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1.
Colorectal Dis ; 24(8): 1007-1014, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35297178

RESUMEN

AIM: The aim of this prospective randomized study was to compare the effectiveness of various educational tools in laparoscopic rectal surgery, including surgical textbooks, animation and cadaveric videos. METHOD: Initially, an electronic assessment test assessing knowledge of laparoscopic rectal surgery was created and validated. The test was sent to graduates completing a general surgery residency programme in Turkey, who were then randomized into four groups based on the type of study material. After a 4 week study period, the volunteers were asked to answer the same electronic assessment test imported into an edited live laparoscopic rectal surgery video. Pre- and posteducation assessment tests among the groups were compared. RESULTS: A total of 168 volunteers completed the pre-education assessment test and were randomized into four groups. Pre-education assessment test scores were similar among the groups (p > 0.05). Of 168 volunteers, 130 (77.3%) completed the posteducation assessment test. Posteducation assessment test scores were significantly higher in the three-dimensional (3D) animation + cadaveric video group (p < 0.01), the 3D animation group (p < 0.01) and the cadaveric group (p < 0.01) compared with the textbook group. Moreover, posteducation assessment test scores were significantly higher in the 3D animation + cadaveric video group than the 3D animation group (p < 0.01). Each group's posteducation assessment test scores were significantly higher than the pre-education assessment test scores, with the exception of the textbook group. CONCLUSION: Our study demonstrates that 3D animation + cadaveric videos, 3D animation alone and cadaveric videos are all superior to a surgical textbook when teaching laparoscopic rectal cancer surgery. Finally, our results show that 3D animation and cadaveric videos are also superior to textbooks in enabling an understanding of rectal surgery.


Asunto(s)
Educación Médica , Internado y Residencia , Laparoscopía , Cadáver , Educación Médica/métodos , Humanos , Estudios Prospectivos
2.
Colorectal Dis ; 23(12): 3141-3151, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34346554

RESUMEN

AIM: The aim of this study is to demonstrate our video training tool developed to teach and standardize complete mesocolic excision (CME) for right-sided colon cancer and also to present our long-term oncological outcomes. METHOD: Educational narrative videos were produced to demonstrate the technical steps of CME. First, a three-dimensional animation video was prepared. Then cadaveric dissections were recorded in a step-by-step fashion, following the sequences of open and minimally invasive surgery. These were followed by videos of real-life demonstrations of surgical procedures, enhanced by superimposed animations of key anatomical structures. In order to demonstrate the impact of this training module on outcomes of patients undergoing CME, we retrospectively queried data from before (2005-2010) and after (2011-2019) implementation of standardized CME in our practice. RESULTS: A total of 180 consecutive patients underwent right hemicolectomy between 2005 and 2019. Fifty-four patients underwent surgery before and 126 patients after CME principles were elaborated and standardized. Of those patients who had surgery after the training module, 58 (46%) underwent open surgery and 68 (54%) underwent laparoscopic colectomy. Demographics, perioperative parameters and morbidity were comparable between the groups. The 5-year overall and disease-free survival rates were significantly improved after implementation of CME training (p = 0.059 and p = 0.041, respectively). Also, 5-year overall and disease-free survival rates for all patients were considerably better than our reported national outcomes. CONCLUSION: Our comprehensive step-by-step training video module for the CME technique demonstrates surgical anatomical planes and important vascular structures and variations. The video also helps standardization of the CME technique and should contribute to improved histopathological and oncological outcomes.


Asunto(s)
Neoplasias del Colon , Laparoscopía , Mesocolon , Colectomía , Neoplasias del Colon/cirugía , Computadores , Humanos , Escisión del Ganglio Linfático , Mesocolon/cirugía , Estándares de Referencia , Estudios Retrospectivos , Resultado del Tratamiento
3.
Proc Natl Acad Sci U S A ; 110(44): 17933-8, 2013 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-24114272

