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Introduction: Hyperalgesia frequently occurs after surgery and is associated with adverse effects on surgical outcomes. Thus, we aimed to examine whether the hypothalamus-pituitary-adrenal (HPA) axis function after surgery is involved in the development of postoperative hyperalgesia. Methods: Surgery- and pain-related variables were measured 24 and 48 h after the first and second total knee arthroplasties (TKAs) in postmenopausal patients undergoing 1-week-interval staged bilateral TKA. Two sets of saliva samples were consecutively collected from patients before (pre-T1) and 1 week after (post-T1) the first TKA (n = 69). HPA axis function was analyzed in a subgroup of 20 patients with a typical cortisol awakening response (CAR) in both the sets of saliva samples. Results: Surgery-related variables were comparable between the first and second TKAs. However, pain-related variables (pain ratings and the amount of opioid analgesics consumed) were greater after the second than the first TKA. Cortisol and dehydroepiandrosterone (DHEA) secretion during the post-awakening period (CARauc and Daucawk, respectively) was higher at post-T1 than at pre-T1, but the molar CARauc/Daucawk ratio was comparable between the time points examined. No relationship was observed between the pre-T1 CARauc and pain ratings after the first TKA. However, post-T1 CARauc showed a positive correlation with pain ratings after the second TKA. Postoperative pain ratings were negatively correlated with Daucawk and positively correlated with the molar CARauc/Daucawk ratio at all examined time points. Discussion/Conclusion: The results suggest that adrenocortical steroidogenic activity favoring the production of cortisol over DHEA after surgery may contribute to the development of hyperalgesia during the early postoperative period.

Supplementary Figure S1. Loss of NF2 protects mechanical stress-induced cell death. Supplementary Figure S2. TβR1 is sensor of physical stimulation. Supplementary Figure S3. TβR1 kinase activity is required for RKIP and NF2 suppression. Supplementary Figure S4. Loss of NF2 induces unbalanced TβR1 and TβR2 expression. Supplementary Figure S5. TβR1-mediated oncogenic signal such as invasion can be blocked by TβR2. Supplementary Figure S6. NF2 blocks the binding between RKIP and TβR1. Supplementary Figure S7. TβR1 phosphorylates RKIP. Supplementary Figure S8. The effect of TβR1 kinase inhibitors on NF2-deficient cells. Supplementary Figure S9. The effect of several kinds of selective TβR1 inhibitors. Supplementary Figure S10. Gene expression analysis. Supplementary Figure S11. TEW7197 induces HEI-193 differentiation into Schwann cell. Supplementary Figure S12. Histological analysis in NF2 syndrome model mouse. Supplementary Figure S13. Mouse phenotype. Supplementary Figure S14. Effect of TEW7197 treatment on the primary tumor cells isolated from vehicle-treated NF2 syndrome model mouse.

Quinacrine (QNC), antiprotozoan drug commonly used against Malaria and Giardiasis, has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest antitumor effects of QNC through suppression of NF-κB and activation of p53. This study demonstrates the anticancer effect of QNC via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-inactivated conditions. Inhibition of p53 by PFT-α or siRNA promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells. Considering that Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by QNC may induce cell death via uncontrolled cell cycle progression. Indeed, QNC reduces Chk1/2 expression under p53-impaired cancer cells and induces cell death in the G2–M phase. QNC increases the binding between p-Chk1/2 and β-TrCP and promotes proteasome-dependent degradation. Moreover, QNC treatment displayed antitumor effects in a Villin-Cre;p53+/LSL-R172H intestinal cancer mouse model system as well as HCT116 p53−/− xenografts.Implications: QNC has been used for the past over 70 years without obvious side effects, as such it is a plausible drug candidate for relapsed cancers, small-cell lung cancer, breast cancer as well as various p53-inactivated human malignancies. Mol Cancer Res; 16(6); 935–46. ©2018 AACR.

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Supplemental figure legends.

Supplemental Figure S1. The effect of oncogenes on DX2 expression. Supplemental Figure S2. Oncogenic property of DX2. Supplemental Figure S3. Small cell lung cancer in DX2 and DK transgenic model. Supplemental Figure S4. DX2 suppresses p14/ARF. Supplemental Figure S5. Screening of specific inhibitor of p14/ARF and DX2. Supplemental Figure S6. SLCB050 as specific binding inhibitor of p14/ARF and DX2. Supplemental Figure S7. The effect of SLCB050 on DX2. Supplemental Figure S8. Anti-tumoral effects of SLCB050 in DK mice. Supplemental Figure S9. Diagram for summary.

Table S1. Clino-pathological information of human samples.

Background Magnesium is known to enhance the effect of rocuronium, but the extent is not quantified. Objectives We aimed to quantify the effect of magnesium on the dose of rocuronium for deep neuromuscular blockade. Design A randomised controlled study. Setting A single tertiary care hospital. Patients Seventy males scheduled to undergo robot-assisted laparoscopic prostatectomy, aged between 20 and 80 years with American Society of Anesthesiologists physical status classification 1 or 2, were enrolled. Interventions Patients were randomised to either the magnesium group or control group. The magnesium group were infused with 50 mg kg-1 of magnesium, followed by a continuous intra-operative infusion at 15 mg kg-1 h-1 while the control group were infused with the same volumes of 0.9% saline. Deep neuromuscular blockade was maintained with a continuous infusion of rocuronium and was reversed using sugammadex. Main outcome measures The primary outcome was the dose of rocuronium administered to maintain deep neuromuscular blockade. The secondary outcomes were recovery time, defined as the time from the administration of sugammadex to train-of-four ratio 0.9, and the incidence of postoperative nausea and vomiting. Results The dose of rocuronium administered to maintain deep neuromuscular blockade was significantly lower in the magnesium group (7.5 vs. 9.4 μg kg-1 min-1, P = 0.01). There was no difference in recovery time or the incidence of nausea and vomiting. Conclusion Magnesium reduced the dose of rocuronium required for deep neuromuscular blockade by approximately 20% without affecting the recovery time after administration of sugammadex. Trial registration ClinicalTrials.gov identifier: NCT04013243.

