Multi-omic profiling reveals potential biomarkers of hepatocellular carcinoma prognosis and therapy response among mitochondria-associated cell death genes in the context of 3P medicine.

Background: Cancer cell growth, metastasis, and drug resistance are major challenges in treating liver hepatocellular carcinoma (LIHC). However, the lack of comprehensive and reliable models hamper the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) strategy in managing LIHC. Methods: Leveraging seven distinct patterns of mitochondrial cell death (MCD), we conducted a multi-omic screening of MCD-related genes. A novel machine learning framework was developed, integrating 10 machine learning algorithms with 67 different combinations to establish a consensus mitochondrial cell death index (MCDI). This index underwent rigorous evaluation across training, validation, and in-house clinical cohorts. A comprehensive multi-omics analysis encompassing bulk, single-cell, and spatial transcriptomics was employed to achieve a deeper insight into the constructed signature. The response of risk subgroups to immunotherapy and targeted therapy was evaluated and validated. RT-qPCR, western blotting, and immunohistochemical staining were utilized for findings validation. Results: Nine critical differentially expressed MCD-related genes were identified in LIHC. A consensus MCDI was constructed based on a 67-combination machine learning computational framework, demonstrating outstanding performance in predicting prognosis and clinical translation. MCDI correlated with immune infiltration, Tumor Immune Dysfunction and Exclusion (TIDE) score and sorafenib sensitivity. Findings were validated experimentally. Moreover, we identified PAK1IP1 as the most important gene for predicting LIHC prognosis and validated its potential as an indicator of prognosis and sorafenib response in our in-house clinical cohorts. Conclusion: This study developed a novel predictive model for LIHC, namely MCDI. Incorporating MCDI into the PPPM framework will enhance clinical decision-making processes and optimize individualized treatment strategies for LIHC patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00362-8.

Exploring promotion factors of resilience among emergency nurses: a qualitative study in Shanghai, China.

OBJECTIVE: To qualitatively explore the factors that enhance resilience among emergency nurses (ENs). DESIGN: This study is an exploratory qualitative investigation. Semistructured in-depth interviews were used for data collection, while qualitative content analysis was applied for data analysis. SETTING: A grade A tertiary hospital in Shanghai, China. PARTICIPANTS: The study subjects comprised 17 ENs, who were selected using a purposive sampling method. RESULTS: Three main themes and the nine subthemes emerged from the study, that is, individual resources, including competency, personality traits and occupational benefits; family resources, including close parent-child attachment and supportive family dynamics; social resources, including peer support, organisational support, resilient leadership and popular support. CONCLUSION: This qualitative study explored the factors promoting resilience among ENs and provided a reference for managers to formulate future management strategies. From the perspective of positive psychology, nurses should receive comprehensive support, focusing on improving their professional accomplishment and role ability while prioritising the development of resilient leadership. These efforts are expected to drive progress and growth across the emergency care team.

Perceptions and experiences of Generation Z nursing students during their practicum in an intensive care unit: A qualitative study.

Background: Influenced by socio-cultural and world events, Chinese society has significant intergenerational differences. With rapid economic and cultural development, the unique characteristics of Generation Z nursing students in China may influence the clinical education environment. However, the research on Generation Z in China is still in its infancy. Objectives: This study aimed to explore the experiences and perceptions of Generation Z nursing students during their practicum in an intensive care unit (ICU) in the context of China's unique cultural and historical background. Methods: A phenomenological approach was used in this qualitative study. Semi-structured, face-to-face interviews were conducted with fifteen Generation Z nursing students doing practicum in the ICU in a third-level hospital in Shanghai, China. The data were analyzed using Colaizzi's seven-step method. Result: Three themes emerged: intelligent medical services empowering critical care, perception of multiple challenges, and affirmation of the teaching work in the ICU. Conclusions and implications: The clinical instructors should use a combination of online and offline pedagogy, give positive guidance through role modeling, and develop the self-learning skills of Generation Z nursing students. This might help Generation Z nursing students relieve the stress of practicum in the ICU, more quickly adapt to the clinical environment, and enter nursing positions. The result of this research provided valuable information to help clinical practicum programs in China effectively educate Generation Z nursing students. Good education ensures that health care is safe and effective, making it easier for patients to get better.

