Recent progress in the development of ursolic acid derivatives as anti-diabetes and anti-cardiovascular agents.

Ursolic acid (UA) is a pentacyclic triterpenoid, which exhibits many biological activities, particularly in anti-cardiovascular and anti-diabetes. The further application of UA is greatly limited due to its low bioavailability and poor water solubility. Up to date, various UA derivatives have been designed to overcome these shortcomings. In this paper, the authors reviewed the development of UA derivatives as the anti-diabetes anti-cardiovascular reagents.

[Effect of fraction of inspired oxygen baseline level on the mask ventilation time before intubation in emergency patients by monitoring of expiratory oxygen concentration].

OBJECTIVE: To investigate the effect of different fraction of inspired oxygen (FiO2) baseline levels before endotracheal intubation on the time of expiratory oxygen concentration (EtO2) reaching the standard in emergency patients with the EtO2 as the monitoring index. METHODS: A retrospective observational study was conducted. The clinical data of patients receiving endotracheal intubation in the emergency department of Peking Union Medical College Hospital from January 1 to November 1 in 2021 were enrolled. In order to avoid interference with the final result due to inadequate ventilation caused by non-standard operation or air leakage, the process of the continuous mechanical ventilation after FiO2 was adjusted to pure oxygen in patients who had been intubated was selected to simulate the process of mask ventilation under pure oxygen before intubation. Combined with the electronic medical record and the ventilator record, the changes of the time required to reach 0.90 of EtO2 (that was, the time required to reach the standard of EtO2) and the respiratory cycle required to reach the standard after adjusting FiO2 to pure oxygen under different baseline levels of FiO2 were analyzed. RESULTS: 113 EtO2 assay records were collected from 42 patients. Among them, 2 patients had only one EtO2 record due to the FiO2 baseline level of 0.80, while the rest had two or more records of EtO2 reaching time and respiratory cycle corresponding to different FiO2 baseline level. Among the 42 patients, most of them were male (59.5%), elderly [median age was 62 (40, 70) years old] patients with respiratory diseases (40.5%). There were significant differences in lung function among different patients, but the majority of patients with normal function [oxygenation index (PaO2/FiO2) > 300 mmHg (1 mmHg ≈ 0.133 kPa), 38.0%]. In the setting of ventilator parameters, combined with the slightly lower arterial partial pressure of carbon dioxide of patients [33 (28, 37) mmHg], mild hyperventilation phenomenon was considered to be widespread. With the increased in FiO2 baseline level, the time of EtO2 reaching standard and the number of respiratory cycles showed a gradually decreasing trend. When the FiO2 baseline level was 0.35, the time of EtO2 reaching the standard was the longest [79 (52, 87) s], and the corresponding median respiratory cycle was 22 (16, 26) cycles. When the FiO2 baseline level was increased from 0.35 to 0.80, the median time of EtO2 reaching the standard was shortened from 79 (52, 78) s to 30 (21, 44) s, and the median respiratory cycle was also reduced from 22 (16, 26) cycles to 10 (8, 13) cycles, with statistically significant differences (both P < 0.05). CONCLUSIONS: The higher the FiO2 baseline level of the mask ventilation in front of the endotracheal intubation in emergency patients, the shorter the time for EtO2 reaching the standard, and the shorter the mask ventilation time.

Incidence and diagnostic validity of difficult airway in emergency departments in China: a cross-sectional survey.

Background: The difficult airway is a topic of concern for any physician performing intubation. Severe adverse events which can happen because of an unexpected difficult airway emphasize the importance of prediction. This study aimed to investigate the incidence of difficult airways in emergency departments in mainland China and ascertain the predictive value of common assessment formulas. Methods: This study was a multicentral, cross-sectional investigation of patients intubated in emergency departments in mainland China between March 1-30, 2021. Frequencies and percentages were calculated for patient characteristics. Diagnostic values were analyzed by sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, the area under the curve, and corresponding P values. Results: Nine hundred and eighty-five patients in 41 hospitals were enrolled in the study. Elderly male patients occupied most of the intubated patients. The difficult face mask ventilation rate (8.2%) was higher, but the difficult glottic exposure (6.8%) and intubation (2.1%) rates were low, while there was widespread use of enhanced visualization equipment (80.6%). Four combined emergency applicable evaluation methods showed a certain predictive value for the difficult airway with a sensitivity [0.71; 95% confidence interval (CI): 0.47-0.89], specificity (0.79; 95% CI: 0.76-0.81), and the area under the curve (0.75; 95% CI: 0.64-0.87, P<0.01). Conclusions: Despite an insufficient predictive ability for current difficult airway evaluation methods, there were relatively low rates of difficult airways during ED intubations in mainland China. Continuing focus on the difficult airway problems and optimizing airway assessment are required.

