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Ajmo, Craig T. "Alternative targets for the treatment of stroke." [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002114.
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Ajmo, Craig T. Jr. "Alternative Targets for the Treatment of Stroke." Scholar Commons, 2007. https://scholarcommons.usf.edu/etd/594.
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Stroke is cerebrovascular injury that has been reported to be the third leading cause of death and the first leading cause of disability in the world (W. H.O. 2007). Currently, there is only one FDA approved treatment for stroke which is recombinant tissue plasminogen activator. This treatment has a narrow therapeutic window of three hours after ischemic stroke and can adversely cause the production of oxygen free radicals and intracranial hemorrhage. These limitations result in only 2-3% of all stroke victims as being candidates for this therapy as many patients do not arrive at the hospital in time to receive treatment, are not properly diagnosed, or do not know that they have had a stroke within this three hour time period. The purpose of these experiments was to elucidate alternative targets of stroke for the benefit of developing new treatments that stimulate neuroprotective and anti-inflammatory effects at the site of injury. It has been shown that transfusion of human umbilical cord blood cells up to 48 hours after stroke significantly reduces infarction and we have examined other targets that mimic these effects. We have shown that sigma receptor activation by DTG, a high affinity universal sigma agonist, reduces infarct volume when administered 24 hours after stroke. This suggests that modulation of neurodegenerative and inflammatory responses can extend the therapeutic window of treatment. For the first time, evidence is provided that shows that the spleen enhances the neurodegeneration caused by stroke as splenectomy prior to stroke profoundly decreased infarction volume. Finally, we studied signaling mechanisms of the splenic reaction to stroke and determined that this response is not directly dependent on neurotransmission via the splenic nerve. Denervation of the spleen prior to stroke showed no changes in neurodegenerative load at the site of injury in rat brains when compared to those subjected to stroke only. Overall, these experiments provide evidence showing that targets mediating neuroprotective and anti-inflammatory effects can lead to novel therapeutic interventions of stroke.
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Yue, Lok-man, and 庾樂民. "Therapeutic targets of arsenic trioxide in lymphoma treatment." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/197540.
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Lymphomas are malignant diseases involving the lymphatic system. Arsenic trioxide (As2O3) is a current therapeutic agent for acute promyelocytic leukaemia (APL).APL cells are sensitive to As2O3, with As2O3directly targeting the PML-RARA protein that plays an important role in the oncogenesis of APL. In order to discover the potential of As2O3as a treatment of lymphoma, understanding of the molecular mechanism of As2O3in human lymphoma cells is essential. In this thesis, we showed that the MYC gene is a therapeutic target for As2O3in B-cell lymphomas and the CCND1 (cyclin D1) gene is another therapeutic target for As2O3in mantle cell lymphoma (MCL), a subtype of non-Hodgkin lymphoma (NHL).
Both real-time RT-PCR and immunoblotting analysis showed that the expression levels of MYC in all B-cell lymphoma cell lines were down-regulated at both mRNA and protein level after As2O3treatment. The expression levels of MYC were also found to positively correlate with the arsenic sensitivity as measured by MTT assay. Hence, the higher the level of MYC expression, the higher the arsenic sensitivity of human B-cell lymphoma cell lines. Besides, the change of downstream genes after modulation of MYC expression level by As2O3 treatment was investigated. The expression level of CDKN1A and CDKN1B was increased after As2O3 treatment. Interestingly, the growth rate of MYC over-expressing lymphoma cell lines decreased significantly after As2O3treatment, while there was no significant decrease in colony formation assay in lymphoma cells without MYC over-expression.
Immunoblotting analysis showed that As2O3could degrade the cyclin D1 protein in mantle cell lymphoma cell lines in a dose-dependent manner. Real-time RT-PCR analysis also showed that the mRNA level of CCND1gene was decreased after As2O3treatment. We also demonstrated that As2O3-induced cyclin D1 protein degradation was related to the proteasome pathway. The growth rate of MCL cell line decreased significantly after As2O3treatmentby using colony formation assay.
Human water channel protein, aquaporin 9 (AQP9) has been demonstrated to facilitate the arsenic uptake in human leukaemia cells. In this thesis, we showed that the expression levels of AQP9were found to positively correlate with the arsenic sensitivity as measured by MTT assay in B-cell lymphoma cells. We also demonstrated that dexamethasone could up-regulate AQP9expressions at both mRNA and protein levels in human B-cell lymphoma cell lines.
These results not only suggest that As2O3is a potential therapy for B-cell lymphomas, especially for those MYC-over-expressed B-cell lymphomas and MCL, but also indicate that MYC may act as a biomarker for predicting the clinical behaviour of B-cell lymphoma patients to the As2O3treatment.Moreover, dexamethasone pre-treatment may enhance the therapeutic effect of As2O3by up-regulating AQP9expression in B-cell lymphomas.published_or_final_version
Medicine
Master
Master of Philosophy
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Aziz, Abdul Maruf Asif. "Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders." Doctoral thesis, Linköpings universitet, Centrum för social och affektiv neurovetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-139884.
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Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD. The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models. In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced “hangover” anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stress-induced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats. Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol. In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993. In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for motivation to work for alcohol and reinstatement of alcohol-seeking behavior. Treatment with CYM-9840 (10 mg/kg) potently attenuated alcohol SA, progressive ratio responding and stress-induced reinstatement using yohimbine as the stressor, while alcohol cue-induced reinstatement was unaffected. Moreover, a range of control behaviors including taste sensitivity, locomotor and pharmacological sensitivity to the sedative effects of alcohol remained unaffected by CYM-9840 pretreatment, indicating that its effects are specific to the rewarding and motivational aspects of alcohol-intake and related behaviors. CYM-9840 also reversed acute alcohol withdrawal-induced “hangover” anxiety measured in the EPM and reduced alcohol-intake in the 4 hour limited access two-bottle free choice preference drinking model. Finally, in the fourth study (Paper IV), the selective MCH1-R antagonist GW803430 was tested in rat models of escalated alcohol-intake. Pretreatment with GW803430 (effective at 10 & 30 mg/kg) dose-dependently reduced alcohol and food-intake in rats that consumed high amounts of alcohol during IA, while it only decreased food-intake in rats that consumed low amounts of alcohol during IA, likely due to a floor effect. Upon protracted abstinence following IA, GW803430 significantly reduced operant alcohol SA and this was associated with adaptations in MCH and MCH1-R gene-expression. In contrast, GW803430 did not affect escalated alcohol SA induced by chronic alcohol vapor exposure and this was accompanied by no change in MCH or MCH1-R gene expression. Overall, these results suggest that the MCH1-R antagonist affects alcohol-intake through regulation of both motivation for caloric-intake and the rewarding properties of alcohol. In conclusion, our results suggest critical roles for these central neuropeptides in the regulation of anxiety and of alcohol reward, making them potential pharmacological targets in the treatment of AUD.
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Cozzi, Sarah-Jane. "Molecular targets of anticancer PKC activators in the treatment of melanoma /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19185.pdf.
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Moilanen, A. M. (Anne-Mari). "Identification of novel drug targets for the treatment of heart failure." Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789514299131.
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Abstract Heart failure (HF) is a complex pathological state, involving simultaneous alterations in several signalling pathways and changes in gene programming. In HF, activation of the neurohumoral factors and renin-angiotensin-aldosterone (RAA) system occurs as a compensatory mechanism to combat the abnormal ventricular function. Developments in cardiac gene delivery methods have exerted a significant impact to treat HF and to discover the novel molecular mechanisms associated with HF and other cardiac diseases. This study demonstrated that adenovirus–mediated gene delivery of B-type natriuretic peptide (BNP) into the anterior wall of the left ventricle decreased myocardial fibrosis and increased capillary density. Post-infarction BNP improved systolic function associated with normalization of cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA) 2 expression and phospholamban phosphorylation at Thr17. On the other hand, (Pro)renin receptor ([P]RR) gene delivery resulted deleterious effects on cardiac function and (P)RR activation induced distinct angiotensin II (Ang II)-independent extracellular matrix remodelling and worsening of cardiac function. (P)RR gene delivery resulted in Ang II-independent activation of extracellular-signal regulated (ERK1/2) phosphorylation and increased myocardial fibrosis. In conclusion, the present study indicates that myocardial BNP gene delivery can achieve pleiotropic, context-dependent, favourable effects on cardiac function and that BNP can act locally as a mechanical load–activated regulator of angiogenesis and fibrosis. These results also implicate that (P)RR blockers may display additional cardiac effects in addition to its ability to evoke effective RAA system blockade. Overall, the findings of this study provide a better understanding of the molecular mechanisms involved in the biological actions of BNP and (P)RR, and identify BNP and (P)RR as potential novel drug targets for the treatment of HFTiivistelmä Neuroendokriinisellä aktivaatiolla, jonka seurauksena aiheutuu muun muassa verisuonten supistumista ja laajenemista sekä nesteen kertymistä elimistöön, on tärkeä merkitys sydämen vajaatoiminnan kehittymisessä. Neuroendokriininen aktivaatio kompensoi sydämen vajaatoiminnan seurauksena tapahtuvaa kammioiden poikkeavaa toimintaa. Yksi keskeisimmistä verisuonia supistavista tekijöistä on reniini-angiotensiini-aldosteroni (RAA) -järjestelmä, ja verisuonia laajentaviin tekijöihin kuuluvat muun muassa natriureettiset peptidit, kuten B-tyypin natriureettinen peptidi (BNP) ja A-tyypin natriureettinen peptidi. Geeninsiirtomenetelmillä on ollut merkittäviä vaikutuksia uusien hoitomenetelmien kehittämisessä, sydämen vajaatoiminnan syiden selvittämisessä ja uusien kohdegeenien tunnistamisessa sydämen vajaatoiminnan hoitoon. Väitöskirjan tutkimustulokset osoittivat, että suora adenovirusvälitteinen geeninsiirto rotan sydämen vasemman kammion etuseinään on toimiva menetelmä uusien kohdegeenien löytämiseksi sydämen vajaatoiminnan hoitoon. BNP:n geeninsiirto vähensi merkitsevästi fibroosin muodostumista ja lisäsi verisuonten uudismuodostumista sydämessä. Sydäninfarktin jälkeen BNP paransi sydämen systolista toimintaa, johon liittyi aktiivisen kalsiumpumpun, SERCA2:n ja fosfolambaani-proteiinin fosforylaation normalisoituminen. (Pro)reniini reseptorin ([P]RR) geeninsiirto aiheutti angiotensiini II:sta riippumatonta solunulkoisen matriksin uudelleenmuotoutumista ja sydämen toiminnan huonontumista sekä lisääntynyttä sydämen fibroosia. Väitöskirjatutkimus antaa uutta tietoa solunsisäisistä molekulaarisista mekanismeista sydänsoluissa. BNP geeninsiirto aiheutti sydämen tautitilasta riippuvia suotuisia tapahtumia, ja se toimi paikallisesti muun muassa fibroosia ehkäisevänä tekijänä. (P)RR geeninsiirtotulosten perusteella voidaan olettaa, että (P)RR:n salpaus saattaa olla uusi tehokas hoitokeino sydämen vajaatoiminnan hoitoon
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Lam, Chi-leung David, and 林志良. "Oncogenic mutations as biomarkers and therapeutic targets in lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/207610.
