Functional outcomes and complications after treatment of distal radius fracture in patients sixty years and over: A systematic review and network meta-analysis

AimThis network meta-analysis aims to compare functional outcomes and complications between conservative treatment and surgery for distal radius fractures in patients aged 60 years and over.MethodsWe searched the PubMed, EMBASE, and Web of Science databases for randomized controlled trials (RCTs) assessing the effect of conservative treatment and surgery for distal radius fractures in patients aged 60 years and over. Primary outcomes included grip strength and overall complications. Secondary outcomes included Disabilities of the Arm, Shoulder, and Hand (DASH) scores, Patient-Rated Wrist Evaluation (PRWE) scores, wrist range of motion and forearm rotation, and radiographic assessment. All continuous outcomes were assessed using standardized mean differences (SMDs) with 95% confidence intervals (CIs), and binary outcomes were assessed using odds ratio (OR) with 95% CIs. The surface under the cumulative ranking curve (SUCRA) was used to determine a hierarchy of treatments. Cluster analysis was performed for grouping treatments based on the SUCRA values of primary outcomes.ResultsFourteen RCTs were included to compare conservative treatment, volar lockedplate (VLP), K-wires fixation, and external-fixation. VLP outperformed conservative treatment for 1-year and minimum 2-year grip strength (SMD; 0.28 [0.07 to 0.48] and 0.27 [0.02 to 0.53], respectively). VLP yielded the optimal grip strength at 1-year and minimum 2-year follow-up (SUCRA; 89.8% and 86.7%, respectively). In a subgroup analysis of patients aged 60 to 80 years old, VLP outperformed conservative treatment in DASH and PRWE scores (SMD, 0.33 [0.10, 0.56] and 0.23 [0.01, 0.45], respectively). In addition, VLP had the fewest complications (SUCRA = 84.3%). Cluster analysis suggested that VLP and K-wire fixation were more effective treatment groups.ConclusionEvidence to date demonstrates that VLP provides measurable benefits in grip strength and fewer complications to those 60 years of age and over, and that benefit is not reflected in current practice guidelines. There is a subgroup of patients where K-wire fixation outcomes are similar to those of VLP; defining this subgroup may yield substantial societal benefits.     

洛克米兰醇对肝癌HepG2细胞的抗增殖作用及其机制研究

目的研究传统中药米仔兰Aglaiaodorata中洛克米兰醇对肝癌细胞HepG2增殖的影响及抗肿瘤作用机制。方法 MTT、细胞克隆形成、EdU染色和CFDA染色方法考察洛克米兰醇对HepG2细胞的抗增殖效果;流式细胞仪检测洛克米兰醇对HepG2细胞细胞周期和细胞凋亡的变化;Western blotting检测洛克米兰醇对细胞周期调控蛋白和丝裂原活化蛋白激酶(MAPK)信号通路相关蛋白表达的影响。结果洛克米兰醇可以时间和浓度依赖性抑制HepG2细胞增殖。同等浓度下洛克米兰醇抗HepG2细胞增殖的效果好于阿霉素,而对正常肝细胞(L02)的毒性弱于阿霉素。流式细胞技术检测发现洛克米兰醇给药48 h能够诱导HepG2细胞G_2/M期细胞周期阻滞,但不诱导细胞凋亡。Western blotting研究发现该化合物抑制调控G_2/M周期相关蛋白cdc25C、cdc2和cyclin B1的表达并且激活细胞外调节蛋白激酶(ERK)和c-Jun氨基末端激酶(JNK)。对其机制深入研究发现,ERK抑制剂(U0126)可以部分逆转洛克米兰醇对HepG2的抗增殖和G_2/M周期阻滞及其抑制蛋白cdc25C和cdc2表达的效果。结论洛克米兰醇在抑制肝癌细胞增殖的效果和对正常肝细胞的选择性方面优于阿霉素。洛克米兰醇能够通过过度活化ERK,从而引起HepG2细胞G_2/M周期阻滞而达到抗增殖效果。     

双吲哚马来酰亚胺衍生物L6诱导白血病细胞凋亡机制的研究

目的探讨双吲哚马来酰亚胺衍生物L6诱导白血病细胞的凋亡作用及其分子机制。方法采用MTT比色法检测L6对白血病细胞HEL、K562、KG1a的杀伤作用。流式细胞术检测L6对HEL细胞凋亡、周期和分化的影响。Western blotting法检测细胞凋亡相关蛋白的表达。通过体内实验研究L6治疗小鼠白血病的作用效果。结果 MTT比色法结果显示L6对HEL、K562、KG1a细胞具有比阳性对照米哚妥林(PKC412)更显著的抑制活性,半数抑制浓度(IC50)分别为(0.05±0.03)、(0.32±0.01)、(0.19±0.10)μmol/L。L6可以诱导HEL细胞发生凋亡和G2/M期阻滞,诱导HEL细胞向巨核细胞方向分化,且呈剂量效应。Western blotting检测结果表明L6主要通过激活Caspase-3执行细胞凋亡。小鼠肝组织苏木精-伊红(HE)染色显示肝组织内HEL细胞浸润有所减轻,但L6组减轻的效果更明显,表明其可延缓白血病细胞的转移,且效果优于米哚妥林。结论双吲哚马来酰亚胺衍生物L6有较强的抗白血病活性,为新型白血病药物的研发提供参考。     