Causal Relationship between Mitochondrial-Associated Proteins and Sepsis in ICU Patients: A Mendelian Randomization Study.

BACKGROUND: The alarming mortality rate of sepsis in ICUs has garnered significant attention. The precise etiology remains elusive. Mitochondria, often referred to as the cellular powerhouses, have been postulated to have a dysfunctional role, correlating with the onset and progression of sepsis. However, the exact causal relationship remains to be defined. METHOD: Employing the Mendelian randomization approach, this study systematically analyzed data from the IEUOpenGWAS and UKbiobank databases concerning mitochondrial function-related proteins and their association with sepsis, aiming to delineate the causal relationship between the two. RESULTS: The findings underscored a statistically significant association of GrpE1 with sepsis, registering a P value of 0.005 and an OR of 0.499 (95% CI: 0.307-0.810). Likewise, HTRA2, ISCU, and CUP3 each manifested significant associations with sepsis, yielding OR values of 0.585, 0.637, and 0.634, respectively. These results suggest potential implications of the aforementioned proteins in the pathogenesis of sepsis. CONCLUSION: The present study furnishes novel evidence elucidating the roles of GrpE1, HTRA2, ISCU, and CUP3 in the pathophysiology of sepsis. Such insights pave the way for a deeper understanding of the pathological mechanisms underpinning sepsis and hint at promising therapeutic strategies for the future.

Post-traumatic growth among emergency nurses after COVID-19 in Shanghai, China: a qualitative study.

OBJECTIVES: This study aims to investigate the post-traumatic growth of emergency nurses (ENs) in Shanghai, China, in 2022 following the COVID-19 pandemic. DESIGN: A phenomenological qualitative research approach was employed, with 17 ENs being interviewed between July and August 2022. Data collection was conducted through semistructured, in-depth interviews, and data analysis was carried out using the Colaizzi's seven-step analysis method. SETTING: A third-level hospital in Shanghai. PARTICIPANTS: A total of 17 ENs were interviewed through face-to-face, semistructured, in-depth interviews. RESULTS: Three main themes and eight subthemes were extracted from the data: (a) stress, (b) restructuring and (c) growth. CONCLUSION: Significant stress was imposed on ENs by the Shanghai COVID-19 pandemic, but cognitive restructuring was successfully undergone by them, leading to the experience of growth. It is recommended that post-traumatic growth levels be enhanced through professional psychological counselling and tailored support measures for different stages.

Nafamostat mesylate versus regional citrate anticoagulation for continuous renal replacement therapy in patients at high risk of bleeding: a retrospective single-center study.

PURPOSE: The choice of continuous renal replacement therapy (CRRT) anticoagulation program for patients at high risk of bleeding has always been a complex problem in clinical practice. Clinical regimens include regional citrate anticoagulation (RCA) and nafamostat mesylate (NM). This study aimed to evaluate the efficacy and safety of these two anticoagulants for CRRT in patients at high risk of bleeding to guide their clinical use better. PATIENTS AND METHODS: Between January 2021 and December 2022, 307 patients were screened for this study. Forty-six patients were finally enrolled: 22 in the regional citrate anticoagulation group and 24 in the nafamostat mesylate group. We collected patients' baseline characteristics, laboratory indicators before CRRT, and CRRT-related data. We then performed a statistical analysis of the data from both groups of patients. RESULTS: In our study, the baseline characteristics did not differ significantly between the two groups; the baseline laboratory indicators before CRRT of patients in the two groups were not significantly different. The duration of CRRT was 600 min in the regional citrate anticoagulation (RCA) group, 615 min in the nafamostat mesylate (NM) group; the success rate was 90.7% in the RCA group, and 85.6% in the NM group, the anticoagulant efficacy between the two groups was comparable. There was no significant difference in the safety of anticoagulation between the two groups. We used Generalized Estimating Equations (GEE) to test whether different anticoagulation methods significantly affected the success rate of CRRT and found no statistical difference between RCA and NM. CONCLUSION: Our study suggests that nafamostat mesylate's anticoagulant efficacy and safety are not inferior to regional citrate anticoagulation for continuous renal replacement therapy in patients at high risk of bleeding.

