Prognostic significance of systemic immune-inflammation index in patients with intrahepatic cholangiocarcinoma undergoing hepatic resection.

BACKGROUND: The prognosis of intrahepatic cholangiocarcinoma (ICC) patients following surgical resection remains poor. It is necessary to investigate effective biomarkers or prognostic models for ICC patients. AIM: To investigate the prognostic effect of systemic immune-inflammation index (SII) to predict long-term outcomes in ICC patients with undergoing hepatic resection. METHODS: Consecutive ICC patients who underwent initial hepatectomy with curative intent from January 2009 to September 2017 were retrospectively reviewed. Receiver-operating characteristic (ROC) curves were used to determine the optimal cut-off values of SII. Kaplan-Meier curves and Cox proportional hazards regression were performed to evaluate the discriminative ability of preoperative SII in predicting overall survival (OS) and recurrence-free survival (RFS). RESULTS: A total of 530 patients were included and randomly divided into derivation (n = 265) and validation cohort (n = 265). The optimal cut-off value for SII was 450. At a median follow-up of 18 mo (range, 1-115.4 mo), 317 (59.8%) patients died and 381 (71.9%) patients experienced tumor relapse. Low SII level was associated with better OS and RFS (both P < 0.05). Multivariate analyses identified multiple tumors, node invasion and high SII level as independent risk factors for OS, while multiple tumors, node invasion and high SII level were identified as independent risk factors for RFS. Validation cohort confirmed the findings of derivation cohort. CONCLUSION: The present study demonstrated the feasibility of preoperative SII as a prognostic indicator for ICC. Patients with increased SII level were associated with worse OS and earlier tumor recurrence. Elevated SII level was an independent risk factor for OS and RFS in patients with ICC after hepatectomy. In the future, the SII could help stratifying patients with ICC, thus guiding therapeutic choices, especially in immunotherapy.

Preoperative gamma-glutamyltransferase to lymphocyte ratio predicts long-term outcomes in intrahepatic cholangiocarcinoma patients following hepatic resection.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous hepatobiliary cancer with limited treatment options. A number of studies have illuminated the relationship between inflammation-based prognostic scores and outcomes in patients with ICC. However, the use of reliable and personalized prognostic algorithms in ICC after resection is pending. AIM: To assess the prognostic value of the gamma-glutamyltransferase to lymphocyte ratio (GLR) in ICC patients following curative resection. METHODS: ICC patients following curative resection (2009-2017) were divided into two cohorts: The derivation cohort and validation cohort. The derivation cohort was used to explore an optimal cut-off value, and the validation cohort was used to further evaluate the score. Overall survival (OS) and recurrence-free survival (RFS) were analyzed, and predictors of OS and RFS were determined. RESULTS: A total of 527 ICC patients were included and randomly divided into the derivation cohort (264 patients) and the validation cohort (263 patients). The two patient cohorts had comparable baseline characteristics. The optimal cut-off value for the GLR was 33.7. Kaplan-Meier curves showed worse OS and RFS in the GLR > 33.7 group compared with GLR ≤ 33.7 group in both cohorts. After univariate and multivariate analysis, the results indicated that GLR was an independent prognostic factor of OS [derivation cohort: hazard ratio (HR) = 1.620, 95% confidence interval (CI): 1.066-2.462, P = 0.024; validation cohort: HR = 1.466, 95%CI: 1.033-2.142, P = 0.048] and RFS [derivation cohort: HR = 1.471, 95%CI: 1.029-2.103, P = 0.034; validation cohort: HR = 1.480, 95%CI: 1.057-2.070, P = 0.022]. CONCLUSION: The preoperative GLR is an independent prognostic factor for ICC patients following hepatectomy. A high preoperative GLR is associated with worse OS and RFS.

Identification of The Aberrantly Expressed LncRNAs in Hepatocellular Carcinoma: A Bioinformatics Analysis Based on RNA-sequencing.

Hepatocellular carcinoma (HCC) is one of the most prevalent subtypes of liver cancer worldwide. LncRNAs have been demonstrated to be associated with the progression of HCC, but a systematic identification and characterization of their clinical roles and molecular mechanisms in HCC has not been conducted. In this study, the aberrantly expressed lncRNAs in HCC tissues were analyzed based on TCGA RNA-seq data. 1162 lncRNAs were found to be aberrantly expressed in HCC tissues, including 232 down-regulated lncRNAs and 930 up-regulated lncRNAs. The top 5 lncRNAs with the highest diagnostic accuracy were further analyzed to evaluate their clinical value and potential mechanism in HCC. Kaplan-Meier curves showed that higher expressions of DDX11-AS1 and AC092171.4 were in correlation with poorer survival in HCC patients. Significant difference was also observed when comparing the expression levels of DDX11-AS1 and SFTA1P in different clinical parameters (p < 0.05). GO analysis showed that genes regulated by the 5 lncRNAs were enriched in certain pathways, such as PI3K pathway. Moreover, GSEA analysis on the expression of DDX11-AS1 showed that DDX11-AS1 affected the gene expressions involved in HCC proliferation, differentiation and cell cycle, indicating an essential role of DDX11-AS1 in hepatocarcinogenesis.

Hematopoietic stem cell-derived exosomes promote hematopoietic differentiation of mouse embryonic stem cells in vitro via inhibiting the miR126/Notch1 pathway.

Cell-derived exosomes (EXs) can modulate target cell differentiation via microRNAs (miRs) that they carried. Previous studies have shown that miR126 is highly expressed in hematopoietic stem cells (HSCs) and plays a role in hematopoiesis via modulating the Notch pathway that participates in progenitors' cell fate decisions. In this study we investigated whether HSC-derived EXs (HSC-EXs) could affect the differentiation of mouse embryonic stem cells (ESCs) into HSCs. We prepared HSC-EXscon, HSC-EXssc and HSC-EXsmiR126 from control HSCs and the HSCs transfected with scramble control or miR126 mimics, respectively. HSC-EXs were isolated by ultracentrifugation and analyzed using nanoparticle tracking analysis. We incubated the collected EXs with mouse ESCs over a 10-d differentiation induction period, during which HSC-EXs and a Notch pathway activator (Jagged1, 100 ng/mL) were added to the cultures every 3 d. After the 10-d differentiation period, the expression levels of miR126, SSEA1, CD117, Sca1, Notch1 and Hes1 in ESCs were assessed. The generated HSCs were validated by flow cytometry using antibodies against HSC markers (CD117, CD34 and Sca1). Our results revealed that: (1) transfection with miR126 mimics significantly increased miR126 levels in HSC-EXsmiR126. (2) HSC-EX co-culture promoted mouse ESCs differentiation into HSCs with the most prominent effect found in the HSC-EXsmiR126 co-culture. (3) HSC differentiation was verified by reduced SSEA1 expression and increased CD117 and Sca1 expression. (4) All the effects caused by HSC-EXs were accompanied by significant reduction of Notch1 and Hes1 expression, thus inhibition of the Notch1/Hes1 pathway, whereas activation of Notch by Jagged1 abolished the effects of HSC-EXsmiR126. In conclusion, HSC-EXs promote hematopoietic differentiation of mouse ESCs in vitro by inhibiting the miR126/Notch1 pathway.

Autophagy inhibitor 3-methyladenine alleviates overload-exercise-induced cardiac injury in rats.

Overload-exercise (OE) causes myocardial injury through inducing autophagy and apoptosis. In this study we examined whether an autophagy inhibitor 3-methyladenine (3-MA) could alleviate OE-induced cardiac injury. Rats were injected with 3-MA (15 mg/kg, iv) or saline before subjected to various intensities of OE, including no swim (control), 2 h swim (mild-intensity exercise, MIE), 2 h swim with 2.5% body weight overload (moderate OE; MOE), 5% overload (intensive OE; IOE) or 2.5% overload until exhausted (exhaustive OE; EOE). After OE, the hearts were harvested for morphological and biochemiacal analysis. The cardiac morphology, autophagosomes and apoptosis were examined with H&E staining, transmission electron microscopy and TUNEL analysis, respectively. Autophagy-related proteins to (LC3-II/I and Beclin-1) and apoptosis-related proteins (Bcl-2/Bax) were assessed using Western blotting. Our results showed that compared with the control, MIE did not change the morphological structures of the heart tissues that exhibited intact myocardial fibers and neatly arranged cardiomyocytes. However, IOE resulted in irregular arrangement of cardiomyocytes and significantly increased width of cardiomyocytes, whereas EOE caused more swollen and even disrupted cardiomyocytes. In parallel with the increased OE intensity (MOE, IOE, EOE), cardiomyocyte autophagy and apoptosis became more and more prominent, evidenced by the increasing number of autophagosomes and expression levels of LC3-II/I and Beclin-1 as well as the increasing apoptotic cells and decreasing Bcl-2/Bax ratio. 3-MA administration significantly attenuated OE-induced morphological changes of cardiomyocytes as well as all the autophagy- and apoptosis-related abnormalities in MOE, IOE and EOE rats. Thus, the autophagy inhibitor 3-MA could alleviate OE-induced heart injury in rats.

Physical exercise induces hippocampal neurogenesis and prevents cognitive decline.

Accumulating evidence from animal and human research indicate that adult hippocampal neurogenesis plays a key role in cognition. Meanwhile, cognitive decline is well known to associate with ageing-related neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Therefore, prevention of hippocampal neurogenesis reduction should be critical for these diseases. Physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential therapy or an adjunctive therapeutic strategy for cognitive decline. In this review, we discuss the recent findings on hippocampal neurogenesis and the incorporation of new born neurons into the neuronal network in humans and in rodents. By focusing on hippocampal neurogenesis, we illustrate the role and possible mechanisms of physical exercise in cognition preservation.

Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats.

AIM: Microvesicles (MVs) are nanoscale membrane fragments released from virtually all cell types upon activation or apoptosis, and may contribute to the beneficial effects of stem cell therapy. In this study, we investigated the therapeutic effects of mesenchymal stem cell (MSC) derived MVs (MSC-MVs) on pulmonary artery hypertension (PAH) in rats. METHODS: MSC-MVs were isolated from rat bone marrow MSCs that were cultured in a serum-free conditioned medium. Transmission electron microscopy (TEM), flow cytometry and nanoparticle tracking analysis (NTA) were used to characterize the MVs. Adult SD rats were injected with monocrotaline (50 mg/kg, sc) to induce PAH. Three weeks later, the rats were intravenously injected with MSCs, MSC-MVs or saline for 2 weeks. At the end of treatments, the hemodynamic parameters and pathological right ventricular and pulmonary arterial remodeling were analyzed in each group. RESULTS: The MSC-MVs showed general morphologic characteristics of MVs and expressed annexin V and CD29 markers under TEM, and their size ranged from 40 to 300 nm. Intravenous injection of MSC-MVs or MSCs significantly ameliorated the mean pulmonary artery pressure (mPAP) and mean right ventricle pressure (mRVP) in PAH rats. Furthermore, intravenous injection of MSC-MVs or MSCs significantly decreased the right ventricle (RV) hypertrophy and pulmonary arteriole area index (AI) and thickness index (TI) in PAH rats. CONCLUSION: Intravenous injection of MSC-MVs or MSCs produces similar beneficial effects for treating PAH, and our results provide a basis for cell-free approach in stem cell therapy.

Angiotensin converting enzyme 2/Ang-(1-7)/mas axis protects brain from ischemic injury with a tendency of age-dependence.

BACKGROUND: The angiotensin (Ang) converting enzyme 2 (ACE2)/Ang-(1-7)/Mas receptor pathway is an important component of the renin-angiotensin system and has been suggested to exert beneficial effects in ischemic stroke. AIMS: This study explored whether the ACE2/Ang-(1-7)/Mas pathway has a protective effect on cerebral ischemic injury and whether this effect is affected by age. METHODS: We used three-month and eight-month transgenic mice with neural over-expression of ACE2 (SA) and their age-matched nontransgenic (NT) controls. Neurological deficits and ischemic stroke volume were determined following middle cerebral artery occlusion (MCAO). In oxygen and glucose deprivation (OGD) experiments on brain slices, the effects of the Mas receptor agonist (Ang1-7) or antagonist (A779) on tissue swelling, Nox2/Nox4 expression reactive oxygen species (ROS) production and cell death were measured. RESULTS: (1) Middle cerebral artery occlusion -induced ischemic injury and neurological deficit were reduced in SA mice, especially in eight-month animals; (2) OGD-induced tissue swelling and cell death were decreased in SA mice with a greater reduction seen in eight-month mice; (3) Ang-(1-7) and A779 had opposite effects on OGD-induced responses, which correlated with changes in Nox2/Nox4 expression and ROS production. CONCLUSIONS: Angiotensin converting enzyme 2/Ang-(1-7)/Mas axis protects brain from ischemic injury via the Nox/ROS signaling pathway, with a greater effect in older animals.

[Levels of serum brain natriuretic peptide and the correlation to heart function in children with Kawasaki disease].

OBJECTIVE: To study serum levels of brain natriuretic peptide (BNP) in children with Kawasaki disease (KD) and the correlation between BNP levels and the heart function. METHODS: Forty-three children with KD and thirty healthy children were enrolled. Serum levels of BNP were measured using ELISA. KD children received an echocardiographic examination, including measurements of left ventricular ejection fraction (LVEF), left ventricular shorten fraction (LVSF), cardiac index (CI) and left ventricular inflow velocity through the mitral annulus. RESULTS: Mean serum level of BNP at the acute stage in children with KD was significantly higher than that at the recovery stage as well as the control group (p<0.01). The LVEF, LVSF and CI levels at the acute stage were significantly lower than those at the recovery stage in children with KD (p<0.05). The linear regression analysis showed that the BNP level was negatively correlated with the levels of LVEF, LVSF and CI (r=-0.63, -0.52, -0.53, p<0.05). CONCLUSIONS: The serum BNP levels increase significantly in KD children at the acute stage, and are negatively correlated with the levels of LVEF, LVSF and CI. Measurement of serum BNP level is useful for the early diagnosis of KD.

[Levels of serum heart-type fatty acid-binding protein and its clinical significance in children with Kawasaki disease].

OBJECTIVE: This study examined serum level of heart-type fatty acid-binding protein (h-FABP) in children with Kawasaki disease (KD) in order to assess its value in KD. METHODS: Forty children with KD and 30 healthy children were enrolled. Serum levels of h-FABP and cardiac troponin I (cTnI) were measured using ELISA. Serum creatine kinase-MB (CK-MB) level was detected using an autoanalyer. The KD group was classified into two subgroups, with or without coronary artery lesions, based on the findings of the echocardiography. RESULTS: Mean serum levels of h-FABP (18.17+/-13.38 ng/mL vs 6.25+/-1.70 ng/mL; P<0.01) and cTnI (0.27+/-0.22 ng/mL vs 0.11+/-0.02 ng/mL; P<0.05) in the KD group was significantly higher than those in the control group. There was no significant difference in serum CK-MB concentrations between the two groups. Twenty-six patients (65%) and eight patients (20%) showed abnormally increased h-FABP and cTnI levels respectively in the KD group, but none of the control group showed increased levels of both. In the KD group, the percentage of patients with increased h-FABP was significantly higher than those with increased CTnI (P<0.01). The patients with coronary artery lesions had higher serum h-FABP level than those without (28.14+/-14.26 ng/mL vs 11.52+/-6.28 ng/mL; P<0.01). CONCLUSIONS: Serum levels of h-FABP and cTnI increase and can be used as the biomarkers of myocardial damage in children with KD. h-FABP appears to be more sensitive and specific. Detection of serum h-FABP level is useful for diagnosis of KD and coronary artery lesions secondary to KD.

[Constructions of Gcn5 shRNAs interfere the histone acetylation modification with stem cell differentiation].

OBJECTIVE: To construct the Gcn5 shRNA plasmids and to explore the Gcn5 shRNA role in histone acetylation modification with the differentiation of stem cells. METHODS: Seven shRNA fragments were recombined into pGenesil-1 vector to form 7. Gcn5 shRNA constructions. The mesenchymal stem cells (MSCs) induced for two weeks with 5-aza were transfected by the plasmids with lipofectamine2000. Polyclonal antibodies labeled with TRITC were used to identify the acetylation in MSCs with or without Gcn5 shRNA constructions. The efficiencies of transfection and RNAi were calculated based on the ratio of GFP (green fluorescence)/DAPI (blue fluorescence) and TRITC (red fluorescence)/DAPI, respectively. RESULTS: Seven Gcn5 shRNA plasmids or constructions were identified by restriction endonucleases Pst I/Sal I and DNA sequencing. Acetylation block was observed after Gcn5 shRNA plasmids transfected into cells. Fluorescent intensity of TRITC in nucleuses were decreased remarkably, or even disappeared in MSCs. The efficiencies of transfection and RNAi were 93.7% and 46.6%, respectively. CONCLUSION: The Gcn5 shRNA plasmids constructed in the present study can decrease the histone acetylation during cell differentiation. It sets the basis for further exploring the role of acetylation in the regulation of cell differentiation.