Organophosphate (OP) poisoning can result in status epilepticus (SE), a medical emergency which can become pharmacoresistant if treatment is delayed. Little to no data exists on pediatric models of OP-induced SE, even though the immature brain is likely to respond differently to OPs, and the optimal therapies are also likely to differ from adults. Our aim is to identify novel drugs that block pharmacoresistant OP-induced SE in children. In the past year, we have provided USAMRICD investigators with the miniature telemetry devices and recording apparatus for recording from P7 and P14 rats. We have developed rat models for DPF exposure for ages P7, P14, P21, and P28. We have found that P7 and P14 rat pups have brief (minutes) seizure behavior in response to DFP, while P21 and P28 animals develop SE which is robust and lasts for several hours. We see extensive neuronal injury in P28 rats using Fluoro-Jade B as a marker. We have developed an electrographic profile for the EEG activity of DFP- treated P21 and P28 animals, and are working on profiles for P7 and P14 DFP- treated rat pups. We have begun characterizing the effects of midazolam on DFP- induced SE in P21 and P28 rat pups, and we find that midazolam ameliorates the SE triggered by the organophosphate.

关键词：惊厥性疾病；抗惊厥药；脑

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The specific aims of this project are to: 1) determine the efficacy, pharmacokinetics, toxicology and imaging capacity of RGDtargeted Nexil; and, 2) determine the ability of other ovarian cancer-specific targeting ligands to enhance the efficacy of Nexil. Substantial progress has been made on both of these specific aims. This is the final report. We have established that there is an excellent correlation between the tumor uptake of Nexil and its ability to deliver paclitaxel in a panel of 8 human tumor xenografts. Although we successfully synthesized RGD-target Nexil we were unable to show improved efficacy in a lung cancer mode. We have shown that the CPE peptide effectively targets the toxin gelonin to human ovarian cancer cells in a claudindependent manner, but that this fusion molecule has a difficult time getting out of the endosomal compartment and reaching the ribosome which is the target of gelonin. We have identified the A6 peptide as a CD44 tumor-targeting peptide worthy of further study.

关键词：纳米颗粒；卵巢；肿瘤细胞（生物学）

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关键词：骨髓；曝光（生理学）；造血干细胞

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The purpose of the present study is to investigate genome-wide DNA methylation changes in prostate specimens from African-American (AA) and European-American (EA) men in order to elucidate the differential DNA methylation changes associated with prostate cancer disparity and identify novel biomarkers for early disease detection. Results: We examined the methylation status of a total of 7 normal prostate tissues and 3 prostate cancer tissue samples from AA men and compared it with 8 normal prostate tissues and 3 prostate cancer tissue samples from EA men using the Infunium 450K (484,968) CpG sites that corresponds to 21,221 genes in microarray (illumina). Pathway analysis of microarray data for the genes with altered methylation patterns showed the involvement of cancer related genes in networks of axonal guidance, RhoA signaling and androgen signaling in AA specimens versus genes involved in epithelial-mesenchymal transition in EA specimens. Conclusion: Our genome-wide methylation analysis suggests differential methylation of several genes in important signaling pathways associated with prostate cancer progression. On-going studies is to validate the illumina microarray results using the methyl-binding domain of MBD2 (qMBD-seq) technique in order to identify regions that are consistently differentially methylated in AA versus EA specimens. For several genes where antibodies are available we will validate expression in tissue microarray analysis using prostate tissues from AA and EA men who have undergone radical prostatectomy.

关键词：基因工程；基因；甲基化；前列腺癌

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The overall objectives of our work on human ovarian carcinoma cells are to determine the mechanisms whereby hyaluronan-CD44-CD147 interactions influence malignant cell behavior and therapy resistance, and to apply our findings to the improvement of therapy, in malignant ovarian carcinoma. In this grant period we have shown that small hyaluronan oligosaccharides, which have previously been shown to antagonize hyaluronan-receptor interactions, sensitize cisplatin-resistant human ovarian carcinoma cells to cisplatin treatment in a mouse xenograft model, as well as in cell culture. Hyaluronan oligosaccharide- decorated nanoparticles containing chemotherapeutic agents are in preparation for maximizing these effects. We have also shown that siRNAs against the hyaluronan receptor, CD44, and the regulator of hyaluronan synthesis, CD147, sensitize cisplatin-resistant ovarian carcinoma cells to cisplatin in cell culture. Nanoparticles containing these siRNAs are in preparation for use in vivo.

