Sir Peter MacCallum Department of Oncology - Research Publications
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ItemIL-15 Preconditioning Augments CAR T Cell Responses to Checkpoint Blockade for Improved Treatment of Solid Tumors(CELL PRESS, 2020-11-04)Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR T cells in solid tumors is limited by tumor-induced immunosuppression, leading to the development of combination approaches, such as adjuvant programmed cell death 1 (PD-1) blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whereas different cytokine preconditioning milieu, such as IL-7/IL-15, have been shown to promote T cell engraftment, the impact of this approach on CAR T cell responses to adjuvant immune-checkpoint blockade has not been assessed. In the current study, we reveal that the preconditioning of CAR T cells with IL-7/IL-15 increased CAR T cell responses to anti-PD-1 adjuvant therapy. This was associated with the emergence of an intratumoral CD8+CD62L+TCF7+IRF4- population that was highly responsive to anti-PD-1 therapy and mediated the vast majority of transcriptional and epigenetic changes in vivo following PD-1 blockade. Our data indicate that preservation of CAR T cells in a TCF7+ phenotype is crucial for their responsiveness to adjuvant immunotherapy approaches and should be a key consideration when designing clinical protocols.
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ItemConserved Tao Kinase Activity Regulates Dendritic Arborization, Cytoskeletal Dynamics, and Sensory Function in Drosophila(SOC NEUROSCIENCE, 2020-02-26)Dendritic arborization is highly regulated and requires tight control of dendritic growth, branching, cytoskeletal dynamics, and ion channel expression to ensure proper function. Abnormal dendritic development can result in altered network connectivity, which has been linked to neurodevelopmental disorders, including autism spectrum disorders (ASDs). How neuronal growth control programs tune dendritic arborization to ensure function is still not fully understood. Using Drosophila dendritic arborization (da) neurons as a model, we identified the conserved Ste20-like kinase Tao as a negative regulator of dendritic arborization. We show that Tao kinase activity regulates cytoskeletal dynamics and sensory channel localization required for proper sensory function in both male and female flies. We further provide evidence for functional conservation of Tao kinase, showing that its ASD-linked human ortholog, Tao kinase 2 (Taok2), could replace Drosophila Tao and rescue dendritic branching, dynamic microtubule alterations, and behavioral defects. However, several ASD-linked Taok2 variants displayed impaired rescue activity, suggesting that Tao/Taok2 mutations can disrupt sensory neuron development and function. Consistently, we show that Tao kinase activity is required in developing and as well as adult stages for maintaining normal dendritic arborization and sensory function to regulate escape and social behavior. Our data suggest an important role for Tao kinase signaling in cytoskeletal organization to maintain proper dendritic arborization and sensory function, providing a strong link between developmental sensory aberrations and behavioral abnormalities relevant for Taok2-dependent ASDs.SIGNIFICANCE STATEMENT Autism spectrum disorders (ASDs) are linked to abnormal dendritic arbors. However, the mechanisms of how dendritic arbors develop to promote functional and proper behavior are unclear. We identified Drosophila Tao kinase, the ortholog of the ASD risk gene Taok2, as a regulator of dendritic arborization in sensory neurons. We show that Tao kinase regulates cytoskeletal dynamics, controls sensory ion channel localization, and is required to maintain somatosensory function in vivo Interestingly, ASD-linked human Taok2 mutations rendered it nonfunctional, whereas its WT form could restore neuronal morphology and function in Drosophila lacking endogenous Tao. Our findings provide evidence for a conserved role of Tao kinase in dendritic development and function of sensory neurons, suggesting that aberrant sensory function might be a common feature of ASDs.
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ItemTissue-specific tumour microenvironments are an emerging determinant of immunotherapy responses(AME PUBL CO, 2020-08-01)
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ItemChallenges of PD-L1 testing in non-small cell lung cancer and beyond(AME PUBL CO, 2020-08-01)
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ItemProfessionals' attitudes towards the use of cognitive enhancers in academic settings.(Public Library of Science (PLoS), 2020)INTRODUCTION AND AIMS: The non-medical use of prescription stimulants such as methylphenidate, dexamphetamine and modafinil is increasing in popularity within tertiary academic settings. There is a paucity of information on awareness, attitudes, and acceptability by professionals of use in this context. This study aimed to investigate professionals' knowledge of and attitudes towards the use of cognitive enhancers (CEs) in academic settings, and their willingness to use a hypothetical CE. DESIGN AND METHODS: A mail survey was sent to doctors, pharmacists, nurses, accountants and lawyers in New Zealand. These disciplines were chosen as they require professional registration to practice. The questionnaire comprised four sections: (1) demographics, (2) knowledge of CEs, (3) attitudes towards the use of CEs, and (4) willingness to use hypothetical CEs. RESULTS: The response rate was 34.5% (414/1200). Overall, participants strongly disagreed that it was fair to allow university students to use CEs for cognitive enhancement (Mdn = 1, IQR: 1,3), or that it is ethical for students without a prescription to use cognitive enhancers for any reason (Mdn = 1, IQR: 1,2). Professions differed in their attitudes towards whether it is ethical for students without a prescription to use CEs for any reason (p = 0.001, H 31.527). DISCUSSION AND CONCLUSION: Divergent views and lack of clear consensus within professions and between professionals on the use of CEs have the potential to influence both professionals and students as future professionals. These divergent views may stem from differences in the core values of self-identity as well as extrinsic factors of acceptability within the profession in balancing the elements of opportunity, fairness and authenticity in cognitive enhancement. Further research is required to inform the development of policy and guidelines that are congruent with all professions.
