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Background: To better understand the pathophysiological mechanisms of patellar fractures, MRI was utilized to identify the imaging signs of various types of patellar fractures., Methods: A retrospective study was performed using MRI images of 52 patients with patellar fractures. Observing the development of patellar and femoral morphology and the imaging manifestations of different fracture types, such as fracture displacement, and damage to accessory ligaments, tendons, and meniscus, type of joint cavity effusion, and damage to surrounding accessory bones were identified., Results: There were 21 tangential fractures (40.4%), 8 transverse fractures (15.4%), 8 longitudinal fractures (15.4%), 4 oblique fractures (7.7%), and 11 comminuted fractures (21.2%) among the 52 patients with patellar fracture. Tangential fractures begin at a younger age than the other four forms of fractures. When tangential fractures were compared to other types of fractures, medial patellar retinaculum and anterior and posterior cruciate ligament injuries were statistically significant (P< 0.05). The detection rate of trochlear dysplasia, type II and type III patellar was higher in patients with tangential fractures than in other fractures., Conclusions: Tangential fractures are less common to cause anterior and posterior cruciate ligament injuries than other types of fractures, but they are more likely to cause medial patellar retinaculum injuries., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hua et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Obesity is a global health issue with increasing prevalence. Surgical procedures, such as surgical stabilization of rib fractures (SSRF), may be affected by obesity-related complications. The objective of the study is to investigate the effects of obesity on SSRF outcomes in multiple rib fractures., Methods: This retrospective study analyzed data from adults aged ≥ 20 years in the Nationwide Inpatient Sample (NIS) database diagnosed with multiple rib fractures who underwent SSRF between 2005 and 2018. It investigated the relationship between obesity and in-patient outcomes, such as discharge status, length of stay (LOS), in-hospital mortality, hospital costs, and adverse events using logistic and linear regression analyses., Results: Analysis of data from 1,754 patients (morbidly obese: 87; obese: 106; normal weight: 1,561) revealed that morbid obesity was associated with longer LOS (aBeta = 0.07, 95% CI: 0.06, 0.07), higher hospital costs (aBeta = 47.35, 95% CI: 38.55, 56.14), increased risks of adverse events (aOR = 1.63, 95% CI: 1.02, 2.61), hemorrhage/need for transfusion (aOR = 1.77, 95% CI: 1.12, 2.79) and mechanical ventilation ≥ 96 hours (aOR = 2.14, 95% CI: 1.28, 3.58) compared to normal weight patients. Among patients with flail chest, morbid obesity was significantly associated with tracheostomy (aOR = 2.13, 95% CI: 1.05, 4.32), ARDS/respiratory failure (aOR = 2.01, 95% CI: 1.09, 3.70), and mechanical ventilation ≥ 96 hours (aOR = 2.80, 95% CI: 1.47, 5.32). In contrast, morbid obesity had no significant associations with these adverse respiratory outcomes among patients without a flail chest (p > 0.05)., Conclusions: Morbid obesity is associated with adverse outcomes following SSRF for multiple rib fractures, especially for flail chest patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To estimate the incidence of foodborne gastroenteritis caused by nontyphoidal Salmonella enterica, Shigella, and Vibrio parahaemolyticus in China, population surveys and sentinel hospital surveillance were implemented in six provinces from July 2010 to July 2011, and a multiplier calculation model for the burden of disease was constructed. The multiplier for salmonellosis and V. parahaemolyticus gastroenteritis was estimated at 4,137 [95% confidence interval (CI) 2,320-5,663], and for shigellosis at 4,356 (95% CI 2,443-5,963). Annual incidence per 100,000 population was estimated as 245 (95% CI 138-336), 67 (95% CI 38-92), and 806 (95% CI 452-1,103) for foodborne