RESUMEN

Calculation of the concentration-time profile in four consecutive, well-mixed compartments that are connected by diffusional transport is a frequently occurring problem for chemists and engineers. Mathematically this is equivalent to many other problems such as the concentration profiles of a parent compound and its three consecutive reaction products resulting from reversible first-order kinetics. Here we present an analytical solution to this problem implemented in a Microsoft Excel spreadsheet (available for download) and we discuss various examples of how this simple-to-use tool can be applied to very different scenarios from various fields of science.

Asunto(s)

Modelos Químicos , Relación Estructura-Actividad Cuantitativa , Cinética

RESUMEN

We report transport measurements on a quantum dot in a partly suspended carbon nanotube. Electrostatic tuning allows us to modify and even switch "on" and "off" the coupling to the quantized stretching vibration across several charge states. The magnetic-field dependence indicates that only the two-electron spin-triplet excited state couples to the mechanical motion, indicating mechanical coupling to both the valley degree of freedom and the exchange interaction, in contrast to standard models.

RESUMEN

We report on the influence of low gamma irradiation (10(4) Gy) on the noise properties of individual carbon nanotube (CNT) field-effect transistors (FETs) with different gate configurations and two different dielectric layers, SiO2 and Al2O3. Before treatment, strong generation-recombination (GR) noise components are observed. These data are used to identify several charge traps related to dielectric layers of the FETs by determining their activation energy. Investigation of samples with a single SiO2 dielectric layer as well as with two dielectric layers allows us to separate traps for each of the two dielectric layers. We reveal that each charge trap level observed in the side gate operation splits into two levels in top gate operation due to a different potential profile along the CNT channel. After gamma irradiation, only reduced flicker noise is registered in the noise spectra, which indicates a decrease of the number of charge traps. The mobility, which is estimated to be larger than 2 × 10(4) cm(2) V(-1) s(-1) at room temperature, decreases only slightly after radiation treatment, demonstrating high radiation hardness of the CNTs. Finally, we study the influence of Schottky barriers at the metal-nanotube interface on the transport properties of FETs, analyzing the behavior of the flicker noise component.

RESUMEN

OBJECTIVE: A cognitive interpersonal maintenance model of anorexia nervosa (AN) was first proposed in 2006 and updated in 2013 (Schmidt and Treasure, J Br J Clin Psychol, 45, 343-366, 2006; Treasure and Schmidt, J Eat Disorders, in press.). The aim of this study was to test the interpersonal component of this model in people with AN requiring intensive hospital treatment (inpatient/day patient). METHOD: On admission to hospital women with AN or eating disorder not otherwise specified (AN subtype; n = 152; P) and their primary carers (n = 152; C) completed questionnaires on eating symptoms (P), depression and anxiety (P, C), accommodation and enabling (C), and psychological control (C). Structural equation modeling was used to examine relationships among these components. RESULTS: Carers' expressed emotion and level of psychological control were significantly related to carers' distress, which in turn, was related to patients' distress. This pathway significantly predicted eating symptoms in patients. DISCUSSION: The cognitive interpersonal maintenance model of eating disorders (EDs) was confirmed in part and suggests that interventions targeting interpersonal maintaining factors such as carer distress might impact on patient outcomes.

Asunto(s)

Anorexia Nerviosa/psicología , Cuidadores/psicología , Depresión/psicología , Relaciones Interpersonales , Modelos Psicológicos , Adolescente , Adulto , Factores de Edad , Anorexia Nerviosa/diagnóstico , Cuidadores/estadística & datos numéricos , Factores de Confusión Epidemiológicos , Depresión/epidemiología , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Controles Informales de la Sociedad , Factores Socioeconómicos , Encuestas y Cuestionarios , Reino Unido/epidemiología , Adulto Joven

RESUMEN

The spectral weight evolution of the low-dimensional Mott insulator TiOCl upon alkali-metal dosing has been studied by photoelectron spectroscopy. We observe a spectral weight transfer between the lower Hubbard band and an additional peak upon electron doping, in line with quantitative expectations in the atomic limit for changing the number of singly and doubly occupied sites. This observation is an unconditional hallmark of correlated bands and has not been reported before. In contrast, the absence of a metallic quasiparticle peak can be traced back to a simple one-particle effect.

