Rozprawy doktorskie na temat „Cox”
Kliknij ten link, aby zobaczyć inne rodzaje publikacji na ten temat: Cox.
Utwórz poprawne odniesienie w stylach APA, MLA, Chicago, Harvard i wielu innych
Sprawdź 50 najlepszych rozpraw doktorskich naukowych na temat „Cox”.
Przycisk „Dodaj do bibliografii” jest dostępny obok każdej pracy w bibliografii. Użyj go – a my automatycznie utworzymy odniesienie bibliograficzne do wybranej pracy w stylu cytowania, którego potrzebujesz: APA, MLA, Harvard, Chicago, Vancouver itp.
Możesz również pobrać pełny tekst publikacji naukowej w formacie „.pdf” i przeczytać adnotację do pracy online, jeśli odpowiednie parametry są dostępne w metadanych.
Przeglądaj rozprawy doktorskie z różnych dziedzin i twórz odpowiednie bibliografie.
1
Dario, Alan de Genaro. "Processos de Cox com intensidade difusiva afim". Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/45/45133/tde-01052013-111713/.
Pełny tekst źródłaStreszczenie:
Esta Tese explora o Processo de Cox quando sua intensidade pertence a uma família de difusões afim. A forma da funçâo densidade de Probabilidade do Processo de Cox é obtida quando a intensidade é descrita por uma difusão fim d-dimensional arbitrária. Analisa-se também o acoplamento e convergência para o Processo de Cox com intensidade afim. Para ilustrar assume-se que a intensidade do Processo é governada por uma difusão de Feller e resultados mais detalhados são obtidos. Adicionalmente, os parâmetros da intensidade do Processo são estimados por meio do Filtro de Kalman conjugado com o estimador de Quase-Máxima Verossimilhança.This Thesis deals with the Cox Process when its intensity belongs to a family of affine diffusions. The form of the probability density function of the Cox process is obtained when the density is described by an arbitrary d-dimensional affine diffusion. Coupling and convergence results are also addressed for a general Cox process with affine intensity. We adopted the Feller diffusion for driving the underlying intensity of the Cox Process to illustrate our results. Additionally the parameters of the underlying intensity processes are estimated by means of the Kalman Filter in conjunction with Quasi-Maximum Likelihood estimation.
2
Cox, Benjamin Samuel. "Assessment of an invasive lake trout population in Swan Lake, Montana". Thesis, Montana State University, 2010. http://etd.lib.montana.edu/etd/2010/cox/CoxB0810.pdf.
Pełny tekst źródłaStreszczenie:
The recent invasion of lake trout into the Swan River drainage in Northwest Montana threatens one of the last remaining recreational bull trout fisheries in the USA. An inter-agency group is implementing an experimental lake trout suppression program on Swan Lake. The objectives of this study were to establish a baseline data set on the lake trout population in Swan Lake concurrently with the experimental removal effort, simulate alternative management scenarios using matrix models and identify spawning locations of lake trout to target adult fish and embryos. A commercial gill-net sampling effort provided data to estimate abundance, size structure, age structure, growth, condition, maturity, fecundity, and mortality of lake trout in Swan Lake. Lake trout in Swan Lake grew rapidly, attained large sizes, and were in high condition. The size and age structure of lake trout sampled was skewed towards juvenile lake trout, indicating the population was growing rapidly. Matrix-model simulations also indicated the lake trout population would continue to grow with no suppression efforts, but suppression efforts could reduce the population growth rate. Population growth was particularly sensitive to changes in age-0 survival in population models. Elasticity analysis of matrix simulations indicated survival from birth to sexual maturity, followed by survival of adult fish contributed most to population growth. Lake trout spawning locations were identified using ultrasonic telemetry, short-set gill nets, and in-situ egg nets. Spawning locations identified with acoustic telemetry were confirmed by capturing gravid lake trout in gill nets and lake trout eggs in the substrate. These results suggest that the inter-agency group should focus removal efforts on sub-adult and adult lake trout at if extirpation of the population is the goal. Given the uncertainty in the vital rates and the potential bias in exploitation rates used to model suppression scenarios, annual suppression efforts should be increased from the 2008 level to ensure a decline in the lake trout population.
3
Martinez, Ruiz Roxana de Jesus, i Rojas Juan Pablo Gomez. "“EFECTIVIDAD DE LA ANALGESIA EN POSOPERADAS DE CESAREA CON TRAMADOL PERIDURAL ASOCIADO A: KETOROLACO IV (COX-1) vs DICLOFENACO IV (COX-2) vs PARACETAMOL IV (COX-3) IV”". Tesis de Licenciatura, Medicina-Quimica, 2014. http://ri.uaemex.mx/handle/123456789/14614.
Pełny tekst źródła
4
De, la Puente Candamo ED José Agustín. "Josefina Ramos de Cox". Pontificia Universidad Católica del Perú, 2014. http://repositorio.pucp.edu.pe/index/handle/123456789/114442.
Pełny tekst źródła
5
Sun, Haipeng. "Regulation of Cyclooxygenase Gene Expression by Glucocorticoids in Cardiomyocytes". Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/194896.
Pełny tekst źródłaStreszczenie:
Glucocorticoids (GCs) are endogenous steroid hormones that regulate a number of critical physiological processes. Psychological stress increases the level of GCs in the circulating system. The biological effect of elevated GCs on the heart is not well understood. We found that GCs induced Cyclooxygenase-1 (COX-1) and COX-2 gene expression in cardiomyocytes. COX-1 or COX-2 encodes the rate-limiting enzyme in the biosynthesis of prostanoids, which modulate crucial physiological and pathophysiological responses. The present studies aim to elucidate the signaling transduction pathway and the mechanism underlying GC induced COX expression.Our data demonstrate that GCs activate COX-1 gene expression through transcriptional regulation. COX-1 gene promoter studies support a role of Sp binding site in CT induced COX-1 gene expression. The nuclear protein binding to this site appears to be Sp3 transcription factor. Co-immunoprecipitation assays indicated a physical interaction between GR and Sp3 protein. Silencing of Sp3 transcription factor with small interfering RNA suppressed CT-induced COX-1 promoter activation. These data suggest that the activated GR interacts with Sp3 transcription factor that binds to COX-1 promoter to up-regulate COX-1 gene expression in cardiomyocytes.We also found that administration of GC in adult mice increased the level of COX-2 in the ventricles. With isolated neonatal cardiomyocytes, corticosterone (CT) induces the transcription of COX-2 gene. This response appears to be cardiomyocyte cell type specific and GC receptor (GR)-dependent. CT causes activation of p38 MAPK and subsequently CREB phosphorylation that mediates COX-2 gene expression. Mifepristone, a GR antagonist, failed to inhibit p38 and CREB activation and p38 inhibition failed to prevent activation of GR. These data suggest that two parallel signaling pathways, GR and p38 MAPK, act in concert to regulate the expression of COX-2 gene in cardiomyocytes.In addition to the investigation of mechanism and signaling transduction pathway, I have explored pharmacological agents that modulate COX expression. LY294002, a commonly used PI3K inhibitor, inhibited COX-2 gene expression via a PI3K-independent mechanism. Whereas GSK-3 inhibitors, such as lithium chloride, upregulated COX-2 gene expression, but suppressed GC-induced COX-1 expression. These data have paved the foundation for pharmacological manipulation of COX-1 and COX-2 gene expression in the heart.
6
Noppakaew, Passawan. "Parabolic projection and generalized Cox configurations". Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.642047.
Pełny tekst źródłaStreszczenie:
Building on the work of Longuet-Higgins in 1972 and Calderbank and Macpherson in 2009, we study the combinatorics of symmetric configurations of hyperplanes and points in projective space, called generalized Cox configurations. To do so, we use the formalism of morphisms between incidence systems. We notice that the combinatorics of Cox configurations are closely related to incidence systems associated to certain Coxeter groups. Furthermore, the incidence geometry of projective space P (V ), where V is a vector space, can be viewed as an incidence system of maximal parabolic subalgebras in a semisimple Lie algebra g, in the special case g = pgl (V ) the projective general linear Lie algebra of V . Using Lie theory, the Coxeter incidence system for the Coxeter group, whose Coxeter diagram is the underlying diagram of the Dynkin diagram of the g, can be embedded into the parabolic incidence system for g. This embedding gives a symmetric geometric configuration which we call a standard parabolic configuration of g. In order to construct a generalized Cox configuration, we project a standard parabolic configuration of type Dn into the parabolic incidence system of projective space using a process called parabolic projection, which maps a parabolic subalgebra of the Lie algebra to a parabolic subalgebra of a lower dimensional Lie algebra. As a consequence of this construction, we obtain Cox configurations and their analogues in higher dimensional projective spaces. We conjecture that the generalized Cox configurations we construct using parabolic projection are nondegenerate and, furthermore, any non-degenerate Cox configuration is obtained in this way. This conjecture yields a formula for the dimension of the space of non-degenerate generalized Cox configurations of a fixed type, which enables us to develop a recursive construction for them. This construction is closely related to Longuet-Higgins’ recursive construction of (generalized) Clifford configurations but our examples are more general and involve the extra parameters.
7
Beyan, Huriya. "Altered monocyte cox-1 & cox-2 levels in human type 1 diabetes". Thesis, Queen Mary, University of London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408256.
Pełny tekst źródła
8
Wright, William. "Investigating the role of COX-1 and COX-2 in Toll-Like Receptor responses". Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/24789.
Pełny tekst źródłaStreszczenie:
COX is the rate-limiting enzyme in the conversion of arachidonic acid to the prostanoids. It is present in humans as two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed and involved in homeostatic functions, while COX-2 expression is mostly limited to sites of inflammation. The precise function of COX isoforms is a subject of debate, particularly with respect to nonsterodial anti-inflammatory drug (NSAID)-induced toxicity. Toll-like receptors (TLRs) trigger the immune response following recognition of pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharide (LPS), which activates TLR4. The role of COX-1 and COX-2 in responses to different TLRs is incompletely understood. The main focus of my PhD was to investigate COX-1 and COX-2 function in innate immunity, using TLR agonists in mice lacking COX-1 or COX-2. I also studied this in relation to lung inflammation using lung fibroblasts, and isolated pulmonary arteries to examine the effect of prostanoids on pulmonary vascular responses. Lung fibroblasts isolated from COX-2-/- mice were more proliferative than lung fibroblasts from wild-type or COX-1-/- mice. They also released greater amounts of cytokines when stimulated with various TLR agonists. Human lung fibroblasts were particularly sensitive to TLR3 agonists, and cytokine release was enhanced in the presence of NSAIDs. The effect of diclofenac may have been caused by inhibition of COX-related prostaglandin (PG) E2. In in vivo studies, Cox2 gene expression was strongly induced by TLR4 activation in all organs and less so by TLR3 activation, where induction was restricted to the spleen and stomach. Mice lacking COX-2 released higher amounts of anti-viral proteins following TLR3 activation with poly (I:C). This suggests that COX-2-specific NSAIDs may boost the anti-viral response, thus proving beneficial over traditional NSAIDs during viral infection. In the pulmonary vasculature, I found that most prostacyclin drugs were limited by actions on EP3 receptors, but that selective peroxisome proliferator-activated receptor (PPAR)β/δ agonists were active as dilators under all conditions. Deletion of COX-1 or COX-2 affected the ability of mouse pulmonary arteries to release endothelial-derived nitric oxide but not to respond to IP or PPARβ/δ agonists. Finally, activation of adenosine monophosphate kinase (AMPK) had no direct dilator effect on pulmonary vessels. However, preliminary data suggest that pretreatment of vessels with an AMPK activator enhanced (additive) dilation induced by PPARβ/δ, indicating a potential benefit in pulmonary arterial hypertension (PAH). In summary, my in vitro and in vivo experiments using mice lacking COX-1 or COX-2 provide insight into the role of COX in immunity and the pulmonary vasculature.
