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Resistência à quimioterapia neo-adjuvante no carcinoma da mama: valor preditivo da Pgp e da mamocintigrafia com Sestamibi-Tc 99m

Frutuoso, Cristina Margarida Ferreira
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Dissertação de Mestrado
POR
Relevância na Pesquisa
27.82%
A quimioterapia neoadjuvante (QTNA) permite a avaliação in vivo da quimiossensibilidade das células tumorais. A glicoproteína P (Pgp) promove o efluxo do citostático da célula tumoral impedindo a acumulação intracelular. A expressão da Pgp antes da QT com substratos da Pgp parece relacionar-se com a taxa de resposta ao tratamento. O Sestamibi-Tc99m é eliminado da célula pela via Pgp e a sua excreção está aumentada nos cancros com aumento de expressão dos genes multidrug resistance (MDR), que codificam a Pgp. No carcinoma da mama foi sugerida a existência de correlação positiva entre a expressão da ciclooxigenase 2 (COX-2) e o MDR1. O celecoxib, inibidor da COX-2, já foi utilizado com sucesso em associação com citostáticos no tratamento do cancro da mama. O objectivo primário deste trabalho foi o de avaliar o valor preditivo de resposta à quimioterapia da expressão da Pgp no fragmento de biópsia e da mamocintigrafia feita com Sestamibi-Tc99m, ambas realizadas antes do início da QT. Os objectivos secundários foram os de correlacionar a expressão da Pgp com a da COX-2 e avaliar o valor preditivo de resposta à quimioterapia de outros marcadores, como as proteínas p53, Bcl 2 e Ki67. Foi feito um estudo prospectivo...

Associação dos polimorfismos do CYP3A5 e da PGP com a farmacocinética do tacrolimus, nefrotoxicidade aguda e rejeição do enxerto após transplante renal; Association of CYP3A5 and PGP polymorphisms and haplotypes with tacrolimus pharmacokinetics, acute nephrotoxicity and allograft rejection after kidney transplantation

Cusinato, Diego Alberto Ciscato
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 01/08/2012 PT
Relevância na Pesquisa
27.46%
Tacrolimus (TAC) é um fármaco imunossupressor muito utilizado na prevenção de rejeição aguda após o transplante de órgãos. Essa droga apresenta um índice terapêutico muito baixo e grande variabilidade intra e interindividual, sendo necessário programas de monitorização terapêutica para se otimizar a eficácia e limitar a toxicidade. O TAC é um fármaco substrato do CYP3A5 e transportado pela proteína de efluxo PGP e acredita-se que o polimorfismos genéticos (SNPs) destas proteínas estejam relacionados a alta variabilidade farmacocinética desta droga. Neste estudo, investigamos a influência dos polimorfismos destas proteínas sobre alguns parâmetros farmacocinéticos do TAC e também, na incidência de lesões renais e rejeição em receptores de transplante renal. Pacientes recebendo TAC a no mínimo 12 meses (n=108) foram genotipados (PCR real time) para os polimorfismos do CYP3A5*3 (rs776746) e do gene ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) e 3435C>T (rs1045642). Dados da concentração plasmática de vale (Co; ng/mL), dose diária normalizada (mg/dia por Kg do paciente) e a concentração plasmática do fármaco normalizada pela dose ingerida (Co/dose...

Implicações clínicas dos polimorfismos do gene de resistência a múltiplas drogas MDR1 (ABCB1)

