Página 1 dos resultados de 17196 itens digitais encontrados em 0.036 segundos

Avaliação da resistência do HIV-1 às drogas anti-retrovirais em 150 pacientes em interrupção terapêutica por mais de seis meses; Evaluation of HIV-1 drug resistance among 150 patients that were in therapeutic interruption for more than 6 months

Kalmar, Erika Maria do Nascimento
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 31/08/2007 PT
Relevância na Pesquisa
66.09%
INTRODUÇÃO: A mudança nos critérios de introdução das drogas anti- retrovirais, assim como a dificuldade na manutenção da terapia anti-retroviral de alta eficácia, tem levado à descontinuação da terapêutica por longo período de tempo em alguns pacientes infectados pelo Vírus da Imunodeficiência Humana Adquirida-Tipo 1 (HIV-1). O objetivo deste estudo foi a caracterização dos fatores que levam à interrupção terapêutica e a avaliação da persistência da resistência aos anti-retrovirais após a interrupção da terapia anti-retroviral. MÉTODOS: Foram incluídos na pesquisa 150 pacientes de dois serviços de atendimento ambulatorial de atenção a pacientes infectados pelo HIV-1 da cidade de São Paulo, os quais se achavam em interrupção terapêutica havia pelo menos 6 meses. Os pacientes foram submetidos a um questionário e houve consulta aos prontuários. Foi realizada coleta de amostra de sangue para teste de genotipagem. O DNA pró-viral foi amplificado e seqüenciado para a região da protease e transcriptase reversa do vírus. As seqüências foram analisadas por meio do algoritmo de Stanford, sendo consideradas resistentes as amostras com resultado parcial ou completo de resistência a pelo menos uma droga. RESULTADOS: Dos 150 pacientes...

Padronização de tecnicas moleculares para o estudo da resistencia a drogas antiretrovirais em crianças infectadas pelo virus da imunodeficiencia humana tipo 1 (HIV-1) via perinatal; Antiretroviral drug resistance in infected Brazilian children by human immunodeficiency virus type 1

Beatriz Aparecida Passos Bismara
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 30/08/2006 PT
Relevância na Pesquisa
66.12%
Investigamos a presença de mutações em crianças infectadas verticalmente pelo vírus da Imunodeficiência Humana tipo 1 (HIV-1) que conferem resistência aos agentes antiretrovirais. Amostras de sangue periférico foram coletadas de sessenta e seis pacientes em seguimento no do Ambulatório de Pediatria do Hospital das Clínicas da Universidade Estadual de Campinas. A partir de leucócitos destas amostras foi extraído o DNA, após diversas lavagens e precipitações. Foi preparado um Mix para 20 reações contendo 100µl de Buffer (50 mM de cloreto de potássio; 20 mM de Tris-HCl - pH 8,4); 100 µl de cloreto de magnésio (25mM); 12µl da mistura desoxirribonucléica - dNTPs (dATP, dGTP, dCTP; dTTP) a 25mM, 10µl de cada ?primer? (25pmoles/µl); 0,5µl de Taq DNA polimerase e 0,5 µl do DNA a ser estudado, para a realização da PCR. As condições da reação foram: Desnaturação: 95ºC - 3 minutos; Anelamento: 55ºC ? 1 minuto; Extensão: 72ºC - 1 minuto (3 ciclos). Desnaturação: 95ºC ? 1 minuto; Anelamento: 55ºC ? 45 segundos; Extensão: 72ºC ? 1 minuto e Extensão final: 72ºC por 10 minutos (35 ciclos). As bandas foram visulizadas em gel de agarose 1%, obtendo-se uma banda de 1008 pares de bases. Os produtos selecionados foram submetidos a seguinte reação de seqüenciamento: 1...

