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1
POMA, GIULIA. "Evaluation of bioaccumulation processes of brominated flame retardants in biotic matrices." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/50902.
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The global reduction in the use of PBDEs and HBCD as flame retardants has opened the way for the introduction of “Novel” BFRs (NBFRs) in place of the banned formulations, indicating those BFRs that are new in the market or newly/recently observed in the environment in respect to PBDEs and HBCD. Consequently, consumption and production of these NBFRs will keep rising, and increasing environmental levels of these chemicals are expected in the near future. Important representatives of this group are decabromodiphenyl ethane (DBDPE), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), hexabromobenzene (HBB), and pentabromoethylbenzene (PBEB).
In Italy, previous studies have shown that some BFRs (PBDEs) were measured at high concentrations in the Varese province due to the presence of a great number of textile and plastic industries, and particularly in the sediments of Lake Maggiore, where those facilities wastewaters are finally collected mainly through two lake tributaries (Bardello and Boesio). For these reasons, the present thesis has the aim to evaluate the presence, and the potential bioaccumulation and biomagnification processes of six different classes of BFRs (PBDEs, HBCD, DBDPE, BTBPE, HBB and PBEB) in the Lake Maggiore ecosystem, with particular regard to zebra mussels (Dreissena polymorpha), zooplankton, one littoral fish species (common roach - Rutilus rutilus), and two different pelagic species (twaite shad – Alosa agone and European whitefish – Coregonus lavaretus). Finally, the study has also considered the BFR contamination in the lake sediments with the aim of characterizing in detail the possible presence of temporal trends and/or identifying potential sources of contamination. Moreover, it is plausible that the BFR uptake by benthic organisms, followed by fish predation, might be a significant source of bioaccumulation.
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Drabick, Christopher L. "The Way We Get By." University of Akron / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=akron1369830067.
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Simoes, Isabella. "Development of a novel probiotic fortified protein bar." Diss., Columbia, Mo. : University of Missouri-Columbia, 2006. http://hdl.handle.net/10355/5868.
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Thesis (M.S.)--University of Missouri-Columbia, 2006.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on August 29, 2007) Includes bibliographical references.
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Vaughn, Samuel. "PXK and Lupus: Novel Immunobiology for a Lupus-Risk Gene." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447690650.
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Walker, Christopher James. "Novel therapies for treatment of Ph+ acute leukemias." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374148492.
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Du, Nan. "Beyond "More than Moore": Novel applications of BiFeO3 (BFO)-based nonvolatile resistive switches." Doctoral thesis, Universitätsbibliothek Chemnitz, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:ch1-qucosa-202508.
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The size reduction of transistors has been the main reason for a successful development of semiconductor integrated circuits over the last decades. Because of the physically limited downscaling of transistors, alternative technologies namely the information processing and nonvolatile resistive switches (also termed memristors) have come into focus. Memristors reveal a fast switching speed, long retention time, and stable endurance. Nonvolatile analog bipolar resistive switching with a considerable large On/Off ratio is reported in BiFeO3 (BFO)-based resistive switches. So far resistive switches are mainly applied in memory applications or logic operations. Given the excellent properties of BFO based memristors, the further exploration of functionalities for memristive devices is required. A new approach for hardware based cryptographic system was developed within the framework of this dissertation. By studying the power conversion efficiencies on BFO memristor at various harmonics, it has been shown that two sets of clearly distinguishable power ratios are achievable when the BFO memristor is set into high or into low resistance state. Thus, a BFO-based binary encoding system can be established. As an example the unrecoverable seizure information from encoded medical data suggests the proper functioning of the proposed encryption system. Aside from cryptographic functionality, the single pairing spike timing dependent plasticity (STDP) in BFO-based artificial synapses is demonstrated, which can be considered as the cornerstone for energy-efficient and fast hardware-based neuromorphic networks. In comparison to the biological driven realistic way, only single one pairing of pre- and postsynaptic spikes is applied to the BFO-based artificial synapse instead of 60-80 pairings. Thus, the learning time constant of STDP function can be reduced from 25 ms to 125 usIn den letzten Jahrzehnten war die Größenreduktion von Transistoren einer der Hauptgründe für die Leistungssteigerung von integrierten Halbleiterschaltungen. Aufgrund des physikalisch beschränkten Skalierungspotentials, werden alternative Technologien für Halbleiterschaltungen entwickelt. Dazu zählen neuartige Widerstandsschalter, sogenannte Memristoren, welche wegen ihrer schnellen Schaltgeschwindigkeit, langen Speicherzeit und stabilen Haltbarkeit in den Fokus der Forschung gerückt sind. Das nichtflüchtige analoge bipolare Schalten des Widerstandwertes mit einem On/Off Verhältnis größer als 100 wurde in BiFeO 3 (BFO)-basierten Widerstands-schaltern beobachtet. Bisher wurden Widerstandsschalter hauptsächlich als Speicher oder in rekonfigurierbaren Logikschaltungen verwendet. Aufgrund der ausgezeichneten Eigenschaften von BFO-basierten Memristoren, ist die Untersuchung weiterer neuer Funktionalitäten vielversprechend. Als neuer Ansatz für ein Hardware-basiertes Kryptosystem wird in der vorliegenden Arbeit die Ausnutzung des Leistungsübertragungskoeffizienten in BFO Memristoren vorgeschlagen. Mit Hilfe der unterschiedlichen Oberschwingungen, welche von einem BFO Memristor im ON und OFF Zustand generiert werden, wurde ein Kryptosystem zum Kodieren binärer Daten entwickelt. Ein Test des Hardware-basierten Kryptosystems an Biodaten ergab, dass die kodierten Biodaten keine vorhersagbare Korrelation mehr enthielten. In der vorliegenden Arbeit wurden darüberhinaus BFO-basierte künstliche Synapsen mit einer Aktionspotentials-Intervall abhängigen Plastizität (STDP) für Einzelpulse entwickelt. Diese Einzelpuls-STDP legt den Grundstein für energieffiziente und schnelle neuromorphe Netzwerke mit künstlichen Synapsen. Im Vergleich zu biologischen Synapsen mit einer 60-80-Puls-STDP und einem Lernfenster auf der ms-Zeitskale, konnte das Lernfenster von BFO-basierten künstlichen Synapsen von 25 ms auf 125 μs reduziert werden. Solch ein schnelles Lernen ermöglicht auch die extreme Reduzierung des Leistungsverbrauchs in neuromorphen Netzwerken
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Clark, Matthew Patterson. "A Novel Aza-Anthrapyrazole BBR 3378 Arrests Th1 Development Preventing Progression of EAE." University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1438091548.
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Colella, Gennaro Giovanni Domenico. "Molecular analysis of DNA damage induced by a novel trinuclear platinum complex (BBR 3464)." Thesis, Open University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343821.
