Adjuvant chemotherapy as a risk factor for chronic postoperative pain after video-assisted thoracoscopic surgery: a 10-year single-centre retrospective study.

OBJECTIVES: The association between adjuvant chemotherapy (AC) and chronic postoperative pain (CPP) after video-assisted thoracoscopic surgery (VATS) for lung cancer resection has not yet been reported. We, therefore, investigated the association between AC and the long-term incidence of CPP after VATS. METHODS: We retrospectively reviewed 3015 consecutive patients who underwent VATS for lung cancer between 2007 and 2016. The patients were divided into 2 groups: those who received (AC group) and those who did not receive (non-AC group) AC within 3 months after VATS. Propensity score analysis was performed to adjust for baseline differences between the 2 groups. The cumulative incidence of CPP at the intervals of 3 months, over 36 months, was compared before and after matching. A Cox proportional hazards regression analysis was used to investigate the predictors of CPP after VATS. RESULTS: We included and assessed 2222 patients in this study. Of these, 320 patients (14.4%) received AC within 3 months post-VATS. The cumulative incidence of CPP during 36 months post-surgery was significantly higher in the AC group than in the non-AC group, before and after matching (log-rank test; P = 0.002 and 0.027, respectively). Cox proportional hazards regression analysis also showed that AC was a significant risk factor for CPP (hazard ratio 1.62, 95% confidence interval 1.16-2.28; P = 0.005). CONCLUSIONS: Our results indicate that AC is an important risk factor for CPP after VATS. Further understanding of the risk factors for CPP may facilitate its prediction and treatment.

Effect of previous emergency psychiatric consultation on suicide re-attempts - A multi-center observational study.

BACKGROUND: The emergency department (ED) is one of the first gateways when suicide attempt patients seek health care services. The purpose of this study was to analyze the hypothesis that people who received emergency psychiatric services in previous suicide attempts will have a lower mortality rate in current ED visits owing to subsequent suicide attempts. METHOD: This retrospective study included patients who visited six EDs, and participated in the injury surveillance and in-depth suicide surveillance for 10 years, from January 2008 to December 2017. The study subjects were adult patients 18 years or older who visited EDs due to suicide attempts. The main explanatory variable is whether psychiatric treatment was provided in previous suicide attempts. The main outcome variable was suicide related mortality. RESULTS: The study included 2144 suicide attempt patients with a previous history of suicide attempts. Among these, 1335 patients (62.2%) had received psychiatric treatment in previous suicide attempts. Mortality was significantly different between the psychiatric consultation group (n = 33, 2.5%) and non-consultation group (n = 47, 5.8%) (P < 0.01). In multivariate logistic regression analysis, previous psychiatric consultation showed a significant association with low mortality (adjusted OR 0.41; 95% CI [0.23-0.72]) and selecting non-fatal suicide methods (adjusted OR 0.47; 95% CI [0.36-0.61]). CONCLUSION: Patients who received psychiatric consultation in previous suicide attempts had a lower suicide-related mortality in current ED visits as compared to patients who did not, and this may have been related to choosing non-fatal suicide methods.

Association between hourly call volume in the emergency medical dispatch center and dispatcher-assisted cardiopulmonary resuscitation instruction time in out-of-hospital cardiac arrest.

OBJECTIVES: Cardiac arrest recognition, ambulance dispatch and dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) by emergency medical dispatch (EMD) are crucial for an optimal outcome of out-of-hospital cardiac arrest (OHCA). In EMD, crowding is caused by a mismatch between the number of emergency calls and the number of dispatchers available per shift. Crowding in the emergency department has been shown to decrease performance and outcomes; however, little is known about the effect of crowding in EMD. We aimed to evaluate the incidence of crowding in the EMD and the effect of emergency call crowding on dispatcher-assisted CPR instruction performance in OHCA calls. METHODS: We used a nationwide OHCA database from 2013 to 2016 consisting of patients with the presumed cardiac origin who were dispatched by Seoul EMD. The main exposure was an hourly number of total incoming emergency calls to EMD. The number of hourly calls was categorized into quartiles (≤40 calls, 41-51 calls, 52-61 calls and ≥62 calls). The primary outcome was successful DA-CPR instruction provision within 120 s. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were estimated to evaluate the association between EMD crowding and outcomes in the multivariable logistic regression model. RESULTS: Of a total of 12,722 patients, the proportion of successful DA instruction was highest in the least-crowded quartile and lowest in the most-crowded quartile (22.7% vs. 15.0%, p < 0.01). The adjusted odds ratio was 0.85 (95% CI 0.74-0.98) in the most-crowded EMD quartile, with a lower proportion of DA instruction within 120 s. Crowding in quartile 4 and quartile 3 was associated with a less favorable neurological outcome in the multivariable logistic regression model (AOR (95% CI) 0.78 (0.60-0.99) and 0.70 (0.54-0.91), respectively). CONCLUSION: Crowding in emergency medicine dispatch caused by increased hourly call volume was associated with delayed dispatcher-assisted CPR instruction provision. Medical directors might consider a strategic approach to addressing crowding in EMD according to the crowding distribution.

