Gastrointestinal bleeding risk factors in type A aortic dissection post-aortic arch replacement.

Background: Gastrointestinal bleeding (GIB) is a notable complication in patients diagnosed with aortic dissection (AD). We evaluated the outcomes and identified the risk factors associated with GIB in patients with AD. Methods: A retrospective case-control study was conducted on patients diagnosed with type A aortic dissection (TAAD) who underwent total aortic arch replacement (TAAR) at our institution from July 2021 to July 2023. Comprehensive clinical data, laboratory findings, and imaging results were meticulously gathered and analyzed to identify potential risk factors linked to GIB in this patient cohort. Results: Of the 198 AD patients who underwent TAAR, 38 (19.2%) developed postoperative GIB (GIB group), with a median interval of 7 days between surgery and bleeding onset. The GIB group exhibited significantly higher mortality (26.3% vs. 3.1%, P<0.001), prolonged intensive care unit (ICU) stay {15 [interquartile range (IQR), 8-25] vs. 7 (IQR, 5-12) days, P<0.001}, and extended duration of ventilation [168 (IQR, 120-372) vs. 71 (IQR, 34-148) hours, P<0.001] compared to the control group (n=160, 80.8%). Logistic regression analysis identified age >54 years [odds ratio (OR): 3.529], intraoperative red blood cell (RBC) transfusion >600 mL (OR: 3.865), and concomitant celiac trunk and superior mesenteric artery (SMA) hypoperfusion (OR: 15.974) as independent risk factors for GIB in AD patients. Conclusions: GIB subsequent to TAAR in AD patients is linked to adverse prognosis. Factors such as advanced age, extensive intraoperative transfusion, and gastrointestinal (GI) perfusion abnormalities may heighten the risk of GIB in this patient population.

A machine learning-based prediction model for postoperative delirium in cardiac valve surgery using electronic health records.

BACKGROUND: Previous models for predicting delirium after cardiac surgery remained inadequate. This study aimed to develop and validate a machine learning-based prediction model for postoperative delirium (POD) in cardiac valve surgery patients. METHODS: The electronic medical information of the cardiac surgical intensive care unit (CSICU) was extracted from a tertiary and major referral hospital in southern China over 1 year, from June 2019 to June 2020. A total of 507 patients admitted to the CSICU after cardiac valve surgery were included in this study. Seven classical machine learning algorithms (Random Forest Classifier, Logistic Regression, Support Vector Machine Classifier, K-nearest Neighbors Classifier, Gaussian Naive Bayes, Gradient Boosting Decision Tree, and Perceptron.) were used to develop delirium prediction models under full (q = 31) and selected (q = 19) feature sets, respectively. RESULT: The Random Forest classifier performs exceptionally well in both feature datasets, with an Area Under the Curve (AUC) of 0.92 for the full feature dataset and an AUC of 0.86 for the selected feature dataset. Additionally, it achieves a relatively lower Expected Calibration Error (ECE) and the highest Average Precision (AP), with an AP of 0.80 for the full feature dataset and an AP of 0.73 for the selected feature dataset. To further evaluate the best-performing Random Forest classifier, SHAP (Shapley Additive Explanations) was used, and the importance matrix plot, scatter plots, and summary plots were generated. CONCLUSIONS: We established machine learning-based prediction models to predict POD in patients undergoing cardiac valve surgery. The random forest model has the best predictive performance in prediction and can help improve the prognosis of patients with POD.

Detection of pathogens from venous or arterial blood of patients with left-sided infective endocarditis by metagenomic next-generation sequencing: A prospective study.