Gonzalez, Tatiana Pereira; Schiengold, Marion; Chies, Jose Artur Bogo
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Artigo de Revista Científica Formato: application/pdf
POR
Relevância na Pesquisa
27.66%
(Implicações clínicas dos polimorfismos do gene de resistência a múltiplas drogas MDR1 (ABCB1)). A Glicoproteína P (Pgp), produto do gene MDR1 (ABCB1), é um transportador de efluxo dependente de ATP que age sobre uma ampla variedade de substratos e constitui um mecanismo de proteção do organismo contra xenobióticos. A Pgp está envolvida na alteração de biodisponibilidade de diversas drogas, afetando a absorção pelo trato gastrintestinal e excreção através dos rins e fígado, sendo também expressa no pulmão e nas barreiras hemato-encefálica e hemato-testicular. O gene MDR1 apresenta um grande número de polimorfismos e um número cada vez maior de estudos mostra que alguns destes podem afetar a expressão e atividade da Pgp. As implicações clínicas destes polimorfismos vêm sendo bastante estudadas e já foi observada influência dos mesmos no desenvolvimento e susceptibilidade a algumas doenças. Além disso, também tem sido muito estudada a relação entre os polimorfismos do gene MDR1 com a resposta a tratamento farmacológico e com o perfil farmacocinético de drogas que são substratos da Pgp. Apesar de muitos estudos procurarem estabelecer relações entre os genótipos resultantes dos polimorfismos de MDR1 e diversos aspectos clínicos...

PGP : prokaryote gene prediction software

Pacheco, José Carlos Ribeiro
Fonte: Universidade do Minho Publicador: Universidade do Minho
Tipo: Dissertação de Mestrado
Publicado em //2013 POR
Relevância na Pesquisa
27.78%
Dissertação de mestrado em Bioinformática; A correta previsão e anotação de genes bacterianos é essencial para a aplicação da informação contida no ADN em muitos tópicos de pesquisa (bio)médica, como microbiologia, imunologia e doenças infeciosas. Embora existam vários softwares de previsão de genes bacterianos como GenemarkHMM, Glimmer e Prodigal e pipelines completos como ISGA, xBASE, Maker e Consensus Prediction, a previsão de genes pode ser melhorada. O principal objetivo deste trabalho foi o desenvolvimento de um pipeline de previsão de genes bacterianos, o Prokaryote Gene Prediction (PGP), que combina métodos de ab initio e de homologia. Uma vez que o software ab initio Prodigal mostrou um melhor desempenho relativamente a outros softwares estudados, foi usado como o passo inicial para o PGP. Considerando as proteínas previstas pelo Prodigal, o PGP a) analisa os alinhamentos obtidos, b) determina a necessidade de encurtar ou estender genes, c) introduz as correções necessárias, d) faz a previsão de ARNr e ARNt utilizando os programas RNAmmer e tRNA-scan2 e e) determina a existência de eventuais genes não identificados nas regiões intergénicas, através de um BLASTx. Quando comparados os resultados do PGP com os dados produzidos pelo Prodigal utilizando 4 genomas com conteúdo G+C% moderado e 3 com conteúdo em G+C% extremo...

The expression of NGFr and PGP 9.5 in leprosy reactional cutaneous lesions: an assessment of the nerve fiber status using immunostaining

Antunes,Sérgio Luiz Gomes; Liang,Yong; Neri,José Augusto da Costa; Haak-Frendscho,Mary; Johansson,Olle
Fonte: Academia Brasileira de Neurologia - ABNEURO Publicador: Academia Brasileira de Neurologia - ABNEURO
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2003 EN
Relevância na Pesquisa
27.57%
The effects of reactional episodes on the cutaneous nerve fibers of leprosy patients was assessed in six patients (three with reversal reactions and three with erythema nodosum leprosum). Cryosections of cutaneous biopsy of reactional lesions taken during the episode and of another sample during the remission period were immunostained with anti-NGFr and anti-PGP 9.5 (indirect immunofluorescence). We found no significant statistical difference in the number of NGFr- and PGP 9.5-positive fibers between the reactional and post-reactional groups. A significant difference was detected between the number of NGFr and PGP 9.5-stained fibers inside of the reactional group of biopsy cryosections but this difference was ascribed to the distinct aspects of the nerve fibers displayed whether stained with anti-NGFr or with anti-PGP 9.5; NGFr-positive branches looked larger and so interpreted as containing more fibers. In addition, a substantial number NGFr-positive fibers were PGP 9.5-negative. No differences in the number of stained fibers among the distinct cutaneous regions examined (epidermis + upper dermis, mid and deep dermis) was detected. In conclusion, the number of PGP- and NGFr-positive fibers were not significantly different in the reactional and post-reactional biopsies in the present study. NGFr-staining of the nerve fibers is different from their PGP-imunoreactivity and the evaluation of the nerve fiber status on an innervated target organ should be carried out choosing markers for both components of nerve fibers (Schwann cells and axons).

