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1.
Zhonghua Nei Ke Za Zhi ; 61(5): 537-542, 2022 May 01.
Artigo em Zh | MEDLINE | ID: mdl-35488604

RESUMO

Objective: To evaluate whether underdilated stent could reduce the occurrence of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) creation. Methods: A total of 197 patients with decompensated liver cirrhosis, who had underwent TIPS creation at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, were analyzed retrospectively, including 110 males and 87 females with age 25-79 (54±11) years old. Uncovered and covered stents with 8 mm diameter were implanted in all subjects, and then dilated by balloon catheters with 6 mm or 8 mm diameter. The patients were divided into two groups, including underdilated group (6 mm, n=105) and control group (8 mm, n=92).Kaplan-Meier curves were used to illustrate cumulative rate of HE, and the differences were assessed with the log-rank test. Multivariate analyses with a Cox regression model were conducted to explore the risk factors for HE. Results: During a median follow-up period of 29 (12-54) months, 16 (15.2%) patients developed HE in the underdilated group and 27 (29.3%) patients in the control group. There was a significant difference in the cumulative rate of HE (P=0.014), but no statistical differences were found in terms of variceal rebleeding, shunt dysfunction and survival between the two groups (P=0.608, P=0.659, P=0.968). In multivariated analysis, group assignment (underdilated vs. control, HR=0.291, 95%CI 0.125-0.674, P=0.004) was identified as an independent risk factor for HE after TIPS creation. Conclusion: Underdilated TIPS could reduced the risk of HE compared with completely dilated TIPS, with comparable risk of variceal rebleeding, shunt dysfunction and mortality. And it is worthy of applying this technique to a large sample of patients in clinical practice.


Assuntos
Encefalopatia Hepática , Derivação Portossistêmica Transjugular Intra-Hepática , Adulto , Idoso , Feminino , Encefalopatia Hepática/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Estudos Retrospectivos , Fatores de Risco , Stents/efeitos adversos
2.
Ann Oncol ; 32(9): 1137-1147, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34139272

RESUMO

BACKGROUND: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). RESULTS: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. CONCLUSION: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Método Duplo-Cego , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Nivolumabe/efeitos adversos , Paclitaxel/efeitos adversos , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas
3.
Fa Yi Xue Za Zhi ; 37(2): 158-165, 2021 Apr.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-34142475

RESUMO

ABSTRACT: Objective To observe the skin ultrastructure change of electric shock death rats and to test the expression changes of hypoxia-inducible factor-2α (HIF-2α) and heart type-fatty acid-binding protein (H-FABP) of myocardial cells, in order to provide basis for forensic identification of electric shock death. Methods The electric shock model of rats was established. The 72 rats were randomly divided into control group, electric shock death group and postmortem electric shock group. Each group was divided into three subgroups, immediate (0 min), 30 min and 60 min after death. The skin changes of rats were observed by HE staining, the changes of skin ultrastructure were observed by scanning electron microscopy, and the expression of HIF-2α and H-FABP in rats myocardium was tested by immunohistochemical staining. Results The skin in the electric shock death group and postmortem electric shock group had no significant difference through the naked eye or by HE staining. Under the scanning electron microscope, a large number of cellular debris, cells with unclear boundaries, withered cracks, circular or elliptical holes scattered on the cell surface and irregular edges were observed. A large number of spherical foreign body particles were observed. Compared with the control group, the expression of HIF-2α in all electric shock death subgroups increased, reaching the peak immediately after death. In the postmortem electric shock group, HIF-2α expression only increased immediately after death, but was lower than that of electric shock death group (P<0.05). Compared with the control group, the expression of H-FABP in all subgroups of electric shock death group and postmortem electric shock group significantly decreased. The expression of H-FABP in all subgroups of electric shock death group was lower than that of the postmortem electric shock group (P<0.05). Conclusion Electric shock can increase HIF-2α expression and decrease H-FABP expression in the myocardium, which may be of forensic significance for the determination of electric shock death and identification of antemortem and postmortem electric shock.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína 3 Ligante de Ácido Graxo/metabolismo , Miocárdio , Miócitos Cardíacos , Pele/ultraestrutura , Animais , Autopsia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Ratos
4.
J Dairy Sci ; 101(7): 6098-6108, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29680656

