Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd

Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function

Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF family, binds to its receptor GITR on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. Structural analysis reveals that the human GITRL (hGITRL) ectodomain self-assembles into an atypical expanded homotrimer with sparse monomer–monomer interfaces. Consistent with the small intersubunit interfaces, hGITRL exhibits a relatively weak tendency to trimerize in solution and displays a monomer–trimer equilibrium not reported for other TNF family members. This unique assembly behavior has direct implications for hGITRL–GITR signaling, because enforced trimerization of soluble hGITRL ectodomain results in an ≈100-fold increase in its receptor binding affinity and also in enhanced costimulatory activity. The apparent reduction in affinity that is the consequence of this dynamic equilibrium may represent a mechanism to realize the biologically optimal level of signaling through the hGITRL–GITR pathway, as opposed to the maximal achievable level

Primary bone tumours of the spine: a 42-year survey from the Leeds Regional Bone Tumour Registry

We conducted a review of the Leeds Regional Bone Tumour Registry for primary bone tumours of the spine since establishment in 1958 until year 2000. To analyse the incidence of primary tumours of the spine and to record the site of occurrence, sex distribution, survival and pathology of these tumours. Primary tumours of the spine are particularly rare, accounting for between 4 and 13% of published series of primary bone tumours. The Leeds Bone Tumour Registry was reviewed and a total of 2,750 cases of bone tumours and tumour-like cases were analysed. Consultants in orthopaedic surgery, neurosurgery, oncology and pathology in North and West Yorkshire and Humberside contribute to the Registry. Primary bone tumours of the osseous spine constitute only 126 of the 2,750 cases (4.6%). Chordoma was the most frequent tumour in the cervical and sacral regions, while the most common diagnosis overall was multiple myeloma and plasmacytoma. Osteosarcoma ranked third. The mean age of presentation was 42 years and pain was the most common presenting symptom, occurring in 95% of malignant and 76% of benign tumours. Neurological involvement occurred in 52% of malignant tumours and usually meant a poor prognosis. The establishment of Bone Tumour Registries is the only way that sufficient data on large numbers of these rare tumours can be accumulated to provide a valuable and otherwise unavailable source of information for research, education and clinical follow-up