No description available.

No description available.

Breast cancer is a multifaceted disease that affects 1 in every 8 women. Triple negative breast cancer (TNBC) accounts for ~15-20% of all diagnosed breast cancers and is characterized by the absence of ER, PR, and HER2 on the tumor cell surface. As most cancer therapies to date target these cell surface receptors, TNBC is the only subtype of breast cancer without a targeted therapy and thus prognosis for it remains poor. The heterogeneity of TNBC also makes finding a targeted therapy particularly difficult. This work focuses on different methods of targeting distinct subpopulations of TNBC in order to identify potential novel therapeutic nodes to exploit as targeted therapies. The first chapter describes the use of a directed siRNA synthetic lethality screen to target vulnerabilities associated with basal TNBC, the most common TNBC subtype. The screen identified multiple dependency genes associated with RNA splicing, particularly those in the U4/U6.U5 tri-snRNP complex (PRPF8, PRPF38A). Depletion of these genes or the upstream splicing inhibitor E7107 in basal TNBC cell lines resulted in intronic retention and altered splicing of transcripts in pathways necessary for TNBC survival, including mitosis and apoptosis. In vivo, E7107 hindered the growth of both basal cell line and patient derived xenographs, a phenotype that was enhanced with the addition of the proteasome inhibitor bortezomib. This suggests that splicing and proteasome inhibition could be an effective basal TNBC treatment. The second chapter investigates the role of G-Protein Pathway Suppressor 2 (GPS2) as a tumor suppressor in the PI3K/AKT pathway in TNBC. Previous work has shown that GPS2 acts as a negative regulator of this pathway through inhibition of Ubc13-mediated activation of AKT in the insulin signaling pathway. In this study, MDA-MB231-GPS2KO cells were found to have increased proliferative, migratory, and invasive properties, which were rescued upon treatment with the allosteric AKT inhibitor MK2206. In vivo, GPS2 depleted cells conferred greater tumor burden in an orthotopic mouse model that was also responsive to AKT inhibition. Transcriptomic analysis showed significant overlap between MB231-GPS2KO and MB231 cells modified to have constitutively active AKT, indicating that the phenotypes observed in MB231-GPS2KO were at least in part due to loss of GPS2-mediated regulation of AKT activation. These studies point to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs. In sum, these studies elucidate interactions and processes that seem to specifically adversely affect TNBC cells, which broaden our knowledge of TNBC biology and its potential weaknesses. / 2022-03-03T00:00:00Z

As human populations rise exponentially, agricultural production systems must be adapted to sustain ecosystem function. Government administered agricultural conservation programs may actualize greater gains in ecosystem services, including wildlife population gains, if conservation practices designed to target specific environmental outcomes are implemented strategically in agricultural landscapes. I evaluated multi-scale, multi-species, and multi-season avian population responses to a targeted native herbaceous buffer practice (CP33: Habitat Buffers for Upland Birds) under the continuous sign-up Conservation Reserve Program administered by the U.S. Department of Agriculture. CP33 is the first conservation practice targeted directly to support habitat and population recovery objectives of a national wildlife conservation initiative (Northern Bobwhite Conservation Initiative). I coordinated breeding season, fall, and winter point transect surveys for northern bobwhite (Colinus virginianus), priority early-succession, and overwintering birds on ≈1,150 buffered and non-buffered fields in 14 states (10 ecoregions) from 2006-2009. I also assessed northern bobwhite-landscape associations within each ecoregion to determine effects of landscape structure on observed northern bobwhite abundances. Breeding season and autumn northern bobwhite densities were 60-74% and 52% greater, respectively, over all survey points in the near term (1-4 years post-establishment). However, breeding season and autumn response and associations between northern bobwhite abundance and landscape structure exhibited substantial regional variation, suggesting northern bobwhite conservation and management should be implemented on a regional basis. Breeding season densities of dickcissel (Spiza americana) and field sparrow (Spizella pusilla) were up to 190% greater on buffered fields, whereas overwintering densities of several Emberizid sparrow species were up to 2,707% greater on buffered fields. Species sensitive to patch area or those requiring vegetation structure different from that provided by buffers exhibited limited, but regionally and annually variable responses to buffered habitats. Increased bird densities of several species in several seasons suggest wildliferiendly farming practices delivered strategically and requiring minimal change in primary land use can benefit species across broad landscapes when conservation practices are targeted toward specific recovery objectives. Targeted conservation systems combining multiple conservation practices to provide an array of ecosystem services may be a mechanism for meeting multifarious conservation objectives and enhancing biodiversity in agricultural landscapes.

