Human Adipose Tissue Lysate-Based Hydrogel for Lasting Immunomodulation to Effectively Improve Spinal Cord Injury Repair.

The long-term inflammatory microenvironment is one of the main obstacles to inhibit acute spinal cord injury (SCI) repair. The natural adipose tissue-derived extracellular matrix hydrogel shows effective anti-inflammatory regulation because of its unique protein components. However, the rapid degradation rate and removal of functional proteins during the decellularization process impair the lasting anti-inflammation function of the adipose tissue-derived hydrogel. To address this problem, adipose tissue lysate provides an effective way for SCI repair due to its abundance of anti-inflammatory and nerve regeneration-related proteins. Thereby, human adipose tissue lysate-based hydrogel (HATLH) with an appropriate degradation rate is developed, which aims to in situ long-term recruit and induce anti-inflammatory M2 macrophages through sustainedly released proteins. HATLH can recruit and polarize M2 macrophages while inhibiting pro-inflammatory M1 macrophages regardless of human or mouse-originated. The axonal growth of neuronal cells also can be effectively improved by HATLH and HATLH-induced M2 macrophages. In vivo experiments reveal that HATLH promotes endogenous M2 macrophages infiltration in large numbers (3.5 × 105/100 µL hydrogel) and maintains a long duration for over a month. In a mouse SCI model, HATLH significantly inhibits local inflammatory response, improves neuron and oligodendrocyte differentiation, enhances axonal growth and remyelination, as well as accelerates neurological function restoration.

Serum ammonia variation predicts mortality in patients with hepatitis B virus-related acute-on-chronic liver failure.

Background: Hyperammonemia is critical to the development of hepatic encephalopathy (HE) and is associated with mortality in end-stage liver disease. This study investigated the clinical value of ammonia variation in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients. Methods: A total of 276 patients with HBV-ACLF were retrospectively recruited. Patients' ammonia levels were serially documented. Baseline ammonia, Peak ammonia (highest level), and Trough ammonia (lowest level) were particularly corrected to the upper limit of normal (AMM-ULN). The primary endpoint was 28-day mortality. Results: The 28-day, 3-month, and 12-month mortality rates were 19.2, 25.7, and 28.2%, respectively. A total of 51 (18.4%) patients had overt HE (grade 2/3/4). Peak AMM-ULN was significantly higher in patients with overt HE and non-survivors compared with their counterparts (P < 0.001). Following adjustment for significant confounders, high Peak AMM-ULN was an independent predictor of overt HE (hazard ratio, 1.031, P < 0.001) and 28-day mortality (hazard ratio, 1.026, P < 0.001). The cut-off of Peak AMM-ULN was 1.8, determined by using the X-tile. Patients with Peak AMM-ULN appearing on days 1-3 after admission had a higher proportion of overt HE and mortality compared to other groups. Patients with decreased ammonia levels within 7 days had better clinical outcomes than those with increased ammonia. Conclusion: Serum Peak ammonia was independently associated with overt HE and mortality in HBV-ACLF patients. Serial serum ammonia may have prognostic value.

Robust Acute Pancreatitis Identification and Diagnosis: RAPIDx.

The occurrence of acute pancreatitis (AP) is increasing significantly worldwide. However, current diagnostic methods of AP do not provide a clear clinical stratification of severity, and the prediction of complications in AP is still limited. Here, we present a robust AP identification and diagnosis (RAPIDx) method by the proteomic fingerprinting of intact nanoscale extracellular vesicles (EVs) from clinical samples. By tracking analysis of circulating biological nanoparticles released by cells (i.e., EVs) via bottom-up proteomics, we obtain close phenotype connections between EVs, cell types, and multiple tissues based on their specific proteomes and identify the serum amyloid A (SAA) proteins on EVs as potential biomarkers that are differentially expressed from AP patients significantly. We accomplish the quantitative analysis of EVs fingerprints using MALDI-TOF MS and find the SAA proteins (SAA1-1, desR-SAA1-2, SAA2, SAA1-2) with areas under the curve (AUCs) from 0.92 to 0.97, which allows us to detect AP within 30 min. We further realize that SAA1-1 and SAA2, combined with two protein peaks (5290.19, 14032.33 m/z), can achieve an AUC of 0.83 for classifying the severity of AP. The RAPIDx platform will facilitate timely diagnosis and treatment of AP before severity development and persistent organ failure and promote precision diagnostics and the early diagnosis of pancreatic cancer.

