Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 602
Filtrar
1.
Int Immunopharmacol ; 101(Pt B): 108271, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34700113

RESUMO

Pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. It is a growing clinical problem which can result in breathlessness or respiratory failure and has an average life expectancy of 3 years from diagnosis. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition and aberrant wound healing of epithelial cells. Targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach for the potential treatment of PF. Clevudine is s a purine nucleoside analogue which in an oral formulation is approved for treatment of patients with hepatitis B virus (HBV). Here, we found that clevudine is capable of suppressing pro-fibrotic phenotype (i.e., CD206, Arg1 and YM1) of M2 macrophages while enhancing anti-fibrotic phenotype (i.e., CD86, IL-6 and IL-10) by inhibiting PI3K/Akt signaling pathway. This effect further alleviates M2-induced myofibroblast activation and epithelial-to-mesenchymal transition (EMT), thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, with a concomitant recover ofpulmonary functions in vivo. Less infiltration of M2 macrophages between α-SMA + cells was also found in clevudine treated mice. Our findings indicate a potential anti-fibrotic effect of clevudine by regulating macrophage polarization and might be meaningful in clinical settings.


Assuntos
Antivirais/uso terapêutico , Arabinofuranosiluracila/análogos & derivados , Macrófagos/imunologia , Fibrose Pulmonar/tratamento farmacológico , Mucosa Respiratória/fisiologia , Animais , Arabinofuranosiluracila/uso terapêutico , Bleomicina , Diferenciação Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Células RAW 264.7 , Células Th2/imunologia
2.
Toxicol In Vitro ; 70: 105010, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33022361

RESUMO

Primary mouse hepatocytes isolated from genetically defined and/or diverse lines and disease models are a valuable resource for studying the impact of genetic and environmental factors on drug response and disease. However, standard monolayer cultures result in a rapid decline in mouse hepatocyte viability and functionality. Therefore, we evaluated 3D spheroid methodology for long-term culture of primary mouse hepatocytes, initially to support investigations of drug-induced liver injury (DILI). Primary hepatocytes isolated from male and female C57BL/6J mice were used to generate spheroids by spontaneous self-aggregation in ultra-low attachment plates. Spheroids with well-defined perimeters were observed within 5 days after seeding and retained morphology, ATP, and albumin levels for an additional 2 weeks in culture. Global microarray profiling and quantitative targeted proteomics assessing 10 important drug metabolizing enzymes and transporters demonstrated maintenance of mRNA and protein levels in spheroids over time. Activities for 5 major P450 enzymes were also stable and comparable to activities previously reported for human hepatocyte spheroids. Time- and concentration-dependent decreases in ATP and albumin were observed in response to the DILI-causing drugs acetaminophen, fialuridine, AMG-009, and tolvaptan. Collectively, our results demonstrate successful long-term culture of mouse hepatocytes as spheroids and their utility to support investigations of DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Modelos Biológicos , Acetaminofen/toxicidade , Trifosfato de Adenosina/metabolismo , Albuminas/metabolismo , Animais , Arabinofuranosiluracila/análogos & derivados , Arabinofuranosiluracila/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Hepatócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fenilacetatos/toxicidade , Proteômica , Esferoides Celulares/metabolismo , Sulfonamidas/toxicidade , Tolvaptan/toxicidade , Transcriptoma
3.
Toxicol Appl Pharmacol ; 403: 115163, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32730777

RESUMO

During its clinical development fialuridine caused liver toxicity and the death of five patients. This case remains relevant due to the continued development of mechanistically-related compounds against a back-drop of simple in vitro models which remain limited for the preclinical detection of such delayed toxicity. Here, proteomic investigation of a differentiated, HepaRG, and proliferating, HepG2 cell model was utilised to confirm the presence of the hENT1 transporter, thymidine kinase-1 and -2 (TK1, TK2) and thymidylate kinase, all essential in order to reproduce the cellular activation and disposition of fialuridine in the clinic. Acute metabolic modification assays could only identify mitochondrial toxicity in HepaRG cells following extended dosing, 2 weeks. Toxic effects were observed around 10 µM, which is within a range of 10-15 X approximate Cmax. HepaRG cell death was accompanied by a significant decrease in mitochondrial DNA content, indicative of inhibition of mitochondrial replication, and a subsequent reduction in mitochondrial respiration and the activity of mitochondrial respiratory complexes, not replicated in HepG2 cells. The structural epimer of fialuridine, included as a pharmacological negative control, was shown to have no cytotoxic effects in HepaRG cells up to 4 weeks. Overall, these comparative studies demonstrate the HepaRG model has translational relevance for fialuridine toxicity and therefore may have potential in investigating the inhibition of mitochondrial replication over prolonged exposure for other toxicants.