Usefulness of the estimation of physiologic ability and surgical stress (E-PASS) system for prediction of complication and prognosis in hepatocellular carcinoma patients after hepatectomy.

Background: Estimation of physiologic ability and surgical stress (E-PASS) system was verified in predicting postoperative complications or mortality in many surgical operations. This research aimed to investigate whether the E-PASS system could predict postoperative complications and was related with long-term prognosis in primary hepatocellular carcinoma (HCC) patients. Methods: A total of 236 HCC patients who underwent liver resection were collected in this study. We performed univariate analyses to determine the potential risk factors for complications after hepatectomy. The potential independent risk factors were then included in the logistic regression for multivariable analysis. The optimal cutoff value of Comprehensive Risk Score (CRS) was identified by a receiver operating characteristic (ROC) curve. Based on this value, the patients were divided into two groups to investigate the relation between CRS with postoperative complications. The relation between CRS and overall survival (OS) or recurrence-free survival (RFS) was analyzed further in these two groups. Results: Postoperative complications occurred in 79 patients. Multivariable analysis suggested that CRS was independent factor for predicting postoperative complications (P<0.001). The optimal CRS cutoff value in our study was 0.126. Patients with high Preoperative Risk Score (PRS) had a higher rate of postoperative complications occurrence, both major and mild complications (P<0.001). Our study showed that HCC patients with higher CRS had poorer survival prognosis [hazard ratio (HR): 3.735, 95% confidence interval (CI): 1.200-11.631, P=0.023]. The 3-year OS rate of high CRS group (CRS ≥0.126) and low CRS group (CRS <0.126) were 66.2% vs. 84.8% (P<0.001), respectively. Conclusions: For HCC patients after liver resection, E-PASS was an effective predictive system for evaluating the risks of postoperative complications and may can predict prognosis in long term.

Primary malignant melanoma in gastroesophageal junction with 36 months' recurrence-free: a case report.

Background: Melanoma is a sinister malignant tumor originates from melanocytes and is characterized by the presence of black pigmentation in the tissue. The vast majority of melanomas are cutaneous melanomas, and primary mucosal melanomas originating from the esophagus are extremely rare. Primary malignant melanoma of esophagus (PMME) accounts for 0.1% to 0.2% of all primary esophageal malignancies. PMME possess high invasiveness but are insensitive to various treatments, so the prognosis is disappointing. Most literature reported that patients are prone to death from complications of tumor metastasis soon, even they undergo radical surgery. Case Description: In this case report, we admitted a 67-year-old female patient with recurrent chest tightness for 2 years and chest pain for 15 days on October 4, 2017. Preoperative imaging examinations, including computerized tomography (CT) and upper gastrointestinal examination by barium revealed stenosis of the lower esophagus and the fundus of the stomach, with mucosa destruction and lymph node metastasis in the hepatic-gastric space. A laparoscope assisted total gastrectomy with D2 lymph node resection and Roux-en-Y anastomosis was performed without adjuvant immunotherapy or targeted therapies. Postoperative pathological examination and immunohistochemical staining indicated malignant melanoma. Meanwhile we did not find a cutaneous lesion, this patient was therefore diagnosed with a rare PMME. There was no sign of recurrence or metastasis during the latest follow-up of 36 months after the operation, which also exceeded the median recurrence-free survival time in the existing cases worldwide. Conclusions: Therefore, we recommend early radical surgery, which may be beneficial to the PMME patient.

Tracheal Intubation in Emergency Departments in China: A National Cross-Sectional Survey.