salmonellosis, shigellosis, and V. parahaemolyticus gastroenteritis, respectively, indicating that foodborne infection caused by these three pathogens constitutes an important burden to the Chinese healthcare system. Continuous implementation of active surveillance of foodborne diseases, combined with multiplier models to estimate disease burden, makes it possible for us to better understand food safety status in China., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We previously revealed the origin of mammalian simple-type glycogen synthase kinase interaction protein (GSKIP), which served as a scavenger and a competitor in the Wnt signaling pathway during evolution. In this study, we investigated the conserved and nonconserved regions of the composite-type GSKIP by utilizing bioinformatics tools, site-directed mutagenesis, and yeast two-hybrid methods. The regions were denoted as the pre-GSK3β binding site, which is located at the front of GSK3β-binding sites. Our data demonstrated that clustered mitochondria protein 1 (CLU1), a type of composite-type GSKIP that exists in the mitochondria of all eukaryotic organisms, possesses the protein known as domain of unknown function 727 (DUF727), with a pre-GSK3β-binding site and a mutant GSK3β-binding flanking region. Another type of composite-type GSKIP, armadillo repeat containing 4 (ARMC4), which is known for cilium movement in vertebrates, contains an unintegrated DUF727 flanking region with a pre-GSK3β-binding site (115SPxF118) only. In addition, the sequence of the GSK3β-binding site in CLU1 revealed that Q126L and V130L were not conserved, differing from the ideal GSK3β-binding sequence of simple-type GSKIP. We further illustrated two exceptions, namely 70 kilodalton heat shock proteins (Hsp70/DnaK) and Mitofilin in nematodes, that presented an unexpected ideal GSK3β-binding region with a pre-GSK3β sequence; this composite-type GSKIP could only occur in vertebrate species. Furthermore, we revealed the importance of the pre-GSK3β-binding site (118F or 118Y) and various mutant GSK3β-binding sites of composite-type GSKIP. Collectively, our data suggest that the new composite-type GSKIP starts with a DUF727 domain followed by a pre-GSK3β-binding site, with the subsequent addition of the GSK3β-binding site, which plays vital roles for CLU1, Mitofilin, and ARMC4 in mitochondria and Wnt signaling pathways during evolution., Competing Interests: The authors have declared that no competing interests exist.

microRNAs (miRNA) in extracellular vesicles (EVs) have been investigated as potential biomarkers for pancreatic ductal adenocarcinoma (PDAC). However, a mixed population of EVs is often obtained using conventional exosome isolation methods for biomarker development. EVs are derived from different cellular processes and present in various sizes, therefore miRNA expression among them is undoubtedly different. We developed a simple protocol utilizing sequential filtration and ultracentrifugation to separate PDAC EVs into three groups, one with an average diameter of more than 220 nm, named operational 3 (OP3); one with average diameters between 100-220 nm, named operational 2 (OP2); and another with average diameters around 100 nm, named operational 1 (OP1)). EVs were isolated from conditioned cell culture media and plasma of human PDAC xenograft mice and early stage PDAC patients, and verified by nanoparticle tracking, western blot, and electronic microscopy. We demonstrate that exosome specific markers are only enriched in the OP1 group. qRT-PCR analysis of miRNA expression in EVs from PDAC cells revealed that expression of miR-196a and miR-1246, two previously identified miRNAs highly enriched in PDAC cell-derived exosomes, is significantly elevated in the OP1 group relative to the other EV groups. This was confirmed using plasma EVs from PDAC xenograft mice and patients with localized PDAC. Our results indicate that OP1 can be utilized for the identification of circulating EV miRNA signatures as potential biomarkers for PDAC., Competing Interests: The authors have declared that no competing interests exist.