Molecular Genetic Analysis of Multi-drug Resistance in Indian Isolates of Mycobacterium tuberculosis

Siddiqi,Noman; Shamim,Md.; Jain,NK; Rattan,Ashok; Amin,Amol; Katoch,VM; Sharma,SK; Hasnain,Seyed E
Fonte: Instituto Oswaldo Cruz, Ministério da Saúde Publicador: Instituto Oswaldo Cruz, Ministério da Saúde
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/1998 EN
Relevância na Pesquisa
66.08%
A total of 116 isolates from patients attending the out-patient department at the All India Institute of Medical Sciences, New Delhi and the New Delhi Tuberculosis Centre, New Delhi, India were collected. They were analyzed for resistance to drugs prescribed in the treatment for tuberculosis. The drug resistance was initially determined by microbiological techniques. The Bactec 460TB system was employed to determine the type and level of resistance in each isolate. The isolates were further characterized at molecular level. The multi-drug loci corresponding to rpo b, gyr A, kat G were studied for mutation(s) by the polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) technique. The SSCP positive samples were sequenced to characterize the mutations in rpo b, and gyr A loci. While previously reported mutations in the gyr A and rpo b loci were found to be present, several novel mutations were also scored in the rpo b locus. Interestingly, analysis of the gyr A locus showed the presence of point mutation(s) that could not be detected by PCR-SSCP. Furthermore, rifampicin resistance was found to be an important marker for checking multi-drug resistance (MDR) in clinical isolates of Mycobacterium tuberculosis. This is the first report on molecular genetic analysis of MDR tuberculosis one from India...

Drug Resistance Patterns among Hospitalized Tuberculous Patients in Rio de Janeiro, Brazil, 1993-1994

Fandinho,FCO; Kritski,AL; Hofer,C; Conde Jr,H; Ferreira,RMC; Silva,MG; Fonseca,LS
Fonte: Instituto Oswaldo Cruz, Ministério da Saúde Publicador: Instituto Oswaldo Cruz, Ministério da Saúde
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/07/1999 EN
Relevância na Pesquisa
66.05%
The purpose of this study was to analyze the prevalence and risk factors for drug resistance among hospitalized patients in two tertiary care centers, an acquired immunodeficiency syndrome (AIDS) reference center and a sanatorium, in Rio de Janeiro, Brazil. From 1993-1994, 389 patients were diagnosed as having tuberculosis (TB). Isolates from 265 patients were tested for in vitro susceptibility to rifampin and isoniazid. Resistance to one or more drugs was detected in 44 patients (16.6%) and was significantly more common among recurrent cases in both hospitals (p=0.03 in the AIDS center and p=0.001 in the sanatorium). Twenty seven patients (10.2%) had isolates resistant to both isoniazid and rifampin. Multi-drug resistance was associated with human immunodeficiency virus (HIV) infection among patients who had never been treated for TB. In conclusion, drug-resistant TB is high in hospitalized patients in Rio de Janeiro, especially among HIV infected patients. Therefore, measures to control TB and prevent nosocomial transmission need urgently to be set up in the Brazilian hospitals.

Human immunodeficiency virus type 1: drug resistance in treated and untreated Brazilian children

Simonetti,SRR; Schatzmayr,HG; Simonetti,JP
Fonte: Instituto Oswaldo Cruz, Ministério da Saúde Publicador: Instituto Oswaldo Cruz, Ministério da Saúde
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2003 EN
Relevância na Pesquisa
66.05%
Twenty-two vertically human immunodeficiency virus type 1 (HIV-1) infected Brazilian children were studied for antiretroviral drug resistance. They were separated into 2 groups according to the administration of antiretroviral therapy into those who presented disease symptoms or without symptoms and no therapy. Viral genome sequencing reactions were loaded on an automated DNA sampler (TruGene, Visible Genetics) and compared to a database of wild type HIV-1. In the former group 8 of 12 children presented isolates with mutations conferring resistance to protease inhibitors (PIs), 7 presented isolates resistant to nucleoside reverse transcriptase inhibitors (NRTIs) and 2 presented isolates resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Ten children were included in the antiretroviral naïve group. Eight were susceptible to NRTIs and all of them were susceptible to PIs; one presented the V108I mutation, which confers low-level resistance to NNRTIs. The data report HIV mutant isolates both in treated and untreated infants. However, the frequency and the level of drug resistance were more frequent in the group receiving antiretroviral therapy, corroborating the concept of selective pressure acting on the emergence of resistant viral strains. The children who presented alterations at polymorphism sites should be monitored for the development of additional mutations occurring at relevant resistance codons.