BACKGROUND: Infective endocarditis is a life-threatening uncommon infectious disease, and we aimed to explore the clinical utility of venous or arterial blood-based metagenomic next-generation sequencing (mNGS) approaches to diagnose left-sided infective endocarditis (LSIE). METHODS: We prospectively studied 79 LSIE patients who received valvular surgery in our hospital. Results of blood culture, valve culture, venous blood-based mNGS, arterial blood-based mNGS, venous blood-based mNGS plus blood culture, and arterial blood-based mNGS plus blood culture were evaluated and compared. RESULTS: Both venous blood- and arterial blood-based mNGS methods displayed significantly higher positive detection rates than blood culture and valve culture (43.0 %, 49.4 % vs. 32.9 %, 19.0 %; P < 0.001). Strikingly, when combining blood-based mNGS and blood culture, the positive rate could be further improved to more than 60 %. Moreover, we found mNGS LSIE detection was closely associated with preoperative leukocyte (P = 0.027), neutrophil value (P = 0.018), vegetation ≥ 14 mm (P = 0.043), and vegetations in aortic valve (P = 0.048). In addition, we discovered that blood-based mNGS had a superir capacity over blood culture to detect gram-negative bacteria, fungi, Bartonella Quintana, and mixed infections than blood culture. CONCLUSION: This study indicates that venous blood- and arterial blood-based mNGS displayed high positive rate in the rapid detection of pathogens in high-risk LSIE patients.

Glial Activation, Mitochondrial Imbalance, and Akt/mTOR Signaling May Be Potential Mechanisms of Cognitive Impairment in Heart Failure Mice.

Heart failure (HF) is a major health burden worldwide, with approximately half of HF patients having a comorbid cognitive impairment (CI). However, it is still unclear how CI develops in patients with HF. In the present study, a mice model of heart failure was established by ligating the left anterior descending coronary artery. Echocardiography 1 month later confirmed the decline in ejection fraction and ventricular remodeling. Cognitive function was examined by the Pavlovian fear conditioning and the Morris water maze. HF group cued fear memory, spatial memory, and learning impairment, accompanied by activation of glial cells (astrocytes, microglia, and oligodendrocytes) in the hippocampus. In addition, the mitochondrial biogenesis genes TFAM and SIRT1 decreased, and the fission gene DRP1 increased in the hippocampus. Damaged mitochondria release excessive ROS, and the ability to produce ATP decreases. Damaged swollen mitochondria with altered morphology and aberrant inner-membrane crista were observed under a transmission electron microscope. Finally, Akt/mTOR signaling was upregulated in the hippocampus of heart failure mice. These findings suggest that activation of Akt/mTOR signaling, glial activation, and mitochondrial dynamics imbalance could trigger cognitive impairment in the pathological process of heart failure mice.

Case report: Acute right ventricular dysfunction after surgery in a pregnant patient with congenital heart disease and aortic dissection.

Pregnant women with aortic dissection are hemodynamically outmost complex patients. The two major diagnoses that should be considered in pregnant patients with congenital heart disease (CHD) and acute type A aortic dissection presenting with postoperative right ventricular dysfunction are pulmonary thromboembolism and right ventricular infarction. We present a rare case of postoperative right ventricular dysfunction in pregnant women with CHD and acute aortic dissection, which was diagnosed by pulmonary computed tomography angiography and treated by percutaneous coronary intervention.

The Determination of Polymyxin B in Critically Ill Patients by the HPLC-MS/MS Method.

Polymyxin B (PB) is a dose-dependent drug used to treat multidrug-resistantgram-negative bacteria, for which a suitable method is needed to determine clinical samples. A simple, economical, and efficient high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method was developed and validated for polymyxin B1 (PB1), polymyxin B1-Ile (PB1-I), polymyxin B2 (PB2), and polymyxin B3 (PB3) in human plasma. Chromatographic column was Waters BEH C18 column (2.1 × 50 mm, 1.7 µm). Phase A was water with 0.2% formic acid (FA), and phase B was acetonitrile containing 0.2% FA. The elution method is gradient elutio. The total analysis time was 5 min. The pretreatment method involved protein precipitation using acetonitrile containing 0.2% trifluoroacetic acid and 0.1% FA as the precipitant. The recovery rate was 92-99%. The total quantity of PB1 and PB1-I was measured in the linear range of 100-8000 ng/mL. Simultaneously, the total amounts of PB2 and PB3 were measured in the linear range of 11.9-948.5 ng/mL. This validated method was successfully applied to the pharmacokinetics of PB in critically ill patients.