Causal associations of gut microbiota and metabolites on sepsis: a two-sample Mendelian randomization study.

Background: Sepsis stands as a dire medical condition, arising when the body's immune response to infection spirals into overdrive, paving the way for potential organ damage and potential mortality. With intestinal flora's known impact on sepsis but a dearth of comprehensive data, our study embarked on a two-sample Mendelian randomization analysis to probe the causal link between gut microbiota and their metabolites with severe sepsis patients who succumbed within a 28-day span. Methods: Leveraging data from Genome-wide association study (GWAS) and combining it with data from 2,076 European descendants in the Framingham Heart Study, single-nucleotide polymorphisms (SNPs) were employed as Instrumental Variables (IVs) to discern gene loci affiliated with metabolites. GWAS summary statistics for sepsis were extracted from the UK Biobank consortium. Results: In this extensive exploration, 93 distinct genome-wide significant SNPs correlated with gut microbial metabolites and specific bacterial traits were identified for IVs construction. Notably, a substantial link between Coprococcus2 and both the incidence (OR of 0.80, 95% CI: 0.68-0.94, P=0.007) and the 28-day mortality rate (OR 0.48, 95% CI: 0.27-0.85, P=0.013) of sepsis was observed. The metabolite α-hydroxybutyrate displayed a marked association with sepsis onset (OR=1.08, 95% CI: 1.02-1.15, P=0.006) and its 28-day mortality rate (OR=1.17, 95% CI: 1.01-1.36, P=0.029). Conclusion: This research unveils the intricate interplay between the gut microbial consortium, especially the genus Coprococcus, and the metabolite α-hydroxybutyrate in the milieu of sepsis. The findings illuminate the pivotal role of intestinal microbiota and their metabolites in sepsis' pathogenesis, offering fresh insights for future research and hinting at novel strategies for sepsis' diagnosis, therapeutic interventions, and prognostic assessments.

The resilience of emergency and critical care nurses: a qualitative systematic review and meta-synthesis.

Background: Due to the unique work environment, emergency and critical care departments nurses face high job pressure, often resulting in burnout and a high turnover rate. Public health emergencies such as the Corona Virus Disease 2019 pandemic tend to exacerbate these problems further. Therefore, improving the resilience of nurses is crucial to enhance their retention rates. Objective: This systematic review and meta-synthesis of qualitative studies on the resilience of emergency and critical nurses were conducted to provide a reference for clinical managers to develop strategies for improving the resilience of nurses. Methods: Following databases were searched for relevant studies: CINAHL Plus, Elsevier, Cochrane Library, Embase, Medline, OVID, Pubmed, Science Direct, LWW and Web of Science, China National Knowledge Network (CNKI), Wanfang Database (CECDB), VIP Database, and Sinomed. Google Scholar and Opengrey were used to search for gray literature. The literature search period was from the establishment of the database to April 2023. The systematic review of qualitative studies followed the Joanna Briggs Institute (JBI) approach, including critical appraisal using the JBI Checklist and synthesis through meta-synthesis. Confidence of evidence was assessed with JBI's ConQual process. Results: A total of 12 articles were identified, with 59 main results and 9 new integrated categories. Also, 3 themes, i.e., risk factors, protective factors, and personal growth, and 9 sub-themes, i.e., working pressure, negative emotion, an organizational issue, active learning, sense of occupational benefit, social support, self-cognition and regulation, learn to adapt, and self-actualization, were formed. Conclusion: The resilience of emergency and critical care nurses depends on various factors. Managers should prioritize the mental health of nurses and implement measures to enhance their resilience through social support, team building, and psychological capital development. Additionally, management models can be updated based on domestic and international experience to improve nurses' job involvement, optimize nursing quality, and promote the advancement of the nursing profession.

