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.

The metastatic spread of tumor cells is the major lethal aspect of cancer, and lymphatic metastasis is one of the most important routes. Recent studies indicated that cyclooxygenase-2 (COX-2) expression is frequently associated with lymph node metastasis and over-expression of COX-2 can enhance lymphatic invasion of cancer cells. The interaction of chemokines and their cognate receptors also plays a critical role in cancer metastasis. Previous results of our laboratory demonstrated that CCR7 is a downstream target for COX-2 and COX-2 up-regulated CCR7 expression via the EP2 and EP4 receptor. We also found that protein kinase A (PKA) and AKT kinase are involved in COX-2-induced CCR7. In this study, we provided further evidences that COX-2 directly stimulates CCR7 expression via promoter activation. Promoter deletion and mutation assay indicated that COX-2 stimulated CCR7 promoter via the Sp1 binding site located at the -61/-52 bp region upstream of the transcription start site. Increase of Sp1 binding to CCR7 promoter by COX-2 was confirmed by chromatin immunoprecipitation (ChIP) assay. Furthermore, knockdown of Sp1 expression resulted in inhibition of PGE2-induced CCR7, and over-expression of Sp1 potently up-regulated CCR7 in MCF-7 cells. In vitro kinase assay indicated that AKT could directly phosphorylate Sp1 at S42, T679 and S698 sites. And the phosphorylation of Sp1 by AKT led to enhanced protein stability and DNA binding affinity of Sp1. The results of immunohistochemistry indicated that CCR7 expression was significantly associated with Sp1 and phosphor-AKT. Taken together, COX-2 may act via the EP receptor/PKA/AKT/Sp1 signaling pathway to stimulate CCR7 expression in breast cancer cells to promote lymphatic spread.

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Nous cherchons à estimer l’intensité de sauts d’un processus de comptage en présence d’un grand nombre de covariables. Nous proposons deux approches. D’abord, nous considérons une intensité non-paramétrique et nous l’estimons par le meilleur modèle de Cox étant donné deux dictionnaires de fonctions. Le premier dictionnaire est utilisé pour construire une approximation du logarithme du risque de base et le second pour approximer le risque relatif. Nous considérons une procédure Lasso, spécifique à la grande dimension, pour estimer simultanément les deux paramètres inconnus du meilleur modèle de Cox approximant l’intensité. Nous prouvons des inégalités oracles non-asymptotiques pour l’estimateur Lasso obtenu. Dans une seconde partie, nous supposons que l’intensité satisfait un modèle de Cox. Nous proposons deux procédures en deux étapes pour estimer les paramètres inconnus du modèle de Cox. La première étape est commune aux deux procédures, il s’agit d’estimer le paramètre de régression en grande dimension via une procédure Lasso. Le risque de base est ensuite estimé soit par sélection de modèles, soit par un estimateur à noyau avec une fenêtre choisie par la méthode de Goldenshluger et Lepski. Nous établissons des inégalités oracles non-asymptotiques pour les deux estimateurs du risque de base ainsi obtenus. Nous menons une étude comparative de ces estimateurs sur des données simulées, et enfin, nous appliquons les procédures implémentées à une base de données sur le cancer du sein. / We consider the problem of estimating the intensity of a counting process adjusted on high-dimensional covariates. We propose two different approaches. First, we consider a non-parametric intensity function and estimate it by the best Cox proportional hazards model given two dictionaries of functions. The first dictionary is used to construct an approximation of the logarithm of the baseline hazard function and the second to approximate the relative risk. In this high-dimensional setting, we consider the Lasso procedure to estimate simultaneously the unknown parameters of the best Cox model approximating the intensity. We provide non-asymptotic oracle inequalities for the resulting Lasso estimator. In a second part, we consider an intensity that rely on the Cox model. We propose two two-step procedures to estimate the unknown parameters of the Cox model. Both procedures rely on a first step which consists in estimating the regression parameter in high-dimension via a Lasso procedure. The baseline function is then estimated either via model selection or by a kernel estimator with a bandwidth selected by the Goldenshluger and Lepski method. We establish non-asymptotic oracle inequalities for the two resulting estimators of the baseline function. We conduct a comparative study of these estimators on simulated data, and finally, we apply the implemented procedure to a real dataset on breast cancer.

Statins can act as preconditioning agents against ischemia reperfusion (IR)-injury through a mechanism involving cyclooxygenase (COX)-2 and the upregulation of prostaglandin synthesis. The following study investigated the effect of selective and non-selective COX inhibition on rosuvastatin-mediated protection against IR-induced endothelial dysfunction in the human forearm vasculature. Healthy volunteers were randomized to drugs with different COX-inhibiting properties: 81mg aspirin (OD), 325mg aspirin (OD), 400mg ibuprofen (QID), 200mg celecoxib (BID) or placebo. A single dose of 40mg rosuvastatin was also administered 24-hours prior to IR. Endothelial function before and after IR was assessed by measuring flow-mediated dilation of the radial artery. Our results show that 81mg and 325mg aspirin (more COX-1 selective), 400mg ibuprofen (similar selectivity for COX-1/2) and 200mg celecoxib (COX-2 selective) all effectively abolished statin-mediated protection against IR-induced endothelial dysfunction in the forearm (2-way ANOVA, p<0.05). These findings indicate that even partial COX-2 inhibition is sufficient to attenuate statin-induced preconditioning.

