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Clinical Translation (clinical + translation)

Distribution by Scientific Domains

Medical Sciences	58%
Life Sciences	16%

Selected Abstracts

Treg-Therapy Allows Mixed Chimerism and Transplantation Tolerance Without Cytoreductive Conditioning

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010
N. Pilat
Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-, induced Tregs) were effective in this setting. Thus, Treg therapy achieves mixed chimerism and tolerance without cytoreductive recipient treatment, thereby eliminating a major toxic element impeding clinical translation of this approach. [source]

pH-Activated Near-Infrared Fluorescence Nanoprobe Imaging Tumors by Sensing the Acidic Microenvironment

ADVANCED FUNCTIONAL MATERIALS, Issue 14 2010
Cong Li
Abstract Imaging tumors in their early stages is crucial to increase the surviving rate of cancer patients. Currently most fluorescence probes visualize the neoplasia by targeting the tumor-associated receptor over-expressed on the cancer cell membrane. However, the expression level of these receptors in vivo is hard to predict, which limits their clinical translation. Furthermore, the signal output of these receptor-targeting probes usually stays at a high level, which leads to a strong background signal in normal tissue due to non-specific binding. In contrast to receptors, characteristics of the tumor microenvironment , such as acidosis , are pervasive in almost all solid tumors and can be easily accessed. In this work, a novel biodegradable nanoprobe InNP1 that demonstrates pH-activated near-infrared (NIR) fluorescence in both human glioblastoma U87MG cancer cells in vitro and the subcutaneous U87MG tumor xenografts in vivo is developed. Bio-distribution, in vivo optical imaging, and autoradiography studies demonstrate that the pH-activated NIR fluorescence is the dominant factor responsible for the high tumor/normal tissue (T/N) ratio of InNP1 in vivo. Overall, the work provides a nanoprobe prototype to visualize the solid tumor in vivo with high sensitivity and minimal systemic toxicity by sensing the tumor acidic microenvironment. [source]

Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape

IMMUNOLOGICAL REVIEWS, Issue 1 2008
Jessica B. Katz
Summary: Indoleamine 2, 3-dioxygenase (IDO) degrades the essential amino acid tryptophan in mammals, catalyzing the initial and rate-limiting step in the de novo biosynthesis nicotinamide adenine dinucleotide (NAD). Broad evidence implicates IDO and the tryptophan catabolic pathway in generation of immune tolerance to foreign antigens in tissue microenvironments. In particular, recent findings have established that IDO is overexpressed in both tumor cells and antigen-presenting cells in tumor-draining lymph nodes, where it promotes the establishment of peripheral immune tolerance to tumor antigens. In the normal physiologic state, IDO is important in creating an environment that limits damage to tissues due to an overactive immune system. However, by fostering immune suppression, IDO can facilitate the survival and growth of tumor cells expressing unique antigens that would be recognized normally as foreign. In preclinical studies, small-molecule inhibitors of IDO can reverse this mechanism of immunosuppression, complementing classical cytotoxic cancer chemotherapeutic agents' ability to trigger regression of treatment-resistant tumors. These results have encouraged the clinical translation of IDO inhibitors, the first of which entered phase I clinical trials in the fall of 2007. In this article, we survey the work defining IDO as an important mediator of peripheral tolerance, review evidence of IDO dysregulation in cancer cells, and provide an overview of the development of IDO inhibitors as a new immunoregulatory treatment modality for clinical trials. [source]

Endomyocardial biopsy derived adherent proliferating cells,A potential cell source for cardiac tissue engineering

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2010
Marion Haag
Abstract Heart diseases are a leading cause of morbidity and mortality. Cardiac stem cells (CSC) are considered as candidates for cardiac-directed cell therapies. However, clinical translation is hampered since their isolation and expansion is complex. We describe a population of human cardiac derived adherent proliferating (CAP) cells that can be reliably and efficiently isolated and expanded from endomyocardial biopsies (0.1,cm3). Growth kinetics revealed a mean cell doubling time of 49.9,h and a high number of 2.54,×,107 cells in passage 3. Microarray analysis directed at investigating the gene expression profile of human CAP cells demonstrated the absence of the hematopoietic cell markers CD34 and CD45, and of CD90, which is expressed on mesenchymal stem cells (MSC) and fibroblasts. These data were confirmed by flow cytometry analysis. CAP cells could not be differentiated into adipocytes, osteoblasts, chondrocytes, or myoblasts, demonstrating the absence of multilineage potential. Moreover, despite the expression of heart muscle markers like ,-sarcomeric actin and cardiac myosin, CAP cells cannot be differentiated into cardiomyocytes. Regarding functionality, CAP cells were especially positive for many genes involved in angiogenesis like angiopoietin-1, VEGF, KDR, and neuropilins. Globally, principal component and hierarchical clustering analysis and comparison with microarray data from many undifferentiated and differentiated reference cell types, revealed a unique identity of CAP cells. In conclusion, we have identified a unique cardiac tissue derived cell type that can be isolated and expanded from endomyocardial biopsies and which presents a potential cell source for cardiac repair. Results indicate that these cells rather support angiogenesis than cardiomyocyte differentiation. J. Cell. Biochem. 109: 564,575, 2010. © 2009 Wiley-Liss, Inc. [source]

