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1.
Endocr Relat Cancer ; 23(9): 759-67, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27552969

RESUMO

The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Capecitabina/uso terapêutico , Dacarbazina/análogos & derivados , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/farmacologia , Proteínas Correpressoras , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Telômero , Temozolomida , Resultado do Tratamento , Proteínas Supressoras de Tumor/metabolismo , Proteína Nuclear Ligada ao X/metabolismo
2.
Eur J Gynaecol Oncol ; 37(3): 430-3, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27352581

RESUMO

Retroperitoneal squamous cell carcinoma (SCC) of unknown primary is very rare with variable survival rates. Standard optimal therapeutic management is not yet established.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Primárias Desconhecidas/patologia , Neoplasias Pélvicas/patologia , Feminino , Humanos , Pessoa de Meia-Idade
3.
Endocr Relat Cancer ; 23(5): 411-8, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27080472

RESUMO

Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29months, we observed a median PFS of 26.7months (95% CI, 11.4-35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4-45.3), and the median TTF was 9.6months (95% CI, 5.5-12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Indazóis/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Axitinibe , Neoplasias do Colo/tratamento farmacológico , Feminino , Humanos , Hipertensão/induzido quimicamente , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Neoplasias Intestinais/tratamento farmacológico , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Retais/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Resultado do Tratamento
4.
Endocr Relat Cancer ; 22(1): 1-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25376618

RESUMO

Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response.


Assuntos
Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Somatostatina/análogos & derivados , Adulto , Idoso , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Receptores de Somatostatina/metabolismo , Somatostatina/administração & dosagem
5.
J Food Sci ; 79(7): C1292-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24961890

RESUMO

UNLABELLED: The objective of this study was to determine the relationship between the protein composition of muscle exudates and meat tenderness in beef. Frozen, intact beef strip loins (n = 24) were each divided into 3 equal portions (anterior, middle, and posterior). Steaks were removed from each portion, individually vacuum packaged, thawed at 4 °C, and aged for 0, 7, or 14 d. After the designated aging period, exudate was collected from the packaging and 1 steak from each strip loin portion was utilized for shear force measurements. Muscle exudates were analyzed for protein content (biuret assay) and composition (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Shear force decreased (P < 0.0001) with aging from 0 to 14 d. The protein concentrations of the muscle exudates were not influenced by the aging period and were not related to the amount of exudate expressed. Electrophoretic analyses of the muscle exudates indicated that with aging the relative abundance of 4 proteins decreased (P < 0.01) and 10 proteins increased (P < 0.05) within the protein profiles of the exudates. The relative abundance of the 167, 97, and 47 kDa proteins in exudates at day 0 were significantly correlated (|r| = 0.57 to 0.77) to shear force at day 14. These data demonstrate that exudate protein composition changes with postmortem aging and beef tenderness. PRACTICAL APPLICATION: This research showed that the protein profiles of exudates that accumulate on the surface and in the packaging of beef change with meat aging and tenderness. These data suggest that muscle exudates may be a good source of protein markers that are useful in the development of rapid, noninvasive methodologies for predicting beef tenderness.


Assuntos
Carne/análise , Proteínas Musculares/química , Animais , Bovinos , Análise de Alimentos , Armazenamento de Alimentos , Músculo Esquelético/química
6.
J Food Sci ; 77(6): C594-602, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22671519

RESUMO

UNLABELLED: Capillary electrophoresis (CE) and reversed-phase high performance liquid chromatography (RP-HPLC) analyses were utilized to detect differences in the sarcoplasmic protein fractions of beef strip loins subjected to aging and hydrodynamic pressure processing (HDP) treatments. At 48 h postmortem, strip loins (n = 12) were halved and subjected to control or HDP treatments. Following treatment, each half was divided into 3 portions which were aged for 0, 5, and 8 d. After each aging period, steaks were removed for Warner-Bratzler shear force (WBSF) analysis and for the extraction of sarcoplasmic proteins which were analyzed by CE and RP-HPLC. Aging by HDP interactions were not detected using either separation technique. With CE analysis, no HDP effects were observed; however, the relative peak area of 8 protein peaks ranging in size from 17 to >200 kDa were influenced by postmortem aging. Separation of proteins by RP-HPLC demonstrated that HDP influenced the relative size of 2 protein peaks while postmortem aging effects were observed in 6 peaks. Alterations in the sarcoplasmic protein fractions detected by both CE and RP-HPLC were correlated to WBSF measurements. Overall, data demonstrate that HDP has minimal effects on sarcoplasmic proteins and that aging related changes in the water soluble protein fractions of muscle may be useful as indirect indicators of beef tenderness. PRACTICAL APPLICATION: Using 2 different postmortem tenderization techniques, aging and hydrodynamic pressure processing, this study demonstrates that postmortem changes in the soluble protein fraction of beef may be useful as potential indicators of meat tenderness.