RESUMO

This study investigated the effects of mulberry (Morus alba L.) leaf flavonoids and Candida tropicalis on the growth, gastrointestinal development, enzyme activity of gastrointestinal digesta, and blood antioxidant function of dairy calves challenged with Escherichia coli O141:K99. A total of 15 Holstein preweaning bull calves (age = 28 d; body weight = 51 ± 3.9 kg, mean ± standard deviation) were randomly divided into 3 homogeneous groups with no supplementation (control, CON), Candida tropicalis added at 1 g/calf per day (CT), and mulberry leaf flavonoids added at 3 g/calf per day (MLF). The feed efficiency was greater in calves fed MLF than in CON either before or after the E. coli challenge test. The fecal score increased after E. coli challenge, but it was greater in the CON group than in the CT treatment and in the MLF group at d 1, 2, and 3 after the E. coli challenge. Calves fed the CT diet showed decreased blood ß-hydroxybutyrate concentrations compared with those on the CON and MLF diets before the E. coli challenge. Dietary supplementation with CT resulted in lower blood superoxide dismutase activity than the CON after E. coli challenge. The calves fed CT and MLF showed much lower blood glutathione peroxidase activity than the CON group after being challenged with E. coli. The tunica mucosa of the duodenum was lower in CT and MLF than in CON. The lactase activity of the jejunal digesta was greater in MLF than in CON and CT. In summary, MLF and CT supplementation might effectively improve antioxidant function and reduce the incidence of oxidative stress after challenge with E. coli in 28-d-old preweaning calves, and this effect may be partially explained by the relative decreases in blood superoxide dismutase and glutathione peroxidase as well as fecal score.


Assuntos
Ração Animal/análise , Candida tropicalis/fisiologia , Bovinos , Flavonoides/administração & dosagem , Trato Gastrointestinal/fisiologia , Animais , Antioxidantes/metabolismo , Antioxidantes/fisiologia , Dieta , Escherichia coli/patogenicidade , Flavonoides/farmacologia , Masculino , Morus/química , Desmame
5.
Fa Yi Xue Za Zhi ; 34(4): 352-358, 2018 Aug.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-30465397

RESUMO

OBJECTIVES: To observe the changes of the formation time of venous thrombus in rats, and to provide new ideas and methods for the estimation on thrombus formation time of the forensic cases died from thrombosis. METHODS: Totally 80 rats were randomly divided into 10 groups (0 h, 3 h, 6 h, 12 h, 1 d, 3 d, 1 week, 2 weeks, 3 weeks and 4 weeks after operation). A vein thrombosis model was established by the "narrow" method. The processes of thrombosis, organization, recanalization and the features of change on hemosiderin and calcium salt were observed by HE stain, Perls stain and Von Kossa stain. The expression changes of CD61, α-SMA and CD34 were observed by immunohistochemical staining technique. RESULTS: Platelets adhered to the exposed blood vessel intima 3 h after operation, and platelet trabeculae were formed by the repeated accumulation of platelets 1 d after operation. The thrombus organization formed through the fibroblasts from vessel wall that grew into the interior of the thrombus 3 d after operation. Endothelial cells covered the surface of thrombus and then the new blood vessels were reformed, and the vessels were reconstructed. The expression of CD61 upregulated at the stages of the thrombus formation (3 h) and thrombus reformation (4 weeks), and reached the peak 1 d after thrombus formation. The release of hemosiderin and the initial expression of α-SMA were detected 3 d later. Calcium deposit and expression of CD34 were observed 1 week later. CONCLUSIONS: The hemosiderin, calcium salt, CD61, α-SMA and CD34 show time-dependent changing characteristics, which is expected to provide a reference for the estimation on thrombus formation time of the forensic cases died from thrombosis.


Assuntos
Antígenos CD34/análise , Hemossiderina/metabolismo , Trombose Venosa/patologia , Animais , Ratos , Trombose Venosa/metabolismo
7.
Langmuir ; 29(37): 11779-85, 2013 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-24010889

RESUMO

Here, we report the first attempt to investigate the liquid crystal (LC) behavior of SO3(-) functionalized imidazolium zwitterionic (SO3(-)ImZI) salts, which display homeotropic alignment on a glass slide without the aid of any aligning approach. Doping lithium salt to ImZI salts lowers the melting temperatures and raises the clearing temperatures substantially to form room temperature ImZILCs. Excellent anisotropic lithium ion conductivity is achieved; which is strengthened by their tendency for homeotropic alignment.