BACKGROUND Incomplete recovery of neuromuscular blockade is a common postoperative adverse event in the postanaesthesia care unit. OBJECTIVE We examined and compared the incidence of residual neuromuscular blockade when the recommended dose of neostigmine or sugammadex was administered according to a qualitative nerve stimulator response. DESIGN A randomised controlled trial. SETTING A tertiary care hospital in South Korea from September 2017 to November 2017. PATIENTS Eighty patients aged between 18 and 69 years were included in this study. All were patients scheduled to undergo elective laparoscopic cholecystectomy and who had an American Society of Anaesthesiologists physical status of one or two were eligible. INTERVENTIONS Patients were allocated randomly to receive neostigmine or sugammadex at the end of surgery. The doses of the reversal agents were based on the response to peripheral nerve stimulation, which was discontinued after administration of the reversal agent. MAIN OUTCOME MEASURES The primary outcome was the incidence of postoperative residual neuromuscular blockade. The secondary outcomes were the incidences of symptoms or signs of residual neuromuscular blockade such as hypoxaemia, inability to maintain head-lift for 5 s and diplopia. RESULTS The incidence of residual neuromuscular blockade on arrival in the recovery room was 44.4% in the neostigmine group and 0% in the sugammadex group (P

Background Reversing a neuromuscular blockade agent with sugammadex is known to lessen postoperative complications by reducing postoperative residual curarization. However, its effects on 90-day mortality are unknown. Therefore, this study aimed to compare the effects of sugammadex and neostigmine in terms of 90-day mortality after non-cardiac surgery. Methods This retrospective cohort study analyzed the medical records of adult patients aged 18 years or older who underwent non-cardiac surgery at a single tertiary care hospital between 2011 and 2016. Propensity score matching and Cox regression analysis were used to investigate the effectiveness of sugammadex and neostigmine in lowering 90-day mortality after non-cardiac surgery. Results A total of 65,702 patients were included in the analysis (mean age: 52.3 years, standard deviation: 15.7), and 23,532 of these patients (35.8%) received general surgery. After propensity score matching, 14,179 patients (3906 patients from the sugammadex group and 10,273 patients from the neostigmine group) were included in the final analysis. Cox regression analysis in the propensity score-matched cohort showed that the risk of 90-day mortality was 40% lower in the sugammadex group than in the neostigmine group (hazard ratio: 0.60, 95% confidence interval: 0.37, 0.98; P = 0.042). These results were similar in the multivariable Cox regression analysis of the entire cohort (hazard ratio: 0.62, 95% confidence interval: 0.39, 0.96; P = 0.036). Conclusions This retrospective cohort study suggested that reversing rocuronium with sugammadex might be associated with lower 90-day mortality after non-cardiac surgery compared to neostigmine. However, since this study did not evaluate quantitative neuromuscular function in the postoperative period due to its retrospective design, the results should be interpreted carefully. Future prospective studies with quantitative neuromuscular monitoring in the postoperative period should be performed to confirm these results.

BackgroundThere is a paucity of clinical data about whether sugammadex forms precipitates with other medications. This laboratory experimental study was performed to determine the drugs that produce precipitate with sugammadex. MethodsSamples of 1 mL of sugammadex were prepared in transparent cylinders, to which 1 mL of test drugs (rocuronium, neostigmine, glycopyrrolate, atropine, nitroglycerin, dobutamine, dopamine, epinephrine, vasopressin, norepinephrine, phenylephrine, ephedrine, esmolol, nicardipine, labetalol) was then added. The precipitation reaction was observed by eyes and light microscope. The pH of each drugs before and after mixing with sugammadex was measured. ResultsWhite crystals were formed when sugammadex mixed with nicardipine or labetalol. ConclusionsSugammadex formed precipitate when mixed with nicardipine or labetalol. Sufficient fluid flushing is required between injections of each drug to prevent these reactions.

Background Although red blood cells (RBC) transfusion is known to be significantly associated with biochemical recurrence in patients undergoing open prostatectomy, its influence on biochemical recurrence after robot-assisted laparoscopic radical prostatectomy remains unclear. Therefore, this study aimed to validate the effect of RBC transfusion on the 5-year biochemical recurrence in patients undergoing robot-assisted laparoscopic radical prostatectomy. Methods This study retrospectively analyzed the medical records of patients who underwent robot-assisted laparoscopic radical prostatectomy at single tertiary academic hospital between October 2007 and December 2014. Univariate and multivariate Cox proportional hazard regression analysis was performed to identify any potential variables associated with 5-year biochemical recurrence. Results A total of 1311 patients were included in the final analysis. Of these, 30 patients (2.3%) were transfused with RBC either during robot-assisted laparoscopic radical prostatectomy or during their hospital stay, which corresponded to 5-year biochemical recurrence of 15.7%. Multivariate Cox proportional hazard regression analysis showed that RBC transfusion had no influence on the 5-year biochemical recurrence. Variables including pathologic T stage (Hazard ratio [HR] 3.5, 95% confidence interval [CI] 2.4–5.1 p < 0.001), N stage (HR 2.3, 95% CI 1.5–3.7, p < 0.001), Gleason score (HR 2.4, 95% CI 1.8–3.2, p < 0.001), and surgical margin (HR 2.0, 95% CI 1.5–2.8, p < 0.001) were independently associated with the 5-year biochemical recurrence. Conclusions RBC transfusion had no significant influence on the 5-year biochemical recurrence in patients undergoing robot-assisted laparoscopic radical prostatectomy.

