LASSO-Based Identification of Risk Factors and Development of a Prediction Model for Sepsis Patients.

Objective: The objective of this study was to utilize LASSO regression (Least Absolute Shrinkage and Selection Operator Regression) to identify key variables in septic patients and develop a predictive model for intensive care unit (ICU) mortality. Methods: We conducted a cohort consisting of septic patients admitted to the ICU between December 2016 and July 2019. The disease severity and laboratory index were analyzed using LASSO regression. The selected variables were then used to develop a model for predicting ICU mortality. AUCs of ROCs were applied to assess the prediction model, and the accuracy, sensitivity and specificity were calculated. Calibration were also used to assess the actual and predicted values of the predictive model. Results: A total of 1733 septic patients were included, among of whom 382 (22%) died during ICU stay. Ten variables, namely mechanical ventilation (MV) requirement, hemofiltration (HF) requirement, norepinephrine (NE) requirement, septicemia, multiple drug-resistance infection (MDR), thrombocytopenia, hematocrit, red-cell deviation width coefficient of variation (RDW-CV), C-reactive protein (CRP), and antithrombin (AT) III, showed the strongest association with sepsis-related mortality according to LASSO regression. When these variables were combined into a predictive model, the area under the curve (AUC) was found to be 0.801. The AUC of the validation group was 0.791. The specificity of the model was as high as 0.953. Within the probability range of 0.25 to 0.90, the predictive performance of the model surpassed that of individual predictors within the cohort. Conclusion: Our findings suggest that a predictive model incorporating the variables of MV requirement, HF requirement, NE requirement, septicemia, MDR, thrombocytopenia, HCT, RDW-CV, CRP, and AT III exhibiting an 80% likelihood of predicting ICU mortality in sepsis and demonstrates high accuracy.

A nomogram based on lymphocyte percentage for predicting hospital mortality in exertional heatstroke patients: a 13-year retrospective study.

BACKGROUND: Exertional heatstroke (EHS) is a life-threatening disease without ideal prognostic markers for predicting hospital mortality. METHODS: This is a single-center retrospective study. Clinical data from EHS patients admitted to the Intensive Care Unit (ICU) of the General Hospital of Southern Theatre Command between January 1, 2008, and December 31, 2020, were recorded and analyzed. Univariate and multivariate logistic regression were used to identify the factors for mortality. The prediction model was developed with the prognostic markers, and a nomogram was established. RESULTS: The study ultimately enrolled 156 patients, and 15 (9.6%) of patients died before discharge. The lymphocyte count (Lym) and percentage (Lym%) were significantly lower in non-survivors (P<0.05). The univariate and multivariate logistic regression analyses indicated that Lym% at the third day of admission (Lym% D3) (OR=0.609, 95%CI: 0.454-0.816) and hematocrit (HCT) (OR=0.908, 95%CI: 0.834-0.988) were independent protective factors for hospital mortality. A nomogram incorporating Lym% D3 with HCT was developed and demonstrated good discrimination and calibration ability. The comparison between the prediction model and scoring systems revealed that the prediction model had the largest area under the curve (AUC) (0.948, 95%CI: 0.900-0.977), with 100.00% sensitivity and 83.69% specificity, and a greater clinical net benefit. CONCLUSION: Severe EHS patients had a higher risk of experiencing prolonged lymphopenia. A nomogram based on Lym% D3 and HCT was developed to facilitate early identification and timely treatment of patients with potentially unfavorable prognoses.

Pathogenetic detection, retrospective and pathogenicity analysis of a fatal case of Vibrio vulnificus in Shenzhen, China.