9
Franco, del Pino David. "Modulación serotonérgica de inhibidores de COX-1 y COX-2 en dolor agudo experimental". Tesis, Universidad de Chile, 2006. http://repositorio.uchile.cl/handle/2250/140302.
Pełny tekst źródłaStreszczenie:
Trabajo de Investigación Requisito para optar al Título de Cirujano DentistaEl dolor es la primera causa de consulta al odontólogo. Por esto que es de suma importancia saber tratarlo correctamente para poder brindar a nuestros pacientes una solución eficaz a su problema. En las últimas décadas se ha centrado el estudio del dolor en animales mediante el uso de métodos algesiométricos que permitan evaluar el efecto antinociceptivo de distintos fármacos analgésicos y sus combinaciones. Un grupo de éstos son los analgésicos antiinflamatorios no esteroidales (AINEs) los cuales son ampliamente utilizados en el dolor; sin embargo, su uso conlleva una serie de efectos adversos que limitan su uso. Para contrarrestarlos, se están desarrollando combinaciones de fármacos que permitan aumentar los efectos analgésicos y disminuir las reacciones adversas. En este trabajo de investigación, se estudio la interacción analgésica de la coadministración de ketorolaco y meloxicam en el test de las contorsiones abdominales inducidas por ácido acético y la participación del sistema serotonérgico en dicha interacción. Se usaron ratones de la cepa CF- 1, a los que se les administró vía intraperitoneal 1/2, 1/4, 1/8, 1/16 de las DE50 de la combinación ketorolaco / meloxicam y por medio de análisis isobolográfico se determinó que la interacción, resultó ser sinérgica o supraaditiva. El pretratamiento con tropisetrón 1mg/kg (i.p.), antagonista selectivo de receptores de serotonina del subtipo 5HT-3, no modificó la naturaleza de la interacción, lo que pone en evidencia que la participación del sistema serotonérgico a través de estos receptores no participa significativamente, en el mecanismo de acción de la combinación ketorolaco / meloxicam.
10
Ghassani, Mohamad. "Dynamiques épidémiques, risques et copules". Thesis, Grenoble, 2012. http://www.theses.fr/2012GRENS027/document.
Pełny tekst źródłaStreszczenie:
Les modèles stochastiques classiques comportent des copules d'interactions linéaires, exprimant en général des interactions de paire. Il sera envisagé d'étendre ces modèles à des interactions non linéaires de type saturation ou de type triplet, en vue de traiter des applications réalistes, comme les diffusions épidémiques.Le but de cette thèse est d'introduire les fonctions copules en épidémiologie, et surtout d'appliquer ces fonctions sur le système de transmission de la Malaria afin de constater la dépendance entre les différents compartiments du système. Nous étudierons quelques modèles compartimentaux, qui sont une généralisation du modèle de Ross-Macdonald, en supposant que la population n'est pas constante et en prenant en compte des paramètres de transmission comme la fécondité, la mortalité et autres. Aussi, nous introduirons les classes d'âges dans certains de ces modèles compartimentaux, afin de trouver une relation entre les individus de ces classes d'âges à l'aide du modèle de Cox et des fonctions copules. Nous donnerons ensuite, deux exemples sur ces modèles : la Malaria au Mali et la peste en Europe au moyen-âge. Nous introduirons aussi les quantiles conditionnels et les fonctions copules archimédiennes, ce qui nous mènera à trouver une dépendance entre les différents compartiments des hôtes et des vecteursThe stochastic classical models include linear interactions copulas, expressing in general pair interactions. It is planned to extend these models to nonlinear interactions of saturation type or triplet type, to treat realistic applications, as the epidemics diffusions.The aim of this thesis is to apply the copulas functions in epidemiology, and especially to apply these functions in the transmission system of malaria to detect the dependence existing between compartments of the epidemic system. We will study some compartmental models, which are a generalization of the Ross-Macdonald model, assuming that the population is not constant and taking into account the transmission parameters such as fertility, mortality, etc. Also, we will introduce the age classes in some of these compartmental models, and study the relationships between individuals of these age classes, using the Cox model and the copulas functions. Then, we will give two examples of these models: the Malaria in Mali and the plague in Europe during the Middle Ages. We will introduce also the conditional quantiles and the Archimedean copulas functions, that will lead us to find dependencies between the different compartments of hosts and vectors
11
Nascimento, Rui Fonseca. "Which factors determine firm survival?" Master's thesis, Instituto Superior de Economia e Gestão, 2015. http://hdl.handle.net/10400.5/13084.
Pełny tekst źródłaStreszczenie:
Mestrado em FinançasEste estudo tem como finalidade analisar quais as variáveis que afectam a sobrevivência das empresas que atuam na indústria transformadora portuguesa. A análise de sobrevivência será efetuada através de 1130 empresas, correspondendo estas as empresas nascidas no período de 2005 a 2009. A base de dados utilizada no estudo SCIE tem como base a publicação reportada pelo Instituto Nacional de Estatística (INE). A nossa análise de sobrevivência é centralizada em cinco variáveis de uma empresa: Crescimento, Dimensão, Tecnologia, Indicadores financeiros e o Sector. De forma a determinar o impacto destas variáveis na sobrevivência utilizamos o modelo de regressão de Cox. Antes de efetuarmos uma análise pelo modelo de regressão de Cox o comportamento das variáveis independentes foi analisado através do modelo de Kaplan-Meier onde podemos concluir que o segundo e terceiro ano de operação apresentam-se como os anos em que as empresas verificam maiores taxas de mortalidade (estas foram de cerca de 10% em cada ano). Analisando o modelo de Cox fomos incapazes de rejeitar todas as hipóteses efetuadas.
The main aim of this empirical study is to determine which factors influence the survival of new Portuguese companies. We will do so through survival analysis of 1130 companies born in the Portuguese manufacturing sector between 2005 and 2009. The database used SCIE, based on the report published by the INE. Our survival analysis is centered on five company variables: Growth, Size, Technological, Dimension, and Sector. To determine the impact of these variables on survival we used the Cox regression model. Before we ran an analysis through the Cox model we also studied the behavior of the variables through a Kaplan-Meier survival estimate, where we concluded that the second and the third year are those in which firms present the highest mortality rates (about 10% in each year). Moving into the Cox regression analysis, we were unable to reject any of our original hypotheses.
info:eu-repo/semantics/publishedVersion
12
Cunha, Daniela Erica de Horta e. Goes Ribeiro da. "Avaliação da expressão de Cox-2 em tumores mamários da gata por imunohistoquímica : correlação com aspetos clinicopatológicos, classificação histopatológica e possíveis implicações clínicas". Master's thesis, Universidade de Lisboa. Faculdade de Medicina Veterinária, 2013. http://hdl.handle.net/10400.5/6098.
Pełny tekst źródłaStreszczenie:
Dissertação de Mestrado Integrado em Medicina VeterináriaA cicloxigenase-2 (Cox-2) é uma enzima que desempenha um papel importante na tumorigénese e encontrando-se sobrexpressa em várias neoplasias humanas, incluindo o cancro da mama. Em medicina veterinária, alguns trabalhos mostram existir uma sobrexpressão da Cox-2 em certas neoplasias da espécie felina, incluindo nos tumores mamários, estando esta associada a pior prognóstico. Tendo em conta estas evidências, a utilização de fármacos anti-Cox-2 como agentes terapêuticos nas neoplasias mamárias é uma hipótese que poderá trazer benefícios importantes. A utilização destes fármacos poderá assumir particular interesse no caso da gata, devido à elevada frequência de tumores mamários nesta espécie e ao seu prognóstico pouco favorável. Desta forma, para além de poder funcionar como alvo terapêutico, a Cox-2 poderá também ser um bom indicador de prognóstico. Neste trabalho pretendeu-se analisar os níveis de expressão da Cox-2, de modo a melhor equacionar a sua importância como futuro alvo terapêutico. Assim, procedeu-se à avaliação dos níveis desta enzima numa amostra de 21 carcinomas mamários felinos de diversos tipos histológicos e graus de malignidade, pela técnica de imunohistoquímica (IHQ), recorrendo ao uso de dois anticorpos anti-Cox-2 distintos. Foi ainda analisada a correlação dos níveis de expressão desta enzima com diversos parâmetros clinicopatológicos e imunohistoquímicos. Com o Clone 33, todas as neoplasias estudadas revelaram expressão de COX-2, apesar de apenas um tumor ter sido classificado de positivo, tendo mostrado um padrão de imunomarcação perinuclear e citoplasmático. Pelo contrário, com o Clone SP21 a maioria dos tumores (20/21) foram considerados positivos, apresentando um padrão predominantemente membranar, mas também marcação citoplasmática e perinuclear. Este padrão citoplasmático e perinuclear foi observado nos mesmos tumores, em ambos os anticorpos. Verificou-se ainda a existencia de uma correlação entre os níveis de marcação da Cox-2 (Clone SP21) e a classificação histológica segundo a OMS. Ainda que mais investigação seja necessária, é possível concluir que o padrão de marcação da Cox-2, associado à classificação histológica poderá ter um papel na identificação de pacientes que irão beneficiar da utilização terapêutica de fármacos anti-Cox-2.
ABSTRACT - Immunohistochemical Evaluation of Cox-2 Expression in Feline Mammary Tumours – Correlation with Clinicopathological Features, Histologic Type and Possible Clinical Implications - Cyclooxygenase-2 (COX-2) is an enzyme that plays an important role in tumorigenesis and is overexpressed in several types of human neoplasia, including breast cancer. In veterinary medicine, some studies show that Cox-2 is overexpressed in several tumours of the cat, including mammary tumours. This overexpression is associated with poor prognosis. All this facts lead to the conclusion that the use of anti-Cox-2 drugs in mammary tumours may yield important benefits. The use of such drugs in the queen is especially attractive since this type of neoplasia is highly frequent and also because of its less favourable prognosis. Cox-2 expression may also be a good prognostic indicator. In the present study the goal was to evaluate Cox-2 expression levels in order to explore its importance as a future therapeutic target. The expression of COX-2 was analysed in 21 tumour samples that included several histological types and grades, by immunohistochemistry (IHQ), using two different anti-Cox-2 antibodies. The correlation between Cox-2 expression and several clinicopathological and immunohistochemical parameters was also investigated. With Clone 33 all samples revealed Cox-2 expression, even though only one tumour was classified as positive, showing perinuclear and cytoplasmic labelling. Conversely, with Clone SP21 most tumours (20/21) were positive, showing mainly membrane labelling but also perinuclear and cytoplasmic staining. The cytoplasmic and perinuclear pattern was constant in the same tumours with both antibodies. A statistically significant correlation between Cox-2 expression levels and histological type according to the WHO classification was also found. Although, more investigation is necessary, it is possible to conclude that immunolabelling pattern associated with the histological classification may play an important role in selecting the patients that can benefit from the therapeutic use of anti-Cox-2 drugs.
13
Cheong, Edward. "Cox-2 in Barrett's oesophageal carcinogenesis". Thesis, University of East Anglia, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426779.
Pełny tekst źródła
14
Ranka, Satish. "COX-2 inhibitors in oesophageal cancer". Thesis, University of East Anglia, 2014. https://ueaeprints.uea.ac.uk/56873/.
