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Background: We aimed to evaluate the whether AFP levels alone is an adequate screening indicator, or a combination of Generally, alpha-fetoprotein (AFP), CA19-9 and CEA could provide a better diagnostic tool in detecting and screening asymptomatic patients with primary hepatic cancer (PHC), and also evaluate the correlation of degree of differentiation with serum biomarker levels., Methods: We retrospectively reviewed the medical records of 1362 patients form 2014-2018 who visited the first Affiliated Hospital of Zhejiang University, Hangzhou, China for health check-ups or were diagnosed with cancer or cirrhosis. We then analyzed preoperative tumor markers level of AFP, CA19-9, and CEA. The standard reference values (AFP ≤20 ng/L CEA ≤ 5 ng/L, and CA19-9 ≤ 37 U/mL) were as positive or negative cut off values. Further, the histological sections of patients were categorized and correlated them with the three serum biomarkers., Results: Serum AFP, CEA, and CA19-9 levels in the PHC group were significantly higher compared to those with liver cirrhosis and healthy control groups ( P < 0.03). With AFP as a single tumor marker for PHC diagnosis, it had a sensitivity of 63.3% with a specificity of 80.8%. AFP combined with CA19-9 and CEA showed specificity of 100%, a sensitivity 2.5% with the positive and negative predictive values of 100% and 22% respectively. Furthermore, histological evaluation revealed the highest AFP level of 9366.14±23902.61 ng/L associated with poorly differentiated HCC, while well-differentiated HCC, had the lowest mean AFP level of 45.19±181.27 ng/L., Conclusion: Combined serum levels of AFP, CA19-9 and CEA does not provide a superior advantage over AFP alone as a screening and diagnostic tool for HCC detection., Competing Interests: Conflict of interests The authors declare that there is no conflict of interests.

Oct4 and Nanog are reported to promote tumor progression in several cancers, but the effect on intrahepatic cholangiocarcinoma (ICC) is unknown. The aim of our present study was to explore the prognostic role of Oct4 and Nanog on patients with ICC. Immunohistochemistry was used to detect the expression of Oct4 and Nanog in a random cohort of 116 ICC patients, and validated in another independent cohort of 103 patients. Prognostic nomograms were formulated for OS and RFS prediction of ICC patients. Our results showed Oct4 and Nanog highly expressed in ICC tumor tissues and were identified as independent prognostic factors for patients' OS and RFS. Significant positive correlation was found between Oct4 and Nanog expression. Co-expression of Oct4 and Nanog implied the poorest OS and RFS in ICC patients. Our nomograms comprising Oct4 and Nanog achieved better predictive accuracy in training and validation cohorts compared with AJCC 7th edition and LCSGJ stage for OS and RFS prediction. Our study support the high expression of Oct4 and Nanog in ICC implies aggressive tumor behaviors and suggest a poor clinical prognosis, which emerges as valuable biomarkers for identifying patients at high risk after curative resection., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Although mode of action (MOA) plays a key role in the understanding of the toxic mechanism of chemicals, the MOAs of class-based compounds to tadpoles have not been investigated. To explore the MOAs, acute toxicity (expressed as log 1/LC 50 ) to Rana chensinensis tadpoles were determined and molecular descriptors were calculated. Quantitative structure-activity relationship (QSAR) showed that toxicity to tadpoles is closely related to the chemical octanol/water partition coefficient (log K OW ), energy of the lowest unoccupied molecular orbital (E LUMO ), and number of hydrogen bond donors and acceptors (NH DA ), representing the bio-uptake potential in tadpoles, the electrophilicity and hydrogen bonding capacity with target site(s), respectively. Comparison of the toxicity values between tadpoles and fish revealed that there were no significant differences for the overlapping compounds (average residual = 0.29 between tadpole and fish toxicity) with P values of interspecies correlation substantially less than 0.001. Classification of MOAs for the class-based compounds based on the excess toxicity calculated from toxicity ratio suggested that baseline, less inert compounds and some reactive or specifically-acting compounds share same MOAs between tadpoles and fish. Fish and tadpoles can serve as surrogates for each other in the safety evaluation of organic pollutants., (Copyright © 2018 Elsevier Inc. All rights reserved.)

S100A11 is reported to associate with progression and poor prognosis in several tumors. We previously reported that S100A11 was highly expressed in intrahepatic cholangiocarcinoma (ICC) cells and promoted TGF-β1-induced EMT through SMAD2/3 signaling pathway. Here, we explored the prognostic role of S100A11 on ICC patients and preliminary molecular mechanisms how S100A11 regulated ICC cell proliferation. Our results showed that S100A11 was obviously increased in ICC tumor tissues. High expression of S100A11 was closely correlated with lymph node metastasis (LNM) and TNM stage and was an independent risk factor for patients' overall survival (OS) and recurrence-free survival (RFS). The nomograms comprising LNM and S100A11 achieved better predictive accuracy compared with TNM staging system for OS and RFS prediction. Silencing S100A11 significantly suppressed RBE cells and HCCC9810 cells proliferation, colony formation, and activation of P38/mitogen-activated protein kinase (MAPK) signaling pathway in vitro and inhibited tumor growth in vivo. In contrast, the overexpression of S100A11 in RBE cells and HCCC9810 cells achieved the opposite results. S100A11-induced proliferation was abolished after treatment with P38 inhibitor. Our findings suggest S100A11/P38/MAPK signaling pathway may be a potential therapeutic target for ICC patients., (© 2018 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.)

Liver fibrosis is a serious threat to human health, and there is currently no effective clinical drug for treatment of the disease. Although Galectin‑1 is effective, its role in liver function, inflammation, matrix metalloproteinases and the activation of hepatic stellate cells (HSCs) remains to be elucidated. The aim of the present study was to elucidate the effect of Galectin‑1 on the activation, proliferation and apoptosis of HSCs in a mouse model of liver fibrosis. Following successful model establishment and tissue collection, mouse HSCs (mHSCs) were identified and an mHSC line was constructed. Subsequently, to determine the role of Galectin‑1 in liver fibrosis, the expression levels of transforming growth factor (TGF)‑β1, connective tissue growth factor (CTGF) and α‑smooth muscle actin (α‑SMA) pre‑ and post‑transfection were evaluated by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. In addition, the effects of Galectin‑1 on the biological behavior and mitochondrial function of mHSCs were determined using a 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay, flow cytometry and a scratch test. It was first observed that the expression levels of Galectin‑1, TGF‑β1, CTGF and α‑SMA were downregulated by silencing the gene expression of Galectin‑1. Additionally, silencing the gene expression of Galectin‑1 inhibited cell cycle progression, proliferation and migration but induced the apoptosis of mHSCs from mice with liver fibrosis. Furthermore, the in vivo experimental results suggested that silencing the gene expression of Galectin‑1 improved liver fibrosis. Collectively, it was concluded that silencing the gene expression of Galectin‑1 ameliorates liver fibrosis and that functionally suppressing Galectin‑1 may be a future therapeutic strategy for liver fibrosis.

This study aims to investigate how microRNA-375 (miR-375) improves immune function by regulating liver macrophages (Kupffer cells) in mice with liver failure. Forty mice were divided into ConA-1h, ConA-3h, ConA-6h, and control groups, with 10 mice in each group. Mice models of liver failure were established by injecting concanavalin A (ConA) solution via the tail veins of mice, and then primary Kupffer cells were isolated and cultured. Reverse transcription quantitative polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbent assay were conducted to examine the expressions of miR-375, astrocyte elevated gene-1 (AEG-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β in Kupffer cells of mice with liver failure as well as after silencing of miR-375. Flow cytometry was used to determine cell apoptosis. During the liver failure process, miR-375, IL-6, TNF-α, and IL-1β expressions were increased over time, while AEG-1 expression decreased over time in the control, ConA-1h, ConA-3h, and ConA-6h groups. Opposite alternations were observed after silencing of miR-375. Dual-luciferase reporter gene assay showed that AEG-1 was a target gene of miR-375. Flow cytometry determination showed that the ratio of apoptotic Kupffer cells decreased after silencing of miR-375. Overexpression of AEG-1 could rescue the suppression of IL-6, TNF-α, and IL-1β expressions in Kupffer cells after the short-term induction of ConA and further inhibit cell apoptosis. Our study provides evidence that miR-375 could regulate Kupffer cells to improve immune function in mice with liver failure., (© 2018 Wiley Periodicals, Inc.)