RESUMEN

Glioblastoma (GBM), the most common brain malignancy, remains fatal with no effective treatment. Analyses of common aberrations in GBM suggest major regulatory pathways associated with disease etiology. However, 90% of GBMs are diagnosed at an advanced stage (primary GBMs), providing no access to early disease stages for assessing disease progression events. As such, both understanding of disease mechanisms and the development of biomarkers and therapeutics for effective disease management are limited. Here, we describe an adult-inducible astrocyte-specific system in genetically engineered mice that queries causation in disease evolution of regulatory networks perturbed in human GBM. Events yielding disease, both engineered and spontaneous, indicate ordered grade-specific perturbations that yield high-grade astrocytomas (anaplastic astrocytomas and GBMs). Impaired retinoblastoma protein RB tumor suppression yields grade II histopathology. Additional activation of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) network drives progression to grade III disease, and further inactivation of phosphatase and tensin homolog (PTEN) yields GBM. Spontaneous missense mutation of tumor suppressor Trp53 arises subsequent to KRAS activation, but before grade III progression. The stochastic appearance of mutations identical to those observed in humans, particularly the same spectrum of p53 amino acid changes, supports the validity of engineered lesions and the ensuing interpretations of etiology. Absence of isocitrate dehydrogenase 1 (IDH1) mutation, asymptomatic low grade disease, and rapid emergence of GBM combined with a mesenchymal transcriptome signature reflect characteristics of primary GBM and provide insight into causal relationships.


Asunto(s)
Astrocitoma/etiología , Evolución Biológica , Modelos Animales de Enfermedad , Ingeniería Genética/métodos , Glioblastoma/etiología , Animales , Secuencia de Bases , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/genética , Ratones , Ratones Transgénicos , Análisis por Micromatrices , Datos de Secuencia Molecular , Mutación Missense/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Análisis de Secuencia de ADN , Proteína p53 Supresora de Tumor/genética
4.
Genomics ; 103(4): 264-75, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24462878

RESUMEN

Type 1 Diabetes (T1D) is an autoimmune disease where local release of cytokines such as IL-1ß and IFN-γ contributes to ß-cell apoptosis. To identify relevant genes regulating this process we performed a meta-analysis of 8 datasets of ß-cell gene expression after exposure to IL-1ß and IFN-γ. Two of these datasets are novel and contain time-series expressions in human islet cells and rat INS-1E cells. Genes were ranked according to their differential expression within and after 24 h from exposure, and characterized by function and prior knowledge in the literature. A regulatory network was then inferred from the human time expression datasets, using a time-series extension of a network inference method. The two most differentially expressed genes previously unknown in T1D literature (RIPK2 and ELF3) were found to modulate cytokine-induced apoptosis. The inferred regulatory network is thus supported by the experimental validation, providing a proof-of-concept for the proposed statistical inference approach.


Asunto(s)
Citocinas/metabolismo , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Células Secretoras de Insulina/fisiología , Animales , Citocinas/farmacología , Proteínas de Unión al ADN/genética , Diabetes Mellitus Tipo 1 , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Interferón gamma/metabolismo , Interferón gamma/farmacología , Islotes Pancreáticos/fisiología , Proteínas Proto-Oncogénicas c-ets/genética , Ratas , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/genética , Reproducibilidad de los Resultados , Factores de Transcripción/genética
5.
Surg Laparosc Endosc Percutan Tech ; 34(1): 101-107, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38134383

RESUMEN

PURPOSE: Total mesorectal excision (TME) is accepted as gold standard method in rectal cancer globally. But there is no standard for lateral lymph nodes. Combination of neoadjuvant treatment plus lateral lymph node dissection (LLND) in select patients might be a promising method. Our purpose is to describe the anatomic landmarks of LLND on cadavers and minimally invasive surgery. MATERIALS AND METHODS: Local advanced rectal cancer and lateral lymph node (LLN) metastasis are accepted as an indication of neoadjuvant treatment. LLND was performed according to preoperative imaging after radiochemotherapy. RESULTS: Twenty-eight (10.5%) of 267 patients with rectal cancer who had suspected lateral lymph node metastasis (LLNM) with magnetic resonance imaging (MRI) underwent LLND in addition to TME after neoadjuvant chemoradiotherapy. Eight of them had LLNM. Three patients had bilateral LLND and only 1 had LLNM. The median number of harvested lymph nodes was 6. The rates of LLNM increased with the presence of poor prognosis markers. One regional and 1 distant recurrence were detected in patients who had no LLN metastasis compared with2 regional and 4 distant recurrences in the LLN-positive group. CONCLUSIONS: Local advanced rectal cancer cases may benefit from LLND, but it does not appear to have an effect on overall survival. There is no consensus whether size and/or morphologic criteria in MRI are the ideal guide for LLND.