Hyperalgesia frequently occurs after surgery and is associated with adverse effects on surgical outcomes. Thus, we aimed to examine whether the hypothalamus-pituitary-adrenal (HPA) axis function after surgery is involved in the development of postoperative hyperalgesia.Surgery- and pain-related variables were measured 24 and 48 hours after the first and second total knee arthroplasties (TKAs) in postmenopausal patients undergoing one-week-interval staged bilateral TKA. Two sets of saliva samples were consecutively collected from patients before (pre-T1) and one week after (post-T1) the first TKA (n = 69). HPA axis function was analyzed in a subgroup of 20 patients with a typical cortisol awakening response (CAR) in both sets of saliva samples.Surgery-related variables were comparable between the first and second TKAs. However, pain-related variables (pain ratings and the amount of opioid analgesics consumed) were greater after the second than the first TKA. Cortisol and dehydroepiandrosterone (DHEA) secretion during the post-awakening period (CARauc and Daucawk, respectively) was higher at post-T1 than at pre-T1, but the molar CARauc/Daucawk ratio was comparable between the time points examined. No relationship was observed between the pre-T1 CARauc and pain ratings after the first TKA. However, post-T1 CARauc showed a positive correlation with pain ratings after the second TKA. Postoperative pain ratings were negatively correlated with Daucawk and positively correlated with the molar CARauc/Daucawk ratio at all examined time points.The results suggest that adrenocortical steroidogenic activity favoring the production of cortisol over DHEA after surgery may contribute to the development of hyperalgesia during the early postoperative period.

The effects of anesthetics on acute kidney injury (AKI) after spine surgery have not been evaluated fully. This study compared propofol-based total intravenous anesthesia (TIVA) and volatile anesthetics in the development of AKI after spine surgery. This retrospective study reviewed patients who underwent spine surgery between 2015 and 2019. A logistic regression analysis was performed to identify risk factors for AKI. Additionally, after propensity score matching, the incidence of AKI was compared between TIVA and volatile groups. Of the 4473 patients, 709 were excluded and 3764 were included in the logistic regression. After propensity score matching, 766 patients from each group were compared, and we found that the incidence of AKI was significantly lower in the TIVA group (1% vs. 4.2%, p < 0.001). In the multivariate logistic regression analysis, the risk factors for postoperative AKI were male sex (OR 1.85, 95% CI 1.18–3.06), hypertension (OR 2.48, 95% CI 1.56–3.94), anemia (OR 2.66, 95% CI 1.76–4.04), and volatile anesthetics (OR 4.69, 95% CI 2.24–9.84). Compared with volatile anesthetics, TIVA is associated with a reduced risk of AKI for patients who have undergone spine surgery.

Postoperative nausea and vomiting (PONV) occurs frequently after bariatric surgery and is a major cause of adverse outcomes. This retrospective study investigated whether opioid-restricted total intravenous anesthesia using dexmedetomidine as a substitute for remifentanil can reduce PONV in bariatric surgery.The electronic medical records of adult patients who underwent laparoscopic bariatric surgery between January and December 2019 were reviewed. The patients were divided into two groups according to the agents used for anesthesia: Group D, propofol and dexmedetomidine; Group R, propofol and remifentanil.A total of 134 patients were included in the analyses. The frequency of postoperative nausea was significantly lower in Group D than that in Group R until 2 h after discharge from the postanesthesia care unit (PACU) (P = 0.005 in the PACU, P = 0.010 at 2 h after PACU discharge) but failed to significantly reduce the overall high incidence rates of 60.5% and 65.5%, respectively (P = 0.592). Postoperative pain score was significantly lower in Group D until 6 h after PACU discharge. The rates of rescue antiemetic and analgesic agent administration in the PACU were significantly lower in Group D than those in Group R.Opioid-restricted total intravenous anesthesia using dexmedetomidine reduces postoperative nausea, pain score, antiemetic, and analgesic requirements in the immediate postoperative period after bariatric surgery.

Insertion of a flexible laryngeal mask airway (LMA Flexible) is known to be more difficult than that of a conventional laryngeal mask airway. The 90° rotation technique can improve the success rate with a conventional laryngeal mask airway but its effect with the LMA Flexible remains unknown. We assessed whether the 90° rotation technique increased the first-attempt success rate of LMA Flexible insertion versus the standard technique. In total, 129 female patients undergoing breast surgery were analyzed. The primary endpoint was success at the first attempt. The insertion time, number of trials, number of manipulations required, and oropharyngeal leak pressure were also evaluated. Heart rate and mean blood pressure were recorded 1 min before and 1 min after insertion. Blood staining on the LMA Flexible after removal and postoperative sore throat were checked. The first-attempt success rates were comparable between the groups (93% vs. 98.3%, P = .20). The insertion time, number of trials and manipulations, hemodynamic variables, and complications, such as blood staining and sore throat, did not differ between the groups. The 90° rotation technique is a good alternative to the standard technique for insertion of the LMA Flexible. ClinicalTrials.gov ( NCT03028896 ). It was registered retrospectively at Jan 19th, 2017.