Accurate prediction of acute pancreatitis severity based on genome-wide cell free DNA methylation profiles.

BACKGROUND: Patients with severe acute pancreatitis (SAP) have a high mortality, thus early diagnosis and interventions are critical for improving survival. However, conventional tests are limited in acute pancreatitis (AP) stratification. We aimed to assess AP severity by integrating the informative clinical measurements with cell free DNA (cfDNA) methylation markers. METHODS: One hundred and seventy-five blood samples were collected from 61 AP patients at multiple time points, plus 24 samples from healthy individuals. Genome-wide cfDNA methylation profiles of all samples were characterized with reduced representative bisulfite sequencing. Clinical blood tests covering 93 biomarkers were performed on AP patients within 24 h. SAP predication models were built based on cfDNA methylation and conventional blood biomarkers separately and in combination. RESULTS: We identified 565 and 59 cfDNA methylation markers informative for acute pancreatitis and its severity. These markers were used to develop prediction models for AP and SAP with area under the receiver operating characteristic of 0.92 and 0.81, respectively. Twelve blood biomarkers were systematically screened for a predictor of SAP with a sensitivity of 87.5% for SAP, and a specificity of 100% in mild acute pancreatitis, significantly higher than existing blood tests. An expanded model integrating 12 conventional blood biomarkers with 59 cfDNA methylation markers further improved the SAP prediction sensitivity to 92.2%. CONCLUSIONS: These findings have demonstrated that accurate prediction of SAP by the integration of conventional and novel blood molecular markers, paving the way for early and effective SAP intervention through a non-invasive rapid diagnostic test.

Accurate prediction of acute pancreatitis severity with integrative blood molecular measurements.

BACKGROUND: Early diagnosis of severe acute pancreatitis (SAP) is essential to minimize its mortality and improve prognosis. We aimed to develop an accurate and applicable machine learning predictive model based on routine clinical testing results for stratifying acute pancreatitis (AP) severity. RESULTS: We identified 11 markers predictive of AP severity and trained an AP stratification model called APSAVE, which classified AP cases within 24 hours at an average area under the curve (AUC) of 0.74 +/- 0.04. It was further validated in 568 validation cases, achieving an AUC of 0.73, which is similar to that of Ranson's criteria (AUC = 0.74) and higher than APACHE II and BISAP (AUC = 0.69 and 0.66, respectively). CONCLUSIONS: We developed and validated a venous blood marker-based AP severity stratification model with higher accuracy and broader applicability, which holds promises for reducing SAP mortality and improving its clinical outcomes. MATERIALS AND METHODS: Nine hundred and forty-five AP patients were enrolled into this study. Clinical venous blood tests covering 65 biomarkers were performed on AP patients within 24 hours of admission. An SAP prediction model was built with statistical learning to select biomarkers that are most predictive for AP severity.

A novel genomic-clinicopathologic nomogram to improve prognosis prediction of hepatocellular carcinoma.

There is a lack of precise and clinical accessible model to predict the prognosis of hepatocellular carcinoma (HCC) in clinic practice currently. Here, an inclusive nomogram was developed by integrating genomic markers and clinicopathologic factors for predicting the outcome of patients with HCC. A total of 365 samples of HCC were obtained from the Cancer Genome Atlas (TCGA) database. The LASSO analysis was carried out to identify HCC-related mRNAs, and the multivariate Cox regression analysis was used to construct a genomic-clinicopathologic nomogram. As results, 9 mRNAs were finally identified as prognostic indicators, including RGCC, CDH15, XRN2, RAB3IL1, THEM4, PIF1, MANBA, FKTN and GABARAPL1, and used to establish a 9-mRNA classifier. Additionally, an inclusive nomogram was built up by combining the 9-mRNA classifier (P < 0.001) and clinicopathologic factors including age (P = 0.006) and metastasis (P < 0.001) to predict the mortality of HCC patients. Time-dependent receiver operating characteristic, index of concordance and calibration analyses indicated favorable accuracy of the model. Decision curve analysis suggested that appropriate intervention according to the established nomogram will bring net benefit when threshold probability was above 25%. The genomic-clinicopathologic model could be a reliable tool for predicting the mortality, helping determining the individualized treatment and probably improving HCC survival.

