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1.
MAGMA ; 35(1): 145-152, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33786695

RESUMEN

OBJECTIVE: Brain atrophy has the potential to become a biomarker for severity of radiation-induced side-effects. Particularly brain tumour patients can show great MRI signal changes over time caused by e.g. oedema, tumour progress or necrosis. The goal of this study was to investigate if such changes affect the segmentation accuracy of normal appearing brain and thus influence longitudinal volumetric measurements. MATERIALS AND METHODS: T1-weighted MR images of 52 glioblastoma patients with unilateral tumours acquired before and three months after the end of radio(chemo)therapy were analysed. GM and WM volumes in the contralateral hemisphere were compared between segmenting the whole brain (full) and the contralateral hemisphere only (cl) with SPM and FSL. Relative GM and WM volumes were compared using paired t tests and correlated with the corresponding mean dose in GM and WM, respectively. RESULTS: Mean GM atrophy was significantly higher for full segmentation compared to cl segmentation when using SPM (mean ± std: ΔVGM,full = - 3.1% ± 3.7%, ΔVGM,cl = - 1.6% ± 2.7%; p < 0.001, d = 0.62). GM atrophy was significantly correlated with the mean GM dose with the SPM cl segmentation (r = - 0.4, p = 0.004), FSL full segmentation (r = - 0.4, p = 0.004) and FSL cl segmentation (r = -0.35, p = 0.012) but not with the SPM full segmentation (r = - 0.23, p = 0.1). CONCLUSIONS: For accurate normal tissue volume measurements in brain tumour patients using SPM, abnormal tissue needs to be masked prior to segmentation, however, this is not necessary when using FSL.


Asunto(s)
Glioblastoma , Sustancia Blanca , Atrofia/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Glioblastoma/diagnóstico por imagen , Glioblastoma/terapia , Sustancia Gris/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética/métodos , Sustancia Blanca/patología
2.
Nucleic Acids Res ; 47(2): 559-569, 2019 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-30496528

RESUMEN

A significant challenge in our understanding of biological systems is the high number of genes with unknown function in many genomes. The fungal genus Aspergillus contains important pathogens of humans, model organisms, and microbial cell factories. Aspergillus niger is used to produce organic acids, proteins, and is a promising source of new bioactive secondary metabolites. Out of the 14,165 open reading frames predicted in the A. niger genome only 2% have been experimentally verified and over 6,000 are hypothetical. Here, we show that gene co-expression network analysis can be used to overcome this limitation. A meta-analysis of 155 transcriptomics experiments generated co-expression networks for 9,579 genes (∼65%) of the A. niger genome. By populating this dataset with over 1,200 gene functional experiments from the genus Aspergillus and performing gene ontology enrichment, we could infer biological processes for 9,263 of A. niger genes, including 2,970 hypothetical genes. Experimental validation of selected co-expression sub-networks uncovered four transcription factors involved in secondary metabolite synthesis, which were used to activate production of multiple natural products. This study constitutes a significant step towards systems-level understanding of A. niger, and the datasets can be used to fuel discoveries of model systems, fungal pathogens, and biotechnology.


Asunto(s)
Aspergillus niger/genética , Regulación Fúngica de la Expresión Génica , Redes Reguladoras de Genes , Genoma Fúngico , Aspergillus niger/metabolismo , Biosíntesis de Péptidos , Metabolismo Secundario/genética , Factores de Transcripción/metabolismo , Transcriptoma
3.
Radiologe ; 58(5): 487-500, 2018 May.
Artículo en Alemán | MEDLINE | ID: mdl-29675694

RESUMEN

Positron emission tomography (PET) is a procedure in nuclear medicine, which is applied predominantly in oncological diagnostics. In the form of modern hybrid machines, such as PET computed tomography (PET/CT) and PET magnetic resonance imaging (PET/MRI) it has found wide acceptance and availability. The PET procedure is more than just another imaging technique, but a functional method with the capability for quantification in addition to the distribution pattern of the radiopharmaceutical, the results of which are used for therapeutic decisions. A profound knowledge of the principles of PET including the correct indications, patient preparation, and possible artifacts is mandatory for the correct interpretation of PET results.


