Individual mortality risk predictive system of patients with acute-on-chronic liver failure based on a random survival forest model.

BACKGROUND: The basis of individualized treatment should be individualized mortality risk predictive information. The present study aimed to develop an online individual mortality risk predictive tool for acute-on-chronic liver failure (ACLF) patients based on a random survival forest (RSF) algorithm. METHODS: The current study retrospectively enrolled ACLF patients from the Department of Infectious Diseases of The First People's Hospital of Foshan, Shunde Hospital of Southern Medical University, and Jiangmen Central Hospital. Two hundred seventy-six consecutive ACLF patients were included in the present study as a model cohort (n = 276). Then the current study constructed a validation cohort by drawing patients from the model dataset based on the resampling method (n = 276). The RSF algorithm was used to develop an individual prognostic model for ACLF patients. The Brier score was used to evaluate the diagnostic accuracy of prognostic models. The weighted mean rank estimation method was used to compare the differences between the areas under the time-dependent ROC curves (AUROCs) of prognostic models. RESULTS: Multivariate Cox regression identified hepatic encephalopathy (HE), age, serum sodium level, acute kidney injury (AKI), red cell distribution width (RDW), and international normalization index (INR) as independent risk factors for ACLF patients. A simplified RSF model was developed based on these previous risk factors. The AUROCs for predicting 3-, 6-, and 12-month mortality were 0.916, 0.916, and 0.905 for the RSF model and 0.872, 0.866, and 0.848 for the Cox model in the model cohort, respectively. The Brier scores were 0.119, 0.119, and 0.128 for the RSF model and 0.138, 0.146, and 0.156 for the Cox model, respectively. The nonparametric comparison suggested that the RSF model was superior to the Cox model for predicting the prognosis of ACLF patients. CONCLUSIONS: The current study developed a novel online individual mortality risk predictive tool that could predict individual mortality risk predictive curves for individual patients. Additionally, the current online individual mortality risk predictive tool could further provide predicted mortality percentages and 95% confidence intervals at user-defined time points.

Increased expression of Ki-67 is a poor prognostic marker for colorectal cancer patients: a meta analysis.

BACKGROUND: The prognostic value of Ki-67 expression in colorectal cancer patients was controversial. Therefore, this meta analysis was conducted to ascertain the prognostic value of Ki-67 expression in colorectal cancer patients. METHODS: The electronic databases, including EMBASE, PubMed, Cochrane Library and Web of Knowledge database, were searched from January 1970 to July 2017. The pooled hazard ratios and 95% confidence intervals were calculated to evaluate the prognostic value of Ki-67 expression for colorectal cancer patients. RESULTS: Totally 34 eligible studies and 6180 colorectal cancer patients were included in the present meta analysis. The pooled hazard ratios were 1.54(95% CI 1.17-2.02, P = 0.005) for overall survival and 1.43(1.12-1.83, P = 0.008) for disease free survival in univariate analysis. After adjustment of other prognostic factors, the pooled HR was 1.50(95% CI 1.02-2.22, P = 0.03) for overall survival in multivariate analysis. CONCLUSION: The present meta analysis demonstrated that high Ki-67 expression is significantly correlated with poor overall survival and disease free survival, indicating that high Ki-67 expression may serve as a valuable predictive method for poor prognosis of colorectal cancer patients.

Development and validation of a prognostic signature for preoperative prediction of overall survival in gastric cancer patients.

BACKGROUND: As a serious challenge for public health, the prognosis of gastric cancer patients is still poor. The current study aimed to develop and validate a prognostic signature to predict the overall survival of gastric cancer patients. PATIENTS AND METHODS: The dataset in the present study was obtained from The Cancer Genome Atlas database. The present study finally included 343 gastric cancer patients with information on long non-coding RNA (lncRNA) expression and overall survival. RESULTS: A prognostic model named Eleven-lncRNA signature was constructed according to the expression values of eleven prognostic lncRNA predictors identified by univariate and multivariate Cox regression model. According to time-dependent receiver operating characteristic curves, the Harrell's concordance indexes of Eleven-lncRNA signature were 0.764 (95% CI 0.720-0.808), 0.776 (95% CI 0.732-0.820), and 0.807 (95% CI 0.763-0.851) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively in the model group. In the validation group, the Harrell's concordance indexes of Eleven-lncRNA signature were 0.748 (95% CI 0.704-0.792), 0.794 (95% CI 0.750-0.838), and 0.798 (95% CI 0.754-0.842) for 1-year overall survival, 3-year overall survival, and 5-year overall survival respectively. The gastric cancer patients (n=343) in the model group could be stratified into low-risk group (n=171) and high-risk group (n=172) according to the median of Eleven-lncRNA signature score. Kaplan-Meier survival curves showed that the mortality rate in the high-risk group was significantly poorer than that in the low-risk group (P<0.001). CONCLUSION: The present study constructed and validated a prognostic model named Eleven-lncRNA signature for preoperative individual mortality risk prediction in gastric cancer patients. This Eleven-lncRNA signature can predict the individual mortality risk of gastric cancer patients and is helpful in improving clinical decision making regarding individualized treatment.

Compound edaravone alleviates lipopolysaccharide (LPS)-induced acute lung injury in mice.

Acute lung injury (ALI) represents an unmet medical need with an urgency to develop effective pharmacotherapies. Compound edaravone, a combination of edaravone and borneol, has been developed for treatment of ischemia stroke in clinical phase III study. The purpose of the present study is to investigate the anti-inflammatory effect of compound edaravone on lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 cells and the therapeutic efficacy on LPS-induced ALI in mice. Edaravone and compound edaravone concentration-dependently decreased LPS-induced interleukin-6 (IL-6) production and cyclooxygenase-2 (COX-2) expression in RAW264.7 cells. The efficiency of compound edaravone was stronger than edaravone alone. In the animal study, compound edaravone was injected intravenously to mice after intratracheal instillation of LPS. It remarkably alleviated LPS-induced lung injury including pulmonary histological abnormalities, polymorphonuclear leukocyte (PMN) infiltration and extravasation. Further study demonstrated that compound edaravone suppressed LPS-induced TNF-α and IL-6 increase in mouse serum and bronchoalveolar lavage (BAL) fluid, and inhibited LPS-induced nuclear factor-κB (NF-κB) activation and COX-2 expression in mice lung tissues. Importantly, our findings demonstrated that the compound edaravone showed a stronger protective effect against mouse ALI than edaravone alone, which suggested the synergies between edaravone and borneol. In conclusion, compound edaravone could be a potential novel therapeutic drug for ALI treatment and borneol might produce a synergism with edaravone.

Clinicopathologic significance and prognostic value of Ki-67 expression in patients with gastric cancer: a meta-analysis.

BACKGROUND: The prognostic value and clinicopathologic significance of Ki-67 expression in gastric cancer patients was controversial. This meta-analysis was performed to clarify the prognostic value and clinicopathologic significance of Ki-67 expression in gastric cancer patients. MATERIALS AND METHODS: Several electronic databases were searched for eligible studies. The pooled odds ratio (OR), hazard ratios (HR) and 95% confidence interval(CI) were calculated to explore the prognostic value and clinicopathologic significance of Ki-67 expression for disease free survival and overall survival. RESULTS: Totally 5600 gastric cancer patients from 29 studies were included in this study. High Ki-67 expression was significantly related with Lauren's classification (OR = 1.70; P = 0.001; 95%CI: 1.40-2.06) and tumor size(OR = 1.54; P = 0.006; 95%CI: 1.14-2.09). However, high Ki-67 expression was not significantly associated with lymph node metastasis (OR = 1.37; P = 0.138; 95% CI: 0.90-2.08) , tumor stage (OR = 1.31; P = 0.296; 95% CI: 0.79-2.16) and tumor differentiation (OR = 1.03; P = 0.839; 95% CI: 0.78-1.35). The pooled HRs were 1.87(P = 0.001; 95% CI 1.30-2.69) for disease free survival and 1.23(P = 0.005; 95% CI 1.06-1.42) for overall survival. CONCLUSIONS: High Ki-67 expression may serve as a predictive biomarker for poor prognosis in gastric cancer patients. Stratification by Ki-67 expression may be a consideration for selection of therapeutic regimen and integrated managements.

Clinicopathologic and prognostic significance of human epidermal growth factor receptor in patients with gastric cancer: An updated meta-analysis.

PURPOSE: The aim of this update meta-analysis was to clarify the clinicopathologic and prognostic significance of human epidermal growth factor receptor(EGFR) expression in gastric cancer patients. EXPERIMENTAL DESIGN: Several electronic databases were searched from January 1970 to May 2016. The odds ratio (OR) was calculated to assess the association between EGFR expression and pathological parameters. The hazard ratio (HR) and 95% CI were calculated to explore the relationship between EGFR expression and overall survival. RESULTS: Finally 7229 patients with gastric cancer from 25 eligible studies were included in the present meta analysis. High EGFR expression was found to be significantly related with tumor differentiation (OR=1.96, 95%CI: 1.14-3.34, Z=2.43, P=0.015), lymph node metastasis (OR=2.20, 95% CI: 1.63-2.96, Z=5.17, P=0.001), and tumor stage (OR=2.13, 95% CI: 1.35-3.36, Z=3.25, P=0.001). However, high EGFR expression was not significantly associated with invasion depth (OR=2.09, 95% CI: 0.4-11.05, Z=0.87, P=0.385). The pooled HR suggested that high EGFR expression was significantly correlated with overall survival (HR=1.19, 95% CI 1.04-1.37, Z=2.44, P=0.015). CONCLUSIONS: The present meta-analysis demonstrated that high EGFR expression significantly predicts poor prognosis, suggesting that high EGFR expression may serve as a predictive biomarker for poor prognosis in patients with gastric cancer.

Inhibition of Wnt/ß-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury.

Idiopathic pulmonary fibrosis is a progressive lung disorder of unknown etiology. Previous studies have shown that aberrant activation of the Wnt/ß-catenin signaling cascade occurs in lungs of patients with idiopathic pulmonary fibrosis. Given the important roles of the Wnt/ß-catenin signaling pathway in the development of pulmonary fibrosis, we targeted this pathway for the intervention of pulmonary fibrosis with XAV939, a small molecule that specifically inhibits Tankyrase 1/2, eventually leading to the degradation of ß-catenin and suppression of the Wnt/ß-catenin signaling pathway. Our results demonstrated that XAV939 significantly inhibited the activation of Wnt/ß-catenin signaling and attenuated bleomycin-induced lung fibrosis in mice, and thus improved the survival of mice with lung injury. Interestingly, previous investigations have confirmed that endogenous and exogenous mesenchymal stem cells could be recruited to the injured lung, although the exact effects of these cells are debatable. To determine the effect of Wnt/ß-catenin signaling in the epithelial differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs), we established a coculture system that contains BM-MSCs and alveolar type II epithelial cells. The in vitro experiments demonstrated that XAV939 could promote the differentiation of BM-MSCs into an epithelium-like phenotype in the coculture system. We also found that XAV939 could inhibit the proliferation and myofibroblast differentiation of NIH/3T3 fibroblasts. This work supports that inhibition of the Wnt/ß-catenin signaling pathway may be exploited for the treatment of idiopathic pulmonary fibrosis for which effective treatment strategies are still lacking.

Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with D-peptides derived from chemokines.

Chemokine receptor CXCR4 plays an important role in the immune system and the cellular entry of human immunodeficiency virus type 1 (HIV-1). To probe the stereospecificity of the CXCR4-ligand interface, d-amino acid peptides derived from natural chemokines, viral macrophage inflammatory protein II (vMIP-II) and stromal cell-derived factor-1alpha (SDF-1alpha), were synthesized and found to compete with (125)I-SDF-1alpha and monoclonal antibody 12G5 binding to CXCR4 with potency and selectivity comparable with or higher than their l-peptide counterparts. This was surprising because of the profoundly different side chain topologies between d- and l-enantiomers, which circular dichroism spectroscopy showed adopt mirror image conformations. Further direct binding experiments using d-peptide labeled with fluorescein (designated as FAM-DV1) demonstrated that d- and l-peptides shared similar or at least overlapping binding site(s) on the CXCR4 receptor. Structure-activity analyses of related peptide analogs of mixed chiralities or containing alanine replacements revealed specific residues at the N-terminal half of the peptides as key binding determinants. Acting as CXCR4 antagonists and with much higher biological stability than l-counterparts, the d-peptides showed significant activity in inhibiting the replication of CXCR4-dependent HIV-1 strains. These results show the remarkable stereochemical flexibility of the CXCR4-peptide interface. Further studies to understand the mechanism of this unusual feature of the CXCR4 binding surface might aid the development of novel CXCR4-binding molecules like the d-peptides that have high affinity and stability.

[Effects of laser in situ keratomileusis (LASIK) retreatment on the central corneal endothelium and retina and optic nerve].

OBJECTIVE: To investigate the effects of laser in situ keratomileusis (LASIK) on the corneal endothelium, retina and optic nerve for correcting residual myopia caused by undercorrection or regression. METHODS: The pre- and post-operative values of central corneal endothelium and electrophysiological functions of retina and optic nerve were analyzed respectively in 23 eyes of 18 patients who received LASIK retreatment. The endothelium checked by contact specular microscopy was analyzed for central cell density (CCD), coefficient of cell variation in size and hexagonality preoperatively and 1, 4, 12 weeks after the operation. The amplitude and latency of P(100) in standard pattern visual evoked potentials (P-VEPs), that of a, b waves of different reactions in flash electroretinograms (F-ERGs) and also the total amplitude of oscillatory potentials (OPs) were evaluated preoperatively and 2, 12 weeks after the operation. RESULTS: The mean CCD decreased significantly (3.94%) one week after the operation (P < 0.01). The change was negatively correlated with the thickness of residual untreated posterior cornea (r = -0.719, P < 0.01) and not significantly correlated with the amount of laser pulse (r = 0.371, P > 0.05). There was no significant difference between preoperative and either 4 or 12 week postoperative CCD (P > 0.05). No significant differences in mean coefficient variation and hexagonality were found between preoperative and postoperative values in the follow up (P > 0.05). Examination of electrophysiological function showed that the amplitude of P(100) increased and the latency of P(100) decreased 2 and 12 weeks postoperatively. The significant changes were only at spatial frequency 34' in the P-VEPs test (P < 0.05). In F-ERGs test, there was no significant change in amplitude, latency of a, b waves or total amplitude of OPs between pre-operative and either 2 or 12 week post-operative values (P > 0.05). CONCLUSIONS: Retreatment after LASIK may cause a reversible reduction of CCD with no morphological changes in a short period (1 week) after the operation. It was not absolutely safe for corneal endothelium when the thickness of residual untreated basal cornea approaches to 200 micro m. These results show that the operation seems not to cause functional impairment in the retina and optic nerve. And it also can improve the quality of vision for some degrees.