Pełny tekst źródłaStreszczenie:
Introduction and Aims: The incidence of Oesophageal cancer (OC) has doubled in the last three decades and is increasing. Due to their poor outcome, strategies are being devised to prevent this disease and look into any association between pre-existing risk factors and medications which may aggravate them. Non-steroidal anti-inflammatory drugs (NSAIDs) may be protective by inhibiting Cycloxygenase-2 (COX-2), an enzyme known to induce malignant transformation in cells. Bronchodilators and Calcium channel blockers (CCB's) that relax the Lower oesophageal sphincter (LOS) may increase Gastro-Oesophageal reflux (GORD) and the risk of Oesophageal adenocarcinoma (OAC). Hence I carried out a case control study looking into any association between ingestion of NSAIDs and drugs which may relax the lower oesophageal sphincter and oesophageal cancer. Case-control study: Methods: 411 patients in Norfolk, with a primary neoplasm of the oesophagus or cardia were matched with 1644 controls with non-melanotic skin lesions. Data on the use of NSAIDs, bronchodilators and CCB's was collected. Results: Compared to nonusers, individuals who used NSAIDs had a significantly reduced risk of oesophageal cancer. Use of NSAIDs was associated with approximately 60-70% reduction in OC. The odds ratios (OR) and 95% Confidence Intervals (CI) for different NSAIDs are as follows Aspirin: 0.38, (0.27-0.54); other NSAIDs: 0.29, (0.19-0.41) and COX-2 Blockers (Coxibs) 0.35, (0.16-0.78). LOS relaxing drugs were consumed more frequently in cases of OC as compared to the controls. Other NSAIDs include propionic acid, acetic acid, enolic acid and fenamic acid derivatives. The OR for LOS relaxing drugs are: Inhaled bronchodilators 3.2 (95% CI 2.2 to 4.7), Theophylline 1.9 (95% CI 1.3 to 5.1) and Calcium channel 12 blockers 2.4 (95% CI 1.2 to 5.0). Data was adjusted for confounding factors like smoking and alcohol consumption. Unadjusted data showed lower negative association with NSAIDs and positive association with drugs which relax the LOS. Conclusion: NSAIDs were protective against OC development while drugs that relax LOS were associated with increased risk in this case-control study. Furthermore, data unadjusted for smoking and alcohol show reduced effect implying smoking and alcohol consumption may be confounding factors. However, due to the undesirable side effects of synthetic COX-2 inhibitors, efforts are now directed towards finding natural compounds which have COX-2 inhibiting or antioxidant properties. Hence I conducted another study of validating a food frequency questionnaire with urinary excretion of quercetin, a naturally occurring Cox-2 inhibitor and naringenin, an antioxidant. With this validation, it would be possible to measure the dietary intake of these compounds in an individual’s diet and recommend dietary changes by conducting further studies. Flavonoid study: Methods: A food frequency questionnaire (FFQ) was used to estimate daily intake of quercetin and naringenin in 49 healthy volunteers. They also provided five 24-hour urine samples over a 2 week period while completing the FFQ. Urinary excretion of quercetin and naringenin was determined by solid phase extraction and high-pressure liquid chromatography. Results: The estimated mean intake of quercetin and naringenin was 29.4 mg (SD 15.0) and 58.08 mg (SD 62.76) per day respectively. Mean urinary excretion of quercetin was 60.1 g (SD 33.1) and naringenin was 0.56 mg (SD 0.42) per 24hrs. The correlation between FFQ-estimated intake and levels excreted in the 24hr urines 13 for quercetin was r = 0.82 (p< 0.0001) and for naringenin was r = 0.251 (p=0.05) respectively. Conclusion: There was a statistically significant correlation between intake and excretion of quercetin and naringenin. Hence, a FFQ may be used as a tool in epidemiological studies requiring an estimate of naturally occurring COX-2 inhibitors or other chemicals following its validation.
15
Tuloup, Jean-François. "Tolérance rénale des Anti Cox-2". Paris 13, 2004. http://www.theses.fr/2004PA130014.
Pełny tekst źródła
16
Zhang, Yue. "Bayesian Cox Models for Interval-Censored Survival Data". University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1479476510362603.
Pełny tekst źródła
17
Hasan, Kamrul. "Clclo-oxygenase (COX) isoforms in the cardiovascular system : Implications for the future of COX-2 selective inhibitors". Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536024.
Pełny tekst źródła
18
Ansin, Elin. "An evaluation of the Cox-Snell residuals". Thesis, Uppsala universitet, Statistiska institutionen, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-256665.
Pełny tekst źródłaStreszczenie:
It is common practice to use Cox-Snell residuals to check for overall goodness of tin survival models. We evaluate the presumed relation of unit exponentially dis-tributed residuals for a good model t and evaluate under some violations of themodel. This is done graphically with the usual graphs of Cox-Snell residual andformally using Kolmogorov-Smirnov goodness of t test. It is observed that residu-als from a correctly tted model follow unit exponential distribution. However, theCox-Snell residuals do not seem to be sensitive to the violations of the model.
19
Vanichbuncha, Tita. "Risk Factors and Predictive Modeling for Aortic Aneurysm". Thesis, Linköpings universitet, Statistik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-80391.
Pełny tekst źródłaStreszczenie:
In 1963 – 1965, a large-scale health screening survey was undertaken in Sweden and this data set was linked to data from the national cause of death register. The data set involved more than 60,000 participants whose age at death less than 80 years. During the follow-up period until 2007, a total of 437 (338 males and 99 females) participants died from aortic aneurysm. The survival analysis, continuation ratio model, and logistic regression were applied in order to identify significant risk factors. The Cox regression after stratification for AGE revealed that SEX, Blood Diastolic Pressure (BDP), and Beta-lipoprotein (BLP) were the most significant risk factors, followed by Cholesterol (KOL), Sialic Acid (SIA), height, Glutamic Oxalactic Transaminase, Urinary glucose (URIN_SOC), and Blood Systolic Pressure (BSP). Moreover, SEX and BDP were found as risk factors in almost every age group. Furthermore, BDP was strongly significant in both male and female subgroup. The data set was divided into two sets: 70 percent for the training set and 30 percent for the test set in order to find the best technique for predicting aortic aneurysm. Five techniques were implemented: the Cox regression, the continuation ratio model, the logistic regression, the back-propagated artificial neural network, and the decision tree. The performance of each technique was evaluated by using area under the receiver operating characteristic curve. In our study, the continuation ratio and the logistic regression outperformed among the other techniques.
20
RANGEL, NAVA ANA MARÍA. "USO, EFICACIA Y SEGURIDAD DE UN AINE COX2 SELECTIVO (FIROCOXIB) EN CABALLOS CON CUADRO CLÍNICO DE OSTEOARTRITIS". Tesis de Licenciatura, Universidad Autónoma del Estado de México, 2019. http://hdl.handle.net/20.500.11799/104514.
Pełny tekst źródłaStreszczenie:
El estudio permitió identificar los diferentes usos de antiinflamatorios no esteroideos (AINE) en
equinos, así como la realización de un artículo científico de revisión de carácter sistémico que
compiló la informacón más relevante y útil sobre el uso de AINE, en especial de un AINE
COX-2 selectivo (firocoxib) en el control de dolor crónico en pacientes equinos, también
permitió identificar los diferentes AINE utilizados en esta especie y su regulación legal en EUA
y la Unión Europea. El trabajo se realizó mediante una búsqueda en PubMed (Centro
Nacional de Información sobre Biotecnología, Biblioteca Nacional de Estados Unidos,
Bethesda, MD) y SCOPUS (Elsevier Inteligencia Investigación). Los documentos compilados
incluyeron estudios de tipo transversal y longitudinal, además de revisiones y estudios
experimentales que involucraron el uso, eficacia ó seguridad del firocoxib sólo o comparado
con otros AINE en caballos sanos, con claudicaciones ó con osteoartritis (OA) crónica,
farmacocinética y farmacodinámica del firocoxib, y fisiopatología de dolor provocado por OA.
Los AINE han sido usados en diversas especies animales domésticas, en equinos se ha
demostrado una gran efectividad en diferentes patologías como analgésicos, antiinflamatorios,
antipiréticos, antitrombóticos y antiendotóxicos, al estar estrechamente relacionados con la
inhibición de síntesis de prostaglandinas. Debido a la diversidad de su aplicación, se han
reportado efectos adversos relacionados a la administración de estos fármacos, lo que ha
llevado a el desarrollo de antiinflamatorios selectivos que disminuyan el riesgo de los efectos
adversos característicos de los antiinflamatorios no selectivos. Una de las enfermedades del
sistema músculo-esquelético más comunes en equinos es OA, una enfermedad con cambios
degenerativos crónicos en las articulaciones sinoviales que conducen a el paciente a padecer
dolor crónico, surgiendo la necesidad de manejar el dolor sin poner en riesgo la salud del
paciente. El uso de AINE específicos a COX-2 en la práctica veterinaria es conveniente,
debido a su fácil administración, seguridad y costo-beneficio, aunque debido a estás razones
se han utilizado en exceso, es por esto que existe regulación de estos medicamentos, la cual
juega un papel importante para el control y administración en equinos de alto rendimiento,
restringiendo la administración de medicamentos no etiquetados para administración en
equinos para así evitar dosis y usos inapropiados, fomentando una dosificación óptima para
lograr concentraciones terapéuticas, preservando la selectividad de COX-2, dando prioridad a
la calidad de vida de nuestros pacientes.
21
de, Toni Uchôa Flávia. "Síntese, avaliação da atividade antiinflamatória e seletividade de novas 5-indol-tiazolidinadionas frente à cicloxigenase-2". Universidade Federal de Pernambuco, 2008. https://repositorio.ufpe.br/handle/123456789/1404.
Pełny tekst źródłaStreszczenie:
Made available in DSpace on 2014-06-12T15:49:47Z (GMT). No. of bitstreams: 2
arquivo1531_1.pdf: 8690443 bytes, checksum: a4fd46296095297945ecfe4e61d99db6 (MD5)
license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)
Previous issue date: 2008Conselho Nacional de Desenvolvimento Científico e Tecnológico
Uma série de novas 5-indol-tiazolidinadionas bioativas foi sintetizada visando a obtenção de um novo protótipo antiinflamatório com ação simbiótica direcionada a dois diferentes alvos relevantes no processo inflamatório: as enzimas cicloxigenases (COXs) e o receptor gama ativado pelo proliferador de peroxissomo (PPAR-γ). A presença de um grupamento indol na posição 5 do anel tiazolidínico central representa uma das particularidades desses compostos, os quais são de um lado relacionados estruturalmente à indometacina, um anti-inflamatório não-esteroidal (AINE), e de outro, ao anti-diabético rosiglitazona, um agonista PPAR-γ. Este estudo conduziu à identificação de moléculas que apresentaram atividade antiinflamatória em modelo in vivo de inflamação, bem como a capacidade de inibir as isoformas COX-1 e COX-2 em ensaio de inibição enzimática in vitro. Dentre as moléculas estudadas, a 5(Z,E)-3-[2-(4-clorofenil)-2-oxoetil]-5-(1H-indol-3-ilmetileno)-1,3- tiazolidin-2,4-diona (PG-15) mostrou excelente atividade antiinflamatória, avaliada através da inibição de migração lucocitária nos modelos de inflamação do air pouch, com uma DE50 de 7,5 mg/Kg (p.o.), e de peritonite, apresentando 30,7% de inibição após administração oral na dose de 3mg/Kg. O composto PG-15, pelos promissores resultados apresentados, foi conduzido a um estudo farmacocinético, onde foram avaliadas as suas concentrações no plasma de rato durante 16 horas, após as administrações intravenosa de 3m/Kg, e oral de 3 e 6 mg/kg. Os resultados mostraram que o PG-15 é rapidamente absorvido após administração oral atingindo o pico de concentração plasmática entre 30 e 60 minutos e uma meia-vida de 5,9 ± 3,8 horas, após administração intravenosa. A quantidade de PG-15 também foi quantificada no sítio da inflamação, através do doseamento do mesmo no exsudato inflamatório do bolsão e da peritonite após a administração oral de 3mg/Kg, onde foram detectadas 83,85 ± 43,46 e 30,51 ± 7,7 ng/mL (média ± erro padrão), respectivamente
22
Borges, Marina. "Função renal de cães hígidos tratados com anti-inflamatórios não-esteroidais". Universidade do Oeste Paulista, 2011. http://bdtd.unoeste.br:8080/tede/handle/tede/242.
