Brefeldin A and M-COPA block the export of RTKs from the endoplasmic reticulum via simultaneous inactivation of ARF1, ARF4, and ARF5.

Normal receptor tyrosine kinases (RTKs) need to reach the plasma membrane (PM) for ligand-induced activation, whereas its cancer-causing mutants can be activated before reaching the PM in organelles, such as the Golgi/trans-Golgi network (TGN). Inhibitors of protein export from the endoplasmic reticulum (ER), such as brefeldin A (BFA) and 2-methylcoprophilinamide (M-COPA), can suppress the activation of mutant RTKs in cancer cells, suggesting that RTK mutants cannot initiate signaling in the ER. BFA and M-COPA block the function of ADP-ribosylation factors (ARFs) that play a crucial role in ER-Golgi protein trafficking. However, among ARF family proteins, the specific ARFs inhibited by BFA or M-COPA, that is, the ARFs involved in RTKs transport from the ER, remain unclear. In this study, we showed that M-COPA blocked the export of not only KIT but also PDGFRA/EGFR/MET RTKs from the ER. ER-retained RTKs could not fully transduce anti-apoptotic signals, thereby leading to cancer cell apoptosis. Moreover, a single knockdown of ARF1, ARF3, ARF4, ARF5, or ARF6 could not block ER export of RTKs, indicating that BFA/M-COPA treatment cannot be mimicked by the knockdown of only one ARF member. Interestingly, simultaneous transfection of ARF1, ARF4, and ARF5 siRNAs mirrored the effect of BFA/M-COPA treatment. Consistent with these results, in vitro pulldown assays showed that BFA/M-COPA blocked the function of ARF1, ARF4, and ARF5. Taken together, these results suggest that BFA/M-COPA targets at least ARF1, ARF4, and ARF5; in other words, RTKs require the simultaneous activation of ARF1, ARF4, and ARF5 for their ER export.

Association between averaged intraoperative nociceptive response index and postoperative complications after lung resection surgery.

OBJECTIVES: Since postoperative complications, defined as Clavien-Dindo grade ≥II, correlate with long-term survival after lung resection surgery in patients with primary lung cancer, identification of intraoperative risk factors for postoperative complications is crucial for better perioperative management. In the present study, we investigated the possible association between intraoperative variables for use in anaesthetic management and Clavien-Dindo grade ≥II. METHODS: In this multi-institutional observational study, consecutive adult patients undergoing video-assisted thoracic surgery for primary lung cancer under general anaesthesia from March 2019 to April 2021 were enrolled. All patients were divided into 2 groups with Clavien-Dindo grade

Association between thoracic epidural block and major complications after pleurectomy/decortication for malignant pleural mesothelioma under general anesthesia.

INTRODUCTION: A curative-intent surgical procedure, pleurectomy/decortication, for malignant pleural mesothelioma is accompanied by a high incidence of major postoperative complications. Although epidural block, which suppresses nociception during and after surgery, reportedly has both benefits and disadvantages in terms of outcomes after thoracic surgery for other diseases, the effects of epidural block on major complications after pleurectomy/decortication have not been evaluated. The aim of this study was to evaluate the association between epidural block and major postoperative complications following pleurectomy/decortication. METHODS: In a single-institutional observational study, consecutive adult patients undergoing pleurectomy/decortication under general anesthesia were enrolled from March 2019 to December 2021. Multivariable logistic regression analysis was performed to determine the association between perioperative variables and major complications. Next, patients were divided into two groups: general anesthesia with and without epidural block. Incidences of major postoperative complications, defined as Clavien-Dindo grades≥III, were compared between groups. RESULTS: In all patients enrolled with American Society of Anesthesiologists (ASA) physical status II or III (n=99), general anesthesia without epidural block was identified as a sole risk factor for major complications among perioperative variables. The incidence of major complications was 32.3% (95% CI 19.1% to 49.2%) in patients with epidural block (n=34), which was significantly lower than 63.1% (95% CI 50.9% to 73.8%) in patients without epidural block (n=65). In sensitivity analysis in patients with ASA physical status II alone, the same results were obtained. CONCLUSION: Epidural block is likely associated with reduction of the incidence of major complications after pleurectomy/decortication for malignant pleural mesothelioma under general anesthesia.

Intra-operative nociceptive responses and postoperative major complications after gastrointestinal surgery under general anaesthesia: A prospective cohort study.

BACKGROUND: Surgical procedures stimulate nociception and induce physiological responses according to the balance between nociception and antinociception. The severity of surgical stimuli is associated with major postoperative complications. Although an intra-operative quantitative index representing surgical invasiveness would be useful for anaesthetic management to predict and prevent major complications, no such index is available. OBJECTIVES: To identify associations between major complications after gastrointestinal surgery and intra-operative quantitative values from intra-operative nociception monitoring. DESIGN: A multi-institutional observational study. SETTING: Two university hospitals. PATIENTS: Consecutive adult patients undergoing gastrointestinal surgery under general anaesthesia. MAIN OUTCOME MEASURES: Averaged values of nociceptive response index from start to end of surgery (mean NR index) and risk scores of the Surgical Mortality Probability Model (S-MPM) were calculated. Pre and postoperative serum C-reactive protein (CRP) levels were obtained. After receiver-operating characteristic (ROC) curve analysis, all patients were divided into groups with high and low mean nociceptive response index. Associations between mean nociceptive response index and postoperative major complications, defined as Clavien-Dindo grade at least IIIa, were examined using logistic regression analysis. RESULTS: ROC curve analysis showed a nociceptive response index cut-off value for major complications of 0.83, and we divided patients into two groups with mean nociceptive response index less than 0.83 and at least 0.83. The incidence of major complications was significantly higher in patients with mean nociceptive response index at least 0.83 (23.1%; n = 346) than in patients with mean nociceptive response index less than 0.83 (7.7%; n = 443; P < 0.001). Multivariate analysis revealed emergency surgery, S-MPM risk score, mean nociceptive response index and postoperative CRP levels as independent risk factors for major complications. CONCLUSION: Mean nociceptive response index during surgery likely correlates with major complications after gastrointestinal surgery. TRIAL REGISTRATION: The current observational study had no intervention, and was therefore, not registered.

