RESUMEN

Chirality causes symmetry breaks in a large variety of natural phenomena ranging from particle physics to biochemistry. We investigate one of the simplest conceivable chiral systems, a laser-excited, oriented, effective one-electron Li target. Prepared in a polarized p state with |m|=1 in an optical trap, the atoms are exposed to co- and counterrotating circularly polarized femtosecond laser pulses. For a field frequency near the excitation energy of the oriented initial state, a strong circular dichroism is observed and the photoelectron energies are significantly affected by the helicity-dependent Autler-Townes splitting. Besides its fundamental relevance, this system is suited to create spin-polarized electron pulses with a reversible switch on a femtosecond timescale at an energy resolution of a few meV.

RESUMEN

The risk of periampullary cancer in patients with classic familial adenomatous polyposis (FAP) is significantly increased compared with the general population. However, the incidence of this extracolonic manifestation in attenuated FAP (AFAP) is unknown. We report the case of a 38 year old woman with no known family history of polyposis or colorectal cancer, who presented with ampullary adenocarcinoma. Diagnosis of AFAP was made only after evaluation of the patient's extended family history and genetic testing. This case report suggests that AFAP should be included in the differential diagnosis of patients with ampullary/duodenal tumours.

Asunto(s)

Adenocarcinoma/genética , Poliposis Adenomatosa del Colon/genética , Ampolla Hepatopancreática , Neoplasias del Conducto Colédoco/genética , Poliposis Adenomatosa del Colon/diagnóstico , Adulto , Femenino , Humanos , Linaje

RESUMEN

To gain insights into the molecular basis for metastasis, we compared the global gene expression profile of metastatic colorectal cancer with that of primary cancers, benign colorectal tumors, and normal colorectal epithelium. Among the genes identified, the PRL-3 protein tyrosine phosphatase gene was of particular interest. It was expressed at high levels in each of 18 cancer metastases studied but at lower levels in nonmetastatic tumors and normal colorectal epithelium. In 3 of 12 metastases examined, multiple copies of the PRL-3 gene were found within a small amplicon located at chromosome 8q24.3. These data suggest that the PRL-3 gene is important for colorectal cancer metastasis and provide a new therapeutic target for these intractable lesions.

Asunto(s)

Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Proteínas Inmediatas-Precoces/genética , Metástasis de la Neoplasia/genética , Proteínas Tirosina Fosfatasas/genética , Adenoma/enzimología , Adenoma/genética , Adenoma/patología , Mapeo Cromosómico , Cromosomas Humanos Par 8 , Colon/enzimología , Neoplasias Colorrectales/patología , Amplificación de Genes , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Biblioteca de Genes , Humanos , Proteínas Inmediatas-Precoces/metabolismo , Mucosa Intestinal/enzimología , Proteínas de Neoplasias , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Proteínas Tirosina Fosfatasas/metabolismo , Recto/enzimología

RESUMEN

Serial analysis of gene expression was used to identify transcripts encoding secreted or cell surface proteins that were expressed in benign and malignant tumors of the colorectum. A total of 290,394 tags were analyzed from normal, adenomatous, and cancerous colonic epithelium. Of the 21,343 different transcripts observed, 957 were found to be differentially expressed between normal tissue and adenoma or between normal tissue and cancer. Forty-nine transcripts were elevated > or =20-fold in adenomas, 40 transcripts were elevated > or =20-fold in cancers, and 9 transcripts were elevated > or =20-fold in both. Products of six of these nine transcripts (TGFBI, LYS, RDP, MIC-1, REGA, and DEHL) were predicted to be secreted or to reside on the cell surface, and these were analyzed in more detail. The abnormal expression levels predicted by serial analysis of gene expression were confirmed by quantitative PCR analyses of each of these six genes. Moreover, the cell types responsible for the elevated expression were identified by in situ hybridization and by PCR analyses of epithelial cells immunoaffinity purified from primary tumors. This study extends knowledge of the differences in gene expression that underlie various stages of neoplasia and suggests specific diagnostic approaches that may be useful for the early detection of colorectal neoplasia.