Padronização normal das fibras nervosas intraepidérmicas em 30 voluntários saudáveis com PGP 9,5

Moura,Luciana; Oliveira,Acary Souza Bulle; Zanoteli,Edmar; Cardoso,Ricardo; Schmidt,Beny; Gabbai,Alberto Alain
Fonte: Academia Brasileira de Neurologia - ABNEURO Publicador: Academia Brasileira de Neurologia - ABNEURO
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2004 PT
Relevância na Pesquisa
37.11%
O recente método de avaliação das fibras nervosas intraepidérmicas com o PGP 9,5 vem se mostrando de grande utilidade no diagnóstico das neuropatias sensitivas de fibras finas, autonômicas e neuropatias periféricas subclínicas. Devido à variação da técnica relatada na literatura é de fundamental importância uma padronização normal. Estudamos 15 homens e 15 mulheres com média de idade de 34,5 anos. Em todos os voluntários foi realizada biopsia de pele na porção distal da perna. A média da densidade linear das fibras nervosas intraepidérmicas foi 5,3/mm com mediana de 6,0 e desvio padrão de 1,94. Essa técnica possui um grande número de vantagens em relação à biopsia de nervo convencional, é simples, pouco invasiva, reproduzível e pode ser repetida no mesmo paciente para avaliar progressão da neuropatia e possíveis respostas terapêuticas.

P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships

Di Pietro,A.; Dayan,G.; Conseil,G.; Steinfels,E.; Krell,T.; Trompier,D.; Baubichon-Cortay,H.; Jault,J.-M.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/1999 EN
Relevância na Pesquisa
27.52%
Resistance to chemotherapy in cancer cells is mainly mediated by overexpression of P-glycoprotein (Pgp), a plasma membrane ATP-binding cassette (ABC) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. Pgp consists of two homologous halves each containing a transmembrane domain and a cytosolic nucleotide-binding domain (NBD) which contains two consensus Walker motifs, A and B, involved in ATP binding and hydrolysis. The protein also contains an S signature characteristic of ABC transporters. The molecular mechanism of Pgp-mediated drug transport is not known. Since the transporter has an extraordinarily broad substrate specificity, its cellular function has been described as a "hydrophobic vacuum cleaner". The limited knowledge about the mechanism of Pgp, partly due to the lack of a high-resolution structure, is well reflected in the failure to efficiently inhibit its activity in cancer cells and thus to reverse multidrug resistance (MDR). In contrast to the difficulties encountered when studying the full-length Pgp, the recombinant NBDs can be obtained in large amounts as soluble proteins. The biochemical and biophysical characterization of recombinant NBDs is shown here to provide a suitable alternative route to establish structure-function relationships. NBDs were shown to bind ATP and analogues as well as potent modulators of MDR...

The expression of two P-glycoprotein (pgp) genes in transgenic Caenorhabditis elegans is confined to intestinal cells.

Lincke, C R; Broeks, A; The, I; Plasterk, R H; Borst, P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1993 EN
Relevância na Pesquisa
27.64%
P-glycoproteins can cause multidrug resistance in mammalian tumor cells by active extrusion of cytotoxic drugs. The natural function of these evolutionarily conserved, membrane-bound ATP binding transport proteins is unknown. In mammals, P-glycoproteins are abundantly present in organs associated with the digestive tract. We have studied the tissue-specific expression of Caenorhabditis elegans P-glycoprotein genes pgp-1 and pgp-3 by transformation of nematodes with pgp-lacZ gene fusion constructs in which the promoter area of the pgp genes was fused to the coding region of lacZ. Expression of pgp-1 and pgp-3, as inferred from pgp-lacZ transgenic nematodes, was confined to the intestinal cells. The expression patterns of both genes were virtually indistinguishable. Quantitative analysis of pgp mRNA levels during development showed that pgp-1, -2, and -3 were expressed throughout the life cycle of C.elegans, albeit with some variation indicating developmental regulation. The expression of P-glycoprotein genes in intestinal cells is an evolutionarily conserved feature of these genes, consistent with the hypothesis that P-glycoproteins provide a mechanism of protection against environmental toxins.

