T-Lymphocytes Enable Osteoblast Maturation via IL-17F during the Early Phase of Fracture Repair

While it is well known that the presence of lymphocytes and cytokines are important for fracture healing, the exact role of the various cytokines expressed by cells of the immune system on osteoblast biology remains unclear. To study the role of inflammatory cytokines in fracture repair, we studied tibial bone healing in wild-type and Rag1−/− mice. Histological analysis, µCT stereology, biomechanical testing, calcein staining and quantitative RNA gene expression studies were performed on healing tibial fractures. These data provide support for Rag1−/− mice as a model of impaired fracture healing compared to wild-type. Moreover, the pro-inflammatory cytokine, IL-17F, was found to be a key mediator in the cellular response of the immune system in osteogenesis. In vitro studies showed that IL-17F alone stimulated osteoblast maturation. We propose a model in which the Th17 subset of T-lymphocytes produces IL-17F to stimulate bone healing. This is a pivotal link in advancing our current understanding of the molecular and cellular basis of fracture healing, which in turn may aid in optimizing fracture management and in the treatment of impaired bone healing

WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% +/- 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% +/- 2% vs. 57.4% +/- 1.8% (p < 0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% +/- 1.5% in lithium treated cells vs. 56.6 +/- 3% (p < 0.01)) accompanied by increased number of.H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% +/- 8% for lithium treated cells vs. 27% +/- 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.B.R.A.I.N Child Canada; Cancer Research UK; Brain Tumour Charity; Hungarian Brain Research Program [KTIA_13_NAP-A-V/3]; Janos Bolyai Scholarship of the Hungarian Academy of Sciences [TAMOP-4.2.2. A-11/1/KONV-2012-0025]; German Cancer Aid/Dr. Mildred Scheel Foundation for Cancer Research; Cure Childhood Cancer Foundation; St. Baldrick's Foundation; Southeastern Brain Tumor Foundation; Action Medical Research; [CZ.1.05/2.1.00/03.0101]; [CZ.1.07/2.3.00/20.0183

Type-1 Collagen differentially alters β-catenin accumulation in primary Dupuytren's Disease cord and adjacent palmar fascia cells

<p>Abstract</p> <p>Background</p> <p>Dupuytren's Disease (DD) is a debilitating contractile fibrosis of the palmar fascia characterised by excess collagen deposition, contractile myofibroblast development, increased Transforming Growth Factor-β levels and β-catenin accumulation. The aim of this study was to determine if a collagen-enriched environment, similar to <it>in vivo </it>conditions, altered β-catenin accumulation by primary DD cells in the presence or absence of Transforming Growth Factor-β.</p> <p>Methods</p> <p>Primary DD and patient matched, phenotypically normal palmar fascia (PF) cells were cultured in the presence or absence of type-1 collagen and Transforming Growth Factor-β1. β-catenin and α-smooth muscle actin levels were assessed by western immunoblotting and immunofluorescence microscopy.</p> <p>Results</p> <p>DD cells display a rapid depletion of cellular β-catenin not evident in patient-matched PF cells. This effect was not evident in either cell type when cultured in the absence of type-1 collagen. Exogenous addition of Transforming Growth Factor-β1 to DD cells in collagen culture negates the loss of β-catenin accumulation. Transforming Growth Factor-β1-induced α-smooth muscle actin, a marker of myofibroblast differentiation, is attenuated by the inclusion of type-1 collagen in cultures of DD and PF cells.</p> <p>Conclusion</p> <p>Our findings implicate type-1 collagen as a previously unrecognized regulator of β-catenin accumulation and a modifier of TGF-β1 signaling specifically in primary DD cells. These data have implications for current treatment modalities as well as the design of <it>in vitro </it>models for research into the molecular mechanisms of DD.</p

Practical Demonstration of the CIEDE2000 Corrections to CIELAB Using a Small Set of Sample Pairs

International audienceA set of 10 color pairs was proposed and produced in 2002 to show the advantages of the CIEDE2000 color-difference formula with respect to CIELAB. These 10 color pairs illustrated each of the five corrections to CIELAB proposed by CIEDE2000. The 10 color pairs were visually assessed, under reference conditions close to those proposed by CIEDE2000, by two groups of 31 and 21 inexperienced observers, using two different gray scales. Average visual results in these experiments fitted CIEDE2000 predictions much better than CIELAB, as shown by a decrease of Standardized Residual Sum of Squares values of about 20 units. Current visual results showed only the improvement of CIEDE2000 upon CIELAB in predictions of perceived color differences, but they are not recommended for testing new advanced color-difference formulas

Treatment of extra - abdominal desmoid tumors with chemotherapy

Fibromatosis, or extra-abdominal desmoid tumor, is a benign disease which often has an aggressive clinical course that can be difficult to treat. We performed a retrospective review of 16 patients (12 females and four males) with a mean age of 34.2 years treated with methotrexate and vinblastine for newly diagnosed or recurrent extra-abdominal desmoid tumor. The mean age of our patient cohort was 34.2 years (range 11-70), and the mean tumor size was 11.5 cm (range 2.5-21.2 cm). The mean duration of therapy was 12 months with an average follow-up of 43 months (range 1-149 months). Fourteen of 16 patients demonstrated a clinical response to treatment. Eight of 14 patients demonstrated a radiologic decrease in tumor size. Only one patient progressed on therapy. Six patients developed recurrent symptoms after discontinuation of treatment. Chemotherapy-related symptoms including neutropenia, nausea, and vomiting were common and observed in most patients, however these side effects were mild and transient. Five patients developed peripheral neuropathy that prompted a change from vinblastine to vinorelbine during treatment. One potentially life-threatening complication (pneumocystis pneumonia) occurred which was diagnosed early and successfully treated. The use of methotrexate and vinblastine/vinorelbine in the management of fibromatosis appears to be an effective treatment with minimal treatment-related side effects