Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
1.
Radiographics ; 40(7): 1916-1931, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33136476

RESUMO

To detect potentially curable hepatocellular carcinoma (HCC), clinical practice guidelines recommend semiannual surveillance US of the liver in adult patients at risk for developing this malignancy, such as those with cirrhosis and some patients with chronic hepatitis B infection. However, cirrhosis and a large body habitus, both of which are increasingly prevalent in the United States and the rest of the world, may impair US visualization of liver lesions and reduce the sensitivity of surveillance with this modality. The low sensitivity of US for detection of early-stage HCC contributes to delayed diagnosis and increased mortality. Abbreviated MRI, a shortened MRI protocol tailored for early-stage detection of HCC, has been proposed as an alternative surveillance option that provides high sensitivity and specificity. Abbreviated MRI protocols include fewer sequences than a complete multiphase MRI examination and are specifically designed to identify small potentially curable HCCs that may be missed at US. Three abbreviated MRI strategies have been studied: (a) nonenhanced, (b) dynamic contrast material-enhanced, and (c) hepatobiliary phase contrast-enhanced abbreviated MRI. Retrospective studies have shown that simulated abbreviated MRI provides high sensitivity and specificity for early-stage HCC, mostly in nonsurveillance cohorts. If it is supported by scientific evidence in surveillance populations, adoption of abbreviated MRI could advance clinical practice by increasing early detection of HCC, allowing effective treatment and potentially prolonging life in the growing number of individuals with this cancer. Online supplemental material is available for this article. ©RSNA, 2020.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Meios de Contraste , Detecção Precoce de Câncer/métodos , Humanos , Aumento da Imagem , Interpretação de Imagem Assistida por Computador , Programas de Rastreamento/métodos , Sensibilidade e Especificidade
2.
Radiology ; 296(1): 76-84, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32315265

RESUMO

Background Prostate MRI is used widely in clinical care for guiding tissue sampling, active surveillance, and staging. The Prostate Imaging Reporting and Data System (PI-RADS) helps provide a standardized probabilistic approach for identifying clinically significant prostate cancer. Despite widespread use, the variability in performance of prostate MRI across practices remains unknown. Purpose To estimate the positive predictive value (PPV) of PI-RADS for the detection of high-grade prostate cancer across imaging centers. Materials and Methods This retrospective cross-sectional study was compliant with the HIPAA. Twenty-six centers with members in the Society of Abdominal Radiology Prostate Cancer Disease-focused Panel submitted data from men with suspected or biopsy-proven untreated prostate cancer. MRI scans were obtained between January 2015 and April 2018. This was followed with targeted biopsy. Only men with at least one MRI lesion assigned a PI-RADS score of 2-5 were included. Outcome was prostate cancer with Gleason score (GS) greater than or equal to 3+4 (International Society of Urological Pathology grade group ≥2). A mixed-model logistic regression with institution and individuals as random effects was used to estimate overall PPVs. The variability of observed PPV of PI-RADS across imaging centers was described by using the median and interquartile range. Results The authors evaluated 3449 men (mean age, 65 years ± 8 [standard deviation]) with 5082 lesions. Biopsy results showed 1698 cancers with GS greater than or equal to 3+4 (International Society of Urological Pathology grade group ≥2) in 2082 men. Across all centers, the estimated PPV was 35% (95% confidence interval [CI]: 27%, 43%) for a PI-RADS score greater than or equal to 3 and 49% (95% CI: 40%, 58%) for a PI-RADS score greater than or equal to 4. The interquartile ranges of PPV at these same PI-RADS score thresholds were 27%-44% and 27%-48%, respectively. Conclusion The positive predictive value of the Prostate Imaging and Reporting Data System was low and varied widely across centers. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Milot in this issue.


Assuntos
Imageamento por Ressonância Magnética/métodos , Neoplasias da Próstata/diagnóstico por imagem , Sistemas de Informação em Radiologia , Idoso , Estudos Transversais , Humanos , Masculino , Valor Preditivo dos Testes , Próstata/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sociedades Médicas
3.
J Am Coll Radiol ; 16(1): 24-29, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30213713