Modulation of superantigen-induced T-cell deletion by antibody anti-Pgp-1 (CD44).

Ayroldi, E; Cannarile, L; Ricardi, C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1996 EN
Relevância na Pesquisa
27.66%
We examined the effects of anti-Pgp-1 (CD44) antibody on the in vitro deletion of murine CD4 and CD8 single positive T cells induced by Staphylococcal enterotoxin B (SEB). Soluble anti-Pgp-1 antibody enhanced the apoptosis and decreased the proliferation of SEB-responding T cells. In contrast, cross-linked anti-Pgp-1 antibody provided costimulatory signals for the T-cell activation induced by anti-CD3 antibody. Hyaluronic acid (HA), a ligand of Pgp-1, did not affect proliferation and deletion induced by SEB, whereas it mimicked the effects of the cross-linked antibody in anti-CD3-driven proliferation. T-cell Pgp-1 surface expression after 48 hr incubation with SEB was unchanged as compared to unstimulated cells. However, when the memory T cells were established, some V beta 8+ (SEB-specific) T cells Pgp-1low became Pgp-1high, displaying a bimodal character. Moreover, the Pgp-1 increased expression correlated with an increase of Pgp-1 soluble form in the supernatant. These findings suggested that signals following the triggering of the Pgp-1 molecule are important in controlling T-cell survival.

Characterization of a 95,000 molecule on sheep leucocytes homologous to murine Pgp-1 and human CD44.

Mackay, C R; Maddox, J F; Wijffels, G L; Mackay, I R; Walker, I D
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1988 EN
Relevância na Pesquisa
27.68%
The phagocyte glycoprotein-1 (Pgp-1) antigen of mice is a 94,000 MW molecule with a wide tissue distribution, but no attributed function. We produced a monoclonal antibody (mAb) termed 25-32 which recognizes the Pgp-1 molecule of numerous mammalian species, including humans and sheep. Preclearing experiments with I42/5, a rat anti-mouse Pgp-1 mAb that cross-reacts with human Pgp-1, established the specificity of 25-32 for human and sheep Pgp-1. Moreover, an antibody recognizing human CD44, termed F10-44-2, also reacted with the same molecule as that recognized by 25-32 and I42/5, so establishing the co-identity of CD44 and Pgp-1. Within the sheep thymus, Pgp-1 was expressed most strongly by medullary thymocytes and stromal cells, and by small numbers of cells at the subcapsular cortex. Pgp-1 was expressed early in thymic ontogeny; all 35-40-day gestation fetal sheep thymocytes were intensely Pgp-1+, but by 80 days the number of reactive thymocytes had decreased to adult levels. The expression of Pgp-1 on lymphocytes was markedly increased after stimulation with mitogens, or with phorbol esters and ionomycin. The highly conserved nature of Pgp-1 through evolution, its expression on virtually all cell types within the body, and its increased expression on rapidly dividing cells indicate that this molecule mediates an important function...

