Structural variation cooperates with permissive chromatin to control enhancer hijacking-mediated oncogenic transcription.

Structural variants (SVs) involving enhancer hijacking can rewire chromatin topologies to cause oncogene activation in human cancers, including hematologic malignancies; however, because of the lack of tools to assess their effects on gene regulation and chromatin organization, the molecular determinants for the functional output of enhancer hijacking remain poorly understood. Here, we developed a multimodal approach to integrate genome sequencing, chromosome conformation, chromatin state, and transcriptomic alteration for quantitative analysis of transcriptional effects and structural reorganization imposed by SVs in leukemic genomes. We identified known and new pathogenic SVs, including recurrent t(5;14) translocations that cause the hijacking of BCL11B enhancers for the allele-specific activation of TLX3 in a subtype of pediatric leukemia. Epigenetic perturbation of SV-hijacked BCL11B enhancers impairs TLX3 transcription, which are required for the growth of t(5;14) leukemia cells. By CRISPR engineering of patient-derived t(5;14) in isogenic leukemia cells, we uncovered a new mechanism whereby the transcriptional output of SV-induced BCL11B enhancer hijacking is dependent on the loss of DNA hypermethylation at the TLX3 promoter. Our results highlight the importance of the cooperation between genetic alteration and permissive chromatin as a critical determinant of SV-mediated oncogene activation, with implications for understanding aberrant gene transcription after epigenetic therapies in patients with leukemia. Hence, leveraging the interdependency of genetic alteration on chromatin variation may provide new opportunities to reprogram gene regulation as targeted interventions in human disease.

Comparison of Catheter Malposition Between Left and Right Ultrasound-Guided Infraclavicular Subclavian Venous Catheterizations: A Randomized Controlled Trial.

OBJECTIVES: Catheter malposition after subclavian venous catheterization (SVC) is not uncommon and can lead to serious complications. This study hypothesized that the left access is superior to the right access in terms of catheter malposition after ultrasound-guided infraclavicular SVC due to the asymmetry of the bilateral brachiocephalic veins. DESIGN: Parallel-armed randomized controlled trial. SETTING: A tertiary referral hospital in Korea. PATIENTS: Patients 20-79 years old who were scheduled to undergo SVC under general anesthesia. INTERVENTIONS: Patients were randomly assigned to either the left (n = 224) or right (n = 225) SVC group. The primary outcome measure was the overall catheter malposition rate. The secondary outcome measures included catheter malposition rates into the ipsilateral internal jugular and contralateral brachiocephalic veins, other catheterization-related complications, and catheterization performance. MEASUREMENTS AND MAIN RESULTS: The catheter malposition rate was lower (10 [4.5%] vs. 31 [13.8%], p = 0.001), especially in the ipsilateral internal jugular vein (9 [4.0%] vs. 24 [10.7%], p = 0.007), in the left SVC group than in the right SVC group. In the left SVC group, catheterization success rates on the first pass (88 [39.3%] vs. 65 [28.9%], p = 0.020) and first-catheterization attempt (198 [88.4%] vs. 181 [80.4%], p = 0.020) were higher whereas times for vein visualization (30 s [18-50] vs. 20 s [13-38], p < 0.001) and total catheterization (134 s [113-182] vs. 132 s [103-170], p = 0.034) were longer. There were no significant differences in other catheterization performance and catheterization-related complications between the two groups. CONCLUSIONS: These findings strengthen the rationale for choosing the left access over the right access for ultrasound-guided infraclavicular SVC.

Synthesis and evaluation of antibody-drug conjugates with high drug-to-antibody ratio using dimaleimide-DM1 as a linker- payload.

The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.

Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma.

Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.

Channelled versus nonchannelled Macintosh videolaryngoscope blades in patients with a cervical collar: a randomized controlled noninferiority trial.