Asunto(s)
Carcinoma , Neoplasias del Recto , Humanos , Estadificación de Neoplasias , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Neoplasias del Recto/cirugía , Terapia Neoadyuvante/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos , Carcinoma/patología , Recurrencia Local de Neoplasia/cirugía , Estudios Retrospectivos
6.
BMC Bioinformatics ; 14: 217, 2013 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-23837656

RESUMEN

BACKGROUND: Biomolecular pathways and networks are dynamic and complex, and the perturbations to them which cause disease are often multiple, heterogeneous and contingent. Pathway and network visualizations, rendered on a computer or published on paper, however, tend to be static, lacking in detail, and ill-equipped to explore the variety and quantities of data available today, and the complex causes we seek to understand. RESULTS: RCytoscape integrates R (an open-ended programming environment rich in statistical power and data-handling facilities) and Cytoscape (powerful network visualization and analysis software). RCytoscape extends Cytoscape's functionality beyond what is possible with the Cytoscape graphical user interface. To illustrate the power of RCytoscape, a portion of the Glioblastoma multiforme (GBM) data set from the Cancer Genome Atlas (TCGA) is examined. Network visualization reveals previously unreported patterns in the data suggesting heterogeneous signaling mechanisms active in GBM Proneural tumors, with possible clinical relevance. CONCLUSIONS: Progress in bioinformatics and computational biology depends upon exploratory and confirmatory data analysis, upon inference, and upon modeling. These activities will eventually permit the prediction and control of complex biological systems. Network visualizations--molecular maps--created from an open-ended programming environment rich in statistical power and data-handling facilities, such as RCytoscape, will play an essential role in this progression.


Asunto(s)
Genoma Humano , Programas Informáticos , Mapeo Cromosómico , Biología Computacional , Glioblastoma/genética , Humanos , Modelos Genéticos
7.
J Can Dent Assoc ; 79: d158, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24309049

RESUMEN

Root fracture injuries affect 0.5%-7% of permanent teeth. Although cervical root fractures are less frequent in children, their serious consequences and poor prognosis may lead to tooth loss. In this case presentation, we discuss a treatment approach chosen to preserve alveolar bone growth following a cervical root fracture in an 8-Year-old boy.


Asunto(s)
Proceso Alveolar/crecimiento & desarrollo , Proceso Alveolar/lesiones , Desarrollo Óseo/fisiología , Incisivo/lesiones , Fracturas de los Dientes/complicaciones , Proceso Alveolar/diagnóstico por imagen , Niño , Humanos , Incisivo/diagnóstico por imagen , Masculino , Radiografía , Fracturas de los Dientes/diagnóstico por imagen
8.
Macromol Rapid Commun ; 33(4): 337-42, 2012 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-22271599

RESUMEN

Elastomeric composites are prepared based on solution styrene butadiene elastomer and zinc-aluminium layered double hydroxides (LDH), using a conventional sulphur cure system. Up to 100 parts per hundred rubber of LDH are incorporated into the elastomer matrix. The composites exhibit an interesting phenomenon of thermoreversible transparency, i.e. the transparent sample becomes opaque at warm condition and restores the transparency at room temperature. The transparency is found to be increased as the amount of LDH was increased. The addition of LDH gradually improved the mechanical, dynamic mechanical performance and thermal stability of the base elastomer. These developped elastomers could be utilised as smart materials in different applications.