Background: Tracheal intubation is a necessary but risky procedure performed in emergency departments (EDs) around the world. Relatively high morbidity has been encountered in Chinese EDs, which has raised concerns about peri-intubation ED management. This study aimed to investigate intubation procedures and identify any areas for improvement in Chinese EDs. Methods: This was a questionnaire-based survey lasting 1 month (March 2021) in 41 tertiary-care hospital EDs in mainland China. The primary outcome was complications associated with intubation. Secondary outcomes were the first-pass success rate and blood pressure variations during intubation. Univariate and binary logistic regression analyses were used to find possible risk factors for first-pass intubation failure. Results: In total, 1,020 replies were analyzed out of 1,080 surveys submitted (94.4% response rate). Most patients were elderly men with severe medical conditions like cardiac arrest (24.8%). In total, 97.2% of patients were given preoxygenation, and 48.1% received some form of pretreatment. Induction drugs (e.g., etomidate and ketamine) were less often used: 39.9% of intubations used sedatives, 5.5% used analgesics, and only 5.3% used muscle relaxants. The overall first-pass intubation success rate was 85.7% and was accompanied by a 19.8% adverse event rate. A marked decrease in blood pressure after intubation was also identified. Conclusion: This survey found an 85.7% tracheal intubation first-pass success rate (which is relatively high compared to other countries) and a 19.8% adverse event rate (which is also relatively high). Given the very low rate of using induction medications (5.3% used muscle relaxants), future education should focus on induction drugs and traditional intubation techniques.

The Estimation of Physiologic Ability and Surgical Stress (E-PASS) model as a predictor of postoperative complications and mortality after digestive surgeries: a meta-analysis and systematic review.

BACKGROUND: Conflicting results exist about the usefulness of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) model in patients undergoing digestive surgeries. Thus, this study aims to analyze and evaluate the E-PASS model for predicting postoperative complications and mortality. METHODS: A literature search strategy for "E-PASS" was carried out in PubMed, Embase, Google Scholar, Ovid, and Cochrane databases for studies published before November 2020. "E-PASS" or "Estimation of Physiologic Ability and Surgical Stress" were used as the search terms in all databases, and a total of 20 published English language studies with available data relating to digestive surgery were selected for this study. Clinical data and indices including preoperative risk score (PRS), surgical stress score (SSS), comprehensive risk score (CRS), postoperative complications, mortality, and overall survival (OS) were collected. Meta-analyses of heterogeneity were performed using Review Manager version 5.3 and STATA 14.0. RESULTS: Twenty studies with 9,136 patients were included in our meta-analysis. Using a random-effects model, the indices of the E-PASS model in patients with postoperative complications were significantly greater than those in patients without complications [PRS: 95% confidence interval (CI): 0.14-1.50; SSS: 95% CI: 0.28-1.06; CRS: 95% CI: 048-1.49]. Moreover, patient morbidity and mortality were associated with a higher CRS (morbidity: 95% CI: 2.17-6.29; mortality: 95% CI: 1.57-4.78), while subgroup analyses showed that a high CRS in the elderly was related to increased morbidity (95% CI: 1.57-4.78) without heterogeneity. In addition, we found that a high E-PASS CRS was significantly associated with shorter OS after digestive surgery (95% CI: 1.24-5.41). DISCUSSION: The higher CRS score in the E-PASS model accompanies with many postoperative complications, increased mortality and shorter OS. Collectively, the E-PASS model is a convenient and effective risk assessment for patients undergoing digestive surgeries. More stringently designed studies are expected to develop better estimates of the application value of this model in digestive surgeries.

Can bag-valve mask ventilation with positive end-expiratory pressure reduce hypoxia during intubation? A prospective, randomized, double-blind trial.

BACKGROUND: Hypoxia is one of the life-threatening complications of endotracheal intubation. Supplemental oxygen and ventilation play a vital role in preventing hypoxia. Bag-valve mask (BVM) ventilation is frequently used before intubation, and its ability to improve oxygenation was recently confirmed. It is still unclear if positive end-expiratory pressure (PEEP) added to BVM ventilation can further reduce hypoxia during intubation. METHODS: This will be a prospective, randomized, double-blind trial to determine if PEEP combined with BVM ventilation can reduce the incidence of hypoxia during intubation compared with conventional BVM ventilation. The lowest oxygen saturation and incidence of complications will be compiled to verify the comparative effectiveness and safety of the two groups. DISCUSSION: BMV ventilation with PEEP is hoped to further reduce the incidence of hypoxia during intubation. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000035156 . Registered on August 2, 2020. It had begun enrollment after passing ethical review but before registration.

Efficacy of prophylactic methylprednisolone on reducing the risk of post-extubation stridor in patients after an emergency intubation: study protocol for a randomized controlled trial.

