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1.
Phys Rev Lett ; 128(24): 247401, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35776456

RESUMO

The ultrafast scattering dynamics of intersubband polaritons in dispersive cavities embedding GaAs/AlGaAs quantum wells are studied directly within their band structure using a noncollinear pump-probe geometry with phase-stable midinfrared pulses. Selective excitation of the lower polariton at a frequency of ∼25 THz and at a finite in-plane momentum k_{‖} leads to the emergence of a narrowband maximum in the probe reflectivity at k_{‖}=0. A quantum mechanical model identifies the underlying microscopic process as stimulated coherent polariton-polariton scattering. These results mark an important milestone toward quantum control and bosonic lasing in custom-tailored polaritonic systems in the mid and far infrared.

2.
AJNR Am J Neuroradiol ; 40(3): 418-425, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30819771

RESUMO

BACKGROUND AND PURPOSE: MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling approaches. We present a transfer learning method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient's own histologic data. MATERIALS AND METHODS: We recruited patients with primary glioblastoma undergoing image-guided biopsies and preoperative imaging, including contrast-enhanced MR imaging, dynamic susceptibility contrast MR imaging, and diffusion tensor imaging. We calculated relative cerebral blood volume from DSC-MR imaging and mean diffusivity and fractional anisotropy from DTI. Following image coregistration, we assessed tumor cell density for each biopsy and identified corresponding localized MR imaging measurements. We then explored a range of univariate and multivariate predictive models of tumor cell density based on MR imaging measurements in a generalized one-model-fits-all approach. We then implemented both univariate and multivariate individualized transfer learning predictive models, which harness the available population-level data but allow individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized transfer learning and generalized one-model-fits-all models. RESULTS: Tumor cell density significantly correlated with relative CBV (r = 0.33, P < .001), and T1-weighted postcontrast (r = 0.36, P < .001) on univariate analysis after correcting for multiple comparisons. With single-variable modeling (using relative CBV), transfer learning increased predictive performance (r = 0.53, mean absolute error = 15.19%) compared with one-model-fits-all (r = 0.27, mean absolute error = 17.79%). With multivariate modeling, transfer learning further improved performance (r = 0.88, mean absolute error = 5.66%) compared with one-model-fits-all (r = 0.39, mean absolute error = 16.55%). CONCLUSIONS: Transfer learning significantly improves predictive modeling performance for quantifying tumor cell density in glioblastoma.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Aprendizado de Máquina , Neuroimagem/métodos , Adulto , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
3.
Food Chem Toxicol ; 94: 227-42, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27288929

RESUMO

Caffeine consumption among US teenagers (13-17y), young adults (18-24y) and adults (25-29y) for a 10 year period was examined using NHANES 2003-12. Of the 85% who consume caffeine 84% consume caffeinated beverages. This percentage remained constant despite new caffeine sources. Less than 7.1% of the population consume energy drinks. While mean caffeine intake among teenage caffeine consumers decreased from 62 to 55 mg/day (p-value = 0.018) over the 10-year period, no discernable trend was observed for other age groups. Caffeine intake from energy drinks increased, and was only statistically significant for age 18-24y accounting for <9% of total caffeine intake. Mean caffeine intake per consumption occasion was equivalent between coffee and energy drinks for teenagers and young adults. During a 30-min period mean caffeine consumption was similar when an energy drink was the only consumption event or when it occurred with other caffeinated beverage products suggestive of a substitution effect. Linear regression models of caffeine intake from energy drinks against caffeine from coffee, tea and soda among energy drink consumers in the upper 50th percentile shows a statistically significant inverse relationship (R2 = 28%, coffee: ß = -0.35, p < 0.001; tea: ß = -0.44, p < 0.001; soda: ß = -0.22, p = 0.036) and further supports the substitution concept.


Assuntos
Cafeína/administração & dosagem , Adolescente , Adulto , Bebidas , Humanos , Inquéritos Nutricionais , Estados Unidos , Adulto Jovem
4.
Oncogene ; 35(17): 2145-55, 2016 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-26300004

RESUMO

UNLABELLED: Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as 'GB multiforme'). GB is the most common and aggressive primary malignant brain tumor and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but is upregulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype; (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue; and (iii) TWEAK: Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells.