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Rodrigues, Binoy Johann. "DYNAMIC FRICTIONAL RESPONSE OF GRANULAR MATERIALS UNDER SEISMICALLY RELEVANT CONDITIONS USING A NOVEL TORSIONAL KOLSKY BAR APPARATUS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1508455191610014.
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Deininger, Michael Werner Nikolaus. "STI571, a novel tyrosine kinase inhibitor : pre-clinical evaluation and application to identify downstream targets of BCR-ABL." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325912.
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McKenna, Mary Kathryn. "NOVEL ROLE OF PROSTATE APOPTOSIS RESPONSE-4 TUMOR SUPPRESSOR IN B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA." UKnowledge, 2017. https://uknowledge.uky.edu/microbio_etds/17.
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Chronic Lymphocytic Leukemia (CLL) is defined by the accumulation of clonally expanded CD5+ and CD19+ B lymphocytes in blood and secondary lymphoid organs with impaired apoptotic mechanisms. CLL represents one third of all leukemia cases with an average age of 72 years at diagnosis making it the most common adult leukemia. The Eµ-Tcl1 mouse serves as an excellent model to study the development of CLL as they progress to a CLL like disease by 9-14 months of age, due to overexpression of an oncogene, T cell Leukemia 1(Tcl1), specifically in B cells through the Ig VH promoter and Eµ enhancer (Bichi et al. PNAS. 2002). In an adoptive transfer model, intravenous or intraperitoneal injection of primary CD5+CD19+ CLL cells from the Eµ-Tcl1 CLL mouse into recipient syngeneic mice leads to the development of a CLL like disease within 3-8 weeks of transfer. We have characterized the growth of CLL cells in these mice by periodic submandibular bleeding, spleen ultrasonography and flow cytometry. We find that Eµ-Tcl1 CLL cells express more Prostate apoptosis response-4 protein (Par-4), a known pro-apoptotic tumor suppressor protein, than normal B-1 or B-2 cells in mice. Par-4 is silenced by promoter methylation in more than 30% of all cancers and has been shown to be secreted and to induce apoptosis selectively in various types of cancer cells but not in normal cells. We found that CLL cells have constitutively active B-cell receptor signaling (BCR) and that inhibition of BCR signaling with FDA approved drugs causes a decrease in Par-4 protein, mRNA levels, and an increase in apoptosis. In particular, activities of Src family kinases, spleen tyrosine kinase and Bruton’s tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling in both Eµ-Tcl1 CLL cells and primary human CLL samples. Consistent with this, lenti-viral shRNA mediated knockdown of Lyn kinase leads to a decrease in Par-4 expression in MEC-1 cells, a human CLL derived cell line. Igα (CD79a) silencing in primary human CLL cells also results in down regulation of Par-4 expression. Additionally, we knocked down expression of Par-4 in MEC-1 cells which resulted in a decrease in cell growth that could be attributed to an increase in p21 expression and a reduction in the G1/S cell cycle transition. We have also observed this phenomenon by crossing mice deficient in Par-4 with the Eµ-Tcl1 mouse where lack of Par-4 delays CLL growth in the mouse significantly (time to euthanization due to poor body condition - Eµ-Tcl1: 8.9mo vs Par4-/-EµTcl1: 11.97 mo, p = 0.0472) and splenic B-CLL cells from these mice also have increased expression of p21. Since mice in this cohort are whole body knockout for Par-4, the difference in survival times between the Par-4 +ve and Par-4 –ve EµTcl1 mice could be due to the influence of Par-4 on CLL cells as well as the effect of Par-4 secreted by the CLL cells on the microenvironment. There could be other potential roles for Par-4 in the context of CLL which are under further investigation. We have also investigated the site of CLL growth in mouse models to determine that the spleen is the primary organ to accumulate the CLL tumor burden. We have found that splenectomy significantly delays the development of CLL in the primary Eμ-Tcl1 mouse model and prevents growth and development in the adoptive transfer model. Interestingly, splenectomy did not delay CLL development as significantly in animals deficient for Par-4 compared to C57BL/6 wild type mice. Par-4 appears to regulate a specific microenvironment required for CLL growth. Current studies are investigating the role of Par-4 in the microenvironment and the cell types that are critical for CLL growth within the splenic niche.
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Peng, Cong. "Novel Therapeutic Targets for Ph+ Chromosome Leukemia and Its Leukemia Stem Cells: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/473.
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The human Philadelphia chromosome (Ph) arises from a translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)]. The resulting chimeric BCR-ABLoncogene encodes a constitutively activated, oncogenic tyrosine kinase that induces chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitor (TKI), imatinib mesylate, induces a complete hematologic and cytogenetic response in the majority of CML patients, but is unable to completely eradicate BCR-ABL–expressing leukemic cells, suggesting that leukemia stem cells are not eliminated. Over time, patients frequently become drug resistant and develop progressive disease despite continued treatment. Two major reasons cause the imatinib resistance. The first one is the BCR-ABL kinase domain mutations which inhibit the interaction of BCR-ABL kinase domain with imatinib; the second one is the residual leukemia stem cells (LSCs) in the patients who are administrated with imatinib. To overcome these two major obstacles in CML treatment, new strategies need further investigation.
As detailed in Chapter II, we evaluated the therapeutic effect of Hsp90 inhibition by using a novel water-soluble Hsp90 inhibitor, IPI-504, in our BCR-ABL retroviral transplantation mouse model. We found that BCR-ABL mutants relied more on the HSP90 function than WT BCR-ABL in CML. More interestingly, inhibition of HSP90 in CML leukemia stem cells with IPI-504 significantly decreases the survival and proliferation of CML leukemia stem cells in vitro and in vivo. Consistent with these findings, IPI-504 treatment achieved significant prolonged survival of CML and B-ALL mice. IPI-504 represents a novel therapeutic approach whereby inhibition of Hsp90 in CML patients and Ph+ ALL may significantly advance efforts to develop a cure for these diseases. The rationale underlying the use of IPI-504 for kinase inhibitor–resistant CML has implications for other cancers that display oncogene addiction to kinases that are Hsp90 client proteins.
Although we proved that inhibition of Hsp90 could restrain LSCs in vitro and in vivo, it is still unclear how to define specific targets in LSCs and eradicate LSCs. In Chapter III, we took advantage of our CML mouse model and compared the global gene expression signature between normal HSCs and LSCs to identify the downregulation of Pten in CML LSCs. CML develops faster when Pten is deleted in Ptenfl/fl mice. On the other hand, Pten overexpression significantly delays the CML development and impairs leukemia stem cell function. mTOR is a major downstream of Pten-Akt pathway and it is always activated or overepxressed when Pten is mutated or deleted in human cancers. In our study, we found that inhibition of mTOR by rapamycin inhibited proliferation and induced apoptosis of LSCs. Notably, our study also confirmed a recent clinical report that Pten has been downregulated in human CML patient LSCs. In summary, our results proved the tumor suppressor role of Pten in CML mouse model. Although the mechanisms of Pten in leukemia stem cells still need further study, Pten and its downstream, such as Akt and mTOR, should be more attractive in LSCs study.