Aggressive alternative splicing events discovered in cecum ligation and puncture induced lung injury.

AIMS: Acute lung injury (ALI) induced by sepsis and its complications have high morbidity and mortality rates globally. The objective of this study was to enhance our understanding of the underlying mechanism of ALI by identifying potential splicing events that are regulated in this condition. MATERIALS AND METHODS: The CLP mouse model was utilized for mRNA sequencing, and the expression and splicing data were analyzed. Verification of the changes in expression and splicing induced by CLP was conducted using qPCR and RT-PCR. RESULTS: Our results showed that splicing-related genes were regulated, suggesting that splicing regulation may be a key mechanism in ALI. We also found that more than 2900 genes displayed alternative splicing in the lungs of mice with sepsis. Using RT-PCR, we verified that TLR4 and other genes had differential splicing isoforms in the lungs of mice with sepsis. We confirmed the presence of TLR4-s in the lungs of mice with sepsis using RNA-fluorescence in situ hybridization. CONCLUSION: Our results suggest that sepsis-induced ALI can significantly alter splicing in the lungs of mice. The list of DASGs and splicing factors is valuable for further study in the search for new treatment approaches for sepsis-induced ALI.

Influence of continuous renal replacement therapy on the plasma concentration of tigecycline in patients with septic shock: A prospective observational study.

Objective: The influence of continuous renal replacement therapy (CRRT) on the steady-state plasma concentration of high-dose tigecycline was investigated in septic shock patients to provide references for drug dosing. Methods: In this prospective observational study, 17 septic shock patients presenting with severe infections needing a broad-spectrum antibiotic therapy with high-dose tigecycline (100 mg per 12 h) in the intensive care unit were included and divided into CRRT group (n = 6) or non-CRRT group (n = 11). The blood samples were collected and plasma drug concentration was determined by SHIMADZU LC-20A and SHIMADZU LCMS 8040. The steady-state plasma concentration was compared between groups using unpaired t-test. Furthermore, between-groups comparisons adjusted for baseline value was also done using multivariate linear regression model. Results: Peak concentration (Cmax) of tigecycline was increased in CRRT group compared to non-CRRT group, but there were no statistical differences (505.11 ± 143.84 vs. 406.29 ± 108.00 ng/mL, p-value: 0.129). Trough concentration (Cmin) of tigecycline was significantly higher in CRRT group than in non-CRRT group, with statistical differences (287.92 ± 41.91 vs. 174.79 ± 33.15 ng/mL, p-value: 0.000, adjusted p-value: 0.000). In safety, Cmin was reported to be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL. In our studies, Cmin of all patients in CRRT group was lower than 474.8 ng/mL. Conclusion: The plasma concentration of tigecycline was increased in septic shock patients with CRRT treatment and only Cmin shown statistical differences. No dose adjustment seems needed in the view of hepatotoxicity. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2000037475.

Association of Blood Glucose Variability with Sepsis-Related Disseminated Intravascular Coagulation Morbidity and Mortality.

Purpose: Sepsis-related disseminated intravascular coagulation (DIC) is closely associated with poor prognosis and high mortality. Higher blood glucose (BG) variability indicates an increased risk of mortality in sepsis; however, its relationship with sepsis-related DIC has not been investigated. This study aimed to determine the association between glucose variability and sepsis-related DIC. Patients and Methods: Patients with sepsis admitted to the intensive care unit were enrolled between October 2017 and January 2021. Baseline data and BG records from the first 72 h were collected. We calculated the glucose liability index (GLI), largest amplitude of glucose excursion, BG standard deviation, and coefficient of variation on days 1 and 3. The relationship between GLI and morbidity of sepsis-related DIC was explored using a competing risk model. In subgroup analysis, we divided patients with and without diabetes into three groups according to the BG range. Results: Of the 238 patients enrolled, 28.2% developed DIC during hospitalization (n=67). GLI on day 3 was found to have the closest relationship with DIC incidence as it has the largest area under the ROC curve and the highest associated odds ratio of death per unit change (GLI3-day: AUC=0.891 OR=1.84), also independently increased the occurrence of DIC after adjusting for the competing risk of death (sub-distribution hazard ratios=1.866, p<0.01). In subgroup analysis, patients with diabetes had worse outcomes under hypoglycemia than under hyperglycemia. Patients without diabetes having stable BG had the best outcomes. Conclusion: Our study suggested that a higher GLI in patients with sepsis at 72 h was independently associated with an increased risk of sepsis-related DIC, which was not associated with pre-existing diabetes.

