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SummaryThe contribution of synovial cells to the pathogenesis of rheumatoid arthritis (RA) is only partly understood. Monoclonal antibody (mAb) 1D5 is one of very few mAb ever raised against RA synovial cells in order to study the biology of these cells. Studies on the expression pattern and structural features of the 1D5 Ag suggest that 1D5 recognizes human vascular cell adhesion molecule-1 (VCAM-1), which is an intercellular adhesion molecule. Vascular cell adhesion molecule-1 may be involved in a number of crucial intercellular interactions in RA. [ABSTRACT FROM AUTHOR]

Prostate cancer morbidity and mortality demonstrate a need for more effective targeted therapies. One potential target is EphA2, although paradoxically, pro- and anti-oncogenic effects have been shown to be mediated by EphA2. We demonstrate that unique activating and blocking EphA2-targeting monoclonal antibodies display opposing tumor-suppressive and oncogenic properties in vivo. To further explore this complexity, we performed detailed phosphoproteomic analysis following ligand-induced EphA2 activation. Our analysis identified altered phosphorylation of 73 downstream proteins related to the PI3K/AKT/mTOR and ERK/MAPK pathways, with the majority implicated in cell junction and cytoskeletal organization, cell motility, and tumor metastasis. We demonstrate that the adapter protein SHB is an essential component in mediating the inhibition of the ERK/MAPK pathway in response to EphA2 receptor activation. Furthermore, we identify the adherence junction protein afadin as an EphA2-regulated phosphoprotein which is involved in prostate cancer migration and invasion., Competing Interests: Competing interests: Provisional patent applications claiming the anti-EphA2 monoclonal antibodies 1F7 and 4B3 that are described in this manuscript have been filed by the QIMR Berghofer Medical Research Institute. Ethics approval and consent to participate: All methods were performed in accordance with the relevant guidelines and regulations. All experimental protocols for the animal studies were approved by the QIMR Berghofer Animal Ethics Committee (Approval number: A0304-620M). The primary human glioblastoma cell lines WK1 and MN1 were generated in-house and have been reported previously [70, 71]. Patient tumor tissues to generate these cell lines were collected following informed consent and with approval from the Royal Brisbane Women’s Hospital and QIMR Berghofer Human Research Ethics Committees (Approval number: P3420, HREC/17/QRBW/577 Novel Therapies for Brain Cancer)., (© 2024. The Author(s).)