Assuntos
Antivirais/farmacologia , Arabinofuranosiluracila/análogos & derivados , Hepatócitos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Arabinofuranosiluracila/farmacologia , Linhagem Celular Tumoral , Replicação do DNA/efeitos dos fármacos , DNA Mitocondrial/fisiologia , Relação Dose-Resposta a Droga , Humanos , Mitocôndrias/fisiologia
4.
Mol Imaging ; 19: 1536012120936876, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32598214

RESUMO

PURPOSE: Imaging is limited in the evaluation of bacterial infection. Direct imaging of in situ bacteria holds promise for noninvasive diagnosis. We investigated the ability of a bacterial thymidine kinase inhibitor ([124I]FIAU) to image pulmonary and musculoskeletal infections. METHODS: Thirty-three patients were prospectively accrued: 16 with suspected musculoskeletal infection, 14 with suspected pulmonary infection, and 3 with known rheumatoid arthritis without infection. Thirty-one patients were imaged with [124I]FIAU PET/CT and 28 with [18F]FDG PET/CT. Patient histories were reviewed by an experienced clinician with subspecialty training in infectious diseases and were determined to be positive, equivocal, or negative for infection. RESULTS: Sensitivity, specificity, positive-predictive value, negative-predictive value, and accuracy of [124I]FIAU PET/CT for diagnosing infection were estimated as 7.7% to 25.0%, 0.0%, 50%, 0.0%, and 20.0% to 71.4% for musculoskeletal infections and incalculable-100.0%, 51.7% to 72.7%, 0.0% to 50.0%, 100.0%, and 57.1% to 78.6% for pulmonary infections, respectively. The parameters for [18F]FDG PET/CT were 75.0% to 92.3%, 0.0%, 23.1% to 92.3%, 0.0%, and 21.4% to 85.7%, respectively, for musculoskeletal infections and incalculable to 100.0%, 0.0%, 0.0% to 18.2%, incalculable, and 0.0% to 18.2% for pulmonary infections, respectively. CONCLUSIONS: The high number of patients with equivocal clinical findings prevented definitive conclusions from being made regarding the diagnostic efficacy of [124I]FIAU. Future studies using microbiology to rigorously define infection in patients and PET radiotracers optimized for image quality are needed.


Assuntos
Arabinofuranosiluracila/análogos & derivados , Infecções Bacterianas/diagnóstico por imagem , Radioisótopos do Iodo/química , Doenças Musculoesqueléticas/diagnóstico por imagem , Doenças Musculoesqueléticas/microbiologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Infecções Respiratórias/diagnóstico por imagem , Infecções Respiratórias/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Arabinofuranosiluracila/química , Feminino , Fluordesoxiglucose F18/química , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade
5.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1126-1127: 121770, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31454720

RESUMO

Purine analogs like aracytine (AraC) are a mainstay for treating acute myeloid leukemia (AML). There are marked differences in drug dosing and scheduling depending on the protocols when treating AML patients with AraC. Large inter-patient pharmacokinetics variability has been reported, and genetic polymorphisms affecting cytidine deaminase (CDA), the liver enzyme responsible for the conversion of Ara-C to inactive uracil arabinoside (AraU) could be a culprit for either life-threatening toxicities or poor efficacy related to substantial changes in plasma exposure levels among patients. The quantitative determination of Ara-C in plasma is challenging due the required sensitivity because of the short half-life of this drug (i.e., <10 min) and the metabolic instability in biological matrix upon sampling possibly resulting in erratic values. We developed and validated a liquid chromatography tandem mass spectrometry method (UPLC-MS/MS) for the simultaneous determination of Ara-C and Ara-U metabolite in human plasma. After simple and rapid precipitation, analytes were successfully separated and quantitated over a 1-500 ng/ml range for Ara-C and 250-7500 ng/ml range for AraU. The performance and reliability of this method was tested as part of an investigational study in AML patients treated with low dose cytarabine and confirmed marked differences in drug exposure levels and metabolic ratio, depending on the CDA status of the patients. Overall, this new method meets the requirements of current bioanalytical guidelines and could be used to monitor drug levels in AML patients with respect to their CDA phenotypes.