Population Pharmacokinetics of Tigecycline: A Systematic Review.

Although tigecycline is widely used in clinical practice, its efficiency and optimal dosage regimens remain controversial. The purpose of this article was to help guide tigecycline dosing in different patient subpopulations through comparing the published population pharmacokinetic models of tigecycline, as well as summarizing and determining the potential covariates that markedly influence tigecycline pharmacokinetics. In this review, literature was systematically searched from the PubMed database from inception to March 2022. The articles focusing on population pharmacokinetics for tigecycline in healthy volunteers or patients were included; finally, a total of eight studies were included in this review. NONMEM methods were used in five studies to generate the population pharmacokinetic models. Tigecycline pharmacokinetics were mostly described by a two-compartment model in these included studies. Estimated clearance and volumes of distribution of tigecycline at steady state (Vss) varied widely in different target patient populations, with a range of 7.5-23.1 L/h and 212.7-1087.7 L, respectively. Body-weight and creatinine clearance were the most important predictors of clearance in these studies, while other predictors include age, gender, bilirubin and aspartate aminotransferase. In conclusion, this review showed the large variability of tigecycline population pharmacokinetics, which can provide guide dosing in different target populations. For clinicians, the individual dosing adjustment should be based not only on the indication and pathogen susceptibility but also on the potential important predictors. However, more studies were needed to confirm the necessity of modified dosage regimens in different patient subpopulations.

AFF4 Predicts the Prognosis of Colorectal Cancer Patients and Suppresses Colorectal Cancer Metastasis via Promoting CDH1 Expression.

INTRODUCTION: AF4/FMR2 family member 4 (AFF4) is a core component of super elongation complex (SEC) and regulates the transcription elongation of many genes. AFF4 depletion or amplification is associated with multiple cancers, but its role in colorectal cancer (CRC) has not been investigated so far. METHODS: qRT-PCR and Western blot analyzed AFF4 expression in the paired clinical CRC tissues. The patients' overall survival curve was determined using the Kaplan-Meier plotter. In vitro experiments, such as cell proliferation, migration, and invasion, were used to preliminarily ascertain the role of AFF4 in CRC. A CRC cell liver metastasis animal model was well established. Livers were harvested and examined histologically by a series of indicators, such as tumor nodules, liver weight, ALT/AST activity, and tumor cell identification by hematoxylin-eosin (HE) staining. RESULTS: We firstly examined the expression of AFF4 in colorectal cancer and normal tissues by collecting paired CRC tissues and adjacent normal tissues, revealing that AFF4 was significantly downregulated in CRC patients and lower expression of AFF4 was correlated with poor prognosis. Next, we observed that presence or absence of AFF4 in CRC cells had no effect on cancer cell proliferation, while AFF4 depletion significantly promoted the migration or invasion of CRC cells in vitro. Furthermore, we confirmed that AFF4 deficiency enhanced the metastatic capacity of CRC cells in vivo. Mechanistically, we found that AFF4 upregulated the transcription of CDH1 gene, which encodes E-cadherin and suppresses the epithelial-mesenchymal transition (EMT). Knockdown of AFF4 interfered with CDH1 transcription, resulting in downregulation of E-cadherin expression and the progression of CRC. Moreover, restored CDH1 expression could rescue the phenotype of CRC cells without AFF4. CONCLUSIONS: Collectively, our data demonstrated that AFF4 served as a significant novel regulator of CRC via CDH1 transcriptional regulation and a potential effective therapy target for patients with CRC.