Complex effects of continuous vasopressor infusion on fluid responsiveness during liver resection: A randomised controlled trial.

BACKGROUND: Fluid responsiveness is an important factor to consider for fluid volume loading during major surgery. The effect of continuous vasopressor infusion on fluid responsiveness during prolonged major surgery is a concern. OBJECTIVE: We hypothesised that continuous vasopressor infusion during major surgery might not exert significant effects on changes in stroke volume variation (SVV) following fluid bolus infusion, and thereby on fluid responsiveness. DESIGN: Randomised controlled trial. SETTING: University hospital from April 2014 to August 2016. PATIENTS: Patients undergoing liver resection who were randomised to receive continuous intravenous infusion of phenylephrine (P group), norepinephrine (N group), or no vasopressor (C group) (n=17/group). Exclusion criteria were cardiac arrhythmia and severe cardiac, pulmonary or renal dysfunction. INTERVENTION: Patients received 4 ml kg fluid boluses of 6% hydroxyethyl starch solution when SVV was at least 12%. Vasopressors were administered continuously to maintain the systemic vascular resistance index at more than 1900 dyn s cm m. MAIN OUTCOME MEASURES: Cardiac index and SVV were measured using the FloTrac/Vigileo system (Version 4.00). The number of fluid boluses with fluid responsiveness (i.e. >15% increase in cardiac index) was compared between groups using multilevel logistic regression analysis. RESULTS: Numbers of fluid responsive boluses in the C, P and N groups were 12 (14%), 22 (34%) and 19 (27%), respectively. Odds ratios on fluid responsiveness for phenylephrine and norepinephrine compared with the control were 3.65 (97.5% confidence interval, 1.15 to 11.6; P = 0.012) and 2.56 (97.5% confidence interval, 0.82 to 8.00; P = 0.064), respectively. Decreases in SVV after fluid bolus infusion for the P and N groups were comparable with the C group (P = 0.23 and 0.53, respectively). CONCLUSION: Continuous administration of phenylephrine increased fluid responsiveness during liver resection, suggesting complex effects of continuous vasopressor infusion involving changes in cardiac preload and afterload. TRIAL REGISTRATION: UMIN000011024.

Development of Wearable Sheet-Type Shear Force Sensor and Measurement System that is Insusceptible to Temperature and Pressure.

A sheet-type shear force sensor and a measurement system for the sensor were developed. The sensor has an original structure where a liquid electrolyte is filled in a space composed of two electrode-patterned polymer films and an elastic rubber ring. When a shear force is applied on the surface of the sensor, the two electrode-patterned films mutually move so that the distance between the internal electrodes of the sensor changes, resulting in current increase or decrease between the electrodes. Therefore, the shear force can be calculated by monitoring the current between the electrodes. Moreover, it is possible to measure two-dimensional shear force given that the sensor has multiple electrodes. The diameter and thickness of the sensor head were 10 mm and 0.7 mm, respectively. Additionally, we also developed a measurement system that drives the sensor, corrects the baseline of the raw sensor output, displays data, and stores data as a computer file. Though the raw sensor output was considerably affected by the surrounding temperature, the influence of temperature was drastically decreased by introducing a simple arithmetical calculation. Moreover, the influence of pressure simultaneously decreased after the same calculation process. A demonstrative measurement using the sensor revealed the practical usefulness for on-site monitoring.

Experimental validation of spatial Fourier transform-based multiple sound zone generation with a linear loudspeaker array.

Generating acoustically bright and dark zones using loudspeakers is gaining attention as one of the most important acoustic communication techniques for such uses as personal sound systems and multilingual guide services. Although most conventional methods are based on numerical solutions, an analytical approach based on the spatial Fourier transform with a linear loudspeaker array has been proposed, and its effectiveness has been compared with conventional acoustic energy difference maximization and presented by computer simulations. To describe the effectiveness of the proposal in actual environments, this paper investigates the experimental validation of the proposed approach with rectangular and Hann windows and compared it with three conventional methods: simple delay-and-sum beamforming, contrast maximization, and least squares-based pressure matching using an actually implemented linear array of 64 loudspeakers in an anechoic chamber. The results of both the computer simulations and the actual experiments show that the proposed approach with a Hann window more accurately controlled the bright and dark zones than the conventional methods.

Remineralization of primary tooth enamel from individuals with Down syndrome.

PURPOSE: The purpose of this study was to clarify the characteristics of primary tooth enamel of Down syndrome patients (DSPs). We examined 9 primary teeth of Down syndrome children and 11 primary teeth of normally developed children to investigate the remineralization processes of enamel by transverse microradiography and X ray micro analyzer (XMA). METHODS: Mineral loss, lesion depth, maximum mineral value, minimum mineral value, depth of maximum mineral value, and depth of minimum mineral value were used to analyze transverse microradiography (TMR). In addition, we calculated the percentage of enamel remineralization. RESULTS: All the parameters in the 2 groups showed marked recovery. The results indicated that the Down syndrome group was significantly remineralized the same way as the control group. According to the comparison of mineral content distribution by XMA, the content distribution of magnesium was different between the 2 groups. CONCLUSION: While recovery through remineralization of primary teeth was similar between Down syndrome children and normally developed children, the mechanism of remineralization process may be different between the 2 groups; consequently, magnesium may be considered as one of the factors affecting recovery.