Modification of a Novel Umami Octapeptide with Trypsin Hydrolysis Sites via Homology Modeling and Molecular Docking.

Increasing the copy number of peptides is an effective method to genetically engineer recombinant expression and obtain umami peptides in large quantities. However, the umami taste value of multicopy number umami peptides is lower than the single ones, thus limiting the industrial application of recombinantly expressed umami peptides. With aims to solve this problem, modification of an umami beefy meaty peptide (BMP) with trypsin hydrolysis sites was carried out via homology modeling and molecular docking in this study. A total of 1286 modified peptide sequences were created and molecularly simulated for docking with the homology modeling-constructed umami receptor (T1R1/T1R3), and 837 peptides were found to be better docked than the BMP. Afterward, the MLSEDEGK peptide with the highest docking score was synthesized. And umami taste evaluation results demonstrated that this modified peptide was close to that of monosodium glutamate (MSG) and BMP, as confirmed by electronic tongue and sensory evaluation (umami value: 8.1 ± 0.2 for BMP; 8.2 ± 0.3 for MLSEDEGK peptide). Meanwhile, mock trypsin digestion of eight copies of MLSEDEGK peptide results showed that the introduced digestion sites were effective. Therefore, the novel modified BMP in this study has the potential for large-scale production by genetic engineering.

Identification of Distinct Clinical Phenotypes of Heterogeneous Mechanically Ventilated ICU Patients Using Cluster Analysis.

This retrospective study aimed to derive the clinical phenotypes of ventilated ICU patients to predict the outcomes on the first day of ventilation. Clinical phenotypes were derived from the eICU Collaborative Research Database (eICU) cohort via cluster analysis and were validated in the Medical Information Mart for Intensive Care (MIMIC-IV) cohort. Four clinical phenotypes were identified and compared in the eICU cohort (n = 15,256). Phenotype A (n = 3112) was associated with respiratory disease, had the lowest 28-day mortality (16%), and had a high extubation success rate (~80%). Phenotype B (n = 3335) was correlated with cardiovascular disease, had the second-highest 28-day mortality (28%), and had the lowest extubation success rate (69%). Phenotype C (n = 3868) was correlated with renal dysfunction, had the highest 28-day mortality (28%), and had the second-lowest extubation success rate (74%). Phenotype D (n = 4941) was associated with neurological and traumatic diseases, had the second-lowest 28-day mortality (22%), and had the highest extubation success rate (>80%). These findings were validated in the validation cohort (n = 10,813). Additionally, these phenotypes responded differently to ventilation strategies in terms of duration of treatment, but had no difference in mortality. The four clinical phenotypes unveiled the heterogeneity of ICU patients and helped to predict the 28-day mortality and the extubation success rate.

Machine learning approach identified clusters for patients with low cardiac output syndrome and outcomes after cardiac surgery.

Background: Low cardiac output syndrome (LCOS) is the most serious physiological abnormality with high mortality for patients after cardiac surgery. This study aimed to explore the multidimensional data of clinical features and outcomes to provide individualized care for patients with LCOS. Methods: The electronic medical information of the intensive care units (ICUs) was extracted from a tertiary hospital in South China. We included patients who were diagnosed with LCOS in the ICU database. We used the consensus clustering approach based on patient characteristics, laboratory data, and vital signs to identify LCOS subgroups. The consensus clustering method involves subsampling from a set of items, such as microarrays, and determines to cluster of specified cluster counts (k). The primary clinical outcome was in-hospital mortality and was compared between the clusters. Results: A total of 1,205 patients were included and divided into three clusters. Cluster 1 (n = 443) was defined as the low-risk group [in-hospital mortality =10.1%, odds ratio (OR) = 1]. Cluster 2 (n = 396) was defined as the medium-risk group [in-hospital mortality =25.0%, OR = 2.96 (95% CI = 1.97-4.46)]. Cluster 3 (n = 366) was defined as the high-risk group [in-hospital mortality =39.2%, OR = 5.75 (95% CI = 3.9-8.5)]. Conclusion: Patients with LCOS after cardiac surgery could be divided into three clusters and had different outcomes.