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Oncogenic mutations in lung cancer further our knowledge about cancer initiation and progression, and may guide personalized treatment. The fact that targeted therapy is most effective in subsets of patients with defined molecular targets indicates the need for classification of clinically-related molecular tumor phenotypes based on the presence of oncogenic mutations, including EGFR mutations and EML4-ALK rearrangements.
The identification of EGFR mutations, in up to half of lung adenocarcinomas in Asians, could predict clinical sensitivity to tyrosine kinase inhibitor (TKI). However, testing for mutations is not always possible due to tumor tissue availability. The therapeutic decision sometimes remains a clinical one especially for elderly lung cancer patients but no known mutation status. We studied the survival outcomes of targeted therapy versus conventional chemotherapy in elderly patients with lung cancer when we did not yet have routine EGFR mutation testing and demonstrated comparable survival outcomes in targeted therapy compared to chemotherapy, implying that survival with targeted therapy could be better if the treatment population could be selected with EGFR mutations.
Though testing for EGFR mutation in tumor biopsy have later become routine practice and remains the accepted reference for therapeutic decision, the detection of EGFR mutations in plasma DNA with high diagnostic performance will be useful adjunct for diagnostic and therapeutic monitoring. Among patients with EGFR mutations in tumor biopsy, the concurrent detection of EGFR mutation in plasma DNA was found to confer a less favorable prognosis in terms of overall survival than those patients with EGFR mutations in tumor biopsy but the corresponding mutation was not detected in plasma.
Other oncogenic mutations with therapeutic implications in lung tumors are yet to be fully explored, like ALK, KRAS, ROS1 or NTRK1 mutations. It is not exactly the tumor – but the mutations in the tumor that need to be explored with reference to clinical behavior. Even with EGFR mutation with well-established clinical implications, further exploration into its mechanistic functions will help in understanding of drug resistance. Lung cancer cell lines established from patients with known mutation profiles could be useful tools for studying the biology of known molecular targets as well as for therapeutic testing. Four new lung adenocarcinoma and one mesothelioma cell lines were established from patients with different clinical characteristics and oncogenic mutation profiles. These cell lines with defined mutation profiles will provide tools for exploration of lung cancer and mesothelioma biology with respect to molecular therapeutic targets.
The Large Tumor Suppressor 2 (LATS2) gene was a differentially expressed gene between EGFR mutant and wildtype lung adenocarcinomas. The differential LATS2 expression levels were predictive of survival in patients with resected lung AD and may modulate tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.
The identification of oncogenic mutations has led to a new paradigm of targeted therapy in lung cancer. Further improvements in outcome of lung cancer management will stem from research into the biology of oncogenic mutations and their clinico-pathological correlations, which would fuel parallel development of clinically efficacious targeted therapies.published_or_final_version
Medicine
Master
Doctor of Medicine
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Weist, Mark D. "Empirical validation of treatment targets for the management of diabetes in children." Diss., Virginia Tech, 1991. http://hdl.handle.net/10919/39865.
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Murabito, Ettore. "Application of differential metabolic control analysis to identify new targets in cancer treatment." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/application-of-differential-metabolic-control-analysis-to-identify-new-targets-in-cancer-treatment(3a9b75ba-027d-449b-af38-263341953418).html.
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In the quest for anti-cancer drugs with high efficacy and low toxicity, cancer metabolism has increasingly been a focus of interest in clinical research. Enhanced glycolysis and robust production of lactate constitute characteristic traits that discriminate many cancerous cells from their normal counterparts. This, in principle, may provide researchers with a general handle on such a complex disease, regardless of the intrinsic genotypic heterogeneity of the single transformed cells. The work carried out during this project and presented in this thesis consists of developing and applying analytical approaches, mainly drawn from the field of metabolic control analysis (MCA), to the study of cancer metabolism. The ultimate goal is to assess whether, and to what extent, the metabolic features of cancer cells may be exploited in the attempt to attack the malignancy more specifically than through traditional clinical approaches. The underlying idea consists of identifying enzymes that represent points of fragility specifically characterising the cancerous metabolic phenotype. These enzymes are such that an alteration in their activity (due for example to the action of an anticancer drug) would elicit the desired response in cancer cells, without affecting their normal counterparts. The application of MCA relies on a mathematical representation of the system under study. Creating such a model is often hampered by the lack of data about the precise kinetic laws governing the different reaction steps and the value of their corresponding parameters. The most important result reached during this project shows that the metabolic quantities defining the normal and cancer phenotypes (such as fluxes and metabolite concentrations), together with heuristic assumptions about the properties of typical enzyme-catalyzed reactions, already allow for a fast and efficient way to explore the effectiveness of putative drug targets with respect to criteria of high efficacy and low toxicity. The relevance of this result lies in the fact that the quantities defining a metabolic phenotype are experimentally more accessible than the kinetic parameters of the different enzymatic steps in the system.
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D'Costa, Z. C. "The identification of novel therapeutic targets for the treatment of TBX2-driven breast cancers." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546040.
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Broadstock, Martin. "Group III metabotropic glutamate receptors as potential targets in the treatment of Parkinson's disease." Thesis, King's College London (University of London), 2006. https://kclpure.kcl.ac.uk/portal/en/theses/group-iii-metabotropic-glutamate-receptors-as-potential-targets-in-the-treatment-of-parkinsons-disease(41881507-54fb-43c0-8bf9-65fe891cbb72).html.
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Finn, Natalie K. "Identifying Targets for Quality Improvement in a Community Child Mental Health Agency." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/6107.
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The implementation of evidence-based practices has great potential to improve the quality of children’s services; however, with a large variety of available practices, it can be challenging to select targets for quality improvement in community-based treatment. This study used a method called relevance mapping to identify how thoroughly evidence-based programs could cover a specific population of children seeking services at a large public agency and identify practice elements relevant to these clients. A therapist survey was used to examine current practice at the agency. Eight therapists at the agency reported on their practice delivery for 141 clients. Results from relevance mapping and therapist surveys were combined to create practice profiles for two predominant diagnostic categories seen at the agency: substance use and depression. These practice profiles were used to identify three areas of interest for agency quality improvement with regard to practice element delivery: Agency Strengths, Opportunities, and Weaknesses. Results demonstrate a potential blueprint for tailoring specific feedback to an agency for use in quality improvement efforts.
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Bartolomeo, Rosa. "Identification of molecular targets for the treatment of the skeletal phenotype in lysosomal storage disorders." Thesis, Open University, 2017. http://oro.open.ac.uk/49147/.
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Autophagy is a lysosomal pathway deputed to the recycling of cellular components. Regulation of autophagy is essential for tissue homeostasis. The mTORC1 kinase tunes autophagy according to nutrient levels and environmental factors. Recently the laboratory in which I performed the experiments used for my thesis has demonstrated that autophagy, by controlling collagen secretion in chondrocytes, is necessary during bone growth. However, whether mTORC1 and autophagy play any role in the pathogenesis of skeletal disorders is still unknown. In this thesis work I show that an altered mTORC1 signaling impairs autophagy and consequently bone growth in lysosomal storage disorders (LSDs). I found that in LSD chondrocytes a proteasome-sensitive increase of mTORC1 signaling inhibits late steps of autophagy through the phosphorylation of the UV radiation resistance-associated gene (UVRAG) protein, a member of the Beclin1/Vps34 complex. Reducing mTORC1 signaling or enhancing Beclin1/Vps34/UVRAG complex activity rescued autophagy flux in LSD chondrocytes. In vivo, normalization of mTORC1 signaling or pharmacological induction of Beclin1 rescued collagen levels in cartilage and bone growth in two different LSD mouse models. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest their modulation as new therapy for the skeletal abnormalities observed in LSDs.
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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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Visser, Jacobus Albertus Koch. "Phytoestrogenic extracts of Cyclopia modulate molecular targets involved in the prevention and treatment of breast cancer." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86718.
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Thesis (PhD)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Phytoestrogen containing extracts of Cyclopia, an indigenous South African fynbos plant used to prepare honeybush tea, may serve as a source of new estrogen analogues. It would be of great benefit if these new analogues would not only prevent the development and progression of breast cancer which, globally, is responsible for the highest number of cancer associated deaths among females, but also have a reduced side-effect profile when compared to current treatments and, in addition, also alleviate menopause associated symptoms. In this study three extracts, P104, SM6Met, and cup-of-tea, from two species of Cyclopia, C. genistoides and C. subternata, were evaluated for their potential to modulate molecular targets involved in prevention and treatment of breast cancer. We show that the phytoestrogenic extracts of Cyclopia antagonise estrogen-induced cell proliferation both in vitro as well as in vivo. Furthermore, our study presents various molecular mechanisms whereby the Cyclopia extracts may be eliciting this effect. Importantly, we show, for the first time, that the Cyclopia extracts behave as ERα antagonists and ERβ agonists which, with respect to the known role of the ER subtypes in breast cancer, where the ERα subtype is associated with the stimulation of cell proliferation and the occurrence of breast cancer, while ERβ ameliorates the action of ERα in breast cancer and could act as an inhibitor of breast cancer development, may be beneficial for the prevention or treatment of breast cancer. In addition, we also show that the extracts of Cyclopia behave as selective estrogen receptor degraders by down-regulating ERα protein levels while stabilising ERβ protein levels, which not only provides a possible molecular explanation for the observed ERα antagonism and ERβ agonism, but, in addition, may be beneficial as higher ERα levels are associated with malignant breast cancer tumours, while higher ERβ levels are associated with benign tumours. Furthermore, we show that the Cyclopia extracts affect the nuclear localization and distribution of both ER subtypes in a manner that provides an additional molecular explanation for the observed ERα antagonism and ERβ agonism. Investigation of the molecular processes involved in the promotion and progression of breast cancer, such as the distribution of cells between the phases of the cell cycle, cancer cell invasion, and the regulation of genes governing these processes provides evidence that the Cyclopia extracts are not as proliferative as estrogen. In addition, Cyclopia extracts display anti-inflammatory properties, which may be beneficial as inflammation is an enabling characteristic in cancer development and progression. Furthermore, this study, for the first time, shows that the phytoestrogenic extracts of Cyclopia are absorbed, are not toxic, and display biological ERα antagonist activity in vivo by retarding uterine growth. Thus, we propose that the Cyclopia extracts act as selective estrogen receptor subtype modulators with potential to be developed as a nutraceutical for the treatment or prevention of breast cancer.