Long-term incidence of chronic postsurgical pain after thoracic surgery for lung cancer: a 10-year single-center retrospective study.

BACKGROUND: The long-term incidence of chronic postsurgical pain (CPSP) after thoracic surgery has not yet been reported. METHODS: We retrospectively reviewed the electronic medical records of 4218 consecutive patients who underwent thoracic surgery for lung cancer between 2007 and 2016. We evaluated the long-term incidence of CPSP after thoracic surgery at intervals of 3 months for 36 months. A Cox proportional hazard regression analysis was performed to investigate the predictors of CPSP after thoracic surgery. RESULTS: A total of 3200 patients were included in the analysis. Of these, 459 (14.3%) and 558 (17.4%) patients were diagnosed with CPSP within 3 and 36 months after surgery, respectively. Furthermore, the incidence of CPSP decreased over time. Additionally, 99 (3.1%) patients were newly diagnosed with CPSP at least 6 months after surgery. Female sex (HR 1.20, 95% CI 1.00 to 1.43; p=0.04), longer duration of surgery (HR 1.11, 95% CI 1.03 to 1.20; p<0.01), higher 11-point Numeric Rating Scale score at first outpatient visit after surgery (HR 1.29, 95% CI 1.24 to 1.34; p<0.001), postoperative chemotherapy (HR 1.55, 95% CI 1.26 to 1.90; p<0.001), and postoperative radiation therapy (HR 1.35, 95% CI 1.05 to 1.74; p=0.02) were significant predictors of CPSP for 36 months after surgery. CONCLUSION: Our study showed a decreasing trend in the incidence of CPSP as well as delayed-onset or recurrent CPSP after thoracic surgery. A better understanding of the progression of CPSP after thoracic surgery may provide important information on its prediction and treatment.

The effect of sevoflurane versus desflurane on postoperative catheter-related bladder discomfort in patients undergoing transurethral excision of a bladder tumour: a randomized controlled trial.

PURPOSE: Catheter-related bladder discomfort (CRBD) due to an indwelling urinary catheter can cause postoperative distress, and the mechanism underlying CRBD is linked to the activation of muscarinic receptors. Inhalation of anesthetic agents, such as sevoflurane and desflurane, has differential inhibitory effects on muscarinic receptors. We aimed to compare the effect of intraoperative sevoflurane vs desflurane inhalation on postoperative CRBD. METHODS: Eighty-nine patients undergoing transurethral resection of a bladder tumour (TURBT) were randomly allocated to two groups. The sevoflurane group (n = 45) and the desflurane group (n = 44) received the respective inhalational agents for maintenance of general anesthesia. The incidence and severity (mild/moderate/severe) of CRBD were assessed at zero, one, six, and 24 hr postoperatively. RESULTS: Catheter-related bladder discomfort during the first 24 hr postoperatively occurred in 34/45 (76%) patients receiving sevoflurane compared with 41/44 (93%) patients receiving desflurane [absolute difference 18%; 95% confidence interval [CI], 2 to 33; P = 0.039]. The differences in the rate of CRBD between the sevoflurane and desflurane groups at zero, one, and six hours postoperatively were 24% (95% CI, 7 to 40; P = 0.012), 33% (95% CI, 15 to 49; P = 0.001), and 26% (95% CI, 6 to 43; P = 0.019), respectively. The incidence of moderate to severe CRBD and the number of patients treated with tramadol for CRBD were comparable between the two groups. CONCLUSIONS: As a maintenance agent of general anesthesia, sevoflurane reduced the incidence of early postoperative CRBD in patients undergoing TURBT when compared with desflurane. The protocol for this clinical trial was registered at ClinicalTrials.gov (NCT02096224).

Proteome-wide discovery of mislocated proteins in cancer.