Function of the Caenorhabditis elegans ABC Transporter PGP-2 in the Biogenesis of a Lysosome-related Fat Storage Organelle

Schroeder, Lena K.; Kremer, Susan; Kramer, Maxwell J.; Currie, Erin; Kwan, Elizabeth; Watts, Jennifer L.; Lawrenson, Andrea L.; Hermann, Greg J.
Fonte: The American Society for Cell Biology Publicador: The American Society for Cell Biology
Tipo: Artigo de Revista Científica
Publicado em /03/2007 EN
Relevância na Pesquisa
27.64%
Caenorhabditis elegans gut granules are intestine specific lysosome-related organelles with birefringent and autofluorescent contents. We identified pgp-2, which encodes an ABC transporter, in screens for genes required for the proper formation of gut granules. pgp-2(−) embryos mislocalize birefringent material into the intestinal lumen and are lacking in acidified intestinal V-ATPase–containing compartments. Adults without pgp-2(+) function similarly lack organelles with gut granule characteristics. These cellular phenotypes indicate that pgp-2(−) animals are defective in gut granule biogenesis. Double mutant analysis suggests that pgp-2(+) functions in parallel with the AP-3 adaptor complex during gut granule formation. We find that pgp-2 is expressed in the intestine where it functions in gut granule biogenesis and that PGP-2 localizes to the gut granule membrane. These results support a direct role of an ABC transporter in regulating lysosome biogenesis. Previously, pgp-2(+) activity has been shown to be necessary for the accumulation of Nile Red–stained fat in C. elegans. We show that gut granules are sites of fat storage in C. elegans embryos and adults. Notably, levels of triacylglycerides are relatively normal in animals defective in the formation of gut granules. Our results provide an explanation for the loss of Nile Red–stained fat in pgp-2(−) animals as well as insight into the specialized function of this lysosome-related organelle.

Development of Idarubicin and Doxorubicin Solid Lipid Nanoparticles to Overcome Pgp–mediated Multiple Drug Resistance in Leukemia

Ma, Ping; Dong, Xiaowei; Swadley, Courtney L.; Gupte, Anshul; Leggas, Markos; Ledebur, Harry C.; Mumper, Russell J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/2009 EN
Relevância na Pesquisa
27.52%
The objectives of these studies were to investigate and compare solid lipid nanoparticles (SLNs) of two anthracyclines, idarubicin (IDA) and doxorubicin (DOX), against Pgp-mediated multiple drug resistance (MDR.) in-vitro and in-vivo using different human and murine cancer cell models. IDA and DOX SLNs were developed from warm microemulsion precursors comprising emulsifying wax as the oil phase, and polyoxyl 20-stearyl ether (Brij 78) and D-alpha-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) as the surfactants. Anionic ion-pairing agents, sodium taurodeoxycholate (STDC) and sodium tetradecyl sulfate (STS), were used to neutralize the charges of the cationic anthracyclines and enhance entrapment of the drugs in the SLN. The in-vitro cytotoxicity results showed that the IC50 value of DOX NPs was 9-fold lower than that of free DOX solution in resistant P388/ADR cell line. In contrast, free IDA had comparable IC50 values as IDA NPs in Pgp-overexpressing P388/ADR and HCT-15 cells. In the in-vivo P388/ADR leukemia mouse model, the median survival time of DOX NPs was significantly greater than that of free DOX, and controls. In contrast, free IDA was equally as effective as IDA NPs in P388 and Pgp-overexpressing HCT-15 mouse tumor models. The cell uptake of IDA formulated as free IDA and IDA NPs was comparable in Pgp-overexpressing cells. In conclusion...

The cystic-fibrosis-associated ΔF508 mutation confers post-transcriptional destabilization on the C. elegans ABC transporter PGP-3

He, Liping; Skirkanich, Jennifer; Moronetti, Lorenza; Lewis, Rosemary; Lamitina, Todd
Fonte: The Company of Biologists Limited Publicador: The Company of Biologists Limited
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.52%
Membrane proteins make up ∼30% of the proteome. During the early stages of maturation, this class of proteins can experience localized misfolding in distinct cellular compartments, such as the cytoplasm, endoplasmic reticulum (ER) lumen and ER membrane. ER quality control (ERQC) mechanisms monitor folding and determine whether a membrane protein is appropriately folded or is misfolded and warrants degradation. ERQC plays crucial roles in human diseases, such as cystic fibrosis, in which deletion of a single amino acid (F508) results in the misfolding and degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl– channel. We introduced the ΔF508 mutation into Caenorhabditis elegans PGP-3, a 12-transmembrane ABC transporter with 15% identity to CFTR. When expressed in intestinal epithelial cells, PGP-3wt was stable and efficiently trafficked to the apical plasma membrane through a COPII-dependent mechanism. However, PGP-3ΔF508 was post-transcriptionally destabilized, resulting in reduced total and apical membrane protein levels. Genetic or physiological activation of the osmotic stress response pathway, which causes accumulation of the chemical chaperone glycerol, stabilized PGP-3ΔF508. Efficient degradation of PGP-3ΔF508 required the function of several C. elegans ER-associated degradation (ERAD) homologs...