AFRIKAANSE OPSOMMING: Fitoëstrogeen-bevattende ekstrakte van Cyclopia, ‘n inheemse Suid Afrikaanse fynbosplant wat gebruik word vir die voorbereiding van heuningbostee, mag as ‘n bron van nuwe estrogeen-analoë dien. Dit sal baie voordelig wees indien hierdie nuwe analoë nie net die ontwikkeling en progressie van borskanker sal voorkom nie, aangesien borskanker wêreldwyd verantwoordelik is vir die grootste getal kankerverwante sterftes onder vroue, maar ook ‘n verminderde newe-effek profiel vertoon in vergelyking met huidige behandelings en ook, boonop, simptome wat met menopouse geassosieer word, sal verlig. In hierdie studie is drie ekstrakte, P104, SM6Met, en cup-of-tea, vanaf twee spesies van Cyclopia, C. genistoides en C. subternata, geëvalueer vir hul potensiaal om die molekulêre teikens betrokke by die voorkoming en behandeling van borskanker te moduleer. Ons wys dat die fitoëstrogeniese ekstrakte van Cyclopia antagoniseer estrogeen-geïnduseerde selproliferasie beide in vitro as ook in vivo. Verder bied ons studie ook verkskeie molekulêre meganismes aan oor hoe die Cyclopia ekstrakte hierdie effek mag ontlok. ‘n Belangrike bevinding is dat ons vir die eerste keer wys dat die Cyclopia ekstrakte hulself as ERα -antagoniste en ERβ-agoniste gedra wat, met betrekking tot die erkende rol van die ER-subtipes in borskanker, waar die ERα-subtipe geassosieer word met die stimulasie van selproliferasie en die gebeurtenis van borskanker, terwyl ERβ die aksie van ERα onderdruk en as ‘n inhibeerder van borskankerontwikkeling kan dien, voordelig mag wees vir die voorkoming of behandeling van borskanker. Ons wys boonop ook dat die ekstrakte van Cyclopia hulself soos selektiewe estrogeen- reseptor-degradeerders gedra deurdat hul ERα-proteïnvlakke verlaag terwyl hul ERβ-proteïnvlakke stabiliseer. Dit verksaf nie net ‘n moontlike molekulêre verduideliking vir die waargeneemde ERα-antagonisme en ERβ-agonisme nie, maar mag ook voordelig wees in borskanker aangesien hoër ERα-vlakke geasosieer word met kwaadaardige borskankertumors en hoër ERβ-vlakke met nie-kwaadaardige tumors. Verder wys ons dat die Cyclopia ekstrakte die lokalisering en verspreiding van beide ER-subtipes in die selkern op so ‘n wyse beïnvloed dat dit ‘n addisionele molekulêre verduideliking bied vir die ERα-antagonisme en ERβ-agonisme wat waargeneem is. Verdere ondersoek van die molekulêre prosesse betrokke by die promosie en progressie van borskanker, soos die verspreiding van selle tussen die fases van die selsiklus, die beweging van kankerselle na omliggende weefsels, en die regulering van gene wat hierdie prosesse beheer, verskaf bewyse dat die Cyclopia-ekstrakte nie so proliferatief is soos estrogeen nie. Die ekstrakte van Cyclopia vertoon boonop ook anti-inflamatoriese eienskappe, wat voordelig mag wees aangesien inflammasie ‘n bydraende eienskap in kankerontwikkeling en -progressie is. Verder wys hierdie studie vir die eerste keer dat die fitoëstrogeniese ekstrakte van Cyclopia geabsorbeer word, nie toksies is nie, en dat hulle biologiese ERα-antagonis aktiwiteit vertoon deurdat hulle uterus-groei vertraag in vivo. Dus stel ons voor dat die Cyclopia-ekstrakte optree soos selektiewe-estrogeen-reseptor-subtipe-moduleerders met die potensiaal om ontwikkel te word as ‘n nutraseutiese middel vir die behandeling of voorkoming van borskanker.
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Tarrado, Castellarnau Miriam. "Targeting metabolic reprogramming associated to cancer cells: search of novel targets and combined therapies in cancer treatment." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/385425.
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Cancer is characterised by the lost of physiological control and the malignant transformation of cells that acquire functional and genetic abnormalities, leading to tumour development and progression. Colon and lung cancer are two of the most common cancers worldwide. In early stages of the disease, surgery is the common choice while chemotherapy is the main treatment for advanced stage cancer. However, the currently available chemotherapeutic treatments exhibit modest efficacy due to their side effects and drug resistance. Therefore, the search for combined chemotherapies with low systemic toxicity and high efficiency holds great promise to decrease the morbidity and mortality of cancer.
Tumour cells present common biological capabilities sequentially acquired during the development of cancer that are considered essential to drive malignancy. In particular, tumour cells switch their core metabolism to meet the increased requirements of cell growth and division. Indeed, oncogenic signals converge to reprogram tumour metabolism by enhancing key metabolic pathways such as glycolysis, pentose phosphate pathway (PPP), glutaminolysis and lipid, nucleic acid and amino acid metabolism. Several oncogenes including c-MYC, hypoxia inducible factor 1 (HIF1), phosphoinositide-3-kinase (PI3K), protein kinase B (PBK or Akt) and the mechanistic target of rapamycin (mTOR), have been known to be involved in the regulation of tumour metabolic reprogramming. Then, the study of the tumour metabolic reprogramming and its connection with oncogenic signalling is an essential strategy to identify new targets for cancer therapy.
Thus, the main objective of this thesis was to explore new possibilities for cancer treatment and diagnosis. To this end, we have analysed the links between metabolism and tumour progression, the tumour metabolic reprogramming associated to the dysregulation of cell cycle, and the use of combination therapies for cancer treatment. In order to accomplish our main objective, the results of this thesis are divided in three chapters:
1. We have identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a potential predictive biomarker for tumour staging and prognosis of human colorectal cancer. In addition, our results clearly discourage the use of GAPDH as a housekeeping marker in colorectal cancer.
2. We have characterised the metabolic reprogramming associated to the inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) in colon cancer cells. CDK4/6 inhibition causes a shift towards enhanced metabolism of glucose, glutamine and amino acids by increasing mitochondrial metabolism and function as well as glycolytic flux. Fluxomics and transcriptomics integrated data analysis revealed that this metabolic reprogramming is directed by MYC, which is accumulated when CDK4/6 are inhibited. In fact, the identification of the tumour metabolic adaptations associated to CDK4/6 inhibition reveals potential metabolic vulnerabilities that can be exploited in combination therapies with CDK4/6 inhibitors. Accordingly, we have obtained synergistic and selective antiproliferative effects in vitro by inhibiting mTOR, PI3K/Akt axis or MYC target genes in combination with CDK4/6 inhibitors. Therefore, we propose new combination therapies that simultaneously target cell cycle and metabolism of cancer cells.
3. We have determined the molecular mechanism of action of the selenium compound methylseleninic acid (MSA) in cancer cells. MSA effects are associated with the inhibition of the Akt pathway, leading to dephosphorylation of FOXO transcription factors and their nuclear translocation which, in turn, activate the expression of FOXO target genes. By targeting the PI3K/Akt/FOXO pathway, MSA synergises with cisplatin in combination therapies to reduce the commonly observed toxicity and overcome the resistance of cisplatin-based chemotherapy.
The completion of these objectives has shed new light on the understanding of tumour metabolic reprogramming as well as the mechanisms of action of compounds potentially useful as antitumour agents. We have used this information to develop new strategies complementing conventional and existing chemotherapies, providing new approaches for cancer treatment and diagnosis.
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Imre. "Group II metabotropic glutamate (mGlu2/3) receptors potential drug targets for the treatment of schizophrenia and anxiety? /." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2006. http://irs.ub.rug.nl/ppn/297586998.
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Fryer, Rosemary Ann. "Development of new drug therapies and the identification of cell signalling targets for treatment of pancreatic cancer." Thesis, St George's, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546780.
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Ordway, Gregory A., W. D. Gill, J. B. Coleman, Hui Wang-Heaton, and Russell W. Brown. "Anti-Inflammatory PARP Inhibitor Demonstrates Antidepressant Activity in Animal Model of Treatment Resistant Depression." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/8643.
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Background: Major depressive disorder is associated with elevated levels of DNA oxidation, DNA damage, and gene expression of DNA repair enzymes including poly (ADP-ribose) polymerase-1 (PARP1). Elevated PARP1 activity is directly linked to neuroinflammation and PARP inhibitors are anti-inflammatory and neuroprotective. We previously showed that PARP inhibitors produce antidepressant-like effects equivalent to fluoxetine in rodent models. Here, we examined whether the PARP inhibitor 3-aminobenzamide (3AB) is effective in a rat model of treatment-resistant depression.
Methods: Treatment-resistant depression was modeled with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily chronic unpredictable stress (CUS) for 28 days. Anhedonia and helplessness were indexed with sucrose preference and forced swim tests, respectively, in 5 groups of rats (n¼6-8 rats/group) including unstressed, CUS, and CUS+LPS rats treated with saline, and CUS+LPS rats treated with either 3AB or fluoxetine.
Results: Anhedonia induced by CUS+LPS was significantly attenuated by 3AB (p¼0.01), while fluoxetine failed to do so. Likewise, 3AB was superior to fluoxetine in reducing helplessness, where latency to immobility times were significantly lower in CUS+LPS rats treated with fluoxetine (p¼0.001) compared to unstressed rats, but not significantly different for 3AB-treated CUS+LPS rats.
