Publications by authors named "Nick Bird"

15 Publications

  • Page 1 of 1

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

Eur J Cancer 2021 Sep 15;157:198-213. Epub 2021 Sep 15.

Hospital for Sick Children, Toronto, Canada.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.
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http://dx.doi.org/10.1016/j.ejca.2021.08.022DOI Listing
September 2021

Methods of 3D printing models of pituitary tumors.

3D Print Med 2021 Aug 31;7(1):24. Epub 2021 Aug 31.

Cambridge Endocrine Molecular Imaging Group, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK.

Background: Pituitary adenomas can give rise to a variety of clinical disorders and surgery is often the primary treatment option. However, preoperative magnetic resonance imaging (MRI) does not always reliably identify the site of an adenoma. In this setting molecular (functional) imaging (e.g. C-methionine PET/CT) may help with tumor localisation, although interpretation of these 2D images can be challenging. 3D printing of anatomicalal models for other indications has been shown to aid surgical planning and improve patient understanding of the planned procedure. Here, we explore the potential utility of four types of 3D printing using PET/CT and co-registered MRI for visualising pituitary adenomas.

Methods: A 3D patient-specific model based on a challenging clinical case was created by segmenting the pituitary gland, pituitary adenoma, carotid arteries and bone using contemporary PET/CT and MR images. The 3D anatomical models were printed using VP, MEX, MJ and PBF 3D printing methods. Different anatomicalal structures were printed in color with the exception of the PBF anatomical model where a single color was used. The anatomical models were compared against the computer model to assess printing accuracy. Three groups of clinicians (endocrinologists, neurosurgeons and ENT surgeons) assessed the anatomical models for their potential clinical utility.

Results: All of the printing techniques produced anatomical models which were spatially accurate, with the commercial printing techniques (MJ and PBF) and the consumer printing techniques (VP and MEX) demonstrating comparable findings (all techniques had mean spatial differences from the computer model of < 0.6 mm). The MJ, VP and MEX printing techniques yielded multicolored anatomical models, which the clinicians unanimously agreed would be preferable to use when talking to a patient; in contrast, 50%, 40% and 0% of endocrinologists, neurosurgeons and ENT surgeons respectively would consider using the PBF model.

Conclusion: 3D anatomical models of pituitary tumors were successfully created from PET/CT and MRI using four different 3D printing techniques. However, the expert reviewers unanimously preferred the multicolor prints. Importantly, the consumer printers performed comparably to the commercial MJ printing technique, opening the possibility that these methods can be adopted into routine clinical practice with only a modest investment.
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http://dx.doi.org/10.1186/s41205-021-00118-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406959PMC
August 2021

Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough.

ERJ Open Res 2021 Jul 2;7(3). Epub 2021 Aug 2.

Division of Infection Immunity and Respiratory Medicine, University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK.

Objective: Airway sensory nerves involved in the cough reflex are activated by adenosine triphosphate (ATP) agonism of P2X purinoceptor 3 (P2X3) receptors. Transient receptor potential vanilloid 4 (TRPV4) channel activation causes ATP release from airway cells, and it is hypothesised that a TRPV4-ATP-P2X3 axis contributes to chronic cough. An adaptive study was run to determine if TRPV4 inhibition, using the selective TRPV4 channel blocker GSK2798745, was effective in reducing cough.

Methods: A two-period randomised, double blinded, placebo-controlled crossover study was designed with interim analyses for futility and sample size adjustment. Refractory chronic cough patients received either GSK2798745 or placebo once daily for 7 days with a washout between treatments. Pharmacokinetic samples were collected for analysis of GSK2798745 at end of study. The primary end-point was total cough counts assessed objectively during day-time hours (10 h) following 7 days of dosing.

Results: Interim analysis was performed after 12 participants completed both treatment periods. This showed a 32% increase in cough counts on Day 7 for GSK2798745 compared to placebo; the pre-defined negative criteria for the study were met and the study was stopped. At this point 17 participants had been enrolled (mean 61 years; 88% female), and 15 had completed the study. Final study results for posterior median cough counts showed a 34% (90% credible interval: -3%, +85%) numerical increase for GSK2798745 compared to placebo.

Conclusion: There was no evidence of an anti-tussive effect of GSK2798745. The study design allowed the decision on lack of efficacy to be made with minimal participant exposure to the investigational drug.
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http://dx.doi.org/10.1183/23120541.00269-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326712PMC
July 2021

Quantifying the survival benefit of completing all the six cycles of radium-223 therapy in patients with castrate-resistant prostate cancer with predominant bone metastases.