PGP expression in Cooperia oncophora before and after ivermectin selection

Areskog, Marlene; Engström, Annie; Tallkvist, Jonas; von Samson-Himmelstjerna, Georg; Höglund, Johan
Fonte: Springer Berlin Heidelberg Publicador: Springer Berlin Heidelberg
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.6%
The aim of this study was to investigate genetic selection and P-glycoprotein (PGP) expression in three different isolates of Cooperia oncophora before treatment and after ivermectin (IVM) injection. Adult parasites were recovered from nine calves experimentally infected with the isolates represented by one IVM susceptible laboratory isolate, and two field isolates showing signs of phenotypic macrocyclic lactone resilience according to the faecal egg count reduction test. Five males and five females per isolate were examined both pre- and post-IVM treatment giving a total of 60 worms. A sequence from C. oncophora (Con-pgp) was identified, showing 83 % similarity to Pgp-9 of Caenorhabditis elegans. Primers specific to putative Con-pgp-9 mRNA were designed, generating a 153-bp PCR product. Total RNA was prepared from all worms, and Con-pgp-9 expression was measured by quantitative real-time reverse transcription PCR. Our results showed that mean PGP concentrations were four to five times higher in female as compared to male worms. No significant differences in gene expression between experimental groups pre- and post-IVM selection were detected. However, PGP gene expression tended to be increased by IVM treatment in male worms (p = 0.091)...

The Strong In Vivo Anti-Tumor Effect of the UIC2 Monoclonal Antibody Is the Combined Result of Pgp Inhibition and Antibody Dependent Cell-Mediated Cytotoxicity

Szalóki, Gábor; Krasznai, Zoárd T.; Tóth, Ágnes; Vízkeleti, Laura; Szöllősi, Attila G.; Trencsényi, György; Lajtos, Imre; Juhász, István; Krasznai, Zoltán; Márián, Teréz; Balázs, Margit; Szabó, Gábor; Goda, Katalin
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 19/09/2014 EN
Relevância na Pesquisa
27.64%
P-glycoprotein (Pgp) extrudes a large variety of chemotherapeutic drugs from the cells, causing multidrug resistance (MDR). The UIC2 monoclonal antibody recognizes human Pgp and inhibits its drug transport activity. However, this inhibition is partial, since UIC2 binds only to 10–40% of cell surface Pgps, while the rest becomes accessible to this antibody only in the presence of certain substrates or modulators (e.g. cyclosporine A (CsA)). The combined addition of UIC2 and 10 times lower concentrations of CsA than what is necessary for Pgp inhibition when the modulator is applied alone, decreased the EC50 of doxorubicin (DOX) in KB-V1 (Pgp+) cells in vitro almost to the level of KB-3-1 (Pgp-) cells. At the same time, UIC2 alone did not affect the EC50 value of DOX significantly. In xenotransplanted severe combined immunodeficient (SCID) mice co-treated with DOX, UIC2 and CsA, the average weight of Pgp+ tumors was only ∼10% of the untreated control and in 52% of these animals we could not detect tumors at all, while DOX treatment alone did not decrease the weight of Pgp+ tumors. These data were confirmed by visualizing the tumors in vivo by positron emission tomography (PET) based on their increased 18FDG accumulation. Unexpectedly...