BACKGROUND: Post-extubation stridor (PES) is one of the most common complications of invasive respiratory support, with severe cases leading to possible extubation failure (reintubation within 48 h) and increased mortality. Previous studies confirmed that prophylactic corticosteroids play an important role in reducing the risk of PES and extubation failure. However, few studies have looked at the efficacy of corticosteroids on preventing PES in patients after an emergency intubation. AIM: To evaluate whether a single dose of methylprednisolone given over a set timeframe before extubation is effective in preventing PES in patients after an emergency intubation. METHODS: A multicenter, randomized, placebo-controlled trial will be performed in an emergency department (ED) setting. The trial will include 132 patients who fail a cuff-leak test (CLT) prior to the intervention. Patients will be randomly assigned to either intravenous methylprednisolone (40 mg) or placebo 4 h prior to extubation. Other eligible patients who pass the CLT will be included in a non-intervention (observation) group. The primary endpoint is the incidence of PES within 48 h after extubation. Secondary endpoints include oxygen therapy, respiratory support requirements, reintubation secondary to PES, adverse effects within 48 h after extubation, hospital length of stay, and hospital mortality. DISCUSSION: Patients who are intubated on an emergency basis have a higher risk of intubation-related complications. Previous studies have examined treatment regimens involving more than 10 different variations on corticosteroid treatments for PES prevention, while for ED therapy, only a simple and effective treatment would be appropriate. Corticosteroid administration is usually accompanied by adverse effects; thus, this study will be important for further risk stratification among intubated ED patients. TRIAL REGISTRATION: Chictr.org.cn ChiCTR2000030349 . Registered on 29 February 2020.

Epigenome-wide DNA methylation profiling of portal vein tumor thrombosis (PVTT) tissues in hepatocellular carcinoma patients.

Aberrant methylation is a hallmark of hepatocellular carcinoma and plays an important role in tumor initiation and progression. However, the epigenome-wide methylation patterns of portal vein tumor thrombosis (PVTTs) have not been fully explored. Here, we performed epigenome-wide DNA methylation of adjacent normal tissues (ANTs), paired tumor tissues and paired PVTTs using an Infinium HumanMethylation450 array (n = 11) and conducted the Sequenom EpiTYPER assays to confirm the aberrantly methylated genes. MTS and apoptosis assay were used to assess the synergistic effect of two drugs on the HCC cell lines. We found the mean global methylation levels of HCC tissues and PVTTs were significantly lower than ANTs (P < 0.01). A total of 864 differentially methylated CpG sites annotated in 532 genes were identified between HCC tissues and paired PVTTs (|mean methylation difference|>10%, P < 0.005). The pathway analysis based on hypermethylated genes in PVTT tissues was interestingly enriched in regulation of actin cytoskeleton pathway (P = 4.48E-5). We found 23 genes whose methylation levels were gradually alternated in HCC tissues and PVTTs. Aberrant methylation status of TNFRSF10A, ZC3H3 and SLC9A3R2 were confirmed in a validation cohort (n = 48). The functional experiments demonstrated the combination of decitabine (DAC) and tumor necrosis factor-related apoptosis-inducing ligand (rh-TRAIL) could synergistically suppress the proliferation and induce apoptosis in SK-Hep-1 and Huh7 cell lines. Together, our findings indicated that DNA methylation plays an important role in the PVTT formation through regulating the metastasis-related pathways. The combination of DAC and rh-TRAIL might be a promising treatment strategy for HCC.

Promoter aberrant methylation status of ADRA1A is associated with hepatocellular carcinoma.

The aim of our study was to explore the relationship between the methylation status of the alpha-1A adrenergic receptor (ADRA1A) gene and hepatocellular carcinoma (HCC). We combined our in-house data-set with the Cancer Genome Atlas (TCGA) data-set to screen and identify the methylation status and expression of adrenergic receptor (AR) genes in HCC. Immunohistochemistry and western blot were performed to assess the expression of ADRA1A in HCC cell lines and tissues. We further evaluated the methylation levels of the ADRA1A promoter region in 160 HCC patients using the Sequenom MassARRAY® platform and investigated the association between methylation of ADRA1A and clinical characteristics. The expression levels of ADRA1A mRNA and protein were significantly decreased in HCC tissues. Compared with that in paired normal tissues, the mean methylation level of the ADRA1A promoter region was significantly increased in tumour tissues from 160 HCC patients (25.2% vs. 17.0%, P < 0.0001). We found that a DNA methyltransferase inhibitor (decitabine) could increase the expression of ADRA1A mRNA in HCC cell lines. Moreover, hypermethylation of the ADRA1A gene in HCC samples was associated with clinical characteristics, including alcohol intake (P = 0.0097) and alpha-fetoprotein (P = 0.0411). Receiver operator characteristic (ROC) curve analysis demonstrated that the mean methylation levels of ADRA1A could discriminate between HCC tissues and adjacent non-cancerous tissues (AUC = 0.700, P < 0.0001). mRNA sequencing indicated that the main enriched pathways were pathways in cancer, cytokine-cytokine receptor interaction and metabolic pathways (P < 0.01). ADRA1A gene hypermethylation might contribute to HCC initiation and is a promising biomarker for the diagnosis of HCC.