Assuntos
Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Receptores do Fator de Necrose Tumoral/genética , Fatores de Necrose Tumoral/genética , Apoptose/genética , Movimento Celular/genética , Citocina TWEAK , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Invasividade Neoplásica/genética , Receptores do Fator de Necrose Tumoral/biossíntese , Receptor de TWEAK , Fator de Necrose Tumoral alfa/genética , Fatores de Necrose Tumoral/biossíntese
5.
Br J Cancer ; 110(5): 1307-15, 2014 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-24518591

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM), a highly invasive primary brain tumour, remains an incurable disease. Rho GTPases and their activators, guanine nucleotide exchange factors (GEFs), have central roles in GBM invasion. Anti-angiogenic therapies may stimulate GBM invasion via HGF/c-Met signalling. We aim to identify mediators of HGF-induced GBM invasion that may represent targets in a combination anti-angiogenic/anti-invasion therapeutic paradigm. METHODS: Guanine nucleotide exchange factor expression was measured by microarray analysis and western blotting. Specific depletion of proteins was accomplished using siRNA. Cell invasion was determined using matrigel and brain slice assays. Cell proliferation and survival were monitored using sulforhodamine B and colony formation assays. Guanine nucleotide exchange factor and GTPase activities were determined using specific affinity precipitation assays. RESULTS: We found that expression of Dock7, a GEF, is elevated in human GBM tissue in comparison with non-neoplastic brain. We showed that Dock7 mediates serum- and HGF-induced glioblastoma cell invasion. We also showed that Dock7 co-immunoprecipitates with c-Met and that this interaction is enhanced upon HGF stimulation in a manner that is dependent on the adaptor protein Gab1. Dock7 and Gab1 also co-immunoprecipitate in an HGF-dependent manner. Furthermore, Gab1 is required for HGF-induced Dock7 and Rac1 activation and glioblastoma cell invasion. CONCLUSIONS: Dock7 mediates HGF-induced GBM invasion. Targeting Dock7 in GBM may inhibit c-MET-mediated invasion in tumours treated with anti-angiogenic regimens.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteínas Ativadoras de GTPase/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inibidores da Angiogênese/genética , Inibidores da Angiogênese/metabolismo , Neoplasias Encefálicas/genética , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Glioblastoma/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Fator de Crescimento de Hepatócito/genética , Humanos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo
6.
Food Chem Toxicol ; 48(11): 3098-108, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20696196

RESUMO

The objective of this study is to evaluate the relationship between dietary AA and hemoglobin adducts using the National Health and Nutrition Examination Survey (NHANES, 2003-04). Measured acrylamide (AA-Hb) and glycidamide (Gly-Hb) hemoglobin adducts for over 7000 participants >3 years, 24-h dietary recall, food frequency questionnaire (FFQ), lifestyle and demographic data, and anthropometric measurements are available from NHANES (2003-04). The 24-h dietary recall and FFQ data were combined with AA concentration data in food from the US FDA to estimate "usual" AA dietary exposure. The associations between dietary AA and AA-Hb and Gly-Hb were evaluated using linear regression models with smoking, age, gender, energy and macronutrient intake, body surface area, and activity level as covariates. Dietary AA positively correlates with AA-Hb and Gly-Hb (p<0.05) but the correlation is small (R-Squared<3.5%). Relative to the background adduct levels, the incremental increase in AA-Hb and Gly-Hb from average dietary AA is small (7% and 9% for AA-Hb and Gly-Hb, respectively). Non-dietary sources of exposure, measurement errors associated with the use of the FFQ, and uncertainty in the data on AA levels in foods are possible explanations for the observed lack of association between dietary AA and AA-Hb and Gly-Hb.


Assuntos
Acrilamida/administração & dosagem , Acrilamida/metabolismo , Contaminação de Alimentos/análise , Hemoglobinas/metabolismo , Acrilamida/efeitos adversos , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Cotinina/sangue , Dieta , Ingestão de Alimentos , Exposição Ambiental/efeitos adversos , Compostos de Epóxi/metabolismo , Comportamento Alimentar , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Inquéritos Nutricionais , Inquéritos e Questionários , Estados Unidos , Adulto Jovem
7.
J Chem Phys ; 130(20): 204307, 2009 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-19485449

RESUMO

Density functional theory (DFT) simulations were used to determine the binding strength of 12 electron-donating analytes to the zinc metal center of a zinc phthalocyanine molecule (ZnPc monomer). The analyte binding strengths were compared to the analytes' enthalpies of complex formation with boron trifluoride (BF(3)), which is a direct measure of their electron donating ability or Lewis basicity. With the exception of the most basic analyte investigated, the ZnPc binding energies were found to correlate linearly with analyte basicities. Based on natural population analysis calculations, analyte complexation to the Zn metal of the ZnPc monomer resulted in limited charge transfer from the analyte to the ZnPc molecule, which increased with analyte-ZnPc binding energy. The experimental analyte sensitivities from chemiresistor ZnPc sensor data were proportional to an exponential of the binding energies from DFT calculations consistent with sensitivity being proportional to analyte coverage and binding strength. The good correlation observed suggests DFT is a reliable method for the prediction of chemiresistor metallophthalocyanine binding strengths and response sensitivities.

8.
J Chem Phys ; 130(17): 174305, 2009 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-19425774

RESUMO

The NO chemisorption dynamics on ordered multilayer iron phthalocyanine (FePc) and quasiamorphous multilayer tetra-t-butyl FePc (ttbu-FePc) films on a Au(111) substrate was investigated using the King and Wells reflection technique. The NO zero coverage or initial sticking probabilities (S(0)) were measured as a function of sample temperature (T(s)) and beam energy (E(i)). The experimental results for both films show a monotonic decrease in S(0) with increasing T(s) and E(i) consistent with NO adsorption occurring via a multiple pathway precursor-mediated mechanism in which the adsorbate initially physisorbs to the FePc organics, diffuses, and chemisorbs to the Fe metal center. The saturation coverage is 3% for the multilayer FePc surface and only 2% for the multilayer ttbu-FePc surface consistent with NO chemisorption occurring only on the Fe metal, where NO chemisorbs to 100% of the surface Fe metal centers. The reduced saturation coverage in the ttbu-FePc film is attributed to fewer Fe metal centers in the less dense ttbu-FePc films. A comparison of NO sticking on a multilayer FePc/Au(111) film with NO sticking on a monolayer FePc/Au(111) film shows that S(0) is greater on the multilayer FePc film for all T(s) and E(i), consistent with an increase in collision inelasticity for NO/multilayer FePc/Au(111).

9.
Cell Mol Life Sci ; 64(4): 458-78, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17260089

RESUMO

Glioblastoma multiforme is the most common and lethal primary malignant brain tumor. Although considerable progress has been made in technical proficiencies of surgical and radiation treatment for brain tumor patients, the impact of these advances on clinical outcome has been disappointing, with median survival time not exceeding 15 months. Over the last 30 years, no significant increase in survival of patients suffering from this disease has been achieved. A fundamental source of the management challenge presented in glioma patients is the insidious propensity of tumor invasion into distant brain tissue. Invasive tumor cells escape surgical removal and geographically dodge lethal radiation exposure and chemotherapy. Recent improved understanding of biochemical and molecular determinants of glioma cell invasion provide valuable insight into the underlying biological features of the disease, as well as illuminating possible new therapeutic targets. These findings are moving forward to translational research and clinical trials as novel antiglioma therapies.


Assuntos
Glioma/metabolismo , Glioma/patologia , Invasividade Neoplásica/patologia , Ensaios Clínicos como Assunto , Matriz Extracelular/metabolismo , Glioma/terapia , Humanos , Invasividade Neoplásica/prevenção & controle , Proteínas de Neoplasias/metabolismo , Células Neoplásicas Circulantes/patologia
10.
Bioinformatics ; 20 Suppl 1: i15-22, 2004 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-15262776

RESUMO

MOTIVATION: In this paper we propose to use recent developments in knowledge representation languages and reasoning methodologies for representing and reasoning about signaling networks. Our approach is different from most other qualitative systems biology approaches in that it is based on reasoning (or inferencing) rather than simulation. Some of the advantages of our approach are, we can use recent advances in reasoning with incomplete and partial information to deal with gaps in signal network knowledge; and can perform various kinds of reasoning such as planning, hypothetical reasoning and explaining observations. RESULTS: Using our approach we have developed the system BioSigNet-RR for representation and reasoning about signaling networks. We use a NFkappaB related signaling pathway to illustrate the kinds of reasoning and representation that our system can currently do. AVAILABILITY: The system is available on the Web at http://www.public.asu.edu/~cbaral/biosignet


Assuntos
Algoritmos , Inteligência Artificial , Perfilação da Expressão Gênica/métodos , Expressão Gênica/fisiologia , Modelos Biológicos , Proteoma/metabolismo , Transdução de Sinais/fisiologia , Simulação por Computador
11.
Food Chem Toxicol ; 40(5): 673-84, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11955674

RESUMO

Heterocylic amine (HA) compounds formed in the cooking of certain foods have been shown to be bacterial mutagens and animal carcinogens, and may be a risk factor for human cancer. To help explain the variation observed in HA formation under different cooking conditions, we have performed heat-flow simulations and experiments on the pan-frying of beef patties. The simulations involve modeling the heat flow within a meat patty using empirically derived thermal transport coefficients for the meat. The predicted temperature profiles are used to integrate the Arrhenius rate equation to estimate the concentration of HAs formed in the meat. We find that our simulations accurately model experimentally determined temperature profiles, cooking times, HA spatial distributions and total HA formation in patties that are flipped once during the pan-frying process. For patties flipped every 60 s, the simulations qualitatively agree with experiment in predicting reduced cooking times and HA formation relative to the singly-flipped patties. However, the simulations overestimate the effect of rapid flipping on cooking times and underestimate the effect of flipping on total HAs formed. These results suggest that the dramatic reductions in HA formation due to rapid flipping may be due to factors other than the heating process or that there is a critical feature of the flipping process that is not captured in our model.


Assuntos
Carcinógenos/química , Culinária , Compostos Heterocíclicos/química , Carne/análise , Mutagênicos/química , Algoritmos , Animais , Bovinos , Simulação por Computador , Análise de Elementos Finitos , Temperatura Alta , Modelos Estatísticos , Termodinâmica
12.
Exp Cell Res ; 270(2): 259-67, 2001 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-11640889

RESUMO

Matrilysin is a matrix metalloprotease (MMP) overexpressed in a number of cancers including skin, head and neck squamous cell carcinomas, and prostate and colon adenocarcinomas. Matrilysin has been shown to play a role in the degradation of the basement membrane that separates epithelium from stroma allowing tumor cells to intravasate into the bloodstream and metastasize. Here, we show that an oral squamous cell carcinoma cell line (SCC-25) expresses low levels of promatrilysin when cultured alone. However, when SCC-25 cells are cocultured with human foreskin fibroblasts (HFF), there is a 40-fold induction of promatrilysin expression. We tested whether this induction of promatrilysin expression was due to the release of paracrine factors, cell-cell interactions, or cell-matrix interactions. Our results indicate induced promatrilysin expression is the result of both cell-cell and cell-matrix interactions. We demonstrate that beta1 integrins as well as cadherins, specifically N-cadherin and E-cadherin, are involved in the induction of promatrilysin expression. Our results are of general interest in relation to the regulation of MMP expression through cell surface receptor regulation. Further investigation may lead to the identification of novel targets for suppression of invasion and metastasis in oral tumors.


Assuntos
Caderinas/metabolismo , Carcinoma de Células Escamosas , Derme/citologia , Integrina beta1/metabolismo , Metaloproteinase 7 da Matriz/genética , Neoplasias Bucais , Western Blotting , Caderinas/análise , Caderinas/genética , Cálcio/metabolismo , Comunicação Celular/fisiologia , Quelantes/farmacologia , Técnicas de Cocultura , Ácido Egtázico/farmacologia , Precursores Enzimáticos/genética , Matriz Extracelular/fisiologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Metaloendopeptidases/genética , Peptídeos/farmacologia , Células Tumorais Cultivadas
13.
Risk Anal ; 20(2): 163-72, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10859777

RESUMO

Driven by differing statutory mandates and programmatic separation of regulatory responsibilities between federal, state, and tribal agencies, distinct chemical and radiation risk management strategies have evolved. In the field this separation poses real challenges since many of the major environmental risk management decisions we face today require the evaluation of both types of risks. Over the last decade, federal, state, and tribal agencies have continued to discuss their different approaches and explore areas where their activities could be harmonized. The current framework for managing public exposures to chemical carcinogens has been referred to as a "bottom up approach." Risk between 10(-4) and 10(-6) is established as an upper bound goal. In contrast, a "top down" approach that sets an upper bound dose limit and couples with site specific As Low As Reasonably Achievable Principle (ALARA), is in place to manage individual exposure to radiation. While radiation risk are typically managed on a cumulative basis, exposure to chemicals is generally managed on a chemical-by-chemical, medium-by-medium basis. There are also differences in the nature and size of sites where chemical and radiation contamination is found. Such differences result in divergent management concerns. In spite of these differences, there are several common and practical concerns among radiation and chemical risk managers. They include 1) the issue of cost for site redevelopment and long-term stewardship, 2) public acceptance and involvement, and 3) the need for flexible risk management framework to address the first two issues. This article attempts to synthesize key differences, opportunities for harmonization, and challenges ahead.


Assuntos
Poluentes Ambientais/efeitos adversos , Poluentes Radioativos/efeitos adversos , Gestão de Riscos , Carcinógenos/administração & dosagem , Carcinógenos/efeitos adversos , Participação da Comunidade , Custos e Análise de Custo , Exposição Ambiental , Governo , Órgãos Governamentais/legislação & jurisprudência , Humanos , Relações Interinstitucionais , Concentração Máxima Permitida , Formulação de Políticas , Opinião Pública , Doses de Radiação , Risco , Gestão de Riscos/legislação & jurisprudência , Governo Estadual , Estados Unidos
14.
Am J Pathol ; 155(3): 787-98, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10487836

RESUMO

In human prostate adenocarcinoma, an association between loss of E-cadherin, increased Gleason score, and extracapsular dissemination has been observed. Further characterization of the E-cadherin/catenin phenotype of human prostate carcinoma cell lines showed loss of E-cadherin and expression of N-cadherin in poorly differentiated prostate carcinoma cell lines (PC-3N derived from PC-3, PC-3, and JCA1). We showed that N-cadherin is concentrated at sites of cell-cell contact in PC-3N cellular extensions. N-cadherin was also expressed in prostate stromal fibroblasts both in vitro and in prostate tissue. Co-cultures of prostate stromal fibroblasts and PC-3N cells showed the immunolocalization of N-cadherin in intercellular contacts. In addition, the isoform expression of the cadherin binding protein p120(ctn) differed in relation to the expression of E- versus N-cadherin by the prostate carcinoma cell lines. The p100 isoform was more highly expressed in E-cadherin-positive carcinoma cell lines, whereas p120 was predominantly expressed only in N-cadherin-positive prostate carcinoma cell lines and prostate stromal fibroblasts. The N-cadherin-positive carcinoma cell line, PC-3N, displayed aggressive invasion into the surface of the diaphragm muscle after intraperitoneal injection of SCID mice. The gain of N-cadherin and loss of E-cadherin by invasive prostate carcinoma cell lines suggests a progression from an epithelial to a mesenchymal phenotype, which may allow for their interaction with surrounding stromal fibroblasts and facilitate metastasis.


Assuntos
Adenocarcinoma/metabolismo , Caderinas/biossíntese , Neoplasias da Próstata/metabolismo , Adenocarcinoma/patologia , Animais , Caderinas/metabolismo , Caderinas/fisiologia , Proteínas de Transporte/metabolismo , Cateninas , Moléculas de Adesão Celular/metabolismo , Agregação Celular/efeitos dos fármacos , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Humanos , Immunoblotting , Imuno-Histoquímica , Masculino , Camundongos , Camundongos SCID , Invasividade Neoplásica , Fosfoproteínas/metabolismo , Neoplasias da Próstata/patologia , RNA Mensageiro/biossíntese , Células Estromais/metabolismo , Células Tumorais Cultivadas , delta Catenina
15.
Curr Pharm Des ; 5(8): 645-63, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10469896

RESUMO

The nitrogen mustard based DNA alkylating agents were the first effective anticancer agents and remain important drugs against many forms of cancer. More than fifty years of research on the nitrogen mustards has yielded a broad range of therapeutically useful compounds and a detailed knowledge of the biochemical mechanism of these drugs. Nevertheless, there is much ongoing research on the phosphosphoramidic and other nitrogen mustards to increase their potency and reduce their toxic and mutagenic side effects. To understand the existing nitrogen mustards, and to design the next generation of these drugs, more knowledge is needed about the effects of chemical modifications on their activation and selectivity. Because of the existing knowledge of these drugs, atomic-level chemical modeling can play an important role in the understanding of the phosphoramidic mustard compounds; however, it has not proved straight forward to directly relate the activity of these mustards with simple chemical properties such as bond lengths or atomic charges. Instead, quantum chemical simulations will be required to simulate the activation and alkylation reactions of these compounds, which will require the newest generation of quantum chemical and solvent modeling methods. Additionally, molecular dynamics simulations of the adducted DNA can provide data on the factors favoring crosslinking and its structural consequences. This review summarizes the extensive literature on the metabolism, activation, and action of the phosphoramidic mustards, with an emphasis on the roles that chemical modeling has and will play in the development of this important class of drugs.


Assuntos
Antineoplásicos Alquilantes/química , Modelos Químicos , Mostardas de Fosforamida/química , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacocinética , Simulação por Computador , Mostardas de Fosforamida/metabolismo , Mostardas de Fosforamida/farmacocinética , Mostardas de Fosforamida/farmacologia
16.
J Public Health Manag Pract ; 5(6): 1-12, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10662058

RESUMO

The practice of environmental health and protection is at a crossroads. Expanded responsibilities throughout this nation's agencies, prescriptive statutory mandates, and shrunken resources for fundamental public health services have combined to change the infrastructure and the workforce. This article presents the results of the Crossroads Colloquium, a forum of leaders in environmental health, convened to address the educational needs of the workforce. Major recommendations from the Crossroads Colloquium include redefining training by moving from discipline-specific to multidisciplinary training, developing collaborations among agencies, academia, and industry for training and education, and providing opportunities ranging from distance education to graduate degree programs.


Assuntos
Conservação dos Recursos Naturais , Saúde Ambiental , Administração em Saúde Pública/educação , Educação Profissionalizante/métodos , Educação Profissionalizante/organização & administração , Relações Interprofissionais , Objetivos Organizacionais , Estados Unidos
17.
J Public Health Manag Pract ; 3(2): 1-12, 1997 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10186707

RESUMO

The success of our national environmental policies depends upon the capacity of states to implement them. This article presents the findings of an examination of the state level organization of environmental health and protection services. The goals of the project were to conduct a descriptive analysis of the structure, functions, and funding of state environmental health and protection services, and to examine the impact of the major federal environmental statutes on the organization of the state infrastructure. Future environmental progress will depend upon an improved understanding of the relationship between human health and the environment. This will require a commitment to improving the public health training of environmental professionals, and improved cooperation between health and environmental agencies to assure that they do not lose sight of their fundamental mission--the protection of public health.


Assuntos
Saúde Ambiental , Serviços Preventivos de Saúde/organização & administração , United States Environmental Protection Agency/organização & administração , Saúde Ambiental/economia , Saúde Ambiental/legislação & jurisprudência , Monitoramento Ambiental , Fiscalização e Controle de Instalações , Humanos , Vigilância da População , Estados Unidos
18.
J Expo Anal Environ Epidemiol ; 7(1): 81-101, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9076611

RESUMO

The Dietary Exposure Potential Model (DEPM) is a computer-based model developed for estimating dietary exposure to chemical residues in food. The DEPM is based on food consumption data from the 1987-1988 Nationwide Food Consumption Survey (NFCS) administered by the United States Department of Agriculture (USDA) and on residue data from government-sponsored monitoring programs. Foods reported in the NFCS were categorized into exposure core foods (ECFs). A computer program for DOS-based personal computers was developed to link consumption of the ECFs with residue values observed in the foods. The data files utilized by the DEPM were designed in dBASE IV with FoxPro for Windows applications programs for queries and reporting. The program calculates exposure estimates for categories of core foods, such as grain dishes, fruits, or vegetables; for individual core foods, such as wheat and apple combination dishes; and for individual foods, such as apples or carrots. The program, residue summary databases, and core food consumption database permit the analyst to evaluate potential exposure of several population groups to various chemicals via the diet. The DEPM is not intended for risk assessments, but is a suitable tool for identifying data gaps and establishing priorities for research, and for identifying potentially significant foods for human exposure monitoring.


Assuntos
Simulação por Computador , Bases de Dados Factuais , Exposição Ambiental/análise , Contaminação de Alimentos/estatística & dados numéricos , Substâncias Perigosas/análise , Resíduos de Praguicidas/análise , Design de Software , Adulto , Criança , Pré-Escolar , Inquéritos sobre Dietas , Monitoramento Ambiental/estatística & dados numéricos , Feminino , Alimentos/classificação , Humanos , Lactente , Masculino
19.
Pharm Res ; 13(7): 1116-21, 1996 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8842055

RESUMO

PURPOSE: The purpose of this study were to evaluate the use of individual compartmental and population compartmental methods for bioequivalence determination, and to determine their utility as adjuncts to the current methods used for bioequivalence assessment. METHODS: Data from three bioequivalence studies of chlorthalidone were analyzed with PCNONLIN using individual compartmental modeling and NONMEM for population analyses. These results were compared with results obtained from the traditional noncompartmental or SHAM (slopes, heights, areas, and moments) approach for bioequivalence assessment and the 90% confidence interval procedure. RESULTS: Individual compartmental modeling and population compartmental modeling techniques performed well on this routine set of bioequivalence data which displayed simple pharmacokinetic properties. A direct assessment of the analysis methods was made by comparing the final estimates and 90% confidence intervals for the test to reference ratios (T/R) of AUC and CMAX. The final estimates and 90% confidence intervals for AUC T/R and CMAX T/R were similar and suggest consistency of results, independent of the method used. CONCLUSIONS: These results demonstrate the utility of modeling techniques as adjuncts to the traditional noncompartmental approach for bioequivalence determination.


Assuntos
Equivalência Terapêutica , Clortalidona/farmacocinética , Estudos Cross-Over , Interpretação Estatística de Dados , Humanos , Modelos Estatísticos
20.
Glia ; 13(1): 64-74, 1995 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-7751057

RESUMO

Attachment sites and biological functions of laminin isolated from murine EHS sarcoma have been well studied. Recently several variants of laminin including human placental laminin have been shown to be distinct from EHS-laminin. This study was undertaken to determine attachment, proliferation, and migration phenomena of human astrocytoma cell lines to human and murine sarcoma EHS-laminin. Using short-term attachment assays human placental laminin was shown to be the better substrate for cell adhesion. EHS-laminin mediated approximately 30-50% of the effect observed on human laminin. The astrocytoma cells expressed beta 1, beta 3, and beta 4 subunit mRNA as determined by RT-PCR. Anti-beta 1 antibodies blocked adhesion to EHS-laminin, but antibodies against beta 1, beta 4, and alpha v subunits were all ineffective in blocking adhesion to human laminin. A migration assay showed that astrocytoma cells on human laminin dispersed from a central seeding area, while cells on EHS-laminin remained where they were seeded. The pattern of dispersion could not be accounted for by changes in growth rates of astrocytoma cells on the different proteins, since both cell lines grew equally well on the two laminins. We conclude that unique epitopes on human laminin are recognized by novel receptors on human astrocytoma cells which confer a migratory phenotype to the cells.


Assuntos
Astrocitoma/patologia , Laminina/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Humanos , Integrinas/biossíntese , Integrinas/imunologia , Integrinas/fisiologia , Laminina/isolamento & purificação , Camundongos , Fenótipo , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , Especificidade da Espécie , Células Tumorais Cultivadas
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