Asunto(s)
Imagen Multimodal , Tomografía de Emisión de Positrones , Artefactos , Humanos , Imagen por Resonancia Magnética , Radiofármacos , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos X
4.
Zentralbl Chir ; 142(1): 54-60, 2017 Feb.
Artículo en Alemán | MEDLINE | ID: mdl-26205985

RESUMEN

Introduction: Surgical education of medical students within "skills labs" have not been standardised throughout Germany as yet; there is a substantial impact of available aspects such as personal and space at the various medical schools. Aim: The aim of this contribution is to illustrate the concept of a surgical skills lab in detail, including curricular teaching and integrated facultative courses at the Medical School, University of Magdeburg ("The Magdeburg Model") in the context of a new and reconstructed area for the skills lab at the Magdeburg's apprenticeship center for medical basic abilities (MAMBA). Method: We present an overview on the spectrum of curricular and facultative teaching activities within the surgical part of the skills lab. Student evaluation of this teaching concept is implemented using the programme "EvaSys" and evaluation forms adapted to the single courses. Results: By establishing MAMBA, the options for a practice-related surgical education have been substantially improved. Student evaluations of former courses presented within the skills lab and the chance of moving the skills lab into a more generous and reconstructed area led to a reorganisation of seminars and courses. New additional facultative courses held by student tutors have been introduced and have shown to be of great effect, in particular, because of their interdisciplinary character. Conclusion: Practice-related surgical education within a skills lab may have the potential to effectively prepare medical students for their professional life. In addition, it allows one to present and teach the most important basic skills in surgery, which need to be pursued by every student. An enthusiastic engagement of the Office for Student Affairs can be considered the crucial and indispensable link between clinical work and curricular as well as facultative teaching with regard to organisation and student evaluation. The practice-related teaching parts and contents at the surgical section of a skills lab should be integrated into the National Competence-based Catalogue of Teaching Aims in Medicine ("NKLM").


Asunto(s)
Competencia Clínica , Educación Médica/organización & administración , Laboratorios/organización & administración , Modelos Educacionales , Preceptoría/organización & administración , Procedimientos Quirúrgicos Operativos/educación , Actitud del Personal de Salud , Curriculum , Femenino , Alemania , Humanos , Masculino , Estudiantes de Medicina/psicología
5.
J Struct Biol ; 186(2): 265-72, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24727133

RESUMEN

Myosin interacting-heads (MIH) motifs are visualized in 3D-reconstructions of thick filaments from striated muscle. These reconstructions are calculated by averaging methods using images from electron micrographs of grids prepared using numerous filament preparations. Here we propose an alternative method to calculate the 3D-reconstruction of a single thick filament using only a tilt series images recorded by electron tomography. Relaxed thick filaments, prepared from tarantula leg muscle homogenates, were negatively stained. Single-axis tilt series of single isolated thick filaments were obtained with the electron microscope at a low electron dose, and recorded on a CCD camera by electron tomography. An IHRSR 3D-recontruction was calculated from the tilt series images of a single thick filament. The reconstruction was enhanced by including in the search stage dual tilt image segments while only single tilt along the filament axis is usually used, as well as applying a band pass filter just before the back projection. The reconstruction from a single filament has a 40 Å resolution and clearly shows the presence of MIH motifs. In contrast, the electron tomogram 3D-reconstruction of the same thick filament - calculated without any image averaging and/or imposition of helical symmetry - only reveals MIH motifs infrequently. This is - to our knowledge - the first application of the IHRSR method to calculate a 3D reconstruction from tilt series images. This single filament IHRSR reconstruction method (SF-IHRSR) should provide a new tool to assess structural differences between well-ordered thick (or thin) filaments in a grid by recording separately their electron tomograms.


