This is the final report that shows the results obtained during the funding. The aim of this study was identify combinations of currently approved drugs that would be effective for treating MPNST. The resources attained along the first phase of this project were valuable for the subsequent drug screen performed in human MPNST cells and in vivo experiments. The inhibition of mammalian target of rapamycin (mTOR) by drugs (Rapamycin and RAD001) or RNA interference shows synergism with ionizing radiation decreasing human MPNST cell proliferation. Cell-based drug screen in combination with mTOR inhibitiors uncovers three potential candidates (toremifene, riluzole and bortezomib) with different mechanism of action. We further characterized the interaction between bortezomib, a proteasome inhibitor, and mTOR signaling inhibition in MPNST cells proliferation, cell cycle and apoptosis. Finally, dual targeting of proteasome and mTOR signaling associated with radiotherapy delay MPNST tumor growth in xenograft nude mice.

关键词：医药；治疗技术；纤维瘤；临床前测试

查看摘要 索取原文[25页]

Project 1: Dilated cardiomyopathy affects approximately 1 in 2,500 individuals in the United States and is the 3rd most common cause of heart failure and the most frequent cause of heart transplantation. Patients that suffer from various muscle diseases, including Duchenne muscular dystrophy (DMD), develop progressive cardiomyopathy. Cellular cardiomyoplasty, which involves the transplantation of exogenous cells into the heart, is a possible approach by which to repair diseased or injured myocardium and improve cardiac function. Though there are a number of drugs prescribed to treat dilated cardiomyopathy, there is no cure and individuals eventually require a heart transplant; therefore the use of cardiomyoplasty to repair the hearts of individuals suffering from cardiomyopathy could possibly be an effective alternative to heart transplantation. Technical Objective No. 1: To investigate the effect of cell survival, proliferation, and differentiation on the regeneration/repair capacity of various human MDSC populations implanted into the heart of mdx/SCID mice. Technical Objective No. 2: To investigate the role that angiogenesis plays in the regeneration/repair capacity of human MDSCs injected into the hearts of mdx/SCID mice. Project 2: This project will determine the extent to which novel sources of hepatocytes can be used for regeneration and repair of injuries to the liver and liver failure. A more complete understanding of the extent to which donor liver cells can be resuscitated from non-traditional sources and expanded for application to reduce liver injury and toxin and/or cancer risk should enhance the number of areas where hepatic stem cell transplantation might be effectively applied. Technical Objectives: (1) to characterize and expand hepatocytes from patients with cirrhosis and end-stage liver disease in immune deficient hosts whose livers permit extensive repopulation with donor cells; (2); to determine the extent to which transplant.

关键词：医药；治疗技术；肌肉干细胞疗法；心肌病

查看摘要 索取原文[83页]

Long bone fractures resulting from high impact trauma can result in delayed healing. Photodynamic therapy (PDT) is a non-surgical, non-ionizing minimally invasive local treatment currently used to treat cancer and skin diseases. Surprisingly, recent findings from studying the effect of PDT on spinal metastases have shown that PDT improved the strength and stiffness of the vertebrae. Although variability in fracture generation led to inconclusive findings with respect to bone generation in the closed tibia fracture model (n=17), higher local levels of VEGF were found in PDT treated animals. A critical size defect fracture of the femur was generated in 20 adult female Sprague-Dawley rats. PDT treatment was applied either 1d (n=6) or 7d (n=6) after fracture generation. Qualitatively, a larger callus was seen in the 7d- PDT group, suggesting an important effect of timing on PDT administration. Both PDT treated groups showed evidence of healing and closing of the fracture gap in this critical defect model. Preliminary, quantitative CT measurements support the qualitative findings. Additional CT based imaging and stereological analysis are underway. Histologic processing and analysis of the serum will also be conducted on these animals.

关键词：医药；治疗技术；光动力疗法；骨折

查看摘要 索取原文[8页]

The research goals of this grant proposal are to: (1) investigate the effect of ETS gene fusions on radiation phenotype in pre-clinical models of prostate cancer, (2) to explore the mechanism of interaction between ERG (the predominant ETS gene fusion product) and the DNA repair protein DNA-PK, and (3) to determine if ETS gene fusion status is a clinical biomarker of radioresistance for prostate cancer. The training goals of this grant proposal included a series of regular meetings with mentors, research seminars, journal clubs, and workshops, all of which are intended to help Dr. Feng develop as a translational scientist. This grant proposal was approved as a five-year award; the current annual report summarizes accomplishments over the second year of the grant, from July 15, 2011 to July 15, 2012. Overall, the first two years of this grant have been very successful. The work accomplished as a result of this grant resulted in two publications in very high impact journals, four national presentations, and three grants (two from the Prostate Cancer Foundation and one from Celgene). Additionally, Dr. Feng has met the training achievements specified in his original grant. The research proposed in this training grant represents an important area within the field of prostate cancer research. Because ETS gene fusions are thought to be driver alterations in over half of all prostate cancers, understanding the mecha-nistic and potential clinical implications of these gene fusions has significant ramifications, particularly in the context of radiation therapy, which represents a primary treatment modality for localized prostate cancer. In the second year of this grant period, we have generated bioluminescent ETS+ and ETS- cells in three different prostate cancer cell lines, and we havereceived institutional approval to proceed with the proposed animal studies and human biomarker tissue studies.

关键词：医药；治疗技术；生物标记；前列腺癌

查看摘要 索取原文[62页]

Trastuzumab, a monoclonal antibody (mAb) targeting HER-2/neu, kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including natural killer (NK) cells, may improve trastuzumab s efficacy. NK cells that encounter trastuzumabcoated, HER2-overexpressing breast cancer cells become activated and express CD137, a costimulatory receptor. CD137 activation, which is dependent on the Fc RIII receptor, occurred both in vitro and in the peripheral blood of women with HER2- expressing breast cancer following trastuzumab treatment. Stimulation of trastuzumab-activated NK cells with an agonistic mAb against CD137 killed breast cancer cells more efficiently in vitro.

关键词：医药；治疗技术；曲妥单抗疗法；乳腺癌

查看摘要 索取原文[15页]

Composite Tissue Allotransplantation (CTA) offers an alternative reconstructive strategy for complicated musculoskeletal injuries incurred during modern warfare where functional outcomes after multipe conventional reconstructions are suboptimal. Broader clinical application of CTA, however, continues to be hampered by requirement for long-term multi-drug immunosuppression to prevent graft rejection. Furthermore, unlike in solid organs, clinical success is dictated not only by graft acceptance, but also by functional outcome. Our study proposes a novel cell-based therapy utilizing mesenchymal stem cells (MSC) that can augment nerve regeneration while minimizing the need for immunosuppression. After transition from University of Pittsburgh to Johns Hopkins University, we optimized our isolation and culture protocol for MSCs. Immunophenotypic and functional characterization of cultured cells demonstrated potent immunomodulatory effects of MSCs in vitro. Preliminary functional outcome analysis using Catwalk showed convergent data with similar loss and return of function among groups. Similarly, compound muscle action potentials at early time points showed small non-significant increases in amplitude in experimental groups. In contrast, normalized gastrocnemius weights showed increased muscle weight in only the systemic injection group. Overall, we continue to monitor both functional and histological outcomes. Consistent with existing literature on nerve regeneration, we expect to observe more evident differences among groups with increased data over the longer term.

关键词：医药；治疗技术；复合组织异体移植术；神经再生

查看摘要 索取原文[16页]

Insomnia is a common complaint in the general population. Hypnotics are the most common treatment for insomnia, despite some unwanted effects such as tolerance and dependence. Cognitive Behavioral Therapy for Insomnia (CBT-I) was shown to be effective in the treatment of chronic insomnia. Recent studies comparing CBT-I treatment with hypnotics further demonstrated that the CBT-I treatment was at least as effective as hypnotics during acute treatment, and may be more effective than medication during long-term follow-ups. This chapter describes the role of neurophysiological and psychological factors in the regulation and dysregulation of sleep. Further, the rationales and procedures of CBT-I are introduced. Lastly, the application of CBT-I with modern information technologies is discussed.

关键词：医药；治疗技术；认知行为治疗；睡眠障碍

查看摘要 索取原文[16页]

Raman spectroscopy is an analytical technique recognised for its structural and conformational specificity. The efficient discrimination of molecular species by Raman is particularly potent for multidimensional microscopic imaging of complex biological environment, as demonstrated in the present book. The commonly admitted problem of Raman, low sensitivity, can often be circumvented due to high output instruments and via approaches like RRS (resonance Raman scattering), SERS (surface-enhanced Raman scattering), TERS (tip-enhanced Raman scattering) or CARS (coherent anti-Stokes Raman scattering). In contrast to the latter, RRS and SERS are realizable with less sophisticated set-up based on common Raman systems. Although more invasive than RRS, SERS provides better sensitivity and quenching of fluorescence. SERRS (surface-enhanced resonance Raman scattering) spectroscopy can be used in coupling with fluorescence and competes in selectivity and sensitivity with spectrofluorimetry. In the chapter below, we use recent applications made in our group to illustrate the use of Raman and SERRS spectral imaging for characterization of biological samples (animal subcutaneous tissue, human cancer cells) and pharmaceutical samples (microparticles for drug delivery, fibres for wound dressing). After a brief description of experimental details on spectral imaging, the chapter will focus on results concerning (i) biocompatible pharmaceutical materials made of alginates and (ii) anticancer drugs in pharmaceutical forms and in biological systems.

关键词：医药；药品；拉曼成像；化学成分

查看摘要 索取原文[13页]

Therapeutic options for patients suffering from end-stage renal disease have improved tremendously over the last decades and can be divided into three categories: hemodialysis, peritoneal dialysis and kidney transplantation. Transplantation remains the treatment of choice, however, lack of donor organs results in the necessity of performing -temporary-dialysis therapies of which hemodialysis is carried out in the majority of patients. To facilitate adequate hemodialysis therapy a reliable vascular access is mandatory and can be provided by either surgically connecting an artery with a vein (arteriovenous fistula), surgically connecting an artery with a vein using an interposition of prosthetic graft material (arterioven-ous graft) or a central venous catheter. This chapter shortly reviews the condition of end-stage renal disease after which history of vascular access, different options to create a vascular access, pre-operative work-up, surgical procedure, monitoring and usage, post-operative complications and the role of hemodynamics will be discussed. Finally, some future directions for vascular access creation and management will be identified.

关键词：医药；治疗技术；血液透析；血管穿刺

查看摘要 索取原文[69页]

In our research, in accordance with the traditional sand therapy practice usually held in Turpan areas, we built an indoor sand therapy laboratory in Xinjiang University. After heating the sand with a heater for one week, we obtained similar temperature in every layer of the sand to that in the sand therapy. Male rabbits were treated with the sand therapy and medication and compared with normal control. The blood, joint fluid and mechanical properties of the bones were compared. The comparison of the mechanical properties of the bone, as well as our clinical experience with the sand therapy shows the effectiveness of such a treatment.

关键词：医药；治疗技术；股骨治疗；维吾尔族砂疗法

查看摘要 索取原文[5页]