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We have studied the magnetization dynamics of single Py( t ) ( t = 20 nm, 50 nm) and trilayer [Py(50)/Pd( t Pd )/Py(20)] nanowire arrays fabricated over large areas using deep ultraviolet lithography technique. The dynamic properties are sensitive to the field orientation and magnetic film thicknesses. A single resonant mode corresponding to the excitations at the bulk part of the wire is detected in all the single-layer nanowire arrays. Furthermore, the spacer layer thickness influenced the dynamic properties in trilayer samples due to the different coupling mechanisms. A single resonant mode is observed in t Pd = 2 nm trilayer nanowires with a sharp frequency jump from 13 GHz to 15 GHz across the reversal regime. This indicates the exchange coupling and the coherence in magnetization precession in the ferromagnetic layers. On the other hand, wires with 10 nm-spacer display two well-resolved modes separated by ∼3 GHz with a gradual change in frequency across the reversal regime from-26mT to-46mT, indicating the presence of long-range dipolar interactions instead of exchange coupling. The spacer layer of the proposed spin-valve-type structure can be tailored for desired microwave splitters or combiners., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Artificial spin ice structures which are networks of coupled nanomagnets arranged on different lattices that exhibit a number of interesting phenomena are promising for future information processing. We report reconfigurable microwave properties in artificial spin ice structures with three different lattice symmetries namely square, kagome, and triangle. Magnetization dynamics are systematically investigated using field angle dependent ferromagnetic resonance spectroscopy. Two distinct ferromagnetic resonance modes are observed in square spin ice structures in contrast with the three well-separated modes in kagome and triangular spin ice structures that are spatially localized at the center of the individual nanomagnets. A simple rotation of the sample placed in magnetic field results in the merging and splitting of the modes due to the different orientations of the nanomagnets with respect to the applied magnetic field. Magnetostatic interactions are found to shift the mode positions after comparing the microwave responses from the array of nanomagnets with control simulations with isolated nanomagnets. Moreover, the extent of the mode splitting has been studied by varying the thickness of the lattice structures. The results have potential implications for microwave filter-type applications which can be operated for a wide range of frequencies with ease of tunability., (© 2023 IOP Publishing Ltd.)

Magnetic skyrmions are topologically protected spin textures and they are suitable for future logic-in-memory applications for energy-efficient, high-speed information processing and computing technologies. In this work, we have demonstrated skyrmion-based 3 bit majority logic gate using micromagnetic simulations. The skyrmion motion is controlled by introducing a gate that works on voltage controlled magnetic anisotropy. Here, the inhomogeneous magnetic anisotropy behaves as a tunable potential barrier/well that modulates the skyrmion trajectory in the structure for the successful implementation of the majority logic gate. In addition, several other effects such as skyrmion-skyrmion topological repulsion, skyrmion-edge repulsion, spin-orbit torque and skyrmion Hall effect have been shown to govern the logic functionalities. We have systematically presented the robust logic operations by varying the current density, magnetic anisotropy, voltage-controlled gate dimension and geometrical parameters of the logic device. The skyrmion Hall angle is monitored to understand the trajectory and stability of the skyrmion as a function of time in the logic device. The results demonstrate a novel method to achieve majority logic by using voltage controlled magnetic anisotropy which further opens up a new route for skyrmion-based low-power and high-speed computing devices., (© 2023 IOP Publishing Ltd.)

In this study, we introduce the area efficient low complex runtime reconfigurable architecture design methodology based on Skyrmion logic for universal logic gate (ULG) i.e. NOR/NAND implementation using micromagnetic simulations. We have modelled the two input 3D device structure using bilayer ferromagnet/heavy metal where the magnetic tunnel junctions inject and detect the input and output skyrmions by exploiting the input reversal mechanism. The implementation of NOR and NAND is performed using this same device where it is reconfigured runtime with enhanced tunability by the ON and OFF state of current passing through a non magnetic metallic gate respectively. This gate acts as a barrier for skyrmion motion (additional control mechanism) to realize the required Skyrmion logic output states. To the best of authors's knowledge the boolean optimizations and the mapping logic have been presented for the first time to demonstrate the functionalities of the NOR/NAND implementation. This proposed architecture design methodology of ULG leads to reduced device footprint with regard to the number of thin film structures proposed, low complexity in terms of fabrication and also providing runtime reconfigurability to reduce the number of physical designs to achieve all truth table entries (∼75% device footprint reduction). The proposed 3D ULG architecture design benefits from the miniaturization resulting in opening up a new perspective for magneto-logic devices., (© 2023 IOP Publishing Ltd.)

