Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Acta Pharm Sin B ; 8(2): 252-260, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29719786

RESUMO

In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3B2, H226, Ovcar3 and N87 were extracted and digested with γLysC and trypsin. The resulting peptide lysate were pre-fractionated and subjected to untargeted quantitative proteomics analysis using a high resolution mass spectrometer. The mass spectra were processed by the MaxQuant and the protein abundances were estimated using total peak area (TPA) method. A total of 6037 proteins were identified, and the analysis resulted in the identification of 2647 membrane proteins. Of those, tumor antigens and absorption, metabolism, disposition and elimination (ADME) proteins including UDP-glucuronosyltransferase, cytochrome P450, solute carriers and ATP-binding cassette transporters were detected and disclosed significant variations among the cell lines. The principal component analysis was performed for the cluster of cell lines. The results demonstrated that H226 is closely related with N87, while Hep3B2 aligned with HepG2. The protein cluster of Ovcar3 was apart from that of other cell lines investigated. By providing for the first time quantitative untargeted proteomics analysis, the results delineated the expression profiles of membrane proteins. These findings provided a useful resource for selecting targets of choice for anticancer therapy through advancing data obtained from preclinical tumor cell line models to clinical outcomes.

2.
Drug Metab Dispos ; 46(2): 178-188, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29162614

RESUMO

Perturbation of organic anion transporter (OAT) 1- and OAT3-mediated transport can alter the exposure, efficacy, and safety of drugs. Although there have been reports of the endogenous biomarkers for OAT1/3, none of these have all of the characteristics required for a clinical useful biomarker. Cynomolgus monkeys were treated with intravenous probenecid (PROB) at a dose of 40 mg/kg in this study. As expected, PROB increased the area under the plasma concentration-time curve (AUC) of coadministered furosemide, a known substrate of OAT1 and OAT3, by 4.1-fold, consistent with the values reported in humans (3.1- to 3.7-fold). Of the 233 plasma metabolites analyzed using a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics method, 29 metabolites, including pyridoxic acid (PDA) and homovanillic acid (HVA), were significantly increased after either 1 or 3 hours in plasma from the monkeys pretreated with PROB compared with the treated animals. The plasma of animals was then subjected to targeted LC-MS/MS analysis, which confirmed that the PDA and HVA AUCs increased by approximately 2- to 3-fold by PROB pretreatments. PROB also increased the plasma concentrations of hexadecanedioic acid (HDA) and tetradecanedioic acid (TDA), although the increases were not statistically significant. Moreover, transporter profiling assessed using stable cell lines constitutively expressing transporters demonstrated that PDA and HVA are substrates for human OAT1, OAT3, OAT2 (HVA), and OAT4 (PDA), but not OCT2, MATE1, MATE2K, OATP1B1, OATP1B3, and sodium taurocholate cotransporting polypeptide. Collectively, these findings suggest that PDA and HVA might serve as blood-based endogenous probes of cynomolgus monkey OAT1 and OAT3, and investigation of PDA and HVA as circulating endogenous biomarkers of human OAT1 and OAT3 function is warranted.


Assuntos
Biomarcadores/sangue , Ácido Homovanílico/sangue , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ácido Piridóxico/sangue , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Células HEK293 , Humanos , Macaca fascicularis , Metabolômica/métodos , Probenecid/metabolismo
3.
J Am Pharm Assoc (2003) ; 57(6): 729-738.e10, 2017 Nov - Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28784299