Reply to: Comments on "Nomograms based on inflammatory biomarkers for predicting tumor grade and micro-vascular invasion in stage I/II hepatocellular carcinoma".

We appreciate to receive commentary from Dr Guangtong Deng and Dr Liang Xiao to our article, "Nomograms based on inflammatory biomarkers for predicting tumor grade and micro-vascular invasion in stage I/II hepatocellular carcinoma". First, neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR) are two different parameters. Some studies show that NLR is inconsistent with dNRL in prognostic value through multivariate Cox regression, therefore, it is reasonable that both NLR and dNLR entered into multivariate analysis simultaneously. Second, it is common that articles of predictive nomograms turned continuous variables into categorical variables. The reason is that the categorization of patient clinical variables is beneficial to doctors to make decisions based on the risk level of individual patients in clinical. At last, multicenter validation is quite difficult and we have listed the shortcomings in the limitations of our article. Further validation will need the joint efforts by other institutions.

LncRNA CASC9 interacts with CPSF3 to regulate TGF-ß signaling in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related death worldwide. Increasing evidence indicates that the deregulation of long noncoding RNAs (lncRNAs) contributes to tumor initiation and progression; however, little is known about the biological role of cancer susceptibility candidate 9 (CASC9) in CRC. METHODS: Novel lncRNAs potentially involved in CRC tumorigenesis were identified from datasets downloaded from The Cancer LncRNome Atlas and The Atlas of Noncoding RNAs in Cancer. The CRC cell lines HCT-116, HCT-116 p53-/-, SW620, SW480, HT-29, LoVo, LS-174T, and RKO were used. Colony-formation, MTS, cell-cycle, apoptosis, and in-vivo tumorigenesis assays were used to determine the role of CASC9 in CRC cell growth in vitro and in vivo. Potential interaction between CASC9 and cleavage and polyadenylation specificity factor subunit 3 (CPSF3) was evaluated using RNA immunoprecipitation and RNA-protein pull-down assays. RNA-sequencing was performed to analyze gene expression following CASC9 knockdown. RT-qPCR, western blotting, and mRNA decay assays were performed to study the mechanisms involved. RESULTS: CASC9 was frequently upregulated in CRC, which was correlated with advanced TNM stage, and higher CASC9 levels were associated with poor patient outcomes. Knockdown of CASC9 inhibited growth and promoted apoptosis in CRC cells, whereas ectopic CASC9 expression promoted cell growth in vitro and in vivo. We demonstrated that CPSF3 is a CASC9-interacting protein, and knockdown of CPSF3 mimicked the effects of CASC9 knockdown in CRC cells. Furthermore, we found that CASC9 exerts its oncogenic activity by modulating TGFß2 mRNA stability and upregulating the levels of TGFß2 and TERT, resulting in an increase in phosphorylated SMAD3 and activation of TGF-ß signaling, and enhanced TERT complex function in CRC cells. Finally, CPSF3 was significantly upregulated in CRC tissues as compared with adjacent or non-adjacent normal colon tissues, and CASC9, CPSF3, and TGFß2 levels in human CRC tissues were positively correlated. CONCLUSIONS: CASC9 is a promising prognostic predictor for patients with CRC and the CASC9-CPSF3-TGFß2 axis is a potential therapeutic target for CRC treatment.

Expression of the Wnt ligands gene family and its relationship to prognosis in hepatocellular carcinoma.