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Rozmus, Jacob. "Novel mechanisms involving B cell receptor (BCR) and B cell activating factor (BAFF) signaling pathways underlying human primary immunodeficiencies and malignancy." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58377.
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The proper differentiation and survival of human peripheral immature B cells relies on two critical signaling pathways: B cell receptor (BCR) signaling and the B cell activating factor (BAFF)/BAFF-receptor (BAFF-R) signaling axis. The quality of the BCR signal is regulated in a developmental manner. Self-reactive early immature B cells are eliminated in response to strong BCR-induced signals, while late immature B cells require BCR-induced signals for survival and further differentiation. Although components and events downstream of the BCR are well known, the mechanisms of BCR signaling and its role in the regulation of BAFF signaling are still poorly understood. Through the use of transgenic and knockout murine models, the effects of BAFF on murine B cell maturation and survival are well characterized. There is a crucial need to better understand the functions of BAFF in humans. High levels of soluble BAFF, reduced expression of BAFF-R and BCR signaling abnormalities in B cells have been identified in a large group of clinically heterogeneous diseases including autoimmune and inflammatory conditions, allergy, viral infections and lymphoid cancers.
In order to better understand BCR signaling mechanisms, functional properties of human BAFF and factors regulating BAFF-R expression, this thesis describes: 1) the phenotypic, molecular and functional characterization of rare unknown inherited monogenic immunodeficiencies involving defects in early B cell development and the BAFF/BAFF-R pathway and, 2) the functional characterization of dysregulated BAFF/BAFF-R signaling in B cell malignancy. This led to the discovery of two novel primary immunodeficiencies involving MALT1 deficiency and gain-of-function PLCγ2 mutation. Our results indicate that MALT1 is essential for antigen-receptor mediated NF-κB activation and plays a role in the surface expression of BAFF-R and proper development of human B cells. The PLCγ2 mutation led to hyper-reactive BCR signaling and increased apoptosis of transitional B cells. Work-up of this patient also allowed us to investigate how soluble BAFF down-modulates surface expression of it’s principal receptor, BAFF-R, through receptor internalization, in normal B cells. Further analysis of the BAFF/BAFF-R pathway in pre-B acute lymphoblastic leukemia provides evidence of different structural and functional BAFF isoforms.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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DeGeer, Donna. "A novel oncogene AHI-1 interacts with BCR-ABL and JAK2 and mediates cellular resistance to tyrosine kinase inhibitors in CML." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/24851.
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Chronic myeloid leukemia is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, encoding a unique fusion gene BCR-ABL. The current first line treatment for patients diagnosed with CML involves administration of the ABL kinase inhibitor imatinib mesylate (IM). However, early relapses and acquired drug resistance remain a current impediment to successful treatment for many patients. This suggests the necessity for alternate treatment options which may include combination therapy targeting multiple vital proteins involved in the malignancy of the leukemia. AHI-1 (Abelson helper integration site 1) is a recently discovered oncogene that is highly deregulated in murine lymphomas and leukemias. AHI-1 displays a significant pattern of overexpression in a Philadelphia chromosome positive cell line K562 cells. To investigate AHI-1’s involvement in CML, AHI-1 was either stably overexpressed or suppressed in K562 cells. Interestingly, an increase in cellular proliferation and colony formation and a decrease in apoptosis were observed in the presence of IM when AHI-1 was overexpressed, while suppression of AHI-1 had the opposite effects. Phosphorylation and total protein expression levels of several proteins known to be involved in BCR-ABL signalling were quantified. Interestingly, elevated phosphorylation and total gene/protein expression levels of several of these proteins were observed when AHI-1 was overexpresessed, in particular NF-κB and JAK2/STAT5 displayed increased expression. Due to the strong effects AHI-1 had on the JAK2/STAT5 signalling cascade, we then inhibited JAK2 activity using a new JAK2 inhibitor, TG101209. AHI-1 overexpression led to a reduction in the cellular response to the inhibitor while suppression of AHI-1 caused an increase in sensitivity in viability, apoptosis, and colony forming cell assays. Finally, a combination of IM and TG101209 was examined in the same K562 cells lines. Results from suggest that using a combination treatment approach was more effective at inhibiting cellular viability and colony formation than either treatment alone. These findings together suggest that AHI-1 may play an important role in mediating cellular resistance to IM and TG101209 and activates several BCR-ABL signalling pathways, and that it may be a vital target in eradicating the malignant leukemic cells arising in CML.
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Gonzalez, Martinez Ignacio Guillermo. "Novel thermal and electron-beam approaches for the fabrication of boron-rich nanowires." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-218019.
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Pursuing the development and implementation of novel synthesis techniques to produce nanostructures with an interesting set of properties is a goal that advances the frontiers of nanotechnology. Also of fundamental importance is to revisit well-established synthesis techniques employing a new set of materials as precursors, substrates and catalysts. Fundamental breakthroughs in the field of nanotechnology can be achieved by developing new synthesis procedures as well as by adapting known procedures to new materials. This thesis focuses on both kinds of experiments.
A variant of chemical vapor deposition (CVD) has been used to produce Al5BO9 nanowires out of sapphire wafers without the need of a catalyst material. The novelty of the work relies on the formation mechanism of the Al5BO9 nanowires. Essentially, the process can be described as a large-scale topological transformation taking place on the substrate’s surface as its chemical composition changes due to the arrival of precursor molecules. Dense mats of Al5BO9 nanowires cover large areas of the substrate that were previously relatively flat. The process is enhanced by a high temperature and the presence of pre-existing superficial defects (cracks, terraces, etc.) on the substrates. Al5BO9 nanowires as well as B/BOX nanowires and BOX nanotubes were also produced via a novel in-situ electron beam-induced synthesis technique. The process was carried out at room temperature and inside a transmission electron microscope. Au nanoparticles were used as catalyst for the case of B/BOX nanowires and BOX nanotubes, while the Al5BO9 nanowires were synthesized without the need of a catalyst material. The formation and growth of the nanostructures is solely driven by the electron beam. The growth mechanism of the B/BOX nanowires and BOX nanotubes relies on interplay between electrostatic charging of the precursor material (to produce and transport feedstock material) and electron stimulated desorption of oxygen which is able to activate the catalytic properties of the Au nanoparticles. For the case Al5BO9 nanowires a nucleation process based on massive atomic rearrangement in the precursor is instigated by the e-beam, afterwards, the length of some of the nanowires can be extended by a mechanism analogous to that of the growth of the B/BOX nanowires.
