RESUMEN
BACKGROUND: Biliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC. METHODS: Relative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival. RESULTS: SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865-0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631-0.873). CONCLUSIONS: SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.
Asunto(s)
Adenocarcinoma/diagnóstico , Neoplasias del Sistema Biliar/diagnóstico , Detección Precoz del Cáncer/métodos , Proteínas de Homeodominio/genética , Septinas/genética , Adenocarcinoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/genética , Biomarcadores de Tumor/genética , Metilación de ADN , Epigénesis Genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Regiones Promotoras Genéticas , Estudios ProspectivosRESUMEN
Here we tested the prognostic impact of genomic alterations in operable localized pancreatic ductal adenocarcinoma (PDAC). Fifty-two formalin-fixed and paraffin-embedded primary PDAC were laser micro-dissected and were investigated by comparative genomic hybridization after whole genome amplification using an adapter-linker PCR. Chromosomal gains and losses were correlated to clinico-pathological parameters and clinical follow-up data. The most frequent aberration was loss on chromosome 17p (65%) while the most frequent gains were detected at 2q (41%) and 8q (41%), respectively. The concomitant occurrence of losses at 9p and 17p was found to be statistically significant. Higher rates of chromosomal losses were associated with a more advanced primary tumor stage and losses at 9p and 18q were significantly associated with presence of lymphatic metastasis (chi-square: p = 0.03, p = 0.05, respectively). Deletions on chromosome 4 were of prognostic significance for overall survival and tumor recurrence (Cox-multivariate analysis: p = 0.026 and p = 0.021, respectively). In conclusion our data suggest the common alterations at chromosome 8q, 9p, 17p and 18q as well as the prognostic relevant deletions on chromosome 4q as relevant for PDAC progression. Our comprehensive data from 52 PDAC should provide a basis for future studies with a higher resolution to discover the relevant genes located within the chromosomal aberrations identified.
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Carcinoma Ductal Pancreático/genética , Deleción Cromosómica , Cromosomas Humanos Par 4 , Neoplasias Pancreáticas/genética , Adenocarcinoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/patología , Aberraciones Cromosómicas , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 18 , Cromosomas Humanos Par 8 , Cromosomas Humanos Par 9 , Hibridación Genómica Comparativa , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Pronóstico , Análisis de SupervivenciaAsunto(s)
Enterococcus , Infecciones por Escherichia coli/etiología , Infecciones por Escherichia coli/cirugía , Fascitis Necrotizante/etiología , Fascitis Necrotizante/cirugía , Infecciones por Bacterias Grampositivas/etiología , Infecciones por Bacterias Grampositivas/cirugía , Perforación Intestinal/complicaciones , Pierna , Absceso del Psoas/etiología , Absceso del Psoas/cirugía , Enfermedades del Sigmoide/complicaciones , Adulto , Desbridamiento , Diverticulitis del Colon/complicaciones , Diverticulitis del Colon/cirugía , Femenino , Humanos , Perforación Intestinal/cirugía , Pierna/cirugía , Masculino , Persona de Mediana Edad , Enfermedades del Sigmoide/cirugía , Neoplasias del Colon Sigmoide/complicaciones , Neoplasias del Colon Sigmoide/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Throughout the past decade the treatment of rectal carcinoma has improved remarkably. Today, individualized multimodality treatment allows local and distant tumor freedom with preservation of anorectal and genitourinary function in a majority of patients. Radiotherapy is elementary in reducing the risk of local recurrence whereas chemotherapy including promising novel agents prevents or eliminates distant metastases. However, surgery revolutionized by TME (total mesorectal excision) remains the only curative treatment for rectal carcinoma. In this study the authors review the developments as well as the current status of modern treatment for rectal carcinoma.