Background: Supratentorial RELA fusion (ST-RELA) ependymomas (EPNs) are resistant tumors without an approved chemotherapeutic treatment. Unfortunately, the molecular mechanisms that lead to chemoresistance traits of ST-RELA remain elusive. The aim of this study was to assess RELA fusion-dependent signaling modules, specifically the role of the Hedgehog (Hh) pathway as a novel targetable vulnerability in ST-RELA., Methods: Gene expression was analyzed in EPN from patient cohorts, by microarray, RNA-seq, qRT-PCR, and scRNA-seq. Inhibitors against Smoothened (SMO) (Sonidegib) and Aurora kinase A (AURKA) (Alisertib) were evaluated. Protein expression, primary cilia formation, and drug effects were assessed by immunoblot, immunofluorescence, and immunohistochemistry., Results: Hh components were selectively overexpressed in EPNs induced by the RELA fusion. Single-cell analysis showed that the Hh signature was primarily confined to undifferentiated, stem-like cell subpopulations. Sonidegib exhibited potent growth-inhibitory effects on ST-RELA cells, suggesting a key role in active Hh signaling; importantly, the effect of Sonidegib was reversed by primary cilia loss. We, thus, tested the effect of AURKA inhibition by Alisertib, to induce cilia stabilization/reassembly. Strikingly, Alisertib rescued ciliogenesis and synergized with Sonidegib in killing ST-RELA cells. Using a xenograft model, we show that cilia loss is a mechanism for acquiring resistance to the inhibitory effect of Sonidegib. However, Alisertib fails to rescue cilia and highlights the need for other strategies to promote cilia reassembly, for treating ST-RELA tumors., Conclusion: Our study reveals a crucial role for the Hh pathway in ST-RELA tumor growth, and suggests that rescue of primary cilia represents a vulnerability of the ST-RELA EPNs., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Medulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies investigating the immune microenvironment of the disease and the impact of current therapies are limited. Preclinical models that recapitulate both the disease and immune environment are essential for understanding immune-tumor interactions and to aid the identification of new and effective immunotherapies. Using an immune-competent mouse model of aggressive Myc -driven medulloblastoma, we characterized the brain immune microenvironment and changes induced in response to craniospinal irradiation, or the medulloblastoma chemotherapies cyclophosphamide or gemcitabine. The role of adaptive immunity in disease progression and treatment response was delineated by comparing survival outcomes in wildtype C57Bl/6J and in mice deficient in Rag1 that lack mature T and B cells. We found medulloblastomas in wildtype and Rag1 -deficient mice grew equally fast, and that craniospinal irradiation and chemotherapies extended survival equally in wildtype and Rag1 -deficient mice, suggesting that tumor growth and treatment response is independent of T and B cells. Medulloblastomas were myeloid dominant, and in wildtype mice, craniospinal irradiation and cyclophosphamide depleted T and B cells in the brain. Gemcitabine treatment was found to minimally alter the immune populations in the brain, resulting only in a depletion of neutrophils. Intratumorally, we observed an abundance of Iba1 + macrophages, and we show that CD45 high cells comprise the majority of immune cells within these medulloblastomas but found that existing markers are insufficient to clearly delineate resident microglia from infiltrating macrophages. Ultimately, brain resident and peripheral macrophages dominate the brain and tumor microenvironment and are not depleted by standard-of-care medulloblastoma therapies. These populations therefore present a favorable target for immunotherapy in combination with front-line treatments., Competing Interests: The 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 © 2022 Abbas, George, Ancliffe, Howlett, Jones, Kuchibhotla, Wechsler-Reya, Gottardo and Endersby.)

Background: Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects., Methods: We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB., Results: Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB., Conclusions: Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan-Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma., Competing Interests: KM was employed by company Brain Cancer Consultancy. 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 © 2021 Buck, Dyer, Hii, Carline, Kuchibhotla, Byrne, Howlett, Whitehouse, Ebert, McDonald, Gottardo and Endersby.)

Medulloblastoma (MB) consists of four core molecular subgroups with distinct clinical features and prognoses. Treatment consists of surgery, followed by radiotherapy and cytotoxic chemotherapy. Despite this intensive approach, outcome remains dismal for patients with certain subtypes of MB, namely, MYC -amplified Group 3 and TP53 -mutated SHH. Using high-throughput assays, six human MB cell lines were screened against a library of 3208 unique compounds. We identified 45 effective compounds from the screen and found that cell cycle checkpoint kinase (CHK1/2) inhibition synergistically enhanced the cytotoxic activity of clinically used chemotherapeutics cyclophosphamide, cisplatin, and gemcitabine. To identify the best-in-class inhibitor, multiple CHK1/2 inhibitors were assessed in mice bearing intracranial MB. When combined with DNA-damaging chemotherapeutics, CHK1/2 inhibition reduced tumor burden and increased survival of animals with high-risk MB, across multiple different models. In total, we tested 14 different models, representing distinct MB subgroups, and data were validated in three independent laboratories. Pharmacodynamics studies confirmed central nervous system penetration. In mice, combination treatment significantly increased DNA damage and apoptosis compared to chemotherapy alone, and studies with cultured cells showed that CHK inhibition disrupted chemotherapy-induced cell cycle arrest. Our findings indicated CHK1/2 inhibition, specifically with LY2606368 (prexasertib), has strong chemosensitizing activity in MB that warrants further clinical investigation. Moreover, these data demonstrated that we developed a robust and collaborative preclinical assessment platform that can be used to identify potentially effective new therapies for clinical evaluation for pediatric MB., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Children with medulloblastoma and ependymoma are treated with a multidisciplinary approach that incorporates surgery, radiotherapy, and chemotherapy; however, overall survival rates for patients with high-risk disease remain unsatisfactory. Data indicate that plant-derived cannabinoids are effective against adult glioblastoma; however, preclinical evidence supporting their use in pediatric brain cancers is lacking. Here we investigated the potential role for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in medulloblastoma and ependymoma. Dose-dependent cytotoxicity of medulloblastoma and ependymoma cells was induced by THC and CBD in vitro, and a synergistic reduction in viability was observed when both drugs were combined. Mechanistically, cannabinoids induced cell cycle arrest, in part by the production of reactive oxygen species, autophagy, and apoptosis; however, this did not translate to increased survival in orthotopic transplant models despite being well tolerated. We also tested the combination of cannabinoids with the medulloblastoma drug cyclophosphamide, and despite some in vitro synergism, no survival advantage was observed in vivo. Consequently, clinical benefit from the use of cannabinoids in the treatment of high-grade medulloblastoma and ependymoma is expected to be limited. This study emphasizes the importance of preclinical models in validating therapeutic agent efficacy prior to clinical trials, ensuring that enrolled patients are afforded the most promising therapies available.

Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K/AKT and Ras/Raf/MEK/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA , upregulation of PDGFRA and AKT2 , inactivating mutations in NF1 , and a gain-of-function mutation in PTPN11 . Additionally, deletion of CDKN2A/B , increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phosphorylated S6, 4EBP1 and ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease.

Background: Although epidermal growth factor receptor (EGFR) and its truncated, autoactive mutant EGFR variant (v)III are bona fide drivers of tumorigenesis in some gliomas, therapeutic antibodies developed to neutralize this axis have not improved patient survival in a limited number of trials. Previous studies using cells transduced to exogenously express EGFRvIII may have compromised mechanistic studies of anti-EGFR therapeutics. Therefore, we re-assessed the activity of clinical EGFR antibodies in patient-derived gliomaspheres that endogenously express EGFRvIII., Methods: The antitumor efficacy of antibodies was assessed using in vitro proliferation assays and intracranial orthografts. Receptor activation status, antibody engagement, oncogenic signaling, and mechanism of action after antibody treatment were analyzed by immunoprecipitation and western blotting. Tracking of antibody receptor complexes was conducted using immunofluorescence., Results: The EGFR domain III-targeting antibodies cetuximab, necitumumab, nimotuzumab, and matuzumab did not neutralize EGFRvIII activation. Chimeric monoclonal antibody 806 (ch806) neutralized EGFRvIII, but not wild-type (wt)EGFR activation. Panitumumab was the only antibody that neutralized both EGFRvIII and wtEGFR, leading to reduction of p-S6 signaling and superior in vitro and in vivo antitumor activity. Mechanistically, panitumumab induced recycling of receptor but not degradation as previously described. Panitumumab, via its unique avidity, stably cross-linked EGFRvIII to prevent its activation, while ch806 induced a marked reduction in the active EGFRvIII disulphide-bonded dimer., Conclusions: We discovered a previously unknown major resistance mechanism in glioma in that most EGFR domain III-targeting antibodies do not neutralize EGFRvIII. The superior in vitro and in vivo antitumor activity of panitumumab supports further clinical testing of this antibody against EGFRvIII-stratified glioma., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Platelets play a vital role in hemostasis and inflammation. The membrane receptor TREM-like transcript-1 (TLT-1) is involved in platelet aggregation, bleeding, and inflammation, and it is localized in the α-granules of platelets. Upon platelet activation, TLT-1 is released from α-granules both in its transmembrane form and as a soluble fragment (sTLT-1). Higher levels of sTLT-1 have been detected in the plasma of patients with acute inflammation or sepsis, suggesting an important role for TLT-1 during inflammation. However, the roles of TLT-1 in hemostasis and inflammation are not well understood. We are developing the mouse model of TLT-1 to mechanistically test clinical associations of TLT-1 in health and disease. To facilitate our studies, monoclonal murine TLT-1 (mTLT-1) antibodies were produced by the immunization of a rabbit using the negatively charged region of the mTLT-1 extracellular domain 122 PPVPGPREGEEAEDEK 139 . In the present study, we demonstrate that two selected clones, 4.6 and 4.8, are suitable for the detection of mTLT-1 by western blot, immunoprecipitation, immunofluorescent staining, flow cytometry and inhibit platelet aggregation in aggregometry assays. In addition, we found that the topical administration of clone 4.8 delayed the wound healing process in an experimental burn model. These results suggest that TLT-1 plays an important role in wound healing and because both clones specifically detect mTLT-1, they are suitable to further develop TLT-1 based models of inflammation and hemostasis in vivo.