Asunto(s)
Extremidades/anatomía & histología , Modelos Moleculares , Músculo Estriado/ultraestructura , Miosinas/ultraestructura , Arañas/anatomía & histología , Animales , Tomografía con Microscopio Electrónico , Imagenología Tridimensional , Microscopía Electrónica
6.
Eur J Paediatr Neurol ; 47: 118-130, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38284996

RESUMEN

BACKGROUND: Acute cerebellitis (AC) in children and adolescents is an inflammatory disease of the cerebellum due to viral or bacterial infections but also autoimmune-mediated processes. OBJECTIVE: To investigate the frequency of autoantibodies in serum and CSF as well as the neuroradiological features in children with AC. MATERIAL AND METHODS: Children presenting with symptoms suggestive of AC defined as acute/subacute onset of cerebellar symptoms and MRI evidence of cerebellar inflammation or additional CSF pleocytosis, positive oligoclonal bands (OCBs), and/or presence of autoantibodies in case of negative cerebellar MRI. Children fulfilling the above-mentioned criteria and a complete data set including clinical presentation, CSF studies, testing for neuronal/cerebellar and MOG antibodies as well as MRI scans performed at disease onset were eligible for this retrospective multicenter study. RESULTS: 36 patients fulfilled the inclusion criteria for AC (f:m = 14:22, median age 5.5 years). Ataxia was the most common cerebellar symptom present in 30/36 (83 %) in addition to dysmetria (15/36) or dysarthria (13/36). A substantial number of children (21/36) also had signs of encephalitis such as somnolence or seizures. In 10/36 (28 %) children the following autoantibodies (abs) were found: MOG-abs (n = 5) in serum, GFAPα-abs (n = 1) in CSF, GlyR-abs (n = 1) in CSF, mGluR1-abs (n = 1) in CSF and serum. In two further children, antibodies were detected only in serum (GlyR-abs, n = 1; GFAPα-abs, n = 1). MRI signal alterations in cerebellum were found in 30/36 children (83 %). Additional supra- and/or infratentorial lesions were present in 12/36 children, including all five children with MOG-abs. Outcome after a median follow-up of 3 months (range: 1 a 75) was favorable with an mRS ≤2 in 24/36 (67 %) after therapy. Antibody (ab)-positive children were significantly more likely to have a better outcome than ab-negative children (p = .022). CONCLUSION: In nearly 30 % of children in our study with AC, a range of abs was found, underscoring that autoantibody testing in serum and CSF should be included in the work-up of a child with suspected AC. The detection of MOG-abs in AC does expand the MOGAD spectrum.


Asunto(s)
Autoanticuerpos , Encefalitis , Adolescente , Niño , Preescolar , Humanos , Ataxia , Cerebelo/diagnóstico por imagen , Encefalitis/diagnóstico por imagen , Inflamación , Estudios Retrospectivos
7.
Clin Transl Radiat Oncol ; 36: 99-105, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35965663

RESUMEN

Background and purpose: Radiotherapy (RT) is an adjuvant treatment option for glioma patients. Side effects include tissue atrophy, which might be a contributing factor to neurocognitive decline after treatment. The goal of this study was to determine potential atrophy of the hippocampus, amygdala, thalamus, putamen, pallidum and caudate nucleus in glioma patients having undergone magnetic resonance imaging (MRI) before and after RT. Materials and methods: Subcortical volumes were measured using T1-weighted MRI from patients before RT (N = 91) and from longitudinal follow-ups acquired in three-monthly intervals (N = 349). The volumes were normalized to the baseline values, while excluding structures touching the clinical target volume (CTV) or abnormal tissue seen on FLAIR imaging. A multivariate linear effects model was used to determine if time after RT and mean RT dose delivered to the corresponding structures were significant predictors of tissue atrophy. Results: The hippocampus, amygdala, thalamus, putamen, and pallidum showed significant atrophy after RT as function of both time after RT and mean RT dose delivered to the corresponding structure. Only the caudate showed no dose or time dependant atrophy. Conversely, the hippocampus was the structure with the highest atrophy rate of 5.2 % after one year and assuming a mean dose of 30 Gy. Conclusion: The hippocampus showed the highest atrophy rates followed by the thalamus and the amygdala. The subcortical structures here found to decrease in volume indicative of radiosensitivity should be the focus of future studies investigating the relationship between neurocognitive decline and RT.