Asunto(s)
Hidróxido de Aluminio/química , Materiales Biocompatibles/química , Butadienos/química , Elastómeros/química , Hidróxidos/química , Estirenos/química , Compuestos de Zinc/química , Ensayo de Materiales , Propiedades de Superficie , Resistencia a la Tracción
9.
APMIS ; 129(10): 587-597, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34117658

RESUMEN

Periodontological grafts are materials used in dentistry to regenerate lost gingival soft tissues or bone parts. In the case of direct contact with blood, the possibility of disease transmission from the source to the patient is high. This source can be an animal or a human. Therefore, the sterilization of grafts before implanting to the patient is of significant importance. The purpose of this study was to evaluate gamma radiation and microwave sterilization processes from microbiological and sterility perspectives and to compare the effectiveness of these two sterilization methods. Grafts were irradiated with 2, 4, 5, 10, 25 and 50 kGy doses of gamma radiation. Another group of same materials was irradiated by microwave for 1, 2, 3 and 4 min at 24,500 MHz and 900 W. Gamma radiation and microwave sterilization methods were evaluated as successful at minimum doses as 5 kGy and 3 min, respectively. Both gamma and microwave sterilization successfu lly sterilized periodontological grafts coded as PBG1, HBG1, HL1, PDG1, MBG3, MDG2 and PDG3. Moreover, microwave sterilization can be used as an alternative novel method to gamma radiation sterilization.


Asunto(s)
Bacillus pumilus/efectos de la radiación , Rayos gamma , Microondas , Esterilización/métodos , Trasplantes/efectos de la radiación , Pérdida de Hueso Alveolar/cirugía , Animales , Bacillus pumilus/crecimiento & desarrollo , Trasplante Óseo/métodos , Colágeno/efectos de la radiación , Recuento de Colonia Microbiana , Relación Dosis-Respuesta en la Radiación , Caballos , Humanos , Porcinos , Trasplantes/microbiología
10.
Sci Rep ; 10(1): 7287, 2020 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-32350364

RESUMEN

Fibroblast growth factor 21 (FGF21) induces weight loss in mouse, monkey, and human studies. In mice, FGF21 is thought to cause weight loss by stimulating thermogenesis, but whether FGF21 increases energy expenditure (EE) in primates is unclear. Here, we explore the transcriptional response and gene networks active in adipose tissue of rhesus macaques following FGF21-induced weight loss. Genes related to thermogenesis responded inconsistently to FGF21 treatment and weight loss. However, expression of gene modules involved in triglyceride (TG) synthesis and adipogenesis decreased, and this was associated with greater weight loss. Conversely, expression of innate immune cell markers was increased post-treatment and was associated with greater weight loss. A lipogenesis gene module associated with weight loss was evaluated by testing the function of member genes in mice. Overexpression of NRG4 reduced weight gain in diet-induced obese mice, while overexpression of ANGPTL8 resulted in elevated TG levels in lean mice. These observations provide evidence for a shifting balance of lipid storage and metabolism due to FGF21-induced weight loss in the non-human primate model, and do not fully recapitulate increased EE seen in rodent and in vitro studies. These discrepancies may reflect inter-species differences or complex interplay of FGF21 activity and counter-regulatory mechanisms.


Asunto(s)
Factores de Crecimiento de Fibroblastos/farmacología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Grasa Subcutánea/metabolismo , Pérdida de Peso/efectos de los fármacos , Animales , Femenino , Humanos , Macaca mulatta , Masculino , Ratones
11.
Nat Commun ; 11(1): 4458, 2020 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-32895383

RESUMEN

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Asunto(s)
Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Factor 1 de Crecimiento de Fibroblastos/administración & dosificación , Hipoglucemiantes/administración & dosificación , Hipotálamo/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteína Relacionada con Agouti/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Glucemia/análisis , Comunicación Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/patología , Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/administración & dosificación , Sacarosa en la Dieta/efectos adversos , Humanos , Hipotálamo/citología , Hipotálamo/patología , Inyecciones Intraventriculares , Leptina/genética , Masculino , Melanocortinas/metabolismo , Hormonas Estimuladoras de los Melanocitos/administración & dosificación , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , RNA-Seq , Receptor de Melanocortina Tipo 4/genética , Receptores de Melanocortina/antagonistas & inhibidores , Receptores de Melanocortina/metabolismo , Inducción de Remisión/métodos , Transducción de Señal/efectos de los fármacos , Análisis de la Célula Individual , Técnicas Estereotáxicas , Transcriptoma/efectos de los fármacos
12.
Nucleic Acids Res ; 35(Database issue): D742-6, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17169983