8.
Br J Cancer ; 106(2): 307-13, 2012 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-22134506

RESUMO

BACKGROUND: There is clinical evidence that very low and safe levels of amplitude-modulated electromagnetic fields administered via an intrabuccal spoon-shaped probe may elicit therapeutic responses in patients with cancer. However, there is no known mechanism explaining the anti-proliferative effect of very low intensity electromagnetic fields. METHODS: To understand the mechanism of this novel approach, hepatocellular carcinoma (HCC) cells were exposed to 27.12 MHz radiofrequency electromagnetic fields using in vitro exposure systems designed to replicate in vivo conditions. Cancer cells were exposed to tumour-specific modulation frequencies, previously identified by biofeedback methods in patients with a diagnosis of cancer. Control modulation frequencies consisted of randomly chosen modulation frequencies within the same 100 Hz-21 kHz range as cancer-specific frequencies. RESULTS: The growth of HCC and breast cancer cells was significantly decreased by HCC-specific and breast cancer-specific modulation frequencies, respectively. However, the same frequencies did not affect proliferation of nonmalignant hepatocytes or breast epithelial cells. Inhibition of HCC cell proliferation was associated with downregulation of XCL2 and PLP2. Furthermore, HCC-specific modulation frequencies disrupted the mitotic spindle. CONCLUSION: These findings uncover a novel mechanism controlling the growth of cancer cells at specific modulation frequencies without affecting normal tissues, which may have broad implications in oncology.


Assuntos
Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/patologia , Proliferação de Células , Neoplasias Hepáticas/patologia , Adenocarcinoma/genética , Neoplasias da Mama/genética , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Hepáticas/genética , Microscopia Confocal , Reação em Cadeia da Polimerase , Análise de Sequência de RNA , Fuso Acromático
9.
Animal ; 16(7): 100562, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35709555

RESUMO

Nitrogen (N) excretion from livestock production systems is of significant environmental concern; however, few studies have investigated the effect of dietary CP concentration on N utilisation efficiency at different stages of lactation, and the interaction between dietary CP levels and stages of lactation on N utilisation. Holstein-Friesian dairy cows (12 primiparous and 12 multiparous) used in the present study were selected from a larger group of cows involved in a whole-lactation study designed to examine the effect of dietary CP concentration on milk production and N excretion rates at different stages of lactation. The total diet CP concentrations evaluated were 114 (low CP), 144 (medium CP) and 173 (high CP) g/kg DM, with diets containing (g/kg DM) 550 concentrates, 270 grass silage and 180 maize silage. During early (70-80 days), mid- (150-160 days) and late (230-240 days) lactation, the same 24 animals were transferred from the main cow house to metabolism units for measurements of feed intake, milk production and faeces and urine outputs. Diet had no effect on BW, body condition score, or milk fat, protein or lactose concentration, but DM intake, milk yield and digestibilities of DM, energy and N increased with increasing diet CP concentration. The effect of diet on milk yield was largely due to differences between the low and medium CP diets. Increasing dietary CP concentration significantly increased urine N/N intake and urine N/manure N, and decreased faecal N/N intake, milk N/N intake and manure N/N intake. Although increasing dietary CP level significantly increased urine N/milk yield and manure N/milk yield, differences in these two variables between low and medium CP diets were not significant. There was no significant interaction between CP level and stage of lactation on any N utilisation variable, indicating that the effects of CP concentration on these variables were similar between stages of lactation. These results demonstrated that a decrease in dietary CP concentration from high (173 g/kg DM) to medium level (144 g/kg DM) may be appropriate for Holstein-Friesian dairy cow to maintain milk production efficiency, whilst reducing both urine N and manure N as a proportion of N intake or milk production.


