Introduction Disorders that affect glucose metabolism, namely diabetes mellitus (DM), may favor the development and/or progression of osteoarthritis (OA). Thus far, little is known regarding the ability of chondrocytes to adjust to variations in the extracellular glucose concentration, resulting from hypoglycemia and hyperglycemia episodes, and so, to avoid deleterious effects resulting from deprivation or intracellular accumulation of glucose. The aim of this study was to compare the ability of normal and OA chondrocytes to regulate their glucose transport capacity in conditions of insufficient or excessive extracellular glucose and to identify the mechanisms involved and eventual deleterious consequences, namely the production of reactive oxygen species (ROS).
Fractures are ubiquitous in the archaeological record but the majority of these are the consequence of a traumatic incident and do not reflect any loss of strength inherent to the bone. So-called fragility fractures, particularly hip fractures, are considered uncommon occurrences in skeletal populations from the past. Nevertheless, evidence of this type of fracture in the archaeological record is increasing. A methodical search for possible hip fractures in the excavation reports, theses and monographs housed in the Department of Anthropology of the University of Coimbra presented an occasion to describe six hip fractures, previously unpublished, from different Portuguese archaeological sites and to challenge the widespread assumption that hip fractures were nearly non-existent in the past.
Chondrocyte survival is a major goal for the effective storage and clinical performance of human osteochondral allografts. The majority of animal and human cryopreservation studies conducted so far have been performed in small osteochondral cylinders. Using human tibial plateaus as a model for large osteochondral pieces, this work sought to evaluate the cryoprotective efficiency of glycerol and dimethylsulfoxide (DMSO), and to identify cryopreservation conditions suitable for use in tissue banks. Human tibial plateaus harvested from 7 cadaveric tissue donors were incubated in the presence or absence of cryoprotective agents (CPA): 10% or 15% glycerol and 10% DMSO in a Ham F-12 nutrient mixture. Chondrocyte viability was assessed immediately after thawing, using the MTT reduction assay and a fluorescence microscopic method. The tibial plateaus frozen in the absence of CPA showed a significant decrease in chondrocyte viability. The use of CPA significantly increased chondrocyte viability compared with cartilage frozen without CPA (nearly 50% versus 80% living chondrocytes with 10% glycerol versus 10% DMSO, respectively) relative to that in fresh cartilage. In this regard, 10% DMSO was slightly more effective than either 10% or 15% glycerol, eliciting the recovery of approximately 15% relative to the living chondrocyte content in fresh cartilage. In all conditions, fluorescence microscopic studies showed that surviving chondrocytes were restricted to the superficial cartilage layer. Human tibial plateaus seemed to be a good experimental model to establish cryopreservation methods applicable to large human osteochondral pieces in tissue banks.
Osteoporosis is an evocative term for a metabolic disorder characterized by loss of bone mass and organization, which predisposes to fracture. The clinical consequences of osteoporosis lie in the problems associated with it, specifically hip, Colles and vertebral fractures. We present here an extracapsular fracture of the proximal femur in an aged female skeleton from the Santa Clara-a-Velha Monastery (14th-17th centuries) in Coimbra, Portugal. This fracture is probably secondary to an osteoporotic disorder. Bone remodeling at the fracture site confirms that this woman survived for a long period after sustaining a fracture of the proximal femur, suggestive of a solid community assistance and support.