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Katsoulas, Athanasia. "Design and mechanism of action of novel agents termed "combi-molecules" engineered for tandem targeting for Bcr-abl expressing leukemia cells." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111884.
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Bcr-abl expression being associated with anti-apoptotic signaling and expression of DNA repair enzymes, we surmised that single molecules capable of blocking abl tyrosine kinase (TK) function and damaging DNA should lead to compounds with potency superior to that of GleevecRTM. To this end, we designed novel agents termed "combi-molecules" programmed to not only behave as bcr-abl inhibitors on their own, but also to further degrade to another inhibitor and a DNA damaging species. The released inhibitor was designed to sustain bcr-abl inhibition following degradation of the combi-molecule and the DNA damaging species to activate pathways leading to apoptosis. To model this strategy termed "combi-targeting", we synthesized ZRCM5 (a monoalkyltriazene) that showed antiproliferative activity superior to that of the classical DNA damaging agent TemodalRTM, but not to that of Gleevec RTM. This result was imputed to the rather weak bcr-abl inhibitory activity of ZRCM5 and its strong DNA damaging property. Another prototype designed to contain an aniline mustard moiety (AK04) was a strong bcr-abl inhibitor but a poor DNA alkylating agent. Its cytotoxic activity was again stronger than that of the clinical alkylating agent chlorambucil but inferior to that of GleevecRTM. Further chemical studies directed at structural modification of the benzamide moiety led to the synthesis of ZRF1 with strong potency against bcr-abl TK and strong DNA damaging property. This novel optimized combi-molecule showed a 1.6-3-fold greater potency than GleevecRTM against bcr-abl expressing cells. Further investigation with ZRF1, showed that its cytotoxic potency was dependent on the p53 wild-type status of the cells. In cells expressing wild-type p53, p21 transactivation was associated with cell cycle arrest and that of Bax with apoptosis. In addition to, the pro-apoptotic effect of bcr-abl inhibition, these multiple mechanisms of action may synergistically enhance the cytotoxic potency of ZRF1 in p53 wild-type cells. The study conclusively demonstrated that p53 is a major determinant for the cytotoxic advantage of the novel combi-molecular approach in chronic myelogenous leukemia (CML), a disease in which 70-85% of all cases express wild-type p53.
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Gilart, Alzuria Núria. "Preparation and application of novel selective and polar materials for sorptive extraction of emerging contaminants from environmental waters." Doctoral thesis, Universitat Rovira i Virgili, 2014. http://hdl.handle.net/10803/275958.
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The aim of this Doctoral Thesis is the development of novel polymeric materials for different sorptive extraction techniques, such as solid-phase extraction (SPE) and stir bar sorptive extraction (SBSE). Both techniques were applied in liquid-chromatography and tandem mass spectrometry (LC-MS/MS) for determining a group of emerging contaminants, such as pharmaceuticals, illicit drugs and personal care products, from wastewater samples.
To improve the detection of these contaminants in several environmental samples at low levels of concentrations, extraction techniques have to enable a high enrichment factor and high selectivity towards the analytes of interest removing interfering compounds. In this Doctoral thesis, a molecularly imprinted polymer (MIP) specific for a group of non-steroidal and anti-inflammatory drugs (NSAIDs) and other polymeric material with strong cation-exchange behaviour were evaluated as sorbents for SPE. Moreover, different monolithic materials with a polar nature were also synthesised to be used as coatings for SBSE and as a result, favour the extraction of more polar compoundsLa present Tesi Doctoral té com a objectiu principal el desenvolupament de nous materials per a diferents tècniques d’extracció per sorció, com són l’extracció en fase sòlida i l’extracció mitjançant barres magnètiques agitadores. Ambdues tècniques van ser aplicades a la cromatografia de líquids seguida de l’espectroscòpia de masses en tàndem (LC-MS/MS) per a la determinació de diversos contaminants orgànics considerats com emergents, com són fàrmacs, drogues d’abús i productes d’higiene personal. Per tal de millorar la detecció d’aquests compostos en diferents mostres mediambientals a baixes concentracions, les tècniques d’extracció han de permetre un gran factor de preconcentració, selectivitat cap als analits d’interès i a la vegada eliminar interferències. En aquesta tesi, un polímer comercial d’empremta molecular específic per a un grup de fàrmacs (non-steroidal and antiinflammatory drugs (NSAIDs)) i un altre polímer d’intercanvi catiònic fort sintetitzat al laboratori van ser avaluats com a sorbents per a l’extracció en fase sòlida. A més a més, diferents materials monolítics de caràcter polar van ser també sintetitzats per recobrir barres magnètiques agitadores i així afavorir l’extracció de compostos de polaritat mitjana i elevada.
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Lai, Damian. "Targeting tyrosine kinase inhibitor-insensitive chronic myeloid leukemia stem/progenitor cells by effective inhibition of a novel PP2A-AHI-1-BCR-ABL-JAK2-complex." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54591.
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Imatinib Mesylate (IM) and other tyrosine kinase inhibitors (TKIs) have had a major impact on treatment of early phase Chronic Myeloid Leukemia (CML) patients. However, TKI monotherapies are not curative and initial and acquired resistance remain challenges. Particularly, CML stem cells are less responsive to TKIs and are a critical target population for TKI resistance. Thus, improved treatments targeting key elements active in CML stem cells are needed. One candidate is Abelson helper integration site-1 (AHI-1), an oncogene that is highly upregulated in CML stem cells and interacts with multiple kinases, including BCR-ABL and JAK2. AHI-1-mediated complexes regulate TKI response/resistance of CML stem/progenitor cells, indicating that AHI-1 is a new therapeutic target in CML. By screening the Prestwick Chemical Library, a specific growth inhibitory compound that potentially targets AHI-1 was identified: Cantharidin (CAN), an inhibitor of protein phosphatase 2A (PP2A). CAN is toxic however, so two new PP2A inhibitors, LB100 and LB102, were identified for this study. These new inhibitors specifically inhibit PP2A activity and suppress growth of CML cell lines. Importantly, these new PP2A inhibitors selectively target CML stem/progenitor cells while sparing healthy stem/progenitor cells. When combined with TKIs there is significant further suppression of growth in cell lines and in CD34+ treatment-naïve IM-nonresponder cells. Furthermore, this combination effect was determined to be synergistic. Cell cycle analysis showed that treatment with PP2A inhibitors alone induced a shift from G1 to G2/M phase. Confocal microscopy confirmed that the G2/M arrest led to mitotic catastrophe. However a similar shift in cell population was observed after combination with IM, suggesting that the G2/M phase arrest is solely due to PP2A inhibition. Mechanistically, the PP2A-PR55α subunit was identified as a new AHI-1 interacting protein. Western blot analysis showed that, compared to single agents, the combination treatment greatly suppresses protein expression of AHI-1, BCR-ABL, JAK2, STAT5, AKT, β-catenin, P-38 and JNK. The combination treatment also affected PP2A and BCR-ABL-mediated β-catenin dephosphorylation/phosphorylation. These results indicate that simultaneously targeting both BCR-ABL and PP2A activities in CML stem/progenitor cells may provide a novel treatment option for CML patients, through destabilization of the protein-protein interactions mediated by AHI-1.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Du, Nan [Verfasser], Oliver [Akademischer Betreuer] Schmidt, Oliver [Gutachter] Schmidt, Christian [Gutachter] Mayr, and Heidemarie [Gutachter] Schmidt. "Beyond "More than Moore": Novel applications of BiFeO3 (BFO)-based nonvolatile resistive switches / Nan Du ; Gutachter: Oliver Schmidt, Christian Mayr, Heidemarie Schmidt ; Betreuer: Oliver Schmidt." Chemnitz : Universitätsbibliothek Chemnitz, 2016. http://d-nb.info/1213815185/34.