Conclusions: The PARP inhibitor 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the TRD rat model. PARP is linked to neuroinflammation through release of microglia-activating factors including poly (ADP-ribose) and HMGB1, and through NF-kB activation, pathways under investigation by our lab. PARP inhibitors are currently used clinically to facilitate cytotoxicity of DNA-damaging anti-cancer treatments. Further research could implicate re-purposing non-cytotoxic PARP inhibitors for treatment-resistant depression.
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Canals, Buj Meritxell. "Molecular and functional interactions between adenosine and dopamine receptors. New therapeutic targets for the treatment of Parkinson's disease." Doctoral thesis, Universitat de Barcelona, 2004. http://hdl.handle.net/10803/2980.
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Adenosine and dopamine receptors are members of the GPCRs family for which a significant segregation between their A2A and D2 subtypes has been demonstrated in the GABAergic striopallidal neurons of the basal ganglia. In addition, several reports suggest an antagonistic interaction between these subtypes at different levels. For this reason the first study has been focused in the characterization of the molecular and functional interaction between A2AR and D2R. Colocalization of these receptors and clustering upon agonist stimulation has been observed by double immunocytochemistry in neuroblastoma SH-SY5Y cells as well as in primary cultures of striatal neurons. In addition, in the neuroblastoma cell line, it has been demonstrated that the internalization of both receptors takes place following their clusterization. Despite the A2AR-D2R heteromerization has been determined by coimmunoprecipitation, we have also studied if this interaction occurs in living cells by using FRET (Fluorescence Resonance Energy Transfer) and BRET (Bioluminescence Resonance Energy Transfer) approaches. Finally, using both, experimental and theoretical modeling data, it is suggested that the helix 5 and 6 and the 3rd intracellular loop of the D2R and the C-terminal tail of the A2AR are important domains for the formation of the A2AR-D2R heteromers.The homodimerization of the adenosine A2AR has also been studied by FRET and BRET. Furthermore, TR-FRET (Time-Resolved FRET) and biotinylation experiments have suggested that the homodimer, not the monomer, is the functional form of the receptor that reaches the cell surface.
The last part of this study has been focused in the identification of the adenosine receptors that mediate the regulation of neuronal differentiation and the molecular mechanisms involved in this effect. Agonist-induced stimulation of A1Rs and A2ARs induces neurite outgrowth processes in the human neuroblastoma SH-SY5Y cell line and also in striatal neuronal precursor cells in primary cultures. The triggering of the expression of TrkB receptor and the arrest of cells in the G1 phase by the activation of adenosine receptors suggest that adenosine may participate in early steps of neuronal differentiation. Furthermore, the signaling transduction pathway involved in these effects have been shown to require both, the MAPK and the PKC activation but in an independent manner.
The results presented in this work, therefore, suggest that adenosine not only acts as a key neuromodulator in information handling but also exerts trophic effects that can enhance neuronal differentiation and neuronal repair.
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Chen, Xi, and 陈曦. "Exploring molecular targets and active compounds from buyang huanwu decoction for promoting neurogenesis in post-ischemic stroke treatment." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193430.
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Ye, Liangtao [Verfasser], and Enrico de [Akademischer Betreuer] Toni. "Novel targets and therapeutic strategies for the treatment of hepatocellular carcinoma (HCC) / Liangtao Ye ; Betreuer: Enrico de Toni." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1211957144/34.
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Murphey, Winifred. "Using ultrasound in Sound Production Treatment for acquired apraxia of speech : a case study of multiple speech sound targets." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/59355.
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Acquired apraxia of speech (AOS) is a disorder of speech production. Treatment approaches and advancements are limited. Technological approaches or additions to current treatment approaches may provide greater benefit to individuals with AOS. This case study examines the effects of treating AOS using an adapted Sound Production Treatment (SPT) hierarchy (Bailey, Eatchel & Wambaugh, 2015) that includes an ultrasound visual feedback component. The goal was to quantify the effects of two speech sound treatment blocks, one using SPT and one using SPT plus Ultrasound (U/S) for a single participant with AOS, and to compare the outcomes from each treatment block with one another. The number of articulatory mismatches for treated and untreated speech sounds were analyzed based on their similarity to the treated speech sounds in terms of phonologic and articulatory features that can be seen on ultrasound. Treated speech sounds showed increases in articulatory accuracy when using SPT with or without ultrasound. This was also true for untreated speech sounds that were maximally phonologically related to the treated speech sounds. Untreated speech sounds that shared articulatory/phonological features visible on ultrasound with the treated speech sounds showed increases in accuracy only in the SPT plus U/S condition. Untreated speech sounds that were minimally phonologically related to the treated speech sounds and were not visible on ultrasound showed limited improvement in either condition
These findings suggest that including a visual feedback route in speech treatment for AOS can be used to induce transfer of learning effects to speech sound targets with visibly similar articulatory gesture as those being treated. Clinically, using ultrasound as visual biofeedback in an SPT treatment may be effective in promoting transfer of positive treatment effects to speech sound targets when trained and untrained targets share characteristics observable on ultrasound.Medicine, Faculty of
Audiology and Speech Sciences, School of
Graduate
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Landuyt, Willy. "Intra-tumoural blood vessels and hypoxia: targets for treatment and imaging to improve anti-cancer therapies pre-clinical investigations /." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 2002. http://arno.unimaas.nl/show.cgi?fid=7247.
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Hayes, Michelle Amanda. "Elevated oxygen delivery and consumption compared with normal haemodynamics as targets for treatment in high risk intensive care patients." Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297188.
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Fortin, Geneviève Rose. "Identifying new therapeutic targets for treatment of Crohn's disease: The role of CD47 and L-carnitine in the pathogenesis and treatment of a murine model of intestinal inflammation." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86517.
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Crohn's disease (CD) is a chronic, relapsing and remitting immune-mediated inflammatory disease of the gastrointestinal tract. While there is currently no cure for this disease, a wide range of treatment options are available. However, these are often associated with a significant set of adverse effects and, despite their use, most CD patients will eventually require hospitalization and/or surgery. The goal of the projects outlined in this thesis was therefore to further our understanding of the mechanisms involved in generating intestinal inflammation and to apply these findings to develop novel therapeutic agents.We first examined the role of interactions between CD47 and its ligand, signal regulatory protein alpha (SIRPα), in the development of TNBS colitis, a murine model of intestinal inflammation sharing many features with human CD. We have demonstrated that dendritic cells (DC) expressing SIRPα promote Th17 responses and the development of experimental colitis. Furthermore, we identify an important role for CD47 in the migration of SIRPα+ DCs to the lamina propria and mesenteric lymph nodes, where they participate in inducing inflammation. Thus, by genetic deletion of CD47 or by impairing its function using a CD47-fc fusion molecule, we have successfully reduced the severity of intestinal inflammation.
L-carnitine is an amino acid derivative normally present in meat and dairy products and is also available as an over-the-counter nutritional supplement. Since mutations in the L-carnitine transporters, OCTN1 and OCTN2, were found to be associated with CD, we sought to examine its role in the development of intestinal inflammation. Remarkably, L-carnitine displayed immunosuppressive properties both in vitro and in vivo, effectively suppressing both the innate and the adaptive arms of the immune response and resulting in a significant reduction in the development of intestinal inflammation.
We have thus identified CD47 as an important regulator of SIRPα+ DC trafficking, and demonstrate that this DC subset is implicated in the development of intestinal inflammation. Additionally, we have identified two promising new therapeutic candidates, CD47-fc and L-carnitine, for the treatment of CD.
La maladie de Crohn (MC) est une maladie inflammatoire chronique impliquant un dérèglement du système immunitaire qui touche à l'ensemble du tube digestif, et qui est caractérisé par des périodes cycliques de rechutes et rémissions. Bien qu'il n'existe aucun traitement curatif contre cette maladie, plusieurs remèdes visant à amoindrir les symptômes sont actuellement disponibles sur le marché. Toutefois, ces derniers sont souvent associés à de multiples effets secondaires néfastes, et, malgré leur utilisation, aucun de ces traitements ne parvient à empêcher la grande majorité des patients atteints d'être éventuellement hospitalisés et/ou de subir une intervention chirurgicale. Par conséquent, l'objectif premier des projets détaillés dans cette thèse a été d'approfondir les connaissances des mécanismes biologiques impliqués dans l'initiation de l'inflammation intestinale ainsi que d'appliquer ces découvertes au développement de nouveaux agents thérapeutiques.
Nous avons d'abord évalué le rôle des interactions entre CD47 et son ligand, SIRPα (signal regulatory protein alpha), dans le développement de la colite induite par TNBS, qui est un modèle murin d'inflammation intestinale partageant plusieurs symptômes similaires à ceux rencontrés chez les patients atteints de la MC. Nous avons démontré que les cellules dendritiques (CD) qui expriment SIRPα induisent une réponse immunitaire Th17 ainsi que le développement de la colite expérimentale. De plus, nous avons identifié un rôle important joué par CD47 dans la migration des CD SIRPα+ vers la lamina propria et les ganglions mésentériques, où ces cellules participent à l'induction de l'inflammation. Ainsi, par la délétion génétique du CD47 ou encore par la manipulation de ses fonctions à l'aide d'une molécule de fusion, le CD47-Fc, nous avons réussi à diminuer avec succès l'inflammation intestinale chez la souris.
L-carnitine (LCAR) est un acide aminé dérivé que l'on retrouve normalement dans la viande et les produits laitiers et qui est également disponible en vente libre en tant que supplément nutritionnel. Puisque des mutations dans le transporteur de LCAR, OCTN1 et OCTN2, ont préalablement été associées avec la MC, nous avons décidé d'examiner le rôle de cette molécule dans le développement de l'inflammation intestinale. LCAR a démontré des propriétés immunosuppressives remarquables, tant in vitro qu'in vivo, en supprimant efficacement les mécanismes de défenses innés et adaptatifs de la réponse immunitaire, résultant en une diminution significative du développement de l'inflammation intestinale.
En résumé, nous avons identifié CD47 comme étant un important régulateur de la migration des CD SIRPα+ et avons démontré que cette sous-population de cellules est impliquée dans le développement de l'inflammation intestinale. De plus, ces travaux ont permis d'identifier deux nouveaux candidats thérapeutiques prometteurs, le CD47-Fc et LCAR, pour le traitement contre la MC.
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Majmudar, Pooja M. "Investigating Molecular Targets of Phosphaplatins: A Class of Novel Non-DNA-Binding Platinum Anticancer Agents in the Treatment of Ovarian Cancer." Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1300373466.
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Dalhart, Adam M. "A Verification of Deformable Dose and Treatment Planning Software in the Evaluation of Dose to Targets and Normal Structures in SBRT Patients." University of Toledo Health Science Campus / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1404777373.