Assuntos
Antimetabólitos Antineoplásicos/sangue , Arabinofuranosiluracila/sangue , Cromatografia Líquida de Alta Pressão/métodos , Citarabina/sangue , Espectrometria de Massas em Tandem/métodos , Antimetabólitos Antineoplásicos/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Arabinofuranosiluracila/metabolismo , Arabinofuranosiluracila/farmacocinética , Arabinofuranosiluracila/uso terapêutico , Citarabina/metabolismo , Citarabina/farmacocinética , Citarabina/uso terapêutico , Monitoramento de Medicamentos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Modelos Lineares , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
6.
Arch Toxicol ; 93(4): 1021-1037, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30915487

RESUMO

Drug-induced liver injury remains a frequent reason for drug withdrawal. Accordingly, more predictive and translational models are required to assess human hepatotoxicity risk. This study presents a comprehensive evaluation of two promising models to assess mechanistic hepatotoxicity, microengineered Organ-Chips and 3D hepatic spheroids, which have enhanced liver phenotype, metabolic activity and stability in culture not attainable with conventional 2D models. Sensitivity of the models to two hepatotoxins, acetaminophen (APAP) and fialuridine (FIAU), was assessed across a range of cytotoxicity biomarkers (ATP, albumin, miR-122, α-GST) as well as their metabolic functionality by quantifying APAP, FIAU and CYP probe substrate metabolites. APAP and FIAU produced dose- and time-dependent increases in miR-122 and α-GST release as well as decreases in albumin secretion in both Liver-Chips and hepatic spheroids. Metabolic turnover of CYP probe substrates, APAP and FIAU, was maintained over the 10-day exposure period at concentrations where no cytotoxicity was detected and APAP turnover decreased at concentrations where cytotoxicity was detected. With APAP, the most sensitive biomarkers were albumin in the Liver-Chips (EC50 5.6 mM, day 1) and miR-122 and ATP in the liver spheroids (14-fold and EC50 2.9 mM, respectively, day 3). With FIAU, the most sensitive biomarkers were albumin in the Liver-Chip (EC50 126 µM) and miR-122 (15-fold) in the liver spheroids, both on day 7. In conclusion, both models exhibited integrated toxicity and metabolism, and broadly similar sensitivity to the hepatotoxicants at relevant clinical concentrations, demonstrating the utility of these models for improved hepatotoxicity risk assessment.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Modelos Biológicos , Esferoides Celulares/efeitos dos fármacos , Acetaminofen/toxicidade , Arabinofuranosiluracila/análogos & derivados , Arabinofuranosiluracila/toxicidade , Biomarcadores/metabolismo , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutationa Transferase/metabolismo , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Esferoides Celulares/metabolismo
7.
Sci Rep ; 8(1): 12618, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135466

RESUMO

Critical bacterial pathogens of public health and biodefense concerns were engineered to constitutively express Escherichia coli enzyme thymidine kinase (TK) that allows for noninvasive nuclear imaging via phosphorylation and entrapment of radiolabeled nucleoside analog 1-(2'deoxy-2'-fluoro-ß-D-arabinofuranosyl)-5-iodouracil (FIAU). Expression of functional TK was established using a nucleoside analog Zidovudine that impeded the growth of tk-engineered bacteria. Significantly, no observable growth differences were detected for FIAU. High resolution mass spectrometry with Pseudomonas aeruginosa PAO1 and its tk variant (PAO1TK) confirmed FIAU phosphorylation and retention only in PAO1TK. In vitro gamma counting with wild-type PAO1, Acinetobacter baumannii and Burkholderia pseudomallei Bp82 and their tk derivatives with [18F]FIAU further confirmed that tk variants selectively incorporated the radiotracer, albeit with varying efficiencies. In vitro [18F]FIAU labeling coupled with in vivo Positron Emission Tomography/Computed Tomography (PET/CT) imaging of PAO1 and PAO1TK confirmed that only PAO1TK can be imaged in mice at sensitivities ≥107 bacteria per infection site. This was further verified by administering [18F]FIAU to animals infected with PAO1 and PAO1TK. Utility of tk-engineered P. aeruginosa in noninvasive PET/CT imaging for bacterial therapeutic evaluation in animals was demonstrated employing antibiotic ciprofloxacin, underscoring the immediate use of PAO1TK and potentially other engineered pathogens for evaluating experimental therapeutics.