RESUMO

OBJECTIVE: Polypharmacy has been linked to a myriad of adverse consequences, and escalating rates of polypharmacy present an emerging concern, particularly among older adults. This systematic review and meta-analysis summarizes the existing literature concerning the association between polypharmacy and mortality. DATA SOURCES: A systematic literature review was done by searching the EMBASE, PubMed, Scopus, and International Pharmaceutical Abstract databases to identify studies assessing the association between polypharmacy and death published until June 2016. STUDY SELECTION: Studies that investigated the association between polypharmacy and mortality were eligible for this systematic review and meta-analysis. DATA EXTRACTION: Data were extracted by the first and second authors independently using a data extraction form. Disagreement was resolved by consensus. A meta-analysis was performed using random effect models. Heterogeneity was assessed using the I2 statistic. RESULTS: Forty-seven studies were included in this meta-analysis. The underlying populations were heterogeneous (I2= 91.5%). When defined as a discrete variable, pooled risk estimates demonstrated a significant association between polypharmacy and death (pooled-adjusted odds ratio [aOR] 1.08 [95% CI 1.04-1.12]). When defined categorically, a dose-response relationship was observed across escalating thresholds for defining polypharmacy. Categorical thresholds for polypharmacy using values of 1-4 medications, 5 medications, and 6-9 medications were significantly associated with death (P <0.05; aOR 1.24 [1.10-1.39], aOR 1.31 [1.17, 1.47], and aOR 1.59 [1.36-1.87], respectively). Excessive polypharmacy (ie, the use of 10 or more medications) was also associated with death (aOR 1.96 [1.42-2.71]). CONCLUSIONS: Pooled risk estimates from this meta-analysis reveal that polypharmacy is associated with increased mortality risk, using both discrete and categorical definitions. The causality of this relationship remains unclear, but it emphasizes the need for approaches to health care delivery that achieve an optimal balance of risk and benefit in medication prescribing.


Assuntos
Interações de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Polimedicação , Causas de Morte , Distribuição de Qui-Quadrado , Relação Dose-Resposta a Droga , Humanos , Razão de Chances , Medição de Risco , Fatores de Risco
4.
PLoS Biol ; 15(8): e2001750, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28821013

RESUMO

As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk) and phosphorylated SH2-containing inositol phosphatase (pSHIP), are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin) is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.


Assuntos
Actinas/metabolismo , Linfócitos B/metabolismo , Proteínas de Transporte/metabolismo , Proteínas do Citoesqueleto/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Tirosina Quinase da Agamaglobulinemia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes , Membrana Celular/metabolismo , Imunidade Humoral , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polimerização , Proteína Companheira de mTOR Insensível à Rapamicina , Tiazolidinas
5.
Am J Pharm Educ ; 81(5): 95, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28720923

RESUMO

Objective. To review published educational interventions focusing on medication non-adherence. Methods. A literature search was performed of educational articles on the topic of medication adherence. Data on interventions and learning assessments were abstracted for relevant studies meeting search criteria. Results. Twenty studies met inclusion criteria. Sixteen included pill-taking experiences with regimens of candies or placebos and varied in their inclusion of novel elements to highlight issues such as stigma, regimen complexity, and adherence measurement. Three studies involved interacting with the public. Qualitative and quantitative methods were used to assess a variety of learning outcomes. Conclusion. Pill-taking experiences can help future providers appreciate the complex logistics of medication-taking, but are less capable of addressing the psychosocial aspects of adherence. A promising area for learning is to interact with actual medication users to understand their experiences and perspectives.


Assuntos
Educação em Farmácia , Ocupações em Saúde/educação , Adesão à Medicação/psicologia , Estudantes de Ciências da Saúde , Humanos , Placebos/administração & dosagem
6.
J Nucl Med ; 58(9): 1452-1458, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28280220

