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Successful Clinical Application (successful + clinical_application)
Selected AbstractsRecent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivativesTHE JOURNAL OF GENE MEDICINE, Issue 8 2005Michael Neu Abstract The continually increasing wealth of knowledge about the role of genes involved in acquired or hereditary diseases renders the delivery of regulatory genes or nucleic acids into affected cells a potentially promising strategy. Apart from viral vectors, non-viral gene delivery systems have recently received increasing interest, due to safety concerns associated with insertional mutagenesis of retro-viral vectors. Especially cationic polymers may be particularly attractive for the delivery of nucleic acids, since they allow a vast synthetic modification of their structure enabling the investigation of structure-function relationships. Successful clinical application of synthetic polycations for gene delivery will depend primarily on three factors, namely (1) an enhancement of the transfection efficiency, (2) a reduction in toxicity and (3) an ability of the vectors to overcome numerous biological barriers after systemic or local administration. Among the polycations presently used for gene delivery, poly(ethylene imine), PEI, takes a prominent position, due to its potential for endosomal escape. PEI as well as derivatives of PEI currently under investigation for DNA and RNA delivery will be discussed. This review focuses on structure-function relationships and the physicochemical aspects of polyplexes which influence basic characteristics, such as complex formation, stability or in vitro cytotoxicity, to provide a basis for their application under in vivo conditions. Rational design of optimized polycations is an objective for further research and may provide the basis for a successful cationic polymer-based gene delivery system in the future. Copyright © 2005 John Wiley & Sons, Ltd. [source] INSULIN-LIKE GROWTH FACTOR-I RECEPTOR AS A CANDIDATE FOR A NOVEL MOLECULAR TARGET IN GASTROINTESTINAL CANCERSDIGESTIVE ENDOSCOPY, Issue 4 2006Yasushi Adachi Abnormal activation of growth factor receptors and their signal pathways are required for neoplastic transformation and tumor progression. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, such as those acting against HER2/neu, epidermal growth factor receptor 1, and c-Kit. In this review, we focus on the next promising therapeutic molecular target of insulin-like growth factor (IGF)-I receptor (IGF-Ir). The IGF/IGF-Ir system is an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity in a number of neoplastic diseases, including human gastrointestinal carcinomas. Preclinical studies demonstrated that downregulation of IGF-Ir signals reversed the neoplastic phenotype and sensitized cells to antitumor treatments. We summarize a variety of ways to disrupt IGF-Ir function. Then, we introduce our strategy of adenoviruses expressing dominant negative of IGF-Ir (IGF-Ir/dn) against gastrointestinal cancers, including stomach, colon, and pancreas. IGF-Ir/dn suppresses tumorigenicity both in vitro and in vivo and increases stressor-induced apoptosis. IGF-Ir/dn expression upregulates chemotherapy-induced apoptosis and these combination therapies with chemotherapy are very effective against tumors in mice. Some drugs blocking IGF-Ir function are now entering clinical trial, thus IGF-Ir might be a candidate for a therapeutic target in several gastrointestinal malignancies. [source] Ex vivo and in vivo evaluation of laser-induced thermotherapy for nodular thyroid diseaseLASERS IN SURGERY AND MEDICINE, Issue 7 2009Jörg-P. Abstract Background and Objective The prevalence of thyroid nodules ranges between 2% and 60% depending on the population studied. However, minimally invasive procedures like laser-induced thermotherapy (LITT) are increasingly used to treat tumors of parenchymatous organs and seem to be suitable for singular thyroid nodules as well. Their successful clinical application depends on the induction of sufficiently large lesions and a knowledge of the energy parameters required for complete thermal ablation. The aim of this study was to establish a dose,response relationship for LITT of thyroid nodules. Materials and Methods Thermal lesions were induced in healthy porcine thyroid glands ex vivo (n,=,110) and in vivo (n,=,10) using an Nd:YAG laser (1,064,nm). Laser energy was applied for 300,seconds in a power range of 10,20,W. During the ablation, continuous temperature measurement at a distance of 5 and 10,mm from the applicator was performed. The lesions were longitudinally and transversally measured, and the volume was calculated. Furthermore, enzyme histochemical analysis of the thyroid tissue was performed. Results The