8.
Cancer Imaging ; 22(1): 53, 2022 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-36138437

RESUMEN

AIM: To compare [68Ga]PSMA-11 PET-CT, [68Ga]PSMA-11 PET-MRI and MRI in a cohort of prostate cancer (PCa) patients in biochemical recurrence after initial curative therapy. MATERIALS AND METHODS: Fifty-three patients with biochemically recurrent PCa underwent whole-body [68Ga]PSMA-11 PET-CT 1 hour post-injection (p.i.) followed by [68Ga]PSMA-11 PET-MRI 2.5 hours p.i., including a multiparametric MRI pelvic protocol examination. Imaging data analysis consisted of visual (qualitative) evaluation of the PET-CT, PET-MRI and MRI scans, as well as semi-quantitative and quantitative analyses of the PET and MRI data, including calculation of the parameters standardized uptake value (SUV) and apparent diffusion coefficient (ADC) derived from the PCa lesions. Association analysis was performed between imaging and clinical data, including PSA level and Gleason score. The results were considered significant for p-values less than 0.05 (p < 0.05). RESULTS: The hybrid imaging modalities [68Ga]PSMA-11 PET-CT and PET-MRI were positive in more patients than MRI alone. In particular, PET-CT detected lesions suggestive of PCa relapse in 34/53 (64.2%), PET-MRI in 36/53 (67.9%) and MRI in 23/53 patients (43.4%). While no significant differences in lesion detection rate were observed between PET-CT and PET-MRI, the latter was particularly efficient in detection of local recurrences in the prostate bed mainly due to the contribution of the MRI part of the modality. Association analysis revealed a statistically significant increase in the probability of a positive scan with increasing PSA levels for all imaging modalities. Accordingly, there was no significant association between scan positivity rate and Gleason score for any imaging modality. No significant correlation was observed between SUV and ADC values in lymph node metastases. CONCLUSION: [68Ga]PSMA-11 PET-CT and PET-MRI provide equally good detection rates for PCa recurrence, both outperforming stand-alone MRI.


Asunto(s)
Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Ácido Edético , Radioisótopos de Galio , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Imagen Multimodal , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología
9.
Proc Natl Acad Sci U S A ; 105(30): 10372-7, 2008 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-18658238

RESUMEN

Actin/myosin interactions in vertebrate striated muscles are believed to be regulated by the "steric blocking" mechanism whereby the binding of calcium to the troponin complex allows tropomyosin (TM) to change position on actin, acting as a molecular switch that blocks or allows myosin heads to interact with actin. Movement of TM during activation is initiated by interaction of Ca(2+) with troponin, then completed by further displacement by strong binding cross-bridges. We report x-ray evidence that TM in insect flight muscle (IFM) moves in a manner consistent with the steric blocking mechanism. We find that both isometric contraction, at high [Ca(2+)], and stretch activation, at lower [Ca(2+)], develop similarly high x-ray intensities on the IFM fourth actin layer line because of TM movement, coinciding with x-ray signals of strong-binding cross-bridge attachment to helically favored "actin target zones." Vanadate (Vi), a phosphate analog that inhibits active cross-bridge cycling, abolishes all active force in IFM, allowing high [Ca(2+)] to elicit initial TM movement without cross-bridge attachment or other changes from relaxed structure. However, when stretched in high [Ca(2+)], Vi-"paralyzed" fibers produce force substantially above passive response at pCa approximately 9, concurrent with full conversion from resting to active x-ray pattern, including x-ray signals of cross-bridge strong-binding and TM movement. This argues that myosin heads can be recruited as strong-binding "brakes" by backward-sliding, calcium-activated thin filaments, and are as effective in moving TM as actively force-producing cross-bridges. Such recruitment of myosin as brakes may be the major mechanism resisting extension during lengthening contractions.