Assuntos
Lactação , Esterco , Ração Animal/análise , Animais , Bovinos , Dieta/veterinária , Proteínas Alimentares/metabolismo , Feminino , Leite/metabolismo , Nitrogênio/metabolismo , Silagem
10.
J Clin Pharm Ther ; 36(6): 716-24, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21143613

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Alcohol is a widely used drug. Our objective was to examine alcohol pharmacokinetics in Chinese subjects through the breath measurement of blood alcohol concentration (BAC) to identify any measurable covariates that may help explain variability between subjects. METHODS: Breath-alcohol measurements of 184 healthy Chinese subjects were collected. Compartmental models including one- and two-compartment process were examined. First-order kinetics was applied to model alcohol absorption and elimination phases. For the sake of simplicity, only the subject's body weight, sex and stomach condition were investigated as covariates in our random effects modelling. RESULTS AND DISCUSSION: The body as a whole behaves as a single compartment, with the suggested one-compartment model being good enough to characterize the biological process. In line with other studies, food ingestion before/with the dose slowed down alcohol absorption into the central compartment. Female subjects exhibited a significantly higher BAC elimination rate than that of males. Body weight also contributed to the observed inter-subject variability in alcohol clearance. WHAT IS NEW AND CONCLUSION: We present a model for estimating blood-alcohol levels from breath-alcohol measurements. The results of our study are useful particularly in relation to drink-driving prosecutions because of the routine use of breath-alcohol measurements as evidence in such cases through the world.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Etanol/farmacocinética , Modelos Biológicos , Povo Asiático , Peso Corporal , Testes Respiratórios , China , Feminino , Humanos , Masculino , Fatores Sexuais
11.
Animal ; 14(2): 295-302, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31554532

RESUMO

There is evidence indicating that using the current UK energy feeding system to ration the present sheep flocks may underestimate their nutrient requirements. The objective of the present study was to address this issue by developing updated maintenance energy requirements for the current sheep flocks and evaluating if these requirements were influenced by a range of dietary and animal factors. Data (n = 131) used were collated from five experiments with sheep (5 to 18 months old and 29.0 to 69.8 kg BW) undertaken at the Agri-Food and Biosciences Institute of the UK from 2013 to 2017. The trials were designed to evaluate the effects of dietary type, genotype, physiological stage and sex on nutrient utilization and energetic efficiencies. Energy intake and output data were measured in individual calorimeter chambers. Energy balance (Eg) was calculated as the difference between gross energy intake and a sum of fecal energy, urine energy, methane energy and heat production. Data were analysed using the restricted maximum likelihood analysis to develop the linear relationship between Eg or heat production and metabolizable energy (ME) intake, with the effects of a range of dietary and animal factors removed. The net energy (NEm) and ME (MEm) requirements for maintenance derived from the linear relationship between Eg and ME intake were 0.358 and 0.486 MJ/kg BW0.75, respectively, which are 40% to 53% higher than those recommended in energy feeding systems currently used to ration sheep in the USA and the UK. Further analysis of the current dataset revealed that concentrate supplement, sire type or physiological stage had no significant effect on the derived NEm values. However, female lambs had a significantly higher NEm (0.352 v. 0.306 or 0.288 MJ/kg BW0.75) or MEm (0.507 v. 0.441 or 0.415 MJ/kg BW0.75) than those for male or castrated lambs. The present results indicate that using present energy feeding systems in the UK developed over 40 years ago to ration the current sheep flocks could underestimate maintenance energy requirements. There is an urgent need to update these systems to reflect the higher metabolic rates of the current sheep flocks.


Assuntos
Ingestão de Energia , Metabolismo Energético , Ovinos/fisiologia , Ração Animal/análise , Animais , Calorimetria/veterinária , Dieta/veterinária , Fezes/química , Feminino , Genótipo , Modelos Lineares , Masculino , Metano/metabolismo , Necessidades Nutricionais , Termogênese
12.
J Biomol Struct Dyn ; 26(1): 65-74, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18533727

RESUMO

RING domain, a cysteine-rich motif that chelates two zinc ions, has been shown to regulate many biological processes such as mediating a crucial step in the ubiquitinylation pathway. In order to investigate the distinct structural features for the RING domains functioning as E3 ligases, several molecular dynamics simulations involving the c-Cbl, CNOT4 (with E3 ligase function), and p44 (no E3 ligase function) RING domains were conducted in this study. Our results reveal that the structural stability of the recognition site is a basic requirement for the RING domains functioning as E3 ligases. The structural stability of the recognition site is maintained by the hydrophobic core and hydrogen bonding network. Another important structural feature of the RING domains functioning as E3 ligases is the stable distances between the recognition site and the zinc ion binding sites S1 and S2. Moreover, the RING domains functioning as E3 ligases seem to exhibit lower beta stability due to the higher proportion of proline residues in their sequences. However, no significant difference of the other secondary (alpha and turn) and the tertiary structural stabilities can be observed among these three RING domains.


