Diagnosis and treatment of posterior shoulder dislocation combined with reverse Hill-Sachs lesion / 中华创伤骨科杂志

Objective:To explore the diagnosis and treatment of posterior shoulder dislocation combined with reverse Hill-Sachs lesion.Methods:Two male patients were treated at Department of Joint Surgery, Affiliated Hospital of Qingdao University for posterior shoulder dislocation combined with reverse Hill-Sachs lesion from August to November 2022. Case 1 was a 46-year-old man, admitted 1 day after right should injury, and case 2 a 57-year-old man, admitted 2 days after right should injury. The injury was caused by electric shock in both, and their fractures were fresh with an injury area>50%. After anatomical reduction of the collapsed humeral head via the pectoralis major deltoid approach, an artificial bone was implanted and fixated with countersunk screws in both cases to reduce the shoulder joint. The Constant-Murley scale and visual analogue scale (VAS) were used to evaluate the functional recovery of the shoulder and pain after treatment.Results:No such perioperative complications as incision infection, brachial plexus injury or vascular injury was observed in either of the 2 patients. Reexamination 3 months after surgery showed in case 1: 110° of shoulder anterior flexion, 90° of shoulder abduction, 30° of external rotation (neutral position), 70° of internal rotation (neutral position), 70 points of Constant-Murley shoulder score, and 3 points of VAS pain score; in case 2: 130° of shoulder anterior flexion, 120° of shoulder abduction, 50° of external rotation (neutral position), 80° of internal rotation (neutral position), 70 points of Constant-Murley shoulder score, and 2 points of VAS pain score.Conclusion:For patients with posterior shoulder dislocation complicated with reverse Hill-Sachs lesion and humeral head collapse greater than 50%, open reduction and screw internal fixation combined with artificial bone grafting can achieve good short-term curative efficacy.

Structure-based drug discovery of novel fused-pyrazolone carboxamide derivatives as potent and selective AXL inhibitors

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC50: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC50: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

Peptidomimetic-based antibody surrogate for HER2

Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on

Design, synthesis and biological evaluation of pyrazolo3,4-

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-

Inhibition of RPMI-8226 myeloma cell xenografted tumor angiogenesis by down-regulation of Notch1 / 国际肿瘤学杂志

Objective To investigate the effects of Notch1 siRNA on VEGF and angiogenesis of myeloma cell line RPMI-8226 in vitro and in vivo.Methods In vitro,Notch siRNA was transfected into RPMI-8226 cells,and then cell supernatant VEGF secretion was detected using ELISA method.Expression levels of Notch1 and VEGF proteins were assayed by Western blotting.RPMI-8226 cells were subcutaneously transplanted in NOD/SCID mice,and then the tumor mice were divided into three groups randomly:NS group (Notch1 siRNA-transfected group),CS group (Control siRNA-transfected group) and UN group (Untransfected group),and the changes of tumor volume were observed.Immunohistochemical staining was used to detect the changes in expression levels of Notch1,VEGF and CD34.Results Notch1 and VEGF proteins expressions of RPMI-8226 cells were significantly decreased by Notch1 siRNA.At 48 h and 72 h,VEGF secretion level in NS group was significantly different with CS group [(120 ± 25) ng/L ∶ (175 ± 15) ng/L,t =3.27,P ＜ 0.05;(145 ± 24)ng/L ∶ (295 ± 17)ng/L,t =8.83,P＜0.01].At 13 d,17 d and 21 d,tumor volume in NS group was significantly reduced,that was significantly different with CS group [(1 548 ± 218) mm3 ∶ (1 820 ± 64) mm3,t =2.68,P ＜0.05;(1 200 ±75)mm3 ∶ (2 180 ±84)mm3,t =19.46,P＜0.01;(1 150 ±88)mm3 ∶ (2 250 ± 145)mm3,t =14.50,P ＜0.01].The expression levels of Notch1 and VEGF protein were decreased by Notch1 siRNA.The expression levels of Notchl and VEGF in NS group were different with CS group [(16.33 ±2.52)％∶ (75.33 ±2.52)％,t=28.71,P＜0.01;(5.00±1.00)％∶29.67±2.08 ％,t=18.50,P ＜ 0.01].Notch1 siRNA reduced the number of transplanted tumor neovascularization in NS group.Microvascular density in NS group was significantly less than that in CS group [(14.67 ± 2.52) ∶ (30.00 ± 5.00),t =4.74,P ＜ 0.01].Conclusion In vitro,Notch siRNA reduces human myeloma cell RPMI-8226 cell supernatant VEGF secretion.In vivo,Notch siRNA can reduce tumor volume and the number of new blood vessels in transplanted-multiple myeloma mice.Thus,Notchl is an effective molecular target for anti-angiogenesis in myeloma.