Genetic And Epigenetic Regulation Of E-Cadherin Signaling In Human Hepatocellular Carcinoma.

E-cadherin is well known as a growth and invasion suppressor and belongs to the large cadherin family. Loss of E-cadherin is widely known as the hallmark of epithelial-to-mesenchymal transition (EMT) with the involvement of transcription factors such as Snail, Slug, Twist and Zeb1/2. Tumor cells undergoing EMT could migrate to distant sites and become metastases. Recently, numerous studies have revealed how the expression of E-cadherin is regulated by different kinds of genetic and epigenetic alteration, which are implicated in several crucial transcription factors and pathways. E-cadherin signaling plays an important role in hepatocellular carcinoma (HCC) initiation and progression considering the highly mutated frequency of CTNNB1 (27%). Combining the data from The Cancer Genome Atlas (TCGA) database and previous studies, we have summarized the roles of gene mutations, chromosome instability, DNA methylation, histone modifications and non-coding RNA in E-cadherin in HCC. In this review, we discuss the current understanding of the relationship between these modifications and HCC. Perspectives on E-cadherin-related research in HCC are provided.

Overexpression of zinc finger protein 384 (ZNF 384), a poor prognostic predictor, promotes cell growth by upregulating the expression of Cyclin D1 in Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly heterogeneous, multigene-driven malignant tumor. ZNF384 is an overexpressed gene with a high frequency of alteration in HCC, but research on the function of ZNF384 in HCC is lacking. In this study, the expression level of ZNF384 in HCC was analyzed through immunohistochemical (IHC) staining, Western blot analysis and qRT-PCR. We also generated ZNF384 knockdown and knockout HCC cell lines using short hairpin RNA (shRNA) and CRISPR/Cas9 systems. MTS, colony formation, and 5-ethynyl-20-deoxyuridine (EdU) assays; flow cytometry; and a xenograft mouse model were used to evaluate the effects of ZNF384 on cell proliferation. Western blot analysis, a dual luciferase reporter assay and a ChIP assay were performed to explore the potential mechanism. We found that overexpression of ZNF384 in HCC and elevated expression of ZNF384 in HCC tissues was significantly correlated with tumor recurrence (P = 0.0097). Kaplan-Meier survival analysis revealed that high expression levels of ZNF384 were correlated with poor overall survival (P = 0.0386). Downregulation of ZNF384 expression suppressed HCC cell proliferation by inhibiting the expression of Cyclin D1. These findings suggest that ZNF384 tends to act as an oncogene in the development of HCC. ZNF384 promotes the proliferation of HCC cells by directly upregulating the expression of Cyclin D1 and might serve as a prognostic predictive factor for HCC patients.

The efficacy of extracorporeal membrane oxygenation in liver transplantation from non-heart-beating donors: A systemic review and meta-analysis.

BACKGROUND: A systematic review and meta-analysis was made to see whether extracorporeal membrane oxygenation (ECMO) in liver transplantation could improve non-heart-beating donors (NHBDs) recipients' outcomes compared with donors after brain death (DBDs) recipients. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for eligible studies. The study eligible criteria are cohort or case-control studies using ECMO in all NHBDs; studies involved a comparison group of DBDs; and studies evaluated 1-year graft and patient survival rate in NHBDs and DBDs groups. RESULTS: Four studies with 704 patients fulfilled the inclusion criteria. The pooled odds ratio (OR) of 1-year patient survival rate in NHBDs recipients compared with DBDs recipients was 0.8 (95% confidence interval [CI], 0.41-1.55). The pooled OR of 1-year graft survival rate in NHBDs recipients compared with DBDs recipients was 0.46 (95% CI, 0.26-0.81). NHBDs recipients were at greater risks to the occurrence of primary nonfunction (PNF) (OR = 7.12, 95% CI, 1.84-27.52) and ischemic cholangiopathy (IC) (OR = 9.46, 95% CI, 2.76-32.4) than DBDs recipients. CONCLUSIONS: ECMO makes 1-year patient survival acceptable in NHBDs recipients. One-year graft survival rate was lower in NHBDs recipients than in DBDs recipients. Compared with DBDs recipients, the risks to develop PNF and IC were increased among NHBDs recipients.