Assuntos
Proteínas na Dieta/análise , Armazenamento de Alimentos , Indústria de Embalagem de Carne/métodos , Carne/análise , Proteínas Musculares/análise , Músculo Esquelético/química , Retículo Sarcoplasmático/química , Animais , Bovinos , Fenômenos Químicos , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Proteínas na Dieta/isolamento & purificação , Eletroforese Capilar , Fenômenos Mecânicos , Peso Molecular , Proteínas Musculares/química , Proteínas Musculares/isolamento & purificação , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/isolamento & purificação , Pressão , Controle de Qualidade , Resistência ao Cisalhamento , Solubilidade
7.
J Food Sci ; 76(3): S210-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21535862

RESUMO

UNLABELLED: Establishing standards for meat tenderness based on Warner-Bratzler shear force (WBSF) is complicated by the lack of methods for certifying WBSF testing among texture systems or laboratories. The objective of this study was to determine the suitability of using gelatin gels as reference materials for performance testing of texture measurement systems. Three replications of 5 gels (15%, 20%, 25%, 30%, and 35% gelatin) were prepared, vacuum packaged, and stored at 4 °C until use. Three randomly selected strips from each gel were subjected to WBSF testing on 4 instruments (A, B, C, or D) on days 1 and 8. Additional strips from each gel were subjected to WBSF testing on instruments A and C on day 29. Regression line estimates for each set of gels were analyzed. Gel WBSF values ranged from 10 to 177 N. The WBSF by gel concentration response was highly linear (P<0.0001) for all replications, instruments, and days of analysis. R2-values across all sets of gels ranged from 0.9562 to 0.9998. On days 1 and 8, instruments A and D exhibited higher slope (P<0.0001) and lower intercept (P<0.0001) estimates than instruments B and C. Regression line parameters (slope, intercept, and R2-values) were not influenced (P>0.05) by length of gel storage (1, 8, and 29 d). Data from this study suggest that gelatin gels can be used for evaluating WBSF values from various instruments and for validating the performance of meat shear force testing. PRACTICAL APPLICATION: Validating the performance of meat shear force testing is vital to establishing meat tenderness standards. The gelatin gel standards developed in this study exhibited a highly linear, repeatable relationship with shear force and were found to be stable for at least a month. These gel standards would provide a tool for the meat industry to harmonize shear force measurements across laboratories and various texture measuring instruments.


Assuntos
Tecnologia de Alimentos/métodos , Gelatina/química , Carne/análise , Carne/normas , Animais , Géis , Modelos Lineares , Concentração Osmolar , Padrões de Referência , Reprodutibilidade dos Testes , Resistência ao Cisalhamento , Pele/química , Sus scrofa
8.
J Agric Food Chem ; 58(9): 5408-13, 2010 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-20384337

RESUMO

The U.S. Food and Drug Administration sets tolerances for veterinary drug residues in muscle but does not specify which type of muscle should be analyzed. To determine if antibiotic residue levels are dependent upon muscle type, seven culled dairy cows were dosed with penicillin G (Pen G) from 1 to 3 days and then sacrificed on day 1, 2, or 5 of withdrawal. A variety (9-15) of muscle samples were collected, along with liver and kidney samples. In addition, corresponding muscle juice samples were prepared. All samples were extracted and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine Pen G levels. Results showed that Pen G residue levels can vary between and within different muscles, although no reproducible pattern was identified between cows or withdrawal times. Muscle juice appeared to be a promising substitute for muscle as a matrix for screening purposes. Because of the potential for variation within muscles, all samples taken need to be large enough to be representative.