RESUMEN

T1DBase (http://T1DBase.org) [Smink et al. (2005) Nucleic Acids Res., 33, D544-D549; Burren et al. (2004) Hum. Genomics, 1, 98-109] is a public website and database that supports the type 1 diabetes (T1D) research community. T1DBase provides a consolidated T1D-oriented view of the complex data world that now confronts medical researchers and enables scientists to navigate from information they know to information that is new to them. Overview pages for genes and markers summarize information for these elements. The Gene Dossier summarizes information for a list of genes. GBrowse [Stein et al. (2002) Genome Res., 10, 1599-1610] displays genes and other features in their genomic context, and Cytoscape [Shannon et al. (2003) Genome Res., 13, 2498-2504] shows genes in the context of interacting proteins and genes. The Beta Cell Gene Atlas shows gene expression in beta cells, islets, and related cell types and lines, and the Tissue Expression Viewer shows expression across other tissues. The Microarray Viewer shows expression from more than 20 array experiments. The Beta Cell Gene Expression Bank contains manually curated gene and pathway annotations for genes expressed in beta cells. T1DMart is a query tool for markers and genotypes. PosterPages are 'home pages' about specific topics or datasets. The key challenge, now and in the future, is to provide powerful informatics capabilities to T1D scientists in a form they can use to enhance their research.


Asunto(s)
Bases de Datos Genéticas , Diabetes Mellitus Tipo 1/genética , Animales , Diabetes Mellitus Tipo 1/metabolismo , Perfilación de la Expresión Génica , Humanos , Internet , Ratones , Páncreas/metabolismo , Polimorfismo de Nucleótido Simple , Ratas , Integración de Sistemas , Interfaz Usuario-Computador
13.
Diabetes ; 56(3): 703-8, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17327439

RESUMEN

Limited organ availability is an obstacle to the widespread use of islet transplantation in type 1 diabetic patients. To address this problem, many studies have explored methods for expanding functional human islets in vitro for diabetes cell therapy. We previously showed that islet cells replicate after monolayer formation under the influence of hepatocyte growth factor and selected extracellular matrices. However, under these conditions, senescence and loss of insulin expression occur after >15 doublings. In contrast, other groups have reported that islet cells expanded in monolayers for months progressed through a reversible epithelial-to-mesenchymal transition, and that on removal of serum from the cultures, islet-like structures producing insulin were formed (1). The aim of the current study was to compare the two methods for islet expansion using immunostaining, real-time quantitative PCR, and microarrays at the following time points: on arrival, after monolayer expansion, and after 1 week in serum-free media. At this time, cell aliquots were grafted into nude mice to study in vivo function. The two methods showed similar results in islet cell expansion. Attempts at cell differentiation after expansion by both methods failed to consistently recover a beta-cell phenotype. Redifferentiation of beta-cells after expansion is still a challenge in need of a solution.


Asunto(s)
Diferenciación Celular , Células Secretoras de Insulina/citología , Islotes Pancreáticos/citología , Animales , Péptido C/sangre , Péptido C/metabolismo , Técnicas de Cultivo de Célula , Proliferación Celular , Regulación de la Expresión Génica , Glucagón/genética , Glucagón/metabolismo , Glucosa/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Ratones , Ratones Desnudos
14.
Acta Med Port ; 31(11): 693-696, 2018 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-30521464

RESUMEN

Aggressive angiomyxoma is an uncommon, benign, slow-growing, and locally infiltrative soft tissue neoplasm which is located primarily in the genital region and pelviperineal interstitial tissue of female patient in the fourth decade of life. Its occurrence in male patients is even more unusual and commonly appears at a later age. The mainstay of treatment typically involves surgical excision with tumor-free margins, and despite complete resection, local recurrences are common. Here, an unusual case of aggressive angiomyxoma occurring in the pelvic region of a 55-year-old man and its treatment is discussed due to its rarity.


O angiomixoma agressivo é uma neoplasia benigna rara, de crescimento lento, localmente infiltrativa que se localiza primariamente no tecido intersticial da região genital, pélvica e perineal de doentes do sexo feminino na quarta década de vida. O aparecimento em doentes do sexo masculino é ainda mais incomum e habitualmente aparece em idade mais avançada. O tratamento tipicamente envolve a excisão cirúrgica com margens livres e, apesar da ressecção completa, a recidiva local é comum. Apresentamos o caso clínico raro de angiomixoma agressivo na região pélvica de um homem de 55 anos de idade bem como o seu tratamento.