BACKGROUND: The Wnt gene family members are known to participate regulating various normal and pathological processes including tumorigenesis. However, the association between Wnt ligands gene family and prognosis in hepatocellular carcinoma has not been systematically studied. Therefore, we evaluated the role of Wnt ligands gene family in hepatocellular carcinoma using publicly available data from The Cancer Genome Atlas (TCGA). METHODS: Clinical information and RNA-Seq mRNA expression data were derived from TCGA hepatocellular carcinoma cohort. Differences in overall survival (OS) and disease-free survival (DFS) between increased and decreased expression groups (defined by X-tile analyses) of Wnt ligands gene family were compared using Kaplan-Meier method and Cox regression model, with p-values calculated via log-rank test. Gene Set Enrichment Analysis (GSEA) was performed. RESULTS: Multivariate analysis adjusted for patient age, sex, BMI, tumor grade, and TMN stage revealed that Wnt1, Wnt3 and Wnt5B expressions were independent prognostic factors for OS and DFS (OS: HR = 0.58, P = 0.006; HR = 0.65, P = 0.03; HR = 0.56, P = 0.023, respectively; DFS: HR = 0.52, P < 0.001; HR = 1.93, P = 0.003; HR = 0.59, P = 0.011, respectively). Furthermore, expression of Wnt1 and Wnt5B was significantly associated with TMN stage (P = 0.02 and P = 0.03 for OS; P = 0.02 and P = 0.02 for DFS). GSEA showed that nucleotide excision repair was differentially enriched in Wnt1 low expression phenotype and aminoacyl trna biosynthesis and basal transcription factors were differentially enriched in Wnt5B low expression phenotype. CONCLUSIONS: Our results identified associations of several Wnt ligands with prognosis of HCC patients, indicating that these genes could serve as prognostic biomarkers of HCC.

NRAL mediates cisplatin resistance in hepatocellular carcinoma via miR-340-5p/Nrf2 axis.

Recent studies have shown that long non-coding RNAs (lncRNAs) play a pivotal role in the pathogenesis and progression of hepatocellular carcinoma (HCC). However, the biological action and potential mechanism of liver cancer cell drug resistance have not been clearly clarified. In this study, lncRNAs were screened and differentially expressed in parental and cisplatin-resistant cell lines (HepG2 and HepG2/CDDP). A novel lncRNA, termed NRAL (Nrf2 regulation-associated lncRNA), was identified, and the initial results indicated that it was highly expressed in HepG2 cisplatin resistant cell lines compared to their parental counterparts. Functionally, NRAL depletion significantly enhanced CDDP-mediated cytotoxicity and apoptosis in two cisplatin-resistant HCC cell lines. Mechanistically, the results indicated that NRAL regulates Nrf2 expression through miR-340-5p serving as a competing endogenous RNA (ceRNA), thus influencing the CDDP-induced phenotype in HCC. Collectively, the present investigation suggest that the NRAL/miR-340-5p/Nrf2 axis mediates cisplatin resistance in HCC, which may provide novel targets for overcoming cisplatin resistance in hepatocellular carcinoma cells.

Nomograms based on inflammatory biomarkers for predicting tumor grade and micro-vascular invasion in stage I/II hepatocellular carcinoma.

Background: Increasing evidences reveal that inflammation plays a critical role in tumorigenesis and progression. We aimed to develop the nomograms based on inflammatory biomarkers to predict micro-vascular invasion (MVI) and tumor grade in stage I/II hepatocellular carcinoma (HCC).Methods: A retrospective cohort of 627 patients with stage I/II HCC between January 2007 and December 2014 was included in the study. Logistic regression was performed to identify the independent risk factors of tumor grade and MVI. The significant predictors including neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), lymphocyte-to-monocyte ratio (LMR), tumor volume age, and tumor size were subsequently incorporated to build the nomograms. The prediction accuracies of the nomograms were evaluated using the area under the receiver operating characteristic (ROC) curve.Results: The independent risk factors for tumor grade were NLR, dNLR, and tumor volume (P<0.001, P=0.001, and P<0.001, respectively), which were assembled into tumor grade nomogram. MVI nomogram was developed by dNLR, LMR, age, and tumor size (P<0.001, P<0.001, P<0.001, and P=0.001, respectively) which were the independent predictors for MVI. The area under the ROC curve of nomograms for predicting tumor grade and MVI were 0.727 (95% confidence intervals [CI]: 0.690-0.761) and 0.839 (95% CI: 0.808-0.867), respectively. Patients who had a nomogram score of less than 100 and 79 were considered to have high possibility of moderate grade and have low risks of MVI presence, respectively.Conclusion: We successfully developed nomograms predicting tumor grade and MVI based on inflammatory biomarkers with high accuracy, leading to a rational therapeutic choice for stage I/II HCC.