Background: Erythropoietin-producing hepatocellular carcinoma A4 (EphA4) is implicated in the pathophysiology of amyotrophic lateral sclerosis. EphA4 fusion protein (EphA4-Fc) inhibits EphA4 function in vivo but is too short-lived for prolonged therapy. NUN-004 (mEphA4-Fc) is a modified EphA4-Fc engineered for an extended half-life., Objective: This first-in-human phase I/Ib study evaluated the safety, tolerability, pharmacokinetics, immunogenicity and efficacy of NUN-004 in healthy volunteers and patients with amyotrophic lateral sclerosis., Methods: In this open-label study, Part 1 enrolled 20 healthy volunteers in five single ascending dose cohorts (1, 3, 10, 20 and 30 mg/kg), followed by Part 2, which enrolled eight patients with amyotrophic lateral sclerosis in two multiple ascending dose cohorts (cycle 1: 15 and 30 mg/kg) who could continue into an extended access phase (cycles 2-6: 15 mg/kg) for a total of 6 months' treatment. All participants received intravenous NUN-004; multiple dosing was administered weekly in 28-day cycles. Primary endpoints included safety assessments, single-dose and multiple-dose pharmacokinetics, and anti-drug antibodies. Efficacy assessments were Amyotrophic Lateral Sclerosis Function Rating Score Revised (ALSFRS-R) and forced vital capacity., Results: NUN-004 was well tolerated, with no serious adverse events or discontinuations. NUN-004 exposure generally increased with dose. Single-dose half-life was 111.7 (± 22.8) h in healthy volunteers (n = 20) and 74.4 (± 19.4) h in patients (n = 6). Steady state was observed in patients by day 8. Steady-state half-life (cycle 1 doses 2-4) was 83.7 (± 26.6) to 101.1 (± 46.0) h. No antibody response was observed. ALSFRS-R showed a slight improvement (+0.09 points/month) to cycle 4 and a slight decline (-0.35 points/month) over the whole study. Forced vital capacity trends were consistent with ALSFRS-R., Conclusions: This study supports the safety, tolerability and extended half-life of NUN-004, and provides preliminary evidence for its ability to ameliorate disease progression in an amyotrophic lateral sclerosis cohort., Clinical Trial Registration: Registered on ANZCTR under identifier ACTRN12621000514808 (3 May, 2021)., Competing Interests: Declarations. Funding: This study was funded by NuNerve Pty Ltd, the manufacturer of NUN-004. NuNerve Pty Ltd was involved in the study design, data collection, data analysis and preparation of the manuscript. Conflict of Interest: Perry F. Bartlett, Andrew W. Boyd, Michael Gerometta and Leanne T. Cooper are inventors of NUN-004 and are thus listed inventors on granted patents. As such, they have a direct interest in the current clinical trial and a potential pecuniary interest if this drug is commercialised. Robert D. Henderson, Richard Friend and Jing Zhao have no relevant financial or non-financial interests that are directly relevant to the content of this article. Ethics Approval: The study was carried out in compliance with the clinical protocol and approved by an independent ethics committee (The Alfred Human Research Ethics Committee, project 743/20 [HREC/71737/Alfred-2020], approved on 18 December, 2020). The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent to Participate: Each participant signed and dated an informed consent form according to the local regulatory and legal requirements and Good Clinical Practices. Consent for Publication: Not applicable. Availability of Data and Material: The data that support the findings of this study are not openly available because of reasons of commercial sensitivity but may be available from the corresponding author upon reasonable request under an appropriate agreement. Code Availability: Not applicable. Authors’ Contributions: PFB, AWB, MG and JZ contributed to the study concept and design and provided ongoing advice to the clinical trial team when requested. RF and RH were involved in the acquisition of study data. LTC contributed to the custom assay design and development. All authors contributed towards the preparation of the manuscript, and read and approved the final submitted version., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A 79-year-old woman, previously treated for congenital pulmonary valve stenosis through surgical and transcatheter procedures, presented with worsening dyspnea. This led to the identification of valve thrombosis in her bioprosthetic pulmonary valve. This report delves into the clinical importance of obstructive valve thrombosis, its diagnostic assessment, and potential therapeutic strategies. This is the first documented case of valve-in-valve thrombosis involving the transcatheter pulmonary valve., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2025 The Authors.)

Sepsis is a life-threatening disease caused by a dysregulated host response to infection, resulting in 11 million deaths globally each year. Vascular endothelial cell dysfunction results in the loss of endothelial barrier integrity, which contributes to sepsis-induced multiple organ failure and mortality. Erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ephrin ligands play a key role in vascular endothelial barrier disruption but are currently not a therapeutic target in sepsis. Using a cecal ligation and puncture (CLP) mouse model of sepsis, we showed that prophylactic or therapeutic treatment of mice with EphA4-Fc, a decoy receptor and pan-ephrin inhibitor, resulted in improved survival and a reduction in vascular leak, lung injury, and endothelial cell dysfunction. EphA2 -/- mice also exhibited reduced mortality and pathology after CLP compared with wild-type mice. Proteomics of plasma samples from mice with sepsis after CLP revealed dysregulation of a number of Eph/ephrins, including EphA2/ephrin A1. Administration of EphA4-Fc to cultured human endothelial cells pretreated with TNF-α or ephrin-A1 prevented loss of endothelial junction proteins, specifically VE-cadherin, with maintenance of endothelial barrier integrity. In children admitted to hospital with fever and suspected infection, we observed that changes in EphA2/ephrin A1 in serum samples correlated with endothelial and organ dysfunction. Targeting Eph/ephrin signaling may be a potential therapeutic strategy to reduce sepsis-induced endothelial dysfunction and mortality.