Statins can act as preconditioning agents against ischemia reperfusion (IR)-injury through a mechanism involving cyclooxygenase (COX)-2 and the upregulation of prostaglandin synthesis. The following study investigated the effect of selective and non-selective COX inhibition on rosuvastatin-mediated protection against IR-induced endothelial dysfunction in the human forearm vasculature. Healthy volunteers were randomized to drugs with different COX-inhibiting properties: 81mg aspirin (OD), 325mg aspirin (OD), 400mg ibuprofen (QID), 200mg celecoxib (BID) or placebo. A single dose of 40mg rosuvastatin was also administered 24-hours prior to IR. Endothelial function before and after IR was assessed by measuring flow-mediated dilation of the radial artery. Our results show that 81mg and 325mg aspirin (more COX-1 selective), 400mg ibuprofen (similar selectivity for COX-1/2) and 200mg celecoxib (COX-2 selective) all effectively abolished statin-mediated protection against IR-induced endothelial dysfunction in the forearm (2-way ANOVA, p<0.05). These findings indicate that even partial COX-2 inhibition is sufficient to attenuate statin-induced preconditioning.

Ketamine is a short-acting dissociative anesthetic and its hallucinogenic side effects have led to increased illicit use among night clubs and party goers. Clinically, ketamine abuse is associated with severe lower urinary tract dysfunction and reduced bladder capacity and hemorrhagic cystitis with irreversible pathological changes which may develop in some cases of long-term drug abuse. Up to now, the mechanisms causing these severe side-effects are still not clear. Herein, a novel ketamine addiction rat model was used to examine the pathological changes and explore the mechanisms of urinary bladders destruction. Rats were divided into groups of control, ketamine injection 14 days and 28 days. Ketamine injection (25 mg/kg/day) was given intraperitoneally while normal saline was given for control group. In vivo isovolumetric cystometrography studies were performed, bladder stiffness parameters were measured, and the bladder tissues were collected for protein analysis and immunohistochemical staining. Ketamine treatment significantly increased micturition pressure but decreased bladder capacity in rats. Ketamine treatment also significantly decreased bladder compliance and increased bladder non-voiding contraction during storage phase. Immunofluorescence studies showing significantly decreased neurofilament staining after ketamine injection 28 days confirmed the neurotoxicity of ketamine. TUNEL staining also showed multiple degenerating cells diffusely distributed in urothelium, suburothelium, and smooth muscle layers in ketamine injected rats. Western blotting demonstrated ketamine injection increased bladder iNOS, eNOS and COX-2 expression. It is concluded that chronic exposure to low, subanesthetic concentrations of ketamine could affect cell survival and impair neuronal morphology which subsequently led to dysfunction of neural networks and altered bladder micturation reflex.

Accumulating evidence suggests that inflammation plays an important role in the progression ofParkinson's disease (PD). Among many inflammatory factors found in the PD brain, cyclooxygenase(COX), especially the inducible isoform, COX-2, is believed to be the critical enzyme in theinflammatory response. Induction of COX-2 is also found in an experimental model of PD producedby administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To investigate whetherinhibition of COX-2 by valdecoxib or deficiency in COX-2 could prevent dopaminergic neuronaltoxicity and locomotor activity impairment, we injected MPTP into valdecoxib-treated C57BL/6N miceand COX-2 deficient mice, respectively. Both automated total distance and vertical activitymeasurements of the open-field test were significantly reduced in the vehicle-treated mice at two weekspost-MPTP injection. In contrast, valdecoxib treatment significantly attenuated these deficits.Similarly, COX-2 deficiency attenuated MPTP-induced loss of coordination on a rotarod assay.Valdecoxib or deficiency of COX-2 reduced microglial activation while preventing loss of tyrosinehydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc). The total number ofactivated microglia in the SNpc had a strong positive correlation with the level of COX-2 anddopaminergic neurodegeneration. The results of this study indicate that reducing the activity of COX-2can mitigate the progressive loss of dopaminergic neurons as well as the motor deficits caused byMPTP neurotoxicity, possibly by suppressing the activation of microglia in the SNpc.

In eukaryotic cells, energy is produced by the coordinated action of the mitochondrial respiratory chain (MRC) and the oxidative phosphorylation system (OXPHOS). Cytochrome c oxidase (COX) is the fourth enzyme of the MRC. COX catalytic activity is mediated by prosthetic groups located in subunits 1 (Cox1) and 2. More than twenty nuclear encoded factors are required for the assembly of the functional enzyme. Cox1 is the center of a regulatory mechanism in which its protein levels depend on the availability of its assembly partners. A key element in the regulatory pathway is the nuclear encoded factor Mss51, a protein essential for COX1 mRNA translation and Cox1 stability. In this thesis work, we show that Mss51 performs these two functions by dynamically interacting with several protein partners, including COX assembly chaperones and the Hsp70 general chaperone Ssc1. We have also characterized functional domains in Mss51. Specifically, we are reporting the presence of two conserved CPX (Val,Leu) heme-binding motifs, essential for in vivo Mss51 functions. Our data supports a system in which the efficiency of Mss51 as a translational activator is regulated by heme levels perhaps in a redox-sensitive manner. This study contributes to the current knowledge and understanding of the COX assembly process by disclosing new mechanisms involved in its intricate regulation.

Thesis (M.S.)--Indiana University, 2008. / Title from screen (viewed on August 28, 2009). Department of Pathology and Laboratory Medicine, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Raymond L. Konger, Jeffrey B. Travers, Dan F. Spandau. Includes vita. Non-Latin script record Includes bibliographical references (leaves 32-36).