RESUMEN

The dye malachite green (MG) is used worldwide as a fungicide in aquaculture. It is a toxic substance which in aqueous solutions is partly converted into its non-ionic colorless form (leucocarbinol). The equilibrium between these two forms is pH-dependent (pK=6.9). To assess the photodegradation of MG under sunlight conditions, both species were irradiated separately in aqueous solutions with different pH values (4.0 and 12.0) using various ultraviolet and visible wavelength ranges (UV/VIS). A 700 W high-pressure mercury lamp with special filters was used. No artificial photooxidizers such as H2O2 or TiO2 were added. MG leucocarbinol proved to be much more sensitive to irradiation than the dye form. Quantum yields Φ were calculated for some wavelength ranges as follows: MG carbinol: Φ((280-312 nm)) is 4.3 × 10⁻³, Φ((313 - 410 nm)) is 5.8 × 10⁻³, and MG dye: Φ((280 - 312 nm)) is 4.8 × 10(-5), Φ((313-365nm)) is 1.1×10⁻5, and Φ((> 365nm)) is 0, respectively. Therefore, the solar photolysis of MG is an important sink and primarily depends on the photodegradation of the colorless leucocarbinol. During the irradiation of MG leucocarbinol with wavelengths > 365 nm, an intermediate was formed which has photocatalytical properties.

Asunto(s)

Fungicidas Industriales/química , Luz , Metanol/química , Fotólisis , Colorantes de Rosanilina/química , Acuicultura , Fungicidas Industriales/efectos de la radiación , Metanol/efectos de la radiación , Oxidantes Fotoquímicos/química , Colorantes de Rosanilina/efectos de la radiación , Contaminantes Químicos del Agua/química , Contaminantes Químicos del Agua/efectos de la radiación

RESUMEN

The conducting interface of LaAlO3/SrTiO3 heterostructures has been studied by hard x-ray photoelectron spectroscopy. From the Ti 2p signal and its angle dependence we derive that the thickness of the electron gas is much smaller than the probing depth of 4 nm and that the carrier densities vary with increasing number of LaAlO3 overlayers. Our results point to an electronic reconstruction in the LaAlO3 overlayer as the driving mechanism for the conducting interface and corroborate the recent interpretation of the superconducting ground state as being of the Berezinskii-Kosterlitz-Thouless type.

RESUMEN

Ongoing deterioration of the riverine environments of the Murray-Darling Basin led the Murray-Darling Basin Ministerial Council to introduce a Cap in 1995 to halt the growth in diversions of water for consumptive use. This initiative recognised the finite nature of water resources in the Basin and sought to introduce a balance between off-stream use of water and protection of the riverine environment. But the cap is only one step, albeit a fundamental one, in restoring the Basin's rivers--it is a "stake in the ground". Parties to the Murray-Darling Basin Initiative recognise the need to reverse decades of creeping decline if the Basin's rivers and riverine environments are to return to a more ecologically sustainable condition. In the last 12 months, Council and Commission have taken far-reaching decisions designed to restore the Basin's Rivers. Many of these decisions, even 10 years ago, would have been unimaginable. The Report Card will explain the need for a number of recent decisions that will impact on the future of the Basin's rivers. For example, Council's decision to establish an Environmental Manager function in the Office of the Commission was made in the context of the recently agreed Integrated Catchment Management (ICM) Policy, and supporting Sustainable Rivers Audit. The role of targets and accountabilities under the ICM Policy will also be discussed. The Report Card will also present a snapshot of the state of the Basin's rivers and the actions being taken at a range of scales and locations in response to identified problems. Because some of the key initiatives are still in development, this Report Card will set the scene by describing where our attention is being focused and why.

Asunto(s)

Monitoreo del Ambiente , Abastecimiento de Agua/normas , Australia , Clima , Ecología , Ambiente , Control de Calidad , Contaminación del Agua/prevención & control

RESUMEN

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen involved in normal and abnormal angiogenesis. VEGF mRNA and protein are abundant in distal epithelium of midtrimester human fetal lung. In the present study, we identified immunoreactivity for KDR, a major VEGF-specific receptor, in distal lung epithelial cells of human fetal lung tissue, suggesting a possible autocrine or paracrine regulatory role for VEGF in pulmonary epithelial cell growth and differentiation. Addition of exogenous VEGF to human fetal lung explants resulted in increased epithelium volume density and lumen volume density in the tissues, both morphometric parameters of tissue differentiation. Cellular proliferation demonstrated by bromodeoxyuridine uptake was prominent in distal airway epithelial cells and increased in the VEGF-treated explants. VEGF-treated explants also demonstrated increased surfactant protein (SP) A mRNA, SP-C mRNA, and SP-A protein levels compared with controls. However, SP-B mRNA levels were unaffected by VEGF treatment. [(3)H]choline incorporation into total phosphatidylcholine was increased by VEGF treatment, but incorporation into disaturated phosphatidylcholine was not affected by exogenous VEGF. Based on these observations, we conclude that VEGF may be an important autocrine growth factor for distal airway epithelial cells in the developing human lung.

Asunto(s)

Factores de Crecimiento Endotelial/farmacología , Pulmón/citología , Linfocinas/farmacología , Mucosa Respiratoria/citología , División Celular/efectos de los fármacos , Colina/farmacocinética , Feto/citología , Expresión Génica/efectos de los fármacos , Humanos , Pulmón/embriología , Pulmón/metabolismo , Técnicas de Cultivo de Órganos , Fosfatidilcolinas/biosíntesis , Proteolípidos/análisis , Proteolípidos/genética , Proteína A Asociada a Surfactante Pulmonar , Proteínas Asociadas a Surfactante Pulmonar , Surfactantes Pulmonares/análisis , Surfactantes Pulmonares/genética , ARN Mensajero/análisis , Proteínas Tirosina Quinasas Receptoras/análisis , Receptores de Factores de Crecimiento/análisis , Receptores de Factores de Crecimiento Endotelial Vascular , Mucosa Respiratoria/embriología , Mucosa Respiratoria/metabolismo , Tritio , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular

RESUMEN

In our study, surfactant protein (SP)-A was characterized in adult human trachea and bronchi. SP-A mRNA and protein were localized to serous cells in submucosal gland by in situ hybridization and immunohistochemistry, respectively. A 2.2 kb SP-A mRNA transcript was detected in tracheal tissues by Northern blot analysis. Primer extension analysis and gene-specific reverse transcriptase polymerase chain reaction (RT-PCR) revealed the predominance of SP-A2 mRNA. However, using nested PCR, we also detected low amounts of SP-A1 mRNA in the tracheal tissues. A approximately 35 kDa SP-A immunoreactive protein was detected in the tracheal tissues by immunoblot analysis and was shown to be modified by the addition of N-linked oligosaccharides. We conclude that submucosal glands in the conducting airways produce a novel SP-A protein with a molecular weight and post-translational modification similar to the SP-A produced in the distal lung. We speculate that this SP-A2 protein, like other serous secretions from airway submucosal glands, functions in local antimicrobial host defense mechanisms in the conducting airways.

Asunto(s)

Bronquios/metabolismo , Proteolípidos/biosíntesis , Surfactantes Pulmonares/biosíntesis , Tráquea/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Northern Blotting , Femenino , Glicosilación , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Persona de Mediana Edad , Membrana Mucosa/metabolismo , Reacción en Cadena de la Polimerasa , Proteína A Asociada a Surfactante Pulmonar , Proteínas Asociadas a Surfactante Pulmonar , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Membrana Serosa/metabolismo

RESUMEN

In environmental chemistry, one often wants to interpret or predict equilibrium partitioning of organic compounds between any two phases. Hence, one needs to understand the partition variability that stems from using different types of compounds and the variability that arises from looking at different natural phases, e.g. different soil organic matter. It is current practice in environmental chemistry to evaluate equilibrium partitioning with the help of double logarithmic correlations between the unknown partition constant and a well-known partition constant of the compounds, e.g., partitioning between natural organic matter and water or air is correlated with the octanol/water or octanol/air partition constant, respectively. However, these relationships (in the following called one-parameter LFERs) can only predict the compound variability within a single substance class. They supply no means to understand the variability between substance classes or the variability between different natural organic phases. The reasons for these limitations are that (a) the complete compound variability cannot be described by a single parameter because partitioning results from different kinds of interactions that vary independently from each other and (b) the specific properties of the studied phase are represented in the slope and intercept of the double logarithmic correlation and not in a variable parameter. In contrastto one-parameter LFERs, polyparameter LFERs are based on a concept that considers all interactions involved in partitioning by separate parameters. They allow for predicting the complete compound variability by a single equation, and they also provide the possibility to evaluate and predict the variability in the sorption characteristics of different natural phases. Thus future research in the field of environmental partition processes should focus on adapting and improving the more comprehensive polyparameter LFERs rather than trying to refine existing one-parameter LFERs.

Asunto(s)

Contaminantes Ambientales/aislamiento & purificación , Compuestos Orgánicos/aislamiento & purificación , Enlace de Hidrógeno , Modelos Lineales , Modelos Químicos , Compuestos Orgánicos/química , Termodinámica

RESUMEN

Bloom's syndrome (BS) is a rare autosomal recessive disorder characterized by pre- and postnatal growth deficiency, immunodeficiency, and a tremendous predisposition to a wide variety of cancers. Cells from BS individuals are characterized by a high incidence of chromosomal gaps and breaks, elevated sister chromatid exchange, quadriradial formations, and locus-specific mutations. BS is the consequence of mutations that lead to loss of function of BLM, a gene encoding a helicase with homology to the RecQ helicase family. To delineate the role of BLM in DNA replication, recombination, and repair we used a yeast two-hybrid screen to identify potential protein partners of the BLM helicase. The C terminus of BLM interacts directly with MLH1 in the yeast-two hybrid assay; far Western analysis and co-immunoprecipitations confirmed the interaction. Cell extracts deficient in BLM were competent for DNA mismatch repair. These data suggest that the BLM helicase and MLH1 function together in replication, recombination, or DNA repair events independent of single base mismatch repair.

Asunto(s)

Adenosina Trifosfatasas/metabolismo , Disparidad de Par Base , ADN Helicasas/metabolismo , Reparación del ADN , Proteínas de Neoplasias/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Adenosina Trifosfatasas/química , Western Blotting , Proteínas Portadoras , Línea Celular , Núcleo Celular/metabolismo , Células Cultivadas , Niño , ADN Helicasas/química , Replicación del ADN , Células HeLa , Humanos , Células K562 , Masculino , Homólogo 1 de la Proteína MutL , Mutación , Proteínas Nucleares , Pruebas de Precipitina , Unión Proteica , RecQ Helicasas , Recombinación Genética , Células Tumorales Cultivadas , Técnicas del Sistema de Dos Híbridos

RESUMEN

Guanylin is a pro-secretory hormone that is expressed in intestinal epithelia. Previously, we mapped the guanylin gene to mouse and human chromosomal regions containing multiple intestinal tumor-modifying loci. Here, we investigate whether guanylin expression is downregulated in precancerous human and mouse intestinal adenomas and whether diminished guanylin expression increases adenoma susceptibility in an animal model of intestinal cancer, the multiple intestinal neoplasia (Min) mouse. In situ hybridization analysis indicated diminished guanylin expression in both mouse and human adenomas. Northern analysis of mouse intestinal tissues showed strain-specific levels of guanylin expression but no correlation with the resistance or susceptibility of each strain to adenoma formation. Similarly, cDNA sequence analysis indicated no inactivating mutations or polymorphisms common to either the high or low adenoma-risk groups. Nonetheless, we have shown that significant loss of guanylin RNA in adenomas of mouse and human is a marker of intestinal epithelial cell transformation.

Asunto(s)

Adenoma/genética , Regulación hacia Abajo , Hormonas Gastrointestinales , Regulación Neoplásica de la Expresión Génica , Neoplasias Intestinales/genética , Péptidos/genética , Adenoma/patología , Alelos , Animales , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Análisis Mutacional de ADN , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Genes APC/genética , Genes APC/fisiología , Predisposición Genética a la Enfermedad/genética , Humanos , Hibridación in Situ , Neoplasias Intestinales/patología , Yeyuno/metabolismo , Ratones , Ratones Endogámicos , Ratones Mutantes , Mutación/genética , Péptidos Natriuréticos , Polimorfismo Genético/genética , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especificidad de la Especie

RESUMEN

The adenomatous polyposis coli (APC) gene was first identified as the gene mutated in an inherited syndrome of colon cancer predisposition known as familial adenomatous polyposis coli (FAP). Mutation of APC is also found in 80% of all colorectal adenomas and carcinomas and is one of the earliest mutations in colon cancer progression. Similar to other tumor suppressor genes, both APC alleles are inactivated by mutation in colon tumors, resulting in the loss of full-length protein in tumor cells. The functional significance of altering APC is the dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, which include cell cycle progression, migration, differentiation, and apoptosis. Roles for APC in some of these processes are in large part attributable to its ability to regulate cytosolic levels of the signaling molecule beta-catenin and to affect the transcriptional profile in cells. This article summarizes numerous genetic, biochemical, and cell biologic studies on the mechanisms of APC-mediated tumor suppression. Mouse models of FAP, in which the APC gene has been genetically inactivated, have been particularly useful in testing therapeutic and chemopreventive strategies. These data have significant implications for colorectal cancer treatment approaches as well as for understanding other disease genes and cancers of other tissue types.

Asunto(s)

Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , Genes Supresores de Tumor , Predisposición Genética a la Enfermedad , Transactivadores , Poliposis Adenomatosa del Colon/patología , Animales , Ciclo Celular , Diferenciación Celular , Neoplasias Colorrectales/etiología , Proteínas del Citoesqueleto/biosíntesis , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Ratones , Transcripción Genética , beta Catenina

RESUMEN

The activin receptor-like kinase 1 (ALK1) is a type I receptor for transforming growth factor-beta (TGF-beta) family proteins. Expression of ALK1 in blood vessels and mutations of the ALK1 gene in human type II hereditary hemorrhagic telangiectasia patients suggest that ALK1 may have an important role during vascular development. To define the function of ALK1 during development, we inactivated the ALK1 gene in mice by gene targeting. The ALK1 homozygous embryos die at midgestation, exhibiting severe vascular abnormalities characterized by excessive fusion of capillary plexes into cavernous vessels and hyperdilation of large vessels. These vascular defects are associated with enhanced expression of angiogenic factors and proteases and are characterized by deficient differentiation and recruitment of vascular smooth muscle cells. The blood vessel defects in ALK1-deficient mice are reminiscent of mice lacking TGF-beta1, TGF-beta type II receptor (TbetaR-II), or endoglin, suggesting that ALK1 may mediate TGF-beta1 signal in endothelial cells. Consistent with this hypothesis, we demonstrate that ALK1 in endothelial cells binds to TGF-beta1 and TbetaR-II. Furthermore, the ALK1 signaling pathway can inhibit TGF-beta1-dependent transcriptional activation mediated by the known TGF-beta1 type I receptor, ALK5. Taken together, our results suggest that the balance between the ALK1 and ALK5 signaling pathways in endothelial cells plays a crucial role in determining vascular endothelial properties during angiogenesis.

Asunto(s)

Receptores de Activinas Tipo I , Neovascularización Fisiológica , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Receptores de Activinas , Animales , Capilares/fisiología , Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , Endotelio Vascular/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/citología , Mutación , Fosfoproteínas/metabolismo , Plasminógeno/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Smad , Proteína Smad5 , Transactivadores/metabolismo , Transfección , Regulación hacia Arriba

RESUMEN

In the present study, pulmonary surfactant protein A (SP-A) messenger RNA (mRNA) and protein were characterized in adult rabbit middle ear and maxillary sinus. Fifteen adult rabbits were used for the study: 6 with evidence of acute middle ear infections and maxillary sinusitis, 6 with infections that were successfully treated with tetracycline, and 3 that were pathogen-free. We detected SP-A mRNA in maxillary sinus and middle ear tissues by Northern blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). The RT-PCR also revealed the presence of SP-B and SP-C mRNA in middle ear and sinus tissues. We detected SP-A protein, of molecular weight approximately 29 and 70 kd, in middle ear and sinus tissues by immunoblot analysis. Unlike the SP-A protein present in the lung, the molecular weight of the SP-A protein present in the middle ear and paranasal sinus was not altered by digestion with an enzyme that cleaves N-linked carbohydrates. Immunostaining and in situ hybridization showed that SP-A protein and mRNA, respectively, were present in surface epithelial cells of the middle ear and in epithelial cells of submucosal glands in sinus tissues. These data provide the first evidence of the presence of pulmonary surfactant proteins in the paranasal sinuses and confirm previous reports of SP-A in the middle ear epithelium.

Asunto(s)

Oído Medio/química , Glicoproteínas/análisis , Seno Maxilar/química , Proteolípidos/análisis , Surfactantes Pulmonares/análisis , Enfermedad Aguda , Factores de Edad , Animales , Oído Medio/patología , Glicoproteínas/genética , Masculino , Seno Maxilar/patología , Sinusitis Maxilar/diagnóstico , Sinusitis Maxilar/microbiología , Membrana Mucosa/química , Membrana Mucosa/patología , Proteolípidos/genética , Proteína A Asociada a Surfactante Pulmonar , Proteínas Asociadas a Surfactante Pulmonar , Surfactantes Pulmonares/genética , ARN Mensajero/análisis , Conejos

RESUMEN

Matrilysin is a matrix metalloproteinase expressed in the tumor cells of greater than 80% of intestinal adenomas. The majority of these intestinal tumors are associated with the accumulation of beta-catenin, a component of the cadherin adhesion complex and, through its association with the T Cell Factor (Tcf) DNA binding proteins, a regulator in the Wnt signal transduction pathway. In murine intestinal tumors, matrilysin transcripts show striking overlap with the accumulation of beta-catenin protein. The matrilysin promoter is upregulated as much as 12-fold by beta-catenin in colon tumor cell lines in a manner inversely proportional to the endogenous levels of beta-catenin/Tcf complex and is dependent upon a single optimal Tcf-4 recognition site. Coexpression of the E-cadherin cytoplasmic domain blocked this induction and reduced basal promoter activity in every colon cancer cell line tested. Inactivation of the Tcf binding site increased promoter activity and overexpression of the Tcf factor, LEF-1, significantly downregulated matrilysin promoter activity, suggesting that beta-catenin transactivates the matrilysin promoter by virtue of its ability to abrogate Tcf-mediated repression. Because genetic ablation of matrilysin decreases tumor formation in multiple intestinal neoplasia (Min) mice, we propose that regulation of matrilysin production by beta-catenin accumulation is a contributing factor to intestinal tumorigenesis.

Asunto(s)

Adenoma/genética , Proteínas del Citoesqueleto/metabolismo , Neoplasias Intestinales/genética , Metaloendopeptidasas/genética , Transactivadores , Adenoma/metabolismo , Animales , Secuencia de Bases , Proteínas del Citoesqueleto/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Intestinales/metabolismo , Factor de Unión 1 al Potenciador Linfoide , Metaloproteinasa 7 de la Matriz , Metaloendopeptidasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional , beta Catenina

RESUMEN

Fatty acid ethyl esters (FAEE), nonoxidative ethanol metabolites present in human organs commonly damaged by ethanol abuse, have been implicated as mediators of organ damage. FAEE are additives in various foods and beverages to provide flavor or fragrance, and therefore are common dietary lipid constituents. We hypothesized that FAEE could be generated during alcoholic beverage production because fatty acids are present within microorganisms and ethanol is generated during the fermentation process. In this report, we demonstrate that FAEE are present in commercially available scotch beverages, and that in the preparation of scotch, FAEE can be produced during the fermentation reaction as a result of FAEE synthase activity in the yeast. Following ingestion of scotch, preformed FAEE are delivered to GI tract. The consequences of ingestion of FAEE in scotch, if any, remain to be determined.

Asunto(s)

Bebidas Alcohólicas/análisis , Ésteres/metabolismo , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Aciltransferasas/metabolismo , Esterificación , Etanol/metabolismo , Fermentación , Cromatografía de Gases y Espectrometría de Masas , Humanos , Levaduras/enzimología

RESUMEN

The demonstration that matrix metalloproteinases [MMPs] play an active role in the invasion and metastasis stages of tumor progression has led to the development of a new class of anti-metastatic chemotherapeutic agent, the matrix metalloproteinase inhibitors [MMPIs]. We present evidence to suggest that the MMP matrilysin, in particular, plays an essential role in much earlier stages of intestinal tumorigenesis. Matrilysin is detected in a high percentage of pre-invasive lesions, in contrast to its absence in most normal tissues, and is expressed by the epithelial-derived tumor cells. Manipulating levels of this enzyme in vitro results in cell lines with enhanced tumorigenic potential, while ablating the gene in vivo leads to a significant reduction in tumor number in two different animal models of intestinal tumorigenesis. Additionally, regulation of matrilysin gene expression appears to be under the control of genetic pathways which are activated very early in the tumor development sequence. Although the precise mechanism by which matrilysin activity contributes to tumor formation is not yet clear, we propose that MMPIs may be of benefit as chemopreventative agents in addition to their therapeutic potential for metastatic disease.

Asunto(s)

Neoplasias Intestinales/enzimología , Metaloendopeptidasas/fisiología , Animales , Regulación Enzimológica de la Expresión Génica , Humanos , Neoplasias Intestinales/etiología , Neoplasias Intestinales/prevención & control , Metaloproteinasa 7 de la Matriz , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/genética

RESUMEN

Both the matrix metalloproteinase matrilysin and the prostaglandin H synthase cyclooxygenase-2 (Cox-2), are thought to play key roles in colorectal carcinogenesis. These enzymes are overexpressed in 85-90% of human colorectal cancers. Furthermore, mice carrying an adenomatous polyposis coli germline mutation that are also nullizygous for either matrilysin or Cox-2 display a significant reduction in tumor multiplicity. To determine if there is a direct link between matrilysin and Cox-2, their expression was characterized in two mouse models of intestinal carcinogenesis and in human colorectal tumor samples. Both matrilysin and Cox-2 expression was increased in the mouse models and in the human colorectal cancers; however, immunohistochemistry and in situ hybridization indicated that their localization within the tumors was different. In the mouse models, Cox-2 was expressed in the superficial stroma, whereas matrilysin expression was localized exclusively to the neoplastic epithelium. In contrast, in human colorectal cancers, both Cox-2 and matrilysin were expressed in the neoplastic epithelium. Although over 80% of the specimens expressed both matrilysin and Cox-2, the levels and localization of matrilysin and Cox-2 expression were distinct. Cox-2 expression was strongest in well-differentiated areas, and matrilysin immunostaining was strongest in the more dysplastic and invasive regions of the tumor. These results indicate that these two important modulators of colorectal tumorigenesis are differentially expressed and imply that the therapeutic benefit may be improved by combination therapy utilizing selective Cox-2 and matrilysin inhibitors.

Asunto(s)

Neoplasias Colorrectales/enzimología , Regulación Neoplásica de la Expresión Génica , Neoplasias Intestinales/enzimología , Isoenzimas/biosíntesis , Metaloendopeptidasas/biosíntesis , Proteínas de Neoplasias/biosíntesis , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Animales , Diferenciación Celular , Pólipos del Colon/enzimología , Neoplasias Colorrectales/genética , Ciclooxigenasa 2 , Inducción Enzimática , Células Epiteliales/enzimología , Genes APC , Humanos , Hibridación in Situ , Neoplasias Intestinales/genética , Isoenzimas/genética , Metaloproteinasa 7 de la Matriz , Proteínas de la Membrana , Metaloendopeptidasas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas de Neoplasias/genética , Prostaglandina-Endoperóxido Sintasas/genética , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Células del Estroma/enzimología