Permanent epicardial pacing in neonates and infants less than 1 year old: 12-year experience at a single center.

Background: Permanent epicardial pacing is the primary choice for neonates and infants with bradyarrhythmia. We reviewed mid-term outcomes after epicardial permanent pacemaker (EPPM) implantation in this age group. Methods: From Dec 1, 2008 to Dec 1, 2019, children who underwent EPPM implantation within the first year of life were included in our study. Patients were followed up for as long as 12 years, until Jun 11, 2021, for all-cause mortality and pacemaker reoperation. Kaplan-Meier and log-rank tests were used for analysis. Results: Of 31 consecutive patients [18 boys (58.1%) and 2 neonates (6.5%)] included in this study, 30 (96.8%) were discharged alive and assessed at a median follow-up of 3.9 years [interquartile range (IQR) 4.7]. The median age and weight of the patients were 156 days (IQR 217) and 5.3 kg (IQR 3.5), respectively, at the time of their operation. Twenty-five (80.6%) patients had congenital heart disease, and the main indication for pacing was postoperative atrioventricular block (AVB) in 21 (67.7%) patients. During follow-up, 3 (9.7%) patients died and there were a total of 9 pacing lead failures in 7 (22.6%) patients. The median longevity of leads (unipolar steroid-eluting) was 2.9 years (IQR 3.6). Freedom from lead reoperation was 90.3%, 72.0%, 65.5% and 49.1% at 1, 3, 5, and 8 years, respectively. The median longevity of the pacing generators was 3.3 years (IQR 2.8). Freedom from generator reoperation was 90.3%, 75.6%, 52.4% and 43.6% at 1, 3, 5 and 6 years, respectively. Conclusions: The mid-term outcome of EPPM implantation in neonates and infants was acceptable. Neonates and infants with EPPM implants face the risk of repeated reoperations and all-cause death. A patient's prognosis can depend on regular follow-up, type of pacing lead and the presence of congenital heart malformations, especially complex congenital heart disease.

Exosomal miR-4800-3p Aggravates the Progression of Hepatocellular Carcinoma via Regulating the Hippo Signaling Pathway by Targeting STK25.

Background: Emerging evidence has shown that exosome microRNAs (miRNAs) regulate the development of hepatocellular carcinoma (HCC). Here, the influences of miR-4800-3p on the progression of HCC were explored. Materials and Methods: The expression of miR-4800-3p in the exosome derived by transforming growth factor beta 1 (TGF-ß1)-treated HCC cells and the serum exosome isolated from HCC patients were identified by real-time PCR. The effects of TGF-ß1 and the influences of Huh7-secreted exosomes and the effects of miR-4800-3p combined with/without STK25 on cell functions were explored using the EdU assay cloning experiments, wound healing assay, and Transwell assay. The corresponding molecular mechanisms were further detected using Western blot and real-time PCR assays. The combination of miR-4800-3p and STK25 was verified by the dual-luciferase and RNA pulldown assays. The influences of miR-4800-3p on the growth and epithelial-mesenchymal transformation (EMT) of implanted tumors were tested in vivo and further confirmed by Western blot. Results: The miR-4800-3p expression was highly expressed in both exosomes derived by TGF-ß1-treated HCC cells and the serum exosomes of HCC patients. In the cases of treatment with both Huh7-derived exosomes, the level of miR-4800-3p expression was highest, and the treatment of TGF-ß1 could greatly promote the proliferation, stemness, migration, and invasion of HCC cells via upregulating the markers of stemness and EMT, including CD44, CD133, OCT4, N-cadherin, E-cadherin, and ZO-1. Similar results could be obtained when miR-4800-3p was overexpressed in HCC cells. Furthermore, downregulation of STK25 expression, a direct target gene of miR-4800-3p, could greatly rescue the malignant biological behaviors aggravated by overexpression of miR-4800-3p. This was achieved by suppressing the expression of CD44, CD133, OCT4, N-cadherin, and PCNA and activating the Hippo pathway while increasing E-cadherin and ZO-1. Similar results were also obtained in vivo that knockdown of miR-4800-3p expression suppressed tumor growth induced by Huh7-derived exosomes by mediating the EMT markers and the Hippo signaling pathway. Conclusion: Exosomal miR-4800-3p could accelerate HCC development by regulating the Hippo signal by targeting STK25, which could be used as a new therapeutic target for HCC treatment.