Assuntos
Bactérias/metabolismo , Bioengenharia/métodos , Timidina Quinase/metabolismo , Acinetobacter baumannii/metabolismo , Animais , Arabinofuranosiluracila/análogos & derivados , Arabinofuranosiluracila/farmacologia , Engenharia Biomédica , Burkholderia pseudomallei/metabolismo , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Radioisótopos do Iodo , Camundongos , Nucleosídeos/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Pseudomonas aeruginosa/metabolismo , Timidina Quinase/genética , Tomografia Computadorizada por Raios X , Zidovudina/farmacologia
8.
Methods Mol Biol ; 1790: 153-163, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29858790

RESUMO

Recent advances in T cell-based immunotherapies from bench to bedside have highlighted the need for improved diagnostic imaging of T cell trafficking in vivo and the means to noninvasively investigate failures in treatment response. T cells expressing tumor-associated T cell receptors (TCRs) or engineered with chimeric antigen receptors (CARs) face multiple challenges, including possible influence of genetic engineering on T cell efficacy, inhibitory effects of the tumor microenvironment, tumor checkpoint proteins and on-target, off-tissue toxicities (Kershaw et al., Nat Rev Cancer 13:525-541, 2013; Corrigan-Curay et al., Mol Ther 22:1564-1574, 2014; June et al., Sci Trans Med 7:280-287, 2015; Whiteside et al., Clin Cancer Res 22:1845-1855, 2016; Rosenberg and Restifo, Science 348:62-68, 2015). Positron emission tomography (PET) imaging with nuclear reporter genes is potentially one of the most sensitive and noninvasive methods to quantitatively track and monitor function of adoptively transferred cells in vivo. However, in vivo PET detection of T cells after administration into patients is limited by the degree of tracer accumulation per cell in situ and cell density in target tissues. We describe here a method for ex vivo radiolabeling of T cells, a reliable and robust technique for PET imaging of the kinetics of T cell biodistribution from the time of administration to subsequent localization in targeted tumors and other tissues of the body. This noninvasive technique can provide valuable information to monitor and identify the potential efficacy of adoptive cell therapies.


Assuntos
Genes Reporter , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/patologia , Linfócitos T/citologia , Animais , Arabinofuranosiluracila/análogos & derivados , Humanos , Masculino , Camundongos , Camundongos SCID , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Linfócitos T/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Methods Mol Biol ; 1790: 165-180, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29858791

RESUMO

Adoptive cell transfer immunotherapy has demonstrated significant promise in the treatment of cancer, with long-term, durable responses. T cells expressing T cell receptors (TCRs) that recognize tumor antigens, or engineered with chimeric antigen receptors (CARs) can recognize and eliminate tumor cells even in advanced disease. Positron emission tomography (PET) imaging with nuclear reporter genes, a noninvasive method to track and monitor function of engineered cells in vivo, allows quantitative, longitudinal monitoring of these cells, including their expansion/contraction, migration, retention at target and off-target sites, and biological state. As an additional advantage, some reporter genes also exhibit "suicide potential" permitting the safe elimination of adoptively transferred T cells in instances of adverse reaction to therapy. Here, we describe the production of human nuclear reporter gene-expressing T cells and noninvasive PET imaging to monitor their cell fate in vivo.


Assuntos
Genes Reporter , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Transferência Adotiva , Animais , Arabinofuranosiluracila/análogos & derivados , Humanos , Camundongos , Camundongos SCID , Proteínas Nucleares/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
10.
Clin Nucl Med ; 43(7): e245-e246, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29742600

RESUMO

We report on an incidental detection of a meningioma on [F]-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (F-FMAU) PET/CT scan that was performed during a prospective investigation of F-FMAU PET/CT for targeted biopsy of potential sites of tumor in men with suspected prostate cancer based on elevated prostate-specific antigen level. Neither prostate multiparamteric MRI nor F-FMAU PET/CT localized small volume Gleason 3 + 3 tumor deposits. However, an incidental focal high accumulation of F-FMAU was observed in high right parietal lobe that displayed characteristics of a meningioma on a subsequent brain MRI.