HIV-1 subtypes and mutations associated to antiretroviral drug resistance in human isolates from Central Brazil

Cerqueira,Daniela Marreco; Ramalho,Eduardo Dias; Oliveira,Claudiner Pereira; Silva,Ruiter Roberto; Franchini,Miriam; Felipe,Maria Sueli Soares; Martins,Cláudia Renata Fernandes
Fonte: Sociedade Brasileira de Microbiologia Publicador: Sociedade Brasileira de Microbiologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2004 EN
Relevância na Pesquisa
66.09%
The detection of polymorphisms associated to HIV-1 drug-resistance and genetic subtypes is important for the control and treatment of HIV-1 disease. Drug pressure selects resistant variants that carry mutations in the viral reverse transcriptase (RT) and protease (PR) genes. For a contribution to the public health authorities in planning the availability of therapeutic treatment, we therefore described the genetic variability, the prevalence of mutations associated to drug resistance and the antiretroviral resistance profile in HIV-1 isolates from infected individuals in Central Brazil. Nineteen HIV-1 RNA samples from a Public Health Laboratory of the Federal District were reversely transcribed and cDNAs were amplified by nested PCR. One fragment of 297 bp coding the entire protease gene, and another of 647 bp, corresponding to the partial RT gene (codons 19-234), were obtained. Automated sequencing and BLAST analysis revealed the presence of 17 B and 2 F1 HIV-1 subtypes. The amino acid sequences were analyzed for the presence of resistance-associated mutations. A total of 6 PR mutations, 2 major and 4 accessory, and 8 RT mutations related to drug resistance were found. Our data suggest a high prevalence of HIV-1 B subtype in the studied population of Federal District as well as the presence of genetically-resistant strains in individuals failing treatment.

Multi drug resistance in strong biofilm forming clinical isolates of Staphylococcus epidermidis

Sahal,Gulcan; Bilkay,Isil Seyis
Fonte: Sociedade Brasileira de Microbiologia Publicador: Sociedade Brasileira de Microbiologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2014 EN
Relevância na Pesquisa
66.12%
Staphylococcus epidermidis which exists in healthy human skin as a commensal inhabitant is also an important pathogen forming biofilms on many surfaces and recently, increased resistance traits were suggested to be acquired in biofilm environments. In this study; clinical Prevalences, antibiotic resistances and biofilm formations of S. epidermidis strains were determined and comparison of all these findings with each other was carried out in order to take precautions against them and figure out if high biofilm forming S. epidermidis strains display multi drug resistance. According to our results; samples of wound and blood were the most S. epidermidis isolated clinical materials (40%; 35%) and cardiothoracic surgery was the most S. epidermidis observed service unit. All of these strains were sensitive to vancomycin, however 65% of them showed resistance to all β-lactam antibiotics (Penicillin, Oxacillin, Amoxicilin / Clavulonic acid), used in this study and 60% of all S. epidermidis strains were found as multi drug resistant. When the results of strong biofilm forming S. epidermidis strains are examined; they were isolated from sample of blood and service unit of cardiovascular surgery in highest frequency and 80% of them were β-lactam resistant whereas 100% of them were multi drug resistant. One of these multi drug resistant strains which was resistant to maximum amount of different antimicrobial classes...

Oral Antiretroviral Drugs as Public Health Tools for HIV Prevention: Global Implications for Adherence, Drug Resistance, and the Success of HIV Treatment Programs

Gupta, Ravindra K.; Wainberg, Mark A.; Brun-Vezinet, Francoise; Gatell, Jose M.; Albert, Jan; Sönnerborg, Anders; Nachega, Jean B.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Publicado em 15/06/2013 EN
Relevância na Pesquisa
66.08%
Recent data from studies on treatment as prevention (TasP) and preexposure prophylaxis (PrEP) show that antiretroviral drugs can be used in prevention, as well as in treatment. The movement from first-generation antiretroviral therapy (ART) coformulations based on thymidine analogues to second-generation ART coformulations based on tenofovir may coincide with future prevention strategies that also use tenofovir/emtricitabine, raising concerns regarding drug resistance. In published studies, failure of prophylaxis was associated with poor adherence and low plasma drug levels. Although rates of drug resistance in cases of failed prevention was low, regular human immunodeficiency virus (HIV) testing was undertaken in these clinical trials. Although legitimate concerns exist about ART adherence and drug resistance associated with PrEP and TasP in real-world settings, efforts to curb the continuing HIV epidemic through use of these novel prevention strategies should move forward because the development and approval of newer drugs reserved for prevention might take many more years. Efforts must be made to monitor ART adherence and to intervene through counseling and other means in order to optimize adherence and retention in care, whenever necessary. Finally...