Assuntos
Simulação por Computador , Proteínas Proto-Oncogênicas c-cbl/química , Fatores de Transcrição/química , Ubiquitina-Proteína Ligases/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Ubiquitina/metabolismo , Zinco/química , Zinco/metabolismo
14.
Forensic Sci Int ; 156(2-3): 95-101, 2006 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-16410158

RESUMO

A study was designed to examine the elimination rate of alcohol from the body of the local Chinese after consumption of different types of alcoholic drinks. The breath alcohol of 184 healthy volunteers was determined and converted into blood alcohol levels after they finished drinking. Information on the type and volume of alcoholic drinks consumed, age group, sex, drinking habit, and drinking on empty stomach or with/after meal was recorded for each participant. The results show that the elimination rate of an individual can be explained in terms of physiological variables including sex and drinking habit. The determined elimination rates allow forensic toxicologists to back calculate the blood alcohol concentration (BAC) of the drivers at the time of accident in drunk driving cases. The elimination rates of blood alcohol at 95% prediction intervals for male and female are in the range of 9.5-23.8 mg/100 ml/h and 11.1-37.1 mg/100 ml/h, respectively.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Depressores do Sistema Nervoso Central/farmacocinética , Etanol/farmacocinética , Adulto , Análise de Variância , Testes Respiratórios , Depressores do Sistema Nervoso Central/sangue , Etanol/sangue , Jejum , Feminino , Hong Kong , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
15.
Vet Parasitol ; 142(1-2): 63-70, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-16876953

RESUMO

The efficacy and economic benefits of Supercox, a live anticoccidial vaccine were examined and compared with an anticoccidial drug in a trial in broiler chickens under modern commercial conditions in China. In total, 40,660 chickens were used in the present study, half of which were vaccinated with the Supercox vaccine comprising a precocious line of Eimeria tenella and non-attenuated lines of Eimeria maxima and Eimeria acervulina, and the other half were medicated with Diclazuril delivered as feed additive at the dosage of 1mg/kg of feed. The vaccine was administered orally to 7-day-old chickens. No clinical diseases were diagnosed in any of the vaccinated birds. However, clinical coccidiosis occurred in a large proportion of medicated control birds and these chickens had to be treated with anticoccidial drugs (Diclazuril and Toltrazuril). Comparison of production performance between vaccinated birds and medicated control birds revealed that the vaccine Supercox performed better than anticoccidial drugs in terms of mortalities, costs and overall economic benefits (profits). These findings demonstrated that the use of the Supercox vaccine could control clinical coccidiosis in broilers and achieve production performance superior to that using anticoccidial drugs, particularly where drug resistance might result in failure to control clinical diseases.


Assuntos
Galinhas , Coccidiose/veterinária , Coccidiostáticos/uso terapêutico , Doenças das Aves Domésticas/prevenção & controle , Vacinas Protozoárias/imunologia , Animais , Galinhas/crescimento & desenvolvimento , China , Coccidiose/economia , Coccidiose/prevenção & controle , Análise Custo-Benefício , Fezes/parasitologia , Feminino , Masculino , Nitrilas/uso terapêutico , Contagem de Ovos de Parasitas/veterinária , Doenças das Aves Domésticas/economia , Vacinas Protozoárias/economia , Distribuição Aleatória , Resultado do Tratamento , Triazinas/uso terapêutico , Vacinação/veterinária
16.
J Natl Cancer Inst ; 92(8): 636-41, 2000 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-10772681