PURPOSE: Channelled blades have the advantage of avoiding stylet use and potential airway injury during videolaryngoscopic intubation. Nevertheless, the effectiveness of channelled Macintosh-type blades has not yet been fully established. We sought to assess the utility of channelled Macintosh-type blades for videolaryngoscopic intubation under cervical spine immobilization. METHODS: We conducted a randomized controlled noninferiority trial in neurosurgical patients with a difficult airway simulated by a cervical collar. Videolaryngoscopic intubation with a reinforced tracheal tube was performed using a channelled Macintosh-type blade without a stylet (channelled group, n = 130) or a nonchannelled Macintosh-type blade with a stylet (nonchannelled group, n = 131). The primary outcome was intubation success rate. Secondary outcomes included time to intubation and incidence or severity of intubation-related complications (subglottic, lingual, and dental injuries; bleeding; sore throat; and hoarseness). RESULTS: The initial intubation success rate was 98% and 99% in the channelled and nonchannelled groups, respectively, showing the noninferiority of the channelled group (difference in proportions -0.8%; 95% confidence interval [CI], -4.8% to 2.9%; predefined noninferiority margin, -5%; P = 0.62). Fewer participants in the channelled group had subglottic injuries than in the nonchannelled group (32% [32/100] vs 57% [54/95]; difference in proportions, -25%; 95% CI, -39% to -11%; P < 0.001). There were no significant differences between the two groups in the overall intubation success rate, time to intubation, and incidence or severity of other intubation-related complications. CONCLUSIONS: For videolaryngoscopic intubation in patients with a cervical collar, channelled Macintosh-type blades are an alternative to nonchannelled Macintosh-type blades, with a noninferior initial intubation success rate and a lower incidence of subglottic injury. STUDY REGISTRATION: CRIS.nih.go.kr ( KCT0005186 ); first submitted 29 June 2020.

RéSUMé: OBJECTIF: Les lames avec canal ont l'avantage de ne pas nécessiter l'utilisation d'un stylet et d'ainsi éviter les lésions potentielles des voies aériennes lors de l'intubation vidéolaryngoscopique. Néanmoins, l'efficacité des lames avec canal de type Macintosh n'a pas encore été pleinement établie. Nous avons cherché à évaluer l'utilité des lames avec canal de type Macintosh pour l'intubation vidéolaryngoscopique lorsque le rachis cervical était immobilisé. MéTHODE: Nous avons mené une étude randomisée contrôlée de non-infériorité chez des patient·es de neurochirurgie présentant des voies aériennes difficiles simulées par le port d'un collier cervical. L'intubation vidéolaryngoscopique avec une sonde trachéale renforcée a été réalisée à l'aide d'une lame Macintosh avec canal sans stylet (groupe avec canal, n = 130) ou d'une lame Macintosh sans canal avec stylet (groupe sans canal, n = 131). Le critère d'évaluation principal était le taux de réussite de l'intubation. Les critères d'évaluation secondaires comprenaient le temps d'intubation et l'incidence ou la gravité des complications liées à l'intubation (lésions sous-glottiques, linguales et dentaires, saignements, maux de gorge et enrouement). RéSULTATS: Le taux de réussite initial de l'intubation était de 98 % et 99 % dans les groupes avec et sans canal, respectivement, montrant la non-infériorité du groupe lame avec canal (différence de proportions −0,8 %; intervalle de confiance [IC] à 95 %, −4,8 % à 2,9 %; marge de non-infériorité prédéfinie, −5 %; P = 0,62). Les lésions sous-glottiques ont été moins nombreuses dans le groupe avec canal que dans le groupe sans canal (32 % [32/100] vs 57 % [54/95]; différence de proportions, −25 %; IC 95 %, −39 % à −11 %; P < 0,001). Il n'y avait pas de différences significatives entre les deux groupes en matière de taux global de réussite de l'intubation, de temps d'intubation et d'incidence ou de gravité des autres complications liées à l'intubation. CONCLUSION: Pour l'intubation vidéolaryngoscopique des patient·es portant un collier cervical, les lames avec canal de type Macintosh constituent une alternative aux lames sans canal de type Macintosh, avec un taux de réussite d'intubation initial non inférieur et une incidence plus faible de lésions sous-glottiques. ENREGISTREMENT DE L'éTUDE: CRIS.nih.go.kr ( KCT0005186 ); première soumission le 29 juin 2020.

Cholecystectomy Increases the Risk of Type 2 Diabetes in the Korean Population: Data From the National Health Insurance Cooperation Health Checkup 2010-2017.