Asunto(s)
Mixoma/diagnóstico por imagen , Neoplasias Pélvicas/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mixoma/patología , Mixoma/cirugía , Neoplasias Pélvicas/patología , Neoplasias Pélvicas/cirugía , Ultrasonografía
15.
Appl Radiat Isot ; 130: 121-130, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28961487

RESUMEN

Guided tissue regeneration (GTR) and guided bone regeneration (GBR) biomaterials have been employed in recent years for periodontal procedures. In the present study, widely used dental GTR/GBR biomaterials (grafts: G1, G2, G3 and membranes: M1, M2, M3, M4) were exposed to gamma irradiation at an absorbed dose range of 0-50kGy and the radiolytic intermediates that have been created in the samples upon irradiation were characterized in detail by Electron Spin Resonance (ESR) spectroscopy. We aimed to standardize the measurement conditions for practical applications of gamma radiation sterilization of GTR/GBR biomaterials. We investigated the characteristic features of free radicals in gamma irradiated GTR/GBR biomaterials and examined the stability of the induced radicals at room temperature and accelerated stability conditions with ESR spectroscopy including dose-response curves, microwave power studies, dosimetric features of the biomaterials, variations of the peak heights with temperature, and long term stabilities of the radical species. Long-term stability studies have shown that G1 is quite stable even in accelerated storage conditions. The signal intensities of graft-type GTR/GBR biomaterials stored in normal and stability conditions have decreased very rapidly even only a few days after gamma irradiation sterilization. Thus, those samples indicating relatively low stability features can be very good candidates for the radiosterilization process. The beta-tricalcium phosphate and PLGA containing G1 and M1 respectively have found to be the most gamma stable bone substitute biomaterials and be safely sterilized by gamma radiation. ESR spectroscopy is an appropriate technique in giving important detailed spectroscopic findings in the gamma radiation sterilization studies of GTR/GBR biomaterials.


Asunto(s)
Materiales Biocompatibles , Espectroscopía de Resonancia por Spin del Electrón/métodos , Equipos y Suministros/microbiología , Rayos gamma , Regeneración Tisular Guiada Periodontal/instrumentación , Esterilización/métodos , Regeneración Ósea , Humanos , Temperatura
16.
Diabetes ; 52(2): 348-55, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12540607

RESUMEN

Pancreatic beta-cells are selectively destroyed during the course of type 1 diabetes. In the early stages of the disease, inflammatory infiltrates of mononuclear cells, containing predominantly monocytes and T-cells, are present in the islets (insulitis). Chemokines, such as monocyte chemoattractant protein-1 (MCP-1), play a key role in the recruitment and activation of these immunocytes. We have previously described cytokine-induced MCP-1 gene expression in human and rat pancreatic islets. In the present study, the transcriptional regulation by cytokines of the rat MCP-1 gene in fluorescence-activated cell sorting-purified rat beta-cells, insulin-producing INS-1E cells, and RINm5F cells was investigated. Transient transfections with luciferase-reporter constructs identified an interleukin (IL)-1beta-responsive enhancer region between -2,180 bp and -2,478 bp. Mutation of either of the two nuclear factor (NF)-kappaB sites present in this region abrogated IL-1beta-induced MCP-1 promoter activity. Binding of NF-kappaB to the two sites was shown in vitro by gel shift assays, while supershift assays revealed the presence of p65/p50 heterodimers and p65 homodimers. In vivo binding of NF-kappaB was confirmed by chromatin immunoprecipitation assay. Blocking of NF-kappaB activation in cytokine-exposed primary beta-cells by an adenovirus overexpressing a nondegradable form of IkappaBalpha or by pyrrolidine dithiocarbamate decreased IL-1beta-induced MCP-1 mRNA expression. We conclude that NF-kappaB plays an important role for MCP-1 expression in beta-cells. This transcription factor may be an interesting target for ex vivo gene therapy before islet transplantation.