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Cheema, Tasbir. "Rational Design, Synthesis and Evaluation of Novel Second Mitochondrial-Derived Activators of Caspase (Smac) Mimetics That Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cell Line." Thesis, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/20737.
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Programmed cell death (apoptosis) is the most common mechanism of cell death in eukaryotes. The ability of cancer cells to evade and inhibit apoptosis has become a hallmark feature of cancer. This is accomplished through a family of proteins known as the inhibitor of apoptosis proteins (IAPs). X-Linked inhibitor of apoptosis protein (XIAP) is one of the best characterized IAPs. XIAP suppresses apoptosis by forming complexes with cysteine-aspartic proteases (caspase), through one of its baculovirus IAP repeat (BIR) domains. Its activity is endogenously antagonized by a second mitochondria derived activator of caspase (Smac). The anti-apoptotic behaviour of XIAP and the critical role it plays in the apoptotic program makes the Smac-XIAP interaction an important drug target. To this end, our laboratory is interested in synthesizing biologically related Smac mimetics which can induce apoptosis in a MDA-MB-231 cell line.
Efforts have focused on (1) understanding BIR domain binding sites which allow for this interaction, and (2) the design and synthesis of molecules which are much more effective at inducing apoptosis compared to other well known analogues.
Through the synthesis and evaluation of various divalent Smac mimetics we have been able to support the hypothesis that the likely binding site on XIAP is the BIR3 domain. As well, through the synthesis of a library of novel compounds, as described in the thesis, we have been able to assess the nature of the linker which joins the two tetrapeptide units. In our effort to understand which domains Smac binds with, various divalent analogues were synthesized containing MeAVPI-linker-IPVMeA (forward-reverse) and MeAVPI-linker-MeAVPI (forward-forward) sequence, which incorporated linkers with varying degrees of flexibility. We hypothesized that the forward-forward divalent mimetics would have decreased activity compared to the peptides synthesized in a forward-reverse fashion.
Lastly, information gathered from structure activity relationship (SAR) studies have shown that substituting the lysine (P2) and isoleucine residues (P4) in the AVPI protein can create more potent inducers of apoptosis than its native AVPI sequence. As one of the most potent Smac mimetic that has been previously made known contains an alkyne bridge at P2 and a large hydrophobic moiety at P4, we hypothesized that similar Smac mimetics containing a propargyl glycine residue at P2 and a bulky hydrophobic moiety at P4 will be much more potent in inducing apoptosis.
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Okada, Masayuki. "A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL positive human leukemic cells : caspase-independent, necrosis-like programmed cell death mediated by serine protease activity." Kyoto University, 2005. http://hdl.handle.net/2433/145297.
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Yokota, Asumi. "INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph[+] leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity." Kyoto University, 2009. http://hdl.handle.net/2433/126449.
Full textAbstract:
Kyoto University (京都大学)0048
新制・課程博士
博士(医学)
甲第14902号
医博第3387号
新制||医||977(附属図書館)
27340
UT51-2009-M816
京都大学大学院医学研究科医学専攻
(主査)教授 武藤 誠, 教授 武田 俊一, 教授 松岡 雅雄, 教授 戸井 雅和
学位規則第4条第1項該当
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Pagliaro, Sarah Beatriz De Oliveira. "Transcriptional control induced by bcr-abl and its role in leukemic stem cell heterogeneity. Single-Cell Transcriptome in Chronic Myeloid Leukemia: Pseudotime Analysis Reveals Evidence of Embryonic and Transitional Stem Cell States Single Cell Transcriptome in Chronic Myeloid Leukemia (CML): Pseudotime Analysis Reveals a Rare Population with Embryonic Stem Cell Features and Druggable Intricated Transitional Stem Cell States A novel neuronal organoid model mimicking glioblastoma (GBM) features from induced pluripotent stem cells (iPSC) Experimental and integrative analyses identify an ETS1 network downstream of BCR-ABL in chronic myeloid leukemia (CML)." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ032.