Asunto(s)
Actinas/química , Músculos/patología , Miosinas/química , Tropomiosina/química , Animales , Calcio/química , Cristalización , Cristalografía por Rayos X/métodos , Insectos , Modelos Biológicos , Contracción Muscular , Proteínas Musculares/metabolismo , Unión Proteica , Estrés Mecánico , Vanadatos/farmacología
10.
Clin Oncol (R Coll Radiol) ; 33(6): 391-399, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33972025

RESUMEN

Local-regional failure for patients with ≥pT3 urothelial carcinoma after radical cystectomy is a significant clinical challenge. Prospective randomised trials have failed to show that chemotherapy reduces the risk of local-regional recurrences. Salvage treatment for local failures is difficult and often unsuccessful. There is promising evidence, particularly from a recent Egyptian National Cancer Institute trial, that radiation therapy plus chemotherapy can significantly reduce local recurrences compared with chemotherapy alone, and that this improvement in local-regional control may translate to meaningful improvements in disease-free and overall survival with acceptable toxicity. In light of the high rates of local failure following cystectomy for locally advanced disease and the progress that has been made in identifying patients at high risk of failure and the patterns of failure in the pelvis, the National Comprehensive Cancer Network guidelines were revised to include postoperative radiotherapy as an option to consider for patients with ≥pT3 disease. Here we review the problem of local-regional failure after cystectomy, identify patients who would probably benefit from adjuvant radiotherapy, review the patterns of pelvic failure after cystectomy, discuss technical details of radiation treatment and review the modern literature on this topic. Adjuvant radiotherapy should be considered as a treatment option for patients with locally advanced disease, especially those with positive margins or squamous cell carcinoma.


Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Carcinoma de Células Transicionales/cirugía , Quimioterapia Adyuvante , Cistectomía , Humanos , Terapia Neoadyuvante , Estudios Prospectivos , Radioterapia Adyuvante , Neoplasias de la Vejiga Urinaria/radioterapia , Neoplasias de la Vejiga Urinaria/cirugía
11.
Radiother Oncol ; 164: 66-72, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34537290

RESUMEN

BACKGROUND AND PURPOSE: Radio(chemo)therapy is standard in the adjuvant treatment of glioblastoma. Inevitably, brain tissue surrounding the target volume is also irradiated, potentially causing acute and late side-effects. Diffusion imaging has been shown to be a sensitive method to detect early changes in the cerebral white matter (WM) after radiation. The aim of this work was to assess possible changes in the mean diffusivity (MD) of WM after radio(chemo)therapy using Diffusion-weighted imaging (DWI) and to compare these effects between patients treated with proton and photon irradiation. MATERIALS AND METHODS: 70 patients with glioblastoma underwent adjuvant radio(chemo)therapy with protons (n = 20) or photons (n = 50) at the University Hospital Dresden. MRI follow-ups were performed at three-monthly intervals and in this study were evaluated until 33 months after the end of therapy. Relative white matter MD changes between baseline and all follow-up visits were calculated in different dose regions. RESULTS: We observed a significant decrease of MD (p < 0.05) in WM regions receiving more than 20 Gy. MD reduction was progressive with dose and time after radio(chemo)therapy (maximum: -7.9 ± 1.2% after 24 months, ≥50 Gy). In patients treated with photons, significant reductions of MD in the entire WM (p < 0.05) were seen at all time points. Conversely, in proton patients, whole brain MD did not change significantly. CONCLUSIONS: Irradiation leads to measurable MD reduction in white matter, progressing with both increasing dose and time. Treatment with protons reduces this effect most likely due to a lower total dose in the surrounding white matter. Further investigations are needed to assess whether those MD changes correlate with known radiation induced side-effects.


Asunto(s)
Glioblastoma , Sustancia Blanca , Imagen de Difusión por Resonancia Magnética , Glioblastoma/diagnóstico por imagen , Glioblastoma/radioterapia , Humanos , Fotones , Protones , Sustancia Blanca/diagnóstico por imagen
13.
Schmerz ; 24(1): 54-61, 2010 Feb.
Artículo en Alemán | MEDLINE | ID: mdl-20143100

RESUMEN

The aim of this study was to examine whether depression is a strong predictor of elevated postoperative pain levels following orthopedic surgery and whether the implementation of standardized pain management is more beneficial for patients with depression. We performed a non-randomized, prospective study with two different groups of patients who underwent orthopedic surgery. Group 1 (n=249) received non-standardized pain therapy whereas group 2 (n = 243) was treated with a standardized pain management concept. Effects of the treatment were monitored with a VAS-based pain assessment protocol. Depression was measured preoperatively with the self-reported Patient Health Questionnaire (PHQ-9). Patients with the probable diagnosis of a current episode of major depression showed significantly higher postoperative pain than patients without a depressive episode. On the other hand, patients with depression benefited from the implementation of standardized pain management. Our data suggest a predictive value of depression for severe postoperative pain. Patients with depression benefited from standardized postoperative pain therapy, but were still suffering from significantly higher postoperative pain.


