This proposal will utilize RNA interference technology to diminish LRRK2 kinase activity in both cell culture and animal models of G2019S-mediated neurotoxicity to establish a novel therapy for PD. To achieve this objective we proposed the following Specific Aims: 1. Inhibition of wild-type LRRK2 and G2019S expression using small interfering RNAs (siRNA), 2. In vitro inhibition of wild-type LRRK2 and G2019S expression using shRNA technology and 3. In vivo inhibition of wild-type LRRK2 and G2019S expression using shRNA technology. During this award period we completed Technical Objective 1: Inhibition of wild- type LRRK2 and G2019S expression using small interfering RNAs in a cell line (MN9D) with LRRK2 or G2019S overexpression to attenuate the expression of wild- type and mutant LRRK2, cell death and neurite extension. We have completed this TO. In addition we made progress on Technical Objective 2: In vitro inhibition of wild-type LRRK2 and G2019S expression using shRNA technology. We have designed and expressed shRNAs that target LRRK2 or G2019S, cloned them into viral vector expression vectors and initiated the efficacy testing in vitro. Lastly, we initiated work on Technical Objective 3: In vivo inhibition of wild- type LRRK2 and G2019S expression using shRNA technology. We have constructed and expressed lentivirus with expression of WT and G2019S LRRK2 and rAAV expressing shRNAs.

关键词：帕金森病；磷转移；核糖核酸细胞（生物学）

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Adolescents are subjected to influences that may increase their risk for substance use or protect them from it. Substance use prevention programs are designed to reduce the influence of risk factors and increase the influence of protective factors. Parents can also affect substance use through conversations that they have with their children. Substance use prevention messages and programs are also provided through the media, schools, and other sources that have all been shown to have an association with alcohol and illicit drug use. Providing adolescents with credible, accurate, and age-appropriate information about the harm associated with substance use is a key component in prevention programming because youth perception of the risks associated with substance use are related to their rates of substance use. Prevention programming can be made more effective by gaining a better understanding how youths receive prevention messages. Similarly, prevention programming can be better targeted to address underserved populations if the demographic characteristics of youths not exposed to prevention messages or programs are known.

关键词：青少年；;滥用药物；预防方案；医药

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E. coli mazEF is a stress-induced toxin-antitoxin system discovered by us as being responsible for Programmed Cell Death (PCD) in the bacteria. Recently, we showed that under condition of severe DNA damage, the triggered mazEF-mediated death pathway leads to the inhibition of an Apoptotic-Like Death (ALD) pathway mediated by recA and lexA. The well known SOS pathway is an additional cellular response to DNA damage mediated by recA-lexA. It is the largest, most complex, and best characterized bacterial network induced by DNA damage Therefore, here we asked whether the mazEF-mediated pathway also inhibits the SOS response. We found that indeed this is the case. Under mild DNA damage, the expression of mazEF inhibits the SOS response. We examined various E. coli strains commonly used for studies of the SOS response. We found that SOS response only took place in E. coli cells in which one or more elements of the E. coli toxin-antitoxin module mazEF was not functioning. Thus, the interplay between the SOS response and the mazEF mediated pathway broaden the degree of the bacterial response to DNA damage. Our work reflects the complexity of the interplays between cellular networks, and as such reflects the importance of personalized medicine.

关键词：细菌细胞（生物学）；毒素和抗毒素；细胞凋亡

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Amplification of 8p11-12 occurs in approximately 15% of human breast cancer (HBC), and this region of amplification is significantly associated with disease-specific survival and distant recurrence in breast cancer patients (1- 5). Earlier, we used genomic analysis of copy number and gene expression to perform a detailed analysis of the 8p11-12 amplicon to identify candidate oncogenes in breast cancer (4). We identified Wolf-Hirschhorn syndrome candidate 1- like 1 (WHSC1L1) as a candidate oncogene based on statistical analysis of copy number increase and overexpression (4). The WHSC1L1 gene encodes a PWWP domain protein that regulates gene transcription and differentiated function of cells through regulation of histone methylation (6, 7). In this proposal, we hypothesize that WHSC1L1 is the major driving oncogene in the 8p11 amplicon that is found in aggressive forms of ER positive, luminal breast cancers. Furthermore, we hypothesize that genetic deregulation of WHSC1L1 induces alterations in the epigenetic histone code resulting in the acquisition of cancer stem cell phenotypes. Based on this hypothesis, we predict that WHSC1L1 will be a good therapeutic target in breast cancer, particularly for those ER positive breast cancers that are, or become, refractory to endocrine therapy.