RESUMO

68Ga-DOTATOC, a somatostatin receptor-targeted ligand, has been used clinically in Europe over the past decade for imaging neuroendocrine tumors (NETs). It appears to be quite sensitive and effective for clinical management decision making. This metaanalysis summarizes the efficacy of 68Ga-DOTATOC for several distinct indications and is intended to support approval of this agent by the U.S. Food and Drug Administration. Methods: The major electronic medical databases were searched for relevant papers over the period from January 2001 to November 2015. Papers were selected for review in 3 categories: clinical trials that reported sensitivity and specificity, comparison studies with 111In-octreotide, and change of management studies. All the eligible papers underwent Quality Assessment of Diagnostic Accuracy Studies (QUADAS) assessment, which was useful in the final selection of papers for review. Results: The initial search yielded 468 papers. After detailed evaluation, 17 papers were finally selected. Five types of studies emerged: workup of patients with symptoms and biomarker findings suggestive of NET, but with negative conventional imaging (3 papers, yield was only 13%); sensitivity (12 papers; sensitivity, 92%) and specificity (7 papers; specificity, 82%); identification of site of unknown primary in patients with metastatic NET (4 papers, yield was 44%); impact on subsequent NET patient management (4 papers, change in management in 51%); and comparison with 111In-octreotide (2 papers, sensitivity of DOTATOC on a per-lesion basis was 100%, for 111In-octreotide it was 78.2%; specificity was not available). Safety was not explicitly addressed in any study, but there were no reports of adverse events. Conclusion:68Ga-DOTATOC is useful for evaluating the presence and extent in disease for staging and restaging and for assisting in treatment decision making for patients with NET. It is also effective in locating the site of an unknown primary in NET patients who present with metastatic NET, but no known primary tumor. It also appears to be more accurate than 111In-octreotide. Although 68Ga-DOTATOC would seem to be useful in evaluating patients with suggestive symptoms and biomarker findings, it does not perform well in this setting and has low yield. Overall, it appears to be an excellent imaging agent to assess patients with known NET and frequently leads to a change in management.


Assuntos
Diagnóstico por Imagem/métodos , Tumores Neuroendócrinos/diagnóstico por imagem , Octreotida/análogos & derivados , Compostos Organometálicos , Humanos , Sensibilidade e Especificidade
7.
Bioorg Med Chem Lett ; 27(4): 855-861, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108251

RESUMO

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.


Assuntos
Aminas/química , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Triazinas/química
8.
J Exp Med ; 213(12): 2707-2727, 2016 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-27799621

RESUMO

FcγRIIB functions to suppress the activation of immune cells. A single-nucleotide polymorphism in the transmembrane (TM) domain of FcγRIIB, FcγRIIB-T232, is associated with lupus. In this study, we investigated the pathogenic mechanism of FcγRIIB-T232 at both functional and structural levels. Our results showed that FcγRIIB-T232 exhibited significantly reduced lateral mobility compared with FcγRIIB-I232 and was significantly less enriched into the microclusters of immune complexes (ICs) after stimulation. However, if sufficient responding time is given for FcγRIIB-T232 to diffuse and interact with the ICs, FcγRIIB-T232 can restore its inhibitory function. Moreover, substituting the FcγRIIB-T232 TM domain with that of a fast floating CD86 molecule restored both the rapid mobility and the inhibitory function, which further corroborated the importance of fast mobility for FcγRIIB to function. Mechanistically, the crippled lateral mobility of FcγRIIB-T232 can be explained by the structural changes of the TM domain. Both atomistic simulations and nuclear magnetic resonance measurement indicated that the TM helix of FcγRIIB-T232 exhibited a more inclined orientation than that of FcγRIIB-I232, thus resulting in a longer region embedded in the membrane. Therefore, we conclude that the single-residue polymorphism T232 enforces the inclination of the TM domain and thereby reduces the lateral mobility and inhibitory functions of FcγRIIB.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de IgG/química , Receptores de IgG/genética , Sequência de Aminoácidos , Complexo Antígeno-Anticorpo/metabolismo , Linfócitos B/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Células Cultivadas , Difusão , Recuperação de Fluorescência Após Fotodegradação , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Lipídeos de Membrana/metabolismo , Modelos Biológicos , Simulação de Dinâmica Molecular , Monócitos/metabolismo , Estrutura Secundária de Proteína , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de IgG/metabolismo , Imagem Individual de Molécula
9.
Bioorg Med Chem Lett ; 26(17): 4256-60, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27476421

RESUMO

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.


