240 research outputs found
Effectiveness of porous silicon nanoparticle treatment at inhibiting the migration of a heterogeneous glioma cell population
BACKGROUND: Approximately 80% of brain tumours are gliomas. Despite treatment, patient mortality remains high due to local metastasis and relapse. It has been shown that transferrin-functionalised porous silicon nanoparticles (Tf@pSiNPs) can inhibit the migration of U87 glioma cells. However, the underlying mechanisms and the effect of glioma cell heterogeneity, which is a hallmark of the disease, on the efficacy of Tf@pSiNPs remains to be addressed. RESULTS: Here, we observed that Tf@pSiNPs inhibited heterogeneous patient-derived glioma cellsâ (WK1) migration across small perforations (3 ÎŒm) by approximately 30%. A phenotypical characterisation of the migrated subpopulations revealed that the majority of them were nestin and fibroblast growth factor receptor 1 positive, an indication of their cancer stem cell origin. The treatment did not inhibit cell migration across large perforations (8 ÎŒm), nor cytoskeleton formation. This is in agreement with our previous observations that cellular-volume regulation is a mediator of Tf@pSiNPsâ cell migration inhibition. Since aquaporin 9 (AQP9) is closely linked to cellular-volume regulation, and is highly expressed in glioma, the effect of AQP9 expression on WK1 migration was investigated. We showed that WK1 migration is correlated to the differential expression patterns of AQP9. However, AQP9-silencing did not affect WK1 cell migration across perforations, nor the efficacy of cell migration inhibition mediated by Tf@pSiNPs, suggesting that AQP9 is not a mediator of the inhibition. CONCLUSION: This in vitro investigation highlights the unique therapeutic potentials of Tf@pSiNPs against glioma cell migration and indicates further optimisations that are required to maximise its therapeutic efficacies
EphA2 as a Diagnostic Imaging Target in Glioblastoma: A Positron Emission Tomography/Magnetic Resonance Imaging Study
Noninvasive imaging is a critical technology for diagnosis, classification, and subsequent treatment planning for patients with glioblastoma. It has been shown that the EphA2 receptor tyrosine kinase (RTK) is overexpressed in a number of tumors, including glioblastoma. Expression levels of Eph RTKs have been linked to tumor progression, metastatic spread, and poor patient prognosis. As EphA2 is expressed at low levels in normal neural tissues, this protein represents an attractive imaging target for delineation of tumor infiltration, providing an improved platform for image-guided therapy. In this study, EphA2-4B3, a monoclonal antibody specific to human EphA2, was labeled with Cu-64 through conjugation to the chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The resulting complex was used as a positron emission tomography (PET) tracer for the acquisition of high-resolution longitudinal PET/magnetic resonance images. EphA2-4B3-NOTA-Cu-64 images were qualitatively and quantitatively compared to the current clinical standards of [F-18] FDOPA and gadolinium (Gd) contrast-enhanced MRI. We show that EphA2-4B3-NOTA-Cu-64 effectively delineates tumor boundaries in three different mouse models of glioblastoma. Tumor to brain contrast is significantly higher in EphA2-4B3-NOTA-Cu-64 images than in [F-18] FDOPA images and Gd contrast-enhanced MRI. Furthermore, we show that nonspecific uptake in the liver and spleen can be effectively blocked by a dose of nonspecific (isotype control) IgG
LUMOS - Low and Intermediate Grade Glioma Umbrella Study of Molecular Guided TherapieS at relapse: Protocol for a pilot study
Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue. Participants in whom no actionable or no druggable mutation is found, or in whom the matching drug is not available, will form a comparator arm and receive standard of care chemotherapy. The objective of the LUMOS trial is to assess the feasibility of this approach in a multicentre study across five sites in Australia, with a view to establishing a national molecular screening platform for patient treatment guided by the mutational analysis of contemporaneous tissue biopsies
Effectiveness of porous silicon nanoparticle treatment at inhibiting the migration of a heterogeneous glioma cell population
Background: Approximately 80% of brain tumours are gliomas. Despite treatment, patient mortality remains high due to local metastasis and relapse. It has been shown that transferrin-functionalised porous silicon nanoparticles (Tf@pSiNPs) can inhibit the migration of U87 glioma cells. However, the underlying mechanisms and the effect of glioma cell heterogeneity, which is a hallmark of the disease, on the efficacy ofTf@pSiNPs remains to be addressed.Results: Here, we observed that Tf@pSiNPs inhibited heterogeneous patient-derived glioma cells' (WK1) migration across small perforations (3 mu m) by approximately 30%. A phenotypical characterisation of the migrated subpopulations revealed that the majority of them were nestin and fibroblast growth factor receptor 1 positive, an indication of their cancer stem cell origin. The treatment did not inhibit cell migration across large perforations (8 mu m), nor cytoskeleton formation. This is in agreement with our previous observations that cellular-volume regulation is a mediator of Tf@pSiNPs'cell migration inhibition. Since aquaporin 9 (AQP9) is closely linked to cellular-volume regulation, and is highly expressed in glioma, the effect of AQP9 expression on WK1 migration was investigated. We showed that WK1 migration is correlated to the differential expression patterns of AQP9. However, AQP9-silencing did not affect WK1 cell migration across perforations, nor the efficacy of cell migration inhibition mediated by Tf@pSiNPs, suggesting that AQP9 is not a mediator of the inhibition.Conclusion: This in vitro investigation highlights the unique therapeutic potentials ofTf@pSiNPs against glioma cell migration and indicates further optimisations that are required to maximise its therapeutic efficacies.</div
Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome
Enlarged vestibular aqueduct (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4. EphA2 forms a protein complex with pendrin controlling pendrin localization, which is disrupted in some pathogenic forms of pendrin. Moreover, point mutations leading to amino acid substitution in the EPHA2 gene are identified from patients bearing mono-allelic mutation of SLC26A4. Ephrin-B2 binds to EphA2 triggering internalization with pendrin inducing EphA2 autophosphorylation weakly. The identified EphA2 mutants attenuate ephrin-B2- but not ephrin-A1-induced EphA2 internalization with pendrin. Our results uncover an unexpected role of the Eph/ephrin system in epithelial function
