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Myeloid immunosuppression and immune checkpoints in the tumor microenvironment

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Cellular & Molecular Immunology 2020年第1期17卷 1-12页

作者： Kyohei Nakamura Mark J.Smyth Immunology in Cancer and Infection Laboratory QIMR Berghofer Medical Research InstituteHerston 4006 QLDAustralia

Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of *** innate immune cells,such as neutrophils,monocytes,and macrophages,are critical mediators for sterile and nonsterile inflammation,persistent inflammation,such as that which occurs in cancer,is known to disturb normal *** disturbance leads to the generation of immunosuppressive myeloid cells,such as myeloid-derived suppressor cells(MDSCs)and tumor-associated macrophages(TAMs).Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment,immunosuppressive myeloid cells act as a major barrier to cancer ***,various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical *** include antiinflammatory agents,therapeutic blockade of the mobilization and survival of myeloid cells,and immunostimulatory *** recently,immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor *** this review,we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.

关键词： myeloid macrophage innate immunity immune checkpoint inflammation

藿朴夏苓汤对进展期胃癌术后行替吉奥治疗患者营养状态相关指标的影响

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肿瘤学杂志 2024年

作者：吴寒常靓宋彦茹刘文博陆雪张明明王冰雨宋步云檀碧波霍炳杰河北医科大学第四医院河北中医药大学 qimr Berghofer医学研究所河北省人民医院

[目的]探讨藿朴夏苓汤联合替吉奥口服对接受辅助化疗的进展期胃癌术后患者营养状态相关指标的影响。[方法]收集30例接受藿朴夏苓汤联合替吉奥治疗的进展期胃癌术后患者治疗前后的营养指标资料作为研究组，以同期接受替吉奥单药口服的30... 详细信息

[目的]探讨藿朴夏苓汤联合替吉奥口服对接受辅助化疗的进展期胃癌术后患者营养状态相关指标的影响。[方法]收集30例接受藿朴夏苓汤联合替吉奥治疗的进展期胃癌术后患者治疗前后的营养指标资料作为研究组，以同期接受替吉奥单药口服的30例患者为对照组。回顾性分析2组患者用药前后的各项指标变化情况。2组患者均接受胃癌根治术，于术后4周开始用药，于用药前及用药第8周期结束1周时检测患者一般情况及营养状态相关指标：包括体质指数、外周血白细胞、中性粒细胞、血红蛋白、血小板及白蛋白、前白蛋白数值；比较2组不良反应发生情况（包括消化道不良反应、骨髓抑制、脱发等）。同时检测30例健康体检者（健康组）的上述各项指标。[结果] 2组患者用药前的各项指标与健康组比较差异均有统计学意义（P均0.05）；用药后，研究组中性粒细胞的水平明显下降，与用药前相比较差异有统计学意义（P<0.05），而对照组体质指数、白细胞、中性粒细胞、白蛋白和前白蛋白的水平与化疗前相比较均明显降低（P<0.05）。研究组患者的不良反应发生率明显低于对照组（P<0.05）。[结论]进展期胃癌患者术后应用藿朴夏苓汤能减轻替吉奥的不良反应并改善患者营养状况。

关键词：胃肿瘤藿朴夏苓汤辅助化疗营养状态

Ferroptosis drives immune-mediated neurodegeneration in multiple sclerosis

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Cellular & Molecular Immunology 2023年第1期20卷 112-113页

作者： Anthony R.White Mental Health and Neuroscience QIMR Berghofer Medical Research InstituteHerstonQld4006Australia

One of the leading issues in multiple sclerosis(MS)research is the lack of understanding regarding the triggers of *** demyelination is a major feature in MS,the degeneration of gray matter neurons contributes to major changes in patient function,but the mechanisms driving this neuronal loss are *** exciting research published by Luoqian et al.[1]in the December issue of Cellular and Molecular Immunology,new insights have shown an important contribution of ferroptosis to T-cell-mediated neurodegeneration in the common animal model of MS,‘experimental autoimmune encephalomyelitis’(EAE).Although a relationship between ferroptosis and T-cell activation has been reported in other disorders,this is the first discovery of a link between abnormal iron homeostasis and T-cell infiltration in *** addition,the authors found that unlike other studies on ferroptosis-T-cell interactions[2,3],ferroptotic activation of T cells in EAE,and potentially MS,involved the infiltration and activation of CD4+T cells,rather than CD8+***,in this study,ferroptosis was a key driver of T-cell activation rather than the opposite interaction where CD8+cells drive ferroptosis[3].The research also mapped a key role for Acsl4 in the early stages of ferroptosis-T-cell-mediated ***4 converts free long-chain fatty acids into fatty acyl-CoA esters and has been identified as a central contributor to ferroptotic processes[4].This study has mapped a major new pathway potentially leading to neurodegeneration in MS,and this opens the possibility of new therapeutic approaches to treat MS based on iron targeting as the authors describe in their final experiments.