Asunto(s)
Quimiocina CCL2/genética , Regulación de la Expresión Génica/fisiología , Islotes Pancreáticos/fisiología , Regiones Promotoras Genéticas , Animales , Secuencia de Bases , Sitios de Unión , Quimiocinas/genética , Cartilla de ADN , Mutagénesis Sitio-Dirigida , FN-kappa B/metabolismo , Reacción en Cadena de la Polimerasa , Ratas , Proteínas Recombinantes/metabolismo , Proteínas Represoras/metabolismo
17.
Diabetes ; 52(11): 2701-19, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14578289

RESUMEN

Locally released cytokines contribute to beta-cell dysfunction and apoptosis in type 1 diabetes. In vitro exposure of insulin-producing INS-1E cells to the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma leads to a significant increase in apoptosis. To characterize the genetic networks implicated in beta-cell dysfunction and apoptosis and its dependence on nitric oxide (NO) production, we performed a time-course microarray analysis of cytokine-induced genes in insulin-producing INS-1E cells. INS-1E cells were exposed in duplicate to IL-1beta + IFN-gamma for six different time points (1, 2, 4, 8, 12, and 24 h) with or without the inducible NO synthase (iNOS) blocker N(G)-monomethyl-L-arginine (NMA). The microarray analysis identified 698 genes as cytokine modified (>or=2.5-fold change compared with control) in at least one time point. Based on their temporal pattern of variation, the cytokine-regulated genes were classified into 15 clusters by the k-means method. These genes were further classified into 14 different groups according to their putative function. Changes in the expression of genes related to metabolism, signal transduction, and transcription factors at all time points studied indicate beta-cell attempts to adapt to the effects of continuous cytokine exposure. Notably, several apoptosis-related genes were modified at early time points (2-4 h) preceding iNOS expression. On the other hand, 46% of the genes modified by cytokines after 8-24 h were NO dependent, indicating the important role of this radical for the late effects of cytokines. The present results increase by more than twofold the number of known cytokine-modified genes in insulin-producing cells and yield comprehensive information on the role of NO for these modifications in gene expression. These data provide novel and detailed insights into the gene networks activated in beta-cells facing a prolonged immune assault.


Asunto(s)
Citocinas/genética , Regulación de la Expresión Génica , Insulina/genética , Insulina/metabolismo , Islotes Pancreáticos/inmunología , Animales , Apoptosis , Secuencia de Bases , Línea Celular , Citocinas/fisiología , Cartilla de ADN , Enzimas/genética , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/patología , Ratones , Necrosis , Óxido Nítrico/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción Genética , Células Tumorales Cultivadas
18.
J Crohns Colitis ; 9(6): 492-506, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25795566

RESUMEN

BACKGROUND AND AIMS: Proper interpretation of data from preclinical animal studies requires thorough knowledge of the pathophysiology of both the human disease and animal models. In this study, the expression of inflammatory bowel disease [IBD]-associated genes was characterised in mouse models of colitis to examine the underlying molecular pathways and assess the similarity between the experimental models and human disease. METHODS: RNA sequencing was performed on colon biopsies from Crohn's disease [CD] patients, ulcerative colitis [UC] patients and non-IBD controls. Genes shown to be significantly dysregulated in human IBD were used to study gene expression in colons from a piroxicam-accelerated colitis interleukin-10 knockout [PAC IL-10 k.o.], an adoptive transfer [AdTr] and a dextran sulfate sodium [DSS] colitis mouse model. RESULTS: Of 115 literature-defined genes linked to IBD, 92 were significantly differentially expressed in inflamed mucosa of CD and/or UC patients compared with non-IBD controls. The most upregulated genes were shared by both diseases, including REG1A, LCN2, NOS2, CXCL1-2, and S100A9. Of those 92 IBD-associated genes, 71 [77%] were significantly dysregulated in PAC IL-10 k.o. mice, whereas 59 [64%] were significantly dysregulated in AdTr mice compared with wild-type controls. Some of the most upregulated genes, including S100a8-9, Nos2, and Lcn2, were shared by the colitis models and correlated with disease activity. CONCLUSIONS: IBD and experimental murine colitis have a high degree of similarity in the colonic transcriptional profile, probably secondary to non-specific inflammatory processes. However, differences do exist between models, emphasising the need for careful selection and interpretation of qualified animal models in preclinical research.