Ethics in Neuroscience Graduate Training Programs: Views and Models from Canada

MIND, BRAIN, AND EDUCATION, Issue 1 2010
Sofia Lombera
Consideration of the ethical, social, and policy implications of research has become increasingly important to scientists and scholars whose work focuses on brain and mind, but limited empirical data exist on the education in ethics available to them. We examined the current landscape of ethics training in neuroscience programs, beginning with the Canadian context specifically, to elucidate the perceived needs of mentors and trainees and offer recommendations for resource development to meet those needs. We surveyed neuroscientists at all training levels and interviewed directors of neuroscience programs and training grants. A total of 88% of survey respondents reported general interest in ethics, and 96% indicated a desire for more ethics content as it applies to brain research and clinical translation. Expert interviews revealed formal ethics education in over half of programs and in 90% of grants-based programs. Lack of time, resources, and expertise, however, are major barriers to expanding ethics content in neuroscience education. We conclude with an initial set of recommendations to address these barriers which includes the development of flexible, tailored ethics education tools, increased financial support for ethics training, and strategies for fostering collaboration between ethics experts, neuroscience program directors, and funding agencies. [source]

Gene-based treatment of motor neuron diseases,

MUSCLE AND NERVE, Issue 3 2006
Thais Federici PhD
Abstract Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neurodegenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration. Therapeutic strategies for MND are designed to confer neuroprotection, using trophic factors, anti-apoptotic proteins, as well as antioxidants and anti-excitotoxicity agents. Although a large number of therapeutic clinical trials have been attempted, none has been shown satisfactory for MND at this time. A variety of strategies have emerged for motor neuron gene transfer. Application of these approaches has yielded therapeutic results in cell culture and animal models, including the SOD1 models of ALS. In this study we describe the gene-based treatment of MND in general, examining the potential viral vector candidates, gene delivery strategies, and main therapeutic approaches currently attempted. Finally, we discuss future directions and potential strategies for more effective motor neuron gene delivery and clinical translation. Muscle Nerve, 2005 [source]

Optimization of magnetosonoporation for stem cell labeling

NMR IN BIOMEDICINE, Issue 5 2010
Daohai Xie
Abstract Recent advances in magnetic cell labeling have taken place with the development of a magnetosonoporation (MSP) technique. The aim of this study was to optimize the MSP protocol in order to achieve high cell viability and intracellular uptake of MR contrast agents. First, we determined the sub-optimal MSP parameters by evaluating the viabilities of C17.2 neural stem cells without Feridex using various MSP intensities ranging from 0.1 to 1,w/cm2, duty cycles at 20%, 50% or 100%, and exposure times from 1,15,min. The sub-optimized MSP parameters with cell viabilities greater than 90% were further optimized by evaluating both cell viability and intracellular iron uptake when Feridex was used. We then used the optimized MSP parameters to determinate the optimal concentration of Feridex for magnetic cell labeling. Subsequently, we validated the feasibility of using MRI to track the migration of neural stem cells from the transplanted sites to glioma masses in four mouse brains when the cells had been labeled with Feridex using the optimized MSP protocol. The MRI findings were confirmed by histological correlations. Invitro experiments demonstrated that the optimal MSP protocol was achieved at 20% duty cycle, 0.3,w/cm2 ultrasound intensity, 5-min exposure time and 1mg/mL Feridex. This study demonstrated that the optimized MSP cell labeling technique can achieve both high cell viability and intracellular uptake of MR contrast agents, and has the potential to be a useful cell labeling technique to facilitate future clinical translation of MRI-integrated cell therapy. Copyright © 2010 John Wiley & Sons, Ltd. [source]

Gene therapy for cartilage defects

THE JOURNAL OF GENE MEDICINE, Issue 12 2005
Magali Cucchiarini
Abstract Focal defects of articular cartilage are an unsolved problem in clinical orthopaedics. These lesions do not heal spontaneously and no treatment leads to complete and durable cartilage regeneration. Although the concept of gene therapy for cartilage damage appears elegant and straightforward, current research indicates that an adaptation of gene transfer techniques to the problem of a circumscribed cartilage defect is required in order to successfully implement this approach. In particular, the localised delivery into the defect of therapeutic gene constructs is desirable. Current strategies aim at inducing chondrogenic pathways in the repair tissue that fills such defects. These include the stimulation of chondrocyte proliferation, maturation, and matrix synthesis via direct or cell transplantation-mediated approaches. Among the most studied candidates, polypeptide growth factors have shown promise to enhance the structural quality of the repair tissue. A better understanding of the basic scientific aspects of cartilage defect repair, together with the identification of additional molecular targets and the development of improved gene-delivery techniques, may allow a clinical translation of gene therapy for cartilage defects. The first experimental steps provide reason for cautious optimism. Copyright © 2005 John Wiley & Sons, Ltd. [source]

Treg-Therapy Allows Mixed Chimerism and Transplantation Tolerance Without Cytoreductive Conditioning

NK Cells Mediate Costimulation Blockade-Resistant Rejection of Allogeneic Stem Cells During Nonmyeloablative Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2006
L. S. Kean
Although T-cell CD28/CD40 costimulation blockade represents a powerful mechanism to promote immune tolerance during murine allotransplantation, it has not yet been successfully translated to clinical transplantation. We determined the impact of natural killer (NK) cells on costimulation blockade-resistant rejection of donor bone marrow. We found that NK cells represent a potent barrier to engraftment: host NK depletion led to increased donor stem cell survival, increased mixed hematopoietic chimerism and to engraftment of low doses of donor marrow (1 × 108/kg) that were otherwise rejected. To understand the mechanisms of NK alloreactivity, we employed an in vivo NK-specific cytotoxicity assay. We found that an increased proportion of target cells were killed between days 2 and 8 after cell transfer, and that NK killing of parental targets was inducible: NK cells preprimed with allotargets were more efficient at their elimination upon reexposure. Finally, both transplant and in vivo NK-killing models were used to determine the contribution of LFA-1 to NK alloreactivity. Blockade of LFA-1 led to decreased NK-mediated killing, and increased alloengraftment. These results identify NK alloreactivity as an integral component to costimulation blockade-resistant rejection, and suggest that its inhibition may represent an important target in the clinical translation of tolerance-induction transplantation. [source]

Tetraamine-Derived Bifunctional Chelators for Technetium-99m Labelling: Synthesis, Bioconjugation and Evaluation as Targeted SPECT Imaging Probes for GRP-Receptor-Positive Tumours,

CHEMISTRY - A EUROPEAN JOURNAL, Issue 7 2010
Keelara Abiraj Dr.
Abstract Owing to its optimal nuclear properties, ready availability, low cost and favourable dosimetry, 99mTc continues to be the ideal radioisotope for medical-imaging applications. Bifunctional chelators based on a tetraamine framework exhibit facile complexation with Tc(V)O2 to form monocationic species with high in vivo stability and significant hydrophilicity, which leads to favourable pharmacokinetics. The synthesis of a series of 1,4,8,11-tetraazaundecane derivatives (01,06) containing different functional groups at the 6-position for the conjugation of biomolecules and subsequent labelling with 99mTc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH (02), N3 (04) and O -succinyl ester (05) groups. A straightforward and easy synthesis of carboxyl-functionalised tetraamine-based chelator 06 was achieved by using inexpensive and commercially available starting materials. Conjugation of 06 to a potent bombesin-antagonist peptide and subsequent labelling with 99mTc afforded the radiotracer 99mTc-N4-BB-ANT, with radiolabelling yields of >97,% at a specific activity of 37,GBq,,mol,1. An IC50 value of (3.7±1.3),nM was obtained, which confirmed the high affinity of the conjugate to the gastrin-releasing-peptide receptor (GRPr). Immunofluorescence and calcium mobilisation assays confirmed the strong antagonist properties of the conjugate. In vivo pharmacokinetic studies of 99mTc-N4-BB-ANT showed high and specific uptake in PC3 xenografts and in other GRPr-positive organs. The tumour uptake was (22.5±2.6),% injected activity per gram (%,IA,g,1) at 1,h post injection (p.i.). and increased to (29.9±4.0),%,IA,g,1 at 4,h p.i. The SPECT/computed tomography (CT) images showed high tumour uptake, clear background and negligible radioactivity in the abdomen. The promising preclinical results of 99mTc-N4-BB-ANT warrant its potential candidature for clinical translation. [source]

Gene therapy for diseases of the cornea , a review

CLINICAL & EXPERIMENTAL OPHTHALMOLOGY, Issue 2 2010
Keryn A Williams PhD
Abstract The cornea is particularly suited to gene therapy. The cornea is readily accessible, normally transparent, and is somewhat sequestrated from the general circulation and the systemic immune system. The principle of genetic therapy for the cornea is to use an appropriate vector system to transfer a gene to the cornea itself, or to the ocular environs, or systemically, so that a transgenic protein will be expressed that will modulate congenital or acquired disease. The protein may be structural such as a collagen, or functionally active such as an enzyme, cytokine or growth factor that may modulate a pathological process. Alternatively, gene expression may be silenced by the use of modalities such as antisense oligonucleotides. Interestingly, despite a very considerable amount of work in animal models, clinical translation directed to gene therapy of the human cornea has been minimal. This is in contrast to gene therapy for monogenic inherited diseases of the retina, where promising early results of clinical trials for Leber's congenital amaurosis have already been published and a number of other trials are ongoing. [source]