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Moreno L.,Children and Young Peoples Unit | Moreno L.,Paediatric Drug Development Unit | Moreno L.,Clinical Research Programme | Marshall L.V.,Children and Young Peoples Unit | And 3 more authors.
British Medical Bulletin | Year: 2013

IntroductionNeuroblastoma is one of the commonest and deadliest forms of childhood cancer and major initiatives are ongoing to improve the outcome of these patients.Sources of dataData for this review were obtained from PubMed and abstracts from the American Society of Clinical Oncology and Advances in Neuroblastoma Research.Areas of agreementCollaborative clinical trials have led to major improvements in treatment outcomes for low and intermediate risk neuroblastoma, and international initiatives such as the International Neuroblastoma Risk Group have produced a very refined risk stratification incorporating clinical and biological risk factors.Areas of controversyDespite many efforts, the outcome for high-risk neuroblastoma is still poor and the only new strategy incorporated into frontline treatment is anti-GD2 immunotherapy. It is unclear how new drugs targeting specific molecular aberrations will be incorporated.Growing pointsGenomic characterization and drug development have undergone major advances in the last 5 years leading to a much deeper understanding of tumour biology as well as active biomarker-driven preclinical and clinical research on new molecules that will hopefully progress faster and more efficiently into frontline combination treatment strategies.Areas timely for developing researchSignificant effort remains to be done in integrating the different new strategies, combining new molecularly targeted agents to maximize therapeutic benefit and incorporate immunotherapy together with targeted therapies. © The Author 2013.

Ayuso C.,IIS Jimenez Diaz Foundation IIS FJD | Ayuso C.,CIBER ISCIII | Millan J.M.,CIBER ISCIII | Millan J.M.,University of Valencia | And 2 more authors.
European Journal of Human Genetics | Year: 2013

The development of new massive sequencing techniques has now made it possible to significantly reduce the time and costs of whole-genome sequencing (WGS). Although WGS will soon become a routine testing tool, new ethical issues have surfaced. In light of these concerns, a systematic review of papers published by expert authors on IC or specific ethical issues related to IC for WGS analysis in the clinical setting has been conducted using the Pubmed, Embase and Cochrane Library databases. Additionally, a search was conducted for international ethical guidelines for genetic studies published by scientific societies and ethical boards. Based on these documents, a minimum set of information to be provided to patients in the IC form was determined. Fourteen and seven documents from the database search and from scientific societies, respectively, were selected. A very high level of consistency between them was found regarding the recommended IC form content. Pre-test counselling and general information common to all genetic tests should be included in the IC form for WGS for diagnostic purposes, but additional information addressing specific issues on WGS are proposed, such as a plan for the ethical, clinically oriented return of incidental findings. Moreover, storage of additional information for future use should also be agreed upon with the patient in advance. Recommendations for WGS studies in the clinical setting concerning both the elements of information and the process of obtaining the IC as well as how to handle the results obtained are proposed. © 2013 Macmillan Publishers Limited.

Calles A.,Clinical Research Programme
Current protocols in pharmacology / editorial board, S.J. Enna (editor-in-chief) ... [et al.] | Year: 2013

The number of therapeutic options for lung and pancreatic cancer is increasing because of the identification of new druggable molecular targets and development of new drug combinations. Reproducible, biologically relevant in vivo pre-clinical models are critical for this effort. The generation of patient-derived tumor xenografts has proven useful for integrating drug screening with biomarker discovery, discovering fundamental information in tumor biology, prioritizing drugs for clinical investigation, and personalizing treatments for these tumors. The protocol described in this unit details how to establish a direct in vivo subcutaneous primary tumorgraft and maintenance passages. The predictive value of a tumorgraft platform to guide personalized medicine is illustrated with the case of a patient with refractory advanced non-small cell lung cancer (NSCLC). The outcome of a patient for whom their own pancreatic tumorgraft revealed a remarkable sensitivity to mitomycin C based on a PALB2 mutation is also detailed. © 2013 by John Wiley & Sons, Inc.

Nyoni B.N.,Clinical Research Programme | Gorman K.,Rothamsted Research | Mzilahowa T.,Clinical Research Programme | Williamson M.S.,Rothamsted Research | And 3 more authors.
Pest Management Science | Year: 2011

BACKGROUND: The tomato red spider mite, Tetranychus evansi (Baker and Pritchard), is a serious pest of solanaceous crops in many African countries. In this study an investigation has been conducted to establish whether mutation of the para-type sodium channel underlies pyrethroid resistance in T. evansi strains collected in Southern Malawi. RESULTS: Two T. evansi strains from Malawi showed tolerance to the organophosphate chlorpyrifos and resistance (20-40-fold) to the pyrethroid bifenthrin, but were susceptible to two contemporary acaricides (abamectin and fenpyroximate) in insecticide bioassays. Cloning of a 3.1 kb fragment (domains IIS5 to IVS5) of the T. evansi para gene from pyrethroid-resistant and pyrethroid-susceptible strains revealed a single non-synonymous mutation in the resistant strains that results in an amino acid substitution (M918T) within the domain II region of the channel. Although novel to mites, this mutation confers high levels of resistance to pyrethroids in several insect species where it has always been associated with another mutation (L1014F). This is the first report of the M918T mutation in the absence of L1014F in any arthropod species. Diagnostic tools were developed that allow sensitive detection of this mutation in individual mites. CONCLUSION: This is the first study of pyrethroid resistance in T. evansi and provides contemporary information for resistance management of this pest in Southern Malawi. © 2011 Society of Chemical Industry.

Leicht S.F.,Clinical Research Programme | Leicht S.F.,Ludwig Maximilians University of Munich | Schwarz T.M.,Ludwig Maximilians University of Munich | Hermann P.C.,Clinical Research Programme | And 3 more authors.
Diabetes | Year: 2011

OBJECTIVE - It has been shown that vascular progenitors from patients with diabetes are dysfunctional. However, therapeutic strategies to counteract their reduced functional capacity are still lacking. Because adiponectin has reported salutary effects on endothelial function, we investigated the functional effects of globular adiponectin (gAcrp), the active domain of adiponectin, on isolated endothelial colony-forming cells (ECFC). RESEARCH DESIGN AND METHODS - ECFC were isolated from peripheral blood of type 2 diabetic patients (dmECFC) and compared with ECFC of healthy young volunteers (yECFC) and nondiabetic age-matched control subjects (hECFC). Cells were treated with gAcrp for 48 h followed by assessment of cell counts, cell cycle analysis, and migration capacity. For in vivo evaluation, human ECFC were injected into normoglycemic or streptozotocininduced hyperglycemic nu/nu mice after hind limb ischemia. RESULTS - Whereas dmECFC were functionally impaired compared with yECFC and hECFC, gAcrp significantly enhanced their in vitro proliferation and migratory activity. In vitro effects were significantly stronger in hECFC compared with dmECFC and were mediated through the cyclooxygenase-2 pathway. Most important, however, we observed a profound and sustained increase of the in vivo neovascularization in mice receiving gAcrp-pretreated dmECFC compared with untreated dmECFC under both normoglycemic and hyperglycemic conditions. CONCLUSIONS - Pretreatment of ECFC with gAcrp enhanced the functional capacity of ECFC in vitro and in vivo in normoglycemic and hyperglycemic environments. Therefore, preconditioning of dmECFC with gAcrp may be a novel approach to counteract their functional impairment in diabetes. © 2011 by the American Diabetes Association.

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