RESUMO

PURPOSE: To investigate the national coverage landscape for prostate MRI services, assessing the presence of updated and accurate coverage requirements by private payers. METHODS: The database Policy Reporter was used to evaluate private payer coverage related to prostate MRI for 81 plans covering 149 million people in the United States. Both the indications and requirements for prostate MRI coverage were recorded in a variety of clinical scenarios, including initial diagnosis, staging, active surveillance, and suspected recurrence. RESULTS: Overall, 11.1% of payers cover prostate MRI in biopsy-naïve patients with suspected prostate cancer, with the remaining 88.9% requiring a prior negative biopsy. Nearly all payers also require either a rising prostate-specific antigen (PSA) or abnormal digital rectal examination (DRE). Rarely, a planned future MRI-targeted biopsy serves as a basis for MRI coverage. Initial staging is covered by most payers, although typically with stringent indications (eg, PSA ≥ 20 ng/mL, Gleason score ≥7 or 8, stage T3 or T4, or ≥20% risk of nodal metastases). Only 10 payers discuss active surveillance, with 8 of these requiring a repeat biopsy before MRI. Coverage for detection of post-treatment recurrence often requires a rising PSA or abnormal DRE, and occasionally only if a CT is first performed; only 10 of 81 payers address coverage after androgen deprivation treatment. CONCLUSION: Prostate MRI coverage varies widely among private payers, fails to recognize major clinical scenarios, is overly restrictive, and is often not reflective of current clinical practice. This creates challenges for patients and referring physicians seeking to obtain ready access to prostate MRI services.


Assuntos
Cobertura do Seguro/estatística & dados numéricos , Imageamento por Ressonância Magnética/economia , Neoplasias da Próstata/diagnóstico por imagem , Adulto , Idoso , Biomarcadores Tumorais/sangue , Humanos , Biópsia Guiada por Imagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Estados Unidos
4.
ACS Infect Dis ; 3(7): 512-526, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28350440

RESUMO

Human African trypanosomiasis (HAT) is a fatal infectious disease caused by the eukaryotic pathogen Trypanosoma brucei (Tb). Available treatments are difficult to administer and have significant safety issues. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the parasite polyamine biosynthetic pathway. Previous attempts to develop TbAdoMetDC inhibitors into anti-HAT therapies failed due to poor brain exposure. Here, we describe a large screening campaign of two small-molecule libraries (∼400,000 compounds) employing a new high-throughput (∼7 s per sample) mass spectrometry-based assay for AdoMetDC activity. As a result of primary screening, followed by hit confirmation and validation, we identified 13 new classes of reversible TbAdoMetDC inhibitors with low-micromolar potency (IC50) against both TbAdoMetDC and T. brucei parasite cells. The majority of these compounds were >10-fold selective against the human enzyme. Importantly, compounds from four classes demonstrated high propensity to cross the blood-brain barrier in a cell monolayer assay. Biochemical analysis demonstrated that compounds from eight classes inhibited intracellular TbAdoMetDC in the parasite, although evidence for a secondary off-target component was also present. The discovery of several new TbAdoMetDC inhibitor chemotypes provides new hits for lead optimization programs aimed to deliver a novel treatment for HAT.


Assuntos
Adenosilmetionina Descarboxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Proteínas de Protozoários/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Adenosilmetionina Descarboxilase/genética , Adenosilmetionina Descarboxilase/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Cães , Inibidores Enzimáticos/química , Expressão Gênica , Humanos , Cinética , Células Madin Darby de Rim Canino , Espectrometria de Massas/instrumentação , Espectrometria de Massas/métodos , Modelos Biológicos , Testes de Sensibilidade Parasitária , Permeabilidade , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Tripanossomicidas/química , Trypanosoma brucei brucei/enzimologia , Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/crescimento & desenvolvimento
5.
J Am Coll Radiol ; 14(1): 65-71, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27717576

RESUMO

PURPOSE: Optimizing the utilization of CT pulmonary angiogram (CTPA) for the diagnosis and workup of acute chest pain can provide an opportunity to reduce unnecessary radiation and health care system expense. METHODS: An attempt to improve CTPA utilization began by measuring overall department and clinician-specific utilization. This was bolstered by retrospectively evaluating patient charts for pulmonary embolism scoring criteria and D-dimer utilization so as to better understand gaps in diagnostic workup. The department-wide and individualized metrics were then provided to each emergency department clinician and differences between the pre- and postintervention data were evaluated. RESULTS: The percentage of positive CTPAs did not change significantly at 8.7% and 9.2% in the pre- and postintervention groups, respectively. Similarly, the workup of patients based on retrospective PERC and Wells-score criteria did not significantly improve after the intervention. However, the percentage of CTPAs ordered on low D-dimer patients did decrease significantly post-intervention. Further observational analysis uncovered marked variability in clinician ordering behavior and diagnostic rates. CONCLUSIONS: Overall, such an intervention seems to have a limited, though not insignificant, impact on the workup of suspected pulmonary embolism. Calculating provider-specific utilization metrics allows both the radiologist and clinician to better understand opportunities to improve health care delivery.