Several studies have sought systematically to identify protein subcellular locations, but an even larger task is to map which of these proteins conditionally relocates in disease (the mislocalizome). Here, we report an integrative computational framework for mapping conditional location and mislocation of proteins on a proteome-wide scale, called a conditional location predictor (CoLP). Using CoLP, we mapped the locations of over 10,000 proteins in normal human brain and in glioma. The prediction showed 0.9 accuracy using 100 location tests of 20 randomly selected proteins. Of the 10,000 proteins, over 150 have a strong likelihood of mislocation under glioma, which is striking considering that few mislocation events have been identified in this disease previously. Using immunofluorescence and Western blotting in both primary cells and tissues, we successfully experimentally confirmed 15 mislocations. The most common type of mislocation occurs between the endoplasmic reticulum and the nucleus; for example, for RNF138, TLX3, and NFRKB. In particular, we found that the gene for the mislocating protein GFRA4 had a nonsynonymous point mutation in exon 2. Moreover, redirection of GFRA4 to its normal location, the plasma membrane, led to marked reductions in phospho-STAT3 and proliferation of glioma cells. This framework has the potential to track changes in protein location in many human diseases.

Distinct transcriptional profiles of angioblasts derived from human embryonic stem cells.

Identification of differentially expressed genes in angioblasts derived from human embryonic stem cells (hESCs) is of great interest for elucidating the molecular mechanisms underlying human vasculogenesis. The aim of this study was to define hESC-derived angioblasts at the clonal level and to perform comparative transcriptional analysis to characterize their distinct gene expression profiles. In a clonal analysis performed in cell-specific differentiation media, hESC-derived CD34(+)CD31(+) cells were identified as angioblasts in that they exhibited a significantly higher ability to form endothelial cell (EC) and smooth muscle cell (SMC) colonies than CD34(+)CD31(-) and CD34(-) cell populations did. Microarray analysis showed that many genes involved in vascular development and signaling transduction were overexpressed in hESC-derived CD34(+)CD31(+) cells, whereas those related to mitosis, the DNA damage response, and translation were substantially downregulated. In addition, comparative gene expression profiling of hESC-derived CD34(+)CD31(+) cells and human somatic primary vascular cells demonstrated that hESC-derived CD34(+)CD31(+) cells expressed key genes involved in the EC and SMC differentiation processes, which supports the result that hESC-derived CD34(+)CD31(+) cells are bipotent angioblasts. Our results may provide insights into the identity and function of hESC-derived angioblasts and may also facilitate further investigation of the molecular mechanisms regulating human embryonic vasculogenesis.

Phospholipase C-epsilon augments epidermal growth factor-dependent cell growth by inhibiting epidermal growth factor receptor down-regulation.

The down-regulation of the epidermal growth factor (EGF) receptor is critical for the termination of EGF-dependent signaling, and the dysregulation of this process can lead to oncogenesis. In the present study, we suggest a novel mechanism for the regulation of EGF receptor down-regulation by phospholipase C-epsilon. The overexpression of PLC-epsilon led to an increase in receptor recycling and decreased the down-regulation of the EGF receptor in COS-7 cells. Adaptor protein complex 2 (AP2) was identified as a novel binding protein that associates with the PLC-epsilon RA2 domain independently of Ras. The interaction of PLC-epsilon with AP2 was responsible for the suppression of EGF receptor down-regulation, since a perturbation in this interaction abolished this effect. Enhanced EGF receptor stability by PLC-epsilon led to the potentiation of EGF-dependent growth in COS-7 cells. Finally, the knockdown of PLC-epsilon in mouse embryo fibroblast cells elicited a severe defect in EGF-dependent growth. Our results indicated that PLC-epsilon could promote EGF-dependent cell growth by suppressing receptor down-regulation.

Siah proteins induce the epidermal growth factor-dependent degradation of phospholipase Cepsilon.

Phospholipase Cepsilon (PLCepsilon) is activated by various growth factors or G-protein-coupled receptor ligands via different activation mechanisms. The Ras association (RA) domain of PLCepsilon is known to be important for its ability to bind with Ras-family GTPase upon growth factor stimulation. In the present study, we identified Siah1 and Siah2 as novel binding partners of the PLCepsilon RA domain. Both Siah1 and Siah2 interacted with the RA2 domain of PLCepsilon, and the mutation of Lys-2186 of the PLCepsilon RA2 domain abolished this association. Moreover, Siah induced the ubiquitination and degradation of PLCepsilon upon epidermal growth factor (EGF) stimulation, and Siah proteins were phosphorylated on multiple tyrosine residues via an Src-dependent pathway upon EGF treatment. The Src inhibitor abolished the EGF-dependent ubiquitination of PLCepsilon, and the Siah1 phosphorylation-deficient mutant could not increase the EGF-dependent ubiquitination and degradation of PLCepsilon. The EGF-dependent degradation of PLCepsilon was blocked in mouse embryonic fibroblast (MEF) cells derived from Siah1a/Siah2 double knockout mice, and the extrinsic expression of wild-type Siah1 restored the degradation of PLCepsilon, whereas the phosphorylation-deficient mutant did not. Siah1 expression abolished PLCepsilon-dependent potentiation of EGF-dependent cell growth. In addition, the expression of wild-type Siah1 in Siah1a/Siah2-double knockout MEF cells inhibited EGF-dependent cell growth, and this inhibition was abolished by PLCepsilon knockdown. Our results suggest that the Siah-dependent degradation of PLCepsilon plays a role in the regulation of growth factor-dependent cell growth.