Oral health status ideally warrants for a holistic biopsychosocial approach to health and wellness. Little is known about the impact of behavioral problems on oral health-related quality of life (OHRQoL) in children due to the paucity of studies in early childhood, particularly in Asian multi-ethnic populations. This study evaluated the relationship between early child's socioemotional factors and OHRQoL, as well as its association with orofacial pain (OFP) and early childhood caries (ECC) in the Asian GUSTO birth cohort. Mother-child dyads were postnatally assessed at 3 time points. The Child Behavior Checklist (CBCL) was used to assess the child's socioemotional and behavioral problems at age 4-4.5 years together with other validated questionnaires to evaluate maternal anxiety and depression. ECC detection was performed at age 5, and OHRQoL (primary) and OFP (secondary) outcomes were assessed at age 6 from a total of 555 mother-child dyads. After a univariate regression analysis was performed to identify potential predictors and confounders, a multivariate regression model was run with predisposing factors (CBCL internalization and externalization problems, OFP, ECC) and adjusted for confounders (maternal psychosocial states, maternal education) to determine associations with OHRQoL. Results showed an association between CBCL internalization scores and poorer OHRQoL (RR = 1.03, p = 0.033, 95% CI 1.01 to 1.05), although the limited risk ratio may not have a practical applicability in psychosocially healthy children, alike the majority of those evaluated in this cohort. The average OHRQoL overall score among children with OFP was 2.39 times more than those without OFP (OR = 2.39, p < 0.001, 95% CI 2.00 to 2.86). Thus, in early childhood, OFP, and to lesser extent internalizing behaviors, may negatively impact OHRQoL. This study therefore highlights the complex relationship between OHRQoL and its predisposing socioemotional and somatic pain factors, and demands further investigations in clinically relevant populations., Competing Interests: Competing interests statement: I have read the journal’s policy and the authors of this manuscript have the following competing interests: L.P.-C. Shek has consultant arrangements with Mead Johnson and Nestle; has received payment for lectures from Danone and Nestle; and has received research funding from Danone. R. Choe, Y.F. Sim, C.H.L. Hong, S. Mohideen, R. Nadarajan, F. Yap, C.Y.S. Hsu, B.F.P. Broekman, and J.N. Ferreira declare no potential conflicts of interest.This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background and Aims: The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely applied staging system for hepatocellular carcinoma (HCC) and is recommended for treatment allocation and prognostic prediction. The BCLC guidelines were modified in 2018 to indicate that Child-Pugh A without any ascites is essential for all stages except stage D. This study sought to provide a description of patients with HCC treated at a high-volume liver surgery center in Taiwan where referral is not needed and all treatment modalities are available and reimbursed by the National Health Insurance program. As such, certain variables that could modulate treatment decisions in clinical practice, including financial constraints, the availability of treatment procedures, and the expertise of the hospital, could be excluded. The study further sought to evaluate the adherence to the modified BCLC guidelines., Methods: This was a retrospective study with prospectively collected data. 1801 consecutive patients with de novo HCC were enrolled through our institution from 2011-2017., Results: There were 302 patients with stage 0, 783 with stage A, 242 with stage B, 358 with stage C, and 116 with stage D HCC. Treatment adhering to the modified BCLC guidelines recommendations was provided to 259 (85.8%) stage 0 patients, 606 (77.4%) stage A patients, 120 (49.6%) stage B patients, 93 (26.0%) stage C patients, and 83 (71.6%) stage D patients., Conclusions: We reported treatment adhering to the modified BCLC guidelines at a high-volume liver surgery center in Taiwan. We found that non-adherence to the modified BCLC staging system was common in treating stage B and C patients., Competing Interests: he authors have declared that no competing interests exist.

In high-density aquaculture, fish health can suffer because of excessive feeding, which causes fatty liver disease. Siberian ginseng (Acanthopanax senticosus) has been used as a feed additive to promote animal growth, immunity, and lipid metabolism. In this study, we explored the effects of A. senticosus on the physiology of hybrid yellow catfish (Tachysurus fulvidraco ♀ × Pseudobagrus vachellii ♂). A control group and five groups fed diets containing A. senticosus (0.5, 1, 2, 4, and 8 g A. senticosus/kg feed) were established and maintained for 8 weeks. Dietary supplementation with A. senticosus at 4 g/kg promoted growth of the hybrid yellow catfish. Serum total cholesterol (TC) and triacylglycerol (TG) levels at 2 g/kg A. senticosus (TC: 1.31 mmol/L; TG: 1.08 mmol/L) were significantly lower than in the control group (TC: 1.51 mmol/L; TG: 1.41 mmol/L), and 4 g/kg A. senticosus (17.20 μmol/g tissue) reduced the liver TG level compared with the control group (21.36 μmol/g tissue) (P <0.05). Comparative transcriptomic analysis of liver tissue between the control group and the group showing optimum growth (4 g/kg A. senticosus) revealed 820 differentially expressed genes and 44 significantly enriched pathways, especially lipid metabolism pathways such as unsaturated fatty acid and fatty acid metabolism. The transcript levels of five lipid metabolism-related genes were determined by quantitative real-time PCR. The results showed that 2-4 g/kg A. senticosus supplementation reduced the FADS2, ELOVL2, CYP24a, and PLPP3 transcript levels and 4 g/kg A. senticosus increased the DIO2 transcript level (P <0.05), leading to altered synthesis of TG and thyroxine and reduced fat deposition in the liver. Our results show that dietary A. senticosus affects the regulation of fat metabolism and promotes the growth of hybrid yellow catfish. A. senticosus is a healthy feed additive, and the appropriate dietary supplementation rate is 2-4 g/kg., Competing Interests: The authors have declared that no competing interests exist.