Downregulated ALKBH5 contributes to myocardial ischemia/reperfusion injury by increasing m6A modification of Trio mRNA.

Background: The modification of N6-methyladenosine (m6A) is a dynamic and reversible course that might play a role in cardiovascular disease. However, the mechanisms of m6A modification in myocardial ischemia/reperfusion injury (MIRI) remain unclear. Methods: A mouse model of MIRI and a cell model of oxygen-glucose deprivation/reperfusion (OGD/R) HL-1 cells were employed. In an in vivo study, the total RNA m6A modification levels were determined by dot blot, and the key genes related to m6A modification were screened by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. In an in vitro study, the effects of AlkB homolog 5 (ALKBH5), an RNA demethylase, on cell proliferation, cell injury, and apoptosis were detected by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, lactate dehydrogenase (LDH) and cardiac troponin-I (cTnI) levels, and flow cytometry. Besides, the m6A modification-changed and differentially expressed messenger RNA (mRNA) were determined by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) in ALKBH5-overexpressed HL-1 cells. Finally, the mRNA levels of the promising targeted gene were examined by RT-qPCR and its m6A modification levels were examined by MeRIP-qPCR. Results: Our results showed that RNA m6A modification was involved in MIRI, in which ALKBH5 was downregulated. Functionally, by overexpressing or silencing ALKBH5 in experimental cells, we verified its protective properties on cell proliferation, cell injury, and apoptosis in the process of MIRI. Besides, we provided a mass of latent different mRNAs with m6A modification variation in ALKBH5-overexpressed HL-1 cells. Mechanistically, we further screened the most potential targeted mRNAs and suggested that triple functional domain (Trio) mRNA could be upregulated by ALKBH5 by reducing m6A level of Trio. Conclusions: This study demonstrated that the downregulated ALKBH5 might contribute to MIRI process by increasing the m6A modification of Trio mRNA and downregulating Trio.

Application of Metagenomic Next-Generation Sequencing in the Etiological Diagnosis of Infective Endocarditis During the Perioperative Period of Cardiac Surgery: A Prospective Cohort Study.

