PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. METHODS: RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. RESULTS: PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. CONCLUSIONS: PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

The optimal dose of dexmedetomidine as a 0.59% ropivacaine adjuvant for epidural anesthesia in great saphenous varicose vein surgery, based on hemodynamics and anesthesia efficacy: a randomized, controlled, double-blind clinical trial.

Objective: This study aimed to explore the optimal dose of dexmedetomidine as a 0.59% ropivacaine adjuvant for epidural anesthesia on perioperative hemodynamics and anesthesia efficacy in patients undergoing great saphenous varicose vein surgery. Methods: A total of 90 patients were randomly divided into three groups: 0.25 µg/kg dexmedetomidine combined with 0.59% ropivacaine epidural infusion group (ED1 group), 0.5 µg/kg dexmedetomidine combined with 0.59% ropivacaine epidural infusion group (ED2 group), and 0.75 µg/kg dexmedetomidine combined with 0.59% ropivacaine epidural infusion group (ED3 group). Hemodynamics, anesthesia efficiency, and adverse reactions were recorded. Main results: Compared with the ED1 group, the ED2 group had lower systolic blood pressure at T1-3 (T1, 95%CIs, 6.52-21.93, p < 0.001; T2, 95%CIs, 2.88-18.21, p = 0.004; T3, 95%CIs, 0.49-18.17, p = 0.035), and the diastolic blood pressure at T1-2 was decreased (T1, 95%CIs, 4.55-14.36, p < 0.001; T2, 95%CIs, 0.37-12.17, p = 0.033). Compared with the ED2 group, the ED3 group had higher systolic blood pressure at T1-2 (T1, 95%CIs, 5.90-21.46, p < 0.001; T2, 95%CIs, 2.07-17.55, p = 0.008) and higher diastolic blood pressure at T1-3 (T1, 95%CIs, 2.91-12.81, p = 0.001; T2, 95%CIs, 1.32-13.23, p = 0.011; T3, 95%CIs, 0.14-11.52, p = 0.043). Compared with the ED2 group, the heart rate was significantly decreased at T1-4 in the ED3 group (T1, 95%CIs, 2.25-15.72, p = 0.005; T2, 95%CIs, 2.35-13.82, p = 0.003; T3, 95%CIs, 0.50-9.79, p = 0.025; T4, 95%CIs, 1.46-10.36, p = 0.005). The myocardial oxygen consumption in all three groups was significantly decreased at each time point compared to T0 (p < 0.05 or < 0.001), and no significant between-group differences were detected (P>0.05). Compared with the ED1 group, the anesthesia efficiency of ED2 and ED3 groups was markedly enhanced, but the risk of bradycardia in ED2 and ED3 groups was dramatically increased (6 of 28 [21.4%] vs. 14 of 30 [46.7%] and 14 of 27 [51.9%], p = 0.023), one patient in the ED3 group experienced difficulty urinating, and remaining adverse reactions were mild in all three groups. Conclusion: A measure of 0.5 µg/kg dexmedetomidine is the optimal dose as a 0.59% ropivacaine adjuvant for epidural anesthesia in patients undergoing great saphenous varicose vein surgery. Clinical trial registration: http://www.chictr.org.cn/, registration number: ChiCTR2200060619.

Comparison of intravenous butorphanol vs. tramadol for post-spinal anesthesia shivering: a meta-analysis and systematic review.

Background: Patients often experience shivering after spinal anesthesia. In recent years, more and more studies have compared the efficacy and side effects of intravenous butorphanol and tramadol in the treatment of shivering after spinal anesthesia. Therefore, we conducted a MATE analysis and systematic review to compare the efficacy and side effects of butorphanol vs. tramadol in the treatment of shivering after spinal anesthesia. Methods: PubMed, Cochrane Library, and Embase databases were searched for randomized controlled trials (RCTs) from inception to 30 December 2022, comparing the effects of butorphanol vs. tramadol for the control of shivering after spinal anesthesia. Data assessment and collection were analyzed using the Review Manager 5.4 software. Results: Five randomized controlled trials involving 302 adult patients were included in this meta-analysis. The results showed that butorphanol has a shorter time to cease shivering (standardized mean difference (SMD) = -0.53; 95% confidence interval (CI) [-0.89, -0.17], P = 0.004, I2 = 0%), a higher rate of cessation of shivering within 1 min after administering the study drugs (relative risk (RR), 1.69; 95% CI [1.15,2.48], P = 0.008, I2 = 0%), and higher incidences of sedation (RR, 2.98; 95% CI [2.11, 4.21], P <0.00001, I2 = 0%), compared with tramadol. Conclusion: In the treatment of shivering after spinal anesthesia, butorphanol has a shorter onset time and a higher rate of cessation of shivering within 1 min after the study drugs were administered than tramadol. Therefore, butorphanol is superior to tramadol in the treatment of shivering after spinal anesthesia.