Predictive value of the C-reactive protein/albumin ratio in severity and prognosis of acute pancreatitis.

Aim: To investigate the predictive value of C-reactive protein (CRP) to serum albumin (ALB) ratio in the severity and prognosis of acute pancreatitis (AP), and compare the predictive value of the CRP/ALB ratio with the Ranson score, modified computed tomography severity index (MCTSI) score, and Bedside Index of Severity in Acute Pancreatitis (BISAP) score. Methods: This cohort study retrospectively analyzed clinical data of AP patients from August 2018 to August 2020 in our hospital. Logistic regression analysis was utilized to determine the effects of CRP/ALB ratio, Ranson, MCTSI, and BISAP score on severe AP (SAP), pancreatic necrosis, organ failure, and death. The predictive values of CRP/ALB ratio, Ranson, MCTSI, and BISAP score were examined with the area under the curve (AUC) of the receiver operator characteristic (ROC) curve analysis. DeLong test was used to compare the AUCs between CRP/ALB ratio, Ranson, MCTSI, and BISAP score. Results: Totally, 284 patients were included in this study, of which 35 AP patients (12.32%) developed SAP, 29 (10.21%) organ failure, 30 (10.56%) pancreatic necrosis and 11 (3.87%) died. The result revealed that CRP/ALB ratio on day 2 was associated with SAP [odds ratio (OR): 1.74, 95% confidence interval (CI): 1.32 to 2.29], death (OR: 1.73, 95%CI: 1.24 to 2.41), pancreatic necrosis (OR: 1.28, 95%CI: 1.08 to 1.50), and organ failure (OR: 1.43, 95%CI: 1.18 to 1.73) in AP patients. Similarly, CRP/ALB on day 3 was related to a higher risk of SAP (OR: 1.50, 95%CI: 1.24 to 1.81), death (OR: 1.8, 95%CI: 1.34 to 2.65), pancreatic necrosis (OR: 1.22, 95%CI: 1.04 to 1.42), and organ failure (OR: 1.21, 95%CI: 1.04 to 1.41). The predictive value of CRP/ALB ratio for pancreatic necrosis was lower than that of MCTSI, for organ failure was lower than that of Ranson and BISAP, and for death was higher than that of MCTSI. Conclusion: The CRP/ALB ratio may be a novel but promising, easily measurable, reproducible, non-invasive prognostic score that can be used to predict SAP, death, pancreatic necrosis, and organ failure in AP patients, which can be a supplement of Ranson, MCTSI, and BISAP scores.

[Modern interpretation of "exterior-interior correlation between lung and large intestine" theory in acute and critical cases].

The "exterior-interior relationship between lung and large intestine" is one of the theories of traditional Chinese medicine, which is scientific in modern medicine. The ancients discovered the specific connection between the lung and large intestine, and constructed the theory of "exterior-interior relationship between lung and large intestine" through the Yin-Yang theory and the meridian attachment. The theory of "exterior-interior relationship between lung and large intestine" has been of great significance in the critical care field since the first study on intestinal tract and acute respiratory distress syndrome (ARDS) was carried out in the emergency medicine in 1980s. This article analyzes the consistence of lung and large intestine in early embryonic development, explains the close connection between the lung and large intestine through the intestinal flora translocation theory in sepsis, and reviews the immunoregulation mechanism of helper T cell 17 (Th17) in intestine and lung, and the possible molecular mechanism of immune response, so as to provide physicians with further exploration of the traditional theory of "exterior-interior relationship between lung and the large intestine".

Significance of tumor protein p53 mutation in cellular process and drug selection in brain lower grade (WHO grades II and III) glioma.

Aim: Tumor protein p53 (TP53) mutant is one of the most frequently mutated genes in glioma. Results: The Cancer Genome Atlas data has shown that TP53 mutation is present in 49% of lower grade (World Health Organization [WHO] grades II and III) glioma patients. Data from The Genomics of Drug Sensitivity in Cancer database showed that three drugs: (5Z)-7-oxozeaenol, dabrafenib and nutlin-3a (-), have shown more resistance in patients with TP53 mutation. We identified 1100 differentially expressed genes. Functional enrichment analysis showed that the differentially expressed genes are mainly concentrated in the transport of ionic and cancer-related pathways. The top ten hub genes were identified and an outcome analysis revealed the most critical genes related to prognosis. Conclusion: Our results identified the key genes and pathways that might provide the basic proof to improve individualized treatment in patients with glioma.