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Gillies, Stuart Graham. "The NRSF and USF transcription factor families regulate pro-convulsant neuropeptides and are targets for anti-convulsant drug treatment: implications for epilepsy." Thesis, University of Liverpool, 2009. http://livrepository.liverpool.ac.uk/1302/.
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Epilepsy is a chronic neurological disorder which can arise following an initial insult that over time, progresses into a condition characterised by recurrent spontaneous seizures. During a latent period between the initial insult and the epilepsy condition proper, major changes occur within the brain at both a cellular and molecular level, in a process known as epileptogenesis. It is postulated that during epileptogenesis, signal transduction pathways are perturbed following the initial insult, which may bring about long term changes in gene expression profiles. For example, the expression of a host of neuropeptides is known to be modulated in response to an initial insult, including the up-regulation of the pro-convulsant tachykinins Substance P and Neurokinin B, encoded by the TAC1 and TAC3 genes, respectively. In this thesis I have explored the regulation of both of these genes by two distinct transcription factor (TF) families; the Neuron Restrictive Silencing Factor (NRSF) isoforms, and the Upstream Stimulatory Factor (USF) proteins. I demonstrate that both NRSF and USF variants regulate TAC3 promoter activity, and that NRSF isoforms can modulate endogenous NKB expression in a human neuroblastoma cell line. Furthermore, these distinct TF families are shown to work in cooperation to regulate the activity of the rat TAC1 promoter. Thus, both NRSF and USF variants are shown to be important in the regulation of pro-convulsant neuropeptides and as both NRSF and USF proteins have been shown to be induced by pro-convulsant stresses here, they are potential key TFs in epileptogenesis, responding to an initial insult, and orchestrating downstream gene expression changes. Consistent with such a model, I have also revealed that both NRSF and USF variants are modulated by anti-convulsant drug treatment. Here, three distinct anti-convulsant drugs, were found to differentially modulate the expression of both the full-length NRSF, and its truncated isoform, as well as the USF proteins USF1 and USF2. Furthermore, whilst the drugs had limited impact upon the localisation of these TFs in human neuroblastoma cells, they did affect the binding of these TFs to target DNA sequences, particularly NRSF binding to its recognition DNA sequence, the NRSE, in a number of genes. In addition, due to an increasingly appreciation of the role of cocaine and the dopaminergic pathways in seizure progression, I explored the impact of cocaine treatment on the expression of these TFs. Cocaine was found to modulate both NRSF and USF variant expression, and NRSF binding to target DNA sequences. These findings suggest that both NRSF and USF variants are important in epileptogenesis and are targets for modulation by the anti-convulsant drugs investigated here. To further explore the significance of NRSF expression in seizure progression, I explored the impact of over-expression of NRSF isoforms, modelling that which occurs in response to seizure in animal models, on global gene expression pathways. I reveal that NRSF isoform over-expression significantly modulates the expression of a host of genes with known associations with epilepsy, supporting a model that NRSF isoforms are key TFs which respond to the initial insult and coordinate long-term changes in gene expression. These findings may help our understanding of the molecular mechanisms at work during epileptogenesis, and may better our understanding of the progression of epilepsy.
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Sentker, Thilo [Verfasser], and Florian [Akademischer Betreuer] Grüner. "Feasibility and uncertainties of 4D dose simulation for post-treatment quality assurance in radiotherapy of moving targets / Thilo Sentker ; Betreuer: Florian Grüner." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2020. http://d-nb.info/121218100X/34.
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Hua, Xiaoqin [Verfasser], and Sonja [Akademischer Betreuer] Schrepfer. "Identifying New Targets, Developing Novel Models, and Investigating Innovative Strategies for the Treatment of Rejection in Thoracic Transplantation / Xiaoqin Hua. Betreuer: Sonja Schrepfer." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2012. http://d-nb.info/1030365601/34.
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Suelves, Caballol Núria. "Evaluation of therapeutic targets for the treatment of behavioral alterations and neuropathology in Huntington’s disease. The role of histone deacetylase 3 and p75 neurotrophin receptor." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663911.
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Huntington’s disease (HD) is a rare genetic disorder caused by an aberrant expansion of a CAG trinucleotide in the huntingtin gene (Htt). The neuropathology of the disease is characterized by progressive neuronal dysfunction and degeneration in specific regions within the central nervous system, which causes a triad of symptoms including motor, cognitive and psychiatric features. Current treatments only alleviate some of these symptoms without preventing the inevitable neuropathological progression and, therefore, there is great need for finding new therapies that act at the root of the illness. Transcriptional dysregulation, somatic CAG repeat instability and neurotrophic signaling alterations appear early in HD and have been considered important underlying pathogenic mechanisms. Additionally, it has been recently suggested that HDAC3 and p75NTR could participate in some of these processes. Accordingly, the main aim of this thesis was to evaluate the potential therapeutic benefits of the pharmacological inhibition of HDAC3 and the genetic reduction of p75NTR in a knock-in mouse model of HD, termed HdhQ7/Q111. Our results have demonstrated that the selective inhibition of HDAC3 ameliorates cognitive deficits (motor learning and long-term memory alterations) in HdhQ7/Q111 mice by restoring the neuronal activity- dependent transcription of important memory-related genes, such as Arc and Nr4a2. This effect could be due to an increase in histone acetylation, leading to a relaxed DNA configuration, as well as an increase in CBP acetylation, potentially promoting its transcriptional activity. Besides, we have observed that chronic HDAC3 inhibition suppresses somatic CAG repeat expansions in Htt gene. Results of this thesis have shown that HDAC3 inhibition increases Msh2 acetylation at lysine 73, probably altering its DNA repair activity, which has been involved in promoting somatic CAG repeat length increases. Finally, our results have shown that p75NTR levels are increased in HdhQ7/Q111 mice from symptomatic stages. Interestingly, p75NTR normalization delays the onset of motor coordination alterations, several neuropathological HD hallmarks and the overall neurotrophic signaling imbalance in HdhQ7/Q111 mice, which comprise a reduction of the neurotrophin BDNF, a reduction and disrupted activation of its specific receptor, TrkB, and an overactivation of the p75NTR-dependent JNK signaling pathway. However, normalization of p75NTR levels at late disease stages is not able to prevent the loss of striatal integrity and motor coordination in KI mice. This might be the result of the unstoppable advance of other pathological mechanisms that do not depend on p75NTR expression. Therefore, a pharmacological strategy aimed to reduce the expression or activity of p75NTR in HD could provide some benefits at early stages of the disease but, as the pathogenic process progresses, the benefits would be limited. Collectively, our results have provided further insight into the contribution of transcriptional dysregulation, somatic CAG instability and neurotrophin signaling disturbances to HD neuropathological progression and highlight HDAC3 and p75NTR as promising therapeutic targets to correct these pathogenic mechanisms and ameliorate cognitive and motor behavioral impairments in HD.La malaltia de Huntington (MH) és un trastorn neurodegeneratiu i hereditari que es caracteritza per la presència d’alteracions motrius, cognitives i psiquiàtriques. Actualment no existeix cap tractament que aconsegueixi frenar la progressió d’aquesta patologia, de manera que l’avaluació de dianes terapèutiques esdevé de vital importància. La desregulació transcripcional, l’expansió somàtica del triplet CAG i l’alteració de la senyalització neurotròfica s’han descrit com importants mecanismes subjacents i s’ha determinat que les proteïnes HDAC3 i p75NTR podrien promoure alguns d’aquests processos. Per això, en aquesta tesi hem avaluat els possibles beneficis resultants de la inhibició farmacològica de la HDAC3 o de la reducció genètica del receptor p75NTR en un model de ratolí de la MH, anomenat HdhQ7/Q111. Els nostres resultats han demostrat que la inhibició de la HDAC3 en ratolins HdhQ7/Q111 aporta millores cognitives degut a la prevenció de les alteracions transcripcionals. Aquest efecte podria ser conseqüència d’un increment de l’acetilació d’histones, promovent una conformació més relaxada de l’ADN, i d’un increment de l’acetilació de la proteïna CBP, estimulant la seva activitat transcripcional. A més, hem demostrat que la inhibició de la HDAC3 suprimeix l’expansió somàtica del triplet CAG en el gen mutat de la proteïna huntingtina, possiblement degut a que s’incrementen els nivells d’acetilació de la proteïna Msh2 en un residu que podria alterar la seva activitat, la qual s’ha vist recentment implicada en l’allargament del tram CAG. Per últim, els nostres resultats han determinat que la normalització del receptor p75NTR en els ratolins HdhQ7/Q111 endarrereix l’aparició de les alteracions en coordinació motora, coincidint amb una millora de diferents característiques neuropatològiques de la MH i amb una recuperació de l’alterada senyalització neurotròfica. No obstant, en etapes avançades de la malaltia, l’efecte d’altres mecanismes patogènics que ocorren de forma progressiva en la MH acaben anul·lant els efectes positius de la reducció en els nivells de p75NTR. Les evidències experimentals recopilades permeten concloure que les proteïnes HDAC3 i p75NTR participen en l’aparició de mecanismes patològics clau per a la correcta funció neuronal en diferents regions cerebrals i, per tant, representen prometedores dianes terapèutiques per tractar la simptomatologia motora i cognitiva de la MH.
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Bladen, John Christopher. "Identification of genetic factors involved in morphoeic basal cell and sebaceous gland carcinoma of human eyelid tumours with a view to identifying potential treatment targets." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/25807.
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Periocular malignancy represents an increasing burden and currently requires disfiguring surgery in an attempt to cure patients. Basal cell carcinoma (BCC) is the commonest cancer worldwide and morphoeic BCC (mBCC) is an aggressive subtype. Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition that often requires blinding surgery to prevent mortality, especially in the pagetoid subtype. MBCC has a high risk of local recurrence compared to the more indolent nodular subtype reflected by a different set of driver genes including FLNB and HECTD4. Surrounding mBCC stroma is abnormal, containing mutations in EPHA3 and GLI3. Four common dysregulated pathways detected using both whole exome and RNA sequencing for mBCC were; 'hedgehog (Hh) signalling pathway', 'BCC', 'Natural killer cell mediated cytotoxicity' and 'Fc Epsilon RI signalling pathway'. Hh mutational profile for nodular BCC was not reflected in the RNA and protein expression. In contrast, Hh overexpression is seen in the tumour and stroma of morphoeic tissue with the latter potentially being partly responsible for its aggressive nature and risk of recurrence that may warrant removal to prevent recurrence. SGC has a low overall mutational burden, no UV signature and defective mismatch repair signature. Driver genes included TP53, RB1 and the dynein family is a novel driver possibly involved in chromatid segregation as marked chromosomal instability was demonstrated on copy number analysis. Correlation of whole exome and RNA sequencing data demonstrated upregulated 'cell cycle', 'ubiquitin mediated proteolysis' and 'wnt signalling'. Subtype analysis of pagetoid and nodular SGC revealed the histone gene cluster family as important to both. Oncomir hsa-miR-21 was overexpressed in both and loss of hsa-miR-199a occurs in pagetoid. Increased protein expression of HIST1H2BD was seen in both subtypes as was Hh expression. These novel SGC findings support a chromosomally unstable cancer with the ability to invade extracellular matrix.