OBJECTIVE: This study assessed whether cholecystectomy is a risk factor for newly developed type 2 diabetes mellitus (T2DM) in the Korean population. BACKGROUND: There is a lack of evidence that cholecystectomy is independently associated with insulin resistance and T2DM. METHODS: This study included all patients aged more than 20 years who had undergone cholecystectomy from 2010 to 2015 (n=55,166) and age-matched and sex-matched control subjects without cholecystectomy (n=110,332) using the National Health Insurance Service database. They were followed up until the date of newly developed T2DM or study end and the incidence of T2DM was traced over a maximum observation period of 7 years. RESULTS: Overall, 55,166 patients who underwent cholecystectomy and 110,332 age-matched and sex-matched controls were followed up for ∼4.7 years, during which, incident T2DM occurred in 5982 (3.61%) patients. Cholecystectomy was associated with 20% higher risk of T2DM after adjustment for all covariates. The cumulative incidence of T2DM also significantly increased in the cholecystectomy group for ∼7 years ( P <0.001). The adjusted hazard ratio (HR) for T2DM was the highest in the group with both cholecystectomy and obesity using the control without both cholecystectomy and obesity as a reference [HR=1.41, 95% confidence interval (CI): 1.29-1.56]. The group with cholecystectomy without obesity showed the comparable risk of incident T2DM compared with the group without cholecystectomy with obesity (HR=1.29, 95% CI: 1.20-1.40 for cholecystectomy without obesity and HR=1.24, 95% CI: 1.14-1.36 for control with obesity). CONCLUSIONS: These results provide evidence that cholecystectomy is associated with an increased risk of newly developed T2DM in the Korean population. Further research is required to elucidate the mechanism of the association between cholecystectomy and incident diabetes.

Effect of driving pressure-guided positive end-expiratory pressure on postoperative pulmonary complications in patients undergoing laparoscopic or robotic surgery: a randomised controlled trial.

BACKGROUND: Individualised positive end-expiratory pressure (PEEP) improves respiratory mechanics. However, whether PEEP reduces postoperative pulmonary complications (PPCs) remains unclear. We investigated whether driving pressure-guided PEEP reduces PPCs after laparoscopic/robotic abdominal surgery. METHODS: This single-centre, randomised controlled trial enrolled patients at risk for PPCs undergoing laparoscopic or robotic lower abdominal surgery. The individualised group received driving pressure-guided PEEP, whereas the comparator group received 5 cm H2O fixed PEEP during surgery. Both groups received a tidal volume of 8 ml kg-1 ideal body weight. The primary outcome analysed per protocol was a composite of pulmonary complications (defined by pre-specified clinical and radiological criteria) within 7 postoperative days after surgery. RESULTS: Some 384 patients (median age: 67 yr [inter-quartile range: 61-73]; 66 [18%] female) were randomised. Mean (standard deviation) PEEP in patients randomised to individualised PEEP (n=178) was 13.6 cm H2O (2.1). Individualised PEEP resulted in lower mean driving pressures (14.7 cm H2O [2.6]), compared with 185 patients randomised to standard PEEP (18.4 cm H2O [3.2]; mean difference: -3.7 cm H2O [95% confidence interval (CI): -4.3 to -3.1 cm H2O]; P<0.001). There was no difference in the incidence of pulmonary complications between individualised (25/178 [14.0%]) vs standard PEEP (36/185 [19.5%]; risk ratio [95% CI], 0.72 [0.45-1.15]; P=0.215). Pulmonary complications as a result of desaturation were less frequent in patients randomised to individualised PEEP (8/178 [4.5%], compared with standard PEEP (30/185 [16.2%], risk ratio [95% CI], 0.28 [0.13-0.59]; P=0.001). CONCLUSIONS: Driving pressure-guided PEEP did not decrease the incidence of pulmonary complications within 7 days of laparoscopic or robotic lower abdominal surgery, although uncertainty remains given the lower than anticipated event rate for the primary outcome. CLINICAL TRIAL REGISTRATION: KCT0004888 (http://cris.nih.go.kr, registration date: April 6, 2020).

Laser guidance for ultrasound-guided radial artery catheterization using smart glasses: a randomized trial.

PURPOSE: The use of smart glasses during ultrasound-guided needle procedures may reduce operators' head movements but has not been shown to improve procedural performance. Laser guidance has been shown to decrease the time required for ultrasound-guided procedures in phantom models but has not been tested clinically. We hypothesized that adding laser guidance to the use of smart glasses for ultrasound-guided radial artery catheterization using the long axis approach would improve performance by relatively inexperienced users unfamilar with these techniques. METHODS: In an unblinded controlled trial, we enrolled 52 patients requiring radial artery catheterization under anesthesia, randomized into two groups: smart glasses only (SO) (control; N = 26) or smart glasses with laser guidance group (SL) (N = 26). We assessed catheterization time (primary outcome), the number of needle redirections, first-pass success rate, and operator satisfaction (100 = most satisfactory; 0 = unsatisfactory). RESULTS: Comparing the SL with the SO group, catheterization time was shorter (median [interquartile range], 13 [9-20] sec vs 24 [18-46] sec, P < 0.001) and the number of needle redirections was lower (0 [0-1] vs 3 [1-3], P < 0.001) while the first-pass success rate (50% vs 12%, P = 0.007) and operator satisfaction score (85 [76-95] vs 52 [44-74], P < 0.001) were higher. CONCLUSION: Laser guidance improved the performance of ultrasound-guided radial artery catheterization using smart glasses in users inexperienced in the long axis in-plane approach. Nevertheless, it is unclear whether these findings are clinically significant. STUDY REGISTRATION DATE: CRIS.nih.go.kr (KCT0007168); registered 8 April 2022.