关键词： neurodegeneration degeneration homeostasis

Patient-specific monocyte-derived microglia as a screening tool for neurodegenerative diseases

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Neural Regeneration Research 2023年第5期18卷 955-958页

作者： Hazel Quek Anthony R.White Mental Health and Neuroscience QIMR Berghofer Medical Research Institute School of Biomedical Science The University of QueenslandBrisbaneQLDAustralia

Microglia, the main driver of neuroinflammation, play a central role in the initiation and exacerbation of various neurodegenerative diseases and are now considered a promising therapeutic target. Previous studies on in vitro human microglia and in vivo rodent models lacked scalability, consistency, or physiological relevance, which deterred successful therapeutic outcomes for the past decade. Here we review human blood monocyte-derived microglia-like cells as a robust and consistent approach to generate a patient-specific microglia-like model that can be used in extensive cohort studies for drug testing. We will highlight the strength and applicability of human blood monocyte-derived microglia-like cells to increase translational outcomes by reviewing the advantages of human blood monocyte-derived microglia-like cells in addressing patient heterogeneity and stratification, the basis of personalized medicine.

关键词： human in vitro microglia models neurodegeneration neuroinflammation patient heterogeneity patient stratification peripheral blood monocyte-derived microglia-like cells therapeutic target transdifferentiation translational outcomes

Lactate as a regulator of iron homeostasis

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Life Metabolism 2023年第5期2卷 8-11页

作者： Gregory J.Anderson David M.Frazer Iron Metabolism Laboratory QIMR Berghofer Medical Research InstituteBrisbaneQueensland 4006Australia Molecular Nutrition Laboratory QIMR Berghofer Medical Research InstituteBrisbaneQueensland 4006Australia

The key metabolic intermediate lactate can increase expression of the liver-derived peptide hepcidin,the central regulator of body iron homeostasis.A new paper by Liu et *** that lactate achieves this by binding to and activating soluble adenylyl cyclase,thereby increasing cellular cyclic adenosine monophosphate(cAMP)and enhancing signaling through the bone morphogenetic protein(BMP)pathway to modulate hepcidin expression.

关键词： expression thereby homeostasis

Differential Effects of Strategies to Improve the Transduction Efficiency of Lentiviral Vector that Conveys an Anti-HIV Protein,Nullbasic,in Human T Cells

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Virologica Sinica 2018年第2期33卷 142-152页

作者： Lina Rustanti Hongping Jin Dongsheng Li Mary Lor Haran Sivakumaran David Harrich Faculty of Medicine The University of Queensland Department of Cell and Molecular Biology QIMR Berghofer Medical Research Institute National Institute of Health Research and Development the Ministry of Health of Republic of Indonesia Central Jakarta

Nullbasic is a mutant form of HIV-1 Tat that has strong ability to protect cells from HIV-1 replication by inhibiting three different steps of viral replication: reverse transcription, Rev export of viral m RNA from the nucleus to the cytoplasm and transcription of viral m RNA by RNA polymerase II. We previously showed that Nullbasic inhibits transduction of human cells including T cells by HIV-1-based lentiviral vectors. Here we investigated whether the Nullbasic antagonists huTat2(a Tat targeting intrabody), HIV-1 Tat or Rev proteins or cellular DDX1 protein could improve transduction by a HIV-1 lentiviral vector conveying Nullbasic-Zs Green1 to human T cells. We show that overexpression of huTat2, Tat-FLAG and DDX1-HA in virus-like particle(VLP) producer cells significantly improved transduction efficiency of VLPs that convey Nullbasic in Jurkat cells. Specifically, co-expression of Tat-FLAG and DDX1-HA in the VLP producer cell improved transduction efficiency better than if used individually. Transduction efficiencies could be further improved by including a spinoculation step. However, the same optimised protocol and using the same VLPs failed to transduce primary human CD4^+T cells. The results imply that the effects of Nullbasic on VLPs on early HIV-1 replication are robust in human CD4^+T cells. Given this significant block to lentiviral vector transduction by Nullbasic in primary CD4^+T cells, our data indicate that gammaretroviral, but not lentiviral, vectors are suitable for delivering Nullbasic to primary human T cells.

关键词： HIV-1 Transduction Lentiviral vector Nullbasic Tat Rev DDX1 lntrabody

Enhanced destabilization of mismatched DNA using gold nanoparticles offers specificity without compromising sensitivity for nucleic acid analyses

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Nano Research 2015年第12期8卷 3922-3933页

作者： Abootaleb Sedighi Vicki Whitehall Paul C. H. Li Department of Chemistry Simon Fraser University Burnaby BC VSA 1S6 Canada qimr Berghofer Medical Research Institute 300 Herston Rd Brisbane QLD 4006 Australia

Here, we report a method that uses gold nanoparticles （AuNPs） to enhance the specificity of DNA hybridization without reducing its detection sensitivity. The conventional stringent wash method utilizes high-temperatureflow-salt conditions to enhance the specificity of DNA hybridization-based assays. This method creates a destabilizing environment for base pairing that affects specific and nonspecific duplexes. Therefore, specificity is achieved at the expense of signal intensity or sensitivity. However, in the proposed wash method, AuNPs predominantly destabilize nonspecific duplexes, offering specificity without compromising sensitivity. This AuNP wash technique has proven to be effective in detecting single nucleotide polymorphisms （SNPs） in genomic samples even at room temperature in a CD-like NanoBioArray （CD-NBA） chip. This method is also robust with sequence variation and is compatible with multiplex DNA analyses on microarrays. Thus, the AuNP wash method could potentially be useful for improving the accuracy of DNA hybridization results.