Kidneys are one of the targets for SARS-CoV-2, it is reported that up to 36% of patients with SARS-CoV-2 infection would develop into acute kidney injury (AKI). AKI is associated with high mortality in the clinical setting and contributes to the transition of AKI to chronic kidney disease (CKD). Up to date, the underlying mechanisms are obscure and there is no effective and specific treatment for COVID-19-induced AKI. In the present study, we investigated the mechanisms and interactions between Quercetin and SARS-CoV-2 targets proteins by using network pharmacology and molecular docking. The renal protective effects of Quercetin on COVID-19-induced AKI may be associated with the blockade of the activation of inflammatory, cell apoptosis-related signaling pathways. Quercetin may also serve as SARS-CoV-2 inhibitor by binding with the active sites of SARS-CoV-2 main protease 3CL and ACE2, therefore suppressing the functions of the proteins to cut the viral life cycle. In conclusion, Quercetin may be a novel therapeutic agent for COVID-19-induced AKI. Inhibition of inflammatory, cell apoptosis-related signaling pathways may be the critical mechanisms by which Quercetin protects kidney from SARS-CoV-2 injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background/aims: A recent study from the United States reported that nearly 12% of hepatocellular carcinomas (HCCs) occurred in patients without cirrhosis. Non-alcoholic fatty liver disease (NAFLD) was the most common liver disease in these patients. We aim to evaluate the characteristics, etiologies, and outcomes of cases of non-cirrhotic HCC in East Asia, where there is a higher prevalence of hepatitis B virus (HBV)-associated non-cirrhotic HCC., Methods: This retrospective study consecutively enrolled de novo HCC patients managed at our institution from 2011 to 2017. The presence of cirrhosis was assessed by histology; if histology was not available, it was assessed by image study., Results: 2055 patients with HCC were enrolled in this study. Among them, 529 (25.7%) were non-cirrhotic. The non-cirrhotic patients were younger (60.9 vs. 62.5 years, p = 0.006), included a greater proportion of males (78.1% vs. 71.3%, p = 0.002), and had a lower body mass index (24.3 vs. 25.3 kg/m2, p<0.001) than the cirrhotic patients. Among the non-cirrhotic patients, HBV was the most common liver disease (49.0%). The patients with non-cirrhotic HCC had larger tumors (5.9 vs. 4.7 cm, p<0.001), underwent liver resection at a higher rate (66.0% vs. 17.4%, p<0.001), and had better overall survival than the cirrhotic HCC patients (median 5.67 vs. 2.83 years, p<0.001)., Conclusions: Nearly 26% of the HCCs occurred in patients without cirrhosis. HBV was the most common liver disease in these patients, and the survival was better in the non-cirrhotic patients than the cirrhotic patients., Competing Interests: The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, and knowledge or beliefs) in the subject matter or materials discussed in this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

miR-92a miRNAs are immune molecules that regulate apoptosis (programmed cell death) during the immune response. Apoptosis helps to maintain the dynamic balance in tissues of fish under hypoxia stress. The aim of this study was to explore the role and potential mechanisms of miR-92a in the liver of tilapia under hypoxia stress. We first confirmed that CaSR (encoding a calcium-sensing receptor) is a target gene of miR-92a in genetically improved farmed tilapia (GIFT) using luciferase reporter gene assays. In GIFT under hypoxia stress, miR-92a was up-regulated and CaSR was down-regulated in a time-dependent manner. Knocked-down CaSR expression led to inhibited expression of p53, TP53INP1, and caspase-3/8, reduced the proportion of apoptotic hepatocytes, and decreased the activity of calcium ions induced by hypoxia in hepatocytes. GIFT injected in the tail vein with an miR-92a agomir showed up-regulation of miR-92a and down-regulation of CaSR, p53, TP53INP1, and caspase-3/8 genes in the liver, resulting in lower serum aspartate aminotransferase and alanine aminotransferase activities under hypoxia stress. These findings suggest that stimulation of miR-92a interferes with hypoxia-induced apoptosis in hepatocytes of GIFT by targeting CaSR, thereby alleviating liver damage. These results provide new insights into the adaptation mechanisms of GIFT to hypoxia stress., Competing Interests: The authors have declared that no competing interests exist