World J Nucl Med 2021 Apr-Jun;20(2):139-144. Epub 2020 Oct 23.

Department of Nuclear Medicine, Cambridge University Hospitals, Cambridge, UK.

A retrospective analysis was performed of epidemiological data assessing the survival of patients who had received radium-223 for castrate-resistant metastatic prostate cancer treated at a regional tertiary referral center over a 5-year period. The patients' age, date of first treatment, and the number of cycles of radium-223 given were obtained from the patients' electronic patient record (EPR). Data on the date of death were provided by national death registrations which update the EPR via a unique national health service number. A total of 187 patients (mean age on the date of first treatment: 73 years; range: 56-93) were treated from April 1, 2014, to June 30, 2019. The median overall survival of the 119 patients (71%) who had died by December 31, 2019, was 15 months. There was no significant age difference between those who had died and survivors (72 vs. 74 years). On a further analysis, it was found that the median overall survival of the 107 patients who had received all the six cycles of radium-223 was 31 months, significantly longer than the median overall survival of only 6 months for those eighty patients who had received less than the full course of six cycles of radium-223 ( = 0.001). Of those who received all the six cycles of treatment, 58 patients had died (58%) and the 1-year survival was 87%. This was compared to the group of patients receiving <6 cycles of radium-223 where 61 patients (76%) had died and the 1-year survival was 30%. Therefore, the hazard ratio of dying before 1 year if the patient did not receive all the six cycles of treatment was 2.9. Where the reason for stopping treatment was recorded on the EPR the most common cause for the cessation of treatment was because of the side effects caused by the treatment itself. Other causes were hospitalization with comorbidities, disease progression, or patient choice. Given the survival advantage of receiving the full course of all the six cycles of treatment, this should be administered if possible and the patients should be managed in such a way as to allow the complete treatment course to be given.
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http://dx.doi.org/10.4103/wjnm.WJNM_74_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286012PMC
October 2020

3D printing F radioactive phantoms for PET imaging.

EJNMMI Phys 2021 Apr 28;8(1):38. Epub 2021 Apr 28.

Department of Nuclear Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK.

Purpose: Phantoms are routinely used in molecular imaging to assess scanner performance. However, traditional phantoms with fillable shapes do not replicate human anatomy. 3D-printed phantoms have overcome this by creating phantoms which replicate human anatomy which can be filled with radioactive material. The problem with these is that small objects suffer to a greater extent than larger objects from the effects of inactive walls, and therefore, phantoms without these are desirable. The purpose of this study was to explore the feasibility of creating resin-based 3D-printed phantoms using F.

Methods: Radioactive resin was created using an emulsion of printer resin and F-FDG. A series of test objects were printed including twenty identical cylinders, ten spheres with increasing diameters (2 to 20 mm), and a double helix. Radioactive concentration uniformity, printing accuracy and the amount of leaching were assessed.

Results: Creating radioactive resin was simple and effective. The radioactive concentration was uniform among identical objects; the CoV of the signal was 0.7% using a gamma counter. The printed cylinders and spheres were found to be within 4% of the model dimensions. A double helix was successfully printed as a test for the printer and appeared as expected on the PET scanner. The amount of radioactivity leached into the water was measurable (0.72%) but not visible above background on the imaging.

Conclusions: Creating an F radioactive resin emulsion is a simple and effective way to create accurate and complex phantoms without inactive walls. This technique could be used to print clinically realistic phantoms. However, they are single use and cannot be made hollow without an exit hole. Also, there is a small amount of leaching of the radioactivity to take into consideration.
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http://dx.doi.org/10.1186/s40658-021-00383-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081805PMC
April 2021

Physiologic and biochemical rationale for treating COVID-19 patients with hyperbaric oxygen.

Undersea Hyperb Med 2021 First Quarter;48(1):1-12

LDS Hospital, Salt Lake City, and Intermountain Medical Center, Murray, Utah.