Assuntos
Aminas/química , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Triazinas/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Artrite/tratamento farmacológico , Artrite/metabolismo , Artrite/patologia , Sítios de Ligação , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
10.
Am J Hematol ; 91(6): 594-605, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26973084

RESUMO

Prior case reports and observational studies indicate that intravenous immune globulin (IVIg) products may cause thromboembolic events (TEEs), leading the FDA to require a boxed warning in 2013. The effect of IVIg treatment on the risk of serious TEEs (acute myocardial infarction, ischemic stroke, or venous thromboembolism) was assessed using adverse event data reported in randomized controlled trials (RCTs) of IVIg. RCTs of IVIg in adult patients from 1995 to 2015 were identified from Pubmed, Embase, ClinicalTrials.Gov, and two large prior reviews of IVIg's therapeutic applications. Trials at high risk of detection or reporting bias for serious adverse events were excluded. 31 RCTs with a total of 4,129 participants (2,318 IVIg-treated, 1,811 control) were eligible for quantitative synthesis. No evidence was found of increased TEE risk among IVIg-treated patients compared with control patients (odds ratio = 1.10, 95% CI: 0.44, 2.88; risk difference = 0.0%, 95% CI: -0.7%, 0.7%, I(2) = 0%). No significant increase in risk was found when arterial and venous TEEs were analyzed as separate endpoints. Trial publications provided little specific information concerning the methods used to ascertain potential adverse events. Care should be taken in extrapolating the results to patients with higher baseline risks of TEE. Am. J. Hematol. 91:594-605, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Imunoglobulinas Intravenosas/efeitos adversos , Tromboembolia/induzido quimicamente , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tromboembolia/etiologia
11.
BMC Geriatr ; 16: 41, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26864215

RESUMO

BACKGROUND: Total knee arthroplasty is an effective treatment when nonsurgical treatments fail, but it is associated with risk of complications which may be increased in advanced age. The purpose of this study was to quantify age-related differences in perioperative morbidity and mortality after total knee arthroplasty through systematic review of existing literature. METHODS: PubMed, the Cochrane database of systematic reviews, Scopus, and clinicaltrials.gov, were queried for relevant studies that compared primary total knee arthroplasty outcomes of mortality, myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE) and functional status, of geriatric patients (>75 years old) with a younger control group (<65 years old). Pertinent journals and reference lists were hand searched. Eligibility criteria included all articles except case reports, meta-analyses, and systematic reviews. Two authors independently extracted data from each paper. Article quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Twenty-two studies were included. Geriatric patients had higher rates of mortality, MI, DVT, and length of stay in older compared to younger patients, however the absolute magnitude of these increases were small. The increase in mortality may have reflected decreased life expectancy in the geriatric populations as opposed to mortality specifically due perioperative risk. There were no differences in PE incidence and improvement in pain and functional status was equal in older and younger patients. Existing studies were limited by non-randomized patient selection, as well as variation in definitions and methodology. CONCLUSIONS: Existing data supports offering primary total knee arthroplasty to select geriatric patients, although the risk of complications may be increased. Much of the data was of poor quality. Future prospective studies are needed to better identify risks and benefits of total knee arthroplasty so that patients and surgeons can make informed decisions.


Assuntos
Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/tendências , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Estudos Prospectivos , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/epidemiologia , Resultado do Tratamento , Trombose Venosa/diagnóstico , Trombose Venosa/epidemiologia
12.
Neural Regen Res ; 10(10): 1635-42, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26692862

RESUMO

We have designed a novel nerve guidance conduit (NGC) made from silk fibroin and poly(lactic-co-glycolic acid) through electrospinning and weaving (ESP-NGCs). Several physical and biological properties of the ESP-NGCs were assessed in order to evaluate their biocompatibility. The physical properties, including thickness, tensile stiffness, infrared spectroscopy, porosity, and water absorption were determined in vitro. To assess the biological properties, Schwann cells were cultured in ESP-NGC extracts and were assessed by morphological observation, the MTT assay, and immunohistochemistry. In addition, ESP-NGCs were subcutaneously implanted in the backs of rabbits to evaluate their biocompatibility in vivo. The results showed that ESP-NGCs have high porosity, strong hydrophilicity, and strong tensile stiffness. Schwann cells cultured in the ESP-NGC extract fluids showed no significant differences compared to control cells in their morphology or viability. Histological evaluation of the ESP-NGCs implanted in vivo indicated a mild inflammatory reaction and high biocompatibility. Together, these data suggest that these novel ESP-NGCs are biocompatible, and may thus provide a reliable scaffold for peripheral nerve repair in clinical application.

