BackgroundTargeting TopoisomeraseII (TopoII) and generate enzyme mediated DNA damage is an effective strategy for treatment of breast cancer. TopoII is known as a validated target for drug discovery and cancer chemotherapy.MethodsXWL-1-48, a new orally podophyllotoxin derivative, was designed and synthesized. The effect of XWL-1-48 on TopoII binding and activity was determined by molecular docking software and kDNA-decatenation assay, respectively. In vitro and in vivo breast cancer models were used to document the antitumor activity of XWL-1-48. Cellular apoptosis, cell cycle and ROS were analyzed by flow cytometry. Alteration of XWL-1-48-mediated downstream pathways was determined by western blot analysis.ResultsThe cytotoxicity of XWL-1-48 is more potent than that of its congener GL331. Molecular docking demonstrated that XWL-1-48 could bind to TopoII through forming two strong hydrogen bonds and potential pi-pi interactions. Noticeably, XWL-1-48 exerts potent antitumor activity in in vitro and in vivo breast cancer model. Treatment with XWL-1-48 caused ROS generation and triggered DNA damage through induction of γ-H2AX and activation of ATM/p53/p21 pathway. Further studies showed that XWL-1-48 led to S-phase arrest and mitochondrial apoptosis. Meanwhile, XWL-1-48 significantly blocked PI3K/Akt/Mdm2 pathway and enhanced Mdm2 degradation.ConclusionXWL-1-48 may be a promising orally topoII inhibitor, its mechanisms are associated with suppression of TopoII, induction of DNA damage and apoptosis, blockage of PI3K/AKT/Mdm2 pathway.

There are inconsistent results regarding the efficacy and safety of intermittent epidural bolus (IPB) versus continuous epidural infusions (CPI) for labor analgesia. This study used a meta-analytic approach to assess the safety and treatment efficacy of IPB versus CPI for labor analgesia based on randomized controlled trials (RCTs). Four electronic databases were used to identify eligible RCTs. Pooled effect estimates at 95% confidence intervals (CIs) were calculated using a random-effects model. Twenty-two RCTs with 2,573 parturients were selected for final analysis. The findings revealed no significant differences between IPB and CPI for the incidences of cesarean and instrumental delivery. IPB was shown to be associated with shorter total duration of labor [weighted mean difference (WMD): −21.46; 95% CI: −25.07 to −17.85; P < 0.001], duration of the first of stage of labor (WMD: −13.41; 95% CI: −21.01 to −5.81; P = 0.001), and duration of the second stage of labor (WMD: −4.98; 95% CI: −9.32 to −0.63; P = 0.025). Furthermore, IPB significantly reduced the incidences of required anesthetic interventions compared with CPI [relative risk (RR): 0.61; 95% CI: 0.39-0.95; P = 0.030], whereas there was no significant difference between IPB and CPI for the time required in the first anesthetic intervention (WMD: 7.73; 95% CI: −33.68-49.15; P = 0.714). The local anesthetic IPB (bupivacaine equivalents) was associated with lower milligrams per hour of local anesthetic (WMD: −0.89; 95% CI: −1.41 to −0.36; P = 0.001) and better maternal satisfaction (WMD: 8.76; 95% CI: 4.18-13.35; P < 0.001). There were no significant differences between IPB and CPI for the risk of adverse events. This study found that parturients with IPB have short total duration of labor and duration of the first and second stage of labor, reduced requirements for additional anesthetic interventions, and improved maternal satisfaction.

Background: Inconsistent results have been obtained regarding postoperative pain control using local infiltration and epidural analgesia for patients after total knee or hip arthroplasty (TKA and THA). We therefore conducted a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of local infiltration vs epidural analgesia for TKA and THA. Methods: Electronic searches were conducted on PubMed, EmBase, and the Cochrane library to identify eligible RCTs conducted up to February 2020. Weighted mean difference (WMD) and relative risk with 95% confidence interval (95%CI) were applied to calculate pooled effect estimates between local infiltration and epidural analgesia using the random-effects model. Results: Seven RCTs including a total of 412 TKA patients, and three RCTs including a total of 200 THA patients were selected for this meta-analysis. We noted that local infiltration was associated with lower visual analog scale (VAS) scores at rest after 48 hours (WMD: −1.31; 95%CI: −2.44 to −0.18; P = .024) and 72 hours (WMD: −0.95; 95%CI: −1.39 to −0.52; P < .001) for patients with TKA, while local infiltration significantly reduced VAS scores at rest after 12 hours for patients with THA (WMD: −1.00; 95%CI: −1.49 to −0.51; P < .001). Moreover, local infiltration was associated with lower VAS scores during movement after 48 hours in TKA patients (WMD: −1.08; 95%CI: −1.86 to −0.29; P = .007), while there were higher VAS scores during movement after 24 hours for patients with THA (WMD: 1.06; 95%CI: 0.67 to 1.45; P < .001). Furthermore, we noted that local infiltration was associated with higher flexion angles compared with epidural analgesia after 24 hours (WMD: 7.11; 95%CI: 2.30–11.93; P = .004), 48 hours (WMD: 6.69; 95%CI: 3.78 to 9.59; P < .001), and 72 hours (WMD: 5.19; 95%CI: 0.95–9.44; P = .016). There were no significant differences between local infiltration and epidural analgesia for the length of hospital stay, nausea, or wound infection. Conclusions: Local infiltration is superior to epidural analgesia for postoperative pain control after TKA, whereas for THA patients inconsistent results were obtained at various times.