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Recurrencia Local de Neoplasia/prevención & control , Neoplasias del Recto/cirugía , Neoplasias del Recto/terapia , Terapia Combinada , Humanos , Neoplasias del Recto/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Among primary hepatic malignancies, sarcomas represent a minority of 2 %. Of those, primary hepatic angiosarcoma is the most common one. In the past its incidence has been related to the exposure of certain chemicals like thorotrast, vinyl-chloride or arsenic. - Patients suffering from this aggressive, highly vascular tumor have a poor prognosis in general. Without treatment most of them die after rapid tumor progression with multifocal dissemination. In case of tumor perforation, fatal abdominal hemorrhage has been observed. - We herein report the successful interdisciplinary treatment of an 81 year-old woman with a perforated primary hepatic angiosarcoma of the left hepatic lobe. Initially, tumor bleeding was stopped by emergency interventional coil embolization. After stabilization of the patient, we performed an elective tumor resection. The patient could eventually be discharged in a good clinical condition. - So far, no standard therapy has established for patients with primary hepatic angiosarcoma. Surgery seems to be the treatment of choice. In addition, preoperative interventional embolization of the tumor supplying vessels reduces the risk of pre- and intraoperative bleeding. The value of adjuvant chemotherapy is not yet clarified. - The outcome of most patients with primary hepatic angiosarcoma remains poor and there is a need for clinical studies.
Asunto(s)
Embolización Terapéutica , Hemangiosarcoma/terapia , Neoplasias Hepáticas/terapia , Anciano de 80 o más Años , Terapia Combinada , Tratamiento de Urgencia , Femenino , Hemangiosarcoma/diagnóstico por imagen , Hemangiosarcoma/cirugía , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Pancreatic cancer is the fourth most common cause of death in malignancies with an incidence of 8-12 cases per 100000 in western world. In spite of numerous modifications in therapeutical approaches, prognosis has not improved. METHODS: In the last few years numerous studies have been performed to reduce tumor mortality with more radical surgical procedures. Several articles of the last 15 years have been investigated to objectivate the benefit of extended lymphadenectomy in pancreatic surgery. Staging of the cancers, prognostic factors, technique and interpretation of lymphadenectomy have been analysed RESULTS: All studies document a lowered perioperative mortality in pancreatic resections. The procedure is counted as a standardized and safe one. However, several controversies exist. The distinct staging systems in Japan and the western world aggravate the comparison in all studies. Japanese authors in mostly retrospective analyses seem to document a survival benefit by radical surgery. Similar results could not be achieved by western authors. CONCLUSION: Over all, a significant benefit in extreme radical surgery could not bee found. However, there are indications of subgroups of patients in whom extended lymphadenectomy might be beneficial. This subgroup should be defined only by large multicentric, prospective, randomized studies.
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Escisión del Ganglio Linfático/métodos , Neoplasias Pancreáticas/cirugía , Humanos , Escisión del Ganglio Linfático/efectos adversos , Escisión del Ganglio Linfático/tendencias , Estadificación de Neoplasias , Neoplasias Pancreáticas/mortalidad , Complicaciones Posoperatorias , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
To investigate the stereoselectivity of the ATP-Mg2+-dependent uptake of noradrenaline, synaptic vesicles were isolated from the rat brain by differential centrifugation and incubated with 3H-(+/-)-, 3H-(-)- or 14C-(+)-noradrenaline in the absence and in the presence of ATP-Mg2+. The Km values of the ATP-Mg2+-dependent uptake were found to be different for the two isomers (mumol/l): 3H-(+/-)-noradrenaline 14.9 +/- 2.2 x 10(-1), 3H-(-)-noradrenaline 7.7 +/- 0.5 x 10(-1), 14C-(+)-noradrenaline 17.3 +/- 3.7 x 10(-1), whereas the Vmax of the racemate was identical with those of the two isomers (pmol/mg protein/min): 3H-(+/-)-noradrenaline 5.5 +/- 0.4, 3H-(-)-noradrenaline 4.9 +/- 0.1, 14C-(+)-noradrenaline 5.1 +/- 0.4. Moreover, (+)-noradrenaline inhibited competitively the ATP-Mg2+-dependent uptake of 3H-(+/-)-noradrenaline (Ki 19.2 +/- 1.0 x 10(-1) mumol/l) and 3H-(-)-noradrenaline (Ki 17.7 +/- 1.8 x 10(-1) mumol/l), the Ki values being nearly identical with the Km of the ATP-Mg2+-dependent uptake of 14C-(+)-noradrenaline. It is concluded that the ATP Mg2+-dependent uptake of noradrenaline into synaptic vesicles of the rat brain is stereoselective and that both isomers share the same transport system.