We report a 36-year-old male patient died of V. vulnificus-induced septicaemia and multiple organ failure syndrome after oyster consumption at a restaurant. We isolated and identified V. vulnificus vv16015 from the patient's blood sample and antibiotic susceptibility tests indicated sensitivity to all 21 antibiotics. Oyster samples were subsequently collected from the restaurant's supplier and three strains of V. vulnificus were isolated. Whole genome sequencing and analysis revealed vv16015 to be distantly related to these strains and confirmed that V. vulnificus contamination was present in the seafood of the restaurant and supplier. Using a Galleria mellonella larvae infection model, the virulence of vv16015 was determined to be higher than that of comparison strains isolated from a surviving patient (vv15018) and an oyster (vv220015). The human and environment distribution of V. vulnificus in Shenzhen is sporadic and heterogeneous, and vv16015 is highly virulent compared to other strains.

Prediction of in-hospital mortality in patients with exertional heatstroke: a 13-year retrospective study.

Hyperactivity of coagulation is common in exertional heatstroke (EHS). Disseminated intravascular coagulation (DIC) is the most severe form of coagulation dysfunction and associated with poor outcome. DIC, temperature and Glasgow coma scale score were identified as independent risk factors for in-hospital mortality by multivariate logistic regression analysis, and we developed a nomogram for predicting in-hospital mortality in a 13-year EHS patient cohort. The nomogram was assessed by calibration curves and bootstrap with 1,000 resamples. The receiver operating characteristic curve was constructed, and the area under the curve (AUC) was compared. Two hundred and ten patients were included. The in-hospital mortality was 9.0%, and the incidence of DIC was 17.6%. The AUC of the nomogram was 0.897 (95% CI 0.848-0.935, p < .0001) and was non-inferior to SOFA and APACHE II scores but superior to SIRS score, which were widely-used score systems of disease severity. The nomogram contributed to the adverse outcome prediction of EHS.

Co-expression module analysis reveals high expression homogeneity for both coding and non-coding genes in sepsis.

Sepsis is a life-threatening condition characterized by a harmful host response to infection with organ dysfunction. Annually about 20 million people are dead owing to sepsis and its mortality rates is as high as 20%. However, no studies have been carried out to investigate sepsis from the system biology point of view, as previous research predominantly focused on individual genes without considering their interactions and associations. Here, we conducted a comprehensive exploration of genome-wide expression alterations in both mRNAs and long non-coding RNAs (lncRNAs) in sepsis, using six microarray datasets. Co-expression networks were conducted to identify mRNA and lncRNA modules, respectively. Comparing these sepsis modules with normal modules, we observed a homogeneous expression pattern within the mRNA/lncRNA members, with the majority of them displaying consistent expression direction. Moreover, we identified consistent modules across diverse datasets, consisting of 20 common mRNA members and two lncRNAs, namely CHRM3-AS2 and PRKCQ-AS1, which are potential regulators of sepsis. Our results reveal that the up-regulated common mRNAs are mainly involved in the processes of neutrophil mediated immunity, while the down-regulated mRNAs and lncRNAs are significantly overrepresented in T-cell mediated immunity functions. This study sheds light on the co-expression patterns of mRNAs and lncRNAs in sepsis, providing a novel perspective and insight into the sepsis transcriptome, which may facilitate the exploration of candidate therapeutic targets and molecular biomarkers for sepsis.

Glasgow Coma Scale as an Indicator of Patient Prognosis: A Retrospective Study of 257 Patients with Heatstroke from 3 Medical Centers in Guangdong, China.

BACKGROUND Coma has been considered as a valuable symptom of heatstroke. This study aimed to evaluate the role of the Glasgow Coma Scale (GCS) as an indicator of prognosis of patients with heatstroke. MATERIAL AND METHODS From Jan 1st, 2013 to Dec 31st, 2020, the clinical courses of 257 heatstroke patients from 3 medical centers in Guangdong, China, were observed. Diagnosis of heatstroke was made according to Expert Consensus in China. GCSs were calculated on the 1st, 3rd, and 5th days after admission to intensive care units (ICUs). GCS £8, as a coma criterion, was employed to predict the outcomes. RESULTS Seventy-five patients (29.18%) were comatose at admission. Twenty-seven (10.50%) patients, including 24 (24/75, 32.00%) coma patients and 3 (3/182,1.65%) non-coma patients died during ICU stay (P<0.0001). Patients with GCS ≤8 had a 2-fold higher risk of death as compared with those with GCS >8. The area under curves (AUCs) of GCSs on the 1st, 3rd, and 5th days to predict mortality were 0.81 (0.70-0.91), 0.91 (0.84-0.98), and 0.91 (0.82-0.99), respectively. Each additional 1 year of age, 1/min of respiratory rate (RR), and 1% of hematocrit (HCT) increased the risk of death of coma patients by 3%, 6%, and 4%, respectively (all P≤0.05). Patients with improving GCSs had lower mortality rates than non-improving patients (5.71% vs 55.00%, P<0.0001) within 5 days after admission. CONCLUSIONS GCS ≤8 at admission predicted worse outcomes in heatstroke patients, which possibly enhanced the risks of death for other factors, including age, RR, and HCT.

28-day sepsis mortality prediction model from combined serial interleukin-6, lactate, and procalcitonin measurements: a retrospective cohort study.

Sepsis is a global medical issue owing to its unacceptably high mortality rate. Therefore, an effective approach to predicting patient outcomes is critically needed. We aimed to search for a novel 28-day sepsis mortality prediction model based on serial interleukin-6 (IL-6), lactate (LAC), and procalcitonin (PCT) measurements. We enrolled 367 septic patients based on Sepsis-3 (Third International Consensus Definitions for Sepsis and Septic Shock). Serum IL-6, LAC, and PCT levels were measured serially. Results collected within 24 and 48-72 h of admission were marked as D1 and D3 (e.g., IL-6D1/D3), respectively; the IL-6, LAC, and PCT clearance (IL-6c, LACc, PCTc) at D3 were calculated. Data were split into training and validation cohorts (7:3). Logistic regression analyses were used to select variables to develop models and choose the best one according to the Akaike information criterion (AIC). Receiver operating characteristic curves (ROC), calibration plots, and decision curve analysis (DCA) were used to test model performance. A nomogram was used to validate the model. There were 314 (85.56%) survivors and 53 (14.44%) non-survivors. Logistic regression analyses showed that IL-6D1, IL-6D3, PCTD1, PCTD3, and LACcD3 could be used to develop the best prediction model. The areas under the curves (AUC) of the training (0.849, 95% CI: 0.787-0.911) and validation cohorts (0.828, 95% CI: 0.727-0.929), calibration plot, and the DCA showed that the model performed well. Thus, the predictive value of the risk nomogram was verified. Combining IL-6D1, IL-6D3, PCTD1, PCTD3, and LACcD3 may create an accurate prediction model for 28-day sepsis mortality. Multiple-center research with a larger quantity of data is necessary to determine its clinical utility.

SP1 Promotes HDAC4 Expression and Inhibits HMGB1 Expression to Reduce Intestinal Barrier Dysfunction, Oxidative Stress, and Inflammatory Response after Sepsis.

As a serious and elusive syndrome caused by infection, sepsis causes a high rate of mortality around the world. Our investigation aims at exploring the role and possible mechanism of specificity protein-1 (SP1) in the development of sepsis. A mouse model of sepsis was established by cecal ligation perforation, and a cellular model was stimulated by lipopolysaccharide (LPS), followed by determination of the SP1 expression. It was determined that SP1 was poorly expressed in the intestinal tissues of septic mice and LPS-treated cells. Next, we examined the interactions among SP1, histone deacetylase 4 (HDAC4), and high mobility group box 1 (HMGB1) and found that SP1 bound to the HDAC4 promoter to upregulate its expression, thereby promoting the deacetylation of HMGB1. Meanwhile, gain- or loss-of-function approaches were applied to evaluate the intestinal barrier dysfunction, oxidative stress, and inflammatory response. Overexpression of SP1 or underexpression of HMGB1 was observed to reduce intestinal barrier dysfunction, oxidative stress, and inflammatory injury. Collectively, these experimental data provide evidence reporting that SP1 could promote the HDAC4-mediated HMGB1 deacetylation to reduce intestinal barrier dysfunction, oxidative stress, and inflammatory response induced by sepsis, providing a novel therapeutic target for sepsis prevention and treatment.

Omega-3 fatty acids impair miR-1-3p-dependent Notch3 down-regulation and alleviate sepsis-induced intestinal injury.

BACKGROUND: Sepsis is a troublesome syndrome that can cause intestinal injury and even high mortality rates. Omega-3 fatty acids (FAs) are known to protect against intestinal damage. Accordingly, the current study set out to explore if omega-3 FAs could affect sepsis-induced intestinal injury with the involvement of the microRNA (miR)-1-3p/Notch3-Smad axis. METHODS: First, cecal ligation and perforation (CLP) was performed to establish septic mouse models in C57BL/6J mice, and mouse intestinal epithelial MODE-K cells were induced by lipopolysaccharide (LPS) to establish sepsis cell models. The CLP-induced septic mice or LPS-exposed cells were subjected to treatment with Omega-3 FAs and activin (Smad signaling activator), miR-1-3p inhibitor and over-expressed/short hairpin RNA (oe-/sh)-Notch3 to explore their roles in inflammation, intestinal oxidative stress and cell apoptosis. A dual-luciferase reporter gene assay was further performed to verify the regulatory relationship between miR-1-3p and Notch3. RESULTS: Omega-3 FAs inhibited CLP-induced intestinal injury and ameliorated LPS-induced intestinal epithelial cell injury by down-regulating miR-1-3p, as evidenced by decreased levels of tumor necrosis factor-α, interleukin-1ß (IL-1ß) and IL-6, in addition to diminished levels of reactive oxygen species, malondialdehyde levels and superoxide dismutase activity. Furthermore, miR-1-3p could down-regulate Notch3, which inactivated the Smad pathway. CONCLUSION: Collectively, our findings indicated that omega-3 FAs elevate the expression of Notch3 by down-regulating miR-1-3p, and then blocking the Smad pathway to alleviate intestinal epithelial inflammation and oxidative stress injury caused by sepsis.

Inferior vena cava thrombosis during extracorporeal membrane oxygenation: a case report and review of the literature.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is an effective cardiopulmonary support therapy, which can provide temporary cardiopulmonary support for critically ill patients whose condition cannot be reversed by conventional therapy. However, there are many complications in the use of ECMO, such as bleeding, thrombosis, and so on. Among them, inferior vena cava (IVC) thrombosis which can cause pulmonary embolism is a rare complication, which may be life-threatening. CASE PRESENTATION: A 75-year-old female patient (Han Chinese ethnicity) with acute heart failure due to acute myocardial infarction in our department was retrospectively analyzed. After regular treatment was unsuccessful, she was treated with venoarterial ECMO (VA-ECMO). After her condition improved, she was withdrawn from ECMO and experienced a complication of IVC thrombosis. Enoxaparin was given immediately for 1 mg/kg every 12 hours hypodermic injection. The thrombus disappeared after anticoagulant therapy. She was discharged on the 60th day. Her level of consciousness returned to normal without residual central nervous system-related complications. CONCLUSIONS: IVC thrombosis is one of the possible serious complications in the process of ECMO therapy. Prevention of thrombosis and optimization of the anticoagulant regimen are the main preventive measures. Anticoagulant therapy is still the main treatment of IVC thrombosis in the process of ECMO therapy. Other interventional strategies need to accumulate clinical experience.

Exosomes Derived From Heat Stroke Cases Carry miRNAs Associated With Inflammation and Coagulation Cascade.

The pathological mechanism underlying heat stroke (HS) is associated with the dysbalanced inflammation and coagulation cascade. Cell-derived circulating extracellular vesicles (EVs), as a novel pathway mediating intercellular communication, are associated with the immune response and inflammation in critical inflammatory syndromes, such as sepsis. Although these vesicles contain genetic material correlated with their biological function, their molecular cargo during HS remains unknown. In this study, we evaluate the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) associated with inflammatory responses and coagulation cascade in exosomes of patients with HS. Blood samples were collected from three patients with HS at the time of admission to the intensive care unit; three healthy volunteers were selected as control. Exosomes were isolated using ultracentrifugation, and their miRNA content was profiled using next-generation sequencing; mRNA content was evaluated using qPCR array. Compared with those from healthy volunteers, exosomes from patients with HS showed substantial changes in the expression of 202 exosomal miRNAs (154 upregulated and 48 downregulated miRNAs). The most upregulated miRNAs included miR-511-3p, miR-122-5p, miR-155-3p, miR-1290, and let7-5p, whereas the most downregulated ones included miR-150-3p, 146a-5p, and 151a-3p. Gene ontology enrichment of the miRNAs of patients with HS compared with control subjects were associated mostly with inflammatory response, including T cell activation, B cell receptor signaling, dendritic cell chemotaxis and leukocyte migration, and platelet activation and blood coagulation. The identified miRNAs were primarily enriched to the signal transduction pathways namely, T cell receptor signaling, Ras signaling, chemokine signaling, platelet activation, and leukocyte transendothelial migration, all of which are associated with inflammation and hemostasis. Multiple targeted mRNAs associated with the inflammatory response, blood coagulation, and platelet activation were further verified in serum exosomes. Exosomes from patients with HS convey miRNAs and mRNAs associated with pathogenic pathways, including inflammatory response and coagulation cascade. Exosomes may represent a novel mechanism for intercellular communication during HS.

Expanding of ST11 Carbapenemase-Producing Klebsiella pneumoniae Subclones in a Chinese Hospital, Shenzhen, China.

BACKGROUND: ST11 is the most prevalent sequence type of clinical Klebsiella pneumoniae in China. METHODS: We investigated the characteristics of the ST11 subclones using core genome multi-locus sequence typing (cgMLST). Ninety-three carbapenemase-producing K. pneumoniae isolates were collected at Shenzhen People's Hospital. Then, whole-genome sequencing and cgMLST were used to discriminate apparent subclones within the ST11 group. RESULTS: We analyzed the prevalence and genetic relationships of these subclones. ST11 and K. pneumoniae carbapenemase (KPC-2) were the predominant genotype and carbapenemase, respectively, in the clinical carbapenemase-producing K. pneumoniae strains. cgMLST scheme genotyping divided the ST11 group into two clades across seven complex types (CTs). CT1313 was the most prevalent subclone. The deletion of galF and a high frequency of SNPs in genes associated with the stress- and SOS-responses were found in CT1291 and CT2405 over time, respectively. CONCLUSION: Our results indicated that the subclones of the ST11 group had different patterns of prevalence. Highly discriminatory genotyping techniques, such as cgMLST scheme, should be used in further molecular epidemiology investigations.

Clinical Experience of Personalized Phage Therapy Against Carbapenem-Resistant Acinetobacter baumannii Lung Infection in a Patient With Chronic Obstructive Pulmonary Disease.

Overuse of antibiotics in clinical medicine has contributed to the global spread of multidrug-resistant bacterial pathogens, including Acinetobacter baumannii. We present a case of an 88-year-old Chinese man who developed hospital-acquired pneumonia caused by carbapenem-resistant A. baumannii (CRAB). A personalized lytic pathogen-specific single-phage preparation was nebulized to the patient continuously for 16 days in combination with tigecycline and polymyxin E. The treatment was well tolerated and resulted in clearance of the pathogen and clinical improvement of the patient's lung function.

A small molecule interacts with pMAC-derived hydroperoxide reductase and enhances the activity of aminoglycosides.

The threat of antimicrobial resistance calls for more efforts in basic science, drug discovery, and clinical development, particularly gram-negative carbapenem-resistant pathogens. We sought to identify novel antibacterial agents against Acinetobacter baumannii ATCC19606 using whole cell-based screening. A small molecule named 6D1 with the chemical structure of 6-fluorobenzo[d]isothiazol-3(2H)-one was identified and exhibited activity against A. baumannii ATCC19606 strain (minimal inhibitory concentration, MIC = 1 mg l-1). The mutation in the plasmid-derived ohrB gene that encodes a peroxidase was identified in spontaneously resistant mutants. Treatment of the bacteria with 6D1 resulted in increased sensitivity to peroxide, such as tert-butyl hydroperoxide. The binding of 6D1 and OhrB was confirmed by surface plasmon resonance. Interestingly, the MIC of kanamycin and gentamicin against spontaneously resistant mutants decreased. Finally, we identified the effect of 6D1 on enhancing the antibacterial activity of kanamycin and gentamicin, including against New Delhi metallo-ß-lactamase (NDM-1)-producing carbapenem-resistant Klebsiella pneumoniae, but not in strains carrying aminoglycosides resistance genes. In this study, we identified a small molecule that suppresses the growth of A. baumannii, interacts with hydroperoxide reductase from A. baumannii ATCC19606 plasmid pMAC, and enhances the antibacterial activity of kanamycin and gentamicin. We propose that peroxidase may be potentially used as a target for aminoglycosides adjuvant development.

Rapid Identification of KL49 Acinetobacter baumannii Associated with Clinical Mortality.

OBJECTIVE: We aimed to establish a tool for rapid identification of KL49 Acinetobacter baumannii. METHODS: Based on the capsular polysaccharide (CPS) synthesis genes database, we investigated the distribution of K locus type 49 (KL49) genes in other KL types and established a rapid identification method for KL49. We collected 61 clinical carbapenem-resistant A. baumannii (CRAB) strains, identified KL49 by gtr100 detection, and used whole genome sequencing (WGS) for verification. A mouse pneumonia model was used to confirm the hypervirulence phenotype. We tested the presence of gtr100 gene in 165 CRAB strains from three provinces in China and evaluated the correlation of gtr100 carrying CRAB infection with mortality. RESULTS: The gtr100 gene is the CPS synthesis gene found only in KL49. We screened out nine WGS-validated KL49 strains from 61 CRAB clinical strains using polymerase chain reaction (PCR) to detect the gtr100 gene. The survival rates of KL49 strains were significantly lower than nonKL49 strains in a mouse pneumonia model. The survival rates of LAC-4 gtr100 knockout strain decreased significantly. Analysis of phylogenetics showed the worldwide spread of KL49 A. baumannii. Infection of gtr100 carrying CRAB is an independent risk for mortality (OR, 10.76; 95%CI: 3.08-37.55; p<0.001). CONCLUSION: The hypervirulence phenotype of KL49 CRAB and the association with mortality highlight the urgent need for implementing control measures. The rapid identification assay has the potential to facilitate early medical intervention and worldwide surveillance.

Knockdown of lncRNA MALAT1 Alleviates LPS-Induced Acute Lung Injury via Inhibiting Apoptosis Through the miR-194-5p/FOXP2 Axis.

PURPOSE: We aimed to identify and verify the key genes and lncRNAs associated with acute lung injury (ALI) and explore the pathogenesis of ALI. Research showed that lower expression of the lncRNA metastasis-associated lung carcinoma transcript 1 (MALAT1) alleviates lung injury induced by lipopolysaccharide (LPS). Nevertheless, the mechanisms of MALAT1 on cellular apoptosis remain unclear in LPS-stimulated ALI. We investigated the mechanism of MALAT1 in modulating the apoptosis of LPS-induced human pulmonary alveolar epithelial cells (HPAEpiC). METHODS: Differentially expressed lncRNAs between the ALI samples and normal controls were identified using gene expression profiles. ALI-related genes were determined by the overlap of differentially expressed genes (DEGs), genes correlated with lung, genes correlated with key lncRNAs, and genes sharing significantly high proportions of microRNA targets with MALAT1. Quantitative real-time PCR (qPCR) was applied to detect the expression of MALAT1, microRNA (miR)-194-5p, and forkhead box P2 (FOXP2) mRNA in 1 µg/ml LPS-treated HPAEpiC. MALAT1 knockdown vectors, miR-194-5p inhibitors, and ov-FOXP2 were constructed and used to transfect HPAEpiC. The influence of MALAT1 knockdown on LPS-induced HPAEpiC proliferation and apoptosis via the miR-194-5p/FOXP2 axis was determined using Cell counting kit-8 (CCK-8) assay, flow cytometry, and Western blotting analysis, respectively. The interactions between MALAT1, miR-194-5p, and FOXP2 were verified using dual-luciferase reporter gene assay. RESULTS: We identified a key lncRNA (MALAT1) and three key genes (EYA1, WNT5A, and FOXP2) that are closely correlated with the pathogenesis of ALI. LPS stimulation promoted MALAT1 expression and apoptosis and also inhibited HPAEpiC viability. MALAT1 knockdown significantly improved viability and suppressed the apoptosis of LPS-stimulated HPAEpiC. Moreover, MALAT1 directly targeted miR-194-5p, a downregulated miRNA in LPS-stimulated HPAEpiC, when FOXP2 was overexpressed. MALAT1 knockdown led to the overexpression of miR-194-5p and restrained FOXP2 expression. Furthermore, inhibition of miR-194-5p exerted a rescue effect on MALAT1 knockdown of FOXP2, whereas the overexpression of FOXP2 reversed the effect of MALAT1 knockdown on viability and apoptosis of LPS-stimulated HPAEpiC. CONCLUSION: Our results demonstrated that MALAT1 knockdown alleviated HPAEpiC apoptosis by competitively binding to miR-194-5p and then elevating the inhibitory effect on its target FOXP2. These data provide a novel insight into the role of MALAT1 in the progression of ALI and potential diagnostic and therapeutic strategies for ALI patients.

Whole blood transcriptomic investigation identifies long non-coding RNAs as regulators in sepsis.

BACKGROUND: Sepsis is a fatal disease referring to the presence of a known or strongly suspected infection coupled with systemic and uncontrolled immune activation causing multiple organ failure. However, current knowledge of the role of lncRNAs in sepsis is still extremely limited. METHODS: We performed an in silico investigation of the gene coexpression pattern for the patients response to all-cause sepsis in consecutive intensive care unit (ICU) admissions. Sepsis coexpression gene modules were identified using WGCNA and enrichment analysis. lncRNAs were determined as sepsis biomarkers based on the interactions among lncRNAs and the identified modules. RESULTS: Twenty-three sepsis modules, including both differentially expressed modules and prognostic modules, were identified from the whole blood RNA expression profiling of sepsis patients. Five lncRNAs, FENDRR, MALAT1, TUG1, CRNDE, and ANCR, were detected as sepsis regulators based on the interactions among lncRNAs and the identified coexpression modules. Furthermore, we found that CRNDE and MALAT1 may act as miRNA sponges of sepsis related miRNAs to regulate the expression of sepsis modules. Ultimately, FENDRR, MALAT1, TUG1, and CRNDE were reannotated using three independent lncRNA expression datasets and validated as differentially expressed lncRNAs. CONCLUSION: The procedure facilitates the identification of prognostic biomarkers and novel therapeutic strategies of sepsis. Our findings highlight the importance of transcriptome modularity and regulatory lncRNAs in the progress of sepsis.

Differential Expression Pattern of Exosome Long Non-Coding RNAs (lncRNAs) and MicroRNAs (miRNAs) in Vascular Endothelial Cells Under Heat Stroke.

BACKGROUND Heat stroke is a life-threatening disease which is characterized by a high body temperature and multiple organ dysfunction syndrome. Vascular endothelial cell injury is a main feature of heat stroke. Little is known about the long noncoding RNA (lncRNA) and microRNA (miRNA) expression alternation in endothelial cell exosomes related to heat stroke. The aim of this study was to explore the changes of lncRNAs and miRNAs expression pattern in exosomes derived from vascular endothelial cells under heat stroke temperature conditions. MATERIAL AND METHODS Cultured medium exosomes from HUVECs (human vascular endothelial cells) either under normal temperature or heat stroke temperature conditions were harvested; then RNA was extracted and the lncRNAs and miRNAs were analyzed by high throughput sequencing. RESULTS Ten significantly upregulated and 10 downregulated lncRNAs were identified in exosomes derived from heat stroke temperature treated cells. Furthermore, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were used to evaluate the signaling pathway of differential expressions in lncRNAs. Finally, the interaction network of lncRNAs-miRNAs-mRNA was uncovered using ceRNA (competing endogenous RNA) principle via prediction software. CONCLUSIONS These results indicate that the identified lncRNAs and miRNAs in endothelial cell exosomes might serve as non-invasive biomarkers for heat stroke.

Correlation analysis of omega-3 fatty acids and mortality of sepsis and sepsis-induced ARDS in adults: data from previous randomized controlled trials.

OBJECTIVE: This study aimed to investigate the possible effect of omega-3 fatty acids on reducing the mortality of sepsis and sepsis-induced acute respiratory distress syndrome (ARDS) in adults. METHODS: Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI) database, WangFang database, and Chinese BioMedical Literature Database from their inception to March 6, 2017, were searched using systematic review researching methods. Five factors were analyzed to investigate the correlation between omega-3 fatty acids (either parenteral or enteral supplementation) and mortality rate. RESULTS: Forty randomized controlled trials (RCTs) were initially included, but only 25 of them assessed mortality. Of these RCTs, nine used enteral nutrition (EN) and 16 used parenteral nutrition (PN). The total mortality rate in the omega-3 fatty acid group was lower than that in the control group. However, the odds ratio (OR) value was not significantly different in the EN or PN subgroup. Eighteen RCTs including 1790 patients with similar severity of sepsis and ARDS were also analyzed. The OR value was not significantly different in the EN or PN subgroup. Omega-3 fatty acids did not show positive effect on improving mortality of sepsis-induced ARDS (p = 0.39). But in EN subgroup, omega-3 fatty acids treatment seemed to have some benefits in reducing mortality rate (p = 0.04). In the RCTs including similar baseline patients, partial correlation analysis found that the concentration ratio of n-6 to n-3 fatty acids had positive correlation with reduction of mortality (RM) (γ = 0.60, P = 0.02), whereas the total number of each RCT had negative correlation with RM (γ = - 0.54, P = 0.05). CONCLUSIONS: This review found that omega-3 fatty acid supplementation could reduce the mortality rate of sepsis and sepsis-induced ARDS. However, further investigation based on suitable concentrations and indications is needed to support the findings.

In vitro study on the role of SOX9 in trastuzumab resistance of adenocarcinoma of the esophagogastric junction.

Trastuzumab is recommended for the treatment of human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagogastric junction (AEG) in combination with chemotherapy; however, drug resistance has severely affected its clinical application. The present study aimed to investigate the effect of sex determining region Y-box 9 (SOX9), a prognostic marker in adjuvant oncological settings, on AEG cell proliferation and apoptosis in the presence or absence of trastuzumab. Furthermore, the molecular mechanism underlying the role of SOX9 in trastuzumab resistance was explored. ESO26 cells were treated with various concentrations of trastuzumab, and trastuzumab induced SOX9 expression in a concentration-dependent manner, as determined by reverse transcription-quantitative polymerase chain reaction and western blotting analyses. Transfection of ESO26 cells with SOX9 small interfering RNA was conducted to knock down SOX9 expression, and the results of MTT and flow cytometry assays demonstrated that SOX9 knockdown sensitized ESO26 cells to trastuzumab by inhibiting cell proliferation and enhancing cell apoptosis. In addition, it was observed that the trastuzumab-induced phosphorylation of AKT was suppressed by SOX9 knockdown. In conclusion, the present study demonstrated that SOX9 participated in trastuzumab resistance by affecting cell proliferation and apoptosis, and indicated that SOX9 may exert its effect on trastuzumab resistance via activation of the phosphatidylinositol-3-kinase/AKT signaling pathway. This study identified a novel mechanism underlying trastuzumab resistance in vitro and may be useful in improving the efficacy of trastuzumab treatment.