Pełny tekst źródłaStreszczenie:
Made available in DSpace on 2016-01-26T18:55:31Z (GMT). No. of bitstreams: 1
DISSERTACAO.pdf: 506827 bytes, checksum: 85183faa6a63e1b561cacb568f6cf77e (MD5)
Previous issue date: 2011-02-24The anti-inflammatory nonsteroidal compounds have extremely widespread use in the therapy of small animals, due to their anti-inflammatory and analgesic properties. However, the use of these drugs can produce changes in kidney function. The present study was conducted to assess kidney function in healthy dogs undergoing therapy with anti-inflammatory nonsteroidal compounds. Thirty mongrel dogs, adults, males and females, clinically healthy, were divided randomly into 5 groups (G) of six animals each receiving the following therapies: Gceto ketoprofen, a 2 mg/kg dose (VO), every 24 hours, during 10 days; Gnime nimesulide, 5 mg/Kg, VO, every 24 hours, during 10 days; Gmelo- meloxican, 0.2 mg/Kg on the first day, followed by 0.1 mg/Kg, VO, every 24 hours, 7 days; Geto etodolac, 15 mg/Kg, VO, every 24 hours, 7 days; Gcele- celecoxibe, 5 mg/Kg, VO, every 12 hours, for 20 days. The physical examination and renal function (urinalysis, urinary GGT, creatinine and sodium, serum urea, creatinine, potassium and sodium, and endogenous creatinine clearance) were assessed prior to the treatment, on the 5th and 10th days (T0, T5 and T10) into the treatment in all groups, and also on the 20th day (T20) into the treatment in Gcele. Few changes were observed in urinalysis parameters, only with significant increase in the presence of renal cells in the urine in T5, in the nimesulide group. There was a significant reduction in sodium elimination in the animals urine in the nimesulide group. The clearance values showed significant decrease in the celecoxibe group in T20, in relation to T5. The enzyme GGT urinary showed no variation among groups or moments. Values of sodium, potassium, urea and creatinine serum remained within normal ranges in all times, in the different groups. In conclusion, minimal changes of renal function occur 10 days after therapy on set with NSAIDS nimesulide, after 10 days with ketoprofen, on the 20th days of therapy with celecoxibe in health dogs.
Os anti-inflamatórios não-esteroidais têm uso extremamente difundido na clínica de pequenos animais, devido às suas propriedades analgésicas e anti-inflamatórias. Entretanto, o uso desses fármacos pode produzir alterações da função renal. O presente estudo teve como objetivo avaliar a função renal de cães saudáveis, submetidos à terapia com anti-inflamatórios não-esteroidais não seletivos, COX-2 preferenciais e COX-2 seletivos. Foram utilizados 30 cães, sem raça definida, adultos, machos e fêmeas, clinicamente sadios, divididos aleatoriamente em 5 grupos (G) de 6 animais cada, que receberam as seguintes terapias: Gceto cetoprofeno, na dose de 2 mg/Kg, por via oral (VO), a cada 24 horas, durante 10 dias; Gnime nimesulida, 5 mg/Kg, VO, a cada 24 horas, durante 10 dias; Gmelo - meloxican, 0,2 mg/Kg no primeiro dia, seguido por 0,1 mg/Kg, VO, a cada 24 horas, por 10 dias; Geto etodolaco, 15 mg/Kg, VO, a cada 24 horas, 10 dias; Gcele - celecoxibe, 5 mg/Kg, VO, a cada 12 horas, por 20 dias. O exame físico e a função renal (urinálise; GGT, creatinina e sódio urinários; uréia, creatinina, sódio e potássio séricos; e clearance endógeno de creatinina) foram avaliados antes, aos 5, 10 dias (T0, T5 e T10) de tratamento em todos os grupos, e também aos 20 dias (T20) de tratamento no Gcele. Poucas alterações foram observadas na urinálise, apenas com aumento significativo da presença de células renais na urina no T5 e T10 em relação ao T0, no grupo nimesulida. Houve redução significativa da eliminação de sódio na urina, nos animais do grupo nimesulida, no T5. Os valores de clearance foram os mais baixos no grupo Cetoprofeno no T10, e revelaram diminuição significativa no grupo Celecoxibe no T20, em relação ao T5. A enzima GGT urinária não apresentou variação entre grupos ou momentos. Valores de sódio, potássio, uréia e creatinina séricos mantiveram-se dentro da normalidade em todos os momentos nos diferentes grupos. Conclui-se que, em cães hígidos, alterações mínimas da função renal ocorrem aos cinco dias de terapia com o AINE nimesulida, aos dez dias com cetoprofeno, e aos vinte dias de terapia com celecoxibe.
23
Schweppenhäuser, Johannes. "Selektive und duale COX-1-COX-2-Inhibitoren aus der Reihe der Methanone Synthese, Testung, Struktur-Wirkungs-Beziehungen /". [S.l.] : [s.n.], 1999. http://deposit.ddb.de/cgi-bin/dokserv?idn=960235728.
Pełny tekst źródła
24
Tarantino, E. "THE ROLE OF CYCLOOXYGENASE-1 (COX-1) AND CYCLOOXYGENASE-2 (COX-2) IN A VENOUS THROMBOSIS MOUSE MODEL". Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/353697.
Pełny tekst źródłaStreszczenie:
Background: Deep vein thrombosis (DVT) is a serious national health problem, and pulmonary thromboembolism (PE) represents the life-threatening most common complication. Venous thromboembolism (VTE), including both these conditions, is traditionally treated with anticoagulant drugs. In particular, vitamin K antagonists and heparins are usually used in the reduction of thrombus development and in secondary prevention. However, the use of these drugs has several limitations: wide variability dose/response relationship between patients and in the same patient, multiple interactions with other drugs/foods, variability of daily doses, need of periodic withdrawals of blood during therapy, problems of overdosing. Then, the discovery of new drugs for VTE needs.
The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyse the formation of prostaglandins and, thromboxane from arachidonic acid, and play a critical role in thrombosis. Recent meta-analysis suggests that low-dose aspirin (ASA) reduces the rate of VTE recurrence. In contrast, the clinical use of COX-2 inhibitors seems associated with increased risk of venous thrombosis. However, the role of COX-1 and COX-2 in venous thrombosis remain unclear.
Aim: We investigated the impact of COX-1 and COX-2 enzymes in venous thrombosis in order to identify the molecular mechanisms responsible for this effect and develop new therapeutic strategies to prevent venous thrombosis. In particular, we focused on the impact of inhibition of COX-pathway on leukocyte activation, important regulators of formation and propagation of venous thrombus.
Methods and Results: Using in vivo and in vitro approaches, we provide evidence that:
a) thromboxane, produced by platelets, triggers activation of leukocytes, with consequent development and propagation of venous thrombus induced by inferior vena cava ligation. In particular, we showed that ASA, by inhibiting irreversibly platelet COX-1, prevents platelet thromboxane production resulting in decreased venous thrombosis.
b) COX-2 deletion induces platelet hyper-activity and hyper-coagulation state, associated with a reduced fibrinolysis and formation of bigger thrombi. In this scenario, the high levels of tissue factor observed in leukocytes of COX-2KO mouse may explain the positive association observed between administration of COX-2 inhibitors and VTE. Thanking advantage of an accurate, and clinically relevant, technique such as ultrasonography, we are setting a method helpful to monitor thrombus growing and to better understand the pathophysiology of venous thromboembolism.
Conclusion: In conclusion, data obtained show that the inhibition of COX-1 and COX-2 in a venous thrombosis mouse model could lead to opposite effect on the thrombus development, stabilization and resolution. In particular, COX-1 inhibition is responsible of an impairment development and growth of venous thrombus, with a mechanism most likely dependent of TXA2/TP pathway. In contrast, COX-2 inhibition caused an increased in thrombus development, growing accompanied with reduction in the thrombus resolution. All data obtained support evidences that both COX-1 and COX-2 play a key role in DVT, opening the way to novel therapeutic approaches.
25
Läuter, Henning. "Estimation in partly parametric additive Cox models". Universität Potsdam, 2003. http://opus.kobv.de/ubp/volltexte/2011/5150/.
Pełny tekst źródłaStreszczenie:
The dependence between survival times and covariates is described e.g. by proportional hazard models. We consider partly parametric Cox models and discuss here the estimation of interesting parameters. We represent the ma- ximum likelihood approach and extend the results of Huang (1999) from linear to nonlinear parameters. Then we investigate the least squares esti- mation and formulate conditions for the a.s. boundedness and consistency of these estimators.
26
Sun, Jiaming. "A generalization of the Cox partial likelihood". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0005/MQ45407.pdf.
Pełny tekst źródła
27
Guillén, Martha M. B. "Relations in the Cox ring of M0,6". Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/56843/.
Pełny tekst źródła
28
Flores, Flores Claudio Jaime. "Modelo de regresión de Cox usando splines". Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2011. https://hdl.handle.net/20.500.12672/211.
Pełny tekst źródłaStreszczenie:
En muchos estudios clínicos es muy frecuente el uso de modelo de riesgos proporcionales de Cox; el cual asume riesgos proporcionales y restringe a que el logaritmo de la razón de riesgo sea lineal en las covariables, lo cual en muchos casos no se verifica. En este sentido, una forma funcional no lineal del efecto de las covariables puede ser aproximada por una función spline. En este trabajo, se presenta la metodología del modelo de regresión de Cox usando splines, particularmente regresión splines y P-splines, para aproximar la forma funcional no-lineal de los efectos de las covariables en la función de riesgo. Como una aplicación, se analiza los datos de pacientes con LNH para determinar los factores pronósticos para la supervivencia global. Los resultados muestran que el efecto de las covariables contínuas como hemoglobina, leucocitos, linfocitos y DHL presentan una forma funcional no lineal en el logaritmo de la razón de riesgo.
-- Palabras claves: Modelo de Cox, regresión splines, P-splines, LNH.-- In many clinical studies, Cox proportional hazard model is very common to use, it assumes proportional hazard and restricts the log hazard ratio to be linear in the covariates; these asumptions can not be verified. In this way, a nonlinear functional form of the covariates effect can be approximated by a spline function. In this paper, we present the methodology and an application of Cox model using splines, particularly regression splines and P-splines, to approximate the nonlinear functional form of the effect of covariates on the hazard function. As an application, we analyse data from patients with NHL to determine prognostic factors for overall survival. These results show that the effect of continuous covariates as: hemoglobin, leukocytes, lymphocytes and LDH have a nonlinear form with the log hazard ratio. -- Keywords: Cox model, regression splines, P-spline, NHL.
Tesis
29
Flores, Flores Claudio Jaime, i Flores Claudio Jaime Flores. "Modelo de regresión de Cox usando splines". Bachelor's thesis, Universidad Nacional Mayor de San Marcos, 2011. http://cybertesis.unmsm.edu.pe/handle/cybertesis/211.
Pełny tekst źródłaStreszczenie:
En muchos estudios clínicos es muy frecuente el uso de modelo de riesgos proporcionales de Cox; el cual asume riesgos proporcionales y restringe a que el logaritmo de la razón de riesgo sea lineal en las covariables, lo cual en muchos casos no se verifica. En este sentido, una forma funcional no lineal del efecto de las covariables puede ser aproximada por una función spline. En este trabajo, se presenta la metodología del modelo de regresión de Cox usando splines, particularmente regresión splines y P-splines, para aproximar la forma funcional no-lineal de los efectos de las covariables en la función de riesgo. Como una aplicación, se analiza los datos de pacientes con LNH para determinar los factores pronósticos para la supervivencia global. Los resultados muestran que el efecto de las covariables contínuas como hemoglobina, leucocitos, linfocitos y DHL presentan una forma funcional no lineal en el logaritmo de la razón de riesgo.
