A synthetic KLHL20 ligand to validate CUL3KLHL20 as a potent E3 ligase for targeted protein degradation.

Targeted protein degradation (TPD) has risen as a promising therapeutic modality. Leveraging the catalytic nature of the ubiquitin-proteasome enzymatic machinery, TPD exhibits higher potency to eliminate disease-causing target proteins such as oncogenic transcription factors that may otherwise be difficult to abrogate by conventional inhibitors. However, there are challenges that remain. Currently, nearly all degraders engage CUL4CRBN or CUL2VHL as the E3 ligase for target ubiquitination. While their immediate efficacies are evident, the narrowed E3 ligase options make TPD vulnerable to potential drug resistance. In addition, E3 ligases show differential tissue expression and have intrinsic limitations in accessing varying types of disease-relevant targets. As the success of TPD is closely associated with the ability of E3 ligases to efficiently polyubiquitinate the target of interest, the long-term outlook of TPD drug development will depend on whether E3 ligases such as CUL4CRBN and CUL2VHL are accessible to the targets of interest. To overcome these potential caveats, a broad collection of actionable E3 ligases is required. Here, we designed a macrocyclic degrader engaging CUL3KLHL20 for targeting BET proteins and validated CUL3KLHL20 as an E3 ligase system suitable for TPD. This work thus contributes to the expansion of usable E3 ligases for potential drug development.

Temporising external fixation of calcaneus fractures prior to definitive plate fixation: a case series.

INTRODUCTION: Surgical management of calcaneus fractures is technically demanding and has a high risk of wound complications. These fractures are traditionally managed with splinting until swelling has subsided, which can take weeks and leaves the fracture fragments displaced. We describe a novel protocol for the management of displaced intraarticular calcaneus fractures that utilises a temporising external fixator and staged conversion to plate fixation through a sinus tarsi approach. The goal of this technique was to enable earlier treatment with open reduction and internal fixation, minimise the amount of manipulation required at the time of definitive fixation and reduce the wound complication rate seen with the traditional extensile approach. METHODS: The records of patients with displaced calcaneus fractures from 2010-2014 were reviewed retrospectively. A total of nine patients with 10 calcaneus fractures were treated using this protocol. All patients underwent ankle-spanning medial external fixation within 48 hours after injury. Patients underwent conversion to open plate fixation through a sinus tarsi approach when skin turgor had returned to normal. Time to surgery, infection rate, wound complications, radiographic alignment, and time to radiographic union were recorded. RESULTS: The average Bohler's angle improved from 13.2 (range -2 to 34) degrees preoperatively to 34.3 (range 26 to 42) degrees postoperatively. The average time from external fixation to conversion to internal fixation was 4.8 (range 3 to 7) days. There were no immediate post-surgical complications. The average time to weight-bearing was 8.5 weeks. The average time to radiographic union was 9.5 (range 8 to 12) weeks. There were no infections or wound complications at the time of last follow-up. CONCLUSION: Early temporising external fixation for the acute management of displaced calcaneus fractures is a safe and effective method to reduce and stabilise the foot and may decrease the time to definitive fixation. There were no complications related to the use of the external fixator in this series.

Scheuermann kyphosis in nonhuman primates.

STUDY DESIGN: A cadaveric survey of the thoracic spines of extant species of nonbipedal primates for the presence of Scheuermann kyphosis. OBJECTIVE: To determine the presence and prevalence of Scheuermann kyphosis in quadrupedal species of the closest living relatives to humans to demonstrate that bipedalism is not an absolute requirement for the development of Scheuermann kyphosis. SUMMARY OF BACKGROUND DATA: The etiology of Scheuermann kyphosis remains poorly understood. Biomechanical factors associated with upright posture are thought to play a role in the development of the disorder. To date, Scheuermann kyphosis has been described only in humans and extinct species of bipedal hominids. METHODS: Thoracic vertebrae from 92 specimens of Pan troglodytes (chimpanzee) and 105 specimens of Gorilla gorilla (gorilla) from the Hamann-Todd Osteological Collection at the Cleveland Museum of Natural History were examined for Scheuermann kyphosis on the basis of Sorenson criteria and the presence of anterior vertebral body extensions and for the presence of Schmorl nodes. RESULTS: Two specimens of P. troglodytes (2.2%) were found to have anatomic features consistent with Scheuermann kyphosis including vertebral body wedging greater than 5° at 3 or more adjacent levels and the presence of anterior vertebral body extensions. One of the affected specimens (50%) demonstrated the presence of Schmorl nodes whereas 2 of the unaffected specimens (2.2%) had Schmorl nodes. None of the specimens of G. gorilla (0%) were found to have anterior vertebral body extensions characteristic of Scheuermann kyphosis or Schmorl nodes. CONCLUSION: Thoracic kyphotic deformity consistent with Scheuermann kyphosis exists in quadrupedal nonhuman primates. Bipedalism is not a strict requirement for the development of Scheuermann kyphosis, and the evolutionary origins of the disease predate the vertebral adaptations of bipedal locomotion.