Impact of Prone Jackknife Position on Intraoperative Hypotension During Percutaneous Nephroscopy: A Retrospective Matched Analysis.

Objective: To investigate the potential relationship between the prone jackknife position during percutaneous nephroscopy and the occurrence of intraoperative hypotension. Methods: A retrospective analysis was conducted on 651 patients who underwent percutaneous nephroscopy at the Second Affiliated Hospital of Hainan Medical University. The primary focus was to investigate the occurrence of hypotension during the surgical procedure and assess the duration of hypotensive episodes. Patients were categorized into the prone jackknife position group and the lateral position group. To compare the incidence of intraoperative hypotension between the two groups, a 1:1 propensity match was performed. Following the matching process, intraoperative hypotension was assessed and compared between the two groups before and after the match. The binary logistic regression analysis determined the probability of intraoperative hypotension occurred in each group. Furthermore, linear regression analysis was used to analyze the duration of hypotensive episodes experienced by patients in both groups. Results: After propensity score matching, a total of 272 patients with similar characteristics were obtained (136 in each group). The prone jackknife group had a significantly higher incidence of intraoperative hypotension than the lateral group after the match, with an odds ratio of 2.71 (95% confidence interval: 1.595-4.605). Binary logistic regression analysis showed that age and body position exhibited statistical significance as risk factors. Linear regression analysis before and after the match indicated that the duration of hypotension was associated with age, surgical time, and a history of hypertension. Conclusion: The prone jackknife position syndrome after general anesthesia could occur in surgeries. The position could contribute to the development of hypotension during the percutaneous nephroscopy procedure.

Randomized controlled trial for anesthesia during gastroscopy: interactions between remimazolam and propofol in combination with sufentanil.

BACKGROUND: Remimazolam is a new short-duration anesthetic currently used for gastroscopy and can be mixed with propofol and potent opioids. AIM: The study aimed to investigate the synergistic interaction between remimazolam and propofol after sufentanil administration and to determine the appropriate dose ratios between remimazolam and propofol. METHOD: This study used a randomized controlled design. Patients scheduled for gastrointestinal endoscopy were included and randomized into five groups. The randomized block design was applied at a randomization ratio of 1:1. Patients in each group received sufentanil (0.1 µg/kg) and the calculated doses of remimazolam and propofol. Using the up and down method, the median effective dose (ED50) and the 95% confidence interval (CI) were determined based on whether the eyelash reflex disappeared in each treatment group. Isobolographic analysis was used to analyze the presence of drug interactions. The interaction coefficient and the dose ratio between remimazolam and propofol were calculated by algebraic analysis. Statistical analysis was performed using interval estimates and 95% CI for statistical attributes. RESULTS: Cross-sectional analysis of the isobologram showed a clinically significant synergistic effect between remimazolam and propofol. When 0.016, 0.032, and 0.047 mg/kg of remimazolam were combined with 0.477, 0.221, and 0.131 mg/kg of propofol, the interaction coefficients were 1.04, 1.21, and 1.06, respectively. The dose ratio of remimazolam to propofol was approximately 1:7. CONCLUSION: Remimazolam and propofol have synergistic clinical effects. A strong synergistic effect was observed when the remimazolam and propofol dose ratio was 1:7 (mg/kg). CLINICAL TRIAL: The study protocol was registered at the Chinese Clinical Trial Registry (ChiCTR2100052425).

Moderate sedation with single-dose remimazolam tosilate in elderly male patients undergoing transurethral resection of the prostate with spinal anesthesia: a prospective, single-arm, single-centre clinical trial.

BACKGROUND: Remimazolam tosilate (RT) is a newly listed benzodiazepine for sedation and anesthesia featuring quick onset of effects, short maintenance and recovery times, which is currently under research. This trial was conducted to determine the median effective dose (ED50) and the 95% effective dose (ED95) of single-dose remimazolam for moderate sedation in elderly patients undergoing transurethral resection of the prostate (TURP) under spinal anesthesia, and to evaluate its efficacy and safety. METHODS: Thirty male patients aged 65-80 years old were recruited for selective TURP. Remimazolam was administered intravenously to pain-free patients (VAS score < 1) within 1 min of successful spinal anesthesia by the same anesthesiologist. We used modified Dixon's up-and-down sequential allocation method to determine the ED50 and ED95 of the agent with an initial dosage of 0.1 mg/kg. Successful sedation was defined as an MOAA/S score ≤ 3 and above 1. A score of > 3 was deemed as failed sedation. Recruitment continued until ten independent pairs (from successful sedation to failed sedation) would give a reliable estimation of the ED50 and ED95 of RT and their 95% confidence intervals. RESULTS: The ED50 of remimazolam was 0.063 (95% C.I. 0.045-0.073) mg/kg. Its ED95 was 0.079 (95% C.I. 0.07-0.137) mg/kg. Remimazolam was safe in its application. CONCLUSIONS: A single-dose of RT proves to be safe for assisted sedation during TURP in elderly male patients under spinal anesthesia with a lower incidence of adverse events. Its ED50 and ED95 were 0.063 mg/kg and 0.079 mg/kg, respectively. TRIAL REGISTRATION: http://www.chictr.org.cn (ChiCTR2100051912).

GPR108 is required for gambogic acid inhibiting NF-κB signaling in cancer.

GPCRs are the most potential targets for drug discovery, however, their role in oncology is underappreciated and GPCR-based anti-cancer drug is not fully investigated. Herein, we identified GPR108, a GPCR protein described in innate immune system, is a potential therapeutic target of cancer. Depletion of GPR108 dramatically inhibited the survival of various cancers. Notably, TNFα activation of NF-κB was totally impaired after GPR108 knockout. We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108. Importantly, GA engaged with GPR108 and promoted its degradation, knockout of GPR108 remarkably blocked GA inhibition of NF-κB signaling. Furthermore, in vitro and in vivo assays demonstrated that GA was dependent on GPR108 to exert anti-cancer activity. Overall, our findings supported GPR108 as a promising therapeutic target of cancer, and provided a small molecule inhibitor GA directly and selectively targeting GPR108 for cancer therapy.

Small molecule targeting topoisomerase 3ß for cancer therapy.

DNA topoisomerases are proved cancer therapeutic targets with clinically successful anticancer drugs for decades. However, the role of RNA topoisomerase (TOP3ß) remained mysterious especially in cancer, and no targeted agent has been reported yet. In a target identification assay of anti-cancer compound using a modified DrugTargetSeqR strategy, mutation of TOP3B was detected in cancer cells acquired resistance to cinobufagin (CBG), a key compound of Huachansu that has been approved for cancer therapy in China. We demonstrated that CBG directly engaged with TOP3ß, and promoted TOP3ß depletion in wildtype but not mutant cancer cells. Notably, knockout of TOP3ß in cancer cells significantly reduced tumor enlargement but not initiation, and inhibited colony formation upon nutrient deprivation. We also demonstrated that CBG induced formation of stress granule, RNA-loop and asymmetric DNA damages in cancer cells, and all these phenotypes were significantly attenuated in TOP3B knockout cells. Of note, examination of a panel of cancer cell lines revealed associations among cell growth inhibition and induction of DNA damage as well as TOP3B depletion upon CBG treatment. Our findings not only highlighted TOP3ß as a promising therapeutic target of cancer, but also identified CBG as a lead chemical inhibitor of TOP3ß for cancer therapy.