The SARS-Cov-2 (COVID-19) pandemic remains a major worldwide public health issue. Initially, improved supportive and anti-inflammatory intervention, often employing known drugs or technologies, provided measurable improvement in management. We have recently seen advances in specific therapeutic interventions and in vaccines. Nevertheless, it will be months before most of the world's population can be vaccinated to achieve herd immunity. In the interim, hyperbaric oxygen (HBO2) treatment offers several potentially beneficial therapeutic effects. Three small published series, one with a propensity-score-matched control group, have demonstrated safety and initial efficacy. Additional anecdotal reports are consistent with these publications. HBO2 delivers oxygen in extreme conditions of hypoxemia and tissue hypoxia, even in the presence of lung pathology. It provides anti-inflammatory and anti-proinflammatory effects likely to ameliorate the overexuberant immune response common to COVID-19. Unlike steroids, it exerts these effects without immune suppression. One study suggests HBO2 may reduce the hypercoagulability seen in COVID patients. Also, hyperbaric oxygen offers a likely successful intervention to address the oxygen debt expected to arise from a prolonged period of hypoxemia and tissue hypoxia. To date, 11 studies designed to investigate the impact of HBO2 on patients infected with SARS-Cov-2 have been posted on clinicaltrials.gov. This paper describes the promising physiologic and biochemical effects of hyperbaric oxygen in COVID-19 and potentially in other disorders with similar pathologic mechanisms.
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March 2021

Detection limit of Zr-labeled T cells for cellular tracking: an in vitro imaging approach using clinical PET/CT and PET/MRI.

EJNMMI Res 2020 Jul 14;10(1):82. Epub 2020 Jul 14.

Department of Radiology, University of Cambridge, Cambridge, UK.

Purpose: Tracking cells in vivo using imaging can provide non-invasive information to understand the pharmacology, efficacy, and safety of novel cell therapies. Zirconium-89 (t = 78.4 h) has recently been used to synthesize [Zr]Zr(oxinate) for cell tracking using positron emission tomography (PET). This work presents an in vitro approach to estimate the detection limit for in vivo PET imaging of Jurkat T cells directly labeled with [Zr]Zr(oxinate) utilizing clinical PET/CT and PET/MRI.

Methods: Jurkat T cells were labeled with varying concentrations of [Zr]Zr(oxinate) to generate different cell-specific activities (0.43-31.91 kBq/10 cells). Different concentrations of labeled cell suspensions (10, 10, and 10 cells) were seeded on 6-well plates and into a 3 × 3 cubic-well plate with 1 cm cubic wells as a gel matrix. Plates were imaged on clinical PET/CT and PET/MRI scanners for 30 min. The total activity in each well was determined by drawing volumes of interest over each well on PET images. The total cell-associated activity was measured using a well counter and correlated with imaging data. Simulations for non-specific signal were performed to model the effect of non-specific radioactivity on detection.

Results: Using this in vitro model, the lowest cell number that could be visualized on 6-well plate images was 6.8 × 10, when the specific activity was 27.8 kBq/10 cells. For the 3 × 3 cubic-well, a plate of 3.3 × 10 cells could be detected on images with a specific activity of 15.4 kBq/10 cells.

Conclusion: The results show the feasibility of detecting [Zr]Zr(oxinate)-labeled Jurkat T cells on clinical PET systems. The results provide a best-case scenario, as in vivo detection using PET/CT or PET/MRI will be affected by cell number, specific activity per cell, the density of cells within the target volume, and non-specific signal. This work has important implications for cell labeling studies in patients, particularly when using radiosensitive cells (e.g., T cells), which require detection of low cell numbers while minimizing radiation dose per cell.
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http://dx.doi.org/10.1186/s13550-020-00667-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360010PMC
July 2020

Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma.

Eur J Cancer 2020 09 9;136:52-68. Epub 2020 Jul 9.

Department of Paediatric Haemaology/Oncology, Our Lady's Children's Hospital, Dublin, Ireland.

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.
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http://dx.doi.org/10.1016/j.ejca.2020.05.010DOI Listing
September 2020

Genetic Characterization of a Wheat Association Mapping Panel Relevant to Brazilian Breeding Using a High-Density Single Nucleotide Polymorphism Array.

G3 (Bethesda) 2020 07 7;10(7):2229-2239. Epub 2020 Jul 7.