Assuntos
Indústria de Laticínios , Resíduos de Drogas/análise , Penicilina G/análise , Animais , Bovinos , Cromatografia Líquida , Feminino , Espectrometria de Massas em Tandem
10.
J Food Prot ; 66(7): 1176-83, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12870750

RESUMO

A lettuce outbreak strain of E. coli O157:H7 was used to quantitate the pathogen's survival in ground beef and its transfer to hands, cutting board surfaces, and lettuce. Overnight storage of inoculated beef at 4 degrees C resulted in no pathogen growth, while room-temperature storage allowed multiplication. Hamburger patty formation allowed the transfer of bacteria to hands. Contaminated fingers subsequently transferred the pathogen to lettuce during handling. E. coli was transferred from hamburgers to cutting board surfaces; overnight storage of boards decreased the numbers of recoverable pathogens by approximately 1 log CFU. A 15-s water rinse failed to remove significant numbers of pathogens from cutting boards whether it was applied immediately after contamination or following overnight room-temperature storage. Three lettuce leaves were successively applied to a single contaminated cutting board area both immediately after contamination and after overnight room-temperature storage of contaminated boards. Another set of leaves was pressed onto boards immediately following contamination and was then stored overnight at 4 degrees C before pathogen enumeration. The numbers of pathogens transferred to the first pressed leaves were larger than those transferred to the second or third leaves. There were no significant differences in the numbers of pathogensrecovered from leaves pressed immediately after contamination whether pathogens were enumerated immediately or following overnight storage at 4 degrees C. However, fewer pathogens were transferred to leaves pressed to boards stored overnight at room temperature prior to contact with lettuce. Twenty-five lettuce pieces were successively pressed onto one area on a board containing 1.25 x 10(2) CFU of E. coli. Pathogens were transferred to 46% of the leaves, including the 25th exposed leaf.


Assuntos
Escherichia coli O157/crescimento & desenvolvimento , Contaminação de Alimentos , Manipulação de Alimentos/métodos , Alface/microbiologia , Produtos da Carne/microbiologia , Animais , Bovinos , Contagem de Colônia Microbiana , Dedos/microbiologia , Microbiologia de Alimentos , Humanos , Temperatura , Fatores de Tempo
11.
J Food Prot ; 65(3): 571-4, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11899060

RESUMO

Hydrodynamic pressure processing (HDP) was investigated as a technology to reduce spoilage microorganisms found in fresh beef. In two separate studies (studies 1 and 2), retail ground beef and beef roasts were purchased (day 0). The roasts were divided into stew pieces (30 to 40 g). All meat samples, including control samples, were stored at 5 degrees C for 20 h in a plastic film. After storage, designated samples were treated with HDP In study 3, ground beef was treated with HDP (day 0) and stored aerobically (5 degrees C) for 14 days with control samples. Each meat type was vacuum-packaged for HDP (100 g binary explosive, steel shock wave container). The pHs and the aerobic plate counts (log10 CFU/g) were measured on day 0 (studies I and 2) and on days 0, 7, and 14 (study 3) for control samples and for HDP-treated samples. There was no pH difference between control and HDP-treated meat types (studies 1 and 2); HDP reduced bacteria in both meat types in study 1 (2 log) and study 2 (1.5 log) on day 0. In study 3, there was a significant difference (P < 0.05) in pH between control meat (8.2) and HDP-treated meat (5.6) after storage. There was an immediate reduction (1.5 log) of microorganisms following HDP (day 0) and a 4.5-log difference between control samples (9 log) and HDP-treated samples (4.5) after 14 days of storage. With HDP, it is possible to reduce spoilage microorganisms found in or on different meat types (ground beef versus stew pieces), which could extend the shelf life of meat products.


Assuntos
Bactérias Aeróbias/crescimento & desenvolvimento , Conservação de Alimentos/métodos , Produtos da Carne/microbiologia , Carne/microbiologia , Pressão , Animais , Bovinos , Contagem de Colônia Microbiana , Microbiologia de Alimentos , Tecnologia de Alimentos/métodos , Concentração de Íons de Hidrogênio , Fatores de Tempo
12.
J Virol ; 75(18): 8461-8, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11507191