Asunto(s)
Trastorno Depresivo Mayor/psicología , Procedimientos Ortopédicos/psicología , Dimensión del Dolor , Dolor Postoperatorio/psicología , Adolescente , Adulto , Anciano , Analgésicos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Vías Clínicas/normas , Trastorno Depresivo Mayor/diagnóstico , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/psicología , Dimensión del Dolor/normas , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/tratamiento farmacológico , Inventario de Personalidad , Estudios Prospectivos , Resultado del Tratamiento , Adulto Joven
14.
N Z Dent J ; 106(2): 43-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20608307

RESUMEN

OBJECTIVE: To determine the range and elemental composition of alloys used for PFM and crown-and-bridge restorations by New Zealand dental laboratories, and to understand the reasons for their selection. MATERIALS AND METHODS: Two waves of data collection were carried out via post and telephone interview. The source population was dental laboratories advertised with the Yellow Pages Group in 2007/2008. RESULTS: A total of 83 out of 109 laboratories (76.1%) responded. Of those, 35 laboratories (42.1%) reported producing fixed-prosthodontic restorations. The range of alloy types (consisting of high noble, noble and base-metal alloys), brand names (55 products) and manufacturers was determined, along with the reasons for their selection. Ten international dental alloy manufacturers were identified as being used, with the leading manufacturer being Ivoclar-Vivadent (40.9%), followed by Argen (25.3%). Most laboratories select their alloys based on price and physical properties. The average laboratory carries three to four alloy products. CONCLUSION: Alloy selection by dentists and dental technicians is strongly influenced by economic factors. While the study identified the range of alloys being used for fixed restorations in terms of alloy type and brand name, further research is needed to determine the proportions of fixed restorations produced from high noble, noble and base metal alloys, together with dental practitioners' attitudes to, and preferences in, alloy selection.


Asunto(s)
Aleaciones Dentales , Técnicos Dentales/estadística & datos numéricos , Dentadura Parcial Fija/estadística & datos numéricos , Laboratorios Odontológicos/estadística & datos numéricos , Pautas de la Práctica en Odontología/estadística & datos numéricos , Coronas/estadística & datos numéricos , Análisis del Estrés Dental , Humanos , Nueva Zelanda , Encuestas y Cuestionarios
15.
Gut ; 58(7): 949-63, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18829980

RESUMEN

BACKGROUND AND AIMS: Emerging evidence suggests that highly treatment-resistant tumour-initiating cells (TICs) play a central role in the pathogenesis of pancreatic cancer. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered to be a novel anticancer agent; however, recent studies have shown that many pancreatic cancer cells are resistant to apoptosis induction by TRAIL due to TRAIL-activated nuclear factor-kappaB (NF-kappaB) signalling. Several chemopreventive agents are able to inhibit NF-kappaB, and favourable results have been obtained--for example, for the broccoli compound sulforaphane-in preventing metastasis in clinical studies. The aim of the study was to identify TICs in pancreatic carcinoma for analysis of resistance mechanisms and for definition of sensitising agents. METHODS: TICs were defined by expression patterns of a CD44(+)/CD24(-), CD44(+)/CD24(+) or CD44(+)/CD133(+) phenotype and correlation to growth in immunodeficient mice, differentiation grade, clonogenic growth, sphere formation, aldehyde dehydrogenase (ALDH) activity and therapy resistance. RESULTS: Mechanistically, specific binding of transcriptionally active cRel-containing NF-kappaB complexes in TICs was observed. Sulforaphane prevented NF-kappaB binding, downregulated apoptosis inhibitors and induced apoptosis, together with prevention of clonogenicity. Gemcitabine, the chemopreventive agents resveratrol and wogonin, and the death ligand TRAIL were less effective. In a xenograft model, sulforaphane strongly blocked tumour growth and angiogenesis, while combination with TRAIL had an additive effect without obvious cytotoxicity in normal cells. Freshly isolated patient tumour cells expressing markers for TICs could be sensitised by sulforaphane for TRAIL-induced cytotoxicity. CONCLUSION: The data provide new insights into resistance mechanisms of TICs and suggest the combination of sulforaphane with TRAIL as a promising strategy for targeting of pancreatic TICs.