Perioperative positive fluid balance (FB) increases postoperative complication and length of hospital stay. We aimed to investigate 30-day unplanned readmission after major abdominal surgery based on perioperative FB (%) on postoperative days (POD) 0 to 3. This retrospective cohort study analyzed medical records of patients who underwent elective major abdominal surgery (surgery time >2 hours, estimated blood loss >500 mL) at a single tertiary academic hospital from January 2010 to December 2017. Cumulative FB was calculated by total input fluid − output fluid in liters × weight (kg)−1 on admission × 100 during POD 0 (24 hours), 0 to 1 (48 hours), 0 to 2 (72 hours), and 0 to 3 (96 hours). Of the 3650 patients in the final analysis, 503 (13.8%) had unplanned readmission within 30 days. In the multivariable logistic regression analysis, FB on POD 0 (24 hours), 0 to 1 (48 hours), 0 to 2 (72 hours), and 0 to 3 (96 hours) showed no significant association with 30-day unplanned readmission (all P > .05). However, an increase of 10 000 points in the total relative value unit scores was associated with 5% increase in 30-day unplanned readmission (odds ratio = 1.05, 95% confidence interval = 1.02-1.07; P = .001), and 1-hour increase in surgery time was associated with 10% increase in 30-day unplanned readmission (odds ratio = 1.10, 95% confidence interval = 1.05-1.15; P < .001). This study showed that perioperative FB is not associated with 30-day unplanned readmission rate after a major abdominal surgery. Total relative value unit scores and duration of surgery were significantly associated with 30-day unplanned readmission rate after major abdominal surgery in a single tertiary academic hospital.

Background Sugammadex is associated with fewer postoperative complications, but its impact on 30-day unplanned readmission is unclear. Methods This was a single-centre retrospective observational study of patients after major abdominal surgery between 2010 and 2017, where rocuronium was the only neuromuscular blocker used. The primary endpoint was the difference in incidence of 30-day unplanned readmission between reversal with sugammadex or neostigmine. The secondary endpoints were the length of hospital stay after surgery and related hospital charges (total charges excluding those related to surgery and anaesthesia). Analysis included propensity score matching and generalised mixed-effects modelling. Results Mixed-effects logistic regression analysis of 1479 patients (sugammadex: 355; neostigmine: 1124) showed that the incidence of 30-day unplanned readmission was 34% lower (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.46–0.96, P=0.031), the length of hospital stay was 20% shorter (exponential regression coefficient: 0.80, 95% CI: 0.77–0.83, P Conclusions Compared with neostigmine, reversal of rocuronium with sugammadex after major abdominal surgery was associated with a lower incidence of 30-day unplanned readmission, a shorter hospital stay, and lower related hospital charges.

p53-mediated cellular senescence has been intensively investigated, because it is important for tumor suppressive function. In addition, p16/INK4A is well known to be critical for cellular senescence. However, detailed molecular mechanism or relevance between p53 and p16-mediated senescence has not been demonstrated yet. Here we show that p53 induces p16 through Lamin A/C stabilization via direct interaction. Stabilized Lamin A/C promotes degradation of BMI-1 and MEL-18 (Polycomb repressor complex 1, PRC1), which sequesters p16 promotor. Increased p53 can reduce BMI-1/MEL-18 and induce p16 expression via Lamin A/C. Elimination of Lamin A/C can abolish p53-induced p16 expression and BMI-1/MEL-18 reduction. As Lamin A/C expression is increased during cell differentiation, this mechanism seems to be very useful for selective induction of senescence in non-stem cells. Our results suggest that Lamin A/C-p53 network is important for p16/INK4A-mediated cellular senescence.

The neuromuscular block state may affect the electroencephalogram-derived index representing the anesthetic depth. We applied an Anesthetic Depth Monitoring for Sedation (ADMS) to patients undergoing laparoscopic cholecystectomy under total intravenous anesthesia, and evaluated the requirement of propofol according to the different neuromuscular block state. Adult patients scheduled to undergo laparoscopic cholecystectomy were enrolled and randomly assigned to either the moderate (MB) or deep neuromuscular block (DB) group. The UniCon sensor of ADMS was applied to monitor anesthetic depth and the unicon value was maintained between 40 and 50 during the operation. According to the group assignment, intraoperative rocuronium was administered to maintain proper neuromuscular block state, moderate or deep block state. The unicon value, electromyography (EMG) index, and total dose of propofol and rocuronium were analyzed. At similar anesthetic depth, less propofol was used in the DB group compared to the MB group (6.19 ± 1.36 in the MB mg/kg/h group vs 4.93 ± 3.02 mg/kg/h in the DM group, p = 0.042). As expected, more rocuronium were used in the DB group than in the MB group (0.8 ± 0.2 mg/kg in the MB group vs 1.2 ± 0.2 mg/kg in the DB group, p = 0.023) and the EMG indices were lower in the DB group than in the MB group, at several time points as follows: at starting operation ( p