Objective: The present study aimed to prospectively evaluate the role of metagenomic next-generation sequencing (mNGS) in the etiological diagnosis of patients with perioperative infective endocarditis (IE). Methods: From May 1st, 2019 to December 31st, 2020, a total of 99 patients with IE were enrolled in the present study according to the modified Duke criteria, etiological, and pathological results. 11 non-IE patients undergoing heart valve surgery in the same period were selected as the control group. A blood culture test was performed immediately after admission, and the valves harvested operatively were examined by blood culture and mNGS. Results: In the IE group, there were 29 cases (29.3%) with positive blood culture, 16 cases (16.2%) with positive valve culture, and 85 cases (85.9%) with positive valve mNGS. Compared to culture-based detection, mNGS achieved better performance with a sensitivity, specificity, area under the curve (AUC) of 0.859, 0.727, and 0.793, respectively. The combined approach using culture and mNGS further improved the diagnostic accuracy (sensitivity 89.9%, specificity 72.7%, AUC 0.813). Preoperative white blood cell (P = 0.029) and neutrophils (P = 0.046) were identified as independent factors affecting the detection rate of mNGS. In the mNGS-positive group, 95 strains of pathogens were found and 10 cases were identified with mixed infection. There were 72 gram-positive bacteria and 14 gram-negative bacteria. mNGS positive group displayed higher species richness than mNGS negative group with enrichment of Streptococcus sanguis, Streptococcus buccalis, and Streptococcus griseus. Proteobacteria and Actinomycetes were enriched in mNGS negative group. Notably, six patients showed disconcordant results between culture and mNGS. Rothia aeria was identified in the blood culture, valve culture, and valve mNGS in one patient. Bartonella Quintana and Coxiella burnetii, which were fastidious intracellular bacteria, were found in two blood and valve culture-negative cases. Conclusions: mNGS outperformed the conventional culture method and displayed high accuracy in detecting pathogens in IE patients. This study provided support for the use of mNGS in the etiological diagnosis of IE.

Weaning critically ill patients from mechanical ventilation: a protocol from a multicenter retrospective cohort study.

BACKGROUND: Mechanical ventilation (MV) is an important lifesaving method in intensive care unit (ICU). Prolonged MV is associated with ventilator associated pneumonia (VAP) and other complications. However, premature weaning from MV may lead to higher risk of reintubation or mortality. Therefore, timely and safe weaning from MV is important. In addition, identification of the right patient and performing a suitable weaning process is necessary. Although several guidelines about weaning have been reported, compliance with these guidelines is unknown. Therefore, the aim of this study is to explore the variation of weaning in China, associations between initial MV reason and clinical outcomes, and factors associated with weaning strategies using a multicenter cohort. METHODS: This multicenter retrospective cohort study will be conducted at 17 adult ICUs in China, that included patients who were admitted in this 17 ICUs between October 2020 and February 2021. Patients under 18 years of age and patients without the possibility for weaning will be excluded. The questionnaire information will be registered by a specific clinician in each center who has been evaluated and qualified to carry out the study. DISCUSSION: In a previous observational study of weaning in 17 ICUs in China, weaning practices varies nationally. Therefore, a multicenter retrospective cohort study is necessary to be conducted to explore the present weaning methods used in China. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) (No. ChiCTR2100044634).

miR-4454 Promotes Hepatic Carcinoma Progression by Targeting Vps4A and Rab27A.

Hepatocellular carcinoma (HCC) has high morbidity and mortality. MicroRNAs (miRNAs), which could be regulated by cancer-derived exosomes, play critical regulatory roles in the initiation and development of cancer. However, the expressions, effects, and mechanisms of abundant miRNAs regulated by HCC cancer-derived exosomes in HCC remain largely unclear. Exosomes of HepG2 cells under heat shock, TGF-ß1, doxorubicin, acid and hypoxia/reoxygenation (H/R) conditions, and exosomes were successfully identified by transmission electron microscopy and Western blot analysis. The identified exosomes were then applied to evaluate the miRNA expression profiles by RNA sequencing. Mechanically, we discovered that doxorubicin was upregulated, TGF-ß1 downregulated the expressions of Vps4A, Rab27A, Alix, and Hrs in HepG2 cells and exosomes, and Vps4A and Rab27A, as target genes for miR-4454, could also be downregulated by miR-4454. Functionally, we revealed that miR-4454 inhibitor and miR-4454 inhibitor-mediated exosomes could markedly suppress proliferation, migration, invasion, and vascularization and accelerate cycle arrest, apoptosis, and ROS of HepG2 cells. This study provided many potential HCC cancer-derived exosome-mediated miRNAs in HCC under 5 different stimulus conditions. Meanwhile, we certified that miR-4454 in exosomes could provide a novel and effective mechanism for HCC function.