RéSUMé: OBJECTIF: L'utilisation de lunettes intelligentes pendant les procédures de ponctions échoguidées peut réduire les mouvements de la tête des opérateurs et opératrices, mais il n'a pas été démontré qu'elle améliorait les performances procédurales. Il a été démontré que le guidage laser réduisait le temps requis pour les interventions échoguidées sur des modèles fantômes, mais cette modalité n'a pas été testée cliniquement. Nous avons émis l'hypothèse que l'ajout d'un guidage laser à l'utilisation de lunettes intelligentes pour le cathétérisme échoguidé de l'artère radiale en utilisant une approche longitudinale (long axe) améliorerait les performances d'utilisateurs et utilisatrices relativement inexpérimenté·es et peu familier·ères avec ces techniques. MéTHODE: Dans une étude contrôlée sans insu, nous avons recruté et randomisé en deux groupes 52 patient·es nécessitant un cathétérisme de l'artère radiale sous anesthésie : lunettes intelligentes uniquement (LIU) (témoin N = 26) ou lunettes intelligentes avec guidage laser (LIL) (N = 26). Nous avons évalué le temps de cathétérisme (critère d'évaluation principal), le nombre de réorientation d'aiguilles, le taux de réussite au premier passage et la satisfaction de l'opérateur·trice (100 = le plus satisfaisant; 0 = insatisfaisant). RéSULTATS: En comparant le groupe LIL au groupe LIU, le temps de cathétérisme était plus court (médiane [écart interquartile], 13 [9-20] sec vs 24 [18­46] sec, P < 0,001) et le nombre de réorientations d'aiguilles était plus faible (0 [0­1] vs 3 [1­3], P < 0,001), tandis que le taux de réussite au premier passage (50 % vs 12 %, P = 0,007) et le score de satisfaction des opératrices et opérateurs (85 [76­95] vs 52 [44­74], P < 0,001) étaient plus élevés. CONCLUSION: Le guidage laser à l'aide de lunettes intelligentes a amélioré les performances du cathétérisme échoguidé de l'artère radiale chez des utilisateurs et utilisatrices inexpérimenté·es en approche longitudinale. Nous ne pouvons toutefois pas déterminer si ces résultats sont cliniquement significatifs. DATE D'ENREGISTREMENT DE L'éTUDE: CRIS.nih.go.kr (KCT0007168); enregistré le 8 avril 2022.

Direct versus indirect epiglottis elevation in cervical spine movement during videolaryngoscopic intubation under manual in-line stabilization: a randomized controlled trial.

BACKGROUND: During videolaryngoscopic intubation, direct epiglottis elevation provides a higher percentage of glottic opening score than indirect epiglottis elevation. In this randomized controlled trial, we compared cervical spine movement during videolaryngoscopic intubation under manual in-line stabilization between the two glottis exposure methods. METHODS: Videolaryngoscopic intubation under manual in-line stabilization was performed using C-MAC® D-blade: direct (n = 51) and indirect (n = 51) epiglottis elevation groups. The percentage of glottic opening score was set equally at 50% during videolaryngoscopic intubation in both groups. The primary outcome measure was cervical spine movement during videolaryngoscopic intubation at the occiput-C1, C1-C2, and C2-C5. The secondary outcome measures included intubation performance (intubation success rate and intubation time). RESULTS: Cervical spine movement during videolaryngoscopic intubation was significantly smaller at the occiput-C1 in the direct epiglottis elevation group than in the indirect epiglottis elevation group (mean [standard deviation] 3.9 [4.0] vs. 5.8 [3.4] °, P = 0.011), whereas it was not significantly different at the C1-C2 and C2-C5 between the two groups. All intubations were successful on the first attempt, achieving a percentage of glottic opening score of 50% in both groups. Intubation time was longer in the direct epiglottis elevation group (median [interquartile range] 29.0 [24.0-35.0] vs. 22.0 [18.0-27.0] s, P < 0.001). CONCLUSIONS: When performing videolaryngoscopic intubation under manual in-line stabilization, direct epiglottis elevation can be more beneficial than indirect epiglottis elevation in reducing cervical spine movement during videolaryngoscopic intubation at the occiput-C1. TRIAL REGISTRATION: Clinical Research Information Service (number: KCT0006239, date: 10/06/2021).