-- Palabras claves: Modelo de Cox, regresión splines, P-splines, LNH.-- In many clinical studies, Cox proportional hazard model is very common to use, it assumes proportional hazard and restricts the log hazard ratio to be linear in the covariates; these asumptions can not be verified. In this way, a nonlinear functional form of the covariates effect can be approximated by a spline function. In this paper, we present the methodology and an application of Cox model using splines, particularly regression splines and P-splines, to approximate the nonlinear functional form of the effect of covariates on the hazard function. As an application, we analyse data from patients with NHL to determine prognostic factors for overall survival. These results show that the effect of continuous covariates as: hemoglobin, leukocytes, lymphocytes and LDH have a nonlinear form with the log hazard ratio. -- Keywords: Cox model, regression splines, P-spline, NHL.
Tesis
30
King, Liam Denson. "COX-2 selective inhibitors as an adjunct to radiotherapy". Thesis, Griffith University, 2018. http://hdl.handle.net/10072/382714.
Pełny tekst źródłaStreszczenie:
Background
Radiotherapy is a common treatment modality for many solid state cancers including prostate cancer (PCa). Unfortunately, up to 50% of patients that undergo radiotherapy for localised PCa will develop biochemical failure. Acute and delayed toxicities and tumour resistance are two key factors limiting the effectiveness of many cancer treatments, including radiotherapy. Toxicity rates in PCa patients that accompany radiotherapy are high with 80% of men experiencing some degree of urinary frequency, 40% bowel frequency and chronic impotence is usual.
Furthermore, tumour radioresistance is driven by a number factors with tumour hypoxia playing a key role. In addition to hypoxia driving tumourigenesis the lack of oxygen reduces the ability of ionizing radiation to produce reactive oxygen species (ROS) necessary to produce DNA damage that results in tumour death. Hypoxia also increases the expression of a number of genes including cyclooxygenase (COX) -2. COX-2 is an inducible enzyme that is upregulated in inflammation and carcinomas, making it a suitable target for new cancer treatment options.
COX-2 expression has been shown to be upregulated in a number of cancers including PCa and found to be involved in proliferation, invasion, apoptosis, host immune response and angiogenesis. Past research has also demonstrated that the major product of COX-2, prostaglandins (PG), provide radioprotection to cancer cells. As well as the ability of COX-2 to directly impact radiosensitivity, it has the ability to influence other cellular products that impact survival and apoptosis. One product that has been linked to COX-2 is the tumour suppressor p53. The p53 protein protects against genomic instability and the development of cancer by inducing cell cycle arrest and apoptosis. COX-2 expression has been shown to be induced by p53 and in turn results in inhibition of p53 mediated apoptosis. To our knowledge no studies have investigated the use of COX-2 inhibitors, at clinically relevant doses, as an adjunct to radiotherapy. In addition, while the direct mechanisms of COX-2 mediated radiosensitivity have been well investigated, research into the indirect mechanisms and also the effect of COX-2 inhibitors as radiosensitising agents in hypoxia is lacking.
This study aims to demonstrate the ability of COX-2 inhibitors to improve treatment outcomes post-radiotherapy for PCa in human patients and also to investigate the mechanisms behind COX-2 inhibitor mediated radiosensitivity in normoxia and hypoxia.
Method
The ability of COX-2 to produce radiosensitisation in cancer cells was investigated in two ways in this research. Firstly, a retrospective human study investigated if the use of the COX-2 inhibitors meloxicam and celecoxib during radiotherapy improves treatment outcomes in PCa patients. Secondly, an in vitro model was developed that investigated the mechanisms behind COX-2 mediated radiosensitivity in human cancer cell lines.
The retrospective human study examined the patient database at Genesis Cancer Care to identify patients that received radiotherapy for primary treatment of localised PCa. Screening of the database then identified patients that had used meloxicam or celecoxib during radiotherapy treatment. Three treatment outcomes were measured; the percentage of patients that demonstrated biochemical relapse at 2 and 5 years post-treatment, the time to biochemical relapse and the prostate specific antigen (PSA) velocity of each group post-treatment.
The in vitro model used HeLa (cervical), PC3 (Prostate), MCF7 (breast) and MeWo (melanoma) cells to investigate, mechanistically, how structurally unrelated COX-2 inhibitors impact radiosensitivity in normoxia and hypoxia. This model utilised resazurin reduction to measure proliferation, siCOX-2 RNA to produce COX-2 knockdown cells and enzyme-linked immunosorbent assays (ELISAs) to measure p53 phosphorylation and prostaglandin E2 (PGE2) production.
Results
PSA velocity was found to be 0.197ng/mL/year (0.939) for the meloxicam group and 0.828 ng/mL/year (3.15) for the celecoxib group. The two treatment groups were found to have significantly lower (p<0.05) PSA velocities than the control group, 1.12 ng/mL/year (3.05). In addition, at the two year time point meloxicam was found to have no patients to have relapsed and the celecoxib and control groups had percentage relapse rates of 6.7% (n=4) and 8.6% (n=5). The percentage relapse at five years post-treatment was 18.9% (n=10), 18.3% (n=11) and 21.0% (n=31%) for the meloxicam, celecoxib and control groups respectively. Mean time to biochemical relapse was found to be 54.15 months (16.08) in the meloxicam group and 46.20 months (31.70) in the celecoxib group, in contrast the control group demonstrated a mean time to biochemical relapse of 35.53 months (20.21).
The in vitro model aimed to provide an insight to the mechanisms behind the results seen in the retrospective analysis. NS398 (10μM), a highly specific COX-2 inhibitor, selectively sensitised hypoxic HeLa (p<0.01) and MCF7 (p<0.05) cells to ioninsing radiation, however did not affect sensitisation in PC3 or MeWo cells. Celecoxib (20μM) and meloxicam (20μM) failed to produce radiosensitisation in any cell line in normoxia or hypoxia. Based on these findings further investigations were carried out in HeLa cells using NS398.
Investigations using COX-2 siRNA demonstrated that knockdown of the COX-2 enzyme did not produce radiosensitisation but resulted in the loss of radiosensitising ability of NS398. Furthermore, PGE2 release was significantly increased in response to hypoxia (p<0.05) and irradiation (p<0.001) and treatment with NS398 significantly (p<0.001) attenuated PGE2. Treatment with misoprostol, a prostaglandin analogue, significantly (p<0.01) increased cell survival in normoxic HeLa cells in response to ionising radiation, but had no effect on hypoxic HeLa cells.
The interaction between COX-2 and p53 was then explored. It was discovered that COX-2 knockdown HeLa cells had significantly (p<0.001) higher levels of p53 protein than wild-type HeLa cells. Furthermore, hypoxia was able to significantly (p<0.001) attenuate p53 phosphorylation at both 30 minutes and 4 hours post-irradiation and treatment of hypoxic HeLa cells with NS398 (10μM) resulted in a significant (p<0.01) increase in phosphorylated p53. The p53 inhibitor pifithrin-α did not effect the radiosensitivity of wild-type HeLa cells in either hypoxia or normoxia, however it significantly (p<0.01) increased cell survival in response to ionizing radiation in HeLa cells transfected with COX-2 siRNA.
Discussion
The findings from the retrospective analysis demonstrated that the use of the COX-2 inhibitors celecoxib and meloxicam may improve treatment outcomes in patients that receive radiation therapy for PCa. Importantly we were able to demonstrate that patients using these agents displayed a significantly lower PSA velocity than those who were not. Importantly, the PSA velocity was found to fall below the threshold of 0.35ng/mL, with PSA velocities that sit above this threshold having been found to have an approximate 5.3 to 10 fold increased risk of PCa. This retrospective analysis also found reduced biochemical relapse rates and reduced time to biochemical relapse in the celecoxib and meloxicam groups in comparison to the control.
The in vitro model was able to demonstrate the ability of COX-2 inhibitors to increase radiosensitivity, however this effect was not demonstrated by all COX-2 inhibitors or all cell lines. This finding suggested that this effect may be drug and cell line specific. Furthermore, COX-2 was found to be necessary for NS398 induced radiosensitivity but knockdown of COX-2 alone did not affect radiosensitivity. Based on these findings it was suggested that COX-2 inhibitor mediated radiosensitivity occurs through both direct and indirect COX-2 mechanisms. We also demonstrated the relationship between COX-2 and p53, with COX-2 knockdown cells demonstrating increased p53 expression. Furthermore, the inhibition of COX-2 by NS398 resulted in increased p53 phosphorylation.
Results from both the retrospective and in vitro studies provide evidence that further study into the role of COX-2 inhibitors as an adjunct treatment option in radiotherapy is warranted. Further studies, including large prospective human studies, are needed to confirm these findings. These large studies should collect tumour biopsies to allow for histological investigations. The research provides further evidence to the potential for COX-2 inhibitors to be used as an adjunct to radiotherapy in cancer.Thesis (Masters)
Master of Medical Research (MMedRes)
School of Medical Science
Griffith Health
Full Text
31
Fritzsche, Julia. "Expression von EGFR, HER-2 und COX-2 beim Zervixkarzinom: Vergleich von Primärtumoren und Rezidiven". Doctoral thesis, Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-119352.
Pełny tekst źródłaStreszczenie:
Ziel dieser Studie war es, die Häufigkeit der Expression von EGFR, HER-2 sowie COX-2 im Zervixkarzinom zu eruieren. Dabei galt es herauszufinden, ob Unterschiede hinsichtlich des Nachweises dieser drei, möglicherweise therapeutisch relevanten Moleküle zwischen den primären, nicht vortherapierten und operierten Karzinomen und den multimodal vorbehandelten Rezidiven gab. In der vorliegenden retrospektiven Arbeit wurden 45 TMMR-operierte Primärtumoren und 28 LEER-operierte Rezidivtumoren der Universitätsfrauenklinik Leipzig (Triersches Institut) einbezogen und zusätzlich hinsichtlich der prognostischen Überlebensanalyse durch das Tumorstadium, Lymphknotenmetastasen und Rezidivauftreten sowie histologischer Charakteristika untersucht. Dazu wurden Tissue - Microarrays angefertigt mit anschließender immunhistochemischer Untersuchung dieser.
Die Ergebnisse zeigten, dass die TMMR-Operation die Überlebensprognose signifikant verbessert, denn lediglich bei den LEER-therapierten Rezidivtumoren erlitten die Patientinnen sowohl Fernmetastasen als auch erneute Rezidive. Weder die Expression der drei untersuchten Moleküle noch die histopathologischen Parameter haben eine prognostische Relevanz. Es gibt keine signifikanten Zusammenhänge zwischen der Häufigkeit der Expression von EGFR, HER-2 sowie COX-2 und Primär-, bzw. Rezidivtumoren, sodass diese Moleküle keine Targets für eine individualisierte, zielgerichtete Therapie beim Zervixkarzinom darstellen.
32
Queiroz, Jean Cesar Farias de. "Análise genotípica da linhagem RT2 de Aspergillus nidulans e caracterização de sua glicoproteína antiinflamatória". Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-07012009-172622/.