13.
Drug Metab Dispos ; 43(11): 1788-94, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26341276

RESUMO

Unbound plasma concentrations may not reflect those in target tissues, and there is a need for methods to predict tissue partitioning. Here, we investigate the unbound liver partitioning (Kpu,u) of rosuvastatin, a substrate of hepatic organic anion transporting peptides, in cynomolgus monkeys and compare it with that determined using hepatocytes in vitro. Rosuvastatin (3 mg/kg) was administered orally to monkeys and plasma and liver (by ultrasound-guided biopsy) collected over time. Uptake into monkey hepatocytes was evaluated up to steady state. Binding in monkey plasma, liver, and hepatocytes was determined using equilibrium dialysis. Mean in vivo Kpu,u was 118 after correcting total liver partitioning by plasma and liver binding. In vitro uptake data were analyzed by compartmental modeling to determine active uptake clearance, passive diffusion, the intracellular unbound fraction, and Kpu,u. In vitro Kpu,u underpredicted that in vivo, resulting in the need for an empirical in vitro to in vivo scaling factor of 10. Adjusting model parameters using hypothetical scaling factors for transporter expression and surface area or assuming no effect of protein binding on active transport increased partitioning values by 1.1-, 6-, and 9-fold, respectively. In conclusion, in vivo rosuvastatin unbound liver partitioning in monkeys was underpredicted using hepatocytes in vitro. Modeling approaches that allow integrating corrections from passive diffusion or protein binding on active uptake could improve the estimation of in vivo intracellular partitioning of this organic anion transporting peptide substrate. A similar assessment of other active hepatic transport mechanisms could confirm and determine the extent to which limited accumulation in isolated hepatocytes needs to be considered in drug development.


Assuntos
Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacologia , Animais , Feminino , Previsões , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Ligação Proteica/fisiologia
14.
ACS Med Chem Lett ; 6(8): 850-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288683

RESUMO

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

15.
Anal Chem ; 86(15): 7642-9, 2014 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-25003239

RESUMO

The covalent conjugation of polyethylene glycol (PEG, typical MW > 10k) to therapeutic peptides and proteins is a well-established approach to improve their pharmacokinetic properties and diminish the potential for immunogenicity. Even though PEG is generally considered biologically inert and safe in animals and humans, the slow clearance of large PEGs raises concerns about potential adverse effects resulting from PEG accumulation in tissues following chronic administration, particularly in the central nervous system. The key information relevant to the issue is the disposition and fate of the PEG moiety after repeated dosing with PEGylated proteins. Here, we report a novel quantitative method utilizing LC-MS/MS coupled with in-source CID that is highly selective and sensitive to PEG-related materials. Both (40K)PEG and a tool PEGylated protein (ATI-1072) underwent dissociation in the ionization source of mass spectrometer to generate a series of PEG-specific ions, which were subjected to further dissociation through conventional CID. To demonstrate the potential application of the method to assess PEG biodistribution following PEGylated protein administration, a single dose study of ATI-1072 was conducted in rats. Plasma and various tissues were collected, and the concentrations of both (40K)PEG and ATI-1072 were determined using the LC-MS/MS method. The presence of (40k)PEG in plasma and tissue homogenates suggests the degradation of PEGylated proteins after dose administration to rats, given that free PEG was absent in the dosing solution. The method enables further studies for a thorough characterization of disposition and fate of PEGylated proteins.