Drug Resistance Mutations for Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update

Bennett, Diane E.; Camacho, Ricardo J.; Otelea, Dan; Fleury, Hervé; Kiuchi, Mark; Heneine, Walid; Kantor, Rami; Jordan, Michael R.; Schapiro, Jonathan M.; Vandamme, Anne-Mieke; Sandstrom, Paul; van de Vijver, David; Rhee, Soo-Yon; Liu, Tommy F.; Pillay,
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
66.17%
Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January 2007, we outlined criteria for developing a list of mutations for drug-resistance surveillance and compiled a list of 80 RT and protease mutations meeting these criteria (surveillance drug resistance mutations; SDRMs). Since January 2007, several new drugs have been approved and several new drug-resistance mutations have been identified. In this paper, we follow the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted drug resistance. The updated SDRM list has 93 mutations including 34 NRTI-resistance mutations at 15 RT positions, 19 NNRTI-resistance mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease positions.

Rapid, Field-Deployable Method for Genotyping and Discovery of Single-Nucleotide Polymorphisms Associated with Drug Resistance in Plasmodium falciparum

Daniels, Rachel Fath; Ndiaye, Daouda; Wall, Mikeal; McKinney, Jason; Séne, Papa Diogoye; Sabeti, Pardis Christine; Volkman, Sarah K.; Mboup, Souleymane; Wirth, Dyann Fergus
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
66.06%
Despite efforts to reduce malaria morbidity and mortality, drug-resistant parasites continue to evade control strategies. Recently, emphasis has shifted away from control and toward regional elimination and global eradication of malaria. Such a campaign requires tools to monitor genetic changes in the parasite that could compromise the effectiveness of antimalarial drugs and undermine eradication programs. These tools must be fast, sensitive, unambiguous, and cost-effective to offer real-time reports of parasite drug susceptibility status across the globe. We have developed and validated a set of genotyping assays using high-resolution melting (HRM) analysis to detect molecular biomarkers associated with drug resistance across six genes in Plasmodium falciparum. We improved on existing technical approaches by developing refinements and extensions of HRM, including the use of blocked probes (LunaProbes) and the mutant allele amplification bias (MAAB) technique. To validate the sensitivity and accuracy of our assays, we compared our findings to sequencing results in both culture-adapted lines and clinical isolates from Senegal. We demonstrate that our assays (i) identify both known and novel polymorphisms, (ii) detect multiple genotypes indicative of mixed infections...

Changes in drug sensitivity and anti-malarial drug resistance mutations over time among Plasmodium falciparum parasites in Senegal

Van Tyne, Daria; Dieye, Baba; Valim, Clarissa; Daniels, Rachel F; Sène, Papa Diogoye; Lukens, Amanda K; Ndiaye, Mouhamadou; Bei, Amy K; Ndiaye, Yaye Die; Hamilton, Elizabeth J; Ndir, Omar; Mboup, Souleymane; Volkman, Sarah K; Wirth, Dyann F; Ndiaye, Daou
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
66.16%
Background: Malaria treatment efforts are hindered by the rapid emergence and spread of drug resistant parasites. Simple assays to monitor parasite drug response in direct patient samples (ex vivo) can detect drug resistance before it becomes clinically apparent, and can inform changes in treatment policy to prevent the spread of resistance. Methods: Parasite drug responses to amodiaquine, artemisinin, chloroquine and mefloquine were tested in approximately 400 Plasmodium falciparum malaria infections in Thiès, Senegal between 2008 and 2011 using a DAPI-based ex vivo drug resistance assay. Drug resistance-associated mutations were also genotyped in pfcrt and pfmdr1. Results: Parasite drug responses changed between 2008 and 2011, as parasites became less sensitive to amodiaquine, artemisinin and chloroquine over time. The prevalence of known resistance-associated mutations also changed over time. Decreased amodiaquine sensitivity was associated with sustained, highly prevalent mutations in pfcrt, and one mutation in pfmdr1 – Y184F – was associated with decreased parasite sensitivity to artemisinin. Conclusions: Directly measuring ex vivo parasite drug response and resistance mutation genotyping over time are useful tools for monitoring parasite drug responses in field samples. Furthermore...