关键词：化疗药物；卵巢肿瘤细胞（生物学）

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About half of schwannomas are driven by loss of the NF2 tumor suppressor gene; however, a major barrier to more effective therapies is the lack of a comprehensive understanding of the genetic events outside of the NF2 gene in these tumors. In this project, we hypothesized that additional point mutations, copy-number changes, and fusion events between distant regions of the genome, drive the development of these tumors. To address this hypothesis, we have obtained schwannoma tissue and matched blood and begun examining the somatic genetic alterations through next-generation sequencing. To date, five pairs have undergone exome sequencing, while two additional samples are undergoing whole-genome sequencing. Many additional samples from new collaborators are scheduled for additional sequencing. Interestingly, among the five whole-exome sequenced schwannoma samples, the mutation rates are low, with three of the five samples harboring NF2 mutations. Additionally, we have identified a mutation in the proto-oncogene CBL in one sample and a genomic translocation disrupting RB1 in another sample, though both of these findings will require further validation. These findings begin to shed some light on the molecular complexity of schwannoma formation, and analysis of additional samples will greatly assist in our efforts.

关键词：遗传学；肿瘤发生；障碍；血液

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The focus of this grant is to investigate immunoprofiles for serum antibodies to aberrant glycans in human and animal models of mesothelioma. This is accomplished using a one of a kind printed glycan array which is at NYU School of Medicine (NYUSoM). It is hoped that these experiments will allow us to diagnose and prognosticate mesothelioma more accurately in the future. We have been severely limited by our ability to start the human mesothelioma glycoprofiles as well as the animal profiles due to delivery and set up times for our one of a kind glycomics laboratory at NYUSoM. We summarize the situation in the progress report with the good news that we will be moving onwards in June with these studies.

关键词：抗体；血清中；癌；结缔组织

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Which is the molecular mechanism that leads to DNA amplification and oncogenes activation in breast cancer cells. This project aims to understand the role of estrogen in inducing re-replication, thus leading to DNA amplifications. I worked on the establishment of cancer cell line models carrying an engineered replication origin that will be tested for undergoing DNA amplification after estrogen treatment. I performed two biological replicates of a preliminary experiment done during Year-One, but I was unable to reproduce the exciting data previously obtained: Drug selection after estrogen exposure was not efficient in selecting cells with DNA amplification at the ectopic replication origin. Optimizing the working system to have multiple possibilities on the selection of cells with DNA amplification induced by estrogen receptor alpha, a new reporter construct have been built and a more efficient cell line model (U2OS/ER-alpha) have been characterized.

关键词：乳腺癌；扩增；脱氧核糖核酸

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This project seeks to identify and validate novel therapeutic targets for triple-negative breast cancer (TNBC). 681 genes showed consistent and highly significant overexpression in TNBC compared to receptor-positive cancers in 2 data sets. For two genes, 3 of the 4 siRNAs showed preferential growth inhibition in TNBC cells. These two genes were the low density lipoprotein receptor-related protein 8 (LRP8) and very low-density lipoprotein receptor (VLDLR). Exposure to their cognate ligands, reelin and apolipoprotein E isoform 4 (ApoE4), stimulated the growth of TNBC cells in vitro. Suppression of the expression of either LRP8 or VLDLR or exposure to RAP (an inhibitor of ligand binding) abolished ligand-induced proliferation. High-throughput protein and metabolic arrays revealed that ApoE4 stimulation rescued TNBC cells from serum-starvation induced up-regulation of genes involved in lipid biosynthesis, increased protein expression of oncogenes involved in the MAPK/ERK and DNA repair pathways, and reduced the serum-starvation induction of biochemicals involved in oxidative stress response and glycolytic metabolism. shLRP8 MDA-MB- 231 xenografts had reduced tumor volume and increased levels of necrotic cells, in comparison to parental and shCON xenografts. These results indicate that LRP8-APOE signaling confers survival advantages to TNBC tumors under reduced nutrient conditions and during environmental stress. As such, they may serve as potential targets for the treatment of triple-negative breast disease.

关键词：乳腺癌；肿瘤；核糖核酸；生物合成

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The central hypothesis of this application is that posterolateral spine fusion can be successfully achieved with a novel and simple minimally invasive percutaneous injection. We propose that this can be done by injection of AdBMP2 transduced human fibroblasts possessing an icasp9M that have been micro-encapsulated with osteoclast degradable hydrogel into the desired fusion site. During this first year, we have initiated the identification of the phenotype of the monocyte-like cells that appear to be capable of bone degradation. We have demonstrated in MSCs, which have a stably integrated icasp9M, can be rapidly induced to undergo apoptosis, after delivery of a chemical inducer of dimerization (CID) after encapsulation in PEG hydrogel. The next step is to start in vivo testing of this system. Additionally we have developed the methodology to non-invasively locate the hydrogel microsphere placement, optically, with respect to the newly forming bone. This has lead to a publication. We have also initiated studies to fuse the spine using our cell based gene therapy system encapsulated in the PEG hydrogel microspheres, in both mouse and rat. We will continue to complete these studies in the upcoming year.

关键词：成纤维细胞；注射液；骨骼；基因疗法

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