Comparison of the recovery profile of remimazolam with flumazenil and propofol anesthesia for open thyroidectomy.

BACKGROUND: Previous studies have consistently reported a slower recovery of consciousness following remimazolam-based total intravenous anesthesia without flumazenil than with propofol. This study aimed to compare the reversal effect of flumazenil on the recovery of consciousness after remimazolam-based total intravenous anesthesia with the propofol recovery profile. METHODS: This prospective, single-blinded, randomized trial included 57 patients undergoing elective open thyroidectomy at a tertiary university hospital. Patients were randomly allocated to receive either remimazolam- or propofol-based total intravenous anesthesia (remimazolam group: 28 patients, propofol group: 29 patients). The primary outcome was the time from the end of general anesthesia to first eye opening (min). The secondary outcomes were the time from the end of the general anesthesia to extubation (min), initial modified Aldrete score measured at the post-anesthesia care unit, length of stay at the post-anesthesia care unit (min), occurrence of postoperative nausea and vomiting during the first 24 h postoperatively, and Korean version of Quality of Recovery-15 score at 24 h postoperatively. RESULTS: The remimazolam group showed significantly faster first eye opening time (2.3 [interquartile range, IQR: 1.8-3.3] min vs. 5.0 [IQR: 3.5-7.8] min, median difference:-2.7 [95% confidence interval, CI: -3.7 to -1.5] min, P < 0.001) and extubation time (3.2 [IQR: 2.4-4.2] min vs. 5.7 [IQR: 4.7-8.3] min, median difference: -2.7 [97.5% CI: -5.0 to -1.6] min, P < 0.001). There were no significant differences in other postoperative outcomes. CONCLUSIONS: The planned incorporation of flumazenil with remimazolam-based total intravenous anesthesia provided rapid and reliable recovery of consciousness.

High peak inspiratory pressure may be associated with intraoperative coughing during neurosurgery under general anesthesia without neuromuscular blockade: a retrospective study.

BACKGROUND: The endotracheal cuff pressure depends on the airway pressure during positive-pressure ventilation. A high endotracheal cuff pressure may be related to intraoperative coughing, which can be detrimental during neurosurgery. We investigated the incidence of intraoperative coughing and its association with peak inspiratory pressure (PIP) during neurosurgery under general anesthesia without neuromuscular blockade. METHODS: This retrospective study divided 1656 neurosurgical patients who underwent total intravenous anesthesia without additional neuromuscular blockade after tracheal intubation into high (PIP > 21.6 cmH2O, n = 318) and low (PIP ≤ 21.6 cmH2O, n = 1338) PIP groups. After propensity score matching, 206 patients were selected in each group. Demographic, preoperative, surgical, and anesthetic data were collected retrospectively from electronic medical records and continuous ventilator, infusion pump, and bispectral index data from a data registry. RESULTS: Intraoperative coughing occurred in 30 (1.8%) patients, including 9 (0.5%) during the main surgical procedure. Intraoperative coughing was more frequent in the high PIP group than in the low PIP group before (14/318 [4.4%] vs. 16/1338 [1.2%], P < 0.001) and after (13/206 [6.3%] vs. 1/206 [0.5%], P = 0.003) propensity score matching. In multivariable logistic regression analysis after propensity score matching, a high PIP (odds ratio [95% confidence interval] 14.22 [1.81-111.73], P = 0.012), tidal volume divided by predicted body weight (mL/kg, 1.36 [1.09-1.69], P = 0.006), and surgical duration (min, 1.01 [1.00-1.01], P = 0.025) predicted intraoperative coughing. CONCLUSION: The incidence of intraoperative coughing was 1.8% in neurosurgical patients undergoing general anesthesia without neuromuscular blockade and might be associated with a high PIP.

Preoperative Prognostic Nutritional Index Is a Prognostic Indicator of Cancer-Specific Survival in Patients Undergoing Endometrial Cancer Surgery.