RESUMO

A sensitive and quantitative cell-free infection assay, utilizing recombinant human T-cell leukemia virus type 1 (HTLV-1)-based vectors, was developed in order to analyze early events in the virus replication cycle. Previous difficulties with the low infectivity and restricted expression of the virus have prevented a clear understanding of these events. Virus stocks were generated by transfecting cells with three plasmids: (i) a packaging plasmid encoding HTLV-1 structural and regulatory proteins, (ii) an HTLV-1 transfer vector containing either firefly luciferase or enhanced yellow fluorescent protein genes, and (iii) an envelope expression plasmid. Single-round infections were initiated by exposing target cells to filtered supernatants and quantified by assaying for luciferase activity in cell extracts or by enumerating transduced cells by flow cytometry. Transduction was dependent on reverse transcription and integration of the recombinant virus genome, as shown by the effects of the reverse transcriptase inhibitor 3'-azido-3'-deoxythymidine (AZT) and by mutation of the integrase gene in the packaging vector, respectively. The 50% inhibitory concentration of AZT was determined to be 30 nM in this HTLV-1 replication system. The stability of HTLV-1 particles, pseudotyped with either vesicular stomatitis virus G protein or HTLV-1 envelope, was typical of retroviruses, exhibiting a half-life of approximately 3.5 h at 37 degrees C. The specific infectivity of recombinant HTLV-1 virions was at least 3 orders of magnitude lower than that of analogous HIV-1 particles, though both were pseudotyped with the same envelope. Thus, the low infectivity of HTLV-1 is determined in large part by properties of the core particle and by the efficiency of postentry processes.


Assuntos
Vetores Genéticos , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Recombinação Genética , Replicação Viral , Linhagem Celular , Linhagem Celular Transformada , Sistema Livre de Células , Genes Reporter , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Luciferases/genética , Transcrição Genética , Células Tumorais Cultivadas , Montagem de Vírus , Integração Viral
13.
Contemp Top Lab Anim Sci ; 40(3): 12-6, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11353518

RESUMO

Of 18 pigs used on a coronary stent experimental protocol, 6 each received a transdermal fentanyl patch to document the patterns of transdermal fentanyl absorption in swine. This approach was taken to reduce animal use and potentially refine the surgical regimen. The objective of the fentanyl portion of the study was to demonstrate that transdermal fentanyl may be useful in the management of postoperative analgesia in swine. This study sought to document that demonstrable levels of fentanyl are achievable in swine plasma via a transdermal system and to compare the magnitude of these levels to data in other species. This study does not directly correlate plasma fentanyl levels with analgesic efficacy. Plasma fentanyl concentration peaked within 42 h in five pigs and within 48 h in the remaining pig. All pigs had similar absorption patterns; the only difference was in magnitude. One pig reached 0.99 ng/ml at 42 h; the next highest concentration was 0.77 ng/ml at 48 h in a different animal. The peak concentration in the others ranged from 0.38 to 0.71 ng/ml.


Assuntos
Analgésicos Opioides/farmacocinética , Fentanila/farmacocinética , Porco Miniatura/metabolismo , Administração Cutânea , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/sangue , Animais , Fentanila/administração & dosagem , Fentanila/sangue , Masculino , Absorção Cutânea , Suínos , Porco Miniatura/cirurgia
14.
Stud Health Technol Inform ; 81: 594-600, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11317816

RESUMO

We describe the use of variational implicit surfaces (level sets of an embedded generating function modeled using radial basis interpolants) in anatomic modeling. This technique allows the practitioner to employ sparsely and unevenly sampled data to represent complex biological surfaces, including data acquired as a series of non-parallel image slices. The method inherently accommodates interpolation across irregular spans. In addition, shapes with arbitrary topology are easily represented without interpolation or aliasing errors arising from discrete sampling. To demonstrate the medical use of variational implicit surfaces, we present the reconstruction of the inner surfaces of blood vessels from a series of endovascular ultrasound images.


Assuntos
Simulação por Computador , Modelos Anatômicos , Interface Usuário-Computador , Animais , Aorta/anatomia & histologia , Bovinos , Gráficos por Computador , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Ultrassonografia de Intervenção
15.
FEBS Lett ; 489(2-3): 159-65, 2001 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-11165242

RESUMO

Casein kinase Iepsilon (CKIepsilon), a central component of the circadian clock, interacts with and phosphorylates human period protein 1 (hPER1) [Keesler, G.A. et al. (2000) NeuroReport 5, 951-955]. A mutation in CKIepsilon causes a shortened circadian period in Syrian Golden hamster. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). Immunohistochemical staining of rat brains demonstrates that CKIdelta protein is localized in the suprachiasmatic nuclei, the central location of the master clock. These results indicate that CKIdelta may play a role similar to CKIepsilon, suggesting that it may also be involved in regulating circadian rhythmicity by post-translation modification of mammalian clock proteins hPER1 and 2.