Introduction: Previous research has shown that podcasts are most frequently consumed using mobile listening devices across a wide variety of environmental, situational, and social contexts. To date, no studies have investigated how an individual's environmental context might influence their attentional engagement in podcast listening experiences. Improving understanding of the contexts in which episodes of listening take place, and how they might affect listener engagement, could be highly valuable to researchers and producers working in the fields of object-based and personalized media., Methods: An online questionnaire on listening habits and behaviors was distributed to a sample of 264 podcast listeners. An exploratory factor analysis was run to identify factors of environmental context that influence attentional engagement in podcast listening experiences. Five aspects of podcast listening engagement were also defined and measured across the sample., Results: The exploratory factor analysis revealed five factors of environmental context labeled as: outdoors, indoors & at home, evenings, soundscape & at work, and exercise. The aspects of podcast listening engagement provided a comprehensive quantitative account of contemporary podcast listening experiences., Discussion: The results presented support the hypothesis that elements of a listener's environmental context can influence their attentional engagement in podcast listening experiences. The soundscape & at work factor suggests that some listeners actively choose to consume podcasts to mask disturbing stimuli in their surrounding soundscape. Further analysis suggested that the proposed factors of environmental context were positively correlated with the measured aspects of podcast listening engagement. The results are highly pertinent to the fields of podcast studies, mobile listening experiences, and personalized media, and provide a basis for researchers seeking to explore how other forms of listening context might influence attentional engagement., Competing Interests: The accompanying PhD project, which this study will form part of, is in partnership with BBC R&D. JF and CP were formerly employed by BBC R&D, and are now employed by Bang & Olufsen and SONOS, respectively. AA-B is employed by BBC Research and Development, London. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Harrison, Archer-Boyd, Francombe, Pike and Murphy.)

The spectro-temporal ripple for investigating processor effectiveness (STRIPES) test is a psychophysical measure of spectro-temporal resolution in cochlear-implant (CI) listeners. It has been validated using direct-line input and loudspeaker presentation with listeners of the Advanced Bionics CI. This article investigates the suitability of an online application using wireless streaming (webSTRIPES) as a remote test. It reports a strong across-listener correlation between STRIPES thresholds obtained using laboratory testing with loudspeaker presentation vs remote testing with streaming presentation, with no significant difference in STRIPES thresholds between the two measures. WebSTRIPES also produced comparable and robust thresholds with users of the Cochlear CI.

Motor neuron disease (MND) comprises a group of fatal neurodegenerative diseases with no effective cure. As progressive motor neuron cell death is one of pathological characteristics of MND, molecules which protect these cells are attractive therapeutic targets. Accumulating evidence indicates that EphA4 activation is involved in MND pathogenesis, and inhibition of EphA4 improves functional outcomes. However, the underlying mechanism of EphA4's function in MND is unclear. In this review, we first present results to demonstrate that EphA4 signalling acts directly on motor neurons to cause cell death. We then review the three most likely mechanisms underlying this effect.

We recently characterised the NUP98-HOXD13 ( NHD13 ) mouse as a model of T-cell pre-leukaemia, featuring thymocytes that can engraft in recipient animals and progress to T-cell acute lymphoblastic leukaemia (T-ALL). However, loss of this engraftment ability by deletion of Lyl1 did not result in any loss of leukemogenesis activity. In the present study, we observe that NHD13 thymocytes overexpress EPHA3, and we characterise thymocyte behaviour in NHD13 mice with deletion of EphA3 , which show a markedly reduced incidence of T-ALL. Deletion of EphA3 from the NHD13 mice does not prevent the abnormal accumulation or transplantation ability of these thymocytes. However, upon transplantation, these cells are unable to block the normal progression of recipient wild type (WT) progenitor cells through the normal developmental pathway. This is in contrast to the EphA3 +/+   NHD13 thymocytes, which block the progression of incoming WT progenitors past the DN1 stage. Therefore, EphA3 is not critical for classical self-renewal, but is essential for mediating an interaction between the abnormally self-renewing cells and healthy progenitors-an interaction that results in a failure of the healthy cells to differentiate normally. We speculate that this may orchestrate a loss of healthy cell competition, which in itself has been demonstrated to be oncogenic, and that this may explain the decrease in T-ALL incidence in the absence of EphA3 . We suggest that pre-leukaemic self-renewal in this model is a complex interplay of cell-intrinsic and -extrinsic factors, and that multiple redundant pathways to leukaemogenesis are active.