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ItemScoping review of pharmacy-based initiatives for preventing unintended pregnancy: protocol.(BMJ, 2020-02-02)INTRODUCTION: Due to a high global incidence of unintended pregnancy, finding novel ways to increase the accessibility of contraceptive products and information is critical. One proposed strategy is to use the accessibility of community pharmacies and expand the role of pharmacists to deliver these services. This protocol reports the methods of a proposed scoping review of pharmacy-based initiatives for preventing unintended pregnancy. We intend to identify the range of interventions employed by pharmacists worldwide and their outcomes and aim to infer the value of task sharing for reducing certain access and equity barriers to contraception. METHODS AND ANALYSIS: This protocol was developed with guidance from the Joanna Briggs Institute Methodology for Scoping Reviews. Reporting is compliant with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocols. The scoping review will be reported according to the PRISMA Extension for Scoping Reviews. Seven electronic databases (PubMed, Ovid Medline, Embase, Cochrane Library, Scopus and Cumulative Index to Nursing and Allied Health Literature) were systematically searched for relevant literature published in English from 2000, on 22 August 2019. Two authors will individually screen articles for eligibility in Covidence and data will be charted and reported using a tool developed for the purpose of this review. ETHICS AND DISSEMINATION: Findings will be disseminated in publications and presentations with relevant stakeholders. Ethical approval is not required as we will be using data from publicly available literature sources. We will map available evidence across the breadth of studies that have been conducted and identify the effectiveness and acceptability of interventions.
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ItemTrastuzumab-related cardiotoxicity: what do we know in 2020?(AME PUBL CO, 2020-07-01)
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ItemNo Preview AvailableAltered visual function in a larval zebrafish knockout of neurodevelopmental risk gene( 2020-09-22)The human PDZK1 gene is located in a genomic susceptibility region for neurodevelopmental disorders. A genome-wide association study (GWAS) identified links between PDZK1 polymorphisms and altered visual contrast sensitivity, an endophenotype for schizophrenia and autism spectrum disorder. The PDZK1 protein is implicated in neurological functioning, interacting with synaptic molecules including post-synaptic density 95 (PSD-95), N-methyl-D-aspartate receptors (NMDAR), corticotropin-releasing factor receptor 1 (CRFR1) and serotonin 2A receptors. To elucidate the role of PDZK1, we generated pdzk1-knockout (pdzk1-KO) zebrafish using CRISPR/Cas-9 genome editing. Visual function of 7-day-old fish was assessed at behavioural and functional levels using the optomotor response (OMR) and scotopic electroretinogram (ERG). We also quantified retinal morphology and densities of PSD-95, NMDAR1, CRFR1 and serotonin in the synaptic inner plexiform layer at 7 days, 4 weeks and 8 weeks of age. Relative to wild-type, pdzk1-KO larvae showed spatial-frequency tuning functions with increased amplitude (likely due to abnormal gain control) and reduced ERG b-waves (suggestive of inner retinal dysfunction). However, these functional differences were not associated with gross synaptic or morphological retinal phenotypes. The findings corroborate a role for pdzk1 in visual function, and our model system provides a platform for investigating other genes associated with abnormal visual behaviour.
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ItemIntegrative computational epigenomics to build data-driven gene regulation hypotheses(OXFORD UNIV PRESS, 2020-06)BACKGROUND: Diseases are complex phenotypes often arising as an emergent property of a non-linear network of genetic and epigenetic interactions. To translate this resulting state into a causal relationship with a subset of regulatory features, many experiments deploy an array of laboratory assays from multiple modalities. Often, each of these resulting datasets is large, heterogeneous, and noisy. Thus, it is non-trivial to unify these complex datasets into an interpretable phenotype. Although recent methods address this problem with varying degrees of success, they are constrained by their scopes or limitations. Therefore, an important gap in the field is the lack of a universal data harmonizer with the capability to arbitrarily integrate multi-modal datasets. RESULTS: In this review, we perform a critical analysis of methods with the explicit aim of harmonizing data, as opposed to case-specific integration. This revealed that matrix factorization, latent variable analysis, and deep learning are potent strategies. Finally, we describe the properties of an ideal universal data harmonization framework. CONCLUSIONS: A sufficiently advanced universal harmonizer has major medical implications, such as (i) identifying dysregulated biological pathways responsible for a disease is a powerful diagnostic tool; (2) investigating these pathways further allows the biological community to better understand a disease's mechanisms; and (3) precision medicine also benefits from developments in this area, particularly in the context of the growing field of selective epigenome editing, which can suppress or induce a desired phenotype.