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Encéfalo/metabolismo , Norepinefrina/metabolismo , Vesículas Sinápticas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Magnesio/metabolismo , Ratas , EstereoisomerismoRESUMEN
Twenty-one male regular long distance runners participated in two 10 km runs one week apart. Their beta-endorphin-like immunoreactivity (beta-EIR) was assayed in plasma before and immediately after running. Mood was monitored by an adjective check list (Eigenschaftswörterliste, EWL) pre- and post-run. beta-EIR was significantly elevated post-run. Self-reliance and good mood scored higher after running. Both mood elevation and plasma beta-EIR increase showed a considerable individual variability but there was a significant correlation in the mean values of the two runs between individual beta-EIR increases (delta beta-EIR) and the changes of ratings in feeling of pleasantness (delta FP). High delta beta-EIR corresponded to positive mood change post-run.
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Emociones/fisiología , Endorfinas/sangre , Carrera , Adulto , Humanos , Masculino , betaendorfinaRESUMEN
Using ultra-filtration steps and HPLC-separation, a low molecular weight ligand of the benzodiazepine receptor was isolated from plasma of various mammalian species including man. The endogenous ligand acts on benzodiazepine receptors agonistically and apparently has a receptor affinity similar to Diazepam. The ligand is not identical with Diazepam as indicated by HPLC and UV-spectroscopy.
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Receptores de GABA-A/metabolismo , Animales , Unión Competitiva , Cromatografía Líquida de Alta Presión , Diazepam/metabolismo , Humanos , Ligandos/sangre , Conejos , Ensayo de Unión Radioligante , Ratas , Receptores de GABA-A/análisis , Especificidad de la Especie , PorcinosRESUMEN
Single channel currents induced by acetylcholine were recorded from nerve growth factor-differentiated clonal rat pheochromocytoma (PC12) cells by using the patch-clamp technique. Inward current amplitudes were heterogeneous and could be related to three classes of unitary current. The three current-voltage relations were linear for patch membrane potentials ranging from -50 mV to -120 mV. At 22 degrees C, conductances of 22 pS, 31 pS and 39 pS were obtained. The extrapolated reversal potential for the channels was 0 mV and the mean open time approximately 10-20 ms. These results may indicate that PC12 cells possess three types of acetylcholine receptor channels.
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Acetilcolina/farmacología , Fibras Adrenérgicas/efectos de los fármacos , Ganglios Simpáticos/efectos de los fármacos , Canales Iónicos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Células Clonales , Potenciales de la Membrana/efectos de los fármacos , Modelos Neurológicos , Neuronas/efectos de los fármacos , Feocromocitoma , RatasRESUMEN
Isolated neuronal cells dissociated from the brain of embryonic rabbits on the sixteenth day of gestation and of perinatal rats (eighteenth embryonic day, to E18, thirteenth day postnatum, p.n. 13) were selectively cultured using a plasma clot technique. The cells grown were shown to be neurons by means of the neuron-specific synaptosomal plasma membrane antibody (SPM). They differentiated at a very high frequency from rounded cells lacking processes into different shapes characteristic for several neuronal cell types. Morphological differences could be distinguished even after 24 h in culture. The neurons differentiated in vitro for up to 11 days, apparently without need of any direct intercellular contact. Cells caught inside the plasma clot were prevented from decreasing in number. This provides the opportunity to culture few neurons even from an extremely small area of a single brain. As an example, different cell types are shown originating from rat cerebella aged E18 to p.n. 13. Their appearance apparently corresponds to the genesis of cerebellar cell types, as is known from the in vivo situation. The high degree of characteristic neuronal differentiation and the prevention of direct intercellular contacts indicate that this culture method may serve as an in vitro assay for genetically fixed properties acquired in vivo.