RESUMO

BACKGROUND: The p14(ARF) protein encoded by the INK4a/ARF locus promotes degradation of the MDM2 protein and thus prevents the MDM2-mediated inhibition of p53. Homozygous deletion of the INK4a/ARF locus is common in human mesothelioma and may result in the loss of p14(ARF) and the inactivation of p53. We designed this study to evaluate the biologic and potential therapeutic roles of p14(ARF) expression in mesothelioma cells. METHODS AND RESULTS: We constructed Adp14, an adenoviral vector carrying human p14(ARF) complementary DNA, and used it to transfect human mesothelioma cell lines H28, H513, H2052, and MSTO-211H. Overexpression of p14(ARF) led to increased amounts of p53 and the p21(WAF) proteins and dephosphorylation of the retinoblastoma protein. The growth rate of mesothelioma cells was inhibited markedly by infection with Adp14 compared with mock infection or infection with a control adenovirus vector, AdCtrl. Overexpression of p14(ARF) induced G(1)-phase cell cycle arrest and apoptotic cell death. Cytotoxicity assays showed that Adp14 had a statistically significantly (P =.002) greater effect on colon cancer (HCT116) cell lines containing two copies of the wild-type p53 gene than on p53-null cells, suggesting that functional p53 is a critical determinant of p14(ARF)-mediated cytotoxicity. CONCLUSIONS: The transfection of p14(ARF) into mesothelioma cells led to the overexpression of p14(ARF), which resulted in G(1)-phase arrest and apoptotic cell death. These results suggest that this gene therapy-based approach may be of use in the treatment of mesothelioma.


Assuntos
Adenoviridae/genética , Técnicas de Transferência de Genes , Mesotelioma/genética , Proteínas/genética , Apoptose , Ciclo Celular , Divisão Celular , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/metabolismo , Vetores Genéticos , Humanos , Mesotelioma/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p14ARF , Proteína Supressora de Tumor p53/metabolismo
17.
Cancer Res ; 60(4): 1009-13, 2000 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-10706117

RESUMO

p53 mutations and loss of heterozygosity (LOH) have been detected in >50% of lung cancers. Wild-type p53 can prevent replication of damaged DNA and promote apoptosis of cells with abnormal DNA. A human adenovirus, ONYX-015, which has a deletion in the E1B region, has shown tumor-specific cytolytic effect in tumor cells with nonfunctional p53 and antitumor efficacy that can be augmented by chemotherapeutic agents. A recent report from an independent group, however, indicates that wild-type p53 is necessary for the infection of this replicating virus, and it is in direct contradiction to previous observations of the ONYX group. In this study, we carried out cytopathic effect (CPE) assays using ONYX-015 on five human lung cancer cell lines with known p53 status. Two of these cell lines, NCI-H522 and NCI-H1703, have mutations and LOH in their p53 gene. Both lines were lysed in a dose-dependent manner and showed 100% cytolysis at a multiplicity of infection of 0.1. Two additional cell lines, NCI-H2347 and NCI-H838, both of which have wild-type p53 gene, showed near complete lysis at a multiplicity of infection of 1. We demonstrate here that the lung cancer cells with nonfunctional p53 are at least 10 times more sensitive to ONYX-015 cytolysis than the lung cancer cells with wild-type p53. In addition, standard chemotherapeutic agents (paclitaxol and cisplatin) showed a synergistic effect when combined with ONYX-015, and this effect was p53 mutant dependent. Furthermore, we tested the cytolytic effect of ONYX-015 on a panel (n = 7) of primary first-passage cultures made from freshly resected lung cancers. ONYX-015 lysed primary lung cancer cells in six of seven (86 %) primary cultures. Two of four primary cultures treated with chemotherapeutic agents had a synergistic effect with ONYX-015. Our data indicate that wild-type p53 is not required for the infection of this replicating virus, and also we demonstrate that ONYX-015 is effective alone and works synergistically with chemotherapeutic agents in lung cancer cell lines and primary cultures. This study suggests that ONYX-015 may be effective, especially in combination with conventional chemotherapy, in the treatment of patients with lung cancer.


Assuntos
Adenoviridae/genética , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Efeito Citopatogênico Viral , Técnicas de Transferência de Genes , Humanos , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/análise
18.
Cancer Res ; 61(16): 5959-63, 2001 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-11507034

RESUMO

ONYX-015 has been reported to kill selectively tumor cells lacking functional p53. Genetic alterations of INK4a/ARF locus, which is a predominant event in malignant pleural mesothelioma, may result in loss of p14(ARF) and subsequent disruption of p53 pathway in cancer cells. In the present study, ONYX-015 was able to kill three mesothelioma cell lines (H28, H513, and 211H) with wild-type p53 but lacking p14(ARF). In contrast, MS-1 mesothelioma cells, which expressed both p53 and p14(ARF), were resistant to ONYX-015. Introducing p14(ARF) gene into the H28 cell, a mesothelioma cell without p14(ARF) expression, significantly increased the resistance of this cell line to the cytolytic effect of ONYX-015. Our results suggest that human mesotheliomas with wild-type p53 yet lacking p14(ARF) are potential candidates for ONYX-015 therapy.


