505 research outputs found
"Er zijn geen ILO-watchers in dit land", Interview met prof. mr. Paul F. van der Heijden
FDR De bescherming van fundamentele rechten in een integrerend Europa ou
TGFβ inhibition stimulates collagen maturation to enhance bone repair and fracture resistance in a murine myeloma model
Multiple myeloma is a plasma cell malignancy that causes debilitating bone disease and fractures, in which TGFβ plays a central role. Current treatments do not repair existing damage and fractures remain a common occurrence. We developed a novel low tumour phase murine model mimicking the plateau phase in patients, as we hypothesized this would be an ideal time to treat with a bone anabolic. Using in vivo microCT we show substantial and rapid bone lesion repair (and prevention) driven by SDâ208 (TGFβ receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266âGFPâluc myeloma. We discovered that lesion repair occurred via an intramembranous fracture repairâlike mechanism and that SDâ208 enhanced collagen matrix maturation to significantly improve fracture resistance. Lesion healing was associated with VEGFA expression in woven bone, reduced osteocyteâderived PTHrP, increased osteoblasts, decreased osteoclasts and lower serum TRACPâ5b. SDâ208 also completely prevented bone lesion development mice with aggressive JJN3 tumors, and was more effective than an antiâTGFβ neutralizing antibody (1D11). We also discovered that SDâ208 promoted osteoblastic differentiation (and overcame the TGFβâinduced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fractureâresistance with SDâ208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality
Preventing and repairing myeloma bone disease by combining conventional antiresorptive treatment with a bone anabolic agent in murine models
Multiple myeloma is a plasma cell malignancy, which develops in the bone marrow and frequently leads to severe bone destruction. Current antiresorptive therapies to treat the bone disease do little to repair damaged bone; therefore, new treatment strategies incorporating bone anabolic therapies are urgently required. We hypothesized that combination therapy using the standard of care antiresorptive zoledronic acid (Zol) with a bone anabolic (anti-TGFβ/1D11) would be more effective at treating myeloma-induced bone disease than Zol therapy alone. JJN3 myeloma-bearing mice (nâ=â8/group) treated with combined Zol and 1D11 resulted in a 48% increase (pâ¤0.001) in BV/TV compared to Zol alone and a 65% increase (pâ¤0.0001) compared to 1D11 alone. Our most significant finding was the substantial repair of U266-induced osteolytic bone lesions with combination therapy (nâ=â8/group), which resulted in a significant reduction in lesion area compared to vehicle (pâ¤0.01) or Zol alone (pâ¤0.01). These results demonstrate that combined antiresorptive and bone anabolic therapy is significantly more effective at preventing myeloma-induced bone disease than Zol alone. Furthermore, we demonstrate that combined therapy is able to repair established myelomatous bone lesions. This is a highly translational strategy which could significantly improve bone outcomes and quality of life for patients with myeloma
Recruitment and retention of studentsâan integrated and holistic vision of mathematics support
Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV
Results are presented from a search for a W' boson using a dataset
corresponding to 5.0 inverse femtobarns of integrated luminosity collected
during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV.
The W' boson is modeled as a heavy W boson, but different scenarios for the
couplings to fermions are considered, involving both left-handed and
right-handed chiral projections of the fermions, as well as an arbitrary
mixture of the two. The search is performed in the decay channel W' to t b,
leading to a final state signature with a single lepton (e, mu), missing
transverse energy, and jets, at least one of which is tagged as a b-jet. A W'
boson that couples to fermions with the same coupling constant as the W, but to
the right-handed rather than left-handed chiral projections, is excluded for
masses below 1.85 TeV at the 95% confidence level. For the first time using LHC
data, constraints on the W' gauge coupling for a set of left- and right-handed
coupling combinations have been placed. These results represent a significant
improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe
- âŚ