173 research outputs found
PLS3 sequencing in childhood-onset primary osteoporosis identifies two novel disease-causing variants
The Summary Altogether 95 children with primary bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Two children with multiple peripheral and spinal fractures and low BMD had novel disease-causing PLS3 variants. Children with milder phenotypes had no pathogenic variants. PLS3 screening is indicated in childhood-onset primary osteoporosis. Introduction The study aimed to determine the role of pathogenic PLS3 variants in children's bone fragility and to elucidate the associated phenotypic features. Methods Two cohorts of children with bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Cohort I comprised 31 patients with childhood-onset primary osteoporosis of unknown etiology. Cohort II comprised 64 children who had sustained multiple fractures but were otherwise healthy. Clinical and radiological data were reviewed. Peripheral blood DNA was Sanger sequenced for coding exons and flanking intronic regions of PLS3. Results In two patients of cohort I, where other common genetic causes had been excluded, we identified two novel disease-causing PLS3 variants. Patient 1 was a male with bilateral femoral fractures at 10 years, low BMD (Z-score -4.1; 18 years), and multiple vertebral compression fractures. He had a novel nonsense variant in PLS3. Patient 2 was a girl with multiple long bone and vertebral fractures and low BMD (Z-score -6.6 at 6 years). She had a de novo missense variant in PLS3; whole exome sequencing and array-CGH identified no other genetic causes. Iliac crest bone biopsies confirmed low-turnover osteoporosis in both patients. In cohort II, no pathogenic PLS3 variants were identified in any of the subjects. Conclusion Two novel disease-causing variants in PLS3 were identified in a boy and a girl with multiple peripheral and spinal fractures and very low BMD while no pathogenic variants were identified in children with less severe skeletal fragility. PLS3 screening is warranted in male and female patients with childhood-onset primary osteoporosis.Peer reviewe
Communicating the amount of windstorm induced forest damage by the maximum wind gust speed in Finland
Windstorms are natural disturbance agents in forests playing a role in
natural forest regeneration. In Finland, the most severe individual
windstorms have commonly damaged 2–4 million m3 of timber. In addition
to financial losses caused to forest owners, windthrown trees have in many
cases seriously disrupted the functionality of the national power grid.
Communicating windstorm risks in duty forecasting is difficult. In this
study, we aimed at developing windstorm impact estimates for forest damage in
Finland to help the forecaster to improve communication of the risks of
windstorms. We have compared the volume of forest damage caused by the most
intense windstorms in Finland during the recent decade to the observed
maximum inland wind gust speeds associated with the same windstorms. It was
found out that the volume of forest damage follows approximately a power
relation as a function of wind gust speed with a power of ∼10. This is
a tentative estimate because of a short time series and small number of
inspected windstorms. Moreover, also wind direction, location of the affected
area and soil properties among other factors have an impact to the amount of
damage as illustrated in our inspection. Despite the shortness of the time
series, we believe that our results demonstrating the steep increase in the
impacts of windstorms with an increasing windstorm intensity are valuable.
However, more detailed investigations with longer time series are needed in
order to more specifically communicate the windstorm risks and their impacts
in boreal forests.</p
Impaired Bone Health in Inflammatory Bowel Disease: A Case-Control Study in 80 Pediatric Patients
Peer reviewe
Fast growth associated with aberrant vasculature and hypoxia in fibroblast growth factor 8b (FGF8b) over-expressing PC-3 prostate tumour xenografts
Background: Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. Methods: Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([F-18] FDG) and hypoxia ([F-18] EF5), and intratumoral polarographic measurements of pO(2). Results: Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO(2) measurements, [F-18] EF5 and [F-18] FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. Conclusion: FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts
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Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine: Brussels, Belgium. 15-18 March 2016.
[This corrects the article DOI: 10.1186/s13054-016-1208-6.]
PLS3 sequencing in childhood-onset primary osteoporosis identifies two novel disease-causing variants
An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis
Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is
a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a
complex disease caused by metastasis of tumor cells from their primary site and
is characterized by intricate interplay of molecular interactions.
Identification of targets for multifactorial diseases such as SBC, the most
frequent complication of breast and prostate cancers, is a challenge. Towards
achieving our aim of identification of targets specific to SBC, we constructed
a 'Cancer Genes Network', a representative protein interactome of cancer genes.
Using graph theoretical methods, we obtained a set of key genes that are
relevant for generic mechanisms of cancers and have a role in biological
essentiality. We also compiled a curated dataset of 391 SBC genes from
published literature which serves as a basis of ontological correlates of
secondary bone cancer. Building on these results, we implement a strategy based
on generic cancer genes, SBC genes and gene ontology enrichment method, to
obtain a set of targets that are specific to bone metastasis. Through this
study, we present an approach for probing one of the major complications in
cancers, namely, metastasis. The results on genes that play generic roles in
cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have
broader implications in understanding the role of molecular regulators in
mechanisms of cancers. Specifically, our study provides a set of potential
targets that are of ontological and regulatory relevance to secondary bone
cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary
information). Revised after critical reviews. Accepted for Publication in
PLoS ON
Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”
Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with “corner fractures” (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of “corner fractures”. An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extra cellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys231Trp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and “corner fracture” appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.Peer reviewe
Critical evaluation of the subcutaneous engraftments of hormone naïve primary prostate cancer
Background: Patient-derived xenografts (PDXs) are considered to better recapitulate the histopathological and molecular heterogeneity of human cancer than other preclinical models. Despite technological advances, PDX models from hormone naïve primary prostate cancer are scarce. We performed a detailed analysis of PDX methodology using a robust subcutaneous model and fresh tissues from patients with primary hormone naïve prostate cancer.Methods: Clinical prostate tumor specimens (n=26, Gleason score 6–10) were collected from robotic-assisted laparoscopic radical prostatectomies at Turku University Hospital (Turku, Finland), cut into pieces, and implanted subcutaneously into 84 immunodeficient mice. Engraftments and the adjacent material from prostatic surgical specimens were compared using histology, immunohistochemistry and DNA sequencing.Results: The probability of a successful engraftment correlated with the presence of carcinoma in the implanted tissue. Tumor take rate was 41%. Surprisingly, mouse hormone supplementation inhibited tumor take rate, whereas the degree of mouse immunodeficiency did not have an effect. Histologically, the engrafted tumors closely mimicked their parental tumors, and the Gleason grades and copy number variants of the engraftments were similar to those of their primary tumors. Expression levels of androgen receptor, prostate-specific antigen, and keratins were retained in engraftments, and a detailed genomic analysis revealed high fidelity of the engraftments with their corresponding primary tumors. However, in the second or third passage of tumors, the carcinoma areas were almost completely replaced by benign tissue with frequent degenerative or metaplastic changes.Conclusions: Subcutaneous primary prostate engraftments preserve the phenotypic and genotypic landscape. Thus, they serve a potential model for personalized medicine and preclinical research but their use may be limited to the first passage.</p
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