"A few good men": Public sector audit in the Swan River Colony, 1828-1835
The appointment of the Auditor General to undertake public sector audit is the primary instrument used to safeguard public finances in most contemporary Westminster-based democracies. It is axiomatic that the independence of the Auditor General from executive government is a critical element in ensuring the effectiveness of the role, yet this separation is a relatively recent phenomenon. Those responsible for nineteenth century public sector audit in the Australian colonies operated in what would today be considered an unacceptable environment, with little, if any, independence from the executive arm of government. Yet, while several other Australian colonies suffered from the mismanagement of government finances, there is nothing to show that the Swan River Colony experienced much more than clerical errors and minor administrative oversights. In this article, we explore the extent to which satisfactory public financial management in the Swan River Colony occurred as a result of both good financial management systems (in the context of the era) and the appointment of competent and ethical administrators â âa few good menâ
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY) : a randomised, controlled, open-label, platform trial
Funding UK Research and Innovation (Medical Research Council) and National Institute for Health and Care Research (Grant ref: MC_PC_19056). Acknowledgements Above all, we would like to thank the patients who participated in this trial. We would also like to thank the many doctors, nurses, pharmacists, other allied health professionals, and research administrators at NHS hospital organisations across the whole of the UK, supported by staff at the National Institute of Health Research (NIHR) Clinical Research Network, NHS DigiTrials, Public Health England, Department of Health & Social Care, the Intensive Care National Audit & Research Centre, Public Health Scotland, National Records Service of Scotland, the Secure Anonymised Information Linkage (SAIL) at University of Swansea, and the NHS in England, Scotland, Wales and Northern Ireland. The RECOVERY trial is supported by grants to the University of Oxford from UK Research and Innovation (UKRI) and NIHR (MC_PC_19056), the Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator, and by core funding provided by the NIHR Oxford Biomedical Research Centre, the Wellcome Trust, the Bill and Melinda Gates Foundation, the Foreign, Commonwealth and Development Office, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. TJ is supported by a grant from UK Medical Research Council (MC_UU_0002/14). WSL is supported by core funding provided by NIHR Nottingham Biomedical Research Centre. Tocilizumab was provided free of charge for this trial by Roche Products Limited. Regeneron Pharmaceuticals supported the trial through provision of casirivimab and imdevimab. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health and Social Care. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The sponsor was not involved in study design, data collection and analysis or manuscript writing.Peer reviewe
Nucleon-Nucleon Interaction: A Typical/Concise Review
Nearly a recent century of work is divided to Nucleon-Nucleon (NN)
interaction issue. We review some overall perspectives of NN interaction with a
brief discussion about deuteron, general structure and symmetries of NN
Lagrangian as well as equations of motion and solutions. Meanwhile, the main NN
interaction models, as frameworks to build NN potentials, are reviewed
concisely. We try to include and study almost all well-known potentials in a
similar way, discuss more on various commonly used plain forms for two-nucleon
interaction with an emphasis on the phenomenological and meson-exchange
potentials as well as the constituent-quark potentials and new ones based on
chiral effective field theory and working in coordinate-space mostly. The
potentials are constructed in a way that fit NN scattering data, phase shifts,
and are also compared in this way usually. An extra goal of this study is to
start comparing various potentials forms in a unified manner. So, we also
comment on the advantages and disadvantages of the models and potentials partly
with reference to some relevant works and probable future studies.Comment: 85 pages, 5 figures, than the previous v3 edition, minor changes, and
typos fixe
ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992
Optoelectronic and Excitonic Properties of Oligoacenes: Substantial Improvements from Range-Separated Time-Dependent Density Functional Theory
The optoelectronic and excitonic properties in a series of linear acenes
(naphthalene up to heptacene) are investigated using range-separated methods
within time-dependent density functional theory (TDDFT). In these rather simple
systems, it is well-known that TDDFT methods using conventional hybrid
functionals surprisingly fail in describing the low-lying La and Lb valence
states, resulting in large, growing errors for the La state and an incorrect
energetic ordering as a function of molecular size. In this work, we
demonstrate that the range-separated formalism largely eliminates both of these
errors and also provides a consistent description of excitonic properties in
these systems. We further demonstrate that re-optimizing the percentage of
Hartree-Fock exchange in conventional hybrids to match wavefunction-based
benchmark calculations still yields serious errors, and a full 100%
Hartree-Fock range separation is essential for simultaneously describing both
of the La and Lb transitions. Based on an analysis of electron-hole transition
density matrices, we finally show that conventional hybrid functionals
overdelocalize excitons and underestimate quasiparticle energy gaps in the
acene systems. The results of our present study emphasize the importance of
both a range-separated and asymptotically-correct contribution of exchange in
TDDFT for investigating optoelectronic and excitonic properties, even for these
simple valence excitations.Comment: Accepted by the Journal of Chemical Theory and Computatio
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