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Suwandhi, Lisa Siu-Lan [Verfasser], Matthias [Akademischer Betreuer] Tschöp, Matthias [Gutachter] Tschöp, and Martin [Gutachter] Klingenspor. "Novel therapeutic targets for the treatment of diabetes and obesity: potential and risks of D-serine and its transporter Asc-1 / Lisa Siu-Lan Suwandhi ; Gutachter: Matthias Tschöp, Martin Klingenspor ; Betreuer: Matthias Tschöp." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1215293143/34.
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Kelch, Sarah [Verfasser], Griensven Martijn [Akademischer Betreuer] van, Griensven Martijn [Gutachter] van, Marion B. [Gutachter] Kiechle, and Florian [Gutachter] Bassermann. "Gender-independent miRNA expression profiles in bone homeostasis as potential cellular biomarkers and targets for osteoporosis diagnosis and treatment / Sarah Kelch ; Gutachter: Martijn van Griensven, Marion B. Kiechle, Florian Bassermann ; Betreuer: Martijn van Griensven." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1165773058/34.
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Williams, A. Lynn. "Target Selection and Treatment Outcomes." Digital Commons @ East Tennessee State University, 2003. https://doi.org/10.1044/lle10.1.12.
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Recent research has demonstrated that target selection is an important link between phonological assessment and intervention. It is a significant variable in treatment efficacy because, as suggested by Camarata and Nelson (1992), acquisition efficiency is at least predicated on the selection of targets that are addressed in intervention.
Typically, speech-language pathologists have relied on phonetic factors that were based on developmental norms and/or stimulability. Specifically, those who adhered to a traditional approach to target selection chose sounds that were stimulable and early developing. This traditional approach to target selection was based on the assumption that earlier, stimulable sounds were easier to produce and followed a developmental sequence of acquisition.
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Saleh, Walaa Mostafa Ahmed [Verfasser]. "Targeted treatment and targeted selective treatment in beef calves in Brandenburg / Walaa Mostafa Ahmed Saleh." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/1138234400/34.
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Michaud, Isaac J. "Targeted Treatment in a Community Model." Fogler Library, University of Maine, 2011. http://www.library.umaine.edu/theses/pdf/MichaudI2011.pdf.
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Ebeid, Kareem Atef Nassar. "Nanoparticles for targeted treatment of cancer." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6567.
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Cancer is the second leading cause of death in the USA, following cardiovascular disease. Treating cancer using conventional therapies is associated with low response rates and high toxicity, because these therapies usually lack specific tumor accumulation. Loading anticancer drugs into intelligently designed polymeric nanoparticles (NPs) can serve in delivering these drugs specifically to the tumor site, thus boosting their efficacy and reducing any associated off target toxicity. Targeting NPs to the tumor site can occur through either passive or active means. In passive targeting, NPs of specific size and surface characteristics can exploit the tumor’s erratic vasculature and occluded lymphatic drainage to extravasate the systemic circulation and accumulate preferentially at the tumor site. Active targeting mandates grafting the surface of NPs with a ligand that specifically interacts with a protein expressed at higher levels at the tumor site, in comparison to elsewhere in the body. In the current research, we independently investigated the utilization of passive and active targeting strategies to treat aggressive forms of cancer.
Initially, passively targeted poly(lactic-co-glycolic acid) (PLGA) NPs to treat aggressive forms of endometrial cancer (EC) were investigated. A novel combination of soluble paclitaxel (PTX), a first line chemotherapy for EC, and soluble BIBF1120 (BIBF, nintedanib), an antiangiogenic molecular inhibitor, was first tested against three EC cell lines bearing different p53 mutations. The results showed that only EC cells with loss of function (LOF) p53 were sensitive to the combination therapy, indicating the potential of this combination to engender synthetic lethality to PTX. Next, NPs loaded with PTX were investigated with respect to the impact of varying the polymer lactic acid to glycolic acid ratio and the surfactant type on the major physicochemical properties of the prepared nanoparticles, drug loading, cellular uptake, cytotoxicity, and drug release. The optimum formulation was then loaded with BIBF and the combination of independently loaded passively targeted NPs were further evaluated for in vivo activity against a xenograft model of LOF p53 EC. The combination of independently loaded NPs exhibited the highest reduction in tumor volume and prolonged survival when compared to soluble PTX, PTX NPs or untreated control. These data highlight this specific combination of NPs as a novel promising therapy for LOF p53 EC.
In a second study, the use of actively targeted NPs to treat liver cancer was explored. In this study, a combination of small interfering RNA (siRNA) against astrocyte elevated gene-1 (AEG-1), and all-trans retinoic acid (ATRA) was investigated as a new therapy for hepatocellular carcinoma (HCC). AEG-1 is a highly expressed oncogene that is directly involved in HCC progression and aggressiveness, in addition to reducing the ability of retinoic acid to induce apoptosis in HCC cells. First, a new conjugate was synthesized that was capable of delivering siRNA selectively to HCC cells, using galactose as a targeting moiety. The conjugate was prepared by linking poly(amidoamine) (PAMAM) dendrimers, polyethylene glycol (PEG) and lactobionic acid (Gal, disaccharide containing galactose) (PAMAM-PEG-Gal). We confirmed the synthesis of the conjugate using 1H-NMR, Mass spectrometry and Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry. Next, nanoplexes of the synthesized conjugate, PAMAM-PEG-Gal, and AEG-1 siRNA were prepared. Nanoplexes were further characterized for their size, surface charge, morphology, and electrophoretic mobility to identify the optimum complexation ratio between PAMAM-PEG-Gal and the siRNA. Then, mice bearing orthotopic luciferase expressing HCC cells were treated with the optimum nanoplex formulation. Results showed that a combination of AEG-1 nanoplexes and ATRA results in a significant reduction in luciferase expression, reduced liver weight, lower AEG-1 mRNA levels and increased apoptosis, when compared to utilizing nanoplexes with silencing control (siCon), siCon+ATRA, or AEG-1 nanoplexes alone. The results indicate that the combination of liver-targeted AEG-1 nanoplexes and ATRA may be a potential treatment for aggressive HCC.
These data place targeted NPs as a promising efficient delivery system for cancer treatment.
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Lin, Zhen. "Chondrocyte : a target for the treatment of osteoarthritis." University of Western Australia. Orthopaedics Unit, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0203.
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[Truncated abstract] Osteoarthritis (OA) is the most common form of arthritis, characterized by progressively degeneration of articular cartilage. Chondrocyte is the only cell type in articular cartilage tissue and responsible for cartilage matrix turnover. This thesis focuses on the biological and genetic behaviors of human chondrocyte and potential therapeutic strategies that target on chondrocyte. Chondrocytes have been used for the tissue-engineered cartilage construction, especially in articular cartilage repair. The technique of chondrocyte-base tissue engineering utilizes in vitro propagated chondrocytes combined with several manufactured biomaterials to regenerate cartilage tissue. Although these technologies have been successfully applied in clinic, the biological characteristics of chondrocyte during in vitro propagation and after implantation remain unclear. This thesis reviewed the present studies of chondrocyte biology and its potential uses in tissue engineering. Particularly, chondrocytes have been shown to de-differentiate into fibroblastic-cells when they are exposed to inflammatory conditions or cultured on monolayer in vitro. This thesis investigated the gene expression profile of chondrocytes when they are cultured and serially passaged on monolayer in vitro. Human chondrocytes obtained from OA patients were cultured up to passage 6. Twenty-eight chondrocyte associated genes were measured by Real-time PCR. The results showed that a number of genes were changed in expression levels at various stages of passage as indications of chondrocyte de-differentiation. Chondrocytes derived from OA patients or normal donors exhibited a very similar gene expression pattern. Interestingly, transcription factor Sox-9, which plays a key role in chondrogenesis remained unchanged with increasing passage number, indicating that the de-differentiation process of chondrocyte is reversible. This thesis also focused on the development of novel pharmacological approaches for OA that target on articular chondrocyte. The clinical feature, etiology, pathogenesis, diagnostic approaches, conventional and potential future treatments for OA were briefly reviewed in this thesis. ... The effects of natural compounds on chondrocyte gene expression, proteoglycan degradation and nitric oxide production were measured. The results showed that parthenolide, a NF-kB inhibitor, regulated chondrocyte function by suppressing the up-regulation of gene expression of inflammatory factors and matrix proteinases induced by lipopolysaccharide, and down-regulating COX-2 expression. Parthenolide was able to reduce proteoglycan degradation in human chondrocytes, but had no effect on nitric oxide production. These results suggest that parthenolide mediates inflammatory-activated NF-kB pathway, and subsequently reduces inflammatory response, prevents cartilage destruction and relieves pain, and hence may be useful for OA treatment.
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Valetti, Sabrina. "Targeted squalenoyl nanomedicines for pancreatic cancer treatment." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114805/document.