Drug Resistance in Cancer: An Overview

Housman, Genevieve; Byler, Shannon; Heerboth, Sarah; Lapinska, Karolina; Longacre, Mckenna; Snyder, Nicole; Sarkar, Sibaji
Fonte: MDPI Publicador: MDPI
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
66.13%
Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study.

The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells

Mumenthaler, Shannon M; Foo, Jasmine; Choi, Nathan C; Heise, Nicholas; Leder, Kevin; Agus, David B; Pao, William; Michor, Franziska; Mallick, Parag
Fonte: Libertas Academica Publicador: Libertas Academica
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
66.09%
Therapeutic resistance arises as a result of evolutionary processes driven by dynamic feedback between a heterogeneous cell population and environmental selective pressures. Previous studies have suggested that mutations conferring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) cells lower the fitness of resistant cells relative to drug-sensitive cells in a drug-free environment. Here, we hypothesize that the local tumor microenvironment could influence the magnitude and directionality of the selective effect, both in the presence and absence of a drug. Using a combined experimental and computational approach, we developed a mathematical model of preexisting drug resistance describing multiple cellular compartments, each representing a specific tumor environmental niche. This model was parameterized using a novel experimental dataset derived from the HCC827 erlotinib-sensitive and -resistant NSCLC cell lines. We found that, in contrast to in the drug-free environment, resistant cells may hold a fitness advantage compared to parental cells in microenvironments deficient in oxygen and nutrients. We then utilized the model to predict the impact of drug and nutrient gradients on tumor composition and recurrence times...

Primary HIV-1 drug resistance in the c-terminal domains of viral reverse transcriptase among drug-na??ve patients from southern Brazil

Santos, Andre Ferreira dos; Silveira, Jussara Maria; Muniz, Claudia Priscila Ramos; Tornatore, Michele; G??es, L??via Ramos; Mendoza-Sassi, Ra??l Andr??s; Martinez, Ana Maria Blanco; Tupinamb??s, Una??; Greco, Dirceu Bartolomeu; Soares, Marcelo Alves
Fonte: Universidade Federal do Rio Grande Publicador: Universidade Federal do Rio Grande
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
66.09%
Background: Major and accessory drug resistance mutations have been recently characterized in the Cterminal RT subdomains of HIV-1, connection and RNase H. However, their presence in treatment-na??ve patients infected with HIV-1 non-B subtypes remains largely unknown. Objectives: To characterize the patterns of primary resistance at the C-terminal RT subdomains of HIV-1 infecting subjects in the southern region of Brazil, where HIV-1 subtypes B and C co-circulate. Study design: Plasma viral RNA was extracted from patients recently diagnosed for HIV infection (2005???2008). The protease and reverse transcriptase regions were PCR-amplified and sequenced. Infecting HIV subtypes were assigned by phylogenetic inference and drug resistance mutations were determined following the IAS consensus and recent reports on C-terminal RT mutations. Results: The major mutation to NNRTI T369I/V was found in 1.8% of patients, while A376S was present in another 8.3%. In the RNase H domain, the compensatory mutation D488E was more frequently observed in subtype C than in subtype B (p = 0.038), while the inverse was observed for mutation Q547K (p < 0.001). The calculated codon genetic barrier showed that 22% of subtype B isolates, but no subtype C, carried T360...

Evaluation and Characterization of Influenza Antiviral Drug Resistance in Portugal: Major Results and Achievements of a 5-Year Study

