SUMMARY Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors, p35 and p25, are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.

Distraction osteogenesis is a unique postnatal bone formation employed by orthopaedic surgeons to treat many conditions, however, the overall time to external frame removal can be extensive. Any strategies that accelerate healing would improve patient care. Distraction osteogenesis research in the past decade has shown that direct stem cell implantation enhances new bone formation. Systemic implantation would be more clinically desirable. Systemically delivered stem cells have been shown to home to a mandibular distraction site; however, effects on bone formation have not been studied. Ten-week-old, male Sprague-Dawley rats underwent surgery to implant an external fixator-distractor and an osteotomy was performed. Twenty-four hours postoperatively, each rat received tail vein injections of either saline or 10^6 fluorescently labeled primary mesenchymal stem cells. Animals in the validation groups were euthanized two days after surgery and the femora processed for histology. Animals in the experimental groups were given five days of latency, then the femur was lengthened once daily for five days (0.75mm/day, 3.75mm total). Following four weeks of consolidation, the animals were euthanized and the femora were evaluated by microCT and histology to quantify new bone formation. Labeled stem cells were found at the distraction site in validation animals. However, there were no differences in any bone or soft tissue outcomes. Systemic stem cell administration 24 hours after surgery does not improve DO outcomes. It is possible that the animal model was not challenging enough to discriminate any augmentation provided by stem cells.

BackgroundComplications caused by heterotopic ossification are a common concern after orthopaedic surgery of the elbow. Little effort has been directed at establishing best practices of management of heterotopic ossification in the elbow, in stark contrast to that in the hip. A survey was distributed to all orthopaedic residency programs in the United States to understand current management of heterotopic ossification in the elbow. MethodsA survey was designed to query prophylaxis and surgical excision of heterotopic ossification in the elbow. Respondents were asked about their use of radiation therapy, nonsteroidal antiinflammatory drugs in the prophylaxis of heterotopic ossification or both, as well as the preference for delaying surgical excision of heterotopic ossification after specific index events. Levels of consensus were determined by one-way binomial tests. Responses were categorized as no consensus (50% or less), weak consensus (51--67%), moderate consensus (68--75%), and strong consensus (> 75%) level practices. ResultsOne third of the surveys were returned. A strong consensus (91%, P < 0.001) indicated the use of prophylactic radiation therapy but there was no agreement on the appropriate dose. Indomethacin is the recommended nonsteroidal antiinflammatory drug (moderate consensus, 84%, P ¼ 0.009) but with disagreement about the treatment duration. Finally, there is very little agreement concerning the time-delay for surgical excision for all index events. ConclusionsThe community of orthopaedic surgeons agrees on the prophylaxis and surgical management of heterotopic ossification in the elbow. However, there is less agreement about the appropriate dose, duration, and surgical delay. These uncertainties reflect the dearth of research about the management practices for heterotopic ossification in the elbow.