We simulated the effect of several automatic gain control (AGC) and AGC-like systems and head movement on the output levels, and resulting interaural level differences (ILDs) produced by bilateral cochlear-implant (CI) processors. The simulated AGC systems included unlinked AGCs with a range of parameter settings, linked AGCs, and two proprietary multi-channel systems used in contemporary CIs. The results show that over the range of values used clinically, the parameters that most strongly affect dynamic ILDs are the release time and compression ratio. Linking AGCs preserves ILDs at the expense of monaural level changes and, possibly, comfortable listening level. Multichannel AGCs can whiten output spectra, and/or distort the dynamic changes in ILD that occur during and after head movement. We propose that an unlinked compressor with a ratio of approximately 3:1 and a release time of 300-500 ms can preserve the shape of dynamic ILDs, without causing large spectral distortions or sacrificing listening comfort.

Cochlear implants (CIs) are neuroprostheses that partially restore hearing for people with severe-to-profound hearing loss. While CIs can provide good speech perception in quiet listening situations for many, they fail to do so in environments with interfering sounds for most listeners. Previous research suggests that this is due to detrimental interaction effects between CI electrode channels, limiting their function to convey frequency-specific information, but evidence is still scarce. In this study, an experimental manipulation called spectral blurring was used to increase channel interaction in CI listeners using Advanced Bionics devices with HiFocus 1J and MS electrode arrays to directly investigate its causal effect on speech perception. Instead of using a single electrode per channel as in standard CI processing, spectral blurring used up to 6 electrodes per channel simultaneously to increase the overlap between adjacent frequency channels as would occur in cases with severe channel interaction. Results demonstrated that this manipulation significantly degraded CI speech perception in quiet by 15% and speech reception thresholds in babble noise by 5 dB when all channels were blurred by a factor of 6. Importantly, when channel interaction was increased just on a subset of electrodes, speech scores were mostly unaffected and were only significantly degraded when the 5 most apical channels were blurred. These apical channels convey information up to 1 kHz at the apical end of the electrode array and are typically located at angular insertion depths of about 250 up to 500°. These results confirm and extend earlier findings indicating that CI speech perception may not benefit from deactivating individual channels along the array and that efforts should instead be directed towards reducing channel interaction per se and in particular for the most-apical electrodes. Hereby, causal methods such as spectral blurring could be used in future research to control channel interaction effects within listeners for evaluating compensation strategies.

Increasing accumulation and retention of nanomedicines within tumor tissue is a significant challenge, particularly in the case of brain tumors where access to the tumor through the vasculature is restricted by the blood-brain barrier (BBB). This makes the application of nanomedicines in neuro-oncology often considered unfeasible, with efficacy limited to regions of significant disease progression and compromised BBB. However, little is understood about how the evolving tumor-brain physiology during disease progression affects the permeability and retention of designer nanomedicines. We report here the development of a modular nanomedicine platform that, when used in conjunction with a unique model of how tumorigenesis affects BBB integrity, allows investigation of how nanomaterial properties affect uptake and retention in brain tissue. By combining different in vivo longitudinal imaging techniques (including positron emission tomography and magnetic resonance imaging), we have evaluated the retention of nanomedicines with predefined physicochemical properties (size and surface functionality) and established a relationship between structure and tissue accumulation as a function of a new parameter that measures BBB leakiness; this offers significant advancements in our ability to relate tumor accumulation of nanomedicines to more physiologically relevant parameters. Our data show that accumulation of nanomedicines in brain tumor tissue is better correlated with the leakiness of the BBB than actual tumor volume . This was evaluated by establishing brain tumors using a spontaneous and endogenously derived glioblastoma model providing a unique opportunity to assess these parameters individually and compare the results across multiple mice. We also quantitatively demonstrate that smaller nanomedicines (20 nm) can indeed cross the BBB and accumulate in tumors at earlier stages of the disease than larger analogues, therefore opening the possibility of developing patient-specific nanoparticle treatment interventions in earlier stages of the disease. Importantly, these results provide a more predictive approach for designing efficacious personalized nanomedicines based on a particular patient's condition., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

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.