Objective: This study was performed to evaluate the impact and underlying mechanisms of hypothermic machine perfusion (HMP) on half-size liver graft regeneration., Methods: Forty rats were randomly assigned to five groups: two in vitro groups (static cold storage [SCS] and HMP) and three in vivo groups (orthotopic liver transplantation, SCS, and HMP). Perfusates and plasma samples were collected for analysis of hepatic enzymes. Liver tissue was obtained for evaluation of histology, immunohistochemistry (Ki67 and proliferating cell nuclear antigen [PCNA]), and the regeneration rate. Cell cycle genes were analyzed by quantitative real-time polymerase chain reaction, and cyclin D1 and cyclin E1 were semiquantified by western blot., Results: HMP improved histopathological outcomes and decreased hepatic enzyme release. The expression of Ki67 and PCNA demonstrated a greater proliferation activity in the HMP than SCS group, and the expression of almost all cell cycle genes was elevated following HMP. Western blot results showed higher protein levels of cyclin D1 and cyclin E1 in the HMP than SCS group., Conclusions: Our findings suggest for the first time that half-size liver graft protection by HMP involves recovery of graft regeneration.

The mode of action (MOA) plays a key role in the risk assessment of pollutants in water. Although fish is a key model organism used in the risk assessment of pollutants in water, the MOAs have not been compared between fish and embryo toxicity for classified compounds. In this paper, regression analysis was carried out for fish and embryo toxicities against the calculated molecular descriptors and MOAs were evaluated from toxicity ratio. The toxicity significantly related with the chemical hydrophobicity for baseline and less inert compounds, respectively, indicates that these two classes of compounds share the same MOAs between fish and embryos. Comparison of the toxicity ratios shows that reactive compounds exhibit excess toxicity to both fish and embryos. These compounds can react covalently with biologically target molecules through nucleophilic addition reactions, Michael addition oxidation, or amination. Comparing with baseline, less inert and reactive compounds, many specifically-acting compounds have strong docking capacity with protein molecules. Some specifically-acting compounds, such as fungicides, have very similar toxic effect to both fish and embryos. However, insecticides are more toxic to fish than embryos; herbicides and medications are more toxic to embryos than fish. Differences in the interactions of chemicals with target molecules or bioconcentration potentials between fish and embryos may result in the differences in toxic effects. There are some factors that influence the identification of MOAs, such as quality of toxicity data, bioavailability and ionization. These factors should be considered in the identification of MOAs in the risk assessment of organic pollutants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To evaluate aesthetic outcomes in patients with bilateral trapezius hypertrophy treated by botulinum toxin type A (BTxA) injection for aesthetic reconstruction of the upper trapezius., Methods: From May 2015 to May 2016, 30 women with a short neck shape resulting from bilateral trapezius hypertrophy were treated with botulinum toxin type A (BTxA) injection at the most affected area of the upper trapezius. Pre- and postoperative values of S ACDF (irregularly shaped area of the four points A, C, D, and F) and S ACDE (irregularly shaped area of the four points A, C, D, and E), responses to patients' and doctors' Global Aesthetic Improvement Scale (GAIS) questionnaires for neck aesthetic assessment, as well as reported adverse events, were recorded and analyzed., Results: Duration of follow-up ranged from 4 to 12 months. Subjects experienced non-severe adverse events and complete recovery after a single BTxA injection. In patients' GAIS questionnaires, "very much improved" accounted for 53%, "much improved" accounted for 13%, and "improved" accounted for 27%. In doctors' GAIS questionnaires, "very much improved" accounted for 27%, "much improved" accounted for 33%, "improved" accounted for 33%, and "no change" accounted for 7%. The overall degree of improvement was high. Statistically significant differences were observed with respect to the "very much improved" response to GAIS questionnaires between patients and doctors (P = 0.035)., Conclusion: A single injection of BTxA for aesthetic reconstruction of the upper trapezius is safe and effective in patients with bilateral trapezius hypertrophy., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background: Fibrotic tumor stroma (FTS) has been implicated in cancer promotion in several neoplasms. The histological features of FTS are convenient and easily accessible in clinical routine in intrahepatic cholangiocarcinoma (ICC) specimens. The goal of this study was to explore prognostic impacts of the quantity and maturity of FTS on surgical ICC patients. Moreover, we aimed to propose an efficient prognostic nomogram for postoperative ICC patients., Materials and Methods: The clinical profiles of 154 consecutive postoperative ICC patients were retrospectively analyzed. Tumor-stroma ratio and morphological maturity of FTS were evaluated on hematoxylin and eosin-stained tumor sections. CD3, CD8, and α-smooth muscle actin (α-SMA) staining were performed on corresponding tissue microarrays. The nomogram was established on variables selected by multivariate analyses and was validated in 10-fold cross-validation., Results: Rich tumor stroma and strong α-SMA expression were associated with poor overall survival (OS). However, in multivariate analyses, these two biomarkers failed to stratify both OS and recurrence-free survival (RFS). Immature FTS was correlated with tumor multiplicity, advanced clinical stage, and sparser CD3 and CD8 positive tumor-infiltrating lymphocytes (TILs) and was identified as an independent prognostic indicator for both OS and RFS. The nomogram comprising FTS maturity, tumor number, microvascular invasion, and lymph node metastasis possessed higher predictive power relative to conventional staging systems., Conclusion: Immature FTS was an independent risk factor for survival and was associated with sparser CD3 and CD8 positive TILs in ICC. The prognostic nomogram integrating the maturity of FTS offers a more accurate risk stratification for postoperative ICC patients., Implications for Practice: Accumulating evidence has suggested that fibrotic components in tumor microenvironment (TME) play a complicated and vital role in TME reprogramming and cancer progression. However, in clinical practice, the evaluation of fibrotic tumor stroma (FTS) is still neglected to some extent. This study's findings indicated that, in intrahepatic cholangiocarcinoma (ICC), the histological maturity of FTS is a robust prognostic indicator for patients who underwent curative resection. Moreover, prognostic nomogram constructed on the maturity of FTS possessed higher predictive power relative to the conventional tumor-node-metastasis staging systems. Taken together, the evaluation of FTS should be emphasized in clinical routine for more accurate prognostic prediction in postoperative ICC patients., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Fluazinam is a pyridinamine fungicide that induces oxidative stress and mitochondrial damage in cells, and it has been reported to be neurotoxic. To characterize the biological effects of fluazinam, we assessed mitochondrial bioenergetics, dopamine system expression, and behavior of early life staged zebrafish (0.01 μM-0.5 μM). Fluazinam at environmentally-relevant levels did not induce sub-lethal effects in larvae, but at the LC 50 (0.5 μM), fluazinam decreased basal and ATP-linked respiration significantly in embryos. As mitochondria are directly related to redox homeostasis and apoptosis, the expression of genes related to oxidative stress and apoptosis were measured. Superoxide dismutase 2 (sod2), heat stock protein 70 (hsp70), bcl2-associated X protein (bax), and caspase 9 (casp9) mRNA levels were up-regulated by 0.5 μM fluazinam. Taken together, there was evidence for mitochondrial dysfunction and oxidative damage at the highest concentration of fluazinam (0.5 μM) tested. As there are reports for fluazinam-induced neurotoxicity in dopamine synthesizing cells, transcriptional targets in the dopamine system were assessed in the zebrafish. Tyrosine hydroxylase 1 (th1) and dopamine receptor 2a (drd2a) mRNA levels were decreased by 0.5 μM fluazinam, suggesting that this fungicide may affect the dopaminergic system. To further assess the potential for fluazinam-mediated neuromodulation, the dark photokinesis response was assessed in larvae following exposure. Larvae exposed to 0.1 μM fluazinam showed hyperactivity, while larvae exposed to 0.2 and 0.3 μM showed hypo-activity. This study demonstrates that fluazinam disrupts mitochondrial bioenergetics in zebrafish, inducing an oxidative stress response, and aberrant behaviors in larvae that are dose dependent., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: With the increased use of extended-criteria donors, static cold storage has failed to provide optimal preservation of liver grafts, resulting in early allograft dysfunction and long-term complications. Machine perfusion (MP) is a beneficial alternative preservation strategy for donor livers, particularly for those considered to be of suboptimal quality, and could expand the limited donor pool., Data Sources: A comprehensive search in PubMed, EMBASE, Ovid databases and ClinicalTrials.gov website was conducted using the medical subject heading terms "machine perfusion", "machine preservation", "liver transplantation", combined with free text terms such as "hypothermic", "normothermic" and "subnormothermic". The deadline for the search was September 30, 2017., Results: MP can be classified as hypothermic, subnormothermic, and normothermic with the temperature maintained at 0-12 °C, 25-34 °C and 35-38 °C, respectively. Twelve clinical trials of MP have been reported in recent years. MP effectively decreased AST/ALT level and the incidence of early allograft dysfunction. However, the graft and patient survival rate after MP were similar to static cold storage. The detailed clinical characteristics such as liver function, graft survival, patient survival and early allograft dysfunction were reviewed., Conclusions: Clinical trial results showed that MP improves delayed graft function, primary non-function and biliary strictures. However, MP still requires validation in large clinical trials and the key parameters during MP still require optimization., (Copyright © 2018. Published by Elsevier B.V.)