Purpose: To evaluate ways to improve the generalizability of a deep learning algorithm for identifying glaucomatous optic neuropathy (GON) using a limited number of fundus photographs, as well as the key features being used for classification., Methods: A total of 944 fundus images from Taipei Veterans General Hospital (TVGH) were retrospectively collected. Clinical and demographic characteristics, including structural and functional measurements of the images with GON, were recorded. Transfer learning based on VGGNet was used to construct a convolutional neural network (CNN) to identify GON. To avoid missing cases with advanced GON, an ensemble model was adopted in which a support vector machine classifier would make final classification based on cup-to-disc ratio if the CNN classifier had low-confidence score. The CNN classifier was first established using TVGH dataset, and then fine-tuned by combining the training images of TVGH and Drishti-GS datasets. Class activation map (CAM) was used to identify key features used for CNN classification. Performance of each classifier was determined through area under receiver operating characteristic curve (AUC) and compared with the ensemble model by diagnostic accuracy., Results: In 187 TVGH test images, the accuracy, sensitivity, and specificity of the CNN classifier were 95.0%, 95.7%, and 94.2%, respectively, and the AUC was 0.992 compared to the 92.8% accuracy rate of the ensemble model. For the Drishti-GS test images, the accuracy of the CNN, the fine-tuned CNN and ensemble model was 33.3%, 80.3%, and 80.3%, respectively. The CNN classifier did not misclassify images with moderate to severe diseases. Class-discriminative regions revealed by CAM co-localized with known characteristics of GON., Conclusions: The ensemble model or a fine-tuned CNN classifier may be potential designs to build a generalizable deep learning model for glaucoma detection when large image databases are not available., Competing Interests: The authors have declared that no competing interests exist.

Background: Our preliminary data showed a slight decrease of estimated glomerular filtration rate (eGFR) after direct-acting antivirals (DAAs) treatment in chronic hepatitis C (CHC). However, long-term outcome of renal evolution after DAAs has not been well documented., Aim: To assess the renal function under DAAs treatment in CHC patients of an Asian population at 6 months and 1 year after complete treatment., Methods: A cohort of 1536 CHC patients who received therapies with DAAs were analyzed. Serial eGFR levels at 24 weeks after treatment (SVR24) and 48 weeks after treatment (SVR48) were evaluated. We compared eGFR at baseline, SVR12, SVR24 and SVR48, and defined renal function deterioration as decrease of eGFR >25% from baseline to SVR24 and SVR48., Results: Overall, there was decline of eGFR from SVR12 to SVR48 in all patients (84.30 ± 27.00 -> 73.20 ± 28.67 mL/min/1.73m2, p<0.001). This trend of decline was similar in all groups. Multivariate analysis for deterioration in renal function from baseline to SVR24 showed liver transplantation, hypertension and baseline eGFR < 60 mL/min/1.73m2 were independent risk factors. Multivariate analysis for persistent deterioration in renal function from baseline to SVR48 showed liver transplantation, baseline eGFR < 60 mL/min/1.73m2 and DCV/ASV use were independent predictive factors., Conclusions: There is a trend of decline in eGFR at 1-year after DAAs treatment regardless of baseline renal function or DAAs. Liver