The John Bingham Laboratory, NIAB, 93 Lawrence Weaver Road, Cambridge, CB3 0LE, United Kingdom,

Bread wheat ( L.) is one of the world's most important crops. Maintaining wheat yield gains across all of its major production areas is a key target toward underpinning global food security. Brazil is a major wheat producer in South America, generating grain yields of around 6.8 million tons per year. Here, we establish and genotype a wheat association mapping resource relevant to contemporary Brazilian wheat breeding programs. The panel of 558 wheat accessions was genotyped using an Illumina iSelect 90,000 single nucleotide polymorphism array. Following quality control, the final data matrix consisted of 470 accessions and 22,475 polymorphic genetic markers (minor allele frequency ≥5%, missing data <5%). Principal component analysis identified distinct differences between materials bred predominantly for the northern Cerrado region, compared to those bred for southern Brazilian agricultural areas. We augmented the genotypic data with 26 functional Kompetitive Allele-Specific PCR (KASP) markers to identify the allelic combinations at genes with previously known effects on agronomically important traits in the panel. This highlighted breeding targets for immediate consideration - notably, increased head blight resistance via the locus. To demonstrate the panel's likely future utility, genome-wide association scans for several phenotypic traits were undertaken. Significant (Bonferroni corrected < 0.05) marker-trait associations were detected for kernel damage (a proxy for type 2 resistance), identifying previously known quantitative trait loci in the panel. This association mapping panel represents an important resource for Brazilian wheat breeding, allowing future genetic studies to analyze multiple agronomic traits within a single genetically diverse population.
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http://dx.doi.org/10.1534/g3.120.401234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341152PMC
July 2020

The effects of conventional physical therapy and eccentric strengthening for insertional achilles tendinopathy.

Int J Sports Phys Ther 2014 Aug;9(4):488-97

Campbell Clinic, Germantown, TN, USA.

Study Design: Single-blind, randomized, clinical trial.

Background: The effect of eccentric training for mid-portion Achilles tendinopathy is well documented; however, its effect on insertional Achilles tendinopathy is inconclusive. The primary purpose of this study was to investigate the effect of eccentric training on pain and function for individuals with insertional Achilles tendinopathy.

Methods: All patients received a 12-week conventional strengthening protocol. Patients who were randomly assigned to the experimental group received additional eccentric exercises. Patients completed the Short Form-36 Health and Bodily Pain Surveys, the Foot and Ankle Outcomes Questionnaire, and the Visual Analog Scale at initial evaluation, after 6 weeks of therapy, and at 12 weeks after therapy.

Results: Thirty-six patients (20 control and 16 experimental; average age 54 years; 72% women) completed the study. Both groups experienced statistically significant decreases in pain and improvements in function. No statistically significant differences were noted between the groups for any of the outcome measures.

Conclusion: Conventional physical therapy consisting of gastrocnemius, soleus and hamstring stretches, ice massage on the Achilles tendon, and use of heel lifts and night splints with or without eccentric training is effective for treating insertional Achilles tendinopathy.

Level Of Evidence: Level 2.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127511PMC
August 2014

Evaluation of the sensitivity and specificity of (11)C-metomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn's adenomas.

J Clin Endocrinol Metab 2012 Jan 23;97(1):100-9. Epub 2011 Nov 23.

Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, UK.

Context: Identification of unilateral aldosterone-producing (Conn's) adenomas has traditionally required lateralization by the invasive and technically difficult procedure of adrenal vein sampling (AVS). (11)C-metomidate, a potent inhibitor of adrenal steroidogenic enzymes, is a positron emission tomography (PET) radiotracer that is selectively accumulated by Conn's adenomas.

Objective: The objective of the study was to compare the sensitivity and specificity of (11)C-metomidate PET-computed tomography (CT) against the current gold standard of AVS.

Design: The design of the study was within-patient comparison of diagnostic techniques.

Setting: The study was conducted at a single center-university teaching hospital.

Patients: Thirty-nine patients with primary hyperaldosteronism (PHA) and five with nonfunctioning adenomas (incidentalomas) participated in the study.

Intervention(s): The first six PHA patients were studied on three occasions to determine whether steroid pretreatment reduced (11)C-metomidate uptake by normal adrenal. Subsequent patients received dexamethasone for 3 d prior to injection of (11)C-metomidate 150-500 MBq.

Main Outcome Measure(s): Maximum standardized uptake values (SUV(max)) over regions of interest determined from 35-45 min after injection were measured.

Results: Dexamethasone increased tumor to normal adrenal SUV(max) ratio by 25.6 ± 5.0% (P < 0.01). PET-CT visualized subcentimeter adenomas and distinguished hot from cold adenomas within a gland. In 25 patients with PHA and AVS lateralization to the side of an adenoma, SUV(max) over tumor (mean ± sem) of 21.7 ± 1.6 was greater than over normal adrenal, 13.8 ± 0.6 (P = 0.00003); this difference was absent in 10 patients without lateralization on AVS (P = 0.28) and in four of five incidentalomas. On receiver-operator characteristics analysis, an SUV(max) ratio of 1.25:1 provided a specificity of 87% [95% confidence interval (69, 104)] and sensitivity of 76% (59, 93); in tumors with SUV(max) greater than 17, the specificity rose to 100%.