The matrikine N-α-PGP couples extracellular matrix fragmentation to endothelial permeability

Hahn, Cornelia S.; Scott, David W.; Xu, Xin; Roda, Mojtaba Abdul; Payne, Gregory A.; Wells, J. Michael; Viera, Liliana; Winstead, Colleen J.; Bratcher, Preston; Sparidans, Rolf W.; Redegeld, Frank A.; Jackson, Patricia L.; Folkerts, Gert; Blalock, J. Edwi
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
27.52%
The compartmentalization and transport of proteins and solutes across the endothelium is a critical biologic function altered during inflammation and disease, leading to pathology in multiple disorders. The impact of tissue damage and subsequent extracellular matrix (ECM) fragmentation in regulating this process is unknown. We demonstrate that the collagen-derived matrikine acetylated proline-glycine-proline (N-α-PGP) serves as a critical regulator of endothelial permeability. N-α-PGP activates human endothelial cells via CXC-chemokine receptor 2 (CXCR2), triggering monolayer permeability through a discrete intracellular signaling pathway. In vivo, N-α-PGP induces local vascular leak after subcutaneous administration and pulmonary vascular permeability after systemic administration. Furthermore, neutralization of N-α-PGP attenuates lipopolysaccharide-induced lung leak. Finally, we demonstrate that plasma from patients with acute respiratory distress syndrome (ARDS) induces VE-cadherin phosphorylation in human endothelial cells, and this activation is attenuated by N-α-PGP blockade with a concomitant improvement in endothelial monolayer impedance. These results identify N-α-PGP as a novel ECM-derived matrikine regulating paracellular permeability during inflammatory disease and demonstrate the potential to target this ligand in various disorders characterized by excessive matrix turnover and vascular leak such as ARDS.

Prevention of multidrug resistance (MDR) in osteosarcoma by NSC23925

Yang, X; Yang, P; Shen, J; Osaka, E; Choy, E; Cote, G; Harmon, D; Zhang, Z; Mankin, H; Hornicek, F J; Duan, Z
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
27.52%
Background: The major limitation to the success of chemotherapy in osteosarcoma is the development of multidrug resistance (MDR). Preventing the emergence of MDR during chemotherapy treatment has been a high priority of clinical and investigational oncology, but it remains an elusive goal. The NSC23925 has recently been identified as a novel and potent MDR reversal agent. However, whether NSC23925 can prevent the development of MDR in cancer is unknown. Therefore, this study aims to evaluate the effects of NSC23925 on prevention of the development of MDR in osteosarcoma. Methods: Human osteosarcoma cell lines U-2OS and Saos were exposed to increasing concentrations of paclitaxel alone or in combination with NSC23925 for 6 months. Cell sublines selected at different time points were evaluated for their drug sensitivity, drug transporter P-glycoprotein (Pgp) expression and activity. Results: We observed that tumour cells selected with increasing concentrations of paclitaxel alone developed MDR with resistance to paclitaxel and other Pgp substrates, whereas cells cultured with paclitaxel–NSC23925 did not develop MDR and cells remained sensitive to chemotherapeutic agents. Paclitaxel-resistant cells showed high expression and activity of the Pgp...

