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Excessive oxidative stress will cause significant injury to osteoblasts, serving as one major pathological mechanism of osteoporosis. Neuroligin-3 (NLGN3) is a postsynaptic cell adhesion protein and is expressed in the bone. We here explored its potential activity against hydrogen peroxide (H 2 O 2)-induced oxidative injury in cultured osteoblasts. In primary murine and human osteoblasts, NLGN3 stimulation dose-dependently induced Akt, Erk1/2 and S6K activation. NLGN3 pretreatment ameliorated H 2 O 2 -induced cytotoxicity and death in osteoblasts. Moreover, H 2 O 2 -induced reactive oxygen species (ROS) production and oxidative injury were alleviated with NLGN3 pretreatment in cultured osteoblasts. Further studies showed that NLGN3 activated Nrf2 signaling cascade and induced Nrf2 protein Serine-40 phosphorylation, Keap1-Nrf2 dissociation, Nrf2 protein stabilization and nuclear translocation in osteoblasts. NLGN3 also increased antioxidant response element (ARE) activity and induced expression of Nrf2-ARE-dependent genes (HO1 , GCLC and NQO1) in osteoblasts. Moreover NLGN3 mitigated osteoblast oxidative injury by dexamethasone or sodium fluoride (NaF). Nrf2 cascade activation is essential for NLGN3-induced cytoprotective activity in osteoblasts. Nrf2 shRNA or knockout (KO) abolished NLGN3-induced osteoblast cytoprotection against H 2 O 2. Contrarily forced Nrf2 cascade activation by Keap1 KO mimicked NLGN3-induced anti-oxidative activity in murine osteoblasts. Importantly, NLGN3-induced Serine-40 phosphorylation and Nrf2 cascade activation were blocked by an Akt inhibitor MK-2206 or by Akt1 shRNA. Importantly, Akt inhibition, Akt1 silencing or Nrf2 S40T mutation largely inhibited NLGN3-induced osteoblast cytoprotection against H 2 O 2. At last, we showed that NLGN3 mRNA and protein expression was significantly downregulated in necrotic bone tissues of dexamethasone-taken patients. Taken together, NLGN3 activated Akt-dependent Nrf2 cascade to protect osteoblasts from oxidative stress. [Display omitted] • NLGN3 activates Akt-dependent Nrf2 cascade in osteoblasts. • NLGN3 ameliorates H 2 O 2 -induced oxidative injury in osteoblasts. • NLGN3 protects osteoblasts from oxidative stress. • NLGN3 is decreased in necrotic bone tissues of DEX-taken patients. [ABSTRACT FROM AUTHOR]

To compare the efficacy and complications of ultrasound-guided percutaneous radiofrequency ablation of hepatocellular carcinoma (HCC) in the hepatocaval confluence with those of HCC in the non-hepatocaval confluence and to explore the risk factors that lead to radiofrequency ablation failure and patient local tumor progression (LTP). From January 2017 to January 2022, 86 patients with HCC in the hepatocaval confluence who had radiofrequency ablation were included. A 1:1 propensity-matched group of patients with HCC in the non-hepatocaval confluence with comparable clinical baseline traits, such as tumor diameter and tumor number, served as the control group. The two groups' complications, primary efficacy rate (PER), technical success rate (TSR), and prognosis were estimated. After PSM, no significant difference of TSR (91.7% vs 95.8%, p = 0.491) and PER (95.8% vs 97.2%, p = 1.000) and 1-, 3-, and 5-year LTP rate (12.5% vs 9.9%, 28.2% vs 27.7%, 40.8% vs 43.8%, p = 0.959) and 1-, 3-, and 5-year DFS rate (87.5% vs 87.5%, 62.3% vs 54.2%, 18.1% vs 22.6%, p = 0.437) and 1-, 3-, and 5-year OS rate (94.3% vs 95.7%, 72.7% vs 69.6%, 20.9% vs 33.6%, p = 0.904) was detected between the two groups. The tumor-to-IVC distance was an independent risk factor for radiofrequency ablation failure in HCC patients in the hepatocaval confluence (OR = 0.611, p = 0.022). Besides, tumor diameter was an independent risk factor for predicting LTP in patients with HCC in the hepatocaval confluence (HR = 2.209, p = 0.046). HCC in the hepatocaval confluence can be effectively treated with radiofrequency ablation. To maximize treatment efficacy, the tumor-to-IVC distance and tumor diameter should be assessed before the operation begins. [ABSTRACT FROM AUTHOR]

This study aimed to assess the outcome of a modified two-stage flexor tendon reconstruction using silicone tubes as antiadhesion devices while performing simultaneous tendon grafting. From April 2008 to October 2019, 16 patients (21 fingers) with zone II flexor tendon injuries, who sustained failed tendon repair or neglected tendon laceration, were treated by a modified two-stage flexor tendon reconstruction. The first stage of treatment comprised flexor tendon reconstruction with interposition of silicone tubes to minimize fibrosis and adhesion around the tendon graft; the second stage of treatment comprised silicone tube removal under local anesthesia. The patient median age was 38 (range, 22–65) years. After a median follow-up period of 14 (range, 12–84) months, the median total active motion (TAM) of fingers was 220° (range, 150–250°). Excellent and good TAM ratings were identified in 71.4%, 76.2%, and 76.2% according to the Strickland, modified Strickland, and American Society for Surgery of the Hand (ASSH) evaluation systems, respectively. At follow-up, complications included superficial infections in two fingers of one patient whose silicone tube was removed 4 weeks postoperatively. The most common complication was a flexion deformity of the proximal interphalangeal joint (four fingers) and/or distal interphalangeal joint (nine fingers). The rate of failed reconstruction was higher in patients with preoperative stiffness and infection. Silicone tubes are suitable antiadhesion devices, and the modified two-stage flexor tendon reconstruction technique is an alternative procedure with a shorter rehabilitation period for complicated flexor tendon injury, compared with current popular reconstructions. Preoperative stiffness and postoperative infection may compromise the final clinical outcome. Therapeutic IV. [ABSTRACT FROM AUTHOR]

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS -mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS -mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS -driven NSCLC. Mitochondrial oxidative phosphorylation induction was a major metabolic rewiring event to confer KRAS -mutant NSCLC resistance to MEK inhibitors. [Display omitted] [ABSTRACT FROM AUTHOR]