The Combined Effect of Nonalcoholic Fatty Liver Disease and Metabolic Syndrome on Osteoporosis in Postmenopausal Females in Eastern China.

The present study evaluated the potential combined effects of NAFLD and MetS on the development of osteoporosis. The relationship between NAFLD and MetS and osteoporosis was assessed in 938 postmenopausal female participants. Moderate and severe NAFLDs were combined as significant NAFLD (SNAFLD). All the subjects were divided into 4 subgroups based on the status of SNAFLD and MetS. Relative excess risk of interaction (RERI), attributable proportion (AP) of interaction, and synergy index (SI) were used to investigate the additive interaction of those two factors. NAFLD, SNAFLD, and MetS were independent factors for osteoporosis with the adjustment of age and other confounders. The incidence of osteoporosis in MetS (+) SNAFLD (+) group was significantly higher than that in other three groups. RERI was 2.556 (95% CI = 0.475-4.636), AP was 0.454 (95% CI = 0.201-0.706), and SI was 2.231 (95% CI = 1.124 to 4.428), indicating the significant combined interaction of SNAFLD and MetS on the development of osteoporosis. SNAFLD and MetS are independent risk factors for osteoporosis in postmenopausal females, respectively. Moreover, SNAFLD and MetS have an additive effect on the development of osteoporosis.

A nomogram integrating hepatic reserve and tumor characteristics for hepatocellular carcinoma following curative liver resection.

BACKGROUND: Because of the mutual influence of liver dysfunction and malignancy, overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC). We developed a nomogram integrating albumin-bilirubin (ALBI) grade, a new index of hepatic reserve, and tumor characteristics of HCC for predicting OS following curative liver resection. METHODS: The nomogram was built to estimate the probabilities of 1, 3, and 5-y OS based on training cohort of 709 HCC, which was validated in an international independent dataset. The prognostic value of the nomogram was determined by concordance index (C-index), time-dependent receiver operating characteristics (tdROC), and decision curves, comparing with ALBI grade alone, the Cancer of the Liver Italian Program (CLIP), the Barcelona Clinic Liver Cancer (BCLC), and Okuda staging systems. RESULTS: Independent factors derived from multivariable Cox analysis of the training cohort to predict OS were tumor grade, microvascular invasion, tumor size and ALBI grade which were assembled into nomogram. The calibration curves for probability of OS showed optimal agreement between nomogram-prediction and actual observation, which was tested in validation cohort. The C-index, tdROC and decision curves showed the nomogram was superior to CLIP, ALBI grade, BCLC and Okuda. The patients could also be stratified into low, intermediate risk, and high risk of the mortality by the normogram in both development and validation cohorts. CONCLUSIONS: The nomogram integrating hepatic reserve and tumor characteristics provided a highly accurate estimation of OS in patients with HCC after curative liver resection, contributing to assess patient prognosis.

NAFL screening score: A basic score identifying ultrasound-diagnosed non-alcoholic fatty liver.

BACKGROUND: Several non-invasive diagnostic scores for non-alcoholic fatty liver (NAFL) have been developed, but the clinical application is limited because of their complexity. AIM: To develop and validate an easy-to-calculate scoring system to identify ultrasound-diagnosed NAFL. METHODS: 48,489 patients from 2 centers were included in this study. Multivariable logistic regression models were employed for model development. Ultrasonography was applied to diagnose NAFL. The selected variables were assigned an integer score proportional to the estimated coefficient from the logistic regression analysis, namely NAFL Screening Score (NSS). The ability of the NSS to identify NAFL was assessed by analyzing the area under the receiver operating characteristic curve (AUROC) and was tested in an independent validation cohort. Additionally, the performance of NSS was compared with existing models. RESULTS: NSS was developed as a basic score comprising of age, body mass index (BMI), triglyceride (TG), ALT/AST, fasting plasma glucose (FPG) and uric acid (UA) in both sexes. NSS showed a relatively good discriminative power (AUROC=0.825 for males, 0.861 for females in the validation cohort) in comparison with other models. The optimal cut-off point was 32 for males and 29 for females. CONCLUSION: We developed and validated NSS, an easy-to-use score sheet identify ultrasound-diagnosed NAFL. NSS may be clinically useful for initial diagnosing NAFL.

Development of a prognostic nomogram for cirrhotic patients with upper gastrointestinal bleeding.

BACKGROUND AND AIM: Upper gastrointestinal bleeding (UGIB) is a complication with a high mortality rate in critically ill patients presenting with cirrhosis. Today, there exist few accurate scoring models specifically designed for mortality risk assessment in critically ill cirrhotic patients with upper gastrointestinal bleeding (CICGIB). Our aim was to develop and evaluate a novel nomogram-based model specific for CICGIB. PATIENTS AND METHODS: Overall, 540 consecutive CICGIB patients were enrolled. On the basis of Cox regression analyses, the nomogram was constructed to estimate the probability of 30-day, 90-day, 270-day, and 1-year survival. An upper gastrointestinal bleeding-chronic liver failure-sequential organ failure assessment (UGIB-CLIF-SOFA) score was derived from the nomogram. Performance assessment and internal validation of the model were performed using Harrell's concordance index (C-index), calibration plot, and bootstrap sample procedures. UGIB-CLIF-SOFA was also compared with other prognostic models, such as CLIF-SOFA and model for end-stage liver disease, using C-indices. RESULTS: Eight independent factors derived from Cox analysis (including bilirubin, creatinine, international normalized ratio, sodium, albumin, mean artery pressure, vasopressin used, and hematocrit decrease>10%) were assembled into the nomogram and the UGIB-CLIF-SOFA score. The calibration plots showed optimal agreement between nomogram prediction and actual observation. The C-index of the nomogram using bootstrap (0.729; 95% confidence interval: 0.689-0.766) was higher than that of the other models for predicting survival of CICGIB. CONCLUSION: We have developed and internally validated a novel nomogram and an easy-to-use scoring system that accurately predicts the mortality probability of CICGIB on the basis of eight easy-to-obtain parameters. External validation is now warranted in future clinical studies.

Scoring model to predict outcome in critically ill cirrhotic patients with acute respiratory failure: comparison with MELD scoring models and CLIF-SOFA score.

BACKGROUND: Critically ill cirrhotic patients have a high mortality, particularly with concomitant respiratory failure on admission. There are no specific models in use for mortality risk assessment in critically ill cirrhotic patients with acute respiratory failure (CICRF). The aim is to develop a risk prediction model specific to CICRF in order to quantify the severity of illness. METHODS: We analyzed 949 CICRF patients extracted from the MIMIC-III database. The novel model (ARF-CLIF-SOFA) was developed from the CLIF-SOFA score. Cox regression analysis and AUROC were implemented to test the predictive accuracy, compared with existing scores including the CLIF-SOFA score and MELD-related scores. RESULTS: ARF-CLIF-SOFA contains PaO2/FiO2 ratio, lactate, MAP, vasopressor therapy, bilirubin and creatinine (1 point each; score range: 0-6). Based on our patient cohort, the ARF-CLIF-SOFA score had good predictive accuracy for predicting the 30-, 90-day and 1-year mortality (AUROC = 0.767 at 30-day, 0.768 at 90-day, 0.765 at 1-year, respectively). Additionally, the performance of the ARF-CLIF-SOFA is superior to existing scores (all P < 0.001). CONCLUSION: The ARF-CLIF-SOFA score can be considered a CICRF specific score with a better predictive accuracy compared to the existing scores.

Stratified Platelet-to-lymphocyte Ratio: A Novel Target for Prognostic Prediction of Hepatocellular Carcinoma after Curative Liver Resection.

Background and Aims: Platelet-to-lymphocyte ratio (PLR) has been shown to predict prognosis of cancers. We aimed to evaluate the prognostic value of stratification of PLR in patients after curative liver resection (CLR) for hepatocellular carcinoma (HCC). Methods: A total of 1804 patients who underwent CLR for suspected HCC between January 2007 and January 2014 were screened for the study. All of the patients were categorized into equal tertiles according to the number of patients and the distribution of PLR. Prognostic significance was determined for overall survival (OS) and was assessed using Kaplan-Meier analysis. Univariate and multivariate Cox proportional hazard regression analyses were evaluated for association of all independent parameters with disease prognosis. Results: The optimal cut-off points of preoperative PLR were: (T1) 11.98-75.00, (T2) 75.00-113.33 and (T3) 113.33-567.50. There were obvious differences in each PLR tertile with mortality within 36 months of CLR (plog-rank < 0.001). Multivariable analysis suggested that the level of PLR (HR = 1.004, 95%CI: 1.001-1.008, p = 0.006), portal vein thrombosis (HR = 3.406, 95%CI: 1.185-9.794, p = 0.023), number of nodules (HR = 1.810, 95%CI: 1.345-2.437, p < 0.001), Child-Turcotte-Pugh score (HR = 1.741, 95%CI: 1.129-2.684, p = 0.012) and microvascular invasion (HR = 2.730, 95%CI: 1.777-4.196, p < 0.001) were significant predictors of mortality. Kaplan-Meier analysis of overall survival (OS) demonstrated that each PLR tertile showed a progressively worse OS and apparent separation (plog-rank = 0.016). The highest 5-year OS rate following CLR (58%) was revealed in tertile 1. In contrast, the lowest 5-year OS rate (30%) was revealed in tertile 3. Conclusion: Stratified preoperative PLR could strengthen the predictive power for OS in HCC patients with CLR.

A microRNA expression profile for vascular invasion can predict overall survival in hepatocellular carcinoma.

BACKGROUND: The presence of vascular invasion (VI) in pathology specimens is a well-known unfavorable prognostic factor of hepatocellular carcinoma (HCC) recurrence and overall survival (OS). We investigated the vascular invasion related microRNA (miRNA) expression profiles and potential of prognostic value in HCC. METHODS: MiRNA and mRNA expression data for HCC were accessed from The Cancer Genome Atlas (TCGA). LASSO logistic regression models were used to develop a miRNA-based classifier for predicting VI. The predictive capability was accessed by area under receiver operating characteristics (AUC). Concordance index (C-index) and time-dependent receiver operating characteristic (td-ROC) were used to determine its prognostic value. We validated the predictive and prognostic accuracy of this classifier in an external independent cohort of 127 patients. Functionally relevant targets of miRNAs were determined using miRNA target prediction, experimental validation and correlation of miRNA and mRNA expression data. RESULTS: A 16-miRNA-based classifier was developed which identified VI accurately, with AUC of 0.731 and 0.727 in TCGA set and validation cohort, respectively. C-index and td-ROC showed that the classifier was able to stratify patients into risk groups strongly associated with OS. When stratified by tumor characteristics, the classifier was still a clinically and statistically significant prognostic model. The predictive and prognostic accuracy of the classifier was confirmed in validation cohort. Vascular invasion related miRNA/target pairs were identified by integrating expression patterns of predicted targets, which were validated in cell lines. CONCLUSIONS: A multi-miRNA-based classifier developed based on the presence of VI, which could effectively predict OS in HCC.

Neutrophil-lymphocyte ratio predicts hospital-acquired bacterial infections in decompensated cirrhosis.

BACKGROUND: Bacterial infection is a frequent complication and severe burden in cirrhotic patients. We determined the utility of neutrophil-to-lymphocyte ratio (NLR) to predict the hospital-acquired (HA) bacterial infections episode in patients with decompensated cirrhosis. METHODS: We retrospectively included 2066 consecutive decompensated cirrhotic patients from two separate tertiary hospitals, divided into training (n=1377) and validation (n=689) set. All data were collected on admission and all overt bacterial infections occurring after >48h of hospital stay were registered. RESULTS: The incidence of HA bacterial infections in training and validation cohort was 35.87% and 31.05% respectively. Multivariate analysis showed that total bilirubin (TBil), albumin, white blood cell count (WBC) and NLR were independent predictors of HA bacterial infections. We established a Model_NTWA using these four variables and a Model_TWA which did not include NLR. Areas under the curves (AUC) of Model_NTWA (0.859) and NLR (0.824) were higher than which of Model_TWA (0.713), WBC (0.675), TBil (0.593) and Albumin (0.583). Consistent with training cohort, validation cohort showed similar results. Patients with NLR of at least 4.33 had a significantly lower survival (P<0.001). CONCLUSIONS: NLR can be used as a novel noninvasive marker to predict the occurrence of HA bacterial infections in decompensated cirrhotic patients.