Background: Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair., Methods: In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships., Results: Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell-like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action., Conclusion: Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Glioblastoma (GBM) is a treatment-refractory central nervous system (CNS) tumour, and better therapies to treat this aggressive disease are urgently needed. Primary GBM models that represent the true disease state are essential to better understand disease biology and for accurate preclinical therapy assessment. We have previously presented a comprehensive transcriptome characterisation of a panel (n = 12) of primary GBM models (Q-Cell). We have now generated a systematic, quantitative, and deep proteome abundance atlas of the Q-Cell models grown in 3D culture, representing 6167 human proteins. A recent study has highlighted the degree of functional heterogeneity that coexists within individual GBM tumours, describing four cellular states (MES-like, NPC-like, OPC-like and AC-like). We performed comparative proteomic analysis, confirming a good representation of each of the four cell-states across the 13 models examined. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified upregulation of a number of GBM-associated cancer pathway proteins. Bioinformatics analysis, using the OncoKB database, identified a number of functional actionable targets that were either uniquely or ubiquitously expressed across the panel. This study provides an in-depth proteomic analysis of the GBM Q-Cell resource, which should prove a valuable functional dataset for future biological and preclinical investigations., Competing Interests: Authors declare no conflict of interest.

The STRIPES (Spectro-Temporal Ripple for Investigating Processor EffectivenesS) test is a psychophysical test of spectro-temporal resolution developed for cochlear-implant (CI) listeners. Previously, the test has been strictly controlled to minimize the introduction of extraneous, nonspectro-temporal cues. Here, the effect of relaxing many of those controls was investigated to ascertain the generalizability of the STRIPES test. Preemphasis compensation was removed from the STRIPES stimuli, the test was presented over a loudspeaker at a level similar to conversational speech and above the automatic gain control threshold of the CI processor, and listeners were tested using the everyday setting of their clinical devices. There was no significant difference in STRIPES thresholds measured across conditions for the 10 CI listeners tested. One listener obtained higher (better) thresholds when listening with their clinical processor. An analysis of longitudinal results showed excellent test-retest reliability of STRIPES over multiple listening sessions with similar conditions. Overall, the results show that the STRIPES test is robust to extraneous cues, and that thresholds are reliable over time. It is sufficiently robust for use with different processing strategies, free-field presentation, and in nonresearch settings.

Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the perivascular niche. Glycosylated αDG is highly expressed and functional on the most aggressive mesenchymal-like (MES-like) GBM tumour compartment. Furthermore, we found that DG acts to maintain an MES-like state via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation in MES-like GBM, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor, not only as a structural element, but also as a critical factor promoting MES-like GBM and the maintenance of GSCs residing in the perivascular niche.