Correia, V.; Santos, L.A.; Giria, M.; Rebelo-de-Andrade, H.
Fonte: Instituto Nacional de Saúde Doutor Ricardo Jorge Publicador: Instituto Nacional de Saúde Doutor Ricardo Jorge
Tipo: Conferência ou Objeto de Conferência
Publicado em /10/2012 ENG
Relevância na Pesquisa
66.07%
In 2007 started to be carried out for the first time in Portugal a study focused on influenza antiviral drug resistance. Three main objectives were established:(1)to determine the antiviral profile of influenza viruses to oseltamivir, zanamivir and amantadine;(2)to determine and monitor the baseline level of susceptibility along winter seasons and for each influenza sub(type);(3)to analyse and characterize the whole genome of viruses that showed phenotypic levels of inhibition to neuraminidase inhibitors(NAIs). NAIs profile was determined phenotypically, using a fluorescence MUNUNA assay, and genotypically by NA and HA sequencing. A total of 340 seasonal viruses(117 A(H3N2),93 A(H1N1),130 B) were tested for oseltamivir and of 297(112 A(H3N2),68 A(H1N1),117 B) for zanamivir. Additionally, 142 A(H1N1)pdm09 viruses were evaluated for both NAIs. Whole genome sequencing was performed in 27 of the A(H1N1)pdm09 viruses. Amantadine profile was determined through M2 pyrosequencing or conventional sequencing in a total of 205 seasonal A viruses(138 A(H3N2),84 A(H1N1)) and of 117 A(H1N1)pdm09 viruses. Main results are: -Resistance to oseltamivir in 27 A(H1N1) seasonal viruses(29%,N=93) from 2007/2008 and 2008/2009 and in one A(H1N1)pdm09 virus(0.7%...

The multifactorial nature of hypoxia-induced drug resistance in cancer: involvement of hypoxia-inducible factor 1

Sullivan, RICHARD
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado Formato: 13259048 bytes; application/pdf
EN; EN
Relevância na Pesquisa
66.12%
The development of intratumoral hypoxia is associated with resistance to therapy in many forms of human cancer, and pre-exposure of tumor cells to hypoxia confers multidrug resistance. Research over the last several years has led to considerable advances in the understanding of the cellular response to oxygen deprivation, however the hypoxia-induced mechanisms that contribute to the chemoresistance phenotype are still not well understood. Recent studies have identified hypoxia-inducible factor 1 (HIF-1), a master transcriptional regulator of oxygen homeostasis, as an important mediator of hypoxia-induced chemoresistance in cancer cells. The research described in this thesis confirms these findings and demonstrates HIF-1 is required for hypoxia-induced resistance to doxorubicin and etoposide in human tumor cells. In addition, novel findings revealed that hypoxia-induced drug resistance occurred independently of changes in the apoptotic fraction and was associated with decreased drug-induced senescence. DNA damage measured at the single-cell level revealed that the increase in survival correlated well with a HIF-1-dependent decrease in etoposide-induced DNA strand breaks, providing direct evidence that exposure of tumor cells to hypoxia leads to protection against some forms of drug-induced DNA damage. Characterization of several classical mechanisms of drug resistance upstream of DNA damage identified multiple determinants of cellular resistance to anticancer agents. The relative contributions of each varied depending on the particular drug and cancer cell line studied. Together...

The Role of Second Generation Antiretroviral Drugs in HIV-1 Subtype B and non-B Variants Harboring Natural Polymorphisms and Drug Resistance Mutations.

Asahchop, Eugene L.
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
EN
Relevância na Pesquisa
66.21%
Cette thèse traite de la résistance du VIH-1 aux antirétroviraux, en particulier de l'activité antivirale de plusieurs inhibiteurs non nucléosidiques de la transcriptase inverse (INNTI) ainsi que des inhibiteurs de protéase (IP). Nous avons exploré l’émergence et la spécificité des voies de mutations qui confèrent la résistance contre plusieurs nouveaux INNTI (étravirine (ETR) et rilpivirine (RPV)) (chapitres 2 et 3). En outre, le profil de résistance et le potentiel antirétroviral d'un nouvel IP, PL-100, est présenté dans les chapitres 4 et 5. Pour le premier projet, nous avons utilisé des sous-types B et non-B du VIH-1 pour sélectionner des virus résistants à ETR, et ainsi montré que ETR favorise l’émergence des mutations V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y et M230L, et ce, en 18 semaines. Fait intéressant, E138K a été la première mutation à émerger dans la plupart des cas. Les clones viraux contenant E138K ont montré un faible niveau de résistance phénotypique à ETR (3,8 fois) et une diminution modeste de la capacité de réplication (2 fois) par rapport au virus de type sauvage. Nous avons également examiné les profils de résistance à ETR et RPV dans les virus contenant des mutations de résistance aux INNTI au début de la sélection. Dans le cas du virus de type sauvage et du virus contenant la mutation unique K103N...