Background: With the rising demands for pancreas transplantation, surgeons are trying to extend the donors pool and set up a more appropriate assessment system. We aim to evaluate the effect of donor hypertension on recipient overall and graft survival rates., Methods: Twenty-four thousand one hundred ninety-two pancreas transplantation patients from the Scientific Registry of Transplant Recipients database were subdivided into hypertension group (HTN, n = 1531) and non-hypertension group (non-HTN, n = 22,661) according to the hypertension status of donors. Recipient overall and graft survival were analyzed and compared by log rank test, and hazard ratios of predictors were estimated using Cox proportional hazard models., Results: Patient overall and graft survival of non-HTN group were higher than that of the HTN group (both p < 0.001). The duration of hypertension negatively influenced both overall and graft survival rates (both p < 0.001). Multivariate analyses demonstrated that hypertension was an independent factor for reduced survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.01-1.18; p < 0.001). Other independent factors included recipient body mass index (HR, 1.02; 95% CI, 1.01-1.05; p < 0.001) and transplant type (pancreas after kidney transplants / pancreas transplant alone vs. simultaneous pancreas-kidney transplants; HR, 1.41; 95% CI, 134-1.55; p < 0.001)., Conclusions: Donor hypertension is an independent factor for recipient survival after pancreas transplantation and could be considered in donor selection as well as post-transplant surveillance in clinical practice.

Pyogenic liver abscess (PLA) of biliary origin in Southeast Asia mainly occurs in patients with intrahepatic bile duct stone (IBDS) and extrahepatic bile duct stone (EBDS), bilioenteric anastomosis, or biliary stent. IBDS, as an endemic to Southeast Asia, remains a frequent etiology of acute cholangitis and PLA. PLA related to IBDS is characterized by high incidences of PLA recurrence and death related to infection, and difficulties in diagnosis of concomitant cholangicarcinoma. PLA of biliary origin is more likely caused by Escherichia coli, more often presented as polymicrobial infections, and more associated with extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae isolates. In this review, the authors summarize the differences on the presumed causes, pathogens, multidrug resistance, treatment, and prognosis of PLA between biliary origin and cryptogenic origin, the latter serving as a first and foremost presumed etiology of PLA. The authors also discuss the existing problems on early diagnosis of concomitant cholangicarcinoma related to IBDS., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: New-onset hyperglycemia (NOH) is a common phenomenon after liver transplantation (LT), but its impact on clinical outcomes has not yet been fully assessed. We aimed to evaluate the etiology and prognosis of NOH within 1 month after LT., Methods: The data of 3339 adult patients who underwent primary LT from donation after citizen death between January 2010 and June 2016 were extracted from China Liver Transplant Registry database and analyzed. NOH was defined as fasting blood glucose ≥7.0 mmol/L confirmed on at least two occasions within the first post-transplant month with or without hypoglycemic agent., Results: Of 3339 liver recipients, 1416 (42.4%) developed NOH. Recipients with NOH had higher incidence of post-transplant complications such as graft and kidney failure, infection, biliary stricture, cholangitis, and tumor recurrence in a glucose concentration-dependent manner as compared to non-NOH recipients (P < 0.05). The independent risk factors of NOH were donor warm ischemic time >10 min, cold ischemic time >10 h, anhepatic time >60 min, recipient model for end-stage liver disease score >30, moderate ascites and corticosteroid usage (P < 0.05). Liver enzymes (alanine aminotransferase and gamma-glutamyltranspeptidase) on post-transplant day 7 significantly correlated with NOH (P < 0.001)., Conclusions: NOH leads to increased morbidity and mortality in liver recipients. Close surveillance and tight control of blood glucose are desiderated immediately following LT particularly in those with delayed graft function and receiving corticosteroid. Strategic targeting graft ischemic injury may help maintain glucose homeostasis., (Copyright © 2018. Published by Elsevier B.V.)

The reliable and stable operation of power apparatus is important for the development of GIS. It is important to utilize condition monitoring technologies and anticipate possible failures in advance. Many papers have been published about the partial discharge detection with UHF or X-ray in laboratory, but seldom in field application. Thus, many engineers at project sites are not familiar with the current professional diagnosis techniques. Recently, during the GIS routine data analysis obtained by partial discharge online monitoring system, it was found that the UHF monitoring signals' developing trend of the 220 kV GIS No. 2 high-voltage side of transformer in phase C at an actual station was abnormal and needed further detection. In order to precisely investigate the problem and then guide the operation and maintenance activities, a series of professional diagnoses were conducted. Three new types of partial discharge detection and positioning methods were applied for accuracy, including UHF partial discharge detection based on multi-stage amplified signal demodulation and multiple weighted averages processing; the partial discharge detection based on the signal radiation hole of insulation disk at the ground connection; and the positioning method based on UHF-SHF. After a series of troubleshooting works, the partial discharge defects have been diagnosed, and the case can be referred in the field monitoring of GIS.

Over recent decades, zebrafish has been established as a sophisticated vertebrate model for studying human ocular diseases due to its high fecundity, short generation time and genetic tractability. With the invention of morpholino (MO) technology, it became possible to study the genetic basis and relevant genes of ocular diseases in vivo . Many genes have been shown to be related to ocular diseases. However, the issue of specificity is the major concern in defining gene functions with MO technology. The emergence of the first- and second-generation genetic modification tools zinc-finger nucleases (ZFNs) and TAL effector nucleases (TALENs), respectively, eliminated the potential phenotypic risk induced by MOs. Nevertheless, the efficiency of these nucleases remained relatively low until the third technique, the clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, was discovered. This review highlights the application of multiple genome engineering techniques, especially the CRISPR/Cas9 system, in the study of human ocular diseases in zebrafish.