Assuntos
Cromatografia Líquida/métodos , Polietilenoglicóis/análise , Proteínas/química , Espectrometria de Massas em Tandem/métodos , Animais , Ratos
16.
Onkologie ; 36(12): 747-52, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24356566

RESUMO

BACKGROUND: Knowing the status of the internal mammary lymph (IML) nodes is important for accurate staging and appropriate selection of subsequent treatment in breast cancer. We conducted a meta-analysis to clarify the rate of IML node metastasis in breast cancer patients and discussed the importance of this finding. METHODS: We retrieved articles from the literature that reported positive rates of IML node metastasis in breast cancer patients. The quality of the selected articles was assessed using the 'Methodological Index for Non-Randomized Studies'. The heterogeneity was tested, and publication bias was assessed using a funnel plot. Finally, the positive rate of IML node metastasis in breast cancer patients was calculated using the random-effects model. RESULTS: 15 articles met the inclusion criteria and a total of 4,248 patients were included in the analysis. Heterogeneity across the studies was statistically significant (p = 0.014); thus, the random-effects model was used and the calculated positive rate of IML node metastasis was 23% (95% confidence interval (CI), 0.21-0.25). CONCLUSIONS: Approximately 23% of the breast cancer patients had IML node metastases, for which the prognosis is generally poor. Accurate staging and integrated treatment are necessary to improve the survival of these patients.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma/mortalidade , Carcinoma/secundário , Linfonodos/patologia , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Carcinoma/patologia , Feminino , Humanos , Incidência , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Taxa de Sobrevida
17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 21(6): 1612-6, 2013 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-24370058

RESUMO

The purpose of this study was to investigate the effect of glutathione (GSH) on blood coagulation. The normal plasma samples and mixed plasma samples were taken randomly, and into which the normal dose and different concentration of GSH were added. The prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) and thrombin time (TT) were detected by using coagulation method before and after treatment with GSH. The detection results of normal plasma and mixed plasma containing GSH of different concentration were compared and analyzed with linear regression. The results showed that the APTT and FIB values of the plasma containing 2.5 mg/L glutathione or more, PT values of the plasma containing 10 mg/L glutathione or more, and TT values of the plasma containing 1250 mg/L glutathione or more were significantly different from those results of normal plasma or mixed plasma (P < 0.01) . There was a linear relation between all of the detection results of PT,APTT, FIB, TT and glutathione concentrations. The results of TT, APTT, PT and FIB detection in patient plasma were statistically different (P < 0.01) before and after treatment with normal concentration GSH. It is concluded that glutathione can influence detection results of coagulation function.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Glutationa/farmacologia , Feminino , Fibrinogênio/análise , Humanos , Masculino , Tempo de Tromboplastina Parcial , Plasma , Tempo de Protrombina , Tempo de Trombina
18.
Cells Tissues Organs ; 194(2-4): 261-7, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21555858

RESUMO

Excessive systemic exposure to fluoride (F) can lead to disturbances in bone homeostasis and dental enamel development. We have previously shown strain-specific responses to F in the development of dental fluorosis (DF) and in bone formation/mineralization. The current study was undertaken to further investigate F responsive variations in bone metabolism and to determine possible relationships with DF susceptibility. Seven-week-old male mice from FVB/NJ, C57BL/6J, C3H/HeJ, A/J, 129S1/SvImJ, AKR/J, DBA/2J, and BALB/cByJ inbred strains were exposed to NaF (0 or 50 ppm as F(-)) in drinking water for 60 days. Sera were collected for F, Ca, Mg, PO(4), iPTH, sRANKL, and ALP levels. Bone marrow cells were subjected to ex vivo cell culture for osteoclast potential and CFU colony assays (CFU-fibroblast, CFU-osteoblast, CFU-erythrocyte/granulocyte/macrophage/megakaryocyte, CFU-granulocyte/macrophage, CFU-macrophage, and CFU-granulocyte). Femurs and vertebrae were subjected to micro-CT analyses, biomechanical testing, and F, Mg, and Ca content assays. DF was evaluated using quantitative fluorescence and clinical criteria. Strain-specific responses to F were observed for DF, serum studies, ex vivo cell culture studies, and bone quality. Among the strains, there were no patterns or significant correlations between DF severity and the actions of F on bone homeostasis (serum studies, ex vivo assays, or bone quality parameters). The genetic background continues to play a role in the actions of F on tooth enamel development and bone homeostasis. F exposure led to variable phenotypic responses between strains involving dental enamel development and bone metabolism.