The oncogene brachyury (TBXT) is a T-box transcription factor that is overexpressed in multiple solid tumors and is associated with tumor aggressiveness and poor patient prognosis. Gliomas comprise the most common and aggressive group of brain tumors, and at the present time the functional and clinical impact of brachyury expression has not been investigated previously in these neoplasms. Brachyury expression (mRNA and protein) was assessed in normal brain (n = 67), glioma tissues (n = 716) and cell lines (n = 42), and further in silico studies were undertaken using genomic databases totaling 3115 samples. Our glioma samples were analyzed for copy number (n = 372), promoter methylation status (n = 170), and mutation status (n = 1569 tissues and n = 52 cell lines) of the brachyury gene. The prognostic impact of brachyury expression was studied in 1524 glioma patient tumors. The functional impact of brachyury on glioma proliferation, viability, and cell death was evaluated both in vitro and in vivo. Brachyury was expressed in the normal brain, and significantly downregulated in glioma tissues. Loss of brachyury was associated with tumor aggressiveness and poor survival in glioma patients. Downregulation of brachyury was not associated with gene deletion, promoter methylation, or inactivating point mutations. Brachyury re-expression in glioma cells was found to decrease glioma tumorigenesis by induction of autophagy. These data strongly suggest that brachyury behaves as a tumor suppressor gene in gliomas by modulating autophagy. It is important to note that brachyury constitutes an independent positive biomarker of patient prognosis. Our findings indicate that the role of brachyury in tumorigenesis may be tissue-dependent and demands additional investigation to guide rational interventions.
Dendritic cell (DC) maturation is essential for the initiation of T-dependent immune responses. Nuclear factor kappa B (NF-κB) transcription factors are ubiquitously expressed signalling molecules, known to regulate the transcription of a large number of genes involved in immune responses, including cytokines and cell surface molecules. In this work, we studied the time-dependent activation of five members of the NF-κB family, p50, p52, p65, RelB and cRel, in a mouse skin DC line in response to stimulation with the strong sensitizer, 2,4-dinitrofluorobenzene (DNFB). Western blot assay revealed that exposure of fetal skin DC (FSDC) to DNFB induced the degradation of the inhibitor of NF-κB (IκB). Three out of its five members, i.e. p50, p52, and RelB, were similarly activated upon DNFB stimulation, with subsequent translocation of these subunits from the cytosol to the nucleus, but with different kinetics. In contrast, p65 expression was diminished in both the nucleus and the cytosol. The electrophoretic mobility shift assay (EMSA) showed that exposure of FSDC to DNFB induced DNA binding to NF-κB. Together, these results show that DNFB differentially activates the various members of the NF-κB family in skin DC. Keywords Skin dendritic cell · DNFB · NF-κB · IκBAbbreviations DC dendritic cell · DNFB 2,4-dinitrofluorobenzene · EMSA electrophoretic mobility shift assay · FSDC fetal skin dendritic cell line · IκB inhibitor of NF-κB · IKK IκB kinase · iNOS inducible nitric oxide synthase · LPS lipopolysaccharide · MAPK mitogen-activated protein kinase · NF-κB transcription nuclear factor kappa B · PMSF phenylmethylsulfonylfluoride
BackgroundPaediatric high grade glioma (pHGG) is a distinct biological entity to histologically similar tumours arising in older adults, and has differing copy number profiles and driver genetic alterations. As functionally important intragenic copy number aberrations (iCNA) and fusion genes begin to be identified in adult HGG, the same has not yet been done in the childhood setting. We applied an iCNA algorithm to our previously published dataset of DNA copy number profiling in pHGG with a view to identify novel intragenic breakpoints.ResultsWe report a series of 288 iCNA events in pHGG, with the presence of intragenic breakpoints itself a negative prognostic factor. We identified an increased number of iCNA in older children compared to infants, and increased iCNA in H3F3A K27M mutant tumours compared to G34R/V and wild-type. We observed numerous gene disruptions by iCNA due to both deletions and amplifications, targeting known HGG-associated genes such as RB1 and NF1, putative tumour suppressors such as FAF1 and KIDINS220, and novel candidates such as PTPRE and KCND2. We further identified two novel fusion genes in pHGG – CSGALNACT2:RET and the complex fusion DHX57:TMEM178:MAP4K3. The latter was sequence-validated and appears to be an activating event in pHGG.ConclusionsThese data expand upon our understanding of the genomic events driving these tumours and represent novel targets for therapeutic intervention in these poor prognosis cancers of childhood.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-23) contains supplementary material, which is available to authorized users.
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