transplantation and baseline eGFR < 60 mL/min/1.73m2 were independent predictive factors of persistent deterioration in renal function from baseline to SVR48. Close monitoring renal function in these patients was suggested., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: The Barcelona Clinic Liver Cancer (BCLC) stage C (BCLC C) of hepatocellular carcinoma (HCC) includes a heterogeneous population for which sorafeninb is one of the recommended therapies. We aim to evaluate the real world clinical treatment and survival of BCLC stage C patients in an Asian cohort., Methods: This is a retrospective cohort study that enrolled 427 consecutive BCLC stage C patients diagnosed between 2011 and 2017 by using the HCC registry data for our hospital. All patients were managed via a multidisciplinary team (MDT) approach., Results: Hepatitis B surface antigen positive was noted in 50.6% of the patients. The patients were classified as performance status (PS)1 alone (n = 83; 19.4%), PS2 alone (n = 23; 5.4%), or macrovascular invasion (MVI) or extrahepatic spread (EHS) (n = 321; 75.2%). The median overall survival (OS) was 11.0 months in the whole cohort. The most frequent treatments were transcatheter arterial embolization (TAE) in the PS1 (45.8%) and PS2 patients (52.2%) and sorafenib (32.4%) in the MVI or EHS patients. The independent prognostic factors were the PS, Child-Pugh class, MVI or EHS, alpha fetoprotein levels, and treatment type., Conclusions: We reported the real world management in BCLC stage C patients in an Asian cohort through the use of personalized management via a MDT approach., Competing Interests: The authors have declared that no competing interests exist

Prednisolone is involved in glucose homeostasis and has been used for treatment for aristolochic acid (AA) nephropathy (AAN), but its effect on glycolysis in kidney has not yet been clarified. This study aims to investigate the effect in terms of altered proteins after prednisolone treatment in a mice model of AAN using a proteomics technique. The six-week C3H/He female mice were administrated AA (0.5 mg/kg/day) for 56 days. AA+P group mice were then given prednisolone (2 mg/kg/day) via oral gavage for the next 14 days, and AA group mice were fed water instead. The tubulointerstitial damage was improved after prednisolone treatment comparing to that of AA group. Kidney homogenates were harvested to perform the proteomics analysis with fluorogenic derivatization-liquid chromatography-tandem mass spectrometry method (FD-LC-MS/MS). On the other hand, urinary methylglyoxal and D-lactate levels were determined by high performance liquid chromatography with fluorescence detection. There were 47 altered peaks and 39 corresponding proteins on day 14 among the groups, and the glycolysis-related proteins, especially glyoxalase 1 (GLO1), fructose-bisphosphate aldolase B (aldolase B), and triosephosphate isomerase (TPI), decreased in the AA+P group. Meanwhile, prednisolone decreased the urinary amount of methylglyoxal (AA+P: 2.004 ± 0.301 μg vs. AA: 2.741 ± 0.630 μg, p < 0.05), which was accompanied with decrease in urinary amount of D-lactate (AA+P: 54.07 ± 5.45 μmol vs. AA: 86.09 ± 8.44 μmol, p < 0.05). Prednisolone thus alleviated inflammation and interstitial renal fibrosis. The renal protective mechanism might be associated with down-regulation of GLO1 via reducing the contents of methylglyoxal derived from glycolysis. With the aid of proteomics analysis and the determination of methylglyoxal and its metabolite-D-lactate, we have demonstrated for the first time the biochemical efficacy of prednisolone, and urinary methylglyoxal and its metabolite-D-lactate might be potential biomarkers for AAN., Competing Interests: The authors have declared that no competing interests exist.

High-density aquaculture and nutritional imbalances may promote fatty liver in genetically improved farmed tilapia (GIFT, Oreochromis niloticus), thus reducing the gains achieved by breeding. In this study, apple peel powder (APP