Background: Deep neuromuscular blockade is considered beneficial for improving the surgical space condition during laparoscopic surgery. Adequacy of the surgical space condition may affect the anesthetists’ decision regarding titration of depth of anesthesia. We investigated whether deep neuromuscular blockade reduces the propofol requirement under bispectral index monitoring compared to moderate neuromuscular blockade. Methods: Adult patients undergoing elective laparoscopic colorectal surgery were randomly allocated to a moderate or deep group. A train-of-four count of 1–2 in the moderate group, and a post-tetanic count of 1–2 in the deep group, were maintained by continuous infusion of rocuronium. The induction and maintenance of anesthesia were achieved by target-controlled infusion of propofol and remifentanil. The dose of propofol was adjusted to maintain the bispectral index in the range of 40–50. The remifentanil dose was titrated to maintain the systolic blood pressure to within 20% of the ward values. Results: A total of 82 patients were included in the analyses. The mean±SD dose of propofol was 7.54 ± 1.66 and 7.42 ± 1.01 mg·kg−1·h−1 in the moderate and deep groups, respectively (P = .104). The mean±SD dose of remifentanil was 4.84 ± 1.74 and 4.79 ± 1.77 μg kg−1 h−1 in the moderate and deep groups, respectively (P = .688). In comparison to the moderate group, the deep group showed significantly lower rates of intraoperative patient movement (42.9% vs 22.5%, respectively, P = .050) and additional neuromuscular blocking agent administration (76% vs 53%, respectively, P = .007). Postoperative complications, including pulmonary complications, wound problems and reoperation, were not different between the two groups. Conclusion: Deep neuromuscular blockade did not reduce the bispectral index-guided propofol requirement compared to moderate neuromuscular blockade during laparoscopic colon surgery, despite reducing movement of the patient and the requirement for a rescue neuromuscular blocking agent. Trial registration: Clinicaltrials.gov (NCT03890406)

The risk of neuromuscular blockade is certainly minimized by sugammadex in combination with monitoring. However, the effect of sugammadex-aided recovery on patients’ satisfaction is unclear. This study compared the Quality of Recovery (QoR)-15 score, which is a patient-reported outcome, in patients undergoing laparoscopic cholecystectomy. Eighty patients were randomly assigned to the neostigmine or sugammadex groups. At the end of surgery, neostigmine or sugammadex was administered, and tracheal extubation was performed after confirmation of a train of four ratio ≥ 0.9. The QoR-15 questionnaire was administered at 1 day before surgery and on post-operative days (POD) 1 and 2. The primary outcome was the QoR-15 score on POD 1. The secondary outcomes were the QoR-15 score on POD 2, modified Aldrete score, length of post-anesthetic care unit stay, post-operative pain, administration of anti-emetics, urinary retention, and length of hospital stay. No significant differences were found in QoR-15 scores on POD 1 (94.4 vs. 95.5, p = 0.87) or 2 (116.3 vs. 122, p = 0.33). Secondary outcomes were also comparable, with the exception of urinary retention (15.8% neostigmine vs. 2.6% sugammadex, p = 0.04). This study demonstrated that the quality of recovery was comparable between the neostigmine and sugammadex groups when reversal and tracheal extubation were performed in accordance with the current guidelines.

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient’s cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of LmnaG609G/G609G mouse for about 10 weeks and increase its body weight. Progerinin can also extend the life span of LmnaG609G/+ mouse for about 14 weeks via oral administration, whereas treatment with lonafarnib (farnesyl-transferase inhibitor) can only extend the life span of LmnaG609G/+ mouse for about two weeks. In addition, progerinin can induce histological and physiological improvement in LmnaG609G/+ mouse. These results indicate that progerinin is a strong drug candidate for HGPS., Kang, Park and colleagues develop and demonstrate the effects of a new drug candidate for treatment of Hutchinson-Gilford progeria syndrome pathologies. Progerinin extends the life span of mice used to model this disease and induces histological and physiological improvements.

The use of sugammadex can reduce post-operative residual neuromuscular blockade, which is known to increase the risk of post-operative respiratory events. However, its effect on post-operative pulmonary complications is not obvious. This study was performed to evaluate the effects of sugammadex on post-operative pulmonary complications in patients undergoing laparoscopic gastrectomy between 2013 and 2017. We performed propensity score matching to correct for selection bias. Post-operative pulmonary complications (i.e., pneumonia, respiratory failure, pleural effusion, atelectasis, pneumothorax, and aspiration pneumonitis) were evaluated from the radiological and laboratory findings. We also evaluated admission to the intensive care unit after surgery, re-admission or an emergency room visit within 30 days after discharge, length of hospital stay, re-operation, and mortality within 90 days post-operatively as secondary outcomes. In the initial cohort of 3802 patients, 541 patients were excluded, and 1232 patients were analyzed after propensity score matching. In the matched cohort, pleural effusion was significantly reduced in the sugammadex group compared to the neostigmine group (neostigmine 23.4% vs. sugammadex 18%, p = 0.02). Other pulmonary complications and secondary outcomes were not significantly different between the groups. In comparison to neostigmine, the use of sugammadex was associated with a lower incidence of post-operative pleural effusion in laparoscopic gastrectomy.

Background and aims An immersive virtual reality tour of the operating theater could reduce preoperative anxiety. This study was designed to determine whether a preoperative immersive virtual reality tour demonstrates a reduction in emergence delirium through reducing the preoperative anxiety in children undergoing general anesthesia. Methods Eighty-six children were randomly allocated into either the control or virtual reality group. The control group received conventional education regarding the perioperative process. The virtual reality group watched a 4-minute virtual reality video showing the operating theater and explaining the perioperative process. Incidence and severity of emergence delirium were the main outcomes. Secondary outcomes included preoperative anxiety using modified Yale Preoperative Anxiety Scale and postoperative behavioral disturbance. Results Eighty children completed the final analysis (control group = 39, virtual reality group = 41). The incidence (risk ratio [95% CI]: 1.1 [0.5-2.8], P = 0.773) and severity of emergence delirium (mean difference [95% CI]: -0.2 [-2.7 to 2.2], P = 0.791) were similar in the two groups. After the intervention, children in the virtual reality group had a significantly lower modified Yale Preoperative Anxiety score than those in the control group (mean difference [95% CI]: 9.2 [0.3-18.2], P = 0.022). No difference was observed regarding postoperative behavioral disturbance between the two groups at postoperative 1 day (mean difference [95% CI]: -0.1 [-0.3 to 0.1], P = 0.671) and 14 day (mean difference [95% CI]: -0.0 [-0.1 to 0.0], P = 0.329). Conclusion Preoperative immersive virtual reality tour of the operating theater did not reduce the incidence and severity of emergence delirium, although it was effective in alleviating preoperative anxiety in children.