Assuntos
Adenovírus Humanos/fisiologia , Terapia Genética/métodos , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Proteínas/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Proteínas E1B de Adenovirus/genética , Adenovírus Humanos/genética , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Ciclinas/genética , Efeito Citopatogênico Viral/genética , Genes p53 , Vetores Genéticos/genética , Humanos , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma/virologia , Neoplasias Pleurais/genética , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/virologia , Biossíntese de Proteínas , Proteínas/genética , Células Tumorais Cultivadas , Proteína Supressora de Tumor p14ARF , Proteína Supressora de Tumor p53/biossíntese
19.
J Clin Oncol ; 16(2): 567-73, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9469342

RESUMO

PURPOSE: To determine the diagnostic value of pleural fluid telomerase activity in distinguishing a malignant from a nonmalignant pleurol effusion in a cohort of patients undergoing thoracentesis. PATIENTS AND METHODS: Using a polymerase chain reaction (PCR)-based assay, telomerase activity was examined in the pleural fluid cells obtained from 144 consecutive, unselected patients. According to the final diagnosis achieved, these patients were classified into three groups: group I consisted of 70 malignant pleural effusions diagnosed by either fluid cytology or pleural biopsy, group II consisted of 52 nonmalignant pleural effusions, and another 22 samples were categorized to be suspicious malignant pleural effusions (group III) due to inconclusive results in effusion cytology and percutaneous pleural biopsy, but were strongly suspicious in clinical settings. RESULTS: The presence of telomerase activity was observed in 64 of 70 samples in group I (91.4%), three of 52 samples in group II (5.8%), and 20 of 22 samples in group III. All three nonmalignant, telomerase-positive pleural effusion samples in group II were obtained from patients with tuberculosis. As a diagnostic criterion for malignant pleural effusion in group I and group II patients, positive telomerase activity had a sensitivity of 91.4%, a specificity of 94.2%, and a positive and negative predictive value of 0.96 and 0.89, respectively. CONCLUSION: Our results indicate that the detection of telomerase activity may be a useful adjunct to cytopathologic methods in the diagnosis of malignant pleural effusions.


Assuntos
Derrame Pleural Maligno/diagnóstico , Telomerase/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/diagnóstico , Derrame Pleural/enzimologia , Derrame Pleural Maligno/enzimologia , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade
20.
Forensic Sci Int ; 151(1): 23-9, 2005 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-15935939

RESUMO

The Widmark formula has been widely adopted in forensic applications to drink driving cases for the last 70 years. It is known that the amount of alcohol consumed and the body weight of the drinkers are important information for the estimation of blood alcohol concentration (BAC). However, the direct application of the Widmark factors derived from Caucasian to the calculation of BAC for the Chinese population often encounters serious challenges. Owing to this inherent weakness, a thorough analysis to determine the theoretical Widmark factors for the Chinese population, r(0) at the start of drinking and the practical factors, r(peak), at peak BAC was conducted. In the present study, other factors such as gender, stomach condition and other physiological conditions are taken into account. The determined theoretical Widmark factors, r(0,) for local Chinese male and female are 0.68 and 0.59 (with BAC in the units of weight/volume), respectively, demonstrating the applicability of the Widmark formula to the Chinese population. The practical factors at peak BAC, r(peak), were also determined to serve the forensic purpose of refuting the "hip-flask" defence in drink driving cases. Findings show that gender and stomach condition are the key factors that could statistically explain the variability of both r(0) and r(peak).


Assuntos
Intoxicação Alcoólica/etnologia , Algoritmos , Condução de Veículo , Depressores do Sistema Nervoso Central/sangue , Etanol/sangue , Adulto , Intoxicação Alcoólica/sangue , Intoxicação Alcoólica/diagnóstico , Depressores do Sistema Nervoso Central/farmacocinética , Ingestão de Alimentos , Etanol/farmacocinética , Feminino , Medicina Legal , Conteúdo Gastrointestinal , Hong Kong , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
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