An Insight by Molecular Sensory Science Approaches to Contributions and Variations of the Key Odorants in Shiitake Mushrooms.

An insight using molecular sensory science approaches to the contributions and variations of the key odorants in shiitake mushrooms is revealed in this study. Odorants were extracted by headspace solid phase microextraction (HS-SPME) and direct solvent extraction combined with solvent-assisted flavor evaporation (DSE-SAFE) in fresh and hot-air-dried shiitake mushrooms. Among them, 18 and 22 predominant odorants were determined by detection frequency analysis (DFA) and aroma extract dilution analysis (AEDA) combined with gas chromatography-olfactometry (GC-O) in the fresh and dried samples, respectively. The contributions of these predominant odorants in the food matrix were determined by quantification and odor activity values (OAVs) with aroma recombination verification. There were 13 and 14 odorants identified as key contributing odorants to overall aroma, respectively. 1-Octen-3-ol and 1-octen-3-one were the most key contributing odorants in the fresh samples in contributing mushroom-like odor. After hot-air-drying, the OAV and concentrations on dry basis of the key contributing odorants changed, due to oxidation, degradation, caramelization and Maillard reactions of fatty acids, polysaccharides and amino acids. 1-Octen-3-ol was reduced most significantly and degraded to 1-hydroxy-3-octanone, while phenylethyl alcohol increased the most and was formed by phenylalanine. In hot-air-dried samples, lenthionine became the most important contributor and samples were characterized by a sulfury odor. Overall contributions and variations of odorants to the aroma of shiitake mushrooms were revealed at the molecular level.

An aorto-oesophageal fistula treated with total arch repair combined with oesophageal repair.

Aorto-oesophageal fistula is a rare but fatal disease. Open surgical repair or endotube repair of aorta and oesophagus save patients from circulatory deterioration, major haematemesis and severe infection. Here we present a rare case of an aorto-oesophageal fistula in the right hemi-arch caused by a fish bone treated with an alternative surgical strategy. Total aortic arch repair using the frozen elephant trunk procedure combined with oesophageal repair were performed. No aortic fistula, oesophageal fistula or artificial graft infection occurred in the follow-up.

Dexmedetomidine Attenuates LPS-Induced Monocyte-Endothelial Adherence via Inhibiting Cx43/PKC-α/NOX2/ROS Signaling Pathway in Monocytes.

Dexmedetomidine is widely used for sedating patients in operation rooms or intensive care units. Its protective functions against oxidative stress, inflammation reaction, and apoptosis have been widely reported. In present study, we explored the effects of dexmedetomidine on monocyte-endothelial adherence. We built lipopolysaccharide- (LPS-) induced monocyte-endothelial adherence models with U937 monocytes and human umbilical vein endothelial cells (HUVECs) and observed the effects of dexmedetomidine on U937-HUVEC adhesion. Specific siRNA was designed to knock-down Connexin43 (Cx43) expression in U937 monocytes. Gö6976, GSK2795039, and NAC were used to inhibit PKC-α, NOX2, and ROS, respectively. Then, we detected whether dexmedetomidine could downregulate Cx43 expression and its downstream PKC-α/NOX2/ROS signaling pathway activation and ultimately result in the decrease of U937-HUVEC adhesion. The results showed that dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), could inhibit adhesion of molecule expression (VLA-4 and LFA-1) and U937-HUVEC adhesion. Simultaneously, it also attenuated Cx43 expression in U937 monocytes. With the downregulation of Cx43 expression, the activity of PKC-α and its related NOX2/ROS signaling pathway were reduced. Inhibiting PKC-α/NOX2/ROS signaling pathway with Gö6976, GSK2795039, and NAC, respectively, VLA-4, LFA-1 expression, and U937-HUVEC adhesion were all decreased. In summary, we concluded that dexmedetomidine, at its clinically relevant concentrations (0.1 nM and 1 nM), decreased Cx43 expression in U937 monocytes and PKC-α associated with carboxyl-terminal domain of Cx43 protein. With the downregulation of PKC-α, the NOX2/ROS signaling pathway was inhibited, resulting in the decrease of VLA-4 and LFA-1 expression. Ultimately, U937-HUVEC adhesion was reduced.