Asunto(s)

Neoplasias Colorrectales/genética , Proteínas de la Membrana/genética , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación in Situ , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/metabolismo , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/genética

RESUMEN

One of the fundamental tenets of oncology is that tumors arise from stem cells. In the colon, stem cells are thought to reside at the base of crypts. In the early stages of tumorigenesis, however, dysplastic cells are routinely found at the luminal surface of the crypts whereas the cells at the bases of these same crypts appear morphologically normal. To understand this discrepancy, we evaluated the molecular characteristics of cells isolated from the bases and orifices of the same crypts in small colorectal adenomas. We found that the dysplastic cells at the tops of the crypts often exhibited genetic alterations of adenomatous polyposis coli (APC) and neoplasia-associated patterns of gene expression. In contrast, cells located at the base of these same crypts did not contain such alterations and were not clonally related to the contiguous transformed cells above them. These results imply that development of adenomatous polyps proceeds through a top-down mechanism. Genetically altered cells in the superficial portions of the mucosae spread laterally and downward to form new crypts that first connect to preexisting normal crypts and eventually replace them.

Asunto(s)

Neoplasias Colorrectales/patología , Secuencia de Bases , División Celular/genética , Neoplasias Colorrectales/genética , Cartilla de ADN , Genes APC , Humanos , Pérdida de Heterocigocidad , Mutación

RESUMEN

The tumor-suppressor protein Dpc4 (Smad4, Madh4) regulates gene expression. On binding of an extracellular ligand of the extensive transforming growth factor (TGF) superfamily to its cognate receptor complex, latent cytoplasmic Dpc4 is activated and translocated into the nucleus to function as part of various DNA-binding transcriptional activator complexes. The most relevant ligand/receptor pair to control the tumor suppressive function of Dpc4 remains uncertain, but is usually assumed to be TGF-beta and its heteromeric receptor. We exploited a fortuitous experiment of nature to directly test this hypothesis: the TGF-beta type II receptor gene is inactivated by mutation in nearly all colorectal carcinomas having microsatellite instability, as seen in hereditary nonpolyposis colorectal cancer (HNPCC) and in sporadic medullary colorectal cancers. Using a specific and sensitive immunohistochemical label for Dpc4, we examined nuclear localization of Dpc4 in 13 HNPCC, six medullary, and 41 sporadic nonmedullary colorectal carcinomas. In agreement with published rates, two (5%) of 41 sporadic tumors showed complete loss of Dpc4 protein, indicative of genetic inactivation. All 13 HNPCC and six medullary tumors had intact cytoplasmic and nuclear Dpc4 localization. The TGFBR2 gene was sequenced in three of the cancers from patients with HNPCC, and all of these harbored inactivating mutations. The specificity of the immunohistochemical assay was demonstrated in xenograft tumors of syngeneic cell lines that differed in DPC4 genetic status because of an engineered gene knockout. Thus, nuclear localization of Dpc4 can be maintained in cells with inactivated TGF-beta type II receptors, suggesting the persistence of tumor-suppressive action of an upstream signaling input, most likely a ligand/receptor complex distinct from TGF-beta. Identification of the relevant input would be expected to have implications for the understanding of tumorigenesis and the design of rational biological therapy.

Asunto(s)

Núcleo Celular/química , Neoplasias Colorrectales/metabolismo , Proteínas de Unión al ADN/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Transactivadores/metabolismo , Animales , Carcinoma Medular/genética , Carcinoma Medular/metabolismo , Carcinoma Medular/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Análisis Mutacional de ADN , Reparación del ADN , ADN de Neoplasias/química , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Genotipo , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Mutación , Trasplante de Neoplasias , Fenotipo , Proteínas Serina-Treonina Quinasas , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteína Smad4 , Transactivadores/genética , Trasplante Heterólogo , Células Tumorales Cultivadas