Background and Objectives: Economic evaluation and decision analysis provide a framework to evaluate incremental costs and effects associated with alternative health interventions. These methods can also be used as a tool to evaluate alternative clinical behaviours or practice patterns. The objective of this thesis was to investigate the impact of current Canadian practices in human epidermal growth factor receptor-2 (HER2) testing to target trastuzumab in early-stage breast cancer (BC). Methods: Project 1: A systematic review of previous trastuzumab and HER2 testing economic analyses was conducted to identify methodological gaps and key lessons. Project 2: A population-level, retrospective cohort was studied to determine HER2 testing and trastuzumab treatment patterns in Ontario early-stage BC patients. Project 3: A cost-utility analysis of alternative test-treat strategies was conducted using a Markov model of BC calibrated to the Canadian setting, and incorporating Project 2 findings. Results: Project 1: Previous economic evaluations demonstrated that HER2 test accuracy and sequencing were key considerations when modelling the cost-effectiveness of trastuzumab treatment. Consideration of local testing and treatment practices was lacking. Project 2: HER2 testing and treatment practice differed from guidelines, where documentation was available. Only 88% of equivocal results were confirmed, while 57% of HER2 positive patients received trastuzumab. Project 3: Calibration of the BC model minimised gaps between trial-based survival and expected Canadian survival patterns. Deviations from guidelines in practice suggest that primary testing with fluorescence in situ hybridization (FISH) would produce greater health gains at a reduced cost vs. primary immunohistochemistry with FISH confirmation. This finding was more apparent as the prevalence of HER2 positive disease increased. Introduction of newer in situ hybridisation tests may be cost-effective as well. Conclusions: Practice deviations from guidelines are an important consideration when modelling the cost-effectiveness of trastuzumab therapy. Underlying local disease progression and prevalence can also significantly impact outcomes. / Dissertation / Doctor of Philosophy (PhD)

The method targeted memory reactivation (TMR) uses specific stimulation when subjects are completing tasks and during sleep. The TMR process is known to influence the consolidation of declarative memories. The aim of this thesis is to conduct a systematic review on the effects of TMR on declarative memory consolidation during slow-wave sleep (SWS). The research question is to answer what effect TMR during SWS has on the consolidation of declarative memory in healthy humans when presented with associated cues of the targeted learning experiences. Eighteen studies were included in this review. Four studies found a significant effect of TMR on declarative memory consolidation, and 10 found a non-significant effect. In four studies the effect of TMR depended on different inclusions, analyses, and factors, for example between slow oscillation up-and down-states and between participants that vary in pre-sleep performance in the examined task. In contrast to previous findings, this review does not provide evidence for the effect of TMR on declarative memories during SWS. More research analysing different factors, such as different cues, age of participants, duration of SWS, and specific experimental tasks, needs to be done in the fields of TMR and auditory cues.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第21715号 / 薬科博第106号 / 新制||薬科||11(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 山下 富義, 教授 髙倉 喜信, 講師 樋口 ゆり子 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

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No description available.

Many attempts have been made to make cancer therapy more selective and less detrimental to the health of the patients. Nanoparticles have emerged as a way to solve some of the problems of traditional chemotherapy. Nanoparticles can provide protection for the therapeutic from degradation or clearance, as well as protection to healthy tissue from the damaging effects of chemotherapy drugs. Researchers are pursuing different strategies but all have the same goals of improving the outcomes of cancer patients. The field of controlled release of drugs has increased significantly in hopes of better treating diseases like cancer. Improved control of drug release has great potential for improving patient outcomes. Still there exist certain barriers such as circulation time, cell specificity, and endosomal escape.In this study a novel drug delivery vehicle was studied in vitro. The novel construct consisted of a liposome containing perfluorocarbon emulsions—an eLiposome—that was activated by ultrasound to break open on demand. Two targeting moieties were attached to the eLiposome to increase cell specificity and induce endocytosis. These studies determined the localization of eLiposomes in vitro using flow cytometry and confocal microscopy. Results indicated that eLiposomes modified with a targeting moiety attached to HeLa cells to a greater extent than non-targeting eLiposomes. Confocal images indicated localization of eLiposomes around the membrane of cells. Flow cytometer results indicated that ultrasound does in fact disrupt the eLiposomes but evidence of significant delivery to the cytoplasm was not obtained. However cells that were incubated with eLiposomes for 24 hours showed over 60% of the cells had green color association indicating eLiposome uptake.