Assuntos
Angiografia por Tomografia Computadorizada/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Uso Excessivo dos Serviços de Saúde/prevenção & controle , Uso Excessivo dos Serviços de Saúde/estatística & dados numéricos , Embolia Pulmonar/sangue , Embolia Pulmonar/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , California/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/epidemiologia , Melhoria de Qualidade/estatística & dados numéricos , Revisão da Utilização de Recursos de Saúde , Adulto Jovem
6.
J Am Coll Radiol ; 13(4): 417-23, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26922594

RESUMO

The application of simulation software in health care has transformed quality and process improvement. Specifically, software based on discrete-event simulation (DES) has shown the ability to improve radiology workflows and systems. Nevertheless, despite the successful application of DES in the medical literature, the power and value of simulation remains underutilized. For this reason, the basics of DES modeling are introduced, with specific attention to medical imaging. In an effort to provide readers with the tools necessary to begin their own DES analyses, the practical steps of choosing a software package and building a basic radiology model are discussed. In addition, three radiology system examples are presented, with accompanying DES models that assist in analysis and decision making. Through these simulations, we provide readers with an understanding of the theory, requirements, and benefits of implementing DES in their own radiology practices.


Assuntos
Modelos Organizacionais , Gerenciamento da Prática Profissional/organização & administração , Melhoria de Qualidade/organização & administração , Radiologia/organização & administração , Software , Fluxo de Trabalho , Simulação por Computador , Modelos Teóricos , Estados Unidos
7.
Proc Natl Acad Sci U S A ; 111(2): 799-804, 2014 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-24381157

RESUMO

Drug resistance emerges in an ecological context where fitness costs restrict the diversity of escape pathways. These pathways are targets for drug discovery, and here we demonstrate that we can identify small-molecule inhibitors that differentially target resistant parasites. Combining wild-type and mutant-type inhibitors may prevent the emergence of competitively viable resistance. We tested this hypothesis with a clinically derived chloroquine-resistant (CQ(r)) malaria parasite and with parasites derived by in vitro selection with Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. We screened a chemical library against CQ(s) and CQ(r) lines and discovered a drug-like compound (IDI-3783) that was potent only in the CQ(r) line. Surprisingly, in vitro selection of Plasmodium falciparum resistant to IDI-3783 restored CQ sensitivity, thereby indicating that CQ might once again be useful as a malaria therapy. In parallel experiments, we selected P. falciparum lines resistant to structurally unrelated PfDHODH inhibitors (Genz-666136 and DSM74). Both selections yielded resistant lines with the same point mutation in PfDHODH:E182D. We discovered a compound (IDI-6273) more potent against E182D than wild-type parasites. Selection of the E182D mutant with IDI-6273 yielded a reversion to the wild-type protein sequence and phenotype although the nucleotide sequence was different. Importantly, selection with a combination of Genz-669178, a wild-type PfDHODH inhibitor, and IDI-6273, a mutant-selective PfDHODH inhibitor, did not yield resistant parasites. These two examples demonstrate that the compromise between resistance and evolutionary fitness can be exploited to design therapies that prevent the emergence and spread of resistant organisms.


Assuntos
Cloroquina/farmacologia , Descoberta de Drogas/métodos , Resistência a Medicamentos/genética , Aptidão Genética/genética , Malária/tratamento farmacológico , Plasmodium falciparum/genética , Análise de Variância , Sequência de Bases , Di-Hidro-Orotato Desidrogenase , Avaliação Pré-Clínica de Medicamentos , Genoma/genética , Dados de Sequência Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Mutação Puntual/genética , Pirimidinas , Análise de Sequência de DNA , Bibliotecas de Moléculas Pequenas , Triazóis
8.
J Digit Imaging ; 27(3): 369-79, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24395597

RESUMO

The quantitative, multiparametric assessment of brain lesions requires coregistering different parameters derived from MRI sequences. This will be followed by analysis of the voxel values of the ROI within the sequences and calculated parametric maps, and deriving multiparametric models to classify imaging data. There is a need for an intuitive, automated quantitative processing framework that is generalized and adaptable to different clinical and research questions. As such flexible frameworks have not been previously described, we proceeded to construct a quantitative post-processing framework with commonly available software components. Matlab was chosen as the programming/integration environment, and SPM was chosen as the coregistration component. Matlab routines were created to extract and concatenate the coregistration transforms, take the coregistered MRI sequences as inputs to the process, allow specification of the ROI, and store the voxel values to the database for statistical analysis. The functionality of the framework was validated using brain tumor MRI cases. The implementation of this quantitative post-processing framework enables intuitive creation of multiple parameters for each voxel, facilitating near real-time in-depth voxel-wise analysis. Our initial empirical evaluation of the framework is an increased usage of analysis requiring post-processing and increased number of simultaneous research activities by clinicians and researchers with non-technical backgrounds. We show that common software components can be utilized to implement an intuitive real-time quantitative post-processing framework, resulting in improved scalability and increased adoption of post-processing needed to answer important diagnostic questions.