The hippocampal dentate gyrus (DG) is a major region of the adult rodent brain in which neurogenesis occurs throughout life. The EphA4 receptor, which regulates neurogenesis and boundary formation in the developing brain, is also expressed in the adult DG, but whether it regulates adult hippocampal neurogenesis is not known. Here, we show that, in the adult mouse brain, EphA4 inhibits hippocampal precursor cell proliferation but does not affect precursor differentiation or survival. Genetic deletion or pharmacological inhibition of EphA4 significantly increased hippocampal precursor proliferation in vivo and in vitro, by blocking EphA4 forward signaling. EphA4 was expressed by mature hippocampal DG neurons but not neural precursor cells, and an EphA4 antagonist, EphA4-Fc, did not activate clonal cultures of precursors until they were co-cultured with non-precursor cells, indicating an indirect effect of EphA4 on the regulation of precursor activity. Supplementation with d-serine blocked the increased precursor proliferation induced by EphA4 inhibition, whereas blocking the interaction between d-serine and N-methyl-d-aspartate receptors (NMDARs) promoted precursor activity, even at the clonal level. Collectively, these findings demonstrate that EphA4 indirectly regulates adult hippocampal precursor proliferation and thus plays a role in neurogenesis via d-serine-regulated NMDAR signaling., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The role of astrocytes is becoming increasingly important to understanding how glioblastoma (GBM) tumor cells diffusely invade the brain. Yet, little is known of the contribution of extracellular vesicle (EV) signaling in GBM/astrocyte interactions. We modeled GBM-EV signaling to normal astrocytes in vitro to assess whether this mode of intercellular communication could support GBM progression. EVs were isolated and characterized from three patient-derived GBM stem cells (NES + /CD133 + ) and their differentiated (diff) progeny cells (NES - /CD133 - ). Uptake of GBM-EVs by normal primary astrocytes was confirmed by fluorescence microscopy, and changes in astrocyte podosome formation and gelatin degradation were measured. Quantitative mass spectrometry-based proteomics was performed on GBM-EV stimulated astrocytes. Interaction networks were generated from common, differentially abundant proteins using Ingenuity® (Qiagen Bioinformatics) and predicted upstream regulators were tested by qPCR assays. Podosome formation and Cy3-gelatin degradation were induced in astrocytes following 24-h exposure to GBM-stem and -diff EVs, with EVs released by GBM-stem cells eliciting a greater effect. More than 1700 proteins were quantified, and bioinformatics predicted activations of MYC, NFE2L2, FN1, and TGFβ1 and inhibition of TP53 in GBM-EV stimulated astrocytes that were then confirmed by qPCR. Further qPCR studies identified significantly decreased Δ133p53 and increased p53β in astrocytes exposed to GBM-EVs that might indicate the acquisition of a pro-inflammatory, tumor-promoting senescence-associated secretory phenotype (SASP). Inhibition of TP53 and activation of MYC signaling pathways in normal astrocytes exposed to GBM-EVs may be a mechanism by which GBM manipulates astrocytes to acquire a phenotype that promotes tumor progression.

Low-passage, serum-free cell lines cultured from patient tumour tissue are the gold-standard for preclinical studies and cellular investigations of glioblastoma (GBM) biology, yet entrenched, poorly-representative cell line models are still widely used, compromising the significance of much GBM research. We submit that greater adoption of these critical resources will be promoted by the provision of a suitably-sized, meaningfully-described reference collection along with appropriate tools for working with them. Consequently, we present a curated panel of 12 readily-usable, genetically-diverse, tumourigenic, patient-derived, low-passage, serum-free cell lines representing the spectrum of molecular subtypes of IDH-wildtype GBM along with their detailed phenotypic characterisation plus a bespoke set of lentiviral plasmids for bioluminescent/fluorescent labelling, gene expression and CRISPR/Cas9-mediated gene inactivation. The cell lines and all accompanying data are readily-accessible via a single website, Q-Cell (qimrberghofer.edu.au/q-cell/) and all plasmids are available from Addgene. These resources should prove valuable to investigators seeking readily-usable, well-characterised, clinically-relevant, gold-standard models of GBM.

This study simulated the effect of unlinked automatic gain control (AGC) and head movement on the output levels and resulting inter-aural level differences (ILDs) produced by bilateral cochlear implant (CI) processors. The angular extent and velocity of the head movements were varied in order to observe the interaction between unlinked AGC and head movement. Static, broadband input ILDs were greatly reduced by the high-ratio, slow-time-constant AGC used. The size of head-movement-induced dynamic ILDs depended more on the velocity and angular extent of the head movement than on the angular position of the source. The profiles of the dynamic, broadband output ILDs were very different from the dynamic, broadband input ILD profiles. Short-duration, high-velocity head movements resulted in dynamic output ILDs that continued to change after head movement had stopped. Analysis of narrowband, single-channel ILDs showed that static output ILDs were reduced across all frequencies, producing low-frequency ILDs of the opposite sign to the high-frequency ILDs. During head movements, low- and high-frequency ILDs also changed with opposite sign. The results showed that the ILDs presented to bilateral CI listeners during head turns were highly distorted by the interaction of the bilateral, unlinked AGC and the level changes induced by head movement.

The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies.