Assuntos
Proteínas Nucleares/metabolismo , Proteínas Quinases/metabolismo , Animais , Caseína Quinases , Proteínas de Ciclo Celular , Linhagem Celular , DNA Recombinante , Proteínas de Fluorescência Verde , Humanos , Imuno-Histoquímica , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Proteínas Nucleares/genética , Proteínas Circadianas Period , Fosforilação , Ligação Proteica , Proteínas Quinases/genética , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Núcleo Supraquiasmático/enzimologia , Fatores de Transcrição , Transfecção
16.
J Am Med Womens Assoc (1972) ; 55(4): 225-7, 240, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10935357

RESUMO

Prenatal providers are reluctant to discuss alcohol use in the clinical setting, even though heavy alcohol use is associated with fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE), sometimes known as alcohol-related neurodevelopmental disorder. Fourteen percent to 20% of pregnant women report drinking some alcohol during pregnancy. Approximately 0.2% to 1% meet the criteria for heavy drinking. Reducing drinking during pregnancy has the potential to reduce the risk for FAS and FAE. Routine screening for alcohol use during pregnancy followed by referrals for those considered to be at risk is recommended. Women are often more receptive to intervention during pregnancy, as they focus on positive health behaviors. A number of brief screening tools designed for use on a routine basis are reviewed. Physicians who learn to comfortably discuss alcohol use during pregnancy can help substantially reduce the impact of these disorders.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos do Espectro Alcoólico Fetal/prevenção & controle , Programas de Rastreamento , Complicações na Gravidez/prevenção & controle , Adulto , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Relações Médico-Paciente , Gravidez , Cuidado Pré-Natal
17.
J Antibiot (Tokyo) ; 52(8): 742-7, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10580387

RESUMO

Cyclopropane carboxylic acid was fed to Saccharopolyspora erythraea NRRL 18643 (6-deoxyerythromycin producer), resulting in the production of 6-deoxy-13-cyclopropyl-erythromycin B. These studies provide further evidence that deoxyerythronolide B synthase has a relaxed specificity for the starter unit.


Assuntos
Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Eritromicina/análogos & derivados , Macrolídeos , Saccharopolyspora/metabolismo , Ciclopropanos/metabolismo , Eritromicina/química , Eritromicina/metabolismo , Eritromicina/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Saccharopolyspora/genética
18.
J Biomed Mater Res ; 48(3): 315-21, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10398036

RESUMO

Human fibrin sealant (HFS) and bovine fibrin sealant (BFS) were delivered as preformulated fibrinogen-thrombin mixtures that are light activated. These formulations were evaluated in the healing of incised cutaneous wounds in beagle dogs. Four groups were differentiated by sealant type and study duration with group: BFS for 10 days, HFS for 10 days, BFS for 30 days, and HFS for 30 days. Healing was evaluated by noting incidences of open wounds, laser Doppler perfusion imaging (LDPI), planimetry, breaking strength, and histopathology. In the absence of tension, both sealants tended to hold wound edges together; however, HFS tended to be better than its controls and BFS. Both sealants augmented suture closure, necessitating fewer sutures for wound closure. At 5 and 30 days BFS wounds had more perfusion than HFS wounds, indicating more inflammation. At 10 and 30 days BFS wounds had larger scar areas than their controls, while scar areas of HFS wounds were smaller than either BFS wounds or controls. Breaking strengths indicated that HFS wounds were stronger than their controls and BFS wounds. Histologically, mild to moderate chronic-active inflammation was observed in wounds receiving either sealant, and this persisted longer in BFS wounds. Overall, HFS had positive qualities, thus showing potential for functional and cosmetic wound closure.