Assuntos
Arabinofuranosiluracila/análogos & derivados , Radioisótopos de Flúor , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos , Idoso , Humanos , Achados Incidentais , Imageamento por Ressonância Magnética , Masculino
11.
Curr Med Chem ; 25(16): 1867-1878, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29189119

RESUMO

BACKGROUND: Developed as an antiviral drug in the 1960s and 1970s, the thymidine analogue 2'-deoxy-2'-fluoro-5-methyl-1-ß-D-arabinofuranosyluracil (FMAU) was translated to clinical application for treatment of herpes simplex virus infection. In phase I clinical trial of FMAU; however, patients experienced neurotoxicity at the pharmacological dose, and FMAU was withdrawn from the trial. More recently, FMAU has been developed as a tracer for positron emission tomography (PET) imaging in early detection of cancer through its binding to human thymidine kinase, which is upregulated in cancer cells. FMAU radiolabeled with 11C or 18F has been examined for PET imaging of tumor cell proliferation and DNA synthesis. Although many reports have been partially published on FMAU, systematic reviews outlining the historic development and imaging probe are lacking. This review is focused on the identification of kinases, the chemistry of FAMU and its application in cancer diagnosis and therapy assessment. OBJECTIVE: The aim of this study was to review the historic development of FMAU, from its synthetic development and antiviral activity studies to its radiolabeling and evaluate it as a PET imaging probe for the early detection of cancer and assessment of treatment response, including published reports on the clinical utility of 18F-FMAU. CONCLUSION: While FMAU was not successful as an antiviral agent, 18F-FMAU is a suitable radiotracer for early detection of cancer and assessment of response to therapy by PET. The process of clinical grade 18F-FMAU production requires further improvement. 18F-FMAU has high potential for clinical application, but further extensive studies are needed to establish this tracer in the diagnosis of various cancers and assessment of their response to therapy.


Assuntos
Antivirais/química , Antivirais/uso terapêutico , Arabinofuranosiluracila/análogos & derivados , Meios de Contraste/química , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Antivirais/síntese química , Arabinofuranosiluracila/síntese química , Arabinofuranosiluracila/química , Arabinofuranosiluracila/uso terapêutico , Radioisótopos de Carbono , Radioisótopos de Flúor , Humanos , Compostos Radiofarmacêuticos/química
13.
J Korean Med Sci ; 32(11): 1857-1860, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28960041

RESUMO

Clevudine was approved as an antiviral agent for hepatitis B virus, which showed marked, rapid inhibition of virus replication without significant toxicity. However, several studies have reported myopathy associated with clevudine therapy. Also, we experienced seven patients who suffered from myopathy during clevudine therapy. To characterize clevudine-induced myopathy, we collected previously reported cases of clevudine myopathy and analyzed all the cases including our cases. We searched electronic databases that were published in English or Korean using PubMed and KoreaMed. Ninety-five cases with clevudine myopathy, including our seven cases, were selected and analyzed for the demographic data, clinical features, and pathologic findings. The 95 patients with clevudine-induced myopathy comprised 52 women and 43 men aged 48.9 years (27-76 years). The patients received clevudine therapy for about 14.2 months (5-24 months) before the development of symptoms. Weakness mainly involved proximal extremities, especially in the lower extremities, and bulbar and neck weakness were observed in some cases (13.7%). Creatine kinase was elevated in the majority of patients (97.9%). Myopathic patterns on electromyography were observed in most patients examined (98.1%). Muscle biopsy presented patterns compatible with mitochondrial myopathy in the majority (90.2%). The weakness usually improved within about 3 months after the discontinuation of clevudine. Though clevudine has been known to be safe in a 6-month clinical trial, longer clevudine therapy for about 14 months may cause reversible mitochondrial myopathy. Careful clinical attention should be paid to patients with long-term clevudine therapy.