A "Trojan horse" strategy to reverse drug-resistance in brain tumors

Pinzón Daza, Martha Leonor
Fonte: Facultad de Ciencias Naturales y Matemáticas Publicador: Facultad de Ciencias Naturales y Matemáticas
Tipo: info:eu-repo/semantics/doctoralThesis; info:eu-repo/semantics/acceptedVersion Formato: application/pdf
Publicado em 21/07/2014 SPA
Relevância na Pesquisa
27.75%
Los gliomas malignos representan una de las formas más agresivas de los tumores del sistema nervioso central (SNC). De acuerdo con la clasificación de los tumores cerebrales de la Organización Mundial de la Salud (OMS), los astrocitomas han sido categorizados en cuatro grados, determinados por la patología subyacente. Es así como los gliomas malignos (o de alto grado) incluyen el glioma anaplásico (grado III) así como el glioblastoma multiforme (GBM, grado IV),estos últimos los más agresivos con el peor pronóstico (1). El manejo terapéutico de los tumores del SNC se basa en la cirugía, la radioterapia y la quimioterapia, dependiendo de las características del tumor, el estadio clínico y la edad (2),(3), sin embargo ninguno de los tratamientos estándar es completamente seguro y compatible con una calidad de vida aceptable (3), (4). En general, la quimioterapia es la primera opción en los tumores diseminados, como el glioblastoma invasivo y el meduloblastoma de alto riesgo o con metástasis múltiple, pero el pronóstico en estos pacientes es muy pobre (2),(3). Solamente nuevas terapias dirigidas (2) como las terapias anti-angiogénicas (4); o terapias génicas muestran un beneficio real en grupos limitados de pacientes con defectos moleculares específicos conocidos (4). De este modo...

From Pretty Good To Great: Enhancing PGP using Bitcoin and the Blockchain

Wilson, Duane; Ateniese, Giuseppe
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
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27.52%
PGP is built upon a Distributed Web of Trust in which the trustworthiness of a user is established by others who can vouch through a digital signature for that particular identity. Preventing its wholesale adoption are a number of inherent weaknesses to include (but not limited to) the following: 1) Trust Relationships are built on a subjective honor system, 2) Only first degree relationships can be fully trusted, 3) Levels of trust are difficult to quantify with actual values, and 4) Issues with the Web of Trust itself (Certification and Endorsement). Although the security that PGP provides is proven to be reliable, it has largely failed to garner large scale adoption. In this paper, we propose several novel contributions to address the aforementioned issues with PGP and associated Web of Trust. To address the subjectivity of the Web of Trust, we provide a new certificate format based on Bitcoin which allows a user to verify a PGP certificate using Bitcoin identity-verification transactions - forming first degree trust relationships that are tied to actual values (i.e., number of Bitcoins transferred during transaction). Secondly, we present the design of a novel Distributed PGP key server that leverages the Bitcoin transaction blockchain to store and retrieve Bitcoin-Based PGP certificates. Lastly...

An?lise de componentes principais de caracter?sticas morfofuncionais, curva e alometria de crescimento de bovinos da ra?a Guzer? em prova de ganho em peso a pasto; Principal components analysis of morphological and functional traits, curve and allometric growth in cattle Guzera evidence of weight gain on pasture

Sousa, Ricardo Costa
Fonte: UFVJM Publicador: UFVJM
Tipo: Dissertação de Mestrado
POR
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27.57%
Foi desenvolvida uma Prova de Ganho em Peso (PGP) a pasto com animais da ra?a Guzer? na fazenda Meleiro no munic?pio Curvelo ? MG, oficializada pela Associa??o Brasileira dos Criadores de Zebu (ABCZ). Foram avaliados 45 machos da ra?a Guzer? rec?m-desmamados, com peso e idade iniciais m?dios e desvio padr?o de 219,9 ? 38,05 kg e 325,8 ? 28,0 dias, respectivamente. Na prova os animais consumiram pastagens de Brachiaria brizantha e suplementa??o m?ltipla, receberam tratamento sanit?rio e foram mantidos em condi??es uniformes de manejo por um per?odo de 294 dias. As avalia??es aconteceram a cada 56 dias. A partir desta PGP buscou-se avaliar uma fun??o n?o-linear que melhor descrevesse a curva de crescimento dos animais, estimar o desenvolvimento relativo da ?rea de olho de lombo, medida por ultrassonografia, da circunfer?ncia escrotal e de medidas morfom?tricas em rela??o ao peso vivo de bovinos da ra?a Guzer? atrav?s do estudo do crescimento alom?trico; avaliou-se tamb?m um conjunto de caracter?sticas, por meio de an?lise de componentes principais, visando identificar as caracter?sticas que representam a maior parte da varia??o fenot?pica. As caracter?sticas avaliadas por componentes principais foram: peso aos 205 dias (P205), peso aos 365 dias (P365)...