Pełny tekst źródłaStreszczenie:
A transformação de Aspergillus nidulans, com RNA de macrófagos de ratos, resultou na linhagem RT2, produtora de uma glicoproteína antiinflamatória. Nosso objetivo foi avaliar esta linhagem genenomicamente e caracterizar esta glicoproteína quanto à natureza bioquímica e sua atividade. Para tal, foi realizado RAPD e análise fenotípica desta linhagem. A Nandina foi purificada e submetida à espectrometria de massa para sequenciamento e identificação dos carboidratos. Testes da atividade antiinflamatória in vivo foram realizados em peritonite e edema de pata e inibição dos receptores de glicocorticóides. Os testes in vitro, sobre a produção das COXs e de PGE2, foram realizados em cultura de macrófagos. Os resultados mostraram que a linhagem RT2 é resultante da UT448, mas contém diferenças em seu genoma. A proteína purificada possui 40KDa. A espectrometria de massa caracterizou dois fragmentos da proteína e sua glicosilação. Os testes in vivo mostraram que a proteína inibe o edema e o influxo leucocitário e que esta atividade não é dependente de glicocorticóides, mas sim da inibição in vitro de COX-2, mas não de COX-1 e nem de PGE2.Aspergillus nidulans transformation with rat macrophage RNA results on RT2 strain, producer of an antiinflammatory glycoprotein. Our objective was to evaluate this strain genomically and characterize biochemically and activity of its glycoprotein. To this, RAPD and fenotipical analysis were performed. The Nandin was purified and mass spectrometry analyzed to sequencing and carbohydrates analysis. Antiinflammatory activity testes in vivo in peritonitis and edema, and glucocorticoid receptors inhibition were performed. The in vitro testes, over expression and activity of COXs and PGE2, were performed in macrophage culture. The results show that RT2 strain came from UT448, but have genomics differences. The purified glycoprotein has been 40KDa. The mass spectrometry sequenced two protein fragments and showed that glycosylation. The in vivo testes showed that the glycoprotein has antiinflammatory activity inhibiting the edema and leukocyte influx. The RU38486 experiments evidenced that activity is not glucocorticoid receptors dependent, but in vivo inhibition of COX-2, but not COX-1 neither its product PGE2.
33
Junior, Sérgio de Melo Alves. "\"Análise da expressão e mecanismos de ação da proteína COX-2 em cultura de células de carcinoma epidermóide bucal humano\"". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/23/23141/tde-13032007-085956/.
Pełny tekst źródłaStreszczenie:
Celecoxib é um antiinflamatório não esteroidal (AINE), inibidor seletivo da ciclooxigenase-2 (COX-2) usado em pesquisas recentes como agente anticarcinogênico. Os seus efeitos anti-neoplásicos dependem por um lado da sua capacidade de inibir a COX-2, mas por outro lado também age por mecanismos que independem da COX-2, em resumo o seu mecanismo de ação ainda não é completamente conhecido. O objetivo desta tese foi estudar os efeitos do celecoxib sobre as taxas de apoptose e os índices de proliferação celular de quatro linhagens celulares, Hn-6, Hn-19, Hn-30, Hn-31, de CECP e uma linhagem de queratinócitos mutada (HaCat), além de verificar se há correlação entre a expressão das proteínas COX-2, pAkt, ß-catenina, CD1 e NFKB e a inibição da proliferação celular. As células foram divididas em dois grupos: a, grupo controle; b, células cultivadas tratadas com celecoxib. A análise da expressão das proteínas pAkt, NFKB, ß-catenina, COX-2 e CD1 foi feita através da técnica de Western-blot. A indução de apoptose foi estudada com o Kit de Anexina. A proliferação celular foi monitorada através de curva de crescimento, com contagem celular na câmara de Neubauer e com o teste de viabilidade celular (Kit Cell Titer96) e a localização intracelular das proteínas foi avaliada por imunofluorescência. Os resultados mostraram significante aumento no índice celular de apoptose e diminuição da proliferação celular. Após o tratamento com celecoxib, a imunofluorescência mostrou que a proteína CD1 teve diminuição da expressão nuclear, a ß-catenina exibiu discreto aumento citoplasmático, o pAkt também passou a ser expresso no citoplasma da Hn6, enquanto as outras proteínas estudadas mantiveram o mesmo padrão de localização na célula. O western blot complementou os resultados da imunofluorescência indicando uma diminuição nos níveis de CD1.Celecoxib, a cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug, is a new anticarcinogenic agent. Its antitumor effects depend on the one hand on its COX-2-inhibiting potency, but on the other hand on COX-2-independent mechanisms, which until now have not been fully understood. The aim of this research was to study the effects of celecoxib in growth inhibition and apoptosis induction in four Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines, HN6, HN19, HN30, HN31 and HaCat an immortalized keratinocyte cell line, and verify if there is a correlation between the growth inhibition and the expression of COX-2, pAkt, ß-catenin, CD1 and NFKB. The Western Blot was used to analyze the COX-2, pAkt, ß-catenin, CD1 and NFKB protein expression level. Apoptosis induction was studied with the Annexin V kit. The cell lines proliferation will be measured through a growth curve with the Neubauer chamber and MTS method (KitCell Titer96), the proteins intracellular site was assed by immunofluorescence technic. The same cell lines without any treatment were used as controls. Results showed a significant increase in apoptotic cells index, and growth inhibition in cell lines treated with celecoxib. The proteins localization was determined through immunofluorescence. In control group the CD1 was located mostly in nucleus, after treatment CD1 nuclear localization was reduced, it could also be noticed an increase in cytoplasmic expression of ß-catenin in all cell lines while pAkt cytoplasmic increase was present exclusevely in Hn6, the other proteins maintained their cellular localization,. The Western Blot results showed considerable reduction in CD1 levels with exception of Hn19 cell line.
34
Silva, Jaqueline Raymondi. "Interações neuro-imunes envolvidas na gênese da hipersensibilidade nociceptiva herpética e pós-herpética". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-26112014-163011/.
Pełny tekst źródłaStreszczenie:
Herpes Zoster é uma doença causada pela reativação do vírus Varicela Zoster nos gânglios sensoriais, caracterizada pelo desenvolvimento de lesões na pele e dor. Não há modelos animais disponíveis para estudo da patofisiologia da doença. No entanto, um modelo murino que utiliza o HSV-1 tem sido usado para tal fim, visto que os animais desenvolvem lesões zosteriformes e desenvolvem hipersensibilidade na pata infectada. Não há dados na literatura acerca da resposta imune que se desenvolve nos gânglios da raiz dorsal destes animais. Logo, o objetivo deste trabalho foi o de avaliar células e mediadores inflamatórios presentes nos gânglios da raiz dorsal e sua relação com a hiperalgesia durante a infecção cutânea por HSV-1. Durante a fase aguda da infecção, os camundongos desenvolveram hiperalgesia nas patas ipsilaterais a partir do 3 dia pós-infecção, que perdurou até o 7 dia pós-infecção. A maior carga viral foi detectada nos gânglios L4, L5 e L6, os quais compõem o nervo ciático, que inerva a área infectada. O tratamento dos animais infectados com dexametasona ou fucoidina resultou na redução do comportamento de hiperalgesia, a partir do 5 dia pós-infecção, que corresponde ao período em que a migração de leucócitos passa a aumentar nos gânglios da raiz dorsal. Macrófagos, neutrófilos e linfócitos T CD4 foram detectados nos gânglios durante a infecção aguda. No entanto, linfócitos T CD8 estavam ausentes. A expressão do mRNA de TNF- e COX-2 estava aumentada nos gânglios, e o tratamento de animais infectados com drogas inibidoras de ambos resultou na redução da hiperalgesia. Os receptores do tipo Toll-like e da IL-1 não participam da geração da hipersensibilidade herpética. Após 50 dias da infecção, constatou-se que alguns animais apresentavam comportamento de hiperalgesia irreversível, semelhante à neuralgia pós-herpética humana (NPH). Não houve diferença significativa na incidência da NPH em animais de linhagens ou sexos diferentes. Ainda, o tratamento com drogas anticonvulsivantes e antidepressivas, mas não com morfina e anti-inflamatórios, resultou na redução transiente da hiperalgesia. Neste período, não há participação da inflamação na manutenção da hiperalgesia. A expressão de TNF- e COX-2 retorna aos níveis basais, e não são mais detectados neutrófilos e macrófagos. No entanto, a migração de linfócitos T CD4+ e CD8+ aos gânglios aumenta de maneira tempo-dependente. Durante a NPH, detectou-se uma intensa ativação das células satélites gliais, que contribuem para a manutenção da hiperalgesia pós-herpética. Nossos resultados demonstram que a manutenção hiperalgesia herpética é resultado da intensa resposta inflamatória que ocorre nos gânglios da raiz dorsal infectados, com aumento da produção de TNF- e COX-2, importantes mediadores para a hipersensibilidade. No entanto, durante a neuralgia pós-herpética, não há participação de células ou mediadores inflamatórios, mas de células da glia, as quais são importantes na manutenção da hiperalgesia.Herpes Zoster is a disease caused by reactivation of varicella zoster virus in sensory ganglia, characterized by dermal rash and pain. There are no animal models available to study the pathophysiology of the disease. A murine model of HSV-1 infection on the hind paw skin has been used to study HZ, since mice develop HZ-like skin lesions and pain-related responses. There are no data available about the immune response in dorsal root ganglion (DRG) of these mice. Thus, the aim of this study was to evaluate cells and inflammatory mediators present in DRGs and its relationship with hiperalgesia during HSV-1 cutaneous infection. During the acute phase of infection, mice developed hyperalgesia in ipsilateral paws from 3 days post-infection, which persisted until 7 days post-infection. The highest viral load was detected in ganglia L4, L5 and L6. Treatment of infected mice with fucoidin or dexamethasone resulted in the reduction of hyperalgesic behavior, from the 5th post-infection day, which corresponds to the period in which leukocyte migration increase in the dorsal root ganglia. Macrophages, neutrophils and CD4 + T lymphocytes were detected in the ganglia during acute infection. However, CD8 + T lymphocytes were absent. The mRNA expression of TNF- and COX-2 was increased in dorsal root ganglia, and the treatment of infected mice with drugs that inhibits both mediators resulted in reduced hyperalgesia. The Toll-like receptors and IL-1 does not participate in the generation of herpetic hypersensitivity. After 50 days of infection, it was found that some animals presented irreversible hyperalgesic behavior, like human post-herpetic neuralgia (PHN). There was no significant difference in the incidence of PHN in animals of different genders or strains. Furthermore, treatment with anticonvulsant and antidepressant drugs, but not morphine and anti-inflammatory, resulted in transient reduction of hyperalgesia. In this period, there is no participation of inflammation in the hyperalgesia maintenance of. The expression of TNF- and COX-2 returns to baseline levels, and neutrophils and macrophages are no longer detected. However, the migration of CD4 + and CD8 + to ganglia increases in a time-dependent manner. During NPH, an intense activation of glial cells satellites was detected, that contributes to the maintenance of post-herpetic hyperalgesia. Our results demonstrate that herpetic hyperalgesia maintenance is a result of an intense inflammatory response that occurs in the infected dorsal root ganglia, with increased production of TNF- and COX-2. However, during post-herpetic neuralgia, there is involvement of glial cells, which are important in hyperalgesia maintenance.
35
Wei, Gang. "Modelling and inference for a class of doubly stochastic point processes". Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260766.
Pełny tekst źródła
36
Crumer, Angela Maria. "Comparison between Weibull and Cox proportional hazards models". Kansas State University, 2011. http://hdl.handle.net/2097/8787.
Pełny tekst źródłaStreszczenie:
Master of ScienceDepartment of Statistics
James J. Higgins
The time for an event to take place in an individual is called a survival time. Examples include the time that an individual survives after being diagnosed with a terminal illness or the time that an electronic component functions before failing. A popular parametric model for this type of data is the Weibull model, which is a flexible model that allows for the inclusion of covariates of the survival times. If distributional assumptions are not met or cannot be verified, researchers may turn to the semi-parametric Cox proportional hazards model. This model also allows for the inclusion of covariates of survival times but with less restrictive assumptions. This report compares estimates of the slope of the covariate in the proportional hazards model using the parametric Weibull model and the semi-parametric Cox proportional hazards model to estimate the slope. Properties of these models are discussed in Chapter 1. Numerical examples and a comparison of the mean square errors of the estimates of the slope of the covariate for various sample sizes and for uncensored and censored data are discussed in Chapter 2. When the shape parameter is known, the Weibull model far out performs the Cox proportional hazards model, but when the shape parameter is unknown, the Cox proportional hazards model and the Weibull model give comparable results.
