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3.  The Ataxia Telangiectasia Mutated Kinase pathway Regulates IL-23 Expression by Human Dendritic Cells 
Little is known of the regulation of interleukin-23 secretion in dendritic cells (DC) despite its importance for human Th17 responses. Here we show for first time that the Ataxia Telangiectasia Mutated (ATM) pathway, involved in DNA-damage-sensing, acts as an IL-23 repressor. Inhibition of ATM with the highly-selective antagonist, KU55933, markedly increased IL-23 secretion human monocyte-derived DC (moDC) and freshly isolated myeloid DC (myDC). In contrast, inhibiting the closely related mammalian target of rapamycin (mTOR) had no effect on IL-23. Priming naïve CD4+ T-cells with ATM-inhibited DC increased Th17 responses over and above those obtained with mature DC. Whilst ATM-blockade increased the abundance of p19, p35 and p40 mRNA, IL-12p70 secretion was unaffected. In order to further examine a role for ATM in IL-23 regulation we exposed DC to low doses of ionizing radiation. Exposure of DC to X-rays resulted in ATM phosphorylation and a corresponding depression of IL-23. Importantly, ATM-inhibition with KU55933 prevented radiation-induced ATM phosphorylation and abrogated the capacity of X-rays to suppress IL-23. To explore how ATM repressed IL-23 we examined a role for ER-stress responses by measuring generation of the spliced form of X-box protein-1 (XBP1s), a key ER-stress transcription factor. Inhibition of ATM increased the abundance of XBP1s mRNA and this was followed 3hr later by increased peak p19 transcription and IL-23 release. In summary, ATM-activation or inhibition respectively inhibited or augmented IL-23 release. This novel role of the ATM pathway represents a new therapeutic target in autoimmunity and vaccine development.
PMCID: PMC3672964  PMID: 23460736
Dendritic Cell; IL-23; Th17; ATM
4.  The Peripheral Myeloid Expansion Driven by Murine Cancer Progression Is Reversed by Radiation Therapy of the Tumor 
PLoS ONE  2013;8(7):e69527.
Expansion of myeloid-lineage leukocytes in tumor-bearing mice has been proposed as a cause of systemic immunosuppression. We demonstrate that radiation therapy of tumors leads to a decline in myeloid cell numbers in the blood and a decrease in spleen size. The frequency of myeloid cells does not decline to the level seen in tumor-free mice: we demonstrate that metastatic disease can prevent myeloid cell numbers from returning to baseline, and that tumor recurrence from residual disease correlates with re-expansion of myeloid lineage cells. Radiation therapy results in increased proliferation of T cells in the spleen and while T cell responses to foreign antigens are not altered by tumor burden or myeloid cell expansion, responses to tumor-associated antigens are increased after radiation therapy. These data demonstrate that myeloid cell numbers are directly linked to primary tumor burden, that this population contracts following radiation therapy, and that radiation therapy may open a therapeutic window for immunotherapy of residual disease.
PMCID: PMC3723876  PMID: 23936036
5.  Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T cell anergy in vivo 
European journal of immunology  2009;39(8):2184-2194.
Tumor-specific CD8 T cell peripheral tolerance occurs through clonal deletion, suppression, and the induction of anergy and can limit the generation of anti-tumor immunity. Several groups have demonstrated that prostate cancer can render tumor-specific CD8 T cells anergic, suggesting reversing tumor-induced anergy may greatly augment anti-tumor immunity. Recent work has demonstrated that signaling through the OX40 (CD134) co-stimulatory receptor, a member of the TNFR super-family, can augment CD4 and CD8 T cell expansion, differentiation, and the generation of memory cells. However, whether OX40 ligation can reverse CD8 T cell anergy, and more specifically, tumor-induced CD8 T cell anergy, remains unclear. In the current study, we demonstrate that OX40 ligation can reverse CD8 T cell anergy to a prostate-specific self-antigen in non-tumor bearing hosts. Furthermore, OX40 engagement reversed tumor-specific CD8 T cell anergy and restored the proliferative capacity of tumor-reactive CD8 T cells, which attenuated tumor growth and enhanced the survival of tumor-bearing hosts. These data demonstrate that OX40 ligation can rescue the function of anergic self or tumor-reactive CD8 T cells in vivo and suggests that OX40-mediated therapy may provide a novel means of boosting anti-tumor immunity by restoring the responsiveness of previously anergic tumor-specific CD8 T cells.