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience.

BACKGROUND: Systemic inflammation is an important feature of post-cardiac arrest syndrome (PCAS). This study was designed to determine whether the plasma concentrations of some circulating pro-inflammatory cytokines (interleukin-17 [IL-8], IL-22, IL-23 and IL-33) are of value in predicting the outcome of patients after return of spontaneous circulation (ROSC) during the post-cardiac arrest period. METHODS: This was a prospective observational clinical study. In total, 21 patients (survivors, n = 10; non-survivors, n = 11) who experienced cardiac arrest and successful ROSC with expected survival of at least 7 days were consecutively enrolled from January 2016 to December 2017. Of the 21 enrolled patients, ten survived were designated "survivors". The other eleven patients died between 2 days and 1 months post ROSC. Venous blood was drawn at three time-points: baseline (< 1 h post ROSC), 2 days post ROSC and 7 days post ROSC. Plasma IL-8, IL-22, IL-23 and IL-33 were determined using commercial enzyme-linked immunosorbent assays. RESULTS: Plasma creatinine levels, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were elevated in non-survivors compared with survivors. Plasma levels of IL-17, IL-22, IL-23 and IL-33 of the 21 total patients did not change at 2 or 7 days post ROSC compared to baseline. In survivors, the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were lower than baseline. In non-survivors, plasma levels of IL-17 increased compared with baseline. Receiver operating characteristic curve analysis showed that the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were able to predict the mortality of PCAS patients, and positively correlated with Acute Physiology and Chronic Health Evaluation (APACHE)-II score and time to ROSC. CONCLUSION: These results provide the first evidence that the elevated plasma IL-17 and IL-23 levels are associated with poor outcome in PCAS patients. The role of IL-17/IL-23 axis post ROSC is worth paying attention to in PCAS patients. TRIAL REGISTRATION: Clinicaltrial.govNCT02297776, 2014-11-21.

Plasma Adipokines in Patients Resuscitated from Cardiac Arrest: Difference of Visfatin between Survivors and Nonsurvivors.

BACKGROUND: Adipokines are a group of cytokines or peptides secreted by adipose tissue to exert numerous biological functions. In the present study, we measured the plasma levels of four adipokines (adiponectin, leptin, fatty acid-binding protein 4 (FABP4), and visfatin) in cardiac arrest patients following return of spontaneous circulation (ROSC). METHODS: Totally, 21 patients who experienced cardiac arrest and successful ROSC with expected survival of at least 48 hours (from January 2016 to December 2017) were consecutively enrolled into this prospective observational clinical study. Of the 21 enrolled patients, ten survived, and other eleven died between 2 days and 6 months post ROSC. Venous blood was drawn at three time points: baseline (<1 hour post ROSC), 2 days post ROSC, and 7 days post ROSC. Plasma concentrations of adiponectin, leptin, FABP4, and visfatin were determined using commercial enzyme-linked immunosorbent assays. RESULTS: The plasma visfatin levels at 2 or 7 days post ROSC increased significantly compared with the baseline (P < 0.01), while plasma levels of adiponectin, leptin, and FABP4 did not change. Moreover, plasma visfatin levels in survivors at 2 or 7 days post ROSC were higher than those in nonsurvivors (P < 0.01). Plasma visfatin levels at 2 or 7 days post ROSC were negatively correlated with Acute Physiology and Chronic Health Evaluation (APACHE) II score and time to ROSC. Moreover, receiver operating characteristic curve analysis showed that the plasma visfatin levels at 2 or 7 days post ROSC were good predictors for survival of the patients. CONCLUSION: Elevated plasma visfatin levels may be a marker for better outcome of cardiac arrest patients post ROSC.