Assuntos
Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Fluoretos/farmacologia , Animais , Fenômenos Biomecânicos , Células da Medula Óssea/metabolismo , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/fisiopatologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Fluorescência , Fluorose Dentária/sangue , Fluorose Dentária/diagnóstico por imagem , Fluorose Dentária/patologia , Fluorose Dentária/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos , Fenótipo , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/patologia , Coluna Vertebral/fisiopatologia , Microtomografia por Raio-X
19.
Med Ref Serv Q ; 29(4): 331-48, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21058177

RESUMO

This study describes the current roles of dental librarians in Evidence-based Dentistry (EBD) education including their perceptions of EBD and barriers to their involvement. A Web-based survey was distributed to the dental librarians in North America, with a 71% response rate. The results showed that the majority of dental librarians are playing multiple and diverse roles in EBD education. The most frequently cited barrier to their involvement is the low level of interest from the dental faculty/student/school. Most dental librarians felt competent in supporting EBD, although continuing education needs in both EBD and teaching skills were pointed out.


Assuntos
Odontologia Baseada em Evidências/educação , Bibliotecários , Papel Profissional , Humanos , América do Norte , Literatura de Revisão como Assunto , Inquéritos e Questionários
20.
Beijing Da Xue Xue Bao Yi Xue Ban ; 41(1): 16-20, 2009 Feb 18.
Artigo em Chinês | MEDLINE | ID: mdl-19221557

RESUMO

Keratocystic odontogenic tumors (KCOTs, previously known as odontogenic keratocysts) are aggressive, noninflammatory jaw lesions with a putative high growth potential and a propensity for recurrence. This article puts together a summary of the serial studies related to KCOTs undertaken by the author's research group in recent years. Intraosseous jaw cysts with a solely orthokeratinized lining epithelium have been suggested to differ from the typical KCOTs. We report 20 cases of such cyst type under the term of 'orthokeratinized odontogenic cyst (OOC)'. Apart from the presence of a keratinizing epithelial lining, the OOC lacks the other histological features of KCOT, exhibits little if any tendency to recur, has no apparent association with NBCCS, may be cured by simple enucleation, and may thus constitute its own clinical entity. Mutations in PTCH1 gene are responsible for NBCCS and are related in tumors associated with this syndrome. We have so far detected 26 PTCH1 mutations (2 mutations occurred twice) in 10 out of 34 (29.4%) sporadic and 14 out of 16 (87.5%) NBCCS-associated KCOTs. The 26 mutations consisted of 10 frameshift, 2 nonsense, 3 aberrant splicing, 4 in-frame insertion/deletion/ duplication and 7 missense mutations. Two missense mutations in PTCH2 were also detected in 2 out of 15 NBCCS related KCOT patients. By contrast, no pathogenic mutation was detected in SMO. Thus, our data, together with reports from other groups, indicate that defects of PTCH1 are involved in the pathogenesis of syndromic as well as sporadic KCOTs. The pathogenic role of PTCH2 requires further investigation. A series of in vitro studies on bone resorption of KCOTs and ameloblastomas were undertaken by this group. The results indicate that odontogenic lesions could promote bone resorption in vitro and it is likely to be related to some of the cytokines secreted by the lesions.


Assuntos
Neoplasias Maxilomandibulares/genética , Mutação , Cistos Odontogênicos/genética , Tumores Odontogênicos/genética , Receptores de Superfície Celular/genética , Humanos , Neoplasias Maxilomandibulares/metabolismo , Cistos Odontogênicos/metabolismo , Cistos Odontogênicos/cirurgia , Tumores Odontogênicos/metabolismo , Receptores Patched , Receptor Patched-1 , Receptor Patched-2 , Receptores Acoplados a Proteínas-G/genética , Receptor Smoothened
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA