Brain metastasis occurs in30% of metastatic breast cancer patients. The prognosis is extremely poor, with a median survival of 4-6 months even with aggressive treatment. Thus, there is an urgent need to develop new treatments that target brain metastases. Radioimmunotherapy (RIT) is a targeted therapy that uses radiolabeled antibodies against tumor-specific antigens to treat lymphoma patients. However, success of RIT in the therapy of solid tumors has generally been limited due to heterogeneous tumor expression of the target antigens and cross-reactivity with normal cells. In preliminary studies, we have demonstrated that phosphatidylserine (PS) is exposed exclusively on tumor vascular endothelium of brain metastases in mouse models. A novel PS-targeting antibody, PGN635, a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically to tumor vascular endothelial cells in multi-focal brain metastases throughout the whole mouse brain. Vascular endothelium in normal brain tissues is negative. Furthermore, pretreatment with 10Gy of whole brain radiation significantly increased PGN635 binding to tumor vascular endothelial cells and tumor cells by increasing their exposure of PS. Vasculature in irradiated normal brain remained negative for exposed PS.

关键词：乳腺癌；转移；抗体；抗原

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Despite multiple therapeutic efforts targeting a variety of underlying pathogenic mechanisms, approaches to cure the mouse the models amyotrophic lateral sclerosis (ALS) have failed. With the exception of Riluzole (the only drug approved by the FDA for treatment of ALS), we have been unsuccessful at translating promising results from pre-clinical mouse trials to effective pharmacotherapies for ALS patients. One of the problems in finding highly efficacious treatments in ALS may derive from the so far underestimated issue of disease-driven pharmacoresistance mediated by the multi-drug resistance (mdr) efflux transporter, P-glycoprotein (P-gp). These are proteins that are present at the blood and spinal cord brain barrier whose function is to protect the brain from xenobiotics including drugs. These proteins actively pump out from the nervous system (CNS) foreign substances. We have shown that in ALS, both in patients and in the ALS mice, there is an increased expression and activity of these efflux transporter P-gps and hypothesized that one of the problem in treating ALS derives from a disease-driven acquired pharmacoresistance due to increased P-gps. Riluzole, which only has a modest effect in patients, is a Pg-p substarate. Thus, it is plausible that administration of Riluzole in combination with a P-gp inhibitor could improve its therapeutic outcome. With this proposal we test the hypothesis that co- administration of Riluzole with a potent P-gp inhibitor (Elacridar) will enhance Riluzole bioavailability and therefore will improve its therapeutic efficacy the SOD1-G93A ALS mice.

关键词：中枢神经系统；临床医学；药物耐受性

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The goal of this research was to compare, in the rescue mode of treatment, the effectiveness of (1) L-N-acetylcysteine (L-NAC); (2) D- Methionine (D-MET); (3) Ebselen SPI-1005; (4) Acetyl-L-carnitine (ALCAR) and (5) Src-PTK inhibitor, KX1-004 in reducing hearing and sensory cell loss as the result of an acute acoustic trauma that simulates blast injury to the auditory system. A shock tube was used to produce a blast injury to the cochlea in a chinchilla model. A secondary goal was to apply the same drug administration protocol to groups of animals exposed to a lower level continuous noise. Data from the treated and control animals consisted of: (1) auditory evoked potential hearing thresholds; (2) cubic distortion product otoacoustic emissions (DPOAE) input/output functions along with DPOAEs as a function of frequency (DPEgram) to estimate sensory cell function; (3) tympanograms to screen for conductive changes; (4) surface preparation histology to estimate the frequency specific sensory cell loss. Statistical analysis of the data employed a mixed model analyses of variance with repeated measures on one factor (frequency) using the SPSS Release 4.0 statistical package. Results: (1) There were no statistically significant differences between drug treated groups and controls. (2) There was a very large inter subject variability for all exposure groups.

关键词：听觉缺陷；药物；治疗；爆炸

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In recent years, machine learning techniques, such as support vector machines (SVMs), have shown significant potential as aids to the practice of medicine and to psychiatric classification. The application of machine learning techniques in psychiatric diagnosis has significant merit, because of the lack of standardized biological diagnostic tests. Conventionally, expert psychiatrists, consciously and unconsciously analyze the language of their patients for assessment purposes using diagnostic classification systems, such as DSM IV and ICD-10. To provide a more objective clinical diagnosis, SVMs have been applied to conversations of patients and clinicians.

关键词：机器学习技术；向量机；医药

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The purpose of this study is to generate a genome-wide association profile of Methyl-CpG Domain-containing (MBD) proteins, such as MeCP2, MBD1, MBD2 and MBD4, in malignant prostate cancer cells and matched normal or benign prostate cells using Chromatin Immunoprecipitation followed by Next Generation Sequencing (ChIP-Seq). The preliminary ChIP-Seq results establish the proof-of- principle that ChIP-Seq can be performed using the limited amounts of material available from these clinical samples (biopsies). This is the most significant result to date because it suggests that this study will be able to generate novel databases identifying the genome-wide MBD association profiles using clinical samples. In addition, our preliminary ChIP-Seq results have identified interesting genes such as a histone demethylase, a tetrahydrofolate synthase and piR-61309 near the association sites of MBD family members. In parallel, RNA expression profiles from the same tissues were generated to allow comparison of differential patterns of gene expression with differential patterns of MBD protein association. Microarray analysis has been performed and has identified genes that are up-regulated and down-regulated by at least 2- fold in Stage 3 prostate cancer cells.

关键词：前列腺癌；脱氧核糖核酸；基因组

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Mutations in mitochondrial DNA (mtDNA) are frequent in prostate cancer and they seem to occur early during prostate malignant transformation. Depletion of mtDNA in prostate cancer cells has been linked to acquisition of androgenindependence, progression to an invasive phenotype that is resistant to conventional chemotherapies, as well as induction of epithelial-mesenchymal transition leading to cancer metastasis. Using long-range genomic polymerase chain reaction, large deletion of mtDNA can be detected in prostate cancer tissues but not benign or normal prostate tissues. Noticeably, our study excludes the germ-line origin of the mutant mtDNA pattern in prostate cancer patient through analysis of the blood of the corresponding patient. Our data conclude that mtDNA deletion is due to carcinogenesis process in somatic prostate cells. In addition, our data have unveiled the molecular alteration in prostate cancer cells resulted from mtDNA deletion. For example, Skp2 protein elevation is often associated in prostate cells with loss of mtDNA. Also, the presence of Skp2 expression can decrease the expression of BRCA2 protein as an early biomarker of prostate neoplastic transformation, which is due to BRCA2 proteolysis.

关键词：脱氧核糖核酸；线粒体；前列腺癌；血细胞（生物学）

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The purpose of this study is to develop specific probes that target various cells populations in the tumor microenvironment. Tumor stroma contains many cell populations, such as vascular endothelial cells, immune cells, mesenchymal cells, and extracellular matrix, which are critical to tumor development and progression. Although various probes have been developed for tumor vasculature, there is a scarcity of markers for tumor macrophages, fibroblasts, nerve cells and the matrix. The goal of our group is to make technical improvements in our phage display system, and find peptides that target carcinoma-associated fibroblasts (CAFs) in breast tumors. To reach the goal, we have improved our phage display technology by involving in the screens iRGD, a tumor-specific tissue-penetrating peptide. iRGD enhanced the penetration of co-applied phage libraries into breast tumor tissue by two fold, allowing the libraries to reach and probe the stromal compartments within the tumors. We have also optimized high throughput sequencing for phage DNA, and methods to isolate CAFs from breast tumor tissue. Multiple phage library screens are underway. In parallel, we have made an unexpected discovery that iRGD itself is an efficient CAF-targeting peptide, and that the iRGD receptor neuropilin-1 is a potential CAF marker in breast tumors. iRGD in combination with novel CAF-targeting peptides may result in an efficient probe for breast tumor imaging and therapy.

关键词：细胞（生物学）；内皮；免疫；体内分析

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During the no-cost extension period, we tried to resolve the problems we were having with attempting to encapsulate NZ51 in various copolymers to facilitate faster release in mouse plasma. Even the use of PLGA or chitosan derivatives did not resolve the problems. Currently, we are postulating that the chemical structure of NZ51 is interfering with the formulation and utility for in vivo experiments. Subsequently, we attempted to encapsulate a different DDX3 inhibitor into PLGA nanoparticle. This appears to be more feasible than NZ51. The manuscript describing the formulation, release kinetics and cytotoxic effects using a different DDX3 inhibitor is in preparation. In addition, we have completed the study with NZ51 as well (in preparation), which indicated that NZ51 although very efficient in killing breast cancer cells in vitro was far less efficient in controlling tumor growth in a preclinical model of breast cancer.

关键词：乳腺癌细胞（生物学）；细胞毒素；动力学

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This paper describes elementary experiments for a technique to estimate the emotion of a user from the biological signals of user's central nervous system, such as cerebral blood flow and brain wave. The proposed technique uses multiple regression analysis in providing a high resolution measure to the emotional valence, which could not be realized with the existing methods based on peripheral nervous system. To demonstrate the effectiveness of the proposed emotion estimation technique in emotion based interaction, we also implemented an emotional painting tool that dynamically adapts the colors of brush and the outline of canvas to the estimated emotion of the user by recording biological signals and analyzing them in real time. The tool allows users to create original images that reflect their emotion.

关键词：情绪估计；生物信号；脑电波

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Neoadjuvant chemotherapy is currently the standard of care for locally advanced breast cancer (LABC). Monitoring tumor response is advantageous for patients. This project aims to using the subharmonic signals from ultrasound contrast agents to improve the monitoring of breast cancer treatment response to neoadjuvant therapies in women diagnosed with LABC by imaging tumor angiogenesis with 3D subharmonic imaging (SHI) and by estimating the interstitial fluid pressure (IFP) using 3D subharmonic aided pressure estimation (SHAPE). To date, software for analyzing RF data from a Logiq 9 ultrasound scanner (GE Healthcare, Milwauke, WI) to produce 3D SHAPE pressure estimates has been successfully developed. Initial in vivo experiments in 2 canines have been completed. SHI and the optimization algorithm implemented indicate that the use of SHAPE for noninvasive evaluation of the IFP in breast lesions is feasible with Definity. Moreover, However, difficulty in obtaining the necessary approvals for our human clinical trial has delayed the project by approximately 8 months.

关键词：乳腺癌；化疗；超声；算法；血管生成

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