Assuntos
Antivirais/efeitos adversos , Arabinofuranosiluracila/análogos & derivados , Miopatias Mitocondriais/etiologia , Adulto , Idoso , Antivirais/uso terapêutico , Arabinofuranosiluracila/efeitos adversos , Arabinofuranosiluracila/uso terapêutico , Creatina Quinase/sangue , Bases de Dados Factuais , Eletromiografia , Feminino , Hepatite B/tratamento farmacológico , Humanos , L-Lactato Desidrogenase/sangue , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Pescoço/fisiopatologia
14.
Dis Markers ; 2017: 7075935, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28396612

RESUMO

Aim. To determine whether nucleot(s)ide analogs therapy has survival benefit for patients with HBV-related HCC after unresectable treatment. Method. A systematic search was conducted through seven electronic databases including PubMed, OVID, EMBASE, Cochrane Databases, Elsevier, Wiley Online Library, and BMJ Best Practice. All studies comparing NA combined with unresectable treatment versus unresectable treatment alone were considered for inclusion. The primary outcome was the overall survival (OS) after unresectable treatment for patients with HBV-related HCC. The secondary outcome was the progression-free survival (PFS). Results were expressed as hazard ratio (HR) for survival with 95% confidence intervals. Results. We included six studies with 994 patients: 409 patients in nucleot(s)ide analogs therapy group and 585 patients without antiviral therapy in control group. There were significant improvements for the overall survival (HR = 0.57; 95% CI = 0.47-0.70; p < 0.001) and progression-free survival (HR = 0.84; 95% CI = 0.71-0.99; p = 0.034) in the NA-treated group compared with the control group. Funnel plot showed that there was no significant publication bias in these studies. When it comes to antiviral drugs and operation method, it also showed benefit in NA-treated group. At the same time, overall mortality as well as mortality secondary to liver failure in NA-treated group was obviously lesser. Sensitivity analyses confirmed the robustness of the results. Conclusions. Nucleot(s)ide analogs therapy after unresectable treatment has potential beneficial effects in terms of overall survival and progression-free survival. NA therapy should be considered in clinical practice.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Arabinofuranosiluracila/análogos & derivados , Arabinofuranosiluracila/uso terapêutico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Guanina/análogos & derivados , Guanina/uso terapêutico , Vírus da Hepatite B/crescimento & desenvolvimento , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/mortalidade , Humanos , Lamivudina/uso terapêutico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Organofosfonatos/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Telbivudina , Tenofovir/uso terapêutico , Timidina/análogos & derivados , Timidina/uso terapêutico
15.
Mol Imaging Biol ; 19(6): 810-816, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28289967

RESUMO

PURPOSE: We conducted a pilot trial utilizing [18F]FMAU [1-(2'-deoxy-2'-[18F]fluoro-ß-D-arabinofuranosyl thymine] as a tumor tracer in positron emission tomography (PET) and evaluated its reproducibility, and changes in maximum and peak standardized uptake value (SUVmax and SUVpeak) with zoledronic acid treatment in castrate resistant prostate cancer (CRPC) patients with bone metastases (BM). PROCEDURES: Eligible patients had CRPC with radiographic evidence of BM and creatinine clearance >30 ml/min. Two baseline [18F]FMAU-PET scans (about 1 week apart, range 2-12 days) were obtained for testing reproducibility. Zoledronic acid 4 mg was infused over 15 min within 1 week after second scan and a third PET scan was obtained 7 days later. The bony lesion with the highest uptake on the first scan was compared with later scans. Bone turnover markers and prostate-specific antigen (PSA) were obtained pre- and post-therapy. PET response was defined as decline in SUVmean of ≥15 % after zoledronic acid. RESULTS: Eleven patients were evaluated, median age was 65 years, five were African-American and six were Caucasian, and median PSA level was 36.3 ng/ml (range 1.0-1209.3). Notably, the range of absolute percent SUVmax changes varied between 0.77 and 54.7, and only nine measurements were greater than one (1.09-2.19). Zoledronic acid did not appreciably change FMAU uptake. No clinical response was noted. Urine N-telopeptide (NTx) was markedly decreased in all patients after zoledronic acid and serum bone-specific alkaline phosphatase (BSAP) registered a modest change. Urine NTx correlated more closely with SUV max than serum BSAP. CONCLUSIONS: FMAU tracer was able to detect bone metastases in CRPC patients but uptake was highly variable in bony lesions. Zoledronic acid did not produce an appreciable change in scans. Future investigations of FMAU tracer as a marker of early response in CRPC is recommended.