Assuntos
Encefalopatias/diagnóstico , Mapeamento Encefálico/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Software , Bases de Dados Factuais , Humanos , Sensibilidade e Especificidade
9.
PLoS Negl Trop Dis ; 8(1): e2628, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24416464

RESUMO

Cofactor-independent phosphoglycerate mutase (iPGAM) is essential for the growth of C. elegans but is absent from humans, suggesting its potential as a drug target in parasitic nematodes such as Brugia malayi, a cause of lymphatic filariasis (LF). iPGAM's active site is small and hydrophilic, implying that it may not be druggable, but another binding site might permit allosteric inhibition. As a comprehensive assessment of iPGAM's druggability, high-throughput screening (HTS) was conducted at two different locations: ∼220,000 compounds were tested against the C. elegans iPGAM by Genzyme Corporation, and ∼160,000 compounds were screened against the B. malayi iPGAM at the National Center for Drug Screening in Shanghai. iPGAM's catalytic activity was coupled to downstream glycolytic enzymes, resulting in NADH consumption, as monitored by a decline in visible-light absorbance at 340 nm. This assay performed well in both screens (Z'-factor >0.50) and identified two novel inhibitors that may be useful as chemical probes. However, these compounds have very modest potency against the B. malayi iPGAM (IC50 >10 µM) and represent isolated singleton hits rather than members of a common scaffold. Thus, despite the other appealing properties of the nematode iPGAMs, their low druggability makes them challenging to pursue as drug targets. This study illustrates a "druggability paradox" of target-based drug discovery: proteins are generally unsuitable for resource-intensive HTS unless they are considered druggable, yet druggability is often difficult to predict in the absence of HTS data.


Assuntos
Brugia Malayi/enzimologia , Inibidores Enzimáticos/isolamento & purificação , Filaricidas/isolamento & purificação , Fosfoglicerato Mutase/antagonistas & inibidores , Animais , Inibidores Enzimáticos/farmacologia , Filaricidas/farmacologia , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50
10.
Magn Reson Imaging Clin N Am ; 21(2): 241-68, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23642552

RESUMO

Although conventional contrast-enhanced MR imaging remains the standard-of-care imaging method in the posttreatment evaluation of gliomas, recent developments in therapeutic options such as chemoradiation and antiangiogenic agents have caused the neuro-oncology community to rethink traditional imaging criteria. This article highlights the latest recommendations. These recommendations should be viewed as works in progress. As more is learned about the pathophysiology of glioma treatment response, quantitative imaging biomarkers will be validated within this context. There will likely be further refinements to glioma response criteria, although the lack of technical standardization in image acquisition, postprocessing, and interpretation also need to be addressed.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Glioma/patologia , Glioma/terapia , Imageamento por Ressonância Magnética/normas , Avaliação de Resultados em Cuidados de Saúde/normas , Guias de Prática Clínica como Assunto , Meios de Contraste , Humanos , Oncologia/normas , Prognóstico , Resultado do Tratamento
11.
PLoS One ; 7(3): e33823, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22457791

RESUMO

Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway.


Assuntos
Apoptose/fisiologia , Ácidos Graxos Monoinsaturados/metabolismo , Neoplasias/patologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Estearoil-CoA Dessaturase/fisiologia
12.
ACS Med Chem Lett ; 2(9): 708-13, 2011 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-24900364

RESUMO

Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.

13.
J Biol Chem ; 285(43): 33054-33064, 2010 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-20702404

RESUMO

Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED(50) values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.