Neurofibromatosis type 2 (NF2) syndrome is a very rare human genetic disease, and there has been no proper treatment for it until now. In our recent study, it has been reported that the loss of NF2 activates MAPK signaling through reduction of RKIP in a mesothelioma model. Here, we show that loss of NF2 induces reduction of the TGFβ receptor 2 (TβR2) expression, and an overwhelming expression of TGFβ receptor 1 (TβR1) is activated by physical stimuli such as pressure or heavy materials. Activated TβR1 induces the phosphorylation and degradation of RKIP. RKIP reduction consequently results in MAPK activation as well as Snail-mediated p53 suppression and occurrence of EMT in NF2-deficient cells by physical stimuli. Thus, TβR1 kinase inhibitors restore cell differentiation and induce growth suppression in NF2-deficient Schwannoma cell line and MEF. Moreover, TEW7197, a specific TβR1 kinase inhibitor, reduces tumor formation in the NF2-model mouse (Postn-Cre;NF2f/f). Gene expression profiling reveals that TEW7197 treatment induces the expression of lipid metabolism–related gene set, such as NF2-restored cells in HEI-193 (NF2-deficient Schwannoma). Our results indicate that reduction or deletion of TβR2 or NF2 induces the TβR1-mediated oncogenic pathway, and therefore inhibition of the unbalanced TGFβ signaling is a putative strategy for NF2-related cancers (NF2 syndrome and mesothelioma) and TβR2-mutated advanced cancers. Mol Cancer Ther; 17(11); 2271–84. ©2018 AACR.

The relationship between preoperative hyperglycemia and postoperative acute kidney injury (AKI) occurrence in non-cardiac surgery including laparoscopic surgery remains unclear. This study aimed to assess the relationship between preoperative chronic hyperglycemia and postoperative AKI occurrence after a major laparoscopic abdominal surgery.We retrospectively reviewed medical records of diabetic patients (≥ 20 years old) who underwent elective major laparoscopic abdominal surgery procedures between 2010 and 2016. Patients were divided into two groups based on a cut-off value of hemoglobin A1c (HbA1c) at 6%. Serum creatinine value was used for the diagnosis of AKI, and all assessments and diagnoses of postoperative AKI were performed on 0-3 postoperative days (POD) using the criteria of Kidney Disease: Improving Global Outcomes.In all, 1885 patients were included in the final analysis, and patients were divided into the following groups: 6.0% group with 1257 patients (66.7%), and ≥ 6.0% group with 628 patients (33.3%). Sixty-nine patients (3.7%) were diagnosed with postoperative AKI within 3 POD. Multivariable logistic regression analysis showed no significant difference in the incidence rate of postoperative AKI between the HbA1c ≥ 6.0% group and the 6.0% group (odds ratio 1.10, 95% confidence interval 0.57-2.15; P = 0.770). In addition, there was no significant interaction between preoperative HbA1c group and exposure to acute hyperglycemia (serum glucose 200 mg/dL) for incidence of AKI on POD 0-3 (P = 0.181).In diabetic patients, preoperative chronic hyperglycemia is not associated with postoperative AKI occurrence within 3 POD after a major laparoscopic abdominal surgery.

To compare between deep neuromuscular blockade (NMB) and moderate NMB with respect to endoscopic surgical conditions and recovery profiles in patients with general anesthesia for transurethral resection of bladder (TURB). 108 patients undergoing elective TURB were randomized into two groups: the moderate NMB (n = 54) or deep NMB (n = 54) group. After the operation, NMB was reversed with 2 mg/kg sugammadex at a train-of-four (TOF) count of 1 or 2 (moderate NMB group) or with 4 mg/kg sugammadex at post-tetanic count (PTC) of 2 (deep NMB group). Surgeons, who were blinded to the study design, rated the endoscopic surgical condition on a 5-point scale (1 = extremely poor, 2 = poor, 3 = acceptable, 4 = good, 5 = optimal) immediately following the operation. Recovery profiles, including postoperative residual curarization (PORC), respiratory complication, and recovery time, were recorded. No difference was observed between the two groups regarding patients and anesthesia characteristics. There were statistically significant differences in endoscopic surgical conditions between the two groups (P

Tak Kyu Oh,1 Sung-Bum Kang,2 In-Ae Song,1 Jung-Won Hwang,1 Sang-Hwan Do,1 Jin Hee Kim,1 Ah-Young Oh1 1Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, 2Department of Surgery, Seoul National University Bundang Hospital, Seoul, South Korea Purpose: This study aimed to identify the effect of preoperative serum total cholesterol on postoperative pain outcome in patients who had undergone laparoscopic colorectal cancer surgery. Methods: We retrospectively reviewed the medical records of patients diagnosed with colorectal cancer who had undergone laparoscopic colorectal surgery from January 1, 2011, to June 30, 2017, to identify the relationship of total cholesterol levels within a month prior to surgery with the numeric rating scale (NRS) scores and total opioid consumption on postoperative days (PODs) 0–2. Results: We included 1,944 patients. No significant correlations were observed between total cholesterol and the NRS (POD 0), NRS (POD 1), and oral morphine equivalents (PODs 0–2) (P>0.05). There was no significant difference between the low (0.05). Furthermore, there was no significant association in multivariate linear regression analysis for postoperative opioid consumption according to preoperative serum total cholesterol level (coefficient 0.08, 95% CI –0.01 to 0.18, P=0.81). Conclusion: This study showed that there was no meaningful association between preoperative total cholesterol level and postoperative pain outcome after laparoscopic colorectal cancer surgery. Keywords: cholesterol, analgesia, colon, rectum, laparoscopy