Assuntos
Arabinofuranosiluracila/análogos & derivados , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Difosfonatos/uso terapêutico , Radioisótopos de Flúor/química , Imidazóis/uso terapêutico , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/patologia , Idoso , Arabinofuranosiluracila/química , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/urina , Neoplasias Ósseas/urina , Remodelação Óssea , Difosfonatos/farmacologia , Humanos , Processamento de Imagem Assistida por Computador , Imidazóis/farmacologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Antígeno Prostático Específico/metabolismo , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X , Ácido Zoledrônico
16.
Anticancer Res ; 37(2): 475-479, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179292

RESUMO

AIM: We assessed the association between the presence and absence of androgen on the normal biodistribution of the positron emission tomography (PET) cellular proliferation imaging biomarker, [18F]-2'-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU), in mice. MATERIALS AND METHODS: Non-castrated (n=4) and castrated (n=4) athymic non-tumor-bearing male mice served as models for presence and absence, respectively, of androgen. MicroPET-CT scans were performed 1 h following tail vein administration of 200 uCi of 18F-FMAU. Imaging was performed at baseline and then at 7-day intervals longitudinally for 35 days only in castrated mice following subcutaneous introduction of a 12.5 mg, 21-day release, dihydrotestosterone pellet. Mean standardized uptake values (SUVmean) were obtained for liver, heart, and muscle. Several two-group comparisons of average of SUVmean were performed. RESULTS: Pre-pellet baseline average SUVmean (±s.d.) values in castrated mice were significantly lower than baseline non-castrated values, increased on day 15 and reached peak values on day 28, at which time they were significantly higher than corresponding baseline levels in both non-castrated and pre-pellet castrated mice. The peak values decreased significantly following dihydrotestosterone withdrawal. CONCLUSION: There is a significant modulatory effect of androgen on normal 18F-FMAU uptake levels in mice liver, heart and muscle tissues.


Assuntos
Androgênios/metabolismo , Arabinofuranosiluracila/análogos & derivados , Compostos Radiofarmacêuticos/farmacocinética , Animais , Arabinofuranosiluracila/farmacocinética , Preparações de Ação Retardada , Di-Hidrotestosterona/administração & dosagem , Radioisótopos de Flúor/análise , Masculino , Camundongos , Camundongos Nus , Orquiectomia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Distribuição Tecidual
17.
Gut Liver ; 11(1): 129-135, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27538443

RESUMO

Background/Aims: Data are lacking regarding the management of chronic hepatitis B (CHB) with resistance to clevudine (CLV). This study evaluated the efficacy of different rescue therapies for CLV-resistant CHB. Methods: Patients with CLV-resistant CHB were enrolled in the cohort, and all patients developed virologic breakthrough during CLV therapy and had confirmed-genotypic resistance to CLV (rtM204I mutation) before enrollment. Results: Of the 107 patients, 12 received adefovir (ADV), 21 received a CLV plus ADV combination (CLV+ADV), 34 received a lamivudine plus ADV combination (LAM+ADV), and 40 received entecavir (ETV) therapy for 48 weeks. The CLV+ADV group had the lowest hepatitis B virus (HBV) DNA level (p<0.0001) and showed the greatest reduction of HBV DNA levels from baseline compared to all other groups (p=0.004) at week 48. HBV DNA was undetectable (<70 IU/mL) in 0%, 57.1%, 21.2%, and 27.5% (p=0.003) of the patients in each group, respectively, at week 48. At the end of the study, the mean alanine transaminase (ALT) level, rate of ALT normalization, and rate of hepatitis B envelope antigen loss or seroconversion did not differ between groups. Conclusions: CLV+ADV combination therapy in patients with CLV-resistant CHB more effectively suppresses HBV replication than ETV, ADV, or LAM+ADV therapy.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Arabinofuranosiluracila/análogos & derivados , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Adenina/uso terapêutico , Adulto , Idoso , Arabinofuranosiluracila/uso terapêutico , Estudos de Coortes , DNA Viral/sangue , Gerenciamento Clínico , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Genótipo , Guanina/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral
18.
Cancer Imaging ; 16(1): 34, 2016 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-27751167