PMCID: PMC3509800  PMID: 19672905
CD8 T cells; OX40; co-stimulation; anergy
6.  Children's surgery: a national survey of consultant clinical practice 
BMJ Open  2012;2(5):e001639.
To survey clinical practice and opinions of consultant surgeons and anaesthetists caring for children to inform the needs for training, commissioning and management of children's surgery in the UK.
The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) hosted an online survey to gather data on current clinical practice of UK consultant surgeons and anaesthetists caring for children.
The questionnaire was circulated to all hospitals and to Anaesthetic and Surgical Royal Colleges, and relevant specialist societies covering the UK and the Channel Islands and was mainly completed by consultants in District General Hospitals.
555 surgeons and 1561 anaesthetists completed the questionnaire.
32.6% of surgeons and 43.5% of anaesthetists considered that there were deficiencies in their hospital's facilities that potentially compromised delivery of a safe children's surgical service. Almost 10% of all consultants considered that their postgraduate training was insufficient for current paediatric practice and 20% felt that recent Continued Professional Development failed to maintain paediatric expertise. 45.4% of surgeons and 39.2% of anaesthetists considered that the current specialty curriculum should have a larger paediatric component. Consultants in non-specialist paediatric centres were prepared to care for younger children admitted for surgery as emergencies than those admitted electively. Many of the surgeons and anaesthetists had <4 h/week in paediatric practice. Only 55.3% of surgeons and 42.8% of anaesthetists participated in any form of regular multidisciplinary review of children undergoing surgery.
There are significant obstacles to consultant surgeons and anaesthetists providing a competent surgical service for children. Postgraduate curricula must meet the needs of trainees who will be expected to include children in their caseload as consultants. Trusts must ensure appropriate support for consultants to maintain paediatric skills and provide the necessary facilities for a high-quality local surgical service.
PMCID: PMC3488724  PMID: 23075572
Paediatric Surgery
7.  Expression of NF-κB p50 in Tumor Stroma Limits the Control of Tumors by Radiation Therapy 
PLoS ONE  2012;7(6):e39295.
Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cancer cells have been proposed to be a source of tumor antigens and may release endogenous immune adjuvants into the tumor environment. For these reasons, radiation therapy may be an effective modality to initiate new anti-tumor adaptive immune responses that can target residual disease and distant metastases. However, tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice, there is an influx of tumor macrophages that ultimately polarize towards immune suppression. We demonstrate using in vitro models that this polarization is mediated by transcriptional regulation by NFκB p50, and that in mice lacking NFκB p50, radiation therapy is more effective. We propose that despite the opportunity for increased antigen-specific adaptive immune responses, the intrinsic processes of repair following radiation therapy may limit the ability to control residual disease.
PMCID: PMC3386283  PMID: 22761754
8.  Signaling through OX40 Enhances Anti-tumor Immunity 
Seminars in oncology  2010;37(5):524-532.
The existence of tumor-specific T cells, as well as their ability to be primed in cancer patients confirms that the immune response can be deployed to combat cancer. However, there are obstacles that must be overcome to convert the ineffective immune response commonly found in the tumor environment to one that leads to sustained destruction of tumor. Members of the tumor necrosis factor (TNF) superfamily direct diverse immune functions. OX40 and its ligand, OX40L, are key TNF members that augment T-cell expansion, cytokine production, and survival. OX40 signaling also controls regulatory T cell differentiation and suppressive function. Studies over the past decade have demonstrated that OX40 agonists enhance anti-tumor immunity in preclinical models using immunogenic tumors; however, treatment of poorly immunogenic tumors has been less successful. Combining strategies that prime tumor-specific T cells together with OX40 signaling could generate and maintain a therapeutic anti-tumor immune response.