Full textAbstract:
La leucémie myéloïde chronique est une hématopoïèse maligne clonale, caractérisée par l'acquisition de la translocation t (9;22) conduisant au chromosome Ph1 et à son homologue l'oncogène BCR-ABL, dans une cellule souche hématopoïétique très primitive. La LMC est un modèle de thérapies ciblées, car il a été démontré que la preuve de la faisabilité du ciblage de l'activité tyrosine kinase (TK) BCR-ABL à l'aide d'inhibiteurs de TK (TKI) entraîne des réponses et des rémissions majeures. Cependant, les problèmes actuels rencontrés dans ces thérapies sont la résistance des cellules souches leucémiques primitives et leur persistance qui serait liée à l'hétérogénéité des cellules souches au moment du diagnostic, ce qui conduit à la sélection clonale de cellules résistant aux thérapies TKI. J'ai appliqué la technologie de l'analyse du transcriptome des cellule uniques aux cellules de la LMC en utilisant un panel de gènes impliqués dans différentes voies, combinée à l'analyse d'inférence de trajectoire au modèle d'expression des gènes. Les résultats ont montré un état transitoire des cellules souches comprenant des gènes embryonnaires identifiés dans les cellules de la LMC au moment du diagnostic, ce qui pourrait contribuer à la résistance et à la persistance de la LSC. En outre, l'oncoprotéine Bcr-Abl est la tyrosine kinase constitutivement active produite par le gène chimérique BCR-ABL dans la leucémie myéloïde chronique (LMC). Les cibles transcriptionnelles de Bcr-Abl dans les cellules leucémiques n'ont pas été étudiées de manière approfondie. Une expérience de transcriptome utilisant la lignée cellulaire UT7 hématopoïétique exprimant BCR-ABL, a identifié la surexpression du facteur d'élongation eucaryote kinase 2 (eEF2K) qui joue un rôle majeur dans la survie des cellules en cas de privation de nutriments. Dans l'ensemble, les données suggèrent que la surexpression de eEF2K dans la LMC est associée à une sensibilité accrue à la privation de nutrimentsChronic myeloid leukemia is a clonal hematopoietic malignancy, characterized by the acquisition of the t (9;22) translocation leading to Ph1 chromosome and its counterpart BCR-ABL oncogene, in a very primitive hematopoietic stem cell. CML is a model of targeted therapies as the proof of concept of the feasibility of targeting the tyrosine kinase (TK) activity BCR-ABL using TK inhibitors (TKI) has been shown to lead to major responses and remissions. However, the current problems encountered in these therapies are primitive leukemic stem cells resistance and their persistence which is thought to be related to the heterogeneity of the stem cells at diagnosis leading to clonal selection of cells resisting to TKI therapies. I have applied the technology of single cell transcriptome analysis to CML cells using a panel of genes involved in different pathways combined with trajectory inference analysis to the gene expression pattern. The results showed a transitional stem cell states including embryonic genes identified in CML cells at diagnosis which could contribute to LSC resistance and persistence. Furthermore, the oncoprotein Bcr-Abl is the constitutively active tyrosine kinase produced by the chimeric BCR-ABL gene in chronic myeloid leukemia (CML). The transcriptional targets of Bcr-Abl in leukemic cells have not been extensively studied. A transcriptome experiment using the hematopoietic UT7 cell line expressing BCR-ABL, has identified the overexpression of eukaryotic elongation factor kinase 2 (eEF2K) which plays a major role in the survival of cells upon nutrient deprivation. Overall, the data suggest that overexpression of eEF2K in CML is associated with an increased sensitivity to nutrient-deprivation
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Du, Nan. "Beyond "More than Moore": Novel applications of BiFeO3 (BFO)-based nonvolatile resistive switches." Doctoral thesis, 2015. https://monarch.qucosa.de/id/qucosa%3A20443.
Full textAbstract:
The size reduction of transistors has been the main reason for a successful development of semiconductor integrated circuits over the last decades. Because of the physically limited downscaling of transistors, alternative technologies namely the information processing and nonvolatile resistive switches (also termed memristors) have come into focus. Memristors reveal a fast switching speed, long retention time, and stable endurance. Nonvolatile analog bipolar resistive switching with a considerable large On/Off ratio is reported in BiFeO3 (BFO)-based resistive switches. So far resistive switches are mainly applied in memory applications or logic operations. Given the excellent properties of BFO based memristors, the further exploration of functionalities for memristive devices is required.
A new approach for hardware based cryptographic system was developed within the framework of this dissertation. By studying the power conversion efficiencies on BFO memristor at various harmonics, it has been shown that two sets of clearly distinguishable power ratios are achievable when the BFO memristor is set into high or into low resistance state. Thus, a BFO-based binary encoding system can be established. As an example the unrecoverable seizure information from encoded medical data suggests the proper functioning of the proposed encryption system.
Aside from cryptographic functionality, the single pairing spike timing dependent plasticity (STDP) in BFO-based artificial synapses is demonstrated, which can be considered as the cornerstone for energy-efficient and fast hardware-based neuromorphic networks. In comparison to the biological driven realistic way, only single one pairing of pre- and postsynaptic spikes is applied to the BFO-based artificial synapse instead of 60-80 pairings. Thus, the learning time constant of STDP function can be reduced from 25 ms to 125 us.In den letzten Jahrzehnten war die Größenreduktion von Transistoren einer der Hauptgründe für die Leistungssteigerung von integrierten Halbleiterschaltungen. Aufgrund des physikalisch beschränkten Skalierungspotentials, werden alternative Technologien für Halbleiterschaltungen entwickelt. Dazu zählen neuartige Widerstandsschalter, sogenannte Memristoren, welche wegen ihrer schnellen Schaltgeschwindigkeit, langen Speicherzeit und stabilen Haltbarkeit in den Fokus der Forschung gerückt sind. Das nichtflüchtige analoge bipolare Schalten des Widerstandwertes mit einem On/Off Verhältnis größer als 100 wurde in BiFeO 3 (BFO)-basierten Widerstands-schaltern beobachtet. Bisher wurden Widerstandsschalter hauptsächlich als Speicher oder in rekonfigurierbaren Logikschaltungen verwendet. Aufgrund der ausgezeichneten Eigenschaften von BFO-basierten Memristoren, ist die Untersuchung weiterer neuer Funktionalitäten vielversprechend. Als neuer Ansatz für ein Hardware-basiertes Kryptosystem wird in der vorliegenden Arbeit die Ausnutzung des Leistungsübertragungskoeffizienten in BFO Memristoren vorgeschlagen. Mit Hilfe der unterschiedlichen Oberschwingungen, welche von einem BFO Memristor im ON und OFF Zustand generiert werden, wurde ein Kryptosystem zum Kodieren binärer Daten entwickelt. Ein Test des Hardware-basierten Kryptosystems an Biodaten ergab, dass die kodierten Biodaten keine vorhersagbare Korrelation mehr enthielten. In der vorliegenden Arbeit wurden darüberhinaus BFO-basierte künstliche Synapsen mit einer Aktionspotentials-Intervall abhängigen Plastizität (STDP) für Einzelpulse entwickelt. Diese Einzelpuls-STDP legt den Grundstein für energieffiziente und schnelle neuromorphe Netzwerke mit künstlichen Synapsen. Im Vergleich zu biologischen Synapsen mit einer 60-80-Puls-STDP und einem Lernfenster auf der ms-Zeitskale, konnte das Lernfenster von BFO-basierten künstlichen Synapsen von 25 ms auf 125 μs reduziert werden. Solch ein schnelles Lernen ermöglicht auch die extreme Reduzierung des Leistungsverbrauchs in neuromorphen Netzwerken.
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Pracht, Catrin [Verfasser]. "The analysis of B-cell antigen receptor (BCR) mutants deficient in antigen independent signaling reveals novel BCR-associated proteins / vorgelegt von Catrin Pracht." 2005. http://d-nb.info/973639431/34.
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Huang, Yu-Wen, and 黃郁文. "A Novel Stir-Bar Sorptive Extraction with Sublimate Sorbent of Aqueous Endocrine Disruptor Pesticides prior to Gas Chromatography- Electron Capture Detection Determination." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/14743253918225236997.