Asunto(s)
Anticarcinógenos/uso terapéutico , Apoptosis/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Neoplasias Pancreáticas/prevención & control , Tiocianatos/uso terapéutico , Animales , Células Cultivadas , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Isotiocianatos , Ratones , Ratones Desnudos , FN-kappa B/metabolismo , Páncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sulfóxidos , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo
16.
J Cell Biol ; 122(5): 1119-30, 1993 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8354695

RESUMEN

Clusterin is a broadly distributed glycoprotein constitutively expressed by various tissues and cell types, that has been shown to be involved in cell-cell adhesion and expressed during cellular differentiation in vitro. To assess the suggested participation of clusterin in these processes in vivo, we have cloned the cDNA encoding murine clusterin and studied the cellular distribution of clusterin mRNA during murine embryogenesis. Sequence analysis of the cDNA encoding murine clusterin revealed 92 and 75% sequence identity with the rat and human cDNAs, respectively, and conservation of the predicted structural features which include alpha-helical regions and heparin-binding domains. From 12.5 d of development onwards, the clusterin gene is widely expressed in developing epithelia, and selectively localized within the differentiating cell layers of tissues such as the developing skin, tooth, and duodenum where proliferating and differentiating compartments are readily distinguished. In addition, transient and localized clusterin gene expression was detected in certain morphogenetically active epithelia. In the lung, abundant gene transcripts were detected in cuboidal epithelial cells of the terminal lung buds during branching morphogenesis, and in the kidney, clusterin gene expression in the epithelial cells of comma and S-shaped bodies coincided with the process of polarization. Our results demonstrate the in vivo expression of the clusterin gene by differentiating epithelial cells during murine embryogenesis, and provide novel evidence suggesting that clusterin may be involved in the differentiation and morphogenesis of certain epithelia.


Asunto(s)
Desarrollo Embrionario y Fetal/genética , Desarrollo Embrionario y Fetal/fisiología , Glicoproteínas/genética , Pulmón/embriología , Chaperonas Moleculares , ARN Mensajero/análisis , ARN Mensajero/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Adhesión Celular , Diferenciación Celular/fisiología , Clonación Molecular , Clusterina , ADN/análisis , ADN/genética , Decidua/química , Decidua/citología , Decidua/embriología , Duodeno/química , Duodeno/citología , Duodeno/embriología , Implantación del Embrión , Embrión de Mamíferos/química , Embrión de Mamíferos/citología , Células Epiteliales , Epitelio/embriología , Femenino , Regulación de la Expresión Génica , Hibridación in Situ , Riñón/química , Riñón/citología , Riñón/embriología , Pulmón/citología , Ratones , Datos de Secuencia Molecular , Morfogénesis/fisiología , Análisis de Secuencia de ADN , Piel/química , Piel/citología , Piel/embriología , Diente/química , Diente/citología , Diente/embriología , Transcripción Genética , Útero/química , Útero/citología
18.
Ann Hematol ; 92(1): 125-7, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22820970

Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Trasplante de Células Madre de Sangre Periférica , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Adulto , Quinasa de Linfoma Anaplásico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Brentuximab Vedotina , Carmustina/administración & dosificación , Cisplatino/administración & dosificación , Terapia Combinada , Ensayos de Uso Compasivo , Crizotinib , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Humanos , Inmunoconjugados/uso terapéutico , Transfusión de Linfocitos , Linfoma Anaplásico de Células Grandes/complicaciones , Linfoma Anaplásico de Células Grandes/enzimología , Linfoma Anaplásico de Células Grandes/cirugía , Masculino , Melfalán/administración & dosificación , Proteínas de Neoplasias/análisis , Prednisona/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/análisis , Inducción de Remisión , Respiración Artificial , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Trasplante Homólogo , Vincristina/administración & dosificación
19.
Nuklearmedizin ; 47(5): 200-4, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18852926

