Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and β3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α1-AR subtype (ADRA1A) and Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gαq and Gαs signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
Publications by Year: 2022
2022
BACKGROUND: The aim of this study was to develop and validate a finite element (FE) model of the patellofemoral joint to analyze the biomechanics of lateral retinacular release after medial patellofemoral ligament (MPFL) reconstruction in patellar malalignment (increased tibial tubercle-trochlear groove distance (TT-TG)). We hypothesized that lateral retinacular release is not appropriate in patellar instability addressed by MPFL reconstruction due to decreased lateral stability and inappropriate adjustment in patellofemoral contact pressures.
METHODS: A FE in-silico model of the patellofemoral joint was developed and validated. The model was used analyze the effect of lateral retinacular release in association with MPFL reconstruction on patellofemoral contact pressures, contact area, and lateral patellar displacement during knee flexion.
RESULTS: MPFL reconstruction alone results in restoration of patellofemoral contact pressures throughout the entire range of motion (0-90°), mimicking the results from healthy condition. The addition of the lateral retinacular release to the MPFL reconstruction resulted in significant reductions in both patellofemoral contact pressure and contact area. Lateral retinacular release resulted in more lateral patellar displacement during the mid-flexion knee range of motion.
CONCLUSIONS: Combination of lateral retinacular release with MPFL reconstruction in patients with increased TT-TG is not recommended as MPFL reconstruction alone for first-line management of recurrent patellar instability offers a greater biomechanical advantage and restoration of contact forces to resemble that of the healthy knee. The presented biomechanical data outlines the effect of concomitant MPFL reconstruction and lateral retinacular release to help guide surgical planning for patients with recurrent patellar instability due to malalignment.
PURPOSE: Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations (FGFR1-4) in pediatric cancers to inform future clinical trial design.
METHODS: Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed.
RESULTS: We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions (FGFR3::TACC3 [n = 3], FGFR1::TACC1 [n = 1], FGFR1::EBF2 [n = 1], FGFR1::CLIP2 [n = 1], and FGFR2::CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor.
CONCLUSION: In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.
»: Standard 3-view ankle radiographs are the first-line imaging modality for suspected neuropathic ankle fractures. Computed tomography is helpful to evaluate for concomitant osseous changes and soft-tissue infection.
»: Nonoperative management may be considered for low-demand, elderly, or comorbid patients for whom surgery and anesthesia are contraindicated. However, the presence of comorbidities alone should not necessarily preclude operative intervention. Given the overall poor results of nonoperative treatment in the neuropathic ankle fracture population, operative intervention may in fact be less risky to the patient.
»: The authors have 2 preferred treatment techniques. For cases in which the vascular supply and bone stock are adequate, open reduction and internal fixation (ORIF) with locking fixation for the fibula, a medial buttress/hook plate with lag screws for the medial malleolus, multiple syndesmotic screws for additional fixation even in the absence of a syndesmotic injury, and temporary transfixation Steinmann pins from the calcaneus into the tibia are used. For cases in which there is a concern for wound healing or previously failed ORIF, minimally invasive surgical tibiotalocalcaneal arthrodesis with a retrograde locked intramedullary nail is used.