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Le cancer pancréatique représente la cinquième cause de décès par cancer dans les pays occidentaux. Son mauvais pronostic (survie à 5 ans inférieure à 3,5 % des cas) est dû à l’absence de facteurs de risques spécifiques interdisant une prévention efficace, et à un diagnostic tardif qui révèle un cancer agressif chez environ 90% des patients. Actuellement, le seul traitement curatif de ce cancer est la chirurgie, mais celle-ci ne peut être envisagée que dans 10 à 15 % des cas. L’adressage de molécules thérapeutiques vers l’organe, le tissu ou la cellule malade constitue aujourd’hui un défi majeur pour le traitement des maladies humaines notamment infectieuses, cancéreuses ou d’origine génétique. C’est pour ces raisons que le développement de nanotechnologies, en tant que vecteurs de médicaments, a pris un essor considérable au cours des dernières années. Dans ce contexte, le concept de squalènisation repose sur le couplage chimique entre le squalène (SQ), un lipide naturel précurseur de la synthèse du cholestérol, et des principes actifs (notamment des molécules anticancéreuses). Les bioconjugués ainsi formés sont alors capables de s’auto-assembler en solution aqueuse pour former des nanoparticules stables de diamètres compris entre 100 et 300 nm. L’exemple de référence dans ce domaine est la nanoparticule de gemcitabine-squalène (SQdFdC) qui a donné lieu à des résultats spectaculaires in vitro sur des lignées de cellules cancéreuses humaines In vivo, les nanoparticules de gemcitabine-squalène se sont avérées beaucoup plus efficaces que la gemcitabine libre sur des tumeurs solides greffées par voie sous-cutanée ainsi que sur des modèles murins de leucémies agressives métastatiques.Au vu de ces résultats encourageants, le projet de thèse a été développé autour de deux axes de recherche. (I) Dans un premier temps, les nanoparticules de gemcitabine-squalène ont été fonctionnalisées par un peptide capable de reconnaître et de cibler spécifiquement les cellules cancéreuses pancréatiques. (II) Le deuxième axe de recherche a visé l’encapsulation d’un second principe actif au sein des nanoparticules de gemcitabine-squalène afin de développer le concept de nanoparticule « multi-thérapeutique »Pancreatic cancer is a lethal disease with the worst prognosis among all solid tumors. In the last decades, progresses in pancreatic cancer therapy had remained exceedingly slow and disappointing offering minimal benefits in median survival which remains of less than 6 months and the maximum of 5 years in the 6% of patients. One of the major requirements for a successful cancer therapy is its ability to selectively kill cancer cells with minimal damage to healthy tissues. In this context, a great deal of attention focused on advanced nanoscale systems (i.e., nanomedicines) with the aim to overcome the limits associated to the traditional drug delivery modalities. Nanomedicines can indeed enhance drug properties by (i) offering protection from degradation, (ii) enabling controlled release and distribution and increasing bioavailability while reducing undesired side effects.In the current work we aimed to propose novel nanoscale-based strategies to optimize pancreatic cancer treatment taking into account the specific physio-pathology of this tumor. The first approach relied on the design of a targeted nanomedicine able to specifically bind receptors mainly expressed onto pancreatic cancer cells in order to selectively increase drug accumulation in these cells saving healthy ones.In a second approach, by combining two therapeutic agents in the same nanoparticle we constructed a multi-therapeutic drug delivery system capable to increase the therapeutic index of the combined therapy. In particular, taking advantages from the “squalenoylation prodrug approach”, the research activity of this Ph.D. work lead to the to design of (i) a novel peptide-functionalized squalenoyl gemcitabine nanoparticle and (ii) a tyrosine kinase inhibitor-loaded squalenoyl gemcitabine nanoparticle. Obtained nanoparticles were investigated with respect to their physico-chemical properties and in vitro antitumor activity. The efficacy of peptide-functionalized nanoparticles in impairing tumor growth was assessed in vivo on an experimental model of pancreatic cancer
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Yau, Chung-cheung, and 邱宗祥. "Molecular targeted therapies in advanced hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48421145.
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With the recent advances in the knowledge of hepato-carcinogenesis, there has been encouraging development in the molecular targeted therapy for patients with advanced hepatocellular carcinoma (HCC). Sorafenib, an anti-angiogenic multi-targeted receptor tyrosine kinase inhibitor, has become the standard of treatment in HCC patients with Child-Pugh A cirrhosis. Nevertheless, the benefits and safety profile of sorafenib in the majority of the unselected advanced HCC patients and other patient subgroups are still unclear. More importantly, the survival benefit associated with sorafenib use is generally modest in Asian population. Therefore, an unmet medical need remains for more effective therapeutic agents.
This thesis studied the impact of molecular targeted therapy in the treatment of advanced HCC patients and it contains 10 original studies divided into six sections. The first section provides a concise overview of the epidemiology, risk factors, and current treatment options for HCC patients. Also, the molecular biology and opportunity for the use of targeted therapy in advanced HCC were discussed.
The second section is about a new prognostic score system that we developed — Advanced Liver Cancer Prognostic System (ALCPS). Our study results showed that ALCPS was able to objectively estimate the 3-month survival probability of advanced HCC patients and thus could enhance patient selection for targeted therapy or clinical trials.
The third section is about the use of sorafenib in the treatment of advanced HCC patients. The results of our single centre phase II study showed that sorafenib had good efficacy and acceptable tolerability in treating advanced HCC patients in hepatitis B endemic area. Furthermore, our retrospective study results confirmed that the overall survival benefits and overall treatment-related adverse events of sorafenib were comparable in elderly and young advanced HCC patients. More importantly, our other retrospective analysis showed that Child-Pugh (CP) A and CP B patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CP B patients, most benefits were observed in patients with score 7. Nevertheless, CP B patients were more susceptible to developing cirrhotic complications. Last but not least, our study also demonstrated that drop in serum alpha-fetoprotein level > 20% in the first 6 weeks of sorafenib treatment was a useful early surrogate endpoint for evaluating antitumor response and survival benefits. All these results are instrumental in guiding future rational use of sorafenib in advanced HCC population.
The fourth section is about the role of targeted therapies in treating sorafenib-refractory advanced HCC patients. In a single arm phase II study, we showed that bevacizumab and erlotinib combination was not effective in treating advanced HCC patients who had failed prior sorafenib treatment.
The fifth section of the thesis comprises results of four early phase novel clinical trials that may potentially improve the therapeutic outcomes in advanced HCC patients. First, our phase I/II study demonstrated that another anti-angiogenic agent — PTK787 had encouraging and possible synergistic activity when combined with intravenous doxorubicin in treating advanced HCC patients. Second, our multi-center phase II study results demonstrated promising activity with good tolerability of a novel combination — sorafenib together with capecitabine and oxaliplatin (SECOX) in the treatment of advanced HCC patients. Third, in a phase I study, we showed that pazopanib, a novel anti-angiogenic agent, had a manageable safety profile and preliminary activity in advanced HCC patients. Moreover, pazopanib reduced tumor vessel leakage, as shown by contrast-enhanced magnetic resonance imaging indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. Lastly, in another phase I study, we evaluated safety, pharmacological parameters, and potential antitumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Our results illustrated that arginine depletion in humans can be achieved safely with peg-rhAgr1 in a dose-response manner and peg-rhArg1 had manageable safety profile and preliminary evidence of activity in advanced HCC patients.
In the last section, the future perspectives about the use of molecular targeted therapy in the treatment of advanced HCC patients were discussed.published_or_final_version
Medicine
Master
Doctor of Medicine
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Wimmer, Wolfgang. "Cytokines in alphavirus induced arthritis as possible targets for novel treatments." Thesis, Curtin University, 2015. http://hdl.handle.net/20.500.11937/48524.
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This study highlighted the involvement of macrophages, muscle cells and adipocytes in the pathogenesis of RRV disease and investigated the release of various cytokines from these cells during infection, such as TNFα, MIF, NO, HMGB proteins, IL-6, IL-18, IL-33, IL-10 and others. Several known cytokine inhibitors were tested for their anti-inflammatory properties in RRV infected cell lines as possible future treatment options. These inhibitors included erythromycin, clarithromycin, roxithromycin, ethyl pyruvate, pentoxifylline and resveratrol.
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Robinson, Richard. "Biomarker and treatment target development in muscle invasive bladder cancer." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/biomarker-and-treatment-target-development-in-muscle-invasive-bladder-cancer(9f7e3dba-9630-4d0d-b7aa-629718d02018).html.
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Introduction: The outcomes following radical treatment for bladder cancer (BC) remain poor, with 5 year overall survival (OS) rates of approximately 50% and over 5000 deaths per year in the U.K. There has been paucity of significant therapeutic developments since the introduction of cisplatinum based chemotherapy in the 1970’s. The aim of this study was to identify putative drug targets for the treatment of this aggressive form of cancer. Methods: A tissue microarray (TMA) was constructed from the cystectomy specimens of 497 BC patients and 70 controls, linked to a clinical database with extended follow up. The online database Oncomine® was interrogated to identify putative treatment targets which were subsequently evaluated using in-vitro models of high grade invasive bladder cancer (using the J82 and T24 cell lines). In-vitro modelling was conducted using siRNA target knockdown during proliferation, chemo-sensitivity, migration and Matrigel™ invasion assays. Expression of the putative targets was then correlated with tumour characteristics and patient outcomes, by IHC and automated image analysis of the TMA. Results: The proteins CYR61 and CTGF were selected from Oncomine® and studied in conjunction with the HGF/MET axis, on the basis of known interactions in other cancer types. siRNA knockdown of both proteins abrogated HGF induced Matrigel™ invasion in both cell lines. CYR61 knockdown significantly reduced HGF induced cell migration and foetal calf serum (FCS) induced Matrigel™ invasion in both cell lines. Knockdown of both proteins also significantly increased the sensitivity of both cell lines to cisplatinum. CYR61 expression was significantly increased in BC samples compared to normal controls and an independent predictor of OS at 6 years (HR 1.493, p=0.030). In contrast, loss of CTGF expression was significantly associated with increasing tumour stage and worse OS. MET expression was reduced in BC compared to controls and not predictive of survival following cystectomy. Conclusions: The in-vitro findings for CTGF as a treatment target were encouraging, although these findings were not supported by the TMA data. CYR61 promotes an aggressive bladder cancer phenotype and knockdown reverses features of EMT and increases chemo-sensitivity. Clinical cohort correlation confirms CYR61 to be a promising treatment target in bladder cancer.
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Young, Robin. "Vascular targeted agents for the treatment of angiosarcoma." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/3251/.