BACKGROUND: The prognostic nutritional index (PNI) reflects systemic inflammation and nutritional status. This study aimed to evaluate the effect of preoperative PNI on postoperative cancer-specific survival in patients with endometrial cancer (EC). METHODS: Demographic, laboratory, and clinical data were retrospectively collected from 894 patients who underwent surgical resection of EC. Preoperative PNIs were determined from the serum albumin concentration and total lymphocyte count, which were measured within 1 month before surgery. Patients were classified into high PNI (n = 619) and low PNI (n = 275) groups according to the preoperative PNI cut-off value of 50.6. The stabilized inverse probability of treatment weighting (IPTW) method was used to reduce bias: a weighting cohort divided into high PNI (n = 615.4) and low PNI (n = 272.3) groups. The primary outcome measure was postoperative cancer-specific survival. RESULTS: The postoperative cancer-specific survival rate was higher in the high PNI group than the low PNI group in the unadjusted cohort (93.1% vs. 81.5%; proportion difference [95% confidence interval; 95% CI], 11.6% [6.6-16.6%]; P < 0.001) and in the IPTW-adjusted cohort (91.4% vs. 86.0%; 5.4% [0.8-10.2%]; P = 0.021). In the multivariate Cox proportional hazard regression model in the IPTW-adjusted cohort, high preoperative PNI (hazard ratio [95% CI], 0.60 [0.38-0.96]; P = 0.032) was an independent determinant of postoperative cancer-specific mortality. The multivariate-adjusted restricted cubic spline curve for the Cox regression model showed a significant negative association between preoperative PNI and postoperative cancer-specific mortality (P < 0.001). CONCLUSION: High preoperative PNI was associated with improved postoperative cancer-specific survival in patients undergoing surgery for EC.

Erratum: Correction of Affiliations in the Article "Preoperative Prognostic Nutritional Index Is a Prognostic Indicator of Cancer-Specific Survival in Patients Undergoing Endometrial Cancer Surgery".

This corrects the article on p. e163 in vol. 38, PMID: 37270918.

Xerostomia and Its Cellular Targets.

Xerostomia, the subjective feeling of a dry mouth associated with dysfunction of the salivary glands, is mainly caused by radiation and chemotherapy, various systemic and autoimmune diseases, and drugs. As saliva plays numerous essential roles in oral and systemic health, xerostomia significantly reduces quality of life, but its prevalence is increasing. Salivation mainly depends on parasympathetic and sympathetic nerves, and the salivary glands responsible for this secretion move fluid unidirectionally through structural features such as the polarity of acinar cells. Saliva secretion is initiated by the binding of released neurotransmitters from nerves to specific G-protein-coupled receptors (GPCRs) on acinar cells. This signal induces two intracellular calcium (Ca2+) pathways (Ca2+ release from the endoplasmic reticulum and Ca2+ influx across the plasma membrane), and this increased intracellular Ca2+ concentration ([Ca2+]i) causes the translocation of the water channel aquaporin 5 (AQP5) to the apical membrane. Consequently, the GPCR-mediated increased [Ca2+]i in acinar cells promotes saliva secretion, and this saliva moves into the oral cavity through the ducts. In this review, we seek to elucidate the potential of GPCRs, the inositol 1,4,5-trisphosphate receptor (IP3R), store-operated Ca2+ entry (SOCE), and AQP5, which are essential for salivation, as cellular targets in the etiology of xerostomia.

Activity-induced synaptic structural modifications by Akt.

The activity-dependent regulation of synaptic structures plays a key role in synaptic development and plasticity; however, the signaling mechanisms involved remain largely unknown. The serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K), plays a pivotal role in a wide range of physiological functions. We focused on the importance of Akt in rapid synaptic structural changes after stimulation at the Drosophila neuromuscular junction, a well-studied model synapse. Compared with wild-type larvae, akt mutants showed significantly reduced muscle size and an increased number of boutons per area, suggesting that Akt is required for proper pre- and postsynaptic growth. In addition, the level of cysteine string protein (CSP) was significantly increased, and its distribution was different in akt mutants. After high K+ single stimulation, the CSP level of akt mutant NMJs increased dramatically compared with that of wild-type NMJs. Interestingly, ghost boutons without postsynaptic specialization were found in akt mutant NMJs, and the number of these boutons was significantly increased by patterned stimulation. In contrast, the postsynaptic change in the subsynaptic reticulum (SSR) in the akt mutant occurred independent of stimulation. These results suggest that Akt functions in both pre- and postsynaptic growth and differentiation, and in particular, presynaptic action occurs in an activity-dependent manner.

Sevoflurane anesthesia rather than propofol anesthesia is associated with 3-month postoperative hypocortisolism in patients undergoing endoscopic transsphenoidal surgery for non-functional pituitary adenoma with preoperative normal hypothalamic-pituitary-adrenal axis.