Assuntos
Materiais Biocompatíveis , Adesivo Tecidual de Fibrina , Pele/lesões , Cicatrização , Animais , Bovinos , Cães , Feminino , Humanos
19.
Environ Mol Mutagen ; 33(3): 211-8, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10334623

RESUMO

The cellular response to multiple carcinogen treatment has not been extensively studied, even though the effect of individual carcinogens is, in many cases, well known. We have previously shown that potassium dichromate can protect normal human fibroblasts from the mutagenic effects of benzo[a]pyrene diolepoxide (BPDE), and that this effect may be via an oxidative stress mechanism [Tesfai et al. (1998) Mutat Res 416:159-168]. Here, we extend our previous work by showing that nickel subsulfide can produce the some effect. Normal human fibroblasts, preincubated with nickel subsulfide for 46 hr followed by a coincubation of nickel subsulfide and BPDE for 2 hr, showed a dramatic reduction in the mutant frequency of the hypoxanthine (guanine)phosphoribosyl-transferase (HPRT) gene when compared to cells treated only with BPDE. The preincubation period with nickel subsulfide was necessary to see the antagonistic effect, since it was not observed if the cells were simply incubated with both carcinogens for 2 hr. The extent of the antagonistic effect was nickel subsulfide dose-dependent and also appeared to be species-specific, since the effect was not observed when Chinese hamster fibroblasts were tested. Finally, the antagonistic effect of the nickel subsulfide was eliminated by vitamin E, suggesting that production of reactive oxygen species by the nickel may be required. This data, along with our previous work, suggest that the antagonistic effect we observe is not chromium-specific, and that it could be species-specific.


Assuntos
Benzopirenos/toxicidade , Fibroblastos/efeitos dos fármacos , Mutagênese/efeitos dos fármacos , Mutagênicos/toxicidade , Níquel/farmacologia , Animais , Linhagem Celular , Células Clonais/efeitos dos fármacos , Cricetinae , Cricetulus , Análise Mutacional de DNA , Relação Dose-Resposta a Droga , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Hipoxantina Fosforribosiltransferase/genética , Mutação/efeitos dos fármacos , Níquel/antagonistas & inibidores , Dicromato de Potássio/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Especificidade da Espécie , Fatores de Tempo , Vitamina E/farmacologia
20.
J Virol ; 73(1): 37-45, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9847304

RESUMO

The visna virus Tat protein is required for efficient viral transcription from the visna virus long terminal repeat (LTR). AP-1 sites within the visna virus LTR, which can be bound by the cellular transcription factors Fos and Jun, are also necessary for Tat-mediated transcriptional activation. A potential mechanism by which the visna virus Tat protein could target the viral promoter is by protein-protein interactions with Fos and/or Jun bound to AP-1 sites in the visna virus LTR. Once targeted to the visna virus promoter, the Tat protein could then interact with basal transcription factors to activate transcription. To examine protein-protein interactions with cellular proteins at the visna virus promoter, we used an in vitro protein affinity chromatography assay and electrophoretic mobility shift assay, in addition to an in vivo two-hybrid assay, to show that the visna virus Tat protein specifically interacts with the cellular transcription factors Fos and Jun and the basal transcription factor TBP (TATA binding protein). The Tat domain responsible for interactions with Fos and Jun was localized to an alpha-helical domain within amino acids 34 to 69 of the protein. The TBP binding domain was localized to amino acids 1 to 38 of Tat, a region previously described by our laboratory as the visna virus Tat activation domain. The bZIP domains of Fos and Jun were found to be important for the interactions with Tat. Mutations within the basic domains of Fos and Jun abrogated binding to Tat in the in vitro assays. The visna virus Tat protein was also able to interact with covalently cross-linked Fos and Jun dimers. Thus, the visna virus Tat protein appears to target AP-1 sites in the viral promoter in a mechanism similar to the interaction of human T-cell leukemia virus type 1 Tax with the cellular transcription factor CREB, by binding the basic domains of an intact bZIP dimer. The association between Tat, Fos, and Jun would position Tat proximal to the viral TATA box, where the visna virus Tat activation domain could contact TBP to activate viral transcription.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Produtos do Gene tat/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Sequências Repetidas Terminais , Fatores de Transcrição/metabolismo , Vírus Visna-Maedi/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica , Sítios de Ligação , Fatores de Ligação G-Box , Humanos , Ovinos , Proteína de Ligação a TATA-Box
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