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Encéfalo/citología , Diferenciación Celular , Animales , Coagulación Sanguínea , Cerebelo/citología , Medios de Cultivo , Femenino , Neuronas/citología , Plasma , Embarazo , Conejos , Ratas , Ratas EndogámicasRESUMEN
A method for the collection of defined small regions from fresh brain under sterile conditions is described. Its reproducibility allows the cultivation of well-defined, corresponding regions from similar brains. After controlled orientation in agarose, the brain can be sectioned by means of a Vibratome in spite of its softness. The section level is defined by co-ordinates of a stereotaxic atlas, produced for this purpose from brains orientated in the same way. Areas desired for cultivation are punched out from tissue slices with 200-550 microns diameter needles according to the atlas pictures. The plugs can then be stored in cold buffer solution until preparation for culture. Exact locations of tissue samples collected can be determined histologically. Either whole or dissociated plugs cultivated by a plasma clot technique lead to morphologically differentiating neurons surviving for more than or up to 14 days, respectively.
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Animales Recién Nacidos/anatomía & histología , Encéfalo/anatomía & histología , Disección/métodos , Neurología/métodos , Animales , Encéfalo/citología , Mapeo Encefálico , Células Cultivadas , Técnicas de Cultivo , Neurología/instrumentación , Neuronas/citología , Conejos , Técnicas EstereotáxicasRESUMEN
Seventy-five rats, divided into five groups, were given D-aspartic acid (D-Asp), L-Asp and D + L-Asp in ratio 1/1 or 1/2 for one week. The body weight, food and fluid intakes, and rectal temperature of the rats received D-Asp or D + L-Asp in 1/1 ratio significantly decreased. The decrease in rectal temperature was antagonized by naloxone. L-Asp given together with D-Asp in 1/2 ratio prevented D-Asp-caused decrease in body weight, food and fluid intakes, and rectal temperature. Although D-amino acids, as antipeptidases have some effects through endorphinergic systems, D-Asp (an inhibitor of L-asparaginase) seems to act at the level of L-asparaginase presumably by increasing the level of endorphins since L-Asp antagonizes the inhibitory effect of both D-Asp and morphine.
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Ácido Aspártico/farmacología , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Naloxona/farmacología , Animales , Ácido Aspártico/antagonistas & inhibidores , Masculino , Ratas , Ratas Endogámicas , EstereoisomerismoAsunto(s)
Catecolaminas/metabolismo , Sistema Cromafín/ultraestructura , Animales , Bario/farmacología , Araña Viuda Negra , Bovinos , Membrana Celular/ultraestructura , Sistema Cromafín/efectos de los fármacos , Sistema Cromafín/metabolismo , Dopamina beta-Hidroxilasa/metabolismo , Técnica del Anticuerpo Fluorescente , Lantano/farmacología , Venenos de Araña/farmacologíaRESUMEN
125 rats which were divided into five groups were deprived of food or given orally D- (a potent inhibitor for L-asparaginase) and/or L-aspartic acids (Asp) for one week. The body weights before and at the end of the experiment were determined as well as post mortem the weights of brain, liver and kidneys, their protein contents, and the liver triglyceride and glycogen contents. D- and D+L-Asp caused significant decreases in the weights of body and liver, and in daily fluid intake; in addition liver and kidney protein, and liver triglyceride and glycogen contents were found to be lower than control. On the other hand, the food-deprived group which was subjected to more or less the same body weight loss due to food deprivation showed only a decrease in the liver triglyceride content. Since D-amino acids cause naloxone reversible analgesia which is, thus, considered as an involvement of endorphinergic system and of vasopressin, the effects of D-Asp were attributed to the changes in the availability of opioids and vasopressin, which simultaneously have an effect on each other as well as an effect of the release of ACTH. L-Asp appeared to antagonize the effects of D-Asp. Because L-Asp antagonizes the acute and chronic effects of morphine, including that on L-asparaginase activity, the hypothesis is proposed that the antagonizing effects of L-Asp observed may be caused at the level of L-asparaginase activity.
