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Pigment cells and neuronal cells both are derived from the neural crest. Here, we describe the Pit-Oct-Unc (POU) domain transcription factor Brn3a, normally involved in neuronal development, to be frequently expressed in melanoma, but not in melanocytes and nevi. RNAi-mediated silencing of Brn3a strongly reduced the viability of melanoma cell lines and decreased tumour growth in vivo. In melanoma cell lines, inhibition of Brn3a caused DNA double-strand breaks as evidenced by Mre11/Rad50-containing nuclear foci. Activated DNA damage signalling caused stabilization of the tumour suppressor p53, which resulted in cell cycle arrest and apoptosis. When Brn3a was ectopically expressed in primary melanocytes and fibroblasts, anchorage-independent growth was increased. In tumourigenic melanocytes and fibroblasts, Brn3a accelerated tumour growth in vivo. Furthermore, Brn3a cooperated with proliferation pathways such as oncogenic BRAF, by reducing oncogene-induced senescence in non-malignant melanocytes. Together, these results identify Brn3a as a new factor in melanoma that is essential for melanoma cell survival and that promotes melanocytic transformation and tumourigenesis.
Background:
Bone-ligament-bone grafts for reconstruction of the scapholunate ligament are a valuable tool to prevent disease progression to carpal collapse. Locally available grafts do not require an additional donor site. The first extensor compartment was evaluated biomechanically regarding its possible use as an autograft.
Methods:
Twelve native fresh-frozen, human cadaver specimens were tested by applying axial tension in a Zwick Roell machine. Load to failure, transplant elongation, and bony avulsion were recorded. The load to failure was quantitated in newtons (N) and the displacement in length (millimeters). Parameters were set at distinct points as start of tension, 1 mm stretch and 1.5 mm dissociation, failure and complete tear, and were evaluated under magnified visual control. Although actual failure occurred at higher tension, functional failure was defined at a stretch of 1.5 mm.
Results:
Mean load at 1 mm elongation was 44.1 ± 28 N and at 1.5 mm elongation 57.5 ± 42 N. Failure occurred at 111 ± 83.1 N. No avulsion of the bony insertion was observed. Half the transplants failed in the central part of the ligament, while the rest failed near the insertion but not at the insertion itself. Analysis of tension strength displayed a wide range from 3.8 to 83.7 N/mm at a mean of 33.4 ± 28.4 N/mm.
Conclusions:
The biomechanical tensile properties of the first dorsal extensor compartment are similar to those of the dorsal part of the scapholunate ligament. A transplant with a larger bone stock and a longer ligament may display an advantage, as insertion is possible in the dorsal, easily accessible part of the carpal bones rather than in the arête-like region adjacent to the insertion of the scapholunate ligament. In this study, 1.5 mm lengthening of the bone–ligament–bone transplant was defined as clinical failure, as such elongation will cause severe gapping and is considered as failure of the transplant.
Background
Gut microbes influence their hosts in many ways, in particular by modulating the impact of diet. These effects have been studied most extensively in humans and mice. In this work, we used whole genome metagenomics to investigate the relationship between the gut metagenomes of dogs, humans, mice, and pigs.
Results
We present a dog gut microbiome gene catalog containing 1,247,405 genes (based on 129 metagenomes and a total of 1.9 terabasepairs of sequencing data). Based on this catalog and taxonomic abundance profiling, we show that the dog microbiome is closer to the human microbiome than the microbiome of either pigs or mice. To investigate this similarity in terms of response to dietary changes, we report on a randomized intervention with two diets (high-protein/low-carbohydrate vs. lower protein/higher carbohydrate). We show that diet has a large and reproducible effect on the dog microbiome, independent of breed or sex. Moreover, the responses were in agreement with those observed in previous human studies.
Conclusions
We conclude that findings in dogs may be predictive of human microbiome results. In particular, a novel finding is that overweight or obese dogs experience larger compositional shifts than lean dogs in response to a high-protein diet.