Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination.

Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C-α-SG protein. We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C-α-SG degradation inhibition. Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.

Adolescent idiopathic scoliosis: evaluating perioperative back pain through a simultaneous morphological and biomechanical approach.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) has been associated with diminished postural stability and a greater prevalence of back pain. Currently, the literature is lacking information on the effect of spinal fusion on both postural stability and its association with back pain. Our objectives were to evaluate the postsurgical effect of spinal morphological changes on static standing balance and assess the influence of these alterations on reported pain throughout the perioperative period. METHODS: Twenty consecutive AIS patients schedule to undergo spinal fusion surgery were recruited and followed prospectively at the Shriners Hospitals for Children-Canada. Data was collected at the preoperative, 6 weeks and 6 months postoperative visits. Spinal morphology data was collected through 3D reconstructed simultaneous standing biplanar radiographs using the SterEOS software. Postural balance was assessed through Moticon© sensor insoles and analyzed through their software. The data was simultaneously collected as part of the Global Biomechanical and morphological Assessment. Pain was evaluated through self-reported questionnaires. RESULTS: Morphological curve parameters were significantly reduced after surgery. Balance parameters did not change significantly throughout the perioperative period with the exception of the Center of Pressure of the left foot medial/lateral transient shift (P = 0.017) at 6 weeks. Of note, preoperative balance parameters were associated with the degree of right thoracic Cobb angles (P = 0.029 R = 0.528). Pain scores significantly improved 6 weeks and 6 months after the surgery. Pain intensity diminished in the thoracic and lumbar spine but worsen in the neck region at the 6 weeks and 6 months postoperative time points (P = 0.044). Greater residual Cobb angle difference between Mid thoracic and Thoracolumbar/Lumbar curves was associated with greater pain severity at 6 weeks postop (P < 0.005). In addition, greater residual thoracic deformity was associated with significant pain severity 6 months after surgery (P < 0.05). CONCLUSIONS: Improved spinal morphology of postsurgical AIS patients has no significant impact on their static standing balance. Suggesting that other factors apart from the spinal morphology may contribute to AIS patients' balance during stance. Although balance did not influence pain severity, spinal morphology and its correction appear to have influenced the intensity and location of back pain.

Back pain in adolescents with idiopathic scoliosis: the contribution of morphological and psychological factors.

PURPOSE: To define the relationship between 3D radiological features, psychological factors, and back pain prevalence and intensity in patients with adolescent idiopathic scoliosis (AIS). METHODS: Consecutive AIS patients answered self-reported questionnaires and underwent simultaneous posterior-anterior and lateral scans of the spine (EOS Imaging, Paris, France). 3D reconstructions of the spine and pelvis reported 18 parameters in the coronal, sagittal, and axial plane. RESULTS: Hundred and twenty-four patients with AIS were included in the study. Overall, 90% of AIS patients reported having some back pain over the last 6 months and 85.8% over the last 30 days. Pain intensity in the last month was reported to be mild in 37.5%, moderate in 31.8%, moderate to severe in 24.3%, and severe in 6.54% of cases. Location of back pain was associated with location of main curve (P = 0.036). Low back pain was associated with higher lumbar apical AVR and lower lumbar lordosis (P < 0.05). Independent risk factors for back pain in AIS were pain catastrophizing (B = 0.061, P = 0.035), poorer self-reported state of mental health (B = - 0.872, P = 0.023), decreased thoracic kyphosis (B = - 0.033, P = 0.044) and greater pelvic asymmetry (B = 0.146, P = 0.047). There was a significant association between self-reported pain intensity in the last 24 h and levels of catastrophizing. Pain catastrophizing level influenced the relationship between deformity severity and pain intensity. In low catastrophizers, there was a significant association between greater deformity severity and higher pain levels. CONCLUSIONS: Back pain in AIS is multifactorial and associated with psychological and morphological parameters. Pain catastrophizing is an important construct in AIS-related pain and should be taken into consideration when evaluating these patients.

Expression pattern of the homeotic gene Bapx1 during early chick gastrointestinal tract development.

Regulation of the Bone Morphogenetic Protein (BMP) signaling pathway is essential for the normal development of vertebrate gastrointestinal (GI) tract, but also for the differentiation of the digestive mesenchymal layer into smooth muscles and submucosal layer. Different studies demonstrated that Bapx1 (for bagpipe homeobox homolog 1) negatively regulates the BMP pathway, but its precise expression pattern during the development and the differentiation of the GI tract mesenchyme actually remains to be examined. Here, we present the spatio-temporal expression profile of Bapx1 in the chick GI tract. We show that Bapx1 is first expressed in the undifferentiated mesenchyme of the gizzard and the colon. After the differentiation of the digestive mesenchyme, we found Bapx1 strongly expressed in the gizzard smooth muscle and in the submucosa layer of the colon. This expression pattern provides new insights into the roles of Bapx1 during the regionalization of the GI tract and the differentiation of the digestive mesenchyme of the colon and the stomach.