PMCID: PMC2997672  PMID: 21074068
10.  GALA: an international multicentre randomised trial comparing general anaesthesia versus local anaesthesia for carotid surgery 
Trials  2008;9:28.
Patients who have severe narrowing at or near the origin of the internal carotid artery as a result of atherosclerosis have a high risk of ischaemic stroke ipsilateral to the arterial lesion. Previous trials have shown that carotid endarterectomy improves long-term outcomes, particularly when performed soon after a prior transient ischaemic attack or mild ischaemic stroke. However, complications may occur during or soon after surgery, the most serious of which is stroke, which can be fatal. It has been suggested that performing the operation under local anaesthesia, rather than general anaesthesia, may be safer. Therefore, a prospective, randomised trial of local versus general anaesthesia for carotid endarterectomy was proposed to determine whether type of anaesthesia influences peri-operative morbidity and mortality, quality of life and longer term outcome in terms of stroke-free survival.
A two-arm, parallel group, multicentre randomised controlled trial with a recruitment target of 5000 patients. For entry into the study, in the opinion of the responsible clinician, the patient requiring an endarterectomy must be suitable for either local or general anaesthesia, and have no clear indication for either type. All patients with symptomatic or asymptomatic internal carotid stenosis for whom open surgery is advised are eligible. There is no upper age limit. Exclusion criteria are: no informed consent; definite preference for local or general anaesthetic by the clinician or patient; patient unlikely to be able to co-operate with awake testing during local anaesthesia; patient requiring simultaneous bilateral carotid endarterectomy; carotid endarterectomy combined with another operation such as coronary bypass surgery; and, the patient has been randomised into the trial previously. Patients are randomised to local or general anaesthesia by the central trial office. The primary outcome is the proportion of patients alive, stroke free (including retinal infarction) and without myocardial infarction 30 days post-surgery. Secondary outcomes include the proportion of patients alive and stroke free at one year; health related quality of life at 30 days; surgical adverse events, re-operation and re-admission rates; the relative cost of the two methods of anaesthesia; length of stay and intensive and high dependency bed occupancy.
Trial registration
Current Controlled Trials ISRCTN00525237
PMCID: PMC2413207  PMID: 18495004
11.  Use of magnetic resonance angiography to select candidates with recently symptomatic carotid stenosis for surgery: systematic review 
BMJ : British Medical Journal  2002;324(7331):198.
To determine if sufficient evidence exists to support the use of magnetic resonance angiography as a means of selecting patients with recently symptomatic high grade carotid stenosis for surgery.
Systematic review of published research on the diagnostic performance of magnetic resonance angiography, 1990-9.
Main outcome measures
Performance characteristics of diagnostic test.
126 potentially relevant articles were identified, but many articles failed to examine the performance of magnetic resonance angiography as a diagnostic test at the surgical decision thresholds used in major clinical trials on endarterectomy. 26 articles were included in a meta-analysis that showed a maximal joint sensitivity and specificity of 99% (95% confidence interval 98% to 100%) for identifying 70-99% stenosis and 90% (81% to 99%) for identifying 50-99% stenosis. Only four articles evaluated contrast enhanced magnetic resonance angiography.
Magnetic resonance angiography is accurate for selecting patients for carotid endarterectomy at the surgical decision thresholds established in the major endarterectomy trials, but the evidence is not very robust because of the heterogeneity of the studies included. Research is needed to determine the diagnostic performance of the most recent developments in magnetic resonance angiography, including contrast enhanced techniques, as well as to assess the impact of magnetic resonance angiography on surgical decision making and outcomes.
What is already known on this topicCarotid endarterectomy for recently symptomatic carotid stenosis is beneficial in patients with 70-99% stenosis as measured by conventional angiographyIt is not known whether the less invasive imaging technique of magnetic resonance angiography can accurately identify patients who will benefit from surgeryWhat this study addsMagnetic resonance angiography is highly sensitive and specific in diagnosing 70-99% carotid stenosisHowever, the studies on which this conclusion is based are of low quality and high heterogeneity
PMCID: PMC64789  PMID: 11809640

Results 1-11 (11)