Full textAbstract:
碩士國立中興大學
化學系所
102
In this study, for the first time, cyclododecane (CDD) has been used as a novel disposable sorbent coating for stir bar sorptive extraction (SBSE) technique for the rapid analysis of endocrine disruptor pesticides in environmental water samples using gas chromatography-electron capture detection (GC-ECD). A magnet bar (0.15 x 1 cm) was coated with CDD and utilized as a sorbent phase to extract endocrine disruptor pesticides in aqueous samples. CDD is solid (melting point of about 61°C) at room temperature with the sublimation character (solid to gas state), and is readily soluble in nonpolar and aromatic solvents. So it was utilized as a sorbent phase at room temperature, called pseudo sorbent material. CDD has no highly electronegative element in it, hence it has no signals of supersaturated solvent to interfere analytes in the electron capture detector. In this work, CDD was dissolved in hexane and used as CDD sorbent coating solution. The magnet stir bar was dipped in the CDD solution to get the desired sorbent coating layer and dried under the room temperature, then it was utilized as sorbent material for SBSE. A ''dumbbell-shaped'' stir bar was assembled by attaching two steel balls at both ends of the stir bar to prevent the sorbent coating in direct contact with the bottom of the extraction vessel during extraction and thus reduce the friction loss. In this extraction procedure, firstly, stir bar were added into the sample solution and followed by the extraction process, and then hexane used to desorb the extraction sorbent phase from the stir bar for GC-ECD analysis. Parameter affecting the experimental conditions such as the extraction solvent (sorbent phase), the sorbent coating thickness, the pH of the sample solution, the salting-out effect, the stirring speed, the extraction time and desorption solvent volume were thoroughly optimized. The maximum extraction efficiency was obtained under the optimized conditions as follows; stir bar (with the CDD coating thickness of 5.2 μm) was added into 10 mL sample solution (at pH 7) and followed by the extraction for 20 minutes at a stirring rate of 600 RPM. Then, the stir bar was gently removed from the sample solution and immersed into the desorption tube consisting of 3 μL hexane to desorb, and then 1 μL of the eluted solution was directly injected into GC-ECD for analysis. Under the optimal condition, linear ranges were ranged from 0.005-5 μgL-1. Coefficients of the determinations were ranged between 0.9950~0.9994. Quantitation limits were ranged between 0.004-0.02 μgL-1. Detection limits were ranged between 0.001-0.006 μgL-1, relative standard deviation (RSD) was below 6.7%. The relative recoveries of the spiked sample were ranged between 82.9-101.3% and RSDs were below 8.8% in farm field wastewater samples. The developed method was obtained excellent enrichment factors (101-834) and provides a simple, rapid and eco-friendly sample preparation method. Thus, the method could be applied for the determination of endocrine disrupting pesticides in the real field environment water samples.
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Gonzalez, Martinez Ignacio Guillermo. "Novel thermal and electron-beam approaches for the fabrication of boron-rich nanowires." Doctoral thesis, 2016. https://tud.qucosa.de/id/qucosa%3A30143.
Full textAbstract:
Pursuing the development and implementation of novel synthesis techniques to produce nanostructures with an interesting set of properties is a goal that advances the frontiers of nanotechnology. Also of fundamental importance is to revisit well-established synthesis techniques employing a new set of materials as precursors, substrates and catalysts. Fundamental breakthroughs in the field of nanotechnology can be achieved by developing new synthesis procedures as well as by adapting known procedures to new materials. This thesis focuses on both kinds of experiments.
A variant of chemical vapor deposition (CVD) has been used to produce Al5BO9 nanowires out of sapphire wafers without the need of a catalyst material. The novelty of the work relies on the formation mechanism of the Al5BO9 nanowires. Essentially, the process can be described as a large-scale topological transformation taking place on the substrate’s surface as its chemical composition changes due to the arrival of precursor molecules. Dense mats of Al5BO9 nanowires cover large areas of the substrate that were previously relatively flat. The process is enhanced by a high temperature and the presence of pre-existing superficial defects (cracks, terraces, etc.) on the substrates. Al5BO9 nanowires as well as B/BOX nanowires and BOX nanotubes were also produced via a novel in-situ electron beam-induced synthesis technique. The process was carried out at room temperature and inside a transmission electron microscope. Au nanoparticles were used as catalyst for the case of B/BOX nanowires and BOX nanotubes, while the Al5BO9 nanowires were synthesized without the need of a catalyst material. The formation and growth of the nanostructures is solely driven by the electron beam. The growth mechanism of the B/BOX nanowires and BOX nanotubes relies on interplay between electrostatic charging of the precursor material (to produce and transport feedstock material) and electron stimulated desorption of oxygen which is able to activate the catalytic properties of the Au nanoparticles. For the case Al5BO9 nanowires a nucleation process based on massive atomic rearrangement in the precursor is instigated by the e-beam, afterwards, the length of some of the nanowires can be extended by a mechanism analogous to that of the growth of the B/BOX nanowires.
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Schafranek, Lisa Rhiannon. "Assessment of critical survival mechanisms exploited by BCR-ABL1+ cells to evade tyrosine kinase inhibitor-induced death: determination of novel therapeutic targets in chronic myeloid leukaemia." Thesis, 2014. http://hdl.handle.net/2440/92213.