Dihydroquercetin Activates AMPK/Nrf2/HO-1 Signaling in Macrophages and Attenuates Inflammation in LPS-Induced Endotoxemic Mice.

Dihydroquercetin (DHQ) is a flavonoid compound known for its anti-oxidant effects. Oxidative stress plays a dominant role in regulating the pathways associated with systemic inflammatory immune activation during endotoxemia. Whether and how DHQ regulates inflammatory responses in endotoxemia remains elusive. Here we show DHQ pretreatment effectively reduced the Ten-day mortality in bacterial endotoxin lipopolyssacharide (LPS)-challenged mice, suppressing LPS-induced inflammatory responses reflected by impaired production of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in the serum of mice. In Raw 264.7 cells, DHQ pretreatment significantly inhibited the transcriptional upregulation of TNF-α, interferon-γ (IFN-γ), interleukin-10 (IL-10) and toll-like receptor 4 (TLR-4) after LPS stimulation. Additionally, knockdown of heme oxygenase-1 (HO-1), one of the most important DHQ induced antioxidant genes, cancelled the inhibition of DHQ treatment on LPS induced TNF-α, IFN-γ production. Nuclear factor erythroid 2-related factor 2 (Nrf2) expression and AMP-activated protein kinase (AMPK) phosphorylation were both enhanced by DHQ in Raw 264.7 cells, indicating a DHQ induced AMPK/Nrf2/HO-1 signal axis. In conclusion, DHQ pretreatment could protect mice against the inflammation and mortality associated with endotoxemia.

Comprehensive network analysis of the molecular mechanisms associated with sorafenib resistance in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is an intractable disease because patients with HCC frequently develop sorafenib resistance after long-term chemotherapy. Although studies has demonstrated the availability of cumulative information on drug-resistant patients, little is known about the strategies and molecular mechanisms to reverse sorafenib resistance. Here, the present study identified critical mRNAs and transcription factors (TFs) associated with sorafenib resistance of HCC and evaluated the significance correlation between drug-resistant genes and TFs in comprehensive network for HCC xenografts mice. METHODS: The expression profiles of mRNAs were compared between sorafenib-acquired resistant tissue and sorafenib sensitive tissue utilizing RNA-Seq data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Gene Ontology and KEGG pathway analysis were performed to investigate the biological function of significantly dysregulated mRNA. Furthermore, the Kaplan-Meier survival analyses were performed to evaluate the effect of mRNA on over survival. Subsequently, TFs were predicted using TRANSFAC and TF-mRNA regulatory networks were visualized using cytoscape software. RESULTS: A total of 827 mRNAs were found to be differentially expressed in sorafenib-acquired resistant tissue compared with control. Thereafter, the results of functional enrichment analysis showed the dysregulated mRNAs involved in drug-resistant signaling pathway, including MAPK, JAK-STAT, TGF-ß and drug-metabolism cytochrome P450 signaling pathway. CDK1, CDKN1A and TAPBP might serve as prognostic signature of resistance of HCC to sorafenib according to the survival analysis. Furthermore, TF-mRNA networks were constructed. There were 18 TFs were predicted to regulate differentially expressed mRNAs, which play an essential role in the regulation of dysfunctional gene networks. NFKB1 was presented in the TF-mRNA networks as the node with the highest degree and MYC was predicted as prognostic TF in drug resistance of HCC CONCLUSIONS: Taken together, our findings showed that novel mRNAs and TFs, which served as critical biomarkers to predict survival and therapeutic targets of resistance to sorafenib in HCC. Furthermore, we constructed the TF-mRNA networks, which provides valuable theoretical references to further evaluate the molecular mechanisms of resistance to sorafenib in HCC.