87 research outputs found
Processing and characterization of chitosan microspheres to be used as templates for layer-by-layer assembly
Chitosan (Ch) microspheres have been developed
by precipitation method, cross-linked with glutaraldehyde
and used as a template for layer-by-layer (LBL)
deposition of two natural polyelectrolytes. Using a LBL
methodology, Ch microspheres were alternately coated with
hyaluronic acid (HA) and Ch under mild conditions. The
roughness of the Ch-based crosslinked microspheres was
characterized by atomic force microscopy (AFM). Morphological
characterization was performed by environmental
scanning electron microscopy (ESEM), scanning
electron microscopy (SEM) and stereolight microscopy.
The swelling behaviour of the microspheres demonstrated
that the ones with more bilayers presented the highest water
uptake and the uncoated cross-linked Ch microspheres
showed the lowest uptake capability. Microspheres presented
spherical shape with sizes ranging from 510 to
840 lm. ESEM demonstrated that a rougher surface with
voids is formed in multilayered microspheres caused by the
irregular stacking of the layers. A short term mechanical
stability assay was also performed, showing that the LBL
procedure with more than five bilayers of HA/Ch over Ch
cross-linked microspheres provide higher mechanical
stability
Post-translational regulation contributes to the loss of LKB1 expression through SIRT1 deacetylase in osteosarcomas
background: The most prevalent form of bone cancer is osteosarcoma (OS), which is associated with poor prognosis in case of metastases formation. Mice harbouring liver kinase B1 (LKB1+/−) develop osteoblastoma-like tumours. Therefore, we asked whether loss of LKB1 gene has a role in the pathogenesis of human OS.
methods: Osteosarcomas (n=259) were screened for LKB1 and sirtuin 1 (SIRT1) protein expression using immunohistochemistry and western blot. Those cases were also screened for LKB1 genetic alterations by next-generation sequencing, Sanger sequencing, restriction fragment length polymorphism and fluorescence in situ hybridisation approaches. We studied LKB1 protein degradation through SIRT1 expression. MicroRNA expression investigations were also conducted to identify the microRNAs involved in the SIRT1/LKB1 pathway.
results: Forty-one per cent (106 out of 259) OS had lost LKB1 protein expression with no evident genetic anomalies. We obtained evidence that SIRT1 impairs LKB1 protein stability, and that SIRT1 depletion leads to accumulation of LKB1 in OS cell lines resulting in growth arrest. Further investigations revealed the role of miR-204 in the regulation of SIRT1 expression, which impairs LKB1 stability.
conclusions: We demonstrated the involvement of sequential regulation of miR-204/SIRT1/LKB1 in OS cases and showed a mechanism for the loss of expression of LKB1 tumour suppressor in this malignancy
Pan-cancer analysis of whole genomes
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe
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