Clinical Research Programme

Madrid, Spain

Clinical Research Programme

Madrid, Spain
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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.

Lonardo E.,Clinical Research Programme | Hermann P.C.,Clinical Research Programme | Heeschen C.,Clinical Research Programme
Molecular Oncology | Year: 2010

Solid tumours are the most common cancers and represent a major therapeutic challenge. The cancer stem cell hypothesis is an attractive model to explain the functional heterogeneity commonly observed in solid tumours. It proposes a hierarchical organization of tumours, in which a subpopulation of stem cell-like cells sustains tumour growth, metastasis, and resistance to therapy. We will present the most recent advances in the cancer stem cell field, with particular emphasis on pancreatic cancer as one of the deadliest human tumours, and highlight open questions and caveats to be addressed in future studies. There is increasing evidence that solid tumours including pancreatic cancer are hierarchically organized and sustained by a distinct subpopulation of cancer stem cells. However, direct evidence for the validity of the cancer stem cell hypothesis in human pancreatic cancer remains controversial due to the limitations of xenograft models but supportive data are now emerging from mouse models using related or different sets of markers for the identification of murine cancer stem cells. Therefore, while the clinical relevance of cancer stem cells remains a fundamental issue for this rapidly emerging field, current findings clearly suggest that specific elimination of these cells is possible and therapeutically relevant. Targeting of signalling pathways that are of particular importance for the maintenance and the elimination of cancer stem cell as the proposed root of the tumour may lead to the development of novel treatment regimens for pancreatic cancer. Here we will review the current literature on pancreatic cancer stem cells and the future perspective of this rapidly emerging field. © 2010 Federation of European Biochemical Societies.

Hermann P.C.,Clinical Research Programme | Bhaskar S.,Clinical Research Programme | Cioffi M.,Clinical Research Programme | Heeschen C.,Clinical Research Programme
Seminars in Cancer Biology | Year: 2010

According to the cancer progression model, several events are required for the progression from normal epithelium to carcinoma. Due to their extended life span, stem cells would represent the most likely target for the accumulation of these genetic events but this has not been formally proven for most of solid cancers. Even more importantly, cancer stem cells seem to harbor mechanisms protecting them from standard cytotoxic therapy. While cancer stem cells have been demonstrated to be responsible for therapy resistance in glioblastoma and pancreatic cancer, further evidence now points to similar mechanisms in colon cancer stem cells. Therefore, it appears reasonable to conclude that there is sufficient evidence now for the existence of cancer stem cells in several epithelial tumors and that these cancer stem cells pose a significant threat via their resistance to standard therapies. Accumulating evidence suggests, however, that novel approaches targeting cancer stem cells are capable of overcoming these resistance mechanisms. To further foster our understanding of in vivo cancer stem cell biology, novel imaging modalities in conjunction with clinically most relevant cancer stem cell models need to be developed and utilized. These studies will then pave the way to better elucidate the underlying regulatory mechanisms of cancer stem cells and develop platforms for targeted theragnostics, which may eventually help improving the prognosis of our patients suffering from these deadly diseases. © 2010 Elsevier Ltd.

Mueller M.-T.,Clinical Research Programme | Hermann P.C.,Clinical Research Programme | Heeschen C.,Clinical Research Programme
Frontiers in Bioscience - Elite | Year: 2010

Over the past decade, increasing evidence suggested that stem cells play a crucial role not only in the generation of complex multicellular organisms, but also in the development and progression of malignant diseases. For the most abundant tumours, it has been shown that they contain a subset of distinct cancer cells that is exclusively responsible for tumour initiation and propagation These cells are termed cancer stem cells or tumour-initiating cells and they are also highly resistant to chemotherapeutic agents. Because CSC are preferentially endowed with the self-renewal capacity, it has further been hypothesized that they are also exclusively responsible for metastasis. Indeed, we were able to show that pancreatic caner stem cells contain a subpopulation of migrating cancer stem cells characterized by CXCR4 co-expression. Only these cells are capable of evading the primary tumour and metastasizing. Laboratories around the world are now aiming to further characterize these cells to eventually identify novel treatment modalities to fight cancer. Thus, cancer stem cells are promising new targets to counteract the growth-promoting and metastatic potential of solid tumours.

Balic A.,Clinical Research Programme | Dorado J.,Clinical Research Programme | Alonso-Gomez M.,Clinical Research Programme | Heeschen C.,Clinical Research Programme
Experimental Cell Research | Year: 2012

Emerging evidence suggests that stem cells play a crucial role not only in the generation and maintenance of different tissues, but also in the development and progression of malignancies. For the many solid cancers, it has now been shown that they harbor a distinct subpopulation of cancer cells that bear stem cell features and therefore, these cells are termed cancer stem cells (CSC) or tumor-propagating cells. CSC are exclusively tumorigenic and essential drivers for tumor progression and metastasis. Moreover, it has been shown that pancreatic ductal adenocarcinoma does not only contain one homogeneous population of CSC rather than diverse subpopulations that may have evolved during tumor progression. One of these populations is called migrating CSC and can be characterized by CXCR4 co-expression. Only these cells are capable of evading the primary tumor and traveling to distant sites such as the liver as the preferred site of metastatic spread. Clinically even more important, however, is the observation that CSC are highly resistant to chemo- and radiotherapy resulting in their relative enrichment during treatment and rapid relapse of disease. Many laboratories are now working on the further in-depth characterization of these cells, which may eventually allow for the identification of their Achilles heal and lead to novel treatment modalities for fighting this deadly disease. © 2011 Elsevier 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.

Moreno L.,Children and Young Peoples Unit | Moreno L.,Clinical Research Programme | Marshall L.V.,Children and Young Peoples Unit | Pearson A.D.J.,Children and Young Peoples Unit
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.

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.

Garcia-Silva S.,Clinical Research Programme | Frias-Aldeguer J.,Clinical Research Programme | Heeschen C.,Clinical Research Programme
Pancreatology | Year: 2013

It is now well established that human pancreatic ductal adenocarcinoma (PDAC) contains a subset of cells with self-renewal capabilities and subsequent exclusive in vivo tumorigenic capacity as assessed by limiting dilution tumorigenic transplantation assays into immunodeficient mice. These cells are considered pancreatic cancer stem cells (CSCs) and are able to form tumors indistinguishable from parental ones. Furthermore they display strong chemotherapy resistance and are implicated in tumor relapses and metastatic spread. Important next steps for advancing the field of pancreatic CSC research include the identification and characterization of CSCs in the unperturbed in vivo setting. This has been achieved just recently for other solid tumors such as glioblastoma using clonal analysis after lineage tracing in mice [1]. In vivo imaging of CSCs during tumor development should not only provide new insights into the in vivo features of CSCs, but also help to further unravel the influence of the stroma on CSC biology. Comprehensive studies of the tumor heterogeneity with respect to the coexistence of different clones potentially generated by distinct population of CSCs that are evolving by stochastic cell fate decisions may actually unite the CSC concept and the model of clonal evolution for pancreatic cancer. Eventually, the design of specific therapies against CSCs should open new alleys to improve survival of patients with PDAC. Combined therapies targeting CSCs and their progenies as well as the supportive stroma may represent the most promising approach for the future treatment of patients with PDAC. Copyright © 2012, IAP and EPC.

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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