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Background: Angiogenesis is the process of new blood vessel formation, and is regulated by angiogenic growth factors including vascular endothelial growth factor (VEGF). Angiosarcomas are rare, aggressive vascular tumours. Studies were performed to investigate the expression of angiogenic growth factors in angiosarcoma, and to assess vascular targeted agents for the treatment of angiosarcoma. Methods: In vitro studies compared two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS) with human dermal microvascular endothelial cells (HuDMECs). The cell lines were compared in functional assays, including cell viability, cell differentiaiton and cell migration assays, and protein expression profiled using antibody arrays. Cell responses to vascular targeted agents were compared, including response to bevacizumab an anti-VEGF antibody, axitinib a VEGF receptor (VEGFR) tyrosine kinase inhibitor, selumetinib a MEK inhibitor, and DMXAA a vascular disrupting agent. Immunohistochemistry studies measured the expression of angiogenic growth factors in angiosarcoma tumour specimens using benign vascular lesions for comparison, and assessed canine angiosarcoma as a model of human angiosarcoma. Results: ASM and ISO-HAS demonstrated accelerated growth kinetics, chaotic tubule formation, and increased cell migration compared to HuDMECs. ASM and ISO-HAS expressed significantly increased VEGF compared to HuDMECs. Only minor responses were observed to VEGF targeted agents in functional assays despite western blot studies that showed target inhibition of VEGFR2 phosphorylation,. Striking responses were seen however to selumetinib and DMXAA. Immunohistochemistry studies demonstrated benign and malignant vascular tumours expressed a range of pro-angiogenic growth factors, however analysis did not distinguish malignant from benign vascular tumours. The morphology of canine angiosarcoma was similar to human angiosarcoma. VEGF and VEGFR2 expression was significantly increased in canine angiosarcoma compared to benign vascular lesions. Conclusion: These studies predict limited in vivo angiosarcoma tumour response to VEGF targeted agents. Selumetinib and DMXAA are suggested for further study. Canine angiosarcomas represent a potential model of human angiosarcoma to be explored in future studies.
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Cheung, Chi-ho, and 張志豪. "Identification of CD47 as a novel therapeutic target for hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46945374.
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Setua, Sonali. "Development of targeted nanomedicine for glioblastoma therapy." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708268.
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Shamseddin, Aly. "Matrix metalloproteinases as potential target in the treatment of vascular dysfunctions." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4113.
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L’endothélium préserve l'homéostasie vasculaire et tissulaire qui contrôle plusieurs processus physiologiques dans les corps humain. Lors de certaines pathologies, l'intégrité vasculaire peut être perturbée par une diversité de médiateurs de perméabilité qui interrompent la fonction barrière de cet épithélium, et provoquer des lésions tissulaires au cours de la progression de la maladie. Par conséquent, l'intégrité de la barrière endothéliale est essentielle pour l'homéostasie vasculaire. Dans le cas de la fièvre hémorragique due à la dengue, de nombreuses voies de signalisation induisent une perméabilité vasculaire qui résulte d'une rupture de la barrière hémato-encéphalique qui, dans certains cas, peuvent permettre la pénétration virale dans le système nerveux central (SNC). La plupart de ces voies de signalisation (y compris le TNF-alpha) sur-activent les enzymes appelées métalloprotéinases matricielles (MMP), qui induisent la dégradation de la matrice extracellulaire (MEC) et des protéines intercellulaires régissant la perméabilité vasculaire. Parmi ces enzymes, les MMP gélatinolytiques (MMP-9 et MMP-2) sont considérées comme la classe la plus importante de MMP puisqu'elles sont capables de dégrader le collagène de type IV, constituant principal de la MEC, et les jonctions cellulaires PECAM- 1 et VE-cadhérine. Ainsi, dans cette étude, nous avons développé deux approches pour inhiber l'activité de MMP-9 et protéger la perméabilité vasculaire in vitro. Ces approches incluent (i) des antagonistes de MMP-9 conçus in silico, tels que le composée HA048 (ii) des composés lipophénoliques synthétiques dérivés du resvératrol. Ce dernier existe naturellement dans les tiges de raisin, les arachides et plusieurs autres plantes et qui est capable d'inhiber l'expression et l'activité de la MMP-9. Bien que le resvératrol ait plusieurs activités biologiques testées in vitro, son utilisation dans des modèles animaux est limitée en raison de sa faible biodisponibilité, de son métabolisme rapide et de son élimination. Par conséquent, cette étude a trois objectifs principaux. Premièrement, de trouver un nouveau composé capable d'inhiber l'activité de MMP-9 in vitro. Deuxièmement, de vérifier s’il peut protéger l'intégrité de la couche endothéliale dans les HUVEC. Enfin, de passer à des études précliniques sur le modèle de souris dengue afin de vérifier son activité, sa toxicité et sa biodisponibilité. Outre le resvératrol et le SB-3CT (inhibiteur commercial de la MMP-9), nous avons constaté que le resvératrol-acide linoléique oméga 6 (RES-LA), le resvératrol-docosanoïque (RES-C22) et le HA048 ont montré la plus forte activité anti-MMP-9 parmi d'autres composés. Cependant, RES-LA a été préférentiellement choisi par rapport à RES-C22 en raison de sa meilleure solubilité. Par conséquent, nous avons utilisé un nouveau concept de formulation de ces composés en les solubilisant dans un solvant compatible et moins toxique pour des expériences in vivo, un solvant eutectique profond naturel (NADES), composé de 1,2-propanediol:ChCl: eau (1:1:1) (NADES/PCW). Les résultats de la perméabilité vasculaire in vitro ont révélé que les inhibiteurs de la MMP-9 ont diminué la perméabilité endothéliale exacerbée induite par le TNF-α dans les HUVEC, mesurée à la fois en temps réel et en fluorescence. En outre, l'examen microscopique des jonctions cellulaires adhérentes a montré qu’il y avait plus de CD31/PECAM-1 entre les HUVEC traitées à la fois par le TNF-α et les inhibiteurs de la gélatinase par rapport au témoin positif (TNF-alpha).Le mécanisme d'action des lipophénols dérivés du resvératrol a été évalué. Nos résultats ont révélé que les lipophénols dérivés du resvératrol ont inhibé l'expression de la MMP-9 en atténuant la phosphorylation des kinases MAPK ERK1/2 et JNK1/2The endothelial barrier preserves the vascular and tissue homeostasis that controls several physiological processes inside the body. In pathologies, vascular integrity could be disrupted by a diverse of permeability mediators that interrupt the barrier function and cause tissue damage during disease progression. Therefore, endothelial barrier integrity is critical for vascular homeostasis. Although the mechanisms leading to vascular leakage have been studied over several past decades, recent approaches have pointed new therapeutic targets in pre-clinical studies. In the pathogenesis of dengue hemorrhagic fever (DHF), many signaling pathways induce vascular permeability that result of disruption of blood brain barrier, that in some cases could allow viral penetration into the central nervous system (CNS). Most of these signaling pathways (including TNF-alpha) activate the overproduction active enzymes called matrix metalloproteinases (MMPs) that induce degradation of the extracellular matrix (ECM) and intercellular proteins governing vascular permeability. Among these enzymes, gelatinolytic MMPs, (MMP-9 and MMP-2), which are considered the most important class of MMPs since they are capable of degrading collagen type-IV, the main constituent of ECM, and cell junctions (PECAM-1 and VE-cadherin). Thus, in this study, we have developed two approaches to inhibit MMP-9 activity and protect the vascular permeability in vitro. Those approaches include, (i) in silico designed MMP-9 antagonists, where we had determined a lead MMP-9 blocker (HA048). The second approach is to synthesize derived lipophenolic compounds from resveratrol, that naturally exists in grape stalks, peanuts, and several other plants, which is capable of inhibiting the expression and activity of active MMP-9 inside the cells. Despite that resveratrol has several biological activities tested in vitro, its use in animal models is limited due to its poor bioavailability, rapid metabolism, and elimination. Therefore, this study has three main goals. First, is to find a novel compound capable of inhibiting MMP-9 activity in vitro. Second, is to verify whether it can preserve the endothelial monolayer integrity. Finally, is to move to the preclinical studies in dengue mouse model to verify its activity in vivo, toxicity, and bioavailability.Besides resveratrol and SB-3CT (commercial MMP-9 inhibitor), we found that resveratrol-linoleic acid, omega-6 (RES-LA), resveratrol-Docosanoic acid (RES-C22) and HA048 (in silico designed inhibitor) have demonstrated the highest MMP-9 inhibitory activity among dozens of synthesized compounds. However, RES-LA was preferably selected over RES-C22 due to for solubility reasons. Moreover, we formulated these compounds in novel solvents that could be compatible and less toxic for in vivo experiments, which is known as natural deep eutectic solvent (NADES) based on 1,2-propanediol:ChCl:water (1:1:1) (NADES/PCW).Results of in vitro vascular permeability revealed that MMP-9 inhibitors have decreased TNF-α induced-exacerbated endothelial permeability in HUVEC, measured in both real-time impedance sensing and fluorescence count. In addition, microscopic examination of cell junction proteins showed that CD31/PECAM-1 were more adherent and attached between HUVEC treated with both TNF-α and gelatinase inhibitors comparing to the positive control (TNF-alpha).The mechanisms of action of resveratrol derived lipophenols were assessed. Our findings revealed that resveratrol derived lipophenols have inhibited MMP-9 expression by attenuating the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinases (JNK) mitogen-activated protein kinases (MAPK)
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Kirby, Anna M. "Optimising Target Volume Definition and Treatment Position for Adjuvant Breast Radiotherapy." Thesis, Institute of Cancer Research (University Of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516272.
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Sooman, Linda. "Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas." Doctoral thesis, Uppsala universitet, Institutionen för radiologi, onkologi och strålningsvetenskap, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-215079.
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The survival for high-grade glioma patients is poor and the treatment may cause severe side effects. A common obstacle in the treatment is chemoresistance. To improve the quality of life and prolong survival for these patients prognostic biomarkers and new approaches for chemotherapy are needed. To this end, a strategy to evade chemoresistance was evaluated by combining chemotherapeutic drugs with agents inhibiting resistance mechanisms identified by a bioinformatic analysis (paper I). The prognostic value of 13 different proteins was analyzed in this thesis (papers II-IV). Two of them, p38 mitogen-activated protein kinase (MAPK) and protein tyrosine phosphatase non-receptor type 6 (PTPN6, also known as SHP1) were analyzed for their potential as targets in combination chemotherapy (in paper III and IV, respectively). We found that: PTPN6 expression and methylation status may be important for survival of anaplastic glioma patients, p38 MAPK phosphorylation may be a potential negative prognostic biomarker for high-grade glioma patients and FGF2 expression may be a potential negative prognostic biomarker for proneural glioma patients. PTPN6 may be a useful target for combination chemotherapy with cisplatin, melphalan or bortezomib in high-grade gliomas. The following drug combinations; camptothecin combined with an EGFR or RAC1 inhibitor, imatinib combined with a Notch or RAC1 inhibitor, temozolomide combined with an EGFR or FAK inhibitor and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for high-grade gliomas.