Cabozantinib reverses multidrug resistance of human hepatoma HepG2/adr cells by modulating the function of P-glycoprotein.

BACKGROUND & AIMS: Cabozantinib, a small-molecule multitargeted tyrosine kinase inhibitor, has entered into a phase III clinical trial for the treatment of hepatocellular carcinoma (HCC). This study assessed the mechanistic effect of cabozantinib on the reversal of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). METHODS: CCK-8 assays and tumour xenografts were used to investigate the reversal of MDR in vitro and in vivo respectively. Substrate retention assays were evaluated by fluorescence microscope and flow cytometry. Western blotting was used to detect protein expression levels. mRNA expression was determined by qPCR. The ATPase activity of P-gp was investigated using Pgp-Glo(™) assay systems. The binding mechanism of cabozantinib to P-gp at the molecular level was evaluated using docking analysis. RESULTS: Cabozantinib enhanced the cytotoxicity of P-gp substrate drugs in HepG2/adr and HEK293-MDR1 cells but had no effect on non-P-gp substrates. In addition, cabozantinib increased the accumulation of P-gp substrates in HepG2/adr cells but had no effect in HepG2 cells. Furthermore, cabozantinib did not alter the expression of P-gp mRNA or protein but did stimulate the activity of P-gp ATPase. The docking study indicated that cabozantinib and verapamil may partially share a binding site on P-gp. The reversal concentrations of cabozantinib did not affect the expression of MET, AKT and ERK1/2. Significantly, cabozantinib increased the inhibitory efficacy of doxorubicin in P-gp-overexpressing HepG2/adr cell xenografts in nude mice. CONCLUSION: Cabozantinib reverses P-gp-mediated MDR by directly inhibiting the efflux function of P-gp, indicating that cabozantinib may help to reverse P-gp-mediated MDR in HCC and other cancer chemotherapy.

[Laparoscopic hepatectomy for recurrent hepatocellular carcinoma after previous open hepatectomy].

OBJECTIVE: To evaluate the feasibility, safety and long-term outcomes of laparoscopic repeat hepatectomy for recurrent hepatocellular carcinoma (HCC) following previous resection. METHODS: Between January 2003 and January 2011, 14 patients with recurrent HCC were carefully selected to undergo repeat laparoscopic hepatectomy, among which 9 patients were male, 5 patients were female, and the average age was 54 years. Prior to re-resection, all patients had undergone at least one open hepatectomy for HCC. The perioperative and long-term outcomes of these patients were retrospectively analyzed. RESULTS: Repeat laparoscopic hepatectomy for these 14 patients were successfully performed without major perioperative complications. The mean operative time, intraoperative blood loss and hospital stay were (124 ± 82) minutes, (112 ± 43) ml and (7 ± 4) days, respectively. The mean follow-up period was 23 months (range 14 to 42 months). At the time of follow-up, 11 patients were still alive, among which 3 patients developed recurrent disease and 8 patients remained disease free. One patient died of liver dysfunction at 21 months, and another 2 patients died of tumor recurrence at 17, 31 months, respectively. CONCLUSION: Laparoscopic surgery for recurrent HCC remains a viable option for repeat hepatectomy in selected patients who have undergone open hepatectomy.

Metal Nanogap Memory: Performances and Switching Mechanism.

The nanogap memory (NGM) device, emerging as a promising nonvolatile memory candidate, has attracted increasing attention for its simple structure, nano/atomic scale size, elevated operating speed, and robustness to high temperatures. In this study, nanogap memories based on Pd, Au, and Pt were fabricated by combining nanofabrication with electromigration technology. Subsequent evaluations of the electrical characteristics were conducted under ambient air or vacuum conditions at room temperature. The investigation unveiled persistent challenges associated with metal NGM devices, including (1) prolonged SET operation time in comparison to RESET, (2) the potential generation of error bits when enhancing switching speeds, and (3) susceptibility to degradation during program/erase cycles. While these issues have been encountered by predecessors in NGM device development, the underlying causes have remained elusive. Employing molecular dynamics (MD) simulation, we have, for the first time, unveiled the dynamic processes of NGM devices during both SET and RESET operations. The MD simulation highlights that the adjustment of the tunneling gap spacing in nanogap memory primarily occurs through atomic migration or field evaporation. This dynamic process enables the device to transition between the high-resistance state (HRS) and the low-resistance state (LRS). The identified mechanism provides insight into the origins of the aforementioned challenges. Furthermore, the study proposes an effective method to enhance the endurance of NGM devices based on the elucidated mechanism.

Fault feature extraction and fusion method for AUV with weak thruster fault based on variational mode decomposition and D-S evidence theory.

This study investigated the fault feature extraction and fusion problem for autonomous underwater vehicles with weak thruster faults. The conventional fault feature extraction and fusion method is effective when thruster faults are serious. However, for a weak thruster fault, that is, when the loss of effectiveness of thrusters is less than 10%, the following two problems occur if the conventional method is used. First, the ratio of fault features to noise features is small. Second, there is no monotonic relationship between the fusion fault features fused by the conventional method and the fault severity. In this paper, the following two methods are proposed to solve this problem: 1) Fault-feature extraction method. Based on negentropy, this method improves the evaluation index of the parameter optimization of the modified variational mode decomposition and finally enhances the fault features extracted by the modified Bayesian classification algorithm. 2) Fault-feature fusion method. To create a monotonic relationship between the fusion fault features and fault severity, this method expands the number of original signals of the traditional fusion method based on D-S evidence theory, improves the focus element of the traditional fusion method, and adopts the strategy of double fusion. Finally, the effectiveness of the proposed method was verified by pool-experiment results on Beaver II prototype.