PURPOSE: The effects of anesthetic technique on intermediate-term postoperative adrenocorticotropic hormone (ACTH) functional outcomes have not been fully determined in non-functioning pituitary adenoma (NFPA) patients. Postoperative hypocortisolism is potentially life-threatening and requires steroid replacement after pituitary surgery. The present study determined whether sevoflurane anesthesia was predictive of 3-month postoperative hypocortisolism in NFPA patients with preoperative normal hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Demographics, preoperative pituitary hormone status, intraoperative data, and tumor characteristics were retrospectively collected from 429 NFPA patients, who had preoperative normal HPA axis and underwent endoscopic transsphenoidal surgery. Patients were divided into two groups based on intraoperative anesthetic technique: sevoflurane-based inhalation anesthesia group (n = 74) and propofol-based intravenous anesthesia group (n = 355). After propensity score matching, 73 patients were selected in each group and the incidence of 3-month postoperative hypocortisolism (primary outcome measure) was compared between the two groups. RESULTS: The incidence of 3-month postoperative hypocortisolism was higher in the sevoflurane anesthesia group than the propofol anesthesia group before (n = 20[27.0%] vs. n = 49[13.8%], P = 0.008) and after (n = 20 [27.4%] vs. n = 5 [6.8%], P = 0.002) propensity score matching, respectively. Sevoflurane anesthetic use (odds ratio [95% CI] 5.37[1.80-15.98], P = 0.003) and postoperative steroid administration (2.89 [1.06-7.92], P = 0.039) were predictors of 3-month postoperative hypocortisolism. CONCLUSION: In patients with preoperative normal HPA axis undergoing endoscopic transsphenoidal surgery for NFPA, sevoflurane anesthesia and postoperative steroid administration were associated with the development of 3-month postoperative hypocortisolism. A large-scale prospective study is needed to confirm the negative association between sevoflurane anesthesia and postoperative ACTH functional outcome.

Intraarterial catheter diameter and dynamic response of arterial pressure monitoring system: a randomized controlled trial.

The dynamic response (DR) of the arterial pressure monitoring system (APMS) may depend on the intraarterial catheter (IAC) diameter. We hypothesized that adequate DR would be more common when using a smaller IAC. We compared the DR of the AMPS (Auto Transducer™) between three IACs (BD Angiocath Plus™) with different diameters. 353 neurosurgical patients were randomized into three groups undergoing catheterization with a 20-, 22-, or 24-gauge IAC: 20G (n = 119), 22G (n = 117), and 24G (n = 117) groups, respectively. The DR, which depends on the natural frequency and damping coefficient, was divided into four types: adequate (primary outcome measure), underdamped, overdamped, and unacceptable. The frequency of intraoperative IAC malfunction was noted. Adequate DR was observed more frequently in the 22G and 24G groups than the 20G group (13.7% and 15.4% vs. 4.2%, P = 0.011 and 0.004, respectively). The frequency of underdamped DR was higher in the 20G group than the 24G group (86.6% vs. 69.2%, P = 0.001), whereas overdamped DR was more frequent in the 24G group than the 20G and 22G groups (6.0% vs. 0.0% and 0.0%, P = 0.007 and 0.014, respectively). IAC malfunctioned more frequently during surgery in the 24G group than the 20G and 22G groups (15.4% vs. 0.0% and 1.7%, P < 0.001 and P < 0.001, respectively). The frequency of adequate DR was low regardless of the IAC diameter. Nonetheless, in terms of DR and IAC malfunction, a 22-gauge BD Angiocath Plus™ was more suitable for invasive blood pressure monitoring with Auto Transducer™ than a 20- or 24-gauge BD Angiocath Plus™. Registration Registry: ClinicalTrials.gov. Registration number: NCT03642756. Date of Registration: July 27, 2018.

LAR-RPTPs Directly Interact with Neurexins to Coordinate Bidirectional Assembly of Molecular Machineries.