Background: Nanotechnology is emerging as a promising tool to perform noninvasive therapy and optical imaging. However, nanomedicine may pose a potential risk of toxicity during in vivo applications. In this study, we aimed to investigate the potential toxicity of rare-earth nanoparticles (RENPs) using mice as models., Methods: We synthesized RENPs through a typical co-precipitation method. Institute of Cancer Research (ICR) mice were randomly divided into seven groups including a control group and six experimental groups (10 mice per group). ICR mice were intravenously injected with bare RENPs at a daily dose of 0, 0.5, 1.0, and 1.5 mg/kg for 7 days. To evaluate the toxicity of these nanoparticles in mice, magnetic resonance imaging (MRI) was performed to assess their uptake in mice. In addition, hematological and biochemical analyses were conducted to evaluate any impairment in the organ functions of ICR mice. The analysis of variance (ANOVA) followed by a one-way ANOVA test was used in this study. A repeated measures' analysis was used to determine any significant differences in white blood cell (WBC), alanine aminotransferase (ALT), and creatinine (CREA) levels at different evaluation times in each group., Results: We demonstrated the successful synthesis of two different sizes (10 nm and 100 nm) of RENPs. Their physical properties were characterized by transmission electron microscopy and a 980 nm laser diode. Results of MRI study revealed the distribution and circulation of the RENPs in the liver. In addition, the hematological analysis found an increase of WBCs to (8.69 ± 0.85) × 10 9 /L at the 28 th day, which is indicative of inflammation in the mouse treated with 1.5 mg/kg NaYbF 4 :Er nanoparticles. Furthermore, the biochemical analysis indicated increased levels of ALT ([64.20 ± 15.50] U/L) and CREA ([27.80 ± 3.56] μmol/L) at the 28 th day, particularly those injected with 1.5 mg/kg NaYbF 4 :Er nanoparticles. These results suggested the physiological and pathological damage caused by these nanoparticles to the organs and tissues of mice, especially to liver and kidney., Conclusion: The use of bare RENPs may cause possible hepatotoxicity and nephritictoxicity in mice., Competing Interests: There are no conflicts of interest

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Liver transplantation (LT) is known as a curative and therapeutic modality. However, the survival rates of recipients after LT are still not good enough because of tumor recurrence. To improve the survival rates of recipients after LT, identifying predictive factors for prognosis after LT and establishing a model assessing prognosis are very important to HCC patients. There has recently been a lot of clinical and basic research on recurrence and prognosis after LT. Progress has been made, especially in selection criteria for LT recipients and risk factors for predicting prognosis after LT. Hangzhou criteria, in line with China's high current incidence rate of primary liver, are first proposed by Chinese scholars of LT, and are accepted world-wide, and make an important contribution to the development of LT.

Background: This study aimed to investigate the efficacy and safety of drug eluting beads transarterial chemoembolization (DEB-TACE) treatment by CalliSpheres® in Chinese patients with hepatocellular carcinoma (HCC) as well as the predicting factors for response., Methods: 99 patients with HCC were consecutively enrolled in this study. All participants were treated by CalliSpheres® DEB-TACE. Clinical response was evaluated according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Common Terminology Criteria for Adverse Events (CTCAE) was used to assess the adverse events and liver dysfunction during and after the operation., Results: Post treatment, 16 patients (16.2%) achieved CR and 59 (59.6%) achieved PR, the ORR was 75.8%. Subgroup analysis showed that patients with higher BCLC stage were of worse CR and ORR rates, and the CR as well as ORR between patients with cTACE history and patients without cTACE history were similar. Univariate logistic regression analysis displayed that number of nodules > 3, higher BCLC stage and previous cTACE might be correlated with worse ORR but with no statistical significance. As to liver function, CTCAE grades of laboratory indexes for liver function were increased at 1 week compared to baseline and recovered to the baseline grades at 1-3 months post operation. Besides, most of the common adverse events were light and moderate in our study., Conclusions: In conclusion, DEB-TACE by CalliSpheres® was efficient and well tolerated in Chinese HCC patients, and BCLC stage, number of nodules and cTACE history were possibly correlated with treatment response.

Background: Our previous study showed that 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) is down-regulated in hepatocellular carcinoma (HCC). But its function in HCC remains unknown. This study aimed to reveal the function of HSD17B13 and its clinical significance in HCC., Methods: mRNA levels of HSD17B13 were analyzed in cohort 1 (30 normal, 30 HBV cirrhosis, 60 HBV-related HCC and 60 peritumoral tissue) by real-time PCR. HSD17B13 protein was evaluated in cohort 2 (15 normal, 33 HBV-cirrhosis, 12 dysplastic nodules, 34 HBV-related HCC, and 9 metastatic HCC) using immunohistochemistry. The association between HSD17B13 and the survival of HCC patients was analyzed in cohort 3 (n = 88). The inhibitory mechanism of HSD17B13 on HCC was explored ., Results: The mRNA of HSD17B13 and its protein expression were significantly down-regulated in HCC compared to non-tumor specimens (P < 0.001). The sensitivity, specificity and area under curve (AUC) values of HSD17B13 expression levels for HCC detection were 81.7%, 83.7% and 0.856, respectively (P < 0.001). Lower HSD17B13 in peritumoral tissue was an independent risk factor of worse recurrence free survival of HCC patients (HR: 0.41; 95% CI: 0.20-0.83; P = 0.014). The study in Huh 7 and SK-HEP-1 cells showed that HSD17B13 induced an accumulation of cells in G1 phase and reduction of cells in S and G2 phases via up-regulating the expression of P21, P27 and MMP2., Conclusions: Lower HSD17B13 in peritumoral tissues was associated with worse recurrence free survival and overall survival of HCC patients. HSD17B13 delayed G1/S progression of HCC cells. HSD17B13 may be a therapeutic target for the treatment of HCC., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: The expression of miR-489 is linked to tumor development and progression; nevertheless, its role in tumor growth and invasion of colorectal cancer (CRC) and the underlying mechanism has not been clarified., Experimental Design: We used quantitative RT-PCR to measure the expression of mature miR-489 in human colorectal tissues and the corresponding CRCs. Targets of miR-489 were predicted with TargetScan and substantiated by dual-luciferase reporter assay. Furthermore, we did in vitro and in vivo analysis with expression vectors and small interfering RNAs, to elucidate the precise role of miR-489 and its target gene histone deacetylase 7 (HDAC7) on cell proliferation, survival, and invasion., Results: Compared to the corresponding non-tumor tissues, miR-489 was frequently downregulated in CRC. By Kaplan-Meier analysis, we found that lower CRC recurrence free survival years in the group with elevated miR-489 expression than those with lower miR-489 expression. In addition, we examined that miR-489 obviously inhibited the migratory and invasive capability in CRC. In further study, we found that miR-489 targets the 3'-UTR of the HDAC7 transcript and downregulates its expression, and HDAC7 expression promoted tumor cell proliferation and invasion. We demonstrated that miR-489 suppresses tumor invasion and metastasis in CRC by targeting HDAC7., Conclusions: We identified that MiR-489 suppresses tumor growth and invasion in CRC by targeting HDAC7. The expression of miR-489 suggests CRC recurrence and metastasis, which shed crucial light on how miR-489 functions in CRC pathogenesis.