Differential effects of heat shock protein 90 and serine 1179 phosphorylation on endothelial nitric oxide synthase activity and on its cofactors.

Endothelial nitric oxide synthase (eNOS) is responsible for maintaining systemic blood pressure, vascular remodeling and angiogenesis. Previous studies showed that bovine eNOS serine 1179 (Serine 1177 for human eNOS) phosphorylation enhanced NO synthesis. Meanwhile, heat shock protein 90 (Hsp90) plays a critical role in maintenance of eNOS structure and function. However, the regulatory difference and importance between Serine 1179 phosphorylation and Hsp90 on eNOS activity have not been evaluated. In current studies, S1179D eNOS was employed to mimic phospho-eNOS and exhibited markedly increased enzyme activity than wild type eNOS (WT eNOS). Hsp90 showed a dose-dependent increase for both WT eNOS and S1179D eNOS activity at the presence of all eNOS cofactors, such as Calcium/Calmodulin (Ca2+ /CaM), BH4, and NADPH etc. The enhancement effects were abolished by dominant-negative mutant Hsp 90 protein. ENOS-cofactors dynamic assay showed that Hsp90 enhanced WT eNOS affinity to NADPH, L-arginine, and CaM but not to Ca2+ and BH4. The impact of eNOS Serine 1179 phosphorylation and Hsp90 on eNOS affinity to cofactors has also been compared. Different from the effect of Hsp90 on eNOS affinity to specific cofactors, Serine 1179 phosphorylation significantly increased eNOS affinity to all cofactors. Moreover, VEGF-induced eNOS phosphorylation in bovine aortic endothelial cells (BAECs) and more NO generation from eNOS compared to control. Inhibition of Hsp90 by geldanamycin decreased eNOS activity and decreased endothelial viability. In conclusion, by changing eNOS structure, Hsp90 profoundly affected eNOS functions, including change of affinity of eNOS to cofactors like Ca2+, L-arginine, BH4 and further affecting NO generation capability. These specific cofactors regulated by Hsp 90 could become potential therapeutic targets of the eNOS-related diseases in future.

ADAR1 is targeted by miR-143 to regulate IL-1ß-induced endothelial activation through the NFκB pathway.

Excessive endothelial activation by inflammatory mediators is a critical contributing factor of sepsis pathophysiology. ADAR1 (adenosine deaminase acting on RNA), an enzyme that binds and edits double-stranded RNAs, exhibits immune regulatory properties. Whether ADAR1 is involved in the pathophysiology of sepsis is unclear. In the present study, we used human umbilical endothelial cells (HUVECs) as an in vitro model system to investigate the roles of ADAR1 in interleukin (IL)-1ß-induced endothelial activation. We found that stimulation with IL-1ß caused opposite changes in the expression of ADAR1 and the adherence molecules VCAM-1 and ICAM-1. ADAR1 overexpression reduced while ADAR1 knockdown enhanced IL-1ß-induced HUVEC activation as assessed by ICAM-1 and VCAM-1 expression and THP-1 monocyte recruitment. Furthermore, ADAR1 was confirmed to be a direct target of miR-143 in HUVECs by a luciferase reporter assay, and miR-143 overexpression promoted while miR-143 knockdown inhibited HUVEC activation by IL-1ß. In addition, ADAR1 overexpression prevented the enhancement effects of miR-143 overexpression on IL-1ß-induced HUVEC activation. Our mechanistic studies revealed that ADAR1 overexpression reduced while ADAR1 knockdown enhanced PKR, IκBα, and NFκB phosphorylation induced by IL-1ß. In addition, blocking NFκB signaling with the specific NFκB inhibitor PDTC (pyrrolidine dithiocarbamate) prevented IL-1ß-induced HUVEC activation enhanced by ADAR1 knockdown. Collectively, these data indicated that ADAR1 is targeted by miR-143 to regulate IL-1ß-induced HUVEC activation, and the NFκB pathway acts as the downstream mediator of ADAR1. In conclusion, miR-143 and ADAR1 may serve as therapeutic targets for sepsis.