37
Malvezi, Aparecida Donizetti. "Efeito do bloqueio de COX-1 e de COX-2 sobre a invasão de células do hospedeiro por Trypanosoma cruzi". Universidade Estadual de Londrina. Centro de Ciências Biológicas. Programa de Pós-Graduação em Patologia Experimental, 2014. http://www.bibliotecadigital.uel.br/document/?code=vtls000194737.
Pełny tekst źródłaStreszczenie:
Trypanosoma cruzi, o agente etiológico da doença de Chagas (DC), afeta milhões de pessoas na América Latina. A invasão por T. cruzi e sua replicação intracelular são essenciais para o ciclo de vida do parasito e para o desenvolvimento da DC. Nós apresentamos evidências sugerindo o envolvimento da ciclooxigenase-1 e 2 (COX-1/COX-2) do hospedeiro durante a invasão por T. cruzi. A inibição farmacológica de COX-1 com aspirina (ASA) provocou marcante inibição da infecção quando macrófagos pré- tratados com ASA por 30 minutos a 37°C antes da inoculação com T. cruzi. Esta inibição foi associada com aumento da produção de TNF-α, óxido nítrico (NO) e IL1-β por macrófagos. O tratamento de macrófagos com inibidores das óxido nítrico sintases (iNOs e cNOs) ou a adição de PGE2 restauraram a capacidade invasora deT.cruzi em macrófagos previamente tratados com ASA. Interessante, o efeito provocado pela ASA foi mediado por Lipoxina iniciada por aspirina. Em adição, o tratamento de células cardíacas de coração de ratos (mioblastos-H9C2) pré-tratadas com inibidores de COX-1 (aspirina) e COX-2 (celecoxibe) por 60 minutos a 37°C, também inibiu a infecção por T. cruzi. Esta inibição está associada com aumento da produção de NO e IL1- β e com redução da produção de TGF-β pelos mioblasto. Nossos resultados indicam que PGE2, NO, lipoxinas e TGF-β estão envolvidos na regulação da atividade anti-T. cruzi por macrófagos e mioblastos, fornecendo um melhor entendimento do papel das prostaglandinas na resposta inflamatória inata durante a infecção por T. cruzi. E abrem novas possibilidades para investigação de novas abordagens terapêuticas contra a doença de Chagas.Trypanosoma cruzi, the etiologic agent of Chagas disease (DC) affects millions of people in Latin America. The invasion by T.cruzi and intracellular replication are essential to the life cycle of the parasite and the development of DC. Here, we present evidence suggesting the involvement of cyclooxygenase -1 and -2 (COX- 1/COX-2) of the host during invasion by T.cruzi. Pharmacological inhibition of COX-1 with aspirin (ASA) caused inhibition of infection when macrophageswere pretreated with ASA for 30 minutes at 37°C before inoculation with T. cruzi. This inhibition was associated with increased production of TNF-α, nitric oxide (NO) and IL1-β by macrophages. Treatment of macrophages with inhibitors of nitric oxide synthase (cNOS and iNOS) or addition of PGE2 restored invasiveness of T. cruzi in macrophages pretreated with ASA. Interestingly, the effect caused by ASA were mediated Lipoxin trigger by aspirin. In addition, treatment of cardiac rat heart cells (myoblast-H9C2) with COX-1 (aspirin) and COX -2 inhibitors (celecoxib) for 60 minutes at 37°C also inhibited infection by T. cruzi. This inhibition is associated with increased production of NO and IL-1β and reduced production of TGF-β by myoblasts. Our results indicate that PGE2 , NO, TGF-β and lipoxins are involved in regulating the activity anti-T.cruzi by macrophages and myoblasts, providing a better understanding of the role of prostaglandins in the innate inflammatory response during infection by T. cruzi, pening new possibilities for new therapeutic approaches against Chagas disease.
38
Hunter, John Cameron. "Multiple Recoding Mechanisms Produce Cyclooxygenase and Cyclooxygenase-Related Proteins from Frameshift-Containing COX-3/COX-1b Transcripts in Rat and Human". BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/6149.
Pełny tekst źródłaStreszczenie:
To increase diversity of enzymes and proteins, cells mix and match exonic and intronic regions retained in mature mRNAs by alternative splicing. An estimated 94% of all multi-exon genes express one or more alternatively spliced transcripts generating proteins with similar or modified functions. Cyclooxygenase is a signaling enzyme that catalyzes the rate-limiting step in the synthesis of diverse bioactive lipids termed prostaglandins. Prostaglandins are involved in myriad physiological and pathopysiological processes including vasoregulation, stomach mucosal maintenance, parturition, pain, fever, inflammation, neoplasia and angiogenesis and are inhibited by aspirin-like drugs known as NSAIDs. In 2002 an alternatively spliced, intron-1 retaining variant of COX-1 was cloned from canine brain tissue. This new variant, termed COX-3 or COX-1b, is an enzymatically active prostaglandin synthase expressed at relatively high levels in a tissue and cell type dependant manner in all species examined. In humans and most rodent species intron-1 is 94 and 98 nucleotides long respectively. Retention of the intron in these species introduces a frameshift and is predicted to result in translation of a very small 8-16kD protein with little similarity to either 72kD COX-1 or COX-2, calling into question the role of this variant. In this dissertation, I present my results from cloning and ectopically expressing a complete and accurate COX-3 cDNA from both rat and human. I confirmed that COX-3 mRNA encodes multiple large molecular weight cyclooxygenase-like proteins in the same reading frame as COX-1. Translation of these proteins relies on several recoding mechanisms including cap-independent translation initiation, alternative start site selection, and ribosomal frameshifting. Using siRNA and Western blotting I have identified some of these proteins in tissues and cells. Two COX-3 encoded proteins are active prostaglandin synthase enzymes with activities similar to COX-1 and represent novel targets of NSAIDs. Other COX-3 proteins have unknown function, but their size and cellular location suggest potential roles as diverse as cytosolic enzymes and nuclear factors.
39
Freytag, Georg Tobias Heinrich. "Die Bedeutung genetischer Polymorphismen im Enzym Cytochrom P450 2C9 für Pharmakokinetik und Wirkungen der nichtsteroidalen Antiphlogistika Diclofenac und Ibuprofen". Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/15236.
Pełny tekst źródłaStreszczenie:
Die Bedeutung genetischer Polymorphismen im Enzym Cytochrom P450 2C9 für Pharmakokinetik und Wirkungen von Diclofenac und Ibuprofen Es wird angenommen, dass Cytochrom-P450 2C9 die 4’-Hydroxylierung des Nichtsteroidalen Antiphlogistikums Diclofenac und die Hydroxylierung von S-Ibuprofen beim Menschen katalysiert. Es existieren zwei Varianten von Cyp2C9. Deren Auswirkungen auf die Diclofenac- bzw. Ibuprofen-Pharmakokinetik und die Hemmung von Cox-1 und -2 wurde an 21 gesunden Probanden, die sämtliche Kombination der genetischen Varianten *2 und *3 aufwiesen, untersucht. Es zeigten sich keinerlei Hinweise auf eine Einschränkung des Metabolismus von Diclofenac bei heterozygoten und homozygoten Trägern der Cyp2C9-Allele *2 und *3. Darüber hinaus lagen auch die Serumkonzentrationen des Metaboliten 4’-OH-Diclofenac bei Trägern der Allele Cyp2C9 *2 und *3 nicht niedriger. Obwohl verschiedene in vitro-Untersuchungen Cyp2C9 als metabolisierendes Enzym identifizierten, ist die Pharmakokinetik von Diclofenac ist beim Menschen entweder überhaupt nicht oder nur in geringem Ausmaß von Cyp2C9-Aminosäurenpolymorphismen abhängig. Möglicherweise sind die Auswirkungen der Cyp2C9-Aminosäurenvarianten substratabhängig, oder es ist in vivo ein anderes Enzym als Cyp2C9 verantwortlich für die Bildung von 4’-OH-Diclofenac. Im Unterschied dazu hing die Pharmakokinetik von razemischem und von S-Ibuprofen vom Cyp2C9 *3-Polymorphismus ab. Die Bildung von Tx B2 (Cox-1) hing signifikant von Cyp2C9 *3-Polymorphismus ab, derselbe Trend ließ sich auch für Pg E2 (Cox-2) beobachten. Die eingeschränkte Clearance von S-Ibuprofen, die mit einer erhöhten pharmakodynamischen Aktivität einhergeht, legt nahe, dass Träger des Allels Cyp2C9*3 ein höheres Risiko tragen, nach Einnahme einer oralen Standarddosis unerwünschte Nebenwirkungen zu erleiden.Consequences of genetic polymorphisms in Cytochrome P450 2C9 for pharmacokinetics and effects of Diclofenac and Ibuprofen. Cytochrome-P450 2C9 is considered to catalyse the 4’-hydroxylation of the nonsteroidal analgesic drug diclofenac and the hydroxylation of S-ibuprofen in humans. There are two variants of Cyp2C9. Their impact on diclofenac/ ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2 was studied in 21 healthy volunteers with all combinations of the Cyp2C9 variants *2 and *3. Blood concentrations of diclofenac/ racemic ibuprofen (and of S-ibuprofen and R-ibuprofen) were measured by HPLC. Thromboxane B2 and prostaglandin E2 were measured with use of an enzyme immunoassay. There was no evidence of impaired metabolism of diclofenac in heterozygous and homozygous carriers of the Cyp2C9 alleles *2 and *3 compared to the wildtype. Furthermore, plasma concentrations of the metabolite 4’-OH-diclofenac were not lower in carriers of Cyp2C9*2 and *3. Marked diclofenac mediated inhibition of Cox-1- and Cox-2 activity was detected in all individuals without any Cyp2C9 genotype dependent differences. Even though several in vitro studies identified Cyp2C9 as the metabolising enzyme, Diclofenac pharmacokinetics in humans is either not or only to a minor extend dependent on the Cyp2C9 amino acid polymorphisms. It may be that the Cyp2C9 amino acid variants have differential effects depending on the substrates. Alternatively, an enzyme other than Cyp2C9 may be responsible for 4’-OH-Diclofenac formation in vivo.In contrast, the pharmacokinetics of racemic and of S-ibuprofen depended on the Cyp2C9 *3-polymorphism. The Cyp2C9 variant *2 exhibited no significant effect. Formation of Tx B2 (cox-1) depended significantly on the Cyp2C9 polymorphism, the same trend was observed for Pg E2 (cox-2). The reduced S-ibuprofen total clearance accompanied by increased pharmacodynamic activity indicates an increased risk for carriers of Cyp2C9*3 to suffer from adverse effects after intake of a standard oral dose.
40
Fredriksson, Teodor. "Fokker Planck for the Cox-Ingersoll-Ross Model". Thesis, Uppsala universitet, Tillämpad matematik och statistik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-331149.
Pełny tekst źródła
41
Sheu, Fong-Shyong. "Characterizations of a tumor-associated antigen COX-1". Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30332.
Pełny tekst źródłaStreszczenie:
By using modified hybridoma technology, monoclonal antibodies against an ovarian tumor cell line, OC-3-VGH, were generated in Dr. Lee's laboratory. Among these antibodies, RP 215 was shown to react specifically with a tumor-associated antigen, COX-1. On SDS gel, COX-1 has a molecular weight of 60 KD and exists as an aggregate in the natural- state. A highly purified COX-1 was obtained mainly by immunoaffirtity chromatography, with RP 215 as the affinity ligand, from the shed medium of cultured tumor cells. A solid phase enzyme immunoassay was established using RP 215 as the capturing and the detecting antibody with a sensitivity of 1 AU/ml. This immunoassay kit could be used to determine the levels of COX-1 in the culture medium and in the sera of cancer patients.