Background: Previous studies have emphasized the need to reduce tacrolimus (TAC) trough levels in the early post-liver transplantation (LT) period. However, whether late-period TAC trough levels influence the long-term outcomes of liver recipients is not clear., Methods: We enrolled 155 adult liver recipients survived more than 3 years after living donor liver transplantation because of non-malignant liver diseases. The maintenance immunosuppressive regimens were TAC monotherapy and combined therapy with mycophenolate mofetil. Patients were divided into three groups according to their late-period TAC trough levels: < 3 ng/mL group, 3-5 ng/mL group, and  >5 ng/mL group. The complications and adverse effects of TAC were analyzed., Results: Each group showed similar rejection, graft loss and mortality. Patients achieved the < 5 ng/mL state in less than 4 years had fewer new-onset diabetes, hyperlipidemia, de novo malignancies, and hepatitis B virus recurrence; the complications of renal dysfunction and hypertension rates were the same among these 3 groups., Conclusions: Collectively, our findings indicated that lower TAC trough levels in the late period of liver transplantation are safe, improve the long-term outcomes., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Bigelovin (BigV) is a sesquiterpene lactone, isolated from Inula helianthus aquatica, which has been reported to induce apoptosis and show anti-inflammatory and anti-angiogenic activities. Nevertheless, the effects of BigV on liver cancer and the underlying mechanisms have not been investigated. In the study, we found that BigV exhibited potential anti-tumor activities against human liver cancer in vitro and in vivo. BigV reduced the cell proliferation and colony formation. BigV induced apoptosis through improving the cleavage of Caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1). The process was along with the activation of autophagy, as proved by the enhanced accumulation of autophagosomes, the microtubule-associated light chain 3B-II (LC3B-II) and Beclin-1, and p62 decrease. Further, the autophagy blockage markedly sensitized BigV-induced cell death, indicating the cytoprotective function of autophagy in liver cancer cell lines. In addition, BigV treatment inactivated the pathway of protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K). Of note, BigV-induced cell death was abolished by over-expressing the phosphorylation of mTOR. Intriguingly, the induction of apoptosis and autophagy were eliminated by the pretreatment of reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC), suggesting that ROS played an important role in the regulation of BigV-induced cell death. Finally, in vivo studies demonstrated that BigV significantly suppressed the growth of HepG2 cancer xenograft tumors through the activation of apoptosis and autophagy in a dose-dependent manner with low systemic toxicity. In conclusion, the results revealed that BigV had significant antitumor effects against human liver cancer and it may potentially be used as a novel antitumor agent for the prevention of liver cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate the falciform ligament as an autologous substitute for mesentericoportal vein reconstruction during pancreaticoduodenectomy., Background: Mesentericoportal vein reconstruction was needed in some certain cases during pancreaticoduodenectomy, and a rapidly available substitute was required., Methods: The falciform ligament was used as an autologous substitute during pancreaticoduodenectomy in 6 patients between June 2016 and May 2017. Anticoagulation was not performed at any stage and venous patency was estimated by Color-Doppler ultrasonography and contrast-enhanced computed tomography., Results: 6 patients underwent vascular resection during pancreaticoduodenectomy for malignant tumors. The falciform ligament graft, with a mean length of 26 mm (10-40), was immediately harvested and used as a lateral patch for reconstruction of the mesentericoportal vein (n = 6). Severe morbidity included Clavien grade-III complications occurred in 1(16.7%) patients but there was no graft-related complications. Histological vascular invasion was present in all the patients (n = 6, 100%), and all had an R0 resection (100%). All venous reconstructions were patent (100%) after a mean follow-up of 12 (6-16) months., Conclusions: An autologous falciform ligament graft can be safely used as a lateral substitute for mesentericoportal vein reconstruction during pancreaticoduodenectomy; this could help improve the radical resection rate of malignant tumors when oncologically required., (Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background and Aim: Cholangitis, bacteremia, and pyogenic liver abscess (PLA) can be often caused by intrahepatic bile ducts stone (IBDS), which is endemic to South-East Asia. The association between IBDS and cholangiocarcinoma has been well recognized. Concomitant cholangiocarcinoma in the PLA related to IBDS is often missed., Methods: A case-control study consisting of 64 patients with PLA related to IBDS and 256 control patients with PLA not related to IBDS was used to investigate clinical features of PLA and incidence of concomitant cholangiocarcinoma in patients with PLA related to IBDS., Results: The main imaging manifestations of PLA related to IBDS was cystic-solid lesions and solid lesions. Of seven patients (10.9%) with pathology-proven cholangiocarcinoma in the same area of PLA related to IBDS among 64 patients, only two patients were initially diagnosed as having concomitant cholangiocarcinoma by biopsy, and other five patients diagnosed as acute inflammatory lesion. Within 60 days after onset, the infection-related death rate and recurrence rate in patients with PLA related to IBDS were 12.9% and 20.3%, respectively, whereas in patients with PLA not related to IBDS were 3.9% and 3.1%, respectively. Only 25% of patients with PLA related to IBDS underwent surgery after admission. The main pathogens in PLA patients related to IBDS were Escherichia coli and extended-spectrum beta-lactamase-producing Enterobacteriaceae., Conclusions: The imaging manifestations of PLA related to IBDS often present cystic-solid or solid lesions. PLA related to IBDS is characterized by high rate of recurrence and infection-related death, difficulty in diagnosis of concomitant cholangicarcinoma., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: To evaluate the two newly established nomograms for predicting lymph node metastasis in penile cancer based on the clinical data on a large cohort of patients., Methods: We retrospectively studied the clinical data on 93 patients with penile cancer treated in the Center for Tumor Prevention and Treatment. Using the two recently established nomograms (Bhagat nomogram and Zhu nomogram), we predicted lymph node metastasis in the patients, analyzed the differences between prediction and the results of postoperative pathology, and compared the accuracy of prediction between the two nomograms with the receiver operating characteristic (ROC) curve and the area under the curve (AUC)., Results: The median age of the patients was 55 (27－82) years. Positive lymph nodes were found in 31 cases (33.3%) postoperatively and in 9 (21.9%) of the 41 clinically negative cases. The AUC of the Bhagat nomogram was 0.739 and that of Zhu nomogram was 0.808, both of which were similar to the prediction accuracy of internal verification and manifested a medium predictive ability., Conclusions: The newly established Bhagat and Zhu nomograms can be used for predicting lymph node metastasis in penile cancer, but with a low precision, and therefore cannot be relied exclusively for the option of inguinal lymphadenectomy.

The present study aimed to investigate the mechanisms by which mannose protects the lung injury induced in rats with acute pancreatitis (AP). An AP combined with Acute Lung Injury (ALI) model was established. A total of 90 healthy adult male Sprague-Dawley rats (300±50g weight) were randomly divided into three groups: sham operation group (SO group), severe acute pancreatitis lung injury group (SAP group), and mannose intervention group (MT group). Subsequently, each group was divided into two subgroups based on the time passed from intervention, namely 6 and 12 h. Each subgroup comprised 15 rats. The ratio of wet/dry weight of the lung tissue exhibited no significant change at different time points in the SO group. This parameter was significantly increased in the SAP group compared with the SO group at each time point of the treatment (P less than 0.05) and it was significantly lower in the MT group than that in the AP group (P less than 0.05) and it was significantly increased in the AP group at each time (P less than 0.05) compared with the SO group. The levels of TNF-α in the lung tissue in the SO group exhibited no significant change at different time points, but they were significantly decreased in the MT group at each time point (P less than 0.05) compared with the SAP group. The mannose receptor (MR) mRNA and protein levels in the lung tissues exhibited no significant change at different time points. The mRNA and protein levels of MR in the SAP group were significantly decreased at each time point (P less than 0.05) compared with the SO group. The mRNA and protein levels of MR, in the lung tissue of the MT group were significantly increased at each time point compared with the SAP group (P less than 0.05). Mannose could reduce the injury caused to the lung tissue of rats with severe acute pancreatitis by up-regulation of the expression of MR mRNA and protein.

Ocular coloboma is a developmental structural defect of the eye that often occurs as complex ocular anomalies. However, its genetic etiology remains largely unexplored. Here we report the identification of mutation (c.331C>T, p.R111C) in the IPO13 gene in a consanguineous family with ocular coloboma, microphthalmia, and cataract by a combination of whole-exome sequencing and homozygosity mapping. IPO13 encodes an importin-B family protein and has been proven to be associated with the pathogenesis of coloboma and microphthalmia. We found that Ipo13 was expressed in the cornea, sclera, lens, and retina in mice. Additionally, the mRNA expression level of Ipo13 decreased significantly in the patient compared with its expression in a healthy individual. Morpholino-oligonucleotide-induced knockdown of ipo13 in zebrafish caused dose-dependent microphthalmia and coloboma, which is highly similar to the ocular phenotypes in the patient. Moreover, both visual motor response and optokinetic response were impaired severely. Notably, these ocular phenotypes in ipo13-deficient zebrafish could be rescued remarkably by full-length ipo13 mRNA, suggesting that the phenotypes observed in zebrafish were due to insufficient ipo13 function. Altogether, our findings demonstrate, for the first time, a new role of IPO13 in eye morphogenesis and that loss of function of IPO13 could lead to ocular coloboma, microphthalmia, and cataract in humans and zebrafish.

We found better liver graft regeneration with hypothermic machine perfusion (HMP) compared with static cold storage (SCS) for the first time in our pilot study, but the underlying mechanisms are unknown. Upregulated heme oxygenase- (HO-) 1 expression has been reported to play a pivotal role in promoting hepatocyte proliferation. Here, we evaluated the novel role of HO-1 in liver graft protection by HMP. Rats with a heterozygous knockout of HO-1 (HO-1 +/- ) were generated and subjected to 3 h of SCS or HMP pre-half-size liver transplantation (HSLT) in vivo or 6 h of SCS or HMP in vitro; control rats were subjected to the same conditions (HO-1 +/+ ). We found that HSLT induced significant elevation of the HO-1 protein level in the regenerated liver and that HO-1 haplodeficiency resulted in decreased proliferation post-HSLT. Compared with SCS, HMP induced significant elevation of the HO-1 protein level along with better liver recovery, both of which were reduced by HO-1 haplodeficiency. HO-1 haplodeficiency-induced decreased proliferation was responsible for the attenuated regenerative ability of HMP. Mechanistically, HO-1 haploinsufficiency resulted in suppression of hepatocyte growth factor (HGF)/Akt activity. Our results suggest that inhibition of HO-1 mitigates HMP-induced liver recovery effects related to proliferation, in part, by downregulating the HGF-Akt axis.

Interleukin-35 (IL-35) is implicated in tumorigenesis, but its exact impact on intrahepatic cholangiocarcinoma (ICC) is not clear. The aim of the present study was to explore the specific effect of IL-35 on patient prognosis. Additionally, we formulated an effective prognostic nomogram for ICC patients after curative resection. Immunohistochemistry was applied to explore IL-35 expression as well as IL-35 receptor (IL-35R) in 102 ICC patients. Results showed that IL-35 was highly expressed in ICC tumor tissues and was positively associated with lymph node metastasis (LNM), TNM stage and vascular invasion and was an independent prognostic factor for patients' overall survival (OS) and recurrence-free survival (RFS). High expression of IL-35R (gp130 and IL-12Rβ2) was also observed in ICC cancer tissues, but only gp130 was an independent prognostic factor for OS and RFS and was indispensable in IL-35-mediated ICC clinical prognosis. The nomogram comprising carcinoembryonic antigen, LNM, IL-35 and gp130 expression achieved better predictive accuracy compared with TNM stage for OS. Our data support that high IL-35 expression correlates with ICC aggressiveness and emerges as a valuable biomarker for evaluating ICC progression and prognosis in clinical work., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Low resectability and poor survival outcome are common for hilar cholangiocarcinoma (HCCA), especially in advanced stages. The present study was to assess the clinical outcome of advanced HCCA, focusing on therapeutic modalities, survival analysis and prognostic assessment., Methods: Clinical data of 176 advanced HCCA patients who had been treated in our hospital between January 2013 and December 2015 were analyzed retrospectively. Prognostic effects of clinicopathological factors were explored by univariate and multivariate analysis. Survival predictors were evaluated by the receiver operating characteristic (ROC) curve., Results: The 3-year overall survival rate was 13% for patients with advanced HCCA. Preoperative total bilirubin (P = 0.009), hepatic artery invasion (P = 0.014) and treatment modalities (P = 0.020) were independent prognostic factors on overall survival. A model combining these independent prognostic factors (area under ROC curve: 0.748; 95% CI: 0.678-0.811; sensitivity: 82.3%, specificity: 53.5%) was highly predictive of tumor death. After R0 resection, the 3-year overall survival was up to 38%. Preoperative total bilirubin was still an independent negative factor, but not for hepatic artery invasion., Conclusions: Surgery is still the best treatment for advanced HCCA. Preoperative biliary drainage should be performed in highly-jaundiced patients to improve survival. Prediction of survival is improved significantly by a model that incorporates preoperative total bilirubin, hepatic artery invasion and treatment modalities., (Copyright © 2018. Published by Elsevier B.V.)

[This corrects the article DOI: 10.18632/oncotarget.17450.].

[This corrects the article DOI: 10.18632/oncotarget.14642.].

Irreversible electroporation (IRE) creates permanent pores in the cell membrane, leading to irreversible cell death. In this study, the impact of IRE on bronchial injury was comprehensively examined in a timed series study. Altogether, 8 Bama miniature pigs were included in this study and were randomly assigned to experimental and control groups. The experimental group underwent IRE that was guided and monitored by spiral computed tomography (CT). The monopole probe of the IRE was positioned at the right pulmonary hilum. Specimens were collected at 0 h, 2 h, 2 d, 7 d, and 14 d after the IRE procedure for a pathological examination. A small amount of needle-tract bleeding occurred in two animals, and mild pneumothorax occurred in another. IRE can elicit acute bronchial inflammation, bleeding, and mucosal injury, but severe complications were not found. Pathological examinations and transmission electron microscopy (TEM) showed dead vascular epithelium cells in the region of the ablation, while the bronchioli and the vascular extracellular matrix were preserved. At 2 hours post-IRE, there were marked increases in bronchoalveolar macrophages (P<0.001), but the inflammation could recover after 14 days and showed no statistical significance when compared with the control group at the same time. In conclusion, CT-guided IRE ablation can elicit acute but recoverable bronchial inflammation, bleeding, and mucosal injury in porcine lung tissues. However, longer follow-up is still required to establish an evaluation of the long-term safety., Competing Interests: None., (IJCEP Copyright © 2018.)

Southwest China is one of the major global biodiversity hotspots. The Tanaka line, extending within southwestern China from its northwest to its southeast, is an important biogeographical boundary between the Sino-Japanese and Sino-Himalayan floristic regions. Understanding the evolutionary history of the regional keystone species would assist with both reconstructing historical vegetation dynamics and ongoing biodiversity management. In this research, we combined phylogeographic methodologies and species distribution models (SDMs) to investigate the spatial genetic patterns and distribution dynamics of Quercus kerrii, a dominant evergreen oak inhabiting southwest China lowland evergreen-broadleaved forests (EBLFs). A total of 403 individuals were sampled from 44 populations throughout southwest China. SDMs and mismatch distribution analysis indicated that Q. kerrii has undergone northward expansion since the Last Glacial Maximum (LGM). Quantitative analysis revealed that the range expansion of Q. kerrii since the LGM exceeded that of the sympatric mid-elevation species Quercus schottkyana, likely owing to their contrasting distribution elevations and habitat availabilities. The historical climate change since the LGM and the latitude gradient of the region played an important role in shaping the genetic diversity of Q. kerrii. The genetic differentiation index and genetic distance surface of Q. kerrii populations east of the Tanaka line exceeded those to its west. The long-term geographic isolation and environmental heterogeneity between the two sides of the Tanaka line might increase species divergence patterns and local adaptation. This study provides new insights into the historical dynamics of subtropical EBLFs and the changing biota of southwest China.

Pristine monocrystalline molybdenum disulfide (MoS 2 ) possesses high mechanical strength comparable to that of stainless steel. Large-area chemical-vapor-deposited monolayer MoS 2 tends to be polycrystalline with intrinsic grain boundaries (GBs). Topological defects and grain size skillfully alter its physical properties in a variety of materials; however, the polycrystallinity and its role played in the mechanical performance of the emerging single-layer MoS 2 remain largely unknown. Here, using large-scale atomistic simulations, GB structures and mechanical characteristics of realistic single-layered polycrystalline MoS 2 of varying grain size prepared by confinement-quenched method are investigated. Depending on misorientation angle, structural energetics of polar-GBs in polycrystals favor diverse dislocation cores, consistent with experimental observations. Polycrystals exhibit grain-size-dependent thermally induced global out-of-plane deformation, although defective GBs in MoS 2 show planar structures that are in contrast to the graphene. Tensile tests show that presence of cohesive GBs pronouncedly deteriorates the in-plane mechanical properties of MoS 2 . Both stiffness and strength follow an inverse pseudo Hall-Petch relation to grain size, which is shown to be governed by the weakest link mechanism. Under uniaxial tension, transgranular crack propagates with small deflection, whereas upon biaxial stretching, the crack grows in a kinked manner with large deflection. These findings shed new light in GB-based engineering and control of mechanical properties of MoS 2 crystals toward real-world applications in flexible electronics and nanoelectromechanical systems.

Preoperative portal vein embolization (PVE) induces compensatory hyperplasia of the future liver remnants (FLR), thus increasing resectability in the non-cirrhotic patients with primary liver cancer (PLC). However, it is unclear if it is similar in patients with liver cirrhosis. Therefore, the present study investigated the PVE value prior to liver resection in patients with PLC, and the liver cirrhotic effects on the compensatory hypertrophy of FLRs following PVE. In the present study, 21 patients with PLC who successfully underwent hepatic resection subsequent to PVE, were retrospectively examined. The patients were divided into a non-cirrhosis group and a cirrhosis group according to the absence or presence of cirrhosis, respectively. The FLR volume between the two groups of patients was compared. There was a significant difference in the FLR volume for all patients prior to, and 4-6 weeks following, PVE (P<0.001). PVE induced significant compensatory hypertrophy in the FLRs whether in the non-cirrhosis group (P=0.002) or cirrhosis group (P<0.001). However, no significant difference was identified between the two groups with respect to FLR volume enlargement 4-6 weeks following PVE (P=0.373). In conclusion, PVE prior to hepatectomy may promote FLR compensatory hypertrophy and an increase in the resectability of PLC tumors. No significant effects of liver cirrhosis were identified on liver lobe hyperplasia following PVE.

Background: Ischemia reperfusion injury (IRI) causes postoperative complications and influences the outcome of the patients undergoing liver surgery and transplantation. Postconditioning (PostC) is a known manual conditioning to decrease the hepatic IRI. Here we aimed to optimize the applicable PostC protocols and investigate the potential protective mechanism., Methods: Thirty Sprague-Dawley rats were randomly divided into 3 groups: the sham group (n = 5), standard orthotopic liver transplantation group (OLT, n = 5), PostC group (OLT followed by clamping and re-opening the portal vein for different time intervals, n = 20). PostC group was then subdivided into 4 groups according to the different time intervals: (10 s × 3, 10 s × 6, 30 s × 3, 60 s × 3, n = 5 in each subgroup). Liver function, histopathology, malondialdehyde (MDA), myeloperoxidase (MPO), expressions of p-Akt and endoplasmic reticulum stress (ERS) related genes were evaluated., Results: Compared to the OLT group, the grafts subjected to PostC algorithm (without significant prolonging the total ischemic time) especially with short stimulus and more cycles (10 s × 6) showed significant alleviation of morphological damage and graft function. Besides, the production of reactive oxidative agents (MDA) and neutrophil infiltration (MPO) were significantly depressed by PostC algorithm. Most of ERS related genes were down-regulated by PostC (10 s × 6), especially ATF4, Casp12, hspa4, ATF6 and ELF2, while p-Akt was up-regulated., Conclusions: PostC algorithm, especially 10 s × 6 algorithm, showed to be effective against rat liver graft IRI. These protective effects may be associated with its antioxidant, inhibition of ERS and activation of p-Akt expression of reperfusion injury salvage kinase pathway., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Our previous study showed that cancer-associated fibroblast MRC-5 promoted hepatocellular carcinoma progression by enhancing migration and invasion capability. However, few studies have explored the role of MRC-5 in pancreatic cancer (PC). In this study, we examined the exact role and associated mechanisms of MRC-5. Methods: The conditioned media for MRC-5 was used to culture PC cell lines SW1990 and PANC-1. Cell proliferation was compared based on colony formation assays of PC cells in normal media and of PC cells cultured with conditioned media of MRC-5. Cell migration and invasion were assayed by transwell chambers. The expression of EMT-related proteins and apoptosis-related proteins was evaluated using Western blot. And confocal microscopy was used to further detect the expression of EMT-related proteins. qRT-PCR was used to confirm the expression changes of related genes at the mRNA level. We also used flow cytometry to examine the cell cycle, apoptotic rate, and expression of CD3, CD4, CD14, CD25, CD45, CD61, CD90, TLR1, and TLR4. Results: MRC-5 repressed the colony formation ability of PC cells and significantly inhibited cell migration and invasion potential. MRC-5 induced S-phase cell cycle arrest but did not augment the apoptotic effects in PC cells. We hypothesized that the weakened malignant biological behavior of PC cells was correlated with MRC-5-induced altered expression of the cancer stem cell marker CD90; the immune-related cell surface molecules CD14, CD25, TLR4, and TLR1; and cell polarity complexes Par, Scribble, and Crumbs. Conclusion: MRC-5 limits the malignant activities of PC cells by suppressing cancer stem cell expansion, remolding epithelial polarity, and blocking the protumoral cascade reaction coupled to TLR4, TLR1, CD14, and CD25., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

An experiment was conducted to investigate the effects of different dietary threonine (Thr) levels and immune stress on Pekin ducklings' growth performance, carcass traits, serum immune parameters, and intestinal mucin 2 (MUC2) and nuclear factor kB (NF-κB) gene expressions. A total of 320 Pekin ducklings was randomly assigned to a 5 × 2 factorial arrangement of treatments. Each treatment group consisted of 4 replicate pens with 8 ducks per pen. Ducklings were fed 5 graded levels of Thr: 0.49, 0.56, 0.60, 0.65, and 0.76% from hatch to 21 d of age. At 11 d of age, ducks in the stressed groups were challenged with bovine serum albumin (BSA), and ducks in the unstressed groups were injected with normal saline water. The results showed that increasing Thr supplementation from 0.49 to 0.56% in the diet can improve BWG; feed consumption; weight and relative weight of breast and leg; weight of liver, bursa of Fabricius, spleen, and thymus; serum natural immune globulin A (IgA) concentration; and MUC2 gene expression in the ileum of 21-day-old Pekin ducks, significantly (P < 0.05). Immune stress with BSA had a significant effect on 21-day-old Pekin ducklings' BWG, feed consumption, and weight and relative weight of breast and thymus (P < 0.05), but no interaction between BSA and dietary Thr content was noticed in our experiment in 21-day-old Pekin ducks (P < 0.05). Dietary Thr requirements of the unstressed groups and stressed groups based on broken-line model analyses for ducks' BWG were 0.705 and 0.603%, respectively, and for ducks' feed consumption were 0.724 and 0.705%, respectively., (© 2017 Poultry Science Association Inc.)

Relationships of toxicities from intravenous (i.v.), intraperitoneal (i.p.), subcutaneous (s.c.) and intragastric (i.g.) exposure routes to mice were investigated. Regression analysis showed that the toxicities from i.v. route is strongly correlated with i.p. and s.c. routes, but poorly with i.g. route. Close toxicities from different routes for some compounds indicate that distribution rate is the determining step and dictates chemical concentration at the target site(s). On the other hand, the absorption rate is the determining step for many compounds, which lead to different toxicities between exposure routes. The classified compounds characterized as having either absorption or distribution rate determining step were based upon the comparison of toxicities from the different routes. We found that some aliphatic acids and benzoic acids have lower toxicity values from i.g. route compared to an i.v. route because of poor absorption. Many compounds show low toxic effects from i.g. route than those from other routes because of the first-pass metabolism in the gastrointestinal tract, resulting in the poor relationship for toxicities between i.g. and i.v. or other routes. Stepwise regression analysis showed that physicochemical properties of a compound, such as molecular volume, polarizability and hydrophobicity, significantly affect adsorption rate, which leads to different toxicities based upon exposure routes. Comparison of the toxicities between mice and rats indicate that toxic effect and the toxicokinetic processes in mice are very similar to that in rats. A universal correlation equation has been developed for the toxicities between rats and mice from different exposure routes, which can be applied to predict toxicities across species.

Background/aims: Pancreatic cancer is an aggressive malignancy as a result of highly metastatic potential. The current study was carried out to alter the expression of LINC01121 in pancreatic cancer, with the aim of elucidating its effects on the biological processes of cell proliferation, migration, invasion, and apoptosis. We hypothesized that both the GLP1R gene and cAMP/PKA signaling pathway participate in the aforementioned process., Methods: Microarray data (GSE14245, GSE27890 and GSE16515) and annotating probe files linked to pancreatic cancer were downloaded through the GEO database. The Multi Experiment Matrix (MEM) site was used to predict the target gene of lncRNA. Both pancreatic cancer tissues (n = 56) and paracancerous tissues (n = 45) were collected from patients diagnosed with pancreatic cancer. Immunohistochemistry was applied to identify the positive expression rate of GLP1R protein. Isolated pancreatic cancer cells and PANC-1 cells were independently classified into the blank, negative control (NC), LINC01121 vector, siRNA-LINC01121, siRNA-GLP1R and siRNA-LINC01121 + siRNA-GLP1R groups. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were applied to detect the expressions of LINC01121, GLP1R, cAMP, PKA, CREB, Bcl-2, Bad and PCNA. Cell proliferation, migration, invasion, cycle progression, and apoptosis were examined by MTT assay, scratch test, Transwell assay and flow cytometry analyses of Annexin V-FITC/PI staining., Results: Observations were made indicating that LINC01121 was highly expressed, while low expressions of GLP1R in pancreatic cancer were detected based on microarray data, which was largely in consistent with the data collected of LINC01121 and GLP1R within the tissues. The target prediction program and luciferase activity analysis was testament to the notion suggesting that GLP1R was indeed a target of LINC01121. In contrast to the blank and NC groups, the LINC01121 vector group exhibited increased expressions of LINC01121; decreased mRNA and protein levels of GLP1R, Bad, cAMP, and PKA; increased protein levels of CREB, Bcl-2, PCNA, p-PKA and p-CREB; increased cell proliferation, migration and invasion; and decreased cell apoptosis. There was no significant difference detected among the blank, NC, and siRNA-LINC01121 + siRNA-GLP1R groups, except that decreased LINC01121 expression was determined in the siRNA-LINC01121 + siRNA-GLP1R group. Parallel data were observed in the pancreatic cancer cells and PANC-1 cells., Conclusion: The current study presents evidence indicating that LINC01121 might inhibit apoptosis while acting to promote proliferation, migration, and invasion of pancreatic cancer cells, supplementing the stance held that LINC01121 functions as a tumor promoter by means of its involvement in the process of translational repression of the GLP1R and inhibition of the cAMP/PKA signaling pathway., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background/aims: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC., Methods: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models., Results: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models., Conclusions: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background: New-onset diabetes after transplantation (NODAT) has become one of the major factors that affect the overall survival and long-term life quality in liver transplantation (LT) recipients. Previous studies found that the serum adiponectin concentration of diabetic patients is significantly lower than that of healthy subjects. Adiponectin regulates the blood glucose level by increasing body sensitivity to insulin through various mechanisms. In this study, we aimed to investigate the impact of diabetes related gene polymorphisms on the development of NODAT in liver recipients., Methods: A total of 256 LT patients in a single-center were selected retrospectively for the study. Genomic DNA was extracted from explanted liver tissues, and tested for twelve diabetes mellitus associated single nucleotide polymorphisms by Sequenom MassARRAY. Modified clinical models in predicting NODAT were established and evaluated., Results: The GG genotype of ADIPOQ rs1501299 gene polymorphism was significantly more frequent in NODAT than non-NODAT LT patients (56% vs 39%, P=0.014). Dominant model (GG vs GT+TT, P=0.030) and recessive model (GT+GG vs TT, P=0.005) also confirmed the genotype distribution difference between NODAT and non-NODAT groups. Age (OR=1.048, P=0.004), BMI (OR=1.107, P=0.041), and blood tacrolimus level at 1-month LT (OR=1.170, P=0.003) were clinical independent risk factors of NODAT. Furthermore, rs1501299 could improve the ability of clinical model in predicting NODAT (AUROC=0.743, P<0.001)., Conclusion: ADIPOQ rs1501299 gene polymorphism is associated with an increased risk of NODAT, which should be added to the clinical models in predicting the occurrence of NODAT in LT recipients., (Copyright © 2017 The Editorial Board of Hepatobiliary & Pancreatic Diseases International. Published by Elsevier B.V. All rights reserved.)

This study aimed to assess coronary microvascular dysfunction (CMD) differences in hypertrophic cardiomyopathy (HCM) patients using cardiac magnetic resonance (CMR) first-pass perfusion and late gadolinium enhancement imaging. Forty-seven patients with HCM and twenty-one healthy volunteers underwent CMR at rest. Imaging protocols included short axis cine, first-pass myocardial perfusion, and late gadolinium enhancement (LGE). Left ventricular end-diastolic wall thickness (EDTH), LGE, time to peak (T peak ), maximal up-slope (Slope max ), and peak signal intensity (SI peak ) were assessed for each myocardial segment. The HCM myocardial segments were grouped by the degree of LGE and hypertrophy. T peak , SI peak , Slope max and EDTH in multiple groups were assessed and compared by ANOVA test/Kruskal-Wallis test. The Spearman correlation test was used to determine the relationships between EDTH, LGE and perfusion parameters (T peak , Slope max and SI peak ). Compared to control group segments, T peak increased while Slope max and SI peak decreased in non-LGE/non-hypertrophic segments and LGE/hypertrophic segments in the HCM group, while T peak increased more significantly in LGE/hypertrophic segments (all p < 0.05). T peak statistically increased with increasing degrees of myocardial LGE (p < 0.01). Differences in T peak , SI peak and EDTH were observed between segments with and without hypertrophy (p < 0.05). EDTH and LGE were positively correlated with T peak (r = 0.279, p = 0.031 and r = 0.237, p < 0.001). 3.0 T magnetic resonance myocardial perfusion imaging identifies abnormal perfusion in non-LGE and non-hypertrophic segments of HCM patients, and it may be helpful in the early diagnosis of coronary microvascular dysfunction in HCM. This abnormal perfusion is associated with the severity of myocardial fibrosis and the degree of hypertrophy.

Background: To investigate the potential mechanisms of hypothermic machine perfusion (HMP)'s beneficial effects on kidney graft over static cold storage (SCS) in vitro., Methods: Ten kidneys of 5 Bama miniature male pigs were paired into 2 groups: SCS group and HMP group. Preservation solutions were taken at 0, 1, 3, and 6 hours for the measurement of K + , Na + , Cl - , blood urea nitrogen (BUN), creatinine (Cr), and lactate dehydrogenase (LDH) using the standard laboratory methods. Renal cortex were harvested at 6 hours for the following measurement: lactic acid (LD), adenosine triphosphate (ATP), malondialdehyde (MDA), neutrophil accumulation (MPO), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β). Ischemia-induced apoptosis and the protein expression levels of total Akt, phospho-Akt, total Erk, and phospho-Erk were analyzed by Western blotting., Results: Almost all of the tested metabolites in preservation solutions were reduced with time in the HMP group. Levels of Na + , Cl - , BUN, Cr, K + , and LDH were lower in the HMP group compared with the SCS group, with differences in the first 4 reaching statistical significance. HMP alleviated ATP degradation and LD accumulation, diminished the MDA (P < .05) and MPO (P = .227) levels, and greatly raised IL-10 and TGF-β (P < .05) expression. A marked decrease of proapoptotic and a large increase of antiapoptotic markers (P < .05) along with greatly raised Akt (P < .05) and Erk (P < .01) phosphorylation was observed in the kidney of the HMP group compared with the SCS group., Conclusion: HMP's kidney graft protection involves inhibition of accumulation of toxic metabolites, oxidative damage, and apoptosis along with upregulation of the Akt and Erk signaling pathway., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Chemicals show diverse modes of action (MOAs) in aquatic organisms depending upon acute and chronic toxicity evaluations. Here, toxicity data for Vibrio fischeri involving 52 compounds for acute and chronic toxicity were used to determine the congruence of acute and chronic toxicity for assessing MOAs. Using toxic ratios, most of the compounds categorized into MOAs that included baseline, less inert or reactive compounds with acute toxicity were also categorized as baseline, less inert or reactive compounds with chronic toxicity. However, significantly different toxic effects were observed with acute and chronic toxicity for the reactive and specific-acting compounds. The acute-chronic toxic ratios were smaller and less variable for the baseline and less inert compounds, but were greater and more variable for the reactive and specific-acting compounds. Baseline and less inert compounds share same MOAs, but reactive and specific-acting compounds have different MOAs between acute and chronic toxicity. Bioconcentration processes cannot reach an equilibrium for highly hydrophilic and ionized compounds with short-term exposure, resulting in lower toxicity compared to long-term exposure. Pronounced differences for the antibiotics were not only due to the difference in bioconcentration, but also due to a predicted difference in MOAs during acute and chronic exposures., (Copyright © 2017 Elsevier B.V. All rights reserved.)