Grb2 negatively regulates epidermal growth factor-induced phospholipase C-gamma1 activity through the direct interaction with tyrosine-phosphorylated phospholipase C-gamma1.

Phospholipase C-gamma1 (PLC-gamma1) plays pivotal roles in cellular growth and proliferation. Upon the stimulation of growth factors and hormones, PLC-gamma1 is rapidly phosphorylated at three known sites; Tyr771, Tyr783 and Tyr1254 and its enzymatic activity is up-regulated. In this study, we demonstrate for the first time that Grb2, an adaptor protein, specifically interacts with tyrosine-phosphorylated PLC-gamma1 at Tyr783. The association of Grb2 with PLC-gamma1 was induced by the treatment with epidermal growth factor (EGF). Replacement of Tyr783 with Phe completely blocked EGF-induced interaction of PLC-gamma1 with Grb2, indicating that tyrosine phosphorylation of PLC-gamma1 at Tyr783 is essential for the interaction with Grb2. Interestingly, the depletion of Grb2 from HEK-293 cells by RNA interference significantly enhanced increased EGF-induced PLC-gamma1 enzymatic activity and mobilization of the intracellular Ca2+, while it did not affect EGF-induced tyrosine phosphorylation of PLC-gamma1. Furthermore, overexpression of Grb2 inhibited PLC-gamma1 enzymatic activity. Taken together, these results suggest Grb2, in addition to its key function in signaling through Ras, may have a negatively regulatory role on EGF-induced PLC-gamma1 activation.

Sorting nexin 16 regulates EGF receptor trafficking by phosphatidylinositol-3-phosphate interaction with the Phox domain.

Sorting nexins (SNXs) containing the Phox (PX) domain are implicated in the regulation of membrane trafficking and sorting processes of epithelial growth factor receptor (EGFR). In this study, we investigated whether SNX16 regulates EGF-induced cell signaling by regulating EGFR trafficking. SNX16 is localized in early and recycling endosomes via its PX domain. Mutation of the PX domain disrupted the association between SNX16 and phosphatidylinositol 3-phosphate [PtdIns(3)P]. Treatment with wortmannin, a PtdIns 3-kinase inhibitor, abolished the endosomal localization of SNX16, suggesting that the intracellular localization of SNX16 is regulated by PtdIns 3-kinase activity. SNX16 was found to associate with EGFR after stimulation with EGF in COS-7 cells. Moreover, overexpression of SNX16 increased the rate of EGF-induced EGFR degradation and inhibited the EGF-induced up-regulation of ERK and serum response element (SRE). In addition, mutation in the PX domain significantly blocked the inhibitory effect of SNX16 on EGF-induced activation of ERK and SRE. From these results, we suggest that SNX16 directs the sorting of EGFR to the endosomal compartment and thus regulates EGF-induced cell signaling.

Phospholipase C-gamma1 is a guanine nucleotide exchange factor for dynamin-1 and enhances dynamin-1-dependent epidermal growth factor receptor endocytosis.

Phospholipase C-gamma1 (PLC-gamma1), which interacts with a variety of signaling molecules through its two Src homology (SH) 2 domains and a single SH3 domain has been implicated in the regulation of many cellular functions. We demonstrate that PLC-gamma1 acts as a guanine nucleotide exchange factor (GEF) of dynamin-1, a 100 kDa GTPase protein, which is involved in clathrin-mediated endocytosis of epidermal growth factor (EGF) receptor. Overexpression of PLC-gamma1 increases endocytosis of the EGF receptor by increasing guanine nucleotide exchange activity of dynamin-1. The GEF activity of PLC-gamma1 is mediated by the direct interaction of its SH3 domain with dynamin-1. EGF-dependent activation of ERK and serum response element (SRE) are both up-regulated in PC12 cells stably overexpressing PLC-gamma1, but knockdown of PLC-gamma1 by siRNA significantly reduces ERK activation. These results establish a new role for PLC-gamma1 in the regulation of endocytosis and suggest that endocytosis of activated EGF receptors may mediate PLC-gamma1-dependent proliferation.