Background Opioid usage is reportedly increased in patients with advanced cancer and low total cholesterol (TC). The aim of this study was to determine the effects of preoperative serum TC levels on postoperative opioid usage in patients undergoing laparoscopic gastric cancer surgery. Methods We retrospectively analyzed the medical records of patients with gastric cancer who underwent laparoscopic gastrectomy at our institution between January 1, 2011 and July 31, 2017. We investigated the correlation between TC levels in the month before surgery and numeric rating scale (NRS) scores and opioid consumption on postoperative days (PODs) 0 to 3. The patients were stratified according to preoperative TC level (< 160 mg/dL, low; 160 to 199 mg/dL, medium; ≥ 200 mg/dL, high). Results TC and NRS scores (PODs 0, 1) for 1,919 eligible patients showed weak but significant positive coefficients (0.074 and 0.098 on POD 0 and POD 1, respectively, P < 0.01). After adjusting for confounders, there were no significant differences in postoperative NRS scores on PODs 0, 1, 2, or 3 or in oral morphine equivalents on PODs 0 to 3 according to TC level. Conclusion Preoperative serum TC levels have no effect on pain outcomes in the 3 days following laparoscopic gastric surgery.

Some short procedures require deep neuromuscular blockade, which needs to be reversed at the end of the procedure. Forty-four patients undergoing elective laryngeal micro-surgery were randomly allocated into two groups: rocuronium 0.45 mg.kg-1 with neostigmine (50 μg.kg-1 with glycopyrrolate 10 μg.kg-1 ) reversal (moderate block group) vs. rocuronium 0.90 mg.kg-1 with sugammadex (4 mg.kg-1 ) reversal (deep block group). The primary outcome was the intubating conditions during laryngoscopy secondary outcomes included recovery of neuromuscular block; conditions for tracheal intubation; satisfaction score as determined by the surgeon; onset of neuromuscular block; and postoperative sore throat. The onset of neuromuscular block was more rapid, and intubation conditions and ease of intra-operative laryngoscopy were more favourable, and the satisfaction score was lower in the moderate block group compared with the deep block group. No difference was found in the incidence of postoperative sore throat. In laryngeal micro-surgery, the use of rocuronium 0.9 mg.kg-1 with sugammadex for reversal was associated with better surgical conditions and a shorter recovery time than rocuronium 0.45 mg.kg-1 with neostigmine.

Scarless remote access endoscopic and robotic thyroidectomy has been recently performed as a safe and feasible method. However, little is known about the laryngo-pharyngeal complications after surgery and the effect of adjusting the endotracheal tube cuff pressure during surgery on laryngo-pharyngeal complications. Patients were randomized into two groups: the control group (n = 52) and adjusted group (n = 52). The initial cuff pressure was set to 25 mmHg and then monitored without adjustment (control group) or with adjustment at approximately 25 mmHg (adjusted group) throughout surgery. The incidences and severity of postoperative sore throat (POST), hoarseness, dysphagia, and cough were recorded at 1, 6, 24, and 48 h after surgery. Cuff pressures of the control group changed significantly over time and were higher than those of the adjusted group. The incidence of POST was lower in the adjusted group at 24 h postoperatively (p = 0.035), and there was a significant difference in the severity of POST at 6 and 24 h postoperatively between the two groups. There were no differences in the incidence of hoarseness, dysphagia, and cough between the two groups, except dysphagia and cough at 6 h postoperatively. Therefore, intraoperative monitoring and adjustment of the cuff pressure can reduce the incidence of laryngo-pharyngeal complications.

Objective: Previous studies have reported that propofol has antitumor, anti-inflammatory, and antioxidant effects in addition to its anesthetic properties. To confirm this, a retrospective investigation was conducted to determine whether different anesthetic agents, particularly propofol and inhalation anesthetics, have an effect on the recurrence of hepatocellular carcinoma (HCC) in patients who were diagnosed with primary HCC and underwent laparoscopic hepatectomy. Subjects and Methods: Patients with Barcelona Clinic Liver Cancer stages 0, A, and B HCC, who underwent laparoscopic hepatic resection, were enrolled in this study. Post­operative HCC recurrence, which was determined from postoperative liver CT, was evaluated 24 months postoperatively with respect to the main anesthetic agents. The characteristics of HCC and other patient-related or surgery-related variables were evaluated together. Results and Conclusion: During the 24-month period after hepatic resection, less HCC patients in the propofol group than in the inhalation group recurred (p = 0.046). The mean time to recurrence was 20.8 months (95% CI, 19.7–22.0) and 19.1 months (95% CI, 17.8–20.4) in the propofol group and the inhalation group, respectively. In addition, multivariable Cox proportional regression analysis revealed that the propofol group showed significantly decreased recurrence versus the inhalation group (hazard ratio, 0.57; 95% CI, 0.47–0.69; p = 0.029). When propofol was used as the main general anesthetic agent for laparoscopic hepatic resection, the postoperative 2-year recurrence rate decreased in early- and intermediate-stage HCC.