关键词： DNA hybridization gold nanoparticles single nucleotidepolymorphism specificity CD-like NanoBioArray chip

A novel saliva-based miRNA profile to diagnose and predict oral cancer

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International Journal of Oral Science 2024年第1期16卷 97-109页

作者： Jaikrishna Balakittnen Chameera Ekanayake Weeramange Daniel F.Wallace Pascal H.G.Duijf Alexandre S.Cristino Gunter Hartel Roberto A.Barrero Touraj Taheri Liz Kenny Sarju Vasani Martin Batstone Omar Breik Chamindie Punyadeera Saliva&Liquid Biopsy Translational Laboratory Griffith Institute for Drug DiscoveryGriffith UniversityNathanQLDAustralia Department of Medical Laboratory Sciences Faculty of Allied Health SciencesUniversity of JaffnaJaffnaSri Lanka Menzies Health Institute Griffith UniversityGold CoastQLDAustralia School of Biomedical Sciences Faculty of HealthQueensland University of TechnologyBrisbaneQLDAustralia Centre for Cancer Biology Clinical and Health SciencesUniversity of South Australia&SA PathologyAdelaideSAAustralia Institute of Clinical Medicine Faculty of MedicineUniversity of OsloOsloNorway Department of Medical Genetics Oslo University HospitalOsloNorway Griffith Institute for Drug Discovery Griffith UniversityNathanQLDAustralia qimr Berghofer Medical Research Institute Statistics UnitBrisbaneQLDAustralia School of Public Health The University of QueenslandBrisbaneQLDAustralia School of Nursing Queensland University of TechnologyBrisbaneQLDAustralia eResearch Research InfrastructureAcademic DivisionQueensland University of TechnologyBrisbaneQLDAustralia Department of Anatomical Pathology Royal Brisbane and Women’s HospitalHerstonQLDAustralia Faculty of Medicine The University of QueenslandBrisbaneQLDAustralia Royal Brisbane and Women’s Hospital Cancer Care ServicesHerstonQLDAustralia Department of Otolaryngology Royal Brisbane and Women’s HospitalHerstonQLDAustralia Department of Oral and Maxillofacial Surgery Royal Brisbane and Women’s HospitalHerstonQLDAustralia

Oral cancer (OC) is the most common form of head and neck cancer. Despite the high incidence and unfavourable patient outcomes, currently, there are no biomarkers for the early detection of OC. This study aims to discover, develop, and validate a novel saliva-based microRNA signature for early diagnosis and prediction of OC risk in oral potentially malignant disorders (OPMD).The Cancer Genome Atlas (TCGA) miRNA sequencing data and small RNA sequencing data of saliva samples were used to discover differentially expressed miRNAs. Identified miRNAs were validated in saliva samples of OC (n=50), OPMD (n=52), and controls(n=60) using quantitative real-time PCR. Eight differentially expressed miRNAs (miR-7-5p, miR-10b-5p, miR-182-5p, miR-215-5p,miR-431-5p, miR-486-3p, miR-3614-5p, and miR-4707-3p) were identified in the discovery phase and were validated. The efficiency of our eight-miRNA signature to discriminate OC and controls was:area under curve (AUC):0.954, sensitivity:86%, specificity:90%,positive predictive value (PPV):87.8%and negative predictive value (NPV):88.5%whereas between OC and OPMD was:AUC:0.911,sensitivity:90%, specificity:82.7%, PPV:74.2%and NPV:89.6%. We have developed a risk probability score to predict the presence or risk of OC in OPMD patients. We established a salivary miRNA signature that can aid in diagnosing and predicting OC,revolutionising the management of patients with OPMD. Together, our results shed new light on the management of OC by salivary miRNAs to the clinical utility of using miRNAs derived from saliva samples.

关键词： specificity salivary diagnosis

Colorectal cancer:Pathways,pathology and practice:From the editor

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World Journal of Gastroenterology 2007年第28期13卷 3783-3791页

作者： Worthley, Daniel L. Conjoint Gastroenterology Laboratory The Queensland Institute of Medical Research the Bancroft Centre rm H07 PO Royal Brisbane Hospital Herston QLD 4029 Australia. daniel.worthley@qimr.edu.au

This 5-part topic review series,'Colorectal cancer:Pathways, pathology and practice', was designed to provide expert opinion and new insights for the Journal's readership. Ideal management of colorectal cancer often

关键词： Gastroenterology