Ethics and Drug Resistance

Selgelid, Michael
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
66.09%
This paper reviews the dynamics behind, and ethical issues associated with, the phenomenon of drug resistance. Drug resistance is an important ethical issue partly because of the severe consequences likely to result from the increase in drug resistant pat

HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors

Sottile, Rosa; Pangigadde, Pradeepa N.; Tan, Thomas; Anichini, Andrea; Sabbatino, Francesco; Trecroci, Francesca; Favoino, Elvira; Orgiano, Laura; Roberts, James; Ferrone, Soldano; K?rre, Klas; Colucci, Francesco; Carbone, Ennio
Fonte: Wiley Publicador: Wiley
Tipo: Article; accepted version
EN
Relevância na Pesquisa
66.08%
This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/eji.201445289; The frequent development of drug resistance to targeted therapies in cancer patients has stimulated interest in strategies counteracting resistance. Combining immunotherapies with targeted therapies is one such strategy. In this context, we asked whether human NK cells can target melanoma cells that have acquired resistance to selective inhibitors targeting activating mutants of the B-Raf kinase (BRAF inhibitors). We generated drug-resistant cell variants in vitro from human BRAF-mutant melanoma cell lines MEL-HO, COLO-38, SK-MEL-37, 1520 and from primary melanoma cells freshly isolated from two patients. All drug-resistant cell variants remained susceptible to lysis by IL-2-activated NK cells; and two BRAFi-resistant lines became significantly more susceptible to NK-cell lysis than their parental lines. This was associated with significant HLA class I antigen downregulation and PD-L1 upregulation on the drug-resistant lines. Although blocking HLA class I enhanced the extent of lysis of both BRAFi-R and parental cells to NK-cell-mediated lysis, antibody-mediated inhibition of PD1- PD-L1 interactions had no detectable effect. HLA class I antigen expression on BRAFi-resistant melanoma variants thus appears to play a major role in their susceptibility to NK-cell cytotoxicity. These findings suggests that NK-cell-based immunotherapy may be a viable approach to treat melanoma patients with acquired resistance to BRAF inhibitors.; This work was supported by the Cambridge the National Institute for Health Research Cambridge Biomedical Research 2 Center Cell Phenotyping Hub and by project grants from the Association for International Cancer Research 3 10-0238 and the Medical Research Council G0900101/1 to Francesco Colucci?s lab and by Associazione Italiana 4 Ricerca Cancro AIRC-IG 15521...

HIV transmitted drug resistance in adult and pediatric populations in Panama

Castillo,Juan; Arteaga,Griselda; Mendoza,Yaxelis; Martínez,Alexander A.; Samaniego,Rigoberto; Estripeaut,Dora; Page,Kathleen R.; Smith,Rebecca E.; Sosa,Nestor; Pascale,Juan M.
Fonte: Organización Panamericana de la Salud Publicador: Organización Panamericana de la Salud
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2011 EN
Relevância na Pesquisa
66.12%
OBJECTIVE: To investigate the prevalence of transmitted drug-resistant HIV among adults in Panama by using a modified World Health Organization Threshold Survey (WHO-TS) and to investigate rates of initial resistance among HIV-positive infants in Panama. METHODS: At the Gorgas Memorial Institute, 47 HIV-positive adults were genotyped for mutations associated with transmitted drug resistance (TDR) in the reverse transcriptase and protease genes of HIV-1, according to WHO-TS guidelines, modified to include patients ≤ 26 years old. Prevalence rates for drug-resistance mutations against three classes of antiretroviral drugs-nucleoside analog reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors-were calculated as low (< 5.0%), moderate (5.0%-15.0%), and high (> 15.0%). Twenty-five infant patients were also geno-typed and prevalence rates for drug-resistance mutations were calculated. RESULTS: TDR among Panamanian adults was moderate: 6 of 47 HIV-positive adults showed one or more mutations associated with TDR. Horizontal TDR mutations were moderate for NRTIs and NNRTIs and low for protease inhibitors. Vertical transmission of HIV in Panama has decreased for 2002-2007...