humanized neutralizing antibody to VEGF-A (bevacizumab, also known as Avastin) and the demonstration of its benefit in numerous human cancers have confirmed the merit of an anti-angiogenesis approach to cancer treatment and have validated the VEGF-A signaling pathway as a therapeutic target. Other members of the VEGF family are now being targeted, and their relevance to human cancer and the development of resistance to anti-VEGF-A treatment are being evaluated in the clinic. Here, we discuss the potential of targeting VEGF family members in the diagnosis and treatment of cancer.

关键词： VEGF-C 癌症治疗信号通路血管内皮生长因子 EGF家族肿瘤生物学道路胎盘生长因子

The suppressor of cytokine signalling 2(SOCS2),traumatic brain injury and microglial/macrophage regulation

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Neural Regeneration research 2016年第9期11卷 1405-1406页

作者： Harleen S.Basrai Ann M.Turnley Department of Anatomy and Neuroscience The University of Melbourne

Traumatic brain injury （TBI） results in a range of neuroinflam- matory events that vary depending on the type and extent of in- jury. Central to this is the activation of tissue resident microglia and infiltration of peripheral macrophages, which phagocytose debris and/or secrete a range of cytokines, chemokines and oth- er factors which modify the injured environment to promote or inhibit repair （Schwartz et al., 2013）. The reactive macro- phages/microglia are broadly divided into two categories.

关键词： SOCS2 Tg WT TBI The suppressor of cytokine signalling 2 traumatic brain injury and microglial/macrophage regulation

P2X7 receptor antagonism in amyotrophic lateral sclerosis

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Neural Regeneration research 2017年第5期12卷 749-750页

作者： Ronald Sluyter Rachael Bartlett Diane Ly Justin J.Yerbury School of Biological Sciences and Center for medical and Molecular Bioscience University of Wollongong Wollongong NSW Australia Illawarra health and medical research Institute NSW Wollongong Australia

Amyotrophic lateral sclerosis（ALS）is a rapidly progressive disorder characterized by the degeneration and subsequent loss of upper and lower motor neurons,resulting in reduced muscle function and paralysis（Mathis et al.,2017）.Current therapies are limited to the oral administration of riluzole,which improves survival by only 3 months（Mathis et al.,2017）.Thus,

关键词： BBG SOD

Low back pain and osteoarthritis pain:a perspective of estrogen

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骨研究:英文版 2023年第3期11卷 443-456页

作者： Huiwen Pang Shihui Chen David M.Klyne David Harrich Wenyuan Ding Sidong Yang Felicity Y.Han australian Institute for Bioengineering and Nanotechnology The University of QueenslandSt.LuciaBrisbaneQLD 4072Australia NHMRC Centre of Clinical research Excellence in Spinal Pain Injury and HealthThe University of QueenslandSt.LuciaBrisbaneQLD 4072Australia Department of Cell and Molecular Biology QIMR Berghofer Medical Research InstituteHerstonQLD 4006Australia Department of Spine Surgery The Third Hospital of Hebei Medical University139 Ziqiang RoadShijiazhuang 050051China Hebei Joint International research Center for Spinal Diseases 139 Ziqiang RoadShijiazhuang 050051China

Low back pain(LBP)is the world's leading cause of disability and is increasing in prevalence more rapidly than any other pain *** disc(IVD)degeneration and facet joint osteoarthritis(FJOA)are two common causes of LBP,and both occur more frequently in elderly women than in other ***,osteoarthritis(OA)and OA pain,regardless of the joint,are experienced by up to twice as many women as men,and this difference is amplified during *** in estrogen may be an important contributor to these pain *** for estrogen have been found within IVD tissue and nearby joints,highlighting the potential roles of estrogen within and surrounding the IVDs and *** addition,estrogen supplementation has been shown to be effective at ameliorating IVD degeneration and OA progression,indicating its potential use as a therapeutic agent for people with LBP and OA *** review comprehensively examines the relationship between estrogen and these pain conditions by summarizing recent preclinical and clinical *** potential molecular mechanisms by which estrogen may relieve LBP associated with IVD degeneration and FJOA and OA pain are discussed.

关键词： agent degeneration pain

Strategies to limit dysmyelination during secondary degeneration following neurotrauma

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Neural Regeneration research 2014年第11期9卷 1096-1099页

作者： Melinda Fitzgerald Experimental and Regenerative Neurosciences School of Animal Biology The University of Western Australia Hackett DriveCrawley WA 6009 Australia

Following trauma to the central nervous system （CNS）, cells in the lesion site die rapidly. In addition, neurons and glia be- yond the initial lesion are vulnerable. These cells can undergo delayed death due to metabolic events that follow the initial trauma, via mechanisms thought to he triggered by gluta- mate-induced excitotoxicity and Ca2＋ overload, leading to mitochondrial dysfunction, associated with increased oxida- tive stress （Camello-Almaraz et al., 2006; Peng and Jou, 2010）. The resultant death of areas of grey and white matter adjacent to the lesion site is termed secondary degeneration, and is a feature of brain and spinal cord injury （Park et al., 2004; Gi- aume et al., 2007）. Secondary degeneration contributes sub- stantially to functional loss following neurotrauma （Profyris et al., 2004; Farkas and Povlishock, 2007） and rescuing this intact, but vulnerable, tissue is considered critical to mini- mising adverse sequelae and improving long term functional outcomes after CNS trauma （Fehlings et al., 2012）. However, our understanding of many of the metabolic events thought to contribute to secondary degeneration is based largely on in vitro studies （Khodorov, 2004; Tretter et al., 2007; Peng and Jou, 2010） and there is a need to confirm the relevance of these mechanisms in vivo, as well as their structural and func- tional consequences.

关键词： Strategies to limit dysmyelination during secondary degeneration following neurotrauma NIR CML