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Background: Radical laparoscopic gastrectomy is an important treatment modality for gastric cancer. Surgery requires general anesthesia, and patients are susceptible to the effects of anesthetic drugs and carbon dioxide insufflation during the procedure, leading to inflammation or severe pain, which can affect patient outcome., Aim: To explore the efficacy of combining dexmedetomidine (DEX) with nalbuphine in patients underwent laparoscopic radical gastrectomy for gastric cancer., Methods: Patients scheduled to undergo laparoscopic radical gastrectomy were selected and randomly assigned to A or B group. In A group, patients received an intravenous injection of nalbuphine 0.2 mg/kg + DEX 0.4 μg/kg 10 min before the end of surgery; in B group, patients received only an intravenous injection of nalbuphine. The trends in hemodynamic parameter fluctuations, awakening quality during the recovery period, serum inflammatory markers, agitation scores, cough severity, incidence, and duration of postoperative delirium (POD) were compared., Results: The mean arterial pressure and heart rate in the A group were more stable ( P < 0.05). The A group had a lower average awakening time, extubation time, and agitation scores during recovery than the B group. Agitation control in the A group was more effective at different time points ( P < 0.05). Patients in the A group had lower serum interleukin (IL)-6, tumour necrosis factor alpha, and IL-10 levels at 1 h after surgery than the B group. The incidence of coughing and duration of POD were lower and shorter in the A group than in the B group. Adverse reactions caused by the two anesthesia methods were less frequent in the A group than in the B group ( P < 0.05)., Conclusion: The use of DEX and nalbuphine in patients undergoing laparoscopic radical gastrectomy for gastric cancer help reducing the inflammatory response, cough severity, and agitation and helps maintain hemodynamic stability., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Many recent studies have uncovered the necessary role for the receptor-interacting protein kinase 1 (RIP1) in regulating apoptosis and necrosis that cells undergo in response to various cellular stresses. However, the functional significance of RIP1 in promoting cancer cells survival remains poorly understood. Here, we report that RIP1 was upregulated and contributed to both intrinsic and acquired resistance of melanoma cells to BRAF/MEK inhibitors through activation of NF-κB. Strikingly, Snail1-mediated suppression of CYLD played a crucial role in promoting RIP1 expression upon ERK activation, particularly, in melanoma cells with acquired resistance to BRAF inhibitors. In addition, RIP1 kinase activity was not required for melanoma cells to survive BRAF/MEK inhibition as RIP1 mediated NF-κB activation through its intermediate domain. Collectively, our findings reveal that targeting RIP1 in combination with BRAF/MEK inhibitors is a potential approach in the treatment of the disease.

The effect of MTH1 inhibition on cancer cell survival has been elusive. Here we report that although silencing of MTH1 does not affect survival of melanoma cells, TH588, one of the first-in-class MTH1 inhibitors, kills melanoma cells through apoptosis independently of its inhibitory effect on MTH1. Induction of apoptosis by TH588 was not alleviated by MTH1 overexpression or introduction of the bacterial homolog of MTH1 that has 8-oxodGTPase activity but cannot be inhibited by TH588, indicating that MTH1 inhibition is not the cause of TH588-induced killing of melanoma cells. Although knockdown of MTH1 did not impinge on the viability of melanoma cells, it rendered melanoma cells sensitive to apoptosis induced by the oxidative stress inducer elesclomol. Of note, treatment with elesclomol also enhanced TH588-induced apoptosis, whereas a reactive oxygen species scavenger or an antioxidant attenuated the apoptosis triggered by TH588. Indeed, the sensitivity of melanoma cells to TH588 was correlated with endogenous levels of reactive oxygen species. Collectively, these results indicate that the cytotoxicity of TH588 toward melanoma cells is not associated with its inhibitory effect on MTH1, although it is mediated by cellular production of ROS., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Oncogenic mutations of BRAF occur in approximately 10% of colon cancers and are associated with their resistance to clinically available therapeutic drugs and poor prognosis of the patients. Here we report that colon cancer cells with mutant BRAF are also resistant to the heat shock protein 90 (HSP90) inhibitor AUY922, and that this is caused by rebound activation of ERK and Akt. Although AUY922 triggered rapid reduction in ERK and Akt activation in both wild-type and mutant BRAF colon cancer cells, activation of ERK and Akt rebounded shortly in the latter leading to resistance of the cells to AUY922-induced apoptosis. Reactivation of ERK was associated with the persistent expression of mutant BRAF, which, despite being a client of HSP90, was only partially degraded by AUY922, whereas reactivation of Akt was related to the activity of the HSP90 co-chaperone, cell division cycle 37 (CDC37), in that knockdown of CDC37 inhibited Akt reactivation in mutant colon cancer cells treated with AUY922. In support, as a HSP90 client protein, Akt was only diminished by AUY922 in wild-type but not mutant BRAF colon cancer cells. Collectively, these results reveal that reactivation of ERK and Akt associated respectively with the activity of mutant BRAF and CDC37 renders mutant BRAF colon cancer cells resistant to AUY922, with implications of co-targeting mutant BRAF and/or CDC37 and HSP90 in the treatment of mutant BRAF colon cancers., Competing Interests: No potential conflicts of interest were disclosed.