Phenotyping rare cftr mutations reveal functional expression defects restored by trikaftatm

The rare Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, c.1826A > G (H609R) and c.3067_3072delATAGTG (I1023_V1024del), are associated with severe lung disease. Despite the existence of four CFTR targeted therapies, none have been approved for individuals with these mutations because the associated molecular defects were not known. In this study we examined the consequences of these mutations on protein processing and channel function in HEK293 cells. We found that, similar to F508del, H609R and I1023_V1024del-CFTR exhibited reduced protein processing and altered channel function. Because the I1023_V1024del mutation can be linked with the mutation, I148T, we also examined the protein conferred by transfection of a plasmid bearing both mutations. Interestingly, together with I148T, there was no further reduction in channel function exhibited by I1023-V1024del. Both H609R and I1023_V1024del failed to exhibit significant correction of their functional expression with lumacaftor and ivacaftor. In contrast, the triple modulator combination found in TRIKAFTA™, i.e., tezacaftor, elexacaftor and ivacaftor rescued trafficking and function of both of these mutants. These in-vitro findings suggest that patients harbouring H609R or I1023_V1024del, alone or with I148T, may benefit clinically from treatment with TRIKAFTA™

Olive Leaf Extract (OLE) as a Novel Antioxidant That Ameliorates the Inflammatory Response in Cystic Fibrosis

The deletion of phenylalanine at position 508 (F508del) produces a misfolded CFTR protein that is retained in the ER and degraded. The lack of normal CFTR channel activity is associated with chronic infection and inflammation which are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. Moreover, LPS-dependent oxidative stress downregulates CFTR function in airway epithelial cells. Olive leaf extract (OLE) is used in traditional medicine for its effects, including anti-oxidant and anti-inflammatory ones. We found that OLE decreased the intracellular ROS levels in a dose-response manner in CFBE cells. Moreover, OLE attenuates the inflammatory response to LPS or IL-1 beta/TNF alpha stimulation, mimicking the infection and inflammatory status of CF patients, in CFBE and primary nasal epithelial (HNE) cells. Furthermore, we demonstrated that OLE restored the LPS-mediated decrease of Trikfafta (TM)-dependent F508del-CFTR function in CFBE and HNE cultures. These findings provide strong evidence of OLE to prevent redox imbalance and inflammation that can cause chronic lung damage by enhancing the antioxidant activity and attenuating inflammation in CF airway epithelial cells. Additionally, OLE might be used in combination with CFTR modulators therapy to improve their efficacy in CF patients

Combined radius addition osteotomy and ulnar shortening to correct extra-articular distal radius fracture malunion with severe radial deviation and ulnar plus

Malunion can occur in 11 to 28% of Distal Radius Fractures and can result in radius shortening and ulnar plus with wrist deviation, pain and disability. We aimed to report particular cases of extra-articular distal radius fracture malunion with severe radial deviation and ulnar plus treated by corrective osteotomy of distal radius with bone graft associated to ulnar procedure. One of these patients was firstly operated with ulna subtraction osteotomy synthesized with plate and in a second stage with distal radius corrective addition osteotomy with homologous bone graft, plate and external fixator. Two other cases were treated in a single-step by radius addition osteotomy and caput ulnae Darrach resection. These three patients were followed-up from 2 to 12 years, successfully observing the maintenance of anatomical correction and recovery of ROM and strength with good pain relief and return to daily activities. After Darrach procedure external-fixation wasn’t needed and pronation-supination was better. Darrach procedure can solve ulna plus and improve ROM in pronationsupination with a quicker healing, avoiding the risk of ulnar non-union. Darrach’s procedure associated to addition corrective osteotomy of distal radius can be a valid treatment for distal radius severe malunion, in patients with low-moderate functional demand. In conclusion, the surgeon should choose the right corrective treatment after the complete evaluation of the patient and his functional needs. (www.actabiomedica.it)