Frequency and Association Of GSTM1 and GSTT1 Gene Polymorphisms with Survival in Breast Cancer Patients

Objective: Glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) are the key detoxification enzymes of xenobiotics, including chemotherapeutic drugs. The deletion polymorphisms of GSTM1 and GSTT1 genes are associated with reduced enzyme activity that influenced clinical outcomes of chemotherapeutic agents in breast cancer. However, there is limited information among Thai patients. This research aims to explore the frequency and role of GSTM1 and GSTT1 polymorphisms on survival among Thai patients with breast cancer. Methods: The retrospective cohort study was performed. Demographic data and clinicopathology characteristics were collected from hospital base registry data and medical records. A multiplex qualitative real-time PCR method was used to detect the presence or absence of the GSTM1 and GSTT1 gene in the genomic DNA samples of the participants. Results: The frequencies of the GSTM1 and GSTT1 null genotypes in 198 breast cancer patients were 65.70% and 33.30%, respectively. The overall survival at 1, 3 and 5 years were 95.00%, 83.00%, 71.00% respectively. The log rank test and Cox proportional hazards revealed a significant different in the 5-years overall survival according to lymph node metastasis and tumor stage (P = 0.014 and P < 0.001). No associations between overall survival and GSTM1 or GSTT1 genotype were found in single or combined genotypes analyses (P = 0.76 and P= 0.15). Conclusion: The results of our study provided the epidemiological information for prognostic of survival in breast cancer patients treated with chemotherapy.     

Bintrafusp Alfa,a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial

IntroductionThe safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β) receptor II (a TGF-β “trap“) fused to a human immunoglobulin G1 antibody blocking programmed death-ligand 1 (PD-L1), was evaluated in patients with advanced NSCLC.MethodsThis expansion cohort of NCT02517398, an ongoing, phase 1, open-label trial, includes 80 patients with advanced NSCLC that progressed after platinum doublet therapy or after platinum-based adjuvant or neoadjuvant treatment and those who also have not received previous immunotherapy. Patients were randomized at a one-to-one ratio to receive either bintrafusp alfa 500 mg or the recommended phase 2 dosage of 1200 mg every 2 weeks. The primary end point was the best overall response (by Response Evaluation Criteria in Solid Tumors 1.1 as adjudicated by independent review committee) and was assessed by the objective response rate (ORR).ResultsA total of 80 patients were randomized to receive bintrafusp alfa 500 or 1200 mg (n = 40 each). Median follow-up was 51.9 weeks (IQR, 19.6–74.0). The ORR in all patients was 21.3% (17 of 80). The ORR was 17.5% (seven of 40) and 25.0% (10 of 40) for the 500 mg dose and the 1200 mg dose (recommended phase 2 dose), respectively. At the 1200 mg dose, patients with PD-L1–positive and PD-L1–high (≥80% expression on tumor cells) had ORRs of 36.0% (10 of 27) and 85.7% (six of seven), respectively.Treatment-related adverse events occurred in 55 of the 80 patients (69%) and were graded as greater than or equal to 3 in 23 of the 80 patients (29%). Of the 80 patients, eight (10%) had a treatment-related adverse event that led to treatment discontinuation; no treatment-related deaths occurred.ConclusionsBintrafusp alfa had encouraging efficacy and manageable tolerability in patients with NSCLC previously treated with platinum.     

Deoxyelephantopin decreases the release of inflammatory cytokines in macrophage associated with attenuation of aerobic glycolysis via modulation of PKM2

Growing evidence suggests that activated immune cells undergo metabolic reprogramming in the regulation of the innate inflammatory response. Remarkably, macrophages activated by lipopolysaccharide (LPS) induce a switch from oxidative phosphorylation to aerobic glycolysis, and consequently results in release of proinflammatory cytokines. Pyruvate Kinase M2 (PKM2) plays a vital role in the process of macrophage activation, promoting the inflammatory response in sepsis and septic shock. Deoxyelephantopin (DET), a naturally occurring sesquiterpene lactone from Elephantopus scaber, has been shown to counteracts inflammation during fulminant hepatitis progression, but the underlying mechanism remains unclear. Here, we studied the function of the DET on macrophage activation and investigated the anti-inflammatory effects of DET associated with interfering with glycolysis in macrophage. Our results first demonstrated that DET attenuates LPS-induced interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1) release in vitro and in vivo and protected mice against lethal endotoxemia. Furthermore, DET decreased the expression of pyruvate dehydrogenase kinase 1 (PDK1), glucose transporter 1(GLUT1), lactate dehydrogenase A (LDHA), and reduced lactate production dose-dependently in macrophages. Moreover, we further revealed that DET attenuates aerobic glycolysis in macrophages associated with regulating the nuclear localization of PKM2. Our results provided a novel mechanism for DET suppression of macrophages activation implicated in anti-inflammatory therapy.