Psychophysical tests of spectro-temporal resolution may aid the evaluation of methods for improving hearing by cochlear implant (CI) listeners. Here the STRIPES (Spectro-Temporal Ripple for Investigating Processor EffectivenesS) test is described and validated. Like speech, the test requires both spectral and temporal processing to perform well. Listeners discriminate between complexes of sine sweeps which increase or decrease in frequency; difficulty is controlled by changing the stimulus spectro-temporal density. Care was taken to minimize extraneous cues, forcing listeners to perform the task only on the direction of the sweeps. Vocoder simulations with normal hearing listeners showed that the STRIPES test was sensitive to the number of channels and temporal information fidelity. An evaluation with CI listeners compared a standard processing strategy with one having very wide filters, thereby spectrally blurring the stimulus. Psychometric functions were monotonic for both strategies and five of six participants performed better with the standard strategy. An adaptive procedure revealed significant differences, all in favour of the standard strategy, at the individual listener level for six of eight CI listeners. Subsequent measures validated a faster version of the test, and showed that STRIPES could be performed by recently implanted listeners having no experience of psychophysical testing.

Amyotrophic lateral sclerosis (ALS) is an untreatable, progressive, neurodegenerative disease specifically affecting motor neurons. Recently, the tyrosine kinase receptor EphA4 was directly implicated in ALS disease progression. We report that a long-lived mutated form of the EphA4 antagonist EphA4-Fc (mutEphA4-Fc), which blocks EphA4 binding to its ligands and inhibits its function, significantly improved functional performance in SOD1 G93A ALS model mice, as assessed by rotarod and hind-limb grip strength tests. Further, heterozygous motor neuron-specific EphA4 gene deletion in SOD1 G93A mice promoted significant improvement in functional performance during the disease course and a delay in disease onset relative to control mice. Importantly, mice in the heterozygous deletion group showed significantly improved survival of motor neurons and architecture of endplates of neuromuscular junctions compared with control and homozygous EphA4-deletion groups. Our novel results show that EphA4 signalling directly regulates motor neuron survival and that mutEphA4-Fc is a promising therapeutic candidate to slow disease progression in ALS.

The signal-to-noise ratio (SNR) benefit of hearing aid directional microphones is dependent on the angle of the listener relative to the target, something that can change drastically and dynamically in a typical group conversation. When a new target signal is significantly off-axis, directional microphones lead to slower target orientation, more complex movements, and more reversals. This raises the question of whether there is an optimal design for directional microphones. In principle an ideal microphone would provide the user with sufficient directionality to help with speech understanding, but not attenuate off-axis signals so strongly that orienting to new signals was difficult or impossible. We investigated the latter part of this question. In order to measure the minimal monitoring SNR for reliable orientation to off-axis signals, we measured head-orienting behaviour towards targets of varying SNRs and locations for listeners with mild to moderate bilateral symmetrical hearing loss. Listeners were required to turn and face a female talker in background noise and movements were tracked using a head-mounted crown and infrared system that recorded yaw in a ring of loudspeakers. The target appeared randomly at ± 45, 90 or 135° from the start point. The results showed that as the target SNR decreased from 0 dB to -18 dB, first movement duration and initial misorientation count increased, then fixation error, and finally reversals increased. Increasing the target angle increased movement duration at all SNRs, decreased reversals (above -12 dB target SNR), and had little to no effect on initial misorientations. These results suggest that listeners experience some difficulty orienting towards sources as the target SNR drops below -6 dB, and that if one intends to make a directional microphone that is usable in a moving conversation, then off-axis attenuation should be no more than 12 dB., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The use of monoclonal antibodies (mAbs) and molecules derived from them has achieved considerable attention and success in recent years, establishing this mode of therapy as an important therapeutic strategy in many cancers, in particular hematological tumors. mAbs recognize cell surface antigens expressed on target cells and mediate their function through various mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, or immune system modulation. The efficacy of mAb therapy can be improved when they are conjugated to a highly potent payloads, including cytotoxic drugs and radiolabeled isotopes. The Eph family of proteins has received considerable attention in recent years as therapeutic targets for treatment of both solid and hematological cancers. High expression of Eph receptors on cancer cells compared with low expression levels in normal adult tissues makes them an attractive candidate for cancer immunotherapy. In this review, we detail the modes of action of antibody-based therapies with a focus on the Eph family of proteins as potential targets for therapy in hematological malignancies., (Copyright © 2017 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)