maximum inducible lesion volumes were between 0.74,±,0.18,cm3 at a laser power of 10,W and 3.80,±,0.41,cm3 at 20,W. The maximum temperatures after ablation were between 72.9,±,2.9°C (10,W) and 112.9,±,9.2°C (20,W) at a distance of 5,mm and between 49.5,±,2.2°C (10,W) and 73.2,±,6.7°C (20,W) at a distance of 10,mm from the applicator. The histochemical analysis demonstrates a complete loss of NADPH dehydrogenase activity in thermal lesions as a sign of irreversible cell damage. Conclusions This study is the first to demonstrate a dose,response relationship for LITT of thyroid tissue. LITT is suitable for singular thyroid nodules and induces reproducible clinically relevant lesions with irreversible cell damage in an appropriate application time. Lasers Surg. Med. 41:479,486, 2009. © 2009 Wiley-Liss, Inc. [source] High-intensity focused ultrasound for noninvasive functional neurosurgery,ANNALS OF NEUROLOGY, Issue 6 2009Ernst Martin MD Transcranial magnetic resonance (MR)-guided high-intensity focused ultrasound (tcMRgHIFU) implies a novel, noninvasive treatment strategy for various brain diseases. Nine patients with chronic neuropathic pain were treated with selective medial thalamotomies. Precisely located thermal ablations of 4mm in diameter were produced at peak temperatures of 51°C to 60°C under continuous visual MR guidance and MR thermometry. The resulting lesions are clearly visible on follow-up MR imaging. All treatments were well tolerated, without side effects or neurological deficits. This is the first report on successful clinical application of tcMRgHIFU in functional brain disorders, portraying it as safe and reliable for noninvasive neurosurgical interventions. Ann Neurol 2009;66:858,861 [source] An in,vitro Assay to Measure Targeted Drug Delivery to Bone MineralCHEMMEDCHEM, Issue 5 2010Wolfgang Jahnke Dr. Abstract Targeted delivery of drugs to their site of action is a promising strategy to decrease adverse effects and enhance efficacy, but successful applications of this strategy have been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, bone mineral has not been targeted in a successful clinical application of drugs that act on bone, such as anti-resorptive or bone anabolic agents. Herein we present an NMR-based in,vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding was shown to be specific and competitive, and the assay can be carried out in a direct binding format or in competition mode. A selection of clinically relevant bisphosphonates was ranked by their binding affinity for HAP. The binding affinity decreases in the order: pamidronate > alendronate > zoledronate > risedronate > ibandronate. The differences in binding affinities span a factor of 2.1 between pamidronate and ibandronate, consistent with previous studies. The rank order is very similar with bone powder, although the binding capacity of bone powder is smaller and binding kinetics are slower. A zoledronate derivative that lacks the central hydroxy group binds to HAP with 2.3-fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to HAP or bone powder, and the binding of common bone-staining agents such as alizarin and its derivatives was confirmed in the new assay. This assay supports a strategy for targeted delivery of drugs to bone by attaching a bone-affinity tag to the active drug substance. [source] Quantitative proteomics and phosphoproteomics reveal novel insights into complexity and dynamics of the EGFR signaling networkPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 21 2008Sandra Morandell Abstract The epidermal growth factor receptor (EGFR/ErbB1/Her1) belongs to the ErbB family of receptor tyrosine kinases (RTKs) and is a key player in the regulation of cell proliferation, differentiation, survival, and migration. Overexpression and mutational changes of EGFR have been identified in a variety of human cancers and the regulation of EGFR signaling plays a critical role in tumor development and progression. Due to its biological significance the EGFR signaling network is a widely used model system for the development of analytical techniques. Novel quantitative proteomics and phosphoproteomics approaches play an important role in the characterization of signaling pathways in a time and stimulus dependent manner. Recent studies discussed in this review provide new insights into different aspects of EGFR signal transduction, such as regulation and dynamics of its phosphorylation sites, association with interaction partners and identification of regulated phosphoproteins. Correlation of data from functional proteomics studies with results from other fields of signal transduction research by systems biology will be necessary to integrate and translate these findings into successful clinical applications. [source] | |||||||||||||