RESUMEN

The analysis of loss of heterozygosity (LOH) is perhaps the most widely used technique in cancer genetics. In primary tumors, however, the analysis of LOH is fraught with technical problems that have limited its reproducibility and interpretation. In particular, tumors are mixtures of neoplastic and nonneoplastic cells, and the DNA from the nonneoplastic cells can mask LOH. We here describe a new experimental approach, involving two components, to overcome these problems. First, a form of digital PCR was employed to directly count, one by one, the number of each of the two alleles in tumor samples. Second, Bayesian-type likelihood methods were used to measure the strength of the evidence for the allele distribution being different from normal. This approach imparts a rigorous statistical basis to LOH analyses, and should be able to provide more reliable information than heretofore possible in LOH studies of diverse tumor types.

Asunto(s)

Cromosomas Humanos Par 18 , Neoplasias Colorrectales/genética , ADN de Neoplasias/genética , Pérdida de Heterocigocidad , Invasividad Neoplásica/genética , Polimorfismo de Nucleótido Simple , Alelos , Teorema de Bayes , Neoplasias Colorrectales/patología , Humanos , Funciones de Verosimilitud , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa/métodos

RESUMEN

To gain a molecular understanding of tumor angiogenesis, we compared gene expression patterns of endothelial cells derived from blood vessels of normal and malignant colorectal tissues. Of over 170 transcripts predominantly expressed in the endothelium, 79 were differentially expressed, including 46 that were specifically elevated in tumor-associated endothelium. Several of these genes encode extracellular matrix proteins, but most are of unknown function. Most of these tumor endothelial markers were expressed in a wide range of tumor types, as well as in normal vessels associated with wound healing and corpus luteum formation. These studies demonstrate that tumor and normal endothelium are distinct at the molecular level, a finding that may have significant implications for the development of anti-angiogenic therapies.

Asunto(s)

Colon/irrigación sanguínea , Neoplasias Colorrectales/irrigación sanguínea , Endotelio Vascular/metabolismo , Perfilación de la Expresión Génica , Neovascularización Patológica/genética , Recto/irrigación sanguínea , Biomarcadores de Tumor , Separación Celular , Células Cultivadas , Colon/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Cuerpo Lúteo/irrigación sanguínea , Cuerpo Lúteo/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/patología , Proteínas de la Matriz Extracelular/genética , Femenino , Expresión Génica , Humanos , Mucosa Intestinal/irrigación sanguínea , Mucosa Intestinal/citología , Mucosa Intestinal/patología , Neoplasias/irrigación sanguínea , Neoplasias/genética , Neoplasias/metabolismo , Neovascularización Fisiológica/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Recto/metabolismo , Células Tumorales Cultivadas

RESUMEN

Although initiating mutations in the ret protooncogene have been found in familial and sporadic medullary thyroid carcinoma (MTC), the molecular events underlying subsequent tumor progression stages are unknown. We now report that changes in trk family neurotrophin receptor expression appear to be involved in both preneoplastic thyroid C cell hyperplasia and later tumor progression. Only a subset of normal C cells expresses trk family receptors, but, in C cell hyperplasia, the affected cells consistently express trkB, with variable expression of trkA and trkC. In later stages of gross MTC tumors, trkB expression was substantially reduced, while trkC expression was increased and often intense. In a cell culture model of MTC, exogenous trkB expression resulted in severely impaired tumorigenicity and was associated with 11-fold lower levels of the angiogenesis factor vascular endothelial growth factor. These results suggest that trk family receptor genes participate in MTC development and progression, and, in particular, that trkB may limit MTC tumor growth by inhibition of angiogenesis.