Full textAbstract:
Chronic myeloid leukaemia (CML) is a clonal myeloid proliferative disease that results from constitutive activation of the Bcr-Abl oncoprotein, which disrupts normal cellular signalling potentiating the survival and maintenance of BCR-ABL1+ cells. Tyrosine kinase inhibitors (TKIs), like imatinib, have revolutionised the treatment of CML and have become the model for therapy in other cancers. Imatinib treatment also founded the paradigm that potent and continuous dosing is required for optimal patient response in patients with CML. In contrast to imatinib, the second generation TKI dasatinib has a short half-life of only 3-5 h, nevertheless a once daily dosing regime is sufficient to achieve equivalent responses to twice daily dosing suggesting that continuous and complete inhibition of Bcr-Abl may not be required for optimal response to TKI therapy. Despite initial studies indicating that a very brief exposure to a potent dose of TKI is sufficient to induce cell death in BCR-ABL1+ cells, recent studies have attributed this to sustained low-level inhibition of Bcr-Abl signalling due to inadequate drug washout. As reported in this thesis, experiments with low dose dasatinib treatment, which does not completely inhibit Bcr-Abl phosphorylation but is sufficient to induce cell death, demonstrated inactivation of STAT5 as a sensitive measure of Bcr-Abl activity. Here, it was also confirmed that <1 h exposure to potent TKI with adequate drug washout is insufficient to commit BCR-ABL1+ cells to death and it is established for the first time that at least 2 h of Bcr-Abl kinase inhibition are required. Furthermore, combinations of efficient TKI washout with specific inhibitors of STAT5, JAK and ERK ascertained sustained inhibition of pSTAT5, potentially independent of JAK2, as the determinant of commitment to cell death. Together, this research established that continuous, complete inhibition of Bcr-Abl is not required to induce cell death, but that continuous blockade of STAT5, indicative of low-level threshold Bcr-Abl inhibition, is essential, thus challenging the imatinib paradigm. Although most CML patients respond well to imatinib, only 40% of patients achieve a complete molecular response and some patients develop resistance. Blockade of Bcr-Abl signalling can drive cells to develop new survival mechanism, and amongst others, autophagy and the acquisition of extrinsic survival signalling have been implicated in resistance to therapy and/or persistent disease. Studies presented in this thesis define a role for the activation of autophagy in response to tyrosine kinase inhibition of Bcr-Abl. Induction of autophagy by TKI was confirmed using established markers of autophagy, such as the conversion of LC3-I to LC3-II, degradation of p62 and cellular morphology. Blockade of anti-apoptotic proteins Bcl-2 and Bcl-xL along with activation of stress response pathways were revealed as potential mechanisms of autophagy induction, however, further investigation into these pathways is required. Importantly, the data presented here also established clarithromycin as a novel inhibitor of TKI-induced autophagy, advocating combination treatment with TKI therapy in resistant patients. Recent observations that overexpression of cytokines and their receptors may contribute to BCR-ABL1+ cell persistence in CML patients undergoing TKI therapy. Here, the expression of IL-3 and GM-CSF cytokine receptors in BCR-ABL1+ cell lines and chronic phase CML CD34+ progenitor cells was established and signalling through those was confirmed to maintain STAT5 survival signalling, thereby protecting cells from TKIinduced death. Inhibition of JAK2 with ruxolitinib inhibited cytokine-dependent, but not Bcr-Abl-dependent, activation of STAT5 and neutralised cytokine-induced protection from cell death while having little effect in the absence of cytokines. Together, the findings of this thesis established the critical mechanisms in Bcr-Abldependent and -independent signalling that may also be targeted in combination therapeutic approaches and provides an in-depth understanding of the potential clinical effectiveness of dose reductions during dasatinib therapy. These studies will have broad implications for the ongoing development of therapeutic strategies in CML, particularly in the setting of TKI-resistance, and will aid the goal of achieving a curative treatment for patients with CML.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2014
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Santos, Jorge Miguel Martins. "A Novel Integrated Metabolic Activated Sludge Model for Enhanced Biological Phosphorus Removal Processes: Development, Calibration, Validation and Application." Doctoral thesis, 2020. http://hdl.handle.net/10362/106688.
Full textAbstract:
Enhanced biological phosphorus removal (EBPR) facilities achieve low effluent phosphorus (P)
levels (below 1 g P.m-3) for long periods of time. However, these facilities are often affected by
unpredictable upsets that increase their operational costs and reduce the potential to recover P from
downstream processes. Thereby, these facilities need to have access to reliable tools, capable of
dynamically predicting EBPR performance and diagnosing plant upsets. To address this need, a novel
integrated metabolic activated sludge model, the META-ASM, was developed with a robust single set
of default parameters to describe the activity of the key organisms and processes relevant to EBPR
systems.
The advances regarding EBPR mechanisms investigated over the last twenty years were integrated
in the META-ASM model to overcome various shortcomings of existing EBPR models. Special attention is given to the effect of operational conditions on the competition between polyphosphate accumulating organisms (PAOs) and glycogen accumulating organisms (GAOs), along with the
capability of PAOs and GAOs to denitrify, the metabolic shifts as a function of storage polymer concentration for each group, the role of these polymers in endogenous processes, and a better description of the fermentation process.
The model was calibrated and validated against 34 data sets describing different EBPR dynamics obtained from bench-scale batch tests inoculated with lab-scale enriched PAO-GAO cultures and full- scale sludge from different EBPR facilities. The overall strong correlations obtained between the
predicted and the measured EBPR profiles demonstrated that this new model reduces calibration efforts and is capable of predicting the microbial and chemical transformations over a wide range of operational
and environmental conditions, supporting the robustness of the unique default parameter set that was generated. A performance comparison between META-ASM and literature models also demonstrated
that existing models require extensive parameter changes and have limited predictive power to describe
different EBPR dynamics.
The capacity of the META-ASM model to describe the long-term performance of a full-scale 3- stage Phoredox (A2/O) EBPR system and to be used as an operational diagnostic tool was evaluated in a 1336-day long-term dynamic simulation, while its performance was compared with the ASM-inCTRL model, a version based on the Barker & Dold model. Overall, the META-ASM provided a better description of PAOs active biomass and storage polymers and was a more powerful operational
diagnostic tool for plant upsets. Viable troubleshooting scenarios were simulated to mitigate the upsets caused by the high aerobic hydraulic retention times (HRTs) and low organic loading rates (OLRs) of
the plant. This thesis demonstrates that the META-ASM model is a powerful operational diagnostic tool for
EBPR systems, capable of predicting plant upsets, optimising performance and evaluating new process designs.
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Chiang, Yuan-Jung, and 蔣沅融. "A Novel LCD Defect Detection Rate Raising Method by Connecting Gate Scanning Lines of TFT Array to Ground with Shorting-Bar and Applying Taguchi P-Diagram for Experiment Design." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/32461899491582534046.
Full textAbstract:
碩士中華大學
電機工程學系碩士在職專班
101
In recent years the TFTs manufacturing technology are with large improvements for various LCD products. The size of glass substrate becomes larger and larger to increase both production rates and application fields. However, the larger the size of glass substrate, the yield rate is the most important factor to reduce the cost. Most of the TFT-LCD detection circuit is shorting bar design, because it has the advantages of simple design, low cost of detection, test fixtures can be shared and glass high utilization,but this design needs to solve the problem of poor positioning of the line defect and easy to produce false defects. This paper proposed a novel LCD defect detection rate raising method by connecting the gate scanning lines of Thin Film Transistor (TFT) array to the ground with a shorting-bar. Thus if an illuminator is applied to the background panel, and all the TFT arrays are without any failures, then the lights of the illuminator can penetrate the scanned pixels, i.e., a bright image should be appeared on the front display. Otherwise, there are defects in the TFT cells with dark patterns. In this paper the P-Diagram of Taguchi method was applied to find the key parameters for the TFT tester design. The simplified testing parameters and conditions can find 90% of the faults, while the pseudo-fault was only increased by 0.34%. By the way the line defect location uncertainty ranges can also be reduced. Thus the proposed method can give a better compromise among the three requirements of better yield rate, lower cost and larger productivity.