RESUMO

BACKGROUND: A principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT), 1-(2'-deoxy-2'-[18F]fluoro-ß-D-arabinofuranosyl) thymidine (18F-FMAU), and 1-(2'-deoxy-2'-[18F]fluoro-ß-D-arabinofuranosyl) uracil (18F-FAU) in patients with advanced cancer. METHODS: Fifteen patients were imaged, five with each imaging agent. Patients had been previously diagnosed with breast, colorectal, gastric, and esophageal cancers and had not received therapy for at least 4 weeks prior to the first scan, and had not been treated with any prior fluoropyrimidines. Subjects were imaged within a week before the start of capecitabine and on the second day of treatment, after the third dose of capecitabine. Tracer uptake was quantified by mean standard uptake value (SUVmean) and using kinetic analysis. RESULTS: Patients imaged with 18F-FLT showed variable changes in retention and two patients exhibited an increase in SUVmean of 172.3 and 89.9 %, while the other patients had changes ranging from +19.4 to -25.4 %. The average change in 18F-FMAU retention was 0.2 % (range -24.4 to 23.1) and 18F-FAU was -10.2 % (range -40.3 to 19.2). Observed changes correlated strongly with SUVmax but not kinetic measurements. CONCLUSIONS: This pilot study demonstrates that patients treated with capecitabine can produce a marked increase in 18F-FLT retention in some patients, which will require further study to determine if this flare is predictive of therapeutic response. 18F-FAU and 18F-FMAU showed little change, on average, after treatment.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Arabinofuranosiluracila/análogos & derivados , Capecitabina/efeitos adversos , Didesoxinucleosídeos/farmacocinética , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Arabinofuranosiluracila/farmacocinética , Capecitabina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico
19.
Mol Imaging Biol ; 18(6): 838-848, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27246312

RESUMO

PURPOSE: We have incorporated a positron emission tomography (PET) functionality in T cells expressing a CD19-specific chimeric antigen receptor (CAR) to non-invasively monitor the adoptively transferred cells. PROCEDURES: We engineered T cells to express CD19-specific CAR, firefly luciferase (ffLuc), and herpes simplex virus type-1 thymidine kinase (TK) using the non-viral-based Sleeping Beauty (SB) transposon/transposase system adapted for human application. Electroporated primary T cells were propagated on CD19+ artificial antigen-presenting cells. RESULTS: After 4 weeks, 90 % of cultured cells exhibited specific killing of CD19+ targets in vitro, could be ablated by ganciclovir, and were detected in vivo by bioluminescent imaging and PET following injection of 2'-deoxy-2'-[18F]fluoro-5-ethyl-1-ß-D-arabinofuranosyl-uracil ([18F]FEAU). CONCLUSION: This is the first report demonstrating the use of SB transposition to generate T cells which may be detected using PET laying the foundation for imaging the distribution and trafficking of T cells in patients treated for B cell malignancies.


Assuntos
Herpesvirus Humano 1/enzimologia , Tomografia por Emissão de Pósitrons/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Timidina Quinase/metabolismo , Transposases/metabolismo , Animais , Arabinofuranosiluracila/análogos & derivados , Arabinofuranosiluracila/química , Linhagem Celular , Ganciclovir/farmacologia , Técnicas de Transferência de Genes , Humanos , Luciferases/metabolismo , Camundongos , Compostos Radiofarmacêuticos/química , Transgenes , Xenopus
20.
Sci Rep ; 6: 25187, 2016 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-27143246

RESUMO

Liver biology and function, drug-induced liver injury (DILI) and liver diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, as their rapid de-differentiation restricts their usefulness substantially. Thus, we have developed and extensively characterized an easily scalable 3D PHH spheroid system in chemically-defined, serum-free conditions. Using whole proteome analyses, we found that PHH spheroids cultured this way were similar to the liver in vivo and even retained their inter-individual variability. Furthermore, PHH spheroids remained phenotypically stable and retained morphology, viability, and hepatocyte-specific functions for culture periods of at least 5 weeks. We show that under chronic exposure, the sensitivity of the hepatocytes drastically increased and toxicity of a set of hepatotoxins was detected at clinically relevant concentrations. An interesting example was the chronic toxicity of fialuridine for which hepatotoxicity was mimicked after repeated-dosing in the PHH spheroid model, not possible to detect using previous in vitro systems. Additionally, we provide proof-of-principle that PHH spheroids can reflect liver pathologies such as cholestasis, steatosis and viral hepatitis. Combined, our results demonstrate that the PHH spheroid system presented here constitutes a versatile and promising in vitro system to study liver function, liver diseases, drug targets and long-term DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/fisiologia , Arabinofuranosiluracila/análogos & derivados , Arabinofuranosiluracila/toxicidade , Células Cultivadas , Humanos , Modelos Biológicos , Estudo de Prova de Conceito , Proteoma/análise
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...