Asunto(s)

Carcinoma Medular/patología , Carcinoma Medular/fisiopatología , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factor de Crecimiento Nervioso/genética , Glándula Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/fisiopatología , Animales , Carcinoma Medular/genética , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Hiperplasia , Ratones , Ratones Desnudos , Embarazo , Receptor de Factor Neurotrófico Ciliar , Receptor trkA , Receptor trkC , Glándula Tiroides/citología , Glándula Tiroides/patología , Neoplasias de la Tiroides/genética , Trasplante Heterólogo , Células Tumorales Cultivadas

RESUMEN

Shingles can cause chronic neuropathic pain (postherpetic neuralgia) long after skin lesions heal. To investigate its causes, we quantitated immunolabeled sensory neurites in skin biopsies from 18 subjects with and 16 subjects without postherpetic neuralgia after unilateral shingles. Subjects rated the intensity of their pain. Punch skin biopsies were evaluated from the site of maximum pain or shingles involvement, the homologous contralateral location, and a site on the back, distant from shingles involvement. Sections were immunostained with anti-PGP9.5 antibody, a pan-axonal marker, and the density of epidermal and dermal neurites determined. The group with postherpetic neuralgia had a mean density of 339 +/- 97 neurites/mm2 in shingles-affected epidermis compared with a density of 1,661 +/- 262 neurites/mm2 for subjects without pain. Neurite loss was more severe in epidermis than dermis. Unexpectedly, the group with pain had also lost half of the neurites in contralateral epidermis. Contralateral damage occurred despite the lack of contralateral shingles eruptions or pain, correlated with the presence and severity of ongoing pain at the shingles site, and did not extend to the distant site. Thus, the pathophysiology of postherpetic neuralgia pain may involve a new bilateral mechanism.

Asunto(s)

Herpes Zóster/fisiopatología , Neuralgia/etiología , Neuritas/patología , Neuronas Aferentes/patología , Anciano , Biopsia , Femenino , Lateralidad Funcional , Herpes Zóster/patología , Humanos , Masculino , Persona de Mediana Edad , Neuralgia/patología , Neuralgia/virología , Neuritas/ultraestructura , Análisis de Regresión , Piel/inervación , Piel/patología

RESUMEN

An accurate description of the population prevalence of temporomandibular disorders (TMDs) would be of value to scientists, health-policy makers, and clinicians but, to date, various unreplicated epidemiologic methodologies have produced disparate prevalence figures. We report on a telephone survey that sought to describe the prevalence of six TMD-related symptoms among a random, non-clinic sample from the Kansas City metropolitan area. The prevalence figures for nocturnal bruxism, diurnal clenching, jaw soreness and joint sounds ranged from 10-19%. Some figures were higher than those from St. Louis, but generally the figures accord well with the results of other prevalence studies. Of the 534 people interviewed, 246 reported one or more of the six TMD-related symptoms. Symptoms were not more prevalent among women than men, but were higher among persons of age 45 and under. Pain was reported more commonly by persons with multiple symptoms. The level of concordance between data from Kansas City and St. Louis supports the validity of the telephone survey method for studying TMD prevalence in non-clinic samples.

Asunto(s)

Recolección de Datos/métodos , Trastornos de la Articulación Temporomandibular/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Bruxismo/epidemiología , Distribución de Chi-Cuadrado , Dolor Facial/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Missouri/epidemiología , Contracción Muscular , Prevalencia , Distribución por Sexo , Encuestas y Cuestionarios , Teléfono , Trastornos de la Articulación Temporomandibular/fisiopatología , Población Urbana

RESUMEN

The diazotrophic cyanobacterium Trichodesmium is a large (about 0.5 by 3 millimeters) phytoplankter that is common in tropical open-ocean waters. Measurements of abundance, plus a review of earlier observations, indicate that it, rather than the picophytoplankton, is the most important primary producer (about 165 milligrams of carbon per square meter per day) in the tropical North Atlantic Ocean. Furthermore, nitrogen fixation by Trichodesmium introduces the largest fraction of new nitrogen to the euphotic zone, approximately 30 milligrams of nitrogen per square meter per day, a value exceeding the estimated flux of nitrate across the thermocline. Inclusion of this organism, plus the abundant diazotrophic endosymbiont Richelia intracellularis that is present in some large diatoms, in biogeochemical studies of carbon and nitrogen may help explain the disparity between various methods of measuring productivity in the oligotrophic ocean. Carbon and nitrogen fixation by these large phytoplankters also introduces a new paradigm in the biogeochemistry of these elements in the sea.