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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
Supplementary Figure 1 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Figure 1 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Figure 2 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Figure 2 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Table 1 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Table 1 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Figure 4 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Figure 4 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Data from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
<div>Abstract<p>Glioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem–like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although <i>ICP6</i> (<i>UL39</i>)–deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of <i>γ34.5</i> significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of <i>α47</i>. Infection with oHSV G47Δ (<i>ICP6<sup>−</sup>, γ34.5<sup>−</sup>, α47<sup>−</sup></i>) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of G47Δ significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis. [Cancer Res 2009;69(8):3472–81]</p></div>
Supplementary Figure 3 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Figure 3 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Figure 4 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Figure 4 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Cancer vaccine trial evaluations: immunobridging and potential immunological endpoints.
Therapeutic cancer vaccines are an emerging class of immunotherapy, but challenges remain in effectively adapting approved vaccines to a growing number of adjuvants, combination therapies, and antigen-selection methods. Phase III clinical trials remain the gold standard in determining clinical benefit, but are slow and resource intensive, whilst radiological surrogates often fail to reliably predict clinical benefit. Using immunological surrogates of efficacy, deployed in 'immunobridging trials', could present a viable alternative, safely speeding up cancer vaccine development in a cost-effective manner. Whilst this approach has proven successful in infectious disease vaccines, identifying reliable immunological correlates of protection has proven difficult for cancer vaccines. Most clinical trials, which present the richest source of data to establish a correlate, rely on peripheral blood samples and standard immunoassays that are ill-equipped to capture the complexity of the vaccine-induced anti-tumour response. This review is the first to outline the importance and challenges of establishing immunological surrogates for cancer vaccines in the context of immunobridging trials, evaluating current immunoassay methods, and highlighting the need for techniques that can characterize tumour-infiltrating lymphocytes and the suppressive tumour microenvironment across a range of patients. The authors propose adapting trial designs for surrogate discovery, including combining phase I/II trials and the use of multi-omics approaches. Successful immunological surrogate development could enable future immunobridging trials to accelerate the optimization of approved cancer vaccines without requiring new phase III trials, promoting faster clinical implementation of scientific advances and patient benefits.
A Novel Primary Cell Line Model of Localized Prostate Cancer and Radioresistance—A Role for Nicotinamide N-Methyltransferase
Prostate cancer cell lines are particularly clinically homogenous, mostly representing metastatic states rather than localized disease. While there has been significant work in the development of additional models, few have been created without oncogenic transformation. We derived a primary prostate cancer cell line from a patient with localized Gleason 7 prostate cancer—designated CaB34—which spontaneously immortalized. We leveraged CaB34 to generate a paired radioresistant subline, CaB34-CF, using a clinically relevant fractionated radiotherapy schedule. These two paired cell lines were investigated extensively to determine their molecular characteristics and therapy responses. Both CaB34 and CaB34-CF express prostate-specific markers, including KRT18, NKX3.1, and AMACR. Multi-omic analyses using RNAseq and shotgun proteomics identified NNMT as the most significantly dysregulated component in CaB34-CF. A bioinformatic analysis determined that NNMT was more abundant within prostate tumors compared to benign prostate, suggesting a role in tumor progression. Knockdown studies of NNMT demonstrated significant radiosensitization of CaB34-CF cells, which was largely a result of increased radiation-induced cellular senescence. Growth as 3D organoids was significantly higher in the CaB34-CF line, and demonstrated a less structured pattern of expression of cytokeratin markers. Radiosensitization with NNMT siRNA was recapitulated in a 3D organoid clonogenic assay in CaB34-CF cells. Our research provides a paired primary model of treatment-naïve and radioresistant disease to address mechanisms of therapy resistance, while expanding the repertoire of localized prostate cancer cell lines for the research community. In addition, our findings present NNMT as a potential therapeutic target for sensitization of radioresistant disease.
Muscarinic receptors mediate motivation via preparatory neural activity in humans.
Motivation depends on dopamine, but might be modulated by acetylcholine which influences dopamine release in the striatum, and amplifies motivation in animal studies. A corresponding effect in humans would be important clinically, since anticholinergic drugs are frequently used in Parkinson's disease, a condition that can also disrupt motivation. Reward and dopamine make us more ready to respond, as indexed by reaction times (RT), and move faster, sometimes termed vigour. These effects may be controlled by preparatory processes that can be tracked using electroencephalography (EEG). We measured vigour in a placebo-controlled, double-blinded study of trihexyphenidyl (THP), a muscarinic antagonist, with an incentivised eye movement task and EEG. Participants responded faster and with greater vigour when incentives were high, but THP blunted these motivational effects, suggesting that muscarinic receptors facilitate invigoration by reward. Preparatory EEG build-up (contingent negative variation [CNV]) was strengthened by high incentives and by muscarinic blockade, although THP reduced the incentive effect. The amplitude of preparatory activity predicted both vigour and RT, although over distinct scalp regions; frontal activity predicted vigour, whereas a larger, earlier, central component predicted RT. The incentivisation of RT was partly mediated by the CNV, though vigour was not. Moreover, the CNV mediated the drug's effect on dampening incentives, suggesting that muscarinic receptors underlie the motivational influence on this preparatory activity. Taken together, these findings show that a muscarinic blocker impairs motivated action in healthy people, and that medial frontal preparatory neural activity mediates this for RT.
Neurosurgery
The nervous system is the principal means with which we negotiate the outside world. Injury to the nervous system (brain, spinal cord and nerves) therefore may result not simply in physical impairments, but psychological, social and economic impairments too. Legal proceedings therefore may focus upon the effect of medical errors on claimants’ psychological, economic or social capacities, not simply on physical harm. The role of neurosurgery in many disorders of the nervous system concerns prevention of secondary injury: despite the sophistication of modern medicine, damage to the nervous system caused by a primary event (for example, head injury, spontaneous bleed, acutely prolapsed disc) is often irreversible and may set a spiral of deterioration in motion that may be beyond the abilities of physicians to halt.The scope of this chapter is to describe current management strategies of nervous system disorders in which a neurosurgeon would be reasonably expected to play a lead role, although not necessarily an exclusive role. Neurosurgery is a ‘tertiary service’ in the NHS, meaning a patient may have been managed by another hospital-based specialist, or even pre-hospital specialist, prior to transfer to the care of a neurosurgeon. Neurosurgeons may therefore become involved in complaints arising from problems with delayed diagnosis or timely transfer to neurosurgical care, in addition to surgical and post-surgical care.