Asunto(s)
Ácido Aspártico/farmacología , Peso Corporal/efectos de los fármacos , Metabolismo/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Animales , Ingestión de Alimentos/efectos de los fármacos , Glucógeno/metabolismo , Morfina/farmacología , Narcóticos/farmacología , Proteínas/metabolismo , Ratas , Estereoisomerismo , Triglicéridos/metabolismoRESUMEN
After chemical stimulation with depolarizing agents (Ba2+ or Ca2+/carbachol) isolated living chromaffin cells display a drastically increased binding capacity for anti-DBH, distributed spotwise on or near the outer cell membrane. This effect is inhibited by noradrenaline; it is not evoked by the non-exocytotically releasing agents tyramine and reserpine. the effect of apparent externalization of DBH is paralleled by the observation of a DBH-dependent binding of 125I-labelled protein A upon the same depolarizing stimuli. These observations are discussed as possible evidence for exocytotic activities.
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Gránulos Cromafines/inmunología , Sistema Cromafín/inmunología , Dopamina beta-Hidroxilasa/inmunología , Exocitosis , Animales , Anticuerpos/análisis , Anticuerpos/inmunología , Especificidad de Anticuerpos , Sitios de Unión de Anticuerpos , Gránulos Cromafines/análisis , Dopamina beta-Hidroxilasa/análisis , Dopamina beta-Hidroxilasa/metabolismo , Exocitosis/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Fármacos Neuromusculares Despolarizantes/farmacología , Conejos , Proteína Estafilocócica A/metabolismo , gammaglobulinas/análisisRESUMEN
Adenylate cyclase activity in rat striatum decreased post mortem. Half-lives were about 2.7 h at 22 degrees C, 72 h at 4 degrees C. Differences in stability after death of adenylate cyclase in human brain and rat striatum, and possible heterogenity of the enzyme, are briefly discussed.
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Adenilil Ciclasas/metabolismo , Cuerpo Estriado/enzimología , Cambios Post Mortem , Animales , Dopamina/farmacología , Activación Enzimática , Semivida , Cinética , Norepinefrina/farmacología , RatasAsunto(s)
Marcadores de Afinidad/síntesis química , ARN Ribosómico , Aminoacil-ARN de Transferencia/farmacología , Ribosomas/metabolismo , Marcadores de Afinidad/farmacología , Fenómenos Químicos , Química , Concentración de Iones de Hidrógeno , Métodos , Fenilalanina , Fotoquímica , Poli U , ARN Ribosómico/metabolismo , ARN Ribosómico/efectos de la radiación , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/efectos de la radiación , Ribosomas/efectos de los fármacos , Rayos UltravioletaRESUMEN
Nonhistone proteins were isolated from human placental and tonsillar chromatins. Antiserum was prepared against a complex from some nonhistone proteins and DNA (NP-DNA) from placental chromatin. With the help of polyacrylamide gel electrophoresis and immunological methods the tissue specificity of human chromatin nonhistone proteins was established. The described organ immunogenic specificity of the complex of DNA and nonhistone protein (NP-DNA) from human chromatin is in accordance with data published on similar complexes from different animal organs. Besides, it is shown that shearing of chromatin leads to large chifts in NP-DNA concentrations required for maximum complement fixation in the presence of the prepared antiserum. This may probably be due to a damage of certain chromatin super structures which involve some of the nonhistone proteins and DNA sequences from both the more condensed and less condensed parts of chromatin.