RESUMEN

AIM: Amino acid PET has become an important diagnostic tool for brain tumour imaging. In this data analysis, the potential impact of amino acid PET with 3-O-methyl-6-[(18)F]fluoro-L-DOPA ([(18)F]OMFD) on radiation treatment planning is addressed by the following questions: 1. Was tumour tissue identified with OMFD-PET which was not covered by the conventionally derived planning target volume (PTV)? 2. Would the PTV have been changed incorporating OMFD-PET? PATIENTS, METHODS: OMFD-PET of 25 patients after subtotal resection of malignant glioma was evaluated. The region of elevated tracer uptake of PET and of contrast enhancing masses on MRI were outlined as separate gross tumour volumes (GTV(MRI) and GTV(OMFD)) and reconstructed in the planning CT for comparison with the conventionally drawn GTV(conv). A PTV(new) based on GTV(conv+MRI) was calculated. Pairwise differential volumes were calculated to estimate overlap and differential volumes delineation by each image modality and the PTV(conv) and PTV(new) respectively. RESULTS: Differential volume analysis showed > 10 cm(3) of GTV(OMFD) outside GTV(conv) and GTV(MRI) in 5/25 patients respectively. From GTV(MRI) > 10 cm(3) were found outside GTV(OMFD) in 8/25 patients. Although all tumour areas indicated by [(18)F]OMFD were covered by the conventionally derived PTV, based on a GTV(OMFD+MRI), the PTV(new) would have been enlarged >20% in seven patients. In seven patients the PTV(new) would have been reduced. CONCLUSION: OMFD-PET indicated tumour tissue outside the tumour region identified with MRI, adding valuable information for the delineation of the GTV in radiation treatment planning. OMFD-PET contains the potential to tailor the high dose radiation to the appropriate tumour volume, especially if dose escalation is desired.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/radioterapia , Dihidroxifenilalanina/análogos & derivados , Glioma/diagnóstico por imagen , Glioma/radioterapia , Planificación de la Radioterapia Asistida por Computador/métodos , Biopsia , Neoplasias Encefálicas/patología , Femenino , Radioisótopos de Flúor , Glioma/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X
20.
Phys Med Biol ; 52(23): 7073-86, 2007 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-18029994

RESUMEN

In order to maintain overall navigation accuracy established by a calibration procedure in our CT-based registration-free navigation system, the CT scanner has to repeatedly generate identical volume images of a target at the same coordinates. We tested the positioning accuracy of the prototype of an advanced workplace for image-guided surgery (AWIGS) which features an operating table capable of direct patient transfer into a CT scanner. Volume images (N = 154) of a specialized phantom were analysed for translational shifting after various table translations. Variables included added weight and phantom position on the table. The navigation system's calibration accuracy was determined (bias 2.1 mm, precision +/- 0.7 mm, N = 12). In repeated use, a bias of 3.0 mm and a precision of +/- 0.9 mm (N = 10) were maintainable. Instances of translational image shifting were related to the table-to-CT scanner docking mechanism. A distance scaling error when altering the table's height was detected. Initial prototype problems visible in our study causing systematic errors were resolved by repeated system calibrations between interventions. We conclude that the accuracy achieved is sufficient for a wide range of clinical applications in surgery and interventional radiology.


Asunto(s)
Inmovilización/instrumentación , Intensificación de Imagen Radiográfica/instrumentación , Interpretación de Imagen Radiográfica Asistida por Computador/instrumentación , Cirugía Asistida por Computador/instrumentación , Tomografía Computarizada por Rayos X/instrumentación , Diseño de Equipo , Análisis de Falla de Equipo , Humanos , Inmovilización/métodos , Modelos Biológicos , Intensificación de Imagen Radiográfica/métodos , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Técnica de Sustracción/instrumentación , Cirugía Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodos
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