关键词：乳腺癌；基因；组蛋白；细胞（生物学）

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The Coverage and Analysis Group at the Centers for Medicare and Medicaid Services (CMS) requested that the Technology Assessment Program (TAP) of the Agency for Healthcare Research and Quality (AHRQ) conduct an update of genetic tests for cancer condition.

关键词：遗传学；癌；技术评估；基因测试；临床医学

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An application of the basic results of deterministic network calculus theory to road traffic flow theory is presented. Network calculus is a theory based on min-plus algebra. This calculus uses algebraic techniques to compute performance bounds in communication networks, such as maximum end-to-end delays and backlogs. The objective of this paper is to investigate the application of those techniques for determining performance bounds on road networks, such as upper bounds for travel times. A traffic model is proposed for cars moving in a single-lane ring road without passing. The model is compatible with network calculus theory and permits derivation of an upper bound of the travel time of cars on the road. An approach for extending the model to calculate upper bounds for the travel times of cars on paths passing through intersections in a whole network is also proposed.

关键词：汽车；交通网络；微积分

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关键词：大数据；数据挖掘；知识发现；医学

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In early 2011, the NCPF and the American Society of Clinical Oncology (ASCO) held a workshop in which stakeholders discussed the changes they planned to implement in response to the IOM goals and recommendations (IOM, 2011). Two years later, on February 11-12, 2013, in Washington, DC, the NCPF and ASCO reconvened stakeholders to report on the changes they have made thus far to address the IOM recommendations.1 At this workshop, representatives from the NCI, the NCTN, comprehensive cancer centers, patient advocacy groups, the Food and Drug Administration (FDA), industry, and other stakeholders highlighted the progress that has been made in achieving the goals for a reinvigorated national cancer clinical trials system, and discussed additional strategies to further improve the system. This report is a summary of that workshop.

关键词：癌症；临床试验；讲习班；癌症研究

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Fe65 is a multidomain adaptor protein with established functions in neuronal cells and neurodegeneration diseases. It forms a multimeric complex with A amyloid precursor protein (APP) and histone acetyl transferase Tip60 to regulate the expression of gene.

关键词：蛋白质；乳腺癌细胞（生物学）；雌激素

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Brain-metastatic breast cancer (BMBC) is common in patients expressing epidermal growth factor receptor1 or 2 (EGFR or HER2). Lapatinib is a small-molecule inhibitor of EGFR and HER2 and EGFR/HER2-associated downstream signaling which result in the suppression of brain colonization propensities of in vivo-selected MDA-MB-231BR variant (BR for brevity). Conversely, heparanase (HPSE) is a potent tumorigenic, angiogenic, and pro-metastatic enzyme known to initiate effects which drastically alter the metastatic outcome. We selected lapatinib-sensitive and lapatinib-resistant clones (BR-Ls and BR-Lr) from BR parental cells and demonstrated that HPSE over-expression in BR-Lr but not BR- Lr clones. Addition of HPSE to BR-Lr cells resulted in EGFR phosphorylation and signaling, and to an augmented HPSE secretion and activity. Second, we used SST0001, a non-anticoagulant heparinoid with a potent anti-HPSE activity, and examined its action on BR-Lr/Ls clones. SST0001 effectively synergized with lapatinib to inhibit cell proliferation of BR-Lr cells. Similarly, HPSE inhibition was associated with reduced EGFR phosphorylation levels in those tyrosine residues not targeted by lapatinib (Y992); and reflecting reduced pSRC, pAKT, and pERK levels. Lastly, SST0001 in combination with lapatinib blocked tumor growth in vivo and BMBC by BR-Lr cells. These results provide novel insights into mechanisms responsible for lapatinib resistance in BMBC.

关键词：乳腺癌；脑细胞（生物学）；菌落（生物学）

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