Neurexins (Nrxns) and LAR-RPTPs (leukocyte common antigen-related protein tyrosine phosphatases) are presynaptic adhesion proteins responsible for organizing presynaptic machineries through interactions with nonoverlapping extracellular ligands. Here, we report that two members of the LAR-RPTP family, PTPσ and PTPδ, are required for the presynaptogenic activity of Nrxns. Intriguingly, Nrxn1 and PTPσ require distinct sets of intracellular proteins for the assembly of specific presynaptic terminals. In addition, Nrxn1α showed robust heparan sulfate (HS)-dependent, high-affinity interactions with Ig domains of PTPσ that were regulated by the splicing status of PTPσ. Furthermore, Nrxn1α WT, but not a Nrxn1α mutant lacking HS moieties (Nrxn1α ΔHS), inhibited postsynapse-inducing activity of PTPσ at excitatory, but not inhibitory, synapses. Similarly, cis expression of Nrxn1α WT, but not Nrxn1α ΔHS, suppressed the PTPσ-mediated maintenance of excitatory postsynaptic specializations in mouse cultured hippocampal neurons. Lastly, genetics analyses using male or female Drosophila Dlar and Dnrx mutant larvae identified epistatic interactions that control synapse formation and synaptic transmission at neuromuscular junctions. Our results suggest a novel synaptogenesis model whereby different presynaptic adhesion molecules combine with distinct regulatory codes to orchestrate specific synaptic adhesion pathways.SIGNIFICANCE STATEMENT We provide evidence supporting the physical interactions of neurexins with leukocyte common-antigen related receptor tyrosine phosphatases (LAR-RPTPs). The availability of heparan sulfates and alternative splicing of LAR-RPTPs regulate the binding affinity of these interactions. A set of intracellular presynaptic proteins is involved in common for Nrxn- and LAR-RPTP-mediated presynaptic assembly. PTPσ triggers glutamatergic and GABAergic postsynaptic differentiation in an alternative splicing-dependent manner, whereas Nrxn1α induces GABAergic postsynaptic differentiation in an alternative splicing-independent manner. Strikingly, Nrxn1α inhibits the glutamatergic postsynapse-inducing activity of PTPσ, suggesting that PTPσ and Nrxn1α might control recruitment of a different pool of postsynaptic machinery. Drosophila orthologs of Nrxns and LAR-RPTPs mediate epistatic interactions in controlling synapse structure and strength at neuromuscular junctions, underscoring the physiological significance in vivo.

Global transcriptional activity dynamics reveal functional enhancer RNAs.

Active enhancers of the human genome generate long noncoding transcripts known as enhancer RNAs (eRNAs). How dynamic transcriptional changes of eRNAs are physically and functionally linked with target gene transcription remains unclear. To investigate the dynamic functional relationships among eRNAs and target promoters, we obtained a dense time series of GRO-seq and ChIP-seq data to generate a time-resolved enhancer activity map of a cell undergoing an innate antiviral immune response. Dynamic changes in eRNA and pre-mRNA transcription activities suggest distinct regulatory roles of enhancers. Using a criterion based on proximity and transcriptional inducibility, we identified 123 highly confident pairs of virus-inducible enhancers and their target genes. These enhancers interact with their target promoters transiently and concurrently at the peak of gene activation. Accordingly, their physical disassociation from the promoters is likely involved in post-induction repression. Functional assessments further establish that these eRNAs are necessary for full induction of the target genes and that a complement of inducible eRNAs functions together to achieve full activation. Lastly, we demonstrate the potential for eRNA-targeted transcriptional reprogramming through targeted reduction of eRNAs for a clinically relevant gene, TNFSF10, resulting in a selective control of interferon-induced apoptosis.

Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains.

Genetic variants associated with autism spectrum disorders (ASDs) are enriched in genes encoding synaptic proteins and chromatin regulators. Although the role of synaptic proteins in ASDs is widely studied, the mechanism by which chromatin regulators contribute to ASD risk remains poorly understood. Upon profiling and analyzing the transcriptional and epigenomic features of genes expressed in the cortex, we uncovered a unique set of long genes that contain broad enhancer-like chromatin domains (BELDs) spanning across their entire gene bodies. Analyses of these BELD genes show that they are highly transcribed with frequent RNA polymerase II (Pol II) initiation and low Pol II pausing, and they exhibit frequent chromatin-chromatin interactions within their gene bodies. These BELD features are conserved from rodents to humans, are enriched in genes involved in synaptic function, and appear post-natally concomitant with synapse development. Importantly, we find that BELD genes are highly implicated in neurodevelopmental disorders, particularly ASDs, and that their expression is preferentially down-regulated in individuals with idiopathic autism. Finally, we find that the transcription of BELD genes is particularly sensitive to alternations in ASD-associated chromatin regulators. These findings suggest that the epigenomic regulation of BELD genes is important for post-natal cortical development and lend support to a model by which mutations in chromatin regulators causally contribute to ASDs by preferentially impairing BELD gene transcription.