COX-1 was characterized under a variety of experimental conditions. At temperatures higher than 50°C or in the presence of trypsin at 37°C, COX-1 immunoactivity was found to decrease with incubation time. However, COX-1 was not affected by incubation with carbohydrate-digestive enzymes including neuraminidase, Beta-galactosidase and fucosidase or carbohydrate modifying agents such as NaIO₄. Concanavalin A had no effect on the immunoactivity of COX-1 to RP 215. Furthermore, rabbit antisera against COX-1 were raised, and these polyclonal antisera were shown to exhibitsimilar immunoactivity to that of RP 215 monoclonal antibody.
Using the established sandwich enzyme immunoassay, serum levels of COX-1 among patients with ovarian or cervical cancers were determined retrospectively through interlaboratory evaluations and collaborations. Compared to those of normal individuals and benign tumors, serum levels of COX-1 were significantly elevated and can be correlated to the progression of the disease among cancer patients. Preliminary data indicated the COX-1 can complement other established tumor markers such as CA 125 for the purpose of monitoring patients with ovarian or cervical cancers.Medicine, Faculty of
Obstetrics and Gynaecology, Department of
Graduate
42
Tse, Wing-on. "Hepatic oxidative stress in COX-1 knockout mice /". View the Table of Contents & Abstract, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36396552.
Pełny tekst źródła
43
Ramesh, Nadarajah Iyer. "Statistical inference for some classes of Cox processes". Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315769.
Pełny tekst źródła
44
Da, Costa Rocha Ines Isabel. "Effect of COX and LOX inhibitors on melanoma". Thesis, University College London (University of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550962.
Pełny tekst źródłaStreszczenie:
The incidence of malignant melanoma is increasing worldwide and becoming resistant to most chemotherapy and immunotherapy. The arachidonic acid pathway, through COX and LaX enzymes, lead to the formation of a variety of metabolically active products, the eicosanoids, with different roles in carcinogenesis beyond their primary homeostatic functions. Importantly, these enzymes were shown to be overexpressed in melanoma. Thus the aim of this PhD thesis was to determine the effect of COX and LOX inhibitors in melanoma survival and how they may influence melanoma development as well as to unveil pharmacological opportunities when using these drugs in combination with chemotherapeutic ones. For our work we selected the mouse melanoma cell line B16F10 as a convenient cancer experimental model. They are highly resistant to chemotherapy and can be easily used both in vitro and in vivo. The direct in vitro cytotoxic effects of the drugs were assessed in two experimental models (MTT and SRB assays), as well as their influence on COX and LaX enzymes expression, cell cycle and activation of caspases. To check how they modulate melanoma development, in vitro 2-D migration studies and an in vivo lung metastasis experimental model were designed and performed. Our study reports for first time on the expression of COX-1, 5-LOX and 15-LOX-1 enzymes, which was not impaired by the treatments. COX-2 and 12-LOX expression also remained unaffected throughout our experiments. Short term incubations with the drugs failed to inhibit their activity and sometimes even stimulated them. Overall, meloxicam, M-861 and baicalein were the best anticancer drugs when given alone. PD-146176 exerted a strong effect in vitro but this was not observed in vivo. Combination treatments with chemotherapeutic drugs seem to afford better results for the COX inhibitors (meloxicam>ASA) than for the LOX inhibitors (M-861> baicalein> PD-146176>MK-886). In conclusion, our project affords for first time a comprehensive overview of the in vitro and in vivo effects of COX and LaX inhibitors in key aspects of the B16F10 mouse melanoma cell line. As per our preclinical studies and previous clinical studies COX-2 inhibitors -alone or in combination with chemotherapeutic drugs - seem to be superior to LOX inhibitors. Interestingly, the mechanisms of their anticancer effects seem not to be entirely explained by their action upon the enzymes of the arachidonate pathway.
45
Tse, Wing-on, i 謝永安. "Hepatic oxidative stress in COX-1 knockout mice". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B4501095X.
Pełny tekst źródła
46
Ahmadinezhad, Hamid. "Del Pezzo fibrations and rank 3 Cox rings". Thesis, University of Kent, 2011. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544067.
Pełny tekst źródła
47
Dutra, Livia Maria. "Exact Bayesian inference for Markov switching Cox processes". Universidade Federal de Minas Gerais, 2015. http://hdl.handle.net/1843/BUBD-9WGFNQ.
Pełny tekst źródłaStreszczenie:
Statistical modelling of point patterns is an important and common problem in several applications. An important point process, and a generalisation of the Poisson process, is the Cox process, where the intensity function is itself stochastic. We focus on Cox processes in which the intensity function is driven by a nite state space continuous-time Markov chain. We refer to these as Markov switching Cox processes (MSCP). We investigate some probabilistic properties of these processes, three new theorems for these processes are derived and we develop a Bayesian methodology to perform exact inference based on MCMC algorithms. Since the likelihood function is tractable, it facilitates the development of an exact methodology. Simulated studies are presented in order to investigate the efficiency of the methodology on the estimation of MSCP's intensity function and the parameters indexing its law. Finally, an analysis with real data is performed.A modelagem estatística de dados pontuais é um problema importante e comum em diversas aplicações. Um importante processo pontual, e uma generalização do processo de Poisson, é o processo de Cox, em que a sua função intensidade é também estocástica. O presente trabalho se concentra nos processos de Cox em que sua função intensidade é uma cadeia de Markov em tempo contínuo com espaço de estados nito. Estes processos s~ao referidos como processos de Cox com mudanças Markovianas (PCMM). Algumas propriedades probabilísticas desses processos são investigadas, três novos teoremas enunciados e é desenvolvida uma metodologia Bayesiana para realizar inferência exata, baseada em algoritmos MCMC. O desenvolvimento de uma metodologia exata é facilitado, uma vez que a função de verossimilhança é tratável. São apresentados estudos simulados a m de investigar a e ciência da metodologia para estimação da função intensidade dos PCMM's e dos parâmetros relacionados a ela. Ao fim, realiza-se uma análise com dados reais.
48
Reis, Cássio Pinho dos. "Delineamentos ótimos visando a possibilidade de transformação na variável resposta". Botucatu, 2019. http://hdl.handle.net/11449/181371.
Pełny tekst źródłaStreszczenie:
Orientador: Luzia Aparecida TrincaResumo: Nas mais diversas áreas do conhecimento se procura aumentar a eficiência dos delineamentos experimentais, principalmente, para minimizar os custos das pesquisas. O uso dos delineamentos ótimos, com seus diferentes critérios de otimização, é fundamental para se obter resultados que maximizam a informação em estudos experimentais. A maioria dos métodos pressupõe homogeneidade de variâncias, a qual nem sempre é veri cada no conjunto de dados. O objetivo deste trabalho é desenvolver uma metodologia para construção de delineamentos ótimos exatos e cientes em situações de variância não homogênea. Assume-se que linearidade e homoscedasticidade são obtidas via o uso de transformações da família Box-Cox e, além de critérios de otimização puros, critérios compostos que combinam duas propriedades são propostos. Resultados para vários exemplos sob os modelos de primeira e segunda ordem são obtidos e discutidos.
Abstract: In several areas of knowledge we seek to increase the efficiency of experimental designs, mainly in order to minimize the costs of reaserch. The use of optimal design with different optimization criteria is fundamental to obtain results that maximize the information in experimental studies. Most of the methods assume homogeneity of variances, which is not always verified in the data set. The goal of this work is to develop a methodology to construct exact optimal or efficient designs in situations of nonhomogeneous variance. It is assumed that application of a transformation from the Box-Cox family accomplish both linearity and homocedasticity. Pure design criterion as well as compound criteria using two desired properties are used. Results for several examples assuming first and second order models are presented and discussed.
Doutor
49
Trujillo, Angeles Lucía Inés. "Una aplicación de la regresión de Cox con puntos de cambio en las covariables". Master's thesis, Pontificia Universidad Católica del Perú, 2014. http://tesis.pucp.edu.pe/repositorio/handle/123456789/6989.
Pełny tekst źródłaStreszczenie:
El siguiente trabajo de tesis, estudiará el modelo de regresión de Cox con puntos de cambio en las covariables propuesto por Jensen y Lutkebohmert (2008), realizando el desarrollo y la aplicación para una base de líneas móviles postpago. El objetivo es obtener los parámetros de las covariables y el nuevo parámetro en el modelo que es el punto de cambio, para analizar la manera como estas covariables tienen influencia en la desactivación de una línea a solicitud del cliente.Tesis
50
Samaniego, Juana Rosa Lindo. "Abordagem clássica e bayesiana em modelos auto-regressivos com transformações de Box & Cox". Universidade de São Paulo, 2002. http://www.teses.usp.br/teses/disponiveis/55/55134/tde-18062015-110335/.
Pełny tekst źródłaStreszczenie:
Atualmente as projeções de demanda e ganho tornam-se variáveis importantes no processo de tomada de decisões para investimentos envolvendo custo e capital, em pesquisa de mercado envolvendo produtos de consumo, em pesquisa de populações e em qualquer outro tipo de previsões que tenham a ver com ganhos ou demandas futuras, por exemplo o volume de água que é preciso para ser gerada determinada quantidade de energia consumido por uma população através de um sistema de operação e planejamento de um sistema hidroelétrico, etc. Em resposta desse interesse muitos estudos examinaram a possibilidade de gerar previsões usando séries temporais, ajustando modelos mediante a metodologia de Box e Jenkins, porém estas séries sugeriam variabilidade maior em diferentes níveis, violando deste modo a suposição de variância constante na formulação dos modelos ARIMA. Nestas situações, é comum na prática, contemplar uma extensão destes modelos, assumindo que alguma transformação da série obedeça um modelo ARIMA, frequentemente são usadas transformações de Box e Cox, porém as previsões destas séries transformadas afeta as interpretações em quanto à série original. Uma abordagem combinada de métodos clássicos e bayesianos é apresentada no tratamento destas transformações, os quais estimam junto com os parâmetros do modelo a potência desta transformação, apresentamos também uma alternativa para examinar a estrutura das auto-covariâncias através do Polinómio de Hermite. A pergunta que surge é, se a incorporação destas transformações resulta numa melhora nas previsões. No caso particular apresentamos resultados em processos auto-regressivos. É feita uma aplicação destes métodos em séries de vazões medias mensais no Reservatório de Furnas.Nowadays the demand and gain projections become important variables in the process of making decisions for investments involving cost and capital, regarding the market research involving consuming products, the population research and any other forecast research which deals with the earnings or the future demands as an example, the water volume which is necessary to generate a determined amount of energy to be consumed by a population through the operation and planning system of a hydroelectric system and so on. In order to answer this demand a lot of studies examined the possibility to generate forecasts by using the time series, and by adjusting the models used in the Box and Jenkins methodology, however, these series suggested a larger variability in different leveis, and therefore violating the constant variance supposition in the ARIMA models formulation. Considering these situations, it is common in the practice to contemplate na extension of these models, assuming that some of these series transformation will follow the ARIMA model. Frequently the Box and Cox transformations are used; however, the forecasts of these transformed series affects the interpretation regarding the original series. An approach combining the classical and bayesian methods is introduced to the consideration of these transformation, which allows us to estimate, along with the parameters of the model, the power of this transformation. Also, we present an option to examine the structure of the autocovariances through the Hermite polynomials. The question that arises is, if the incorporation of these transformations will result in an improvement in the forecasts. Considering this particular case we present results in the auto-regressive processes. An application of these methods is made in a regular flow series measured monthly at Reservoir of Furnas.