Conclusions: (11)C-metomidate PET-CT is a sensitive and specific noninvasive alternative to AVS in the management of PHA.
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http://dx.doi.org/10.1210/jc.2011-1537DOI Listing
January 2012

Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury.

Eur J Pain 2011 Nov 14;15(10):1040-8. Epub 2011 May 14.

Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College, London, UK.

Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side-effects. p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double-blind, placebo-controlled, two-period, cross-over trial was undertaken to evaluate the effect of dilmapimod (SB-681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2 weeks, with an intervening washout period of 2-4 weeks. Subjects attended weekly for efficacy and safety assessments, which included evaluation of daily and current pain intensity using an 11-point numerical rating scale (NRS), quantitative sensory testing, allodynia and global impression of change. There was a statistically significant reduction in the primary endpoint of average daily pain score during the second week of treatment among patients treated with dilmapimod (15 mg/day) compared to placebo using NRS [0.80; 95% CI (0.28, 1.33); p=0.0034]. A similar trend for effect was seen in some secondary endpoints. Dilmapimod was well tolerated, with no clinically relevant safety findings. p38 MAPK inhibitors merit further evaluation for neuropathic pain in larger clinical trials, particularly for clinically meaningful analgesic effect size.
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http://dx.doi.org/10.1016/j.ejpain.2011.04.005DOI Listing
November 2011

A multi-center randomized proof-of-concept clinical trial applying [¹⁸F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease.

J Alzheimers Dis 2010 ;22(4):1241-56

GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital, London, UK.

Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.
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http://dx.doi.org/10.3233/JAD-2010-100939DOI Listing
May 2011

The complex whiJ locus mediates environmentally sensitive repression of development of Streptomyces coelicolor A3(2).

Antonie Van Leeuwenhoek 2010 Aug 20;98(2):225-36. Epub 2010 Apr 20.

Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Colney, Norwich NR4 7UH, UK.

A segment of DNA was isolated that complemented several poorly characterised sporulation-defective white-colony mutants of Streptomyces coelicolor A3(2) from an early collection (Hopwood et al., J Gen Microbiol 61: 397-408, 1970). Complementation was attributable to a gene, SCO4543, named whiJ, encoding a likely DNA-binding protein. Surprisingly, although some mutations in whiJ had a white colony phenotype, complete deletion of the wild-type or mutant gene gave a wild-type morphology. The whiJ gene is a member of a large paralogous set of S. coelicolor genes including abaAorfA, which regulates antibiotic production; and genes flanking whiJ are paralogues of other gene classes that are often associated with whiJ-like genes (Gehring et al., Proc Natl Acad Sci USA 97: 9642-9647, 2000). Thus, the small gene SCO4542 encodes a paralogue of the abaAorfD gene product, and SCO4544 encodes a paralogue of a family of likely anti-sigma factors (including the product of abaAorfB). Deletion of SCO4542 resulted in a medium-dependent bald- or white-colony phenotype, which could be completely suppressed by the simultaneous deletion of whiJ. A model is proposed in which WhiJ binds to operator sequences to repress developmental genes, with repression being released by interaction with the WhiJ-associated SCO4542 protein. It is suggested that this activity of SCO4542 protein is prevented by an unknown signal.
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http://dx.doi.org/10.1007/s10482-010-9443-3DOI Listing
August 2010

Genital uptake in renal transplant scintigraphy: is it normal blood pooling?

Clin Nucl Med 2002 May;27(5):345-7

Department of Nuclear Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.

Although visualization of the genitalia on Tc-99m DTPA transplant renography has been reported previously, its frequency and clinical significance have not been fully evaluated. The authors conducted a retrospective evaluation of 153 renal transplant scintigrams obtained in 129 patients during a 2-year period. The results showed that significant genital blood pooling occurred in nearly 50% of studies. Because the finding was commonly associated with little or no radioactive urine in the bladder, as in acute tubular necrosis or poor graft function, exaggeration of the normal blood pool was thought to be the possible cause for its occurrence. It is, however, important to distinguish genital blood-pool activity from the bladder with radioactive urine to avoid making an incorrect diagnosis.
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http://dx.doi.org/10.1097/00003072-200205000-00006DOI Listing
May 2002
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