Maintaining deep neuromuscular block during surgery improves surgical space conditions. However, its effects on patient outcomes have not been well documented. We examined whether maintaining deep neuromuscular blockade during surgery could decrease the stress response compared to moderate neuromuscular blockade. Patients undergoing laparoscopic gastrectomy were randomly allocated to either the moderate (train-of-four counts of 1–2) or deep (post-tetanic counts of 1–2) neuromuscular blockade group. The primary outcome variable was the postoperative blood level of interleukin-6, and the secondary outcome variables were intraoperative or postoperative blood levels of tumor necrosis factor-α, interleukin-1β, interleukin-8, and C-reactive protein. A total of 96 patients were recruited and 88 (44 in each group) were included in the analyses. The levels of tumor necrosis factor-α and interleukin-1β measured at the end of surgery, interleukin-6 and interleukin-8 measured at 2 h postoperatively, and C-reactive protein measured at 48 h postoperatively were all significantly increased compared to the preoperative values, but there were no differences between the moderate and deep neuromuscular block groups. We found no differences in surgical stress response measured using determining levels of interleukin-6 and other mediators released between the moderate and deep neuromuscular blockade groups in patients undergoing laparoscopic gastrectomy.

Catheter-related bladder discomfort (CRBD) is one of the most difficult symptoms during the postoperative period. Nefopam is a non-narcotic analgesic agent, which also has anticholinergic action. This study was performed to evaluate the effects of nefopam on CRBD in male patients undergoing robotic nephrectomy. A total of 109 male patients were randomly divided into two groups: the control group (n = 55) received 20 mL of normal saline, and the nefopam group (n = 54) received 20 mg of nefopam 1 h before the end of the operation. At postoperative times of 20 min, 1 h, 2 h, and 6 h, the severity of CRBD was measured using an 11-point numeric rating scale, respectively. The severity of CRBD in the nefopam group was significantly lower than that in the control group at 20 min (4.8 &plusmn, 1.3 vs. 2.3 &plusmn, 1.0, respectively, p = 0.012) and at 1, 2, and 6 h (3.5 &plusmn, 1.2, 2.7 &plusmn, 0.9, and 2.5 &plusmn, 1.0 vs. 4.1 &plusmn, 0.8, 1.6 &plusmn, 0.8, and 1.3 &plusmn, 0.6, respectively, p &lt, 0001). Intraoperative nefopam administration reduced the severity of CRBD in patients undergoing robotic nephrectomy.

Magnesium sulfate can be used as a co-adjuvant drug during the perioperative period and has multiple benefits. Recent evidence suggested that perioperative magnesium sulfate infusion may lower the risk of postoperative acute kidney injury (AKI). We investigated the association between intraoperative magnesium sulfate infusion and incidence of AKI after major laparoscopic abdominal surgery. We retrospectively analyzed the medical records of adult patients 20 years or older who underwent elective major laparoscopic abdominal surgery (>2 hours) between 2010 and 2016. We investigated the association between intraoperative magnesium sulfate infusion and the incidence of postoperative AKI until postoperative day (POD) 3 using a multivariable logistic regression analysis. We included 3,828 patients in this analysis; 357 patients (9.3%) received an intraoperative magnesium sulfate infusion and 186 patients (4.9%) developed postoperative AKI by POD 3. A multivariable logistic regression analysis showed that magnesium infusion was associated with a significant decrease (63%) in postoperative AKI (odds ratio, 0.37; 95% confidence interval, 0.14–0.94; P = 0.037). Our study suggested that intraoperative magnesium sulfate infusion is associated with a reduced risk of postoperative AKI until POD 3 for patients who underwent laparoscopic major abdominal surgery. Well-designed, prospective studies should be conducted to further substantiate these findings.

Thyroid storm (TS) is a life-threatening emergency endocrine condition. Thyroid hormones should be normalized before thyroidectomy is performed in patients with Graves&rsquo, disease. However, thyroid hormone levels are inevitably high in patients undergoing surgery. This study analyzed differences in vital sign changes during thyroidectomy between patients with controlled and uncontrolled Graves&rsquo, disease and assessed thyroid hormone cutoffs for TS. Preoperative levels of the thyroid hormones free T4 (FT4), T3, and thyroid stimulating hormone (TSH) were retrospectively analyzed in patients who underwent total thyroidectomy for Graves&rsquo, disease. Patients were divided into those with uncontrolled Graves&rsquo, (UG) disease, defined as preoperative TSH &lt, 0.3 &micro, IU/mL and FT4 &gt, 1.7 ng/dL, those with controlled Graves&rsquo, (CG) disease, those with extremely uncontrolled Graves&rsquo, (EUG) disease, defined as TSH &lt, 3.4 ng/dL, and finally, those without EUG (non-EUG). The 29 patients with Graves&rsquo, disease included 12 with CG group and 17 with UG. FT4 and T3 concentrations were significantly higher in the UG group. There were no differences in vital sign and anesthetic agent. These 29 patients could also be divided into those with (n = 4) and without EUG (n = 25). The mean age was lower (21.5 vs. 40.9 years, p &lt, 0.001) and the mean operation time was shorter (121.4 vs. 208.8 min, p = 0.003) in the EUG group. Requirements for anesthetic agents were greater in the EUG group. Mean FT4 concentration in the EUG group was 3.8 ng/dL, and there were no changes in vital signs during surgery. Vital sign change during thyroid surgery was not observed in patients with uncontrolled Graves&rsquo, disease up to the twice upper normal limit of T4 level.

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient's cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of Lmna