Asunto(s)
Colitis/genética , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Mucosa Intestinal/química , ARN/análisis , Análisis de Secuencia de ARN , Traslado Adoptivo , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Estudios de Casos y Controles , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/inmunología , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Sulfato de Dextran , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Interleucina-10/genética , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Piroxicam/uso terapéutico , Linfocitos T Colaboradores-Inductores , Transcriptoma
19.
Ann N Y Acad Sci ; 1037: 41-58, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15699492

RESUMEN

Beta cell dysfunction and death in type 1 diabetes mellitus (T1DM) is caused by direct contact with activated macrophages and T lymphocytes and by exposure to soluble mediators secreted by these cells, such as cytokines and nitric oxide. Cytokine-induced apoptosis depends on the expression of pro- and anti-apoptotic genes that remain to be characterized. Using microarray analyses, we identified several transcription factor and "effector" gene networks regulated by interleukin-1beta and/or interferon-gamma in beta cells. This suggests that beta cell fate following exposure to cytokines is a complex and highly regulated process, depending on the duration and severity of perturbation of key gene networks. In order to draw correct conclusions from these massive amounts of data, we need to utilize novel bioinformatics and statistical tools. Thus, we are presently performing in silico analysis for the localization of binding sites for the transcription factor NF-kappaB (previously shown to be pivotal for beta cell apoptosis) in 15 temporally related gene clusters, identified by time-course microarray analysis. In silico analysis is based on a broad range of computational techniques used to detect motifs in a DNA sequence corresponding to the binding site of a transcription factor. These computer-based findings must be validated by use of positive and negative controls, and by "ChIP on chip" analysis. Moreover, new statistical approaches are required to decrease false positive findings. These novel approaches will constitute a "proof of principle" for the integrated use of bioinformatics and functional genomics in the characterization of relevant cytokine-regulated beta cell gene networks leading to beta cell apoptosis in T1DM.


Asunto(s)
Citocinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Análisis por Micromatrices , FN-kappa B/metabolismo , Animales , Apoptosis , Sitios de Unión , Biología Computacional , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/fisiopatología , Humanos , Interferón gamma/farmacología , Interleucina-1/farmacología , Islotes Pancreáticos/fisiopatología , Cinética , FN-kappa B/antagonistas & inhibidores , FN-kappa B/farmacología , Óxido Nítrico/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética
20.
Ann N Y Acad Sci ; 1005: 55-74, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14679040

RESUMEN

The beta cell fate following immune-mediated damage depends on an intricate pattern of dozens of genes up- or downregulated in parallel and/or sequentially. We are utilizing microarray analysis to clarify the pattern of gene expression in primary rat beta cells exposed to the proapoptotic cytokines, IL-1beta and/or IFN-gamma. The picture emerging from these experiments is that beta cells are not passive bystanders of their own destruction. On the contrary, beta cells respond to damage by activating diverse networks of transcription factors and genes that may either lead to apoptosis or preserve viability. Of note, cytokine-exposed beta cells produce and release chemokines that may contribute to the homing and activation of T cells and macrophages during insulitis. Several of the effects of cytokines depend on the activation of the transcription factor, NF-kappaB. NF-kappaB blocking prevents cytokine-induced beta cell death, and characterization of NF-kappaB-dependent genes by microarray analysis indicated that this transcription factor controls diverse networks of transcription factors and effector genes that are relevant for maintenance of beta cell differentiated status, cytosolic and ER calcium homeostasis, attraction of mononuclear cells, and apoptosis. Identification of this and additional "transcription factor networks" is being pursued by cluster analysis of gene expression in insulin-producing cells exposed to cytokines for different time periods. Identification of complex gene patterns poses a formidable challenge, but is now technically feasible. These accumulating evidences may finally unveil the molecular mechanisms regulating the beta cell "decision" to undergo or not apoptosis in early T1DM.


Asunto(s)
Apoptosis/fisiología , Islotes Pancreáticos/fisiopatología , Análisis de Secuencia por Matrices de Oligonucleótidos , Factores de Transcripción/fisiología
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