Assuntos
Antimaláricos/farmacologia , Inibidores Enzimáticos/farmacologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/enzimologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Animais , Linhagem Celular , Di-Hidro-Orotato Desidrogenase , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Plasmodium berghei/enzimologia , Plasmodium vivax/enzimologia , Ratos
15.
Exp Cell Res ; 316(2): 258-71, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19732767

RESUMO

The PSMD14 (POH1, also known as Rpn11/MPR1/S13/CepP1) protein within the 19S complex (19S cap; PA700) is responsible for substrate deubiquitination during proteasomal degradation. The role of PSMD14 in cell proliferation and senescence was explored using siRNA knockdown in carcinoma cell lines. Our results reveal that down-regulation of PSMD14 by siRNA transfection had a considerable impact on cell viability causing cell arrest in the G0-G1 phase, ultimately leading to senescence. The molecular events associated with decreased cell proliferation, cell cycle arrest and senescence include down-regulation of cyclin B1-CDK1-CDC25C, down-regulation of cyclin D1 and up-regulation of p21(/Cip) and p27(/Kip1). Most notably, phosphorylation of the retinoblastoma protein was markedly reduced in PSMD14 knockdown cells. A comparative study with PSMB5, a subunit of the 20S proteasome, revealed that PSMB5 and PSMD14 have different effects on cell cycle, senescence and associated molecular events. These data support the view that the 19S and 20S subunits of the proteasome have distinct biological functions and imply that targeting 19S and 20S would have distinct molecular consequences on tumor cells.


Assuntos
Ciclo Celular/genética , Senescência Celular/genética , Complexo de Endopeptidases do Proteassoma/deficiência , Transativadores/deficiência , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Proteínas Inibidoras de Quinase Dependente de Ciclina/metabolismo , DNA/análise , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fase G1/genética , Expressão Gênica/genética , Células HeLa , Humanos , Fosforilação/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Interferente Pequeno/genética , Fase de Repouso do Ciclo Celular/genética , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Sulfotransferases/metabolismo , Transativadores/genética , Transativadores/metabolismo , Transfecção , Proteínas Ubiquitinadas/metabolismo , Regulação para Cima/genética , beta-Galactosidase/metabolismo , Fosfatases cdc25/genética , Fosfatases cdc25/metabolismo
17.
J Biol Chem ; 283(50): 35078-85, 2008 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-18842591

RESUMO

Plasmodium falciparum causes the most deadly form of malaria and accounts for over one million deaths annually. The malaria parasite is unable to salvage pyrimidines and relies on de novo biosynthesis for survival. Dihydroorotate dehydrogenase (DHOD), a mitochondrially localized flavoenzyme, catalyzes the rate-limiting step of this pathway and is therefore an attractive antimalarial chemotherapeutic target. Using a target-based high throughput screen, we have identified a series of potent, species-specific inhibitors of P. falciparum DHOD (pfDHOD) that are also efficacious against three cultured strains (3D7, HB3, and Dd2) of P. falciparum. The primary antimalarial mechanism of action of these compounds was confirmed to be inhibition of pfDHOD through a secondary assay with transgenic malaria parasites, and the structural basis for enzyme inhibition was explored through in silico structure-based docking and site-directed mutagenesis. Compound-mediated cytotoxicity was not observed with human dermal fibroblasts or renal epithelial cells. These data validate pfDHOD as an antimalarial drug target and provide chemical scaffolds with which to begin medicinal chemistry efforts.


Assuntos
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Plasmodium falciparum/enzimologia , Animais , Antimaláricos/farmacologia , Química Farmacêutica/métodos , Di-Hidro-Orotato Desidrogenase , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/metabolismo , Fibroblastos/metabolismo , Humanos , Concentração Inibidora 50 , Malária/tratamento farmacológico , Modelos Químicos , Mutagênese Sítio-Dirigida
18.
J Med Humanit ; 17(2): 91-102, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-11645779

RESUMO

Since 1986, we have seen a rise in the occurrence of tuberculosis in the United States. Long considered defeated in this country, the disease is returning with distressing vigor. Outbreaks of MDR-TB, tuberculosis resistant to more than one medication, have been reported around the country. This article analyzes the Centers for Disease Control and Prevention's National Action Plan to Combat Multidrug-Resistant Tuberculosis, with particular focus on the moral dimensions of mandatory directly observed treatment (DOT) and involuntary quarantine. It is proposed that a moral response to the control of tuberculosis must be one which is sustainable and which can effectively curtail the spread of the disease at a minimal cost to individual rights.


Assuntos
Coerção , Controle de Doenças Transmissíveis/história , Doenças Transmissíveis , Programas Obrigatórios , Assistência ao Paciente , Cooperação do Paciente , Saúde Pública , Política Pública , Quarentena , Tuberculose/história , Altruísmo , Centers for Disease Control and Prevention, U.S. , Internação Compulsória de Doente Mental , Governo Federal , Governo , História do Século XX , Direitos Humanos , Humanos , Jurisprudência , Preparações Farmacêuticas , Quarentena/história , Fatores Socioeconômicos , Sociologia/história , Governo Estadual , Estados Unidos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...