The current proposal aims to directly compare the psychotherapy and medication treatments for PTSD considered to have the most evidence for effectiveness. While both SSRI and PE have demonstrated efficacy, there are significant individual differences in clinical responses to both treatments. To achieve best clinical outcomes and to utilize available treatment most effectively, it is critical to examine how PTSD and related psychopathology and functional impairment change with these treatments alone and in combination. Further, in order to inform clinical practice, we plan to examine psychological and neurobiological predictors of response to treatment and mechanisms of change during treatment (pre to post treatment change) based on previously identified predictors, including emotion regulation and processing with fMRI in response to emotional challenge tasks, DNA and mRNA (pre and post treatment), and cortisol response to awakening. Start-up activities were completed in 2012Q1 and the primary activity and focus is this year has been on recruitment. To date, we have recruited and randomized 45 Veterans.

关键词：医药；治疗技术；创伤后应激障碍；临床医学；军事人员

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During the past 12 months, we have received IRB approval from Mount Sinai School of Medicine, the James P. Peters VA Medical Center IRBs, and the Department of Defense. We have also held three focus groups with prostate cancer patients undergoing hormone therapy and multiple research team meetings were held to discuss focus group results, software development, and study protocol. We are currently integrating feedback from the final focus group into the vasomotor symptom intervention (VSI) and plan to run a final focus group to test the usability of the application. Our progress over the previous project period has led us to refine the methodology and software development, and this will allow us to begin the intervention phase during Y2 of the award.

关键词：医药；治疗技术；激素治疗；前列腺癌

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There is no cure for metastatic breast cancer, which kills 40,000 American women (and 500 men) each year: all presently available treatments are palliative. Gene therapy techniques are used to introduce chimeric immunoglobulin-T cell receptors (IgTCR) into autologous patient T cells to create designer T cells that redirect the T cell immune system in a new type of immuno-gene therapy against breast cancer. Designer T cells have been created against the carcinoembryonic antigen (CEA) that is prominently present on many metastatic breast tumors (30-60). This exceeds the fraction that are Her2/neu overexpressing (20-25), making CEA an even better immune target for attacking breast cancer. Building on a prior study of CEA designer T cells in breast and colon cancer, 2nd generation designer T cells were created by incorporating into the IgTCR a CD28 co-stimulation cassette that was shown to oppose activation-induced cell death (AICD) of the T cells after tumor contact. This advanced generation modification leads to improved designer T cell survival and improved anti-tumor potency in preclinical models. Although the 2nd generation designer T cells produce interleukin 2 (IL2) growth factor on contact with tumor, interleukin 2 (IL2) supplementation is anticipated still to be required for optimal clinical therapeutic effect. However, the CBER/FDA has mandated a Phase I.

关键词：医药；治疗技术；弥漫性乳腺癌；基因治疗

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We aimed to develop a virus-Au NS assembly to specifically target breast cancer cells, and to use localized heat of NIR radiation of Au NS to destroy breast cancer cells in synergy with gene therapy. We proposed to develop virus-nanoshell assemblies by attaching adeno-associated virus (AAV) to gold nanoshells (Au NS) through chemical bonds. We have successfully completed majority of tasks 1 and 2 of our Statement of Work. Specifically, we have designed and synthesized a linker molecule with dual functionalities to be able to covalently attach AAV to Au NS surface. Au NS was successfully functionalized with the linker molecules. AAV capsid surface was modified with a benzaldehyde functional group. Using higher titer AAV8, we were able to confirm and quantify the successful conjugation. Recombinant AAV vectors encoding a gene under regulation of a heat-responsive promoter were generated. By combining breast cancer targeting, gene therapy, and hyperthermia, the virus- NS assemblies have the potential to greatly reduce the recurrence of cancer, reduce side effects, increase patient survival rates, and improve the quality of life of breast cancer patients.

关键词：医药；治疗技术；乳腺癌；基因治疗

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Vascular disruption agents (VDAs) have been shown to selectively destroy established tumor vasculature, which results in the ischemic death of up to 99of tumor cells. The weakness of VDA monotherapy is that it often leaves a rim of surviving tumor cells which can then regrow and spread. The overall goal of this study (addressed in Task 2) is to enhance VDA therapy by inducing hyperthermia, targeted to the neovascular endothelium, through the use of superparamagnetic iron oxide nanoparticles (SPIONs), in order to halt, or significantly slow down tumor growth. Therefore, the first aim of this study (Task 1) is to maximize the delivery of SPIONs to the tumor rim, through a combination of neovascular targeting and increased vascular permeability induced by the VDA. Covalent coupling of a primary amine on the antibody to a carboxyl on the SPIONs activated by EDC/Sulfo-NHS resulted in colloidally- stable particles that showed specific binding to VEGFR-2 expressing cells in vitro. Current in vivo results suggest a synergistic enhancement of SPION delivery to the tumor rim when VEGFR-2 targeting of PEG-coated particles and 15 min pre-administration of DMXAA (a VDA) are employed. The results suggest that the combination of targeting the neovasculature and increasing vascular permeability through the action of the VDA is an effective SPION delivery strategy. Quantitative chemical analysis of tumor samples are ongoing to obtain statistically-significant iron quantitation. In vitro testing of SPION heating in the presence of an alternating magnetic field has been successful and demonstrates that heating is optimized using 20 nm SPIONs. However, in vivo testing of hyperthermia therapy in mice receiving targeted SPIONs after DMXAA pre-treatment is currently on hold, pending a solution to the problem of poor long-term survival of the mice after DMXAA administration.

关键词：医药；治疗技术；转移性乳腺癌；磁性纳米粒子热疗

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In the current funding period, we completed studies on the protective effects of adenoviral induced VEGF-D and compared this effect to VEGF-C. These findings were correlated with lymphatic and blood vessel density and support our hypothesis that lymphatic vessel induction is protective in IBD. These findings support lymphatic expansion as a controlling element of blood vessel expansion. We next examined the effects of VEGFR-2 kinase inhibitor, SU1498 and a VEGFR-2 competitor antibody on acute erosive colitis. VEGFR-2 blockade was protective in some phases of colitis and appears to reflect suppression of blood vessels. We also explored whether and how blockade of the pro-lymphangiogenic VEGF receptor, VEGFR-3 (using MAZ51, a VEGFR-3 kinase blocker) would affect acute erosive colitis. We found that VEGFR-3 blockade lead to significant increases in gut tissue injury, particularly when given during the recovery phase of the DSS model. This suggests to us that lymphatics may exert protective influences colitis by hastening recovery from disease rather than preventing its induction.

关键词：医药；治疗技术；血管疾病；淋巴系统

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During the most recent period the Center of Excellence continued to collect and process human breast cancer tissues for patients receiving chemotherapy for metastatic disease. These tissues have been annotated clinically, examined by the study pathologist for QC/QA purposes, entered into our data analysis system, and distributed to the appropriate laboratory investigators for evaluation. An initial analysis of patients with metastatic breast cancer treated with the antimetabolite prodrug capecitabine was performed, and revealed striking correlations between thymidylate synthase (as measured by fluorescence in situ hybridization) and outcome.

关键词：医药；治疗技术；乳腺癌；转移性治疗

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The project was intended to determine whether cytotoxic ionizing radiation induces upregulation of Hif1-alpha via a nitric oxide(NO)-mediated tumor stress response pathway and whether this effect can be inhibited by the administration of dietary glycine supplementation, which can suppress activation of the macrophages responsible for the NO. The ultimate goal was to test whether glycine effects tumor growth delay after ionizing radiation by suppressing this pathway. PC-3 cells transfected with a Hif-1 reporter detectable via bioluminescence imaging were implanted into nude mice and subjected to ionizing radiation (2-6 Gy), with or without prior and concurrent feeding with a glycine-rich diet. The results established the feasibility of this experimental model and confirm an increase in Hif-1; expression after ionizing radiation. Furthermore, the administration of dietary glycine supplementation suppressed radiation-induced Hif-1; expression and created a favorable growth delay in the xenograft model.

关键词：医药；治疗技术；前列腺癌；甘氨酸；放射疗法

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Operation brain trauma therapy (OBTT) is a multicenter, pre-clinical, drug screening and brain injury biomarker development consortium for TBI. OBTT includes investigators at the Safar Center (University of Pittsburgh), the University of Miami, WRAIR, Virginia Commonwealth University, and Banyan Biomarkers. Three rodent models (controlled cortical impact, parasagittal fluid percussion, and penetrating ballistic-like brain injury) are used for drug screening with the most promising candidates tested in a micropig model. We have completed studies with nicotinamide, erypthropoietin (EPO), and cyclosporine-A (CsA), and have just begun testing of simvastatin. We plan to test Minocycline and levetiracetam this year of funding. Studies with nicotinamide suggest some benefit of 50 mg/kg on motor outcomes, but variable benefit on cognitive outcomes. Studies with EPO did not appear promising. Studies with CsA have been completed; data analysis is ongoing. Studies of the serum brain injury biomarker GFAP from these rats have provided the first ever cross-model biomarker comparison and suggest that GFAP may be useful for drug screening, since nicotinamide treatment significantly reduced serum GFAP levels in two models. A consortium overview was published in Journal of Trauma and numerous abstracts were presented at the 2011 ATACCC, the 2012 NNT congress, and the 2012 MHSRS conference.

关键词：医药；治疗技术；创伤性脑损伤；临床医学

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The objective of this proposal is to test targeted carbon nanotubes for their ability to thermally ablate kidney cancer. Carbon nanotubes (CNTs) are efficient transducers of near-infrared radiation (NIR) for laser-induced thermal therapy of kidney cancer in mouse models. Our goal is to improve the anti-tumor efficacy of CNTs by designing them to target cancer cells and surrounding endothelial cells following systemic administration. Specifically, we will develop carbon nanotubes that bind to uPAR, a surface receptor overexpressed in kidney cancers and supporting endothelium. We will use D5, a peptide designed in the laboratory, as the targeting ligand. In the past year, we developed a new chemical approach to conjugating the targeting peptide to nanotubes. We demonstrated that the peptide is cytotoxic to kidney cancer cells. We also showed that the combination of nanotubes and NIR is effective in inhibiting the clonogenic survival of cultured kidney cancer cells. Next year, we will assess the flow of nanotubes in the vasculature and their ability to accumulate and exert an anti-tumor effect in a mouse tumor model. This grant is a mentor/predoctoral award that also focuses on training of a predoctoral candidate. The predoctoral fellow carried out the experiments described in this progress report, attended the national AACR cancer meeting, presented his work in seminars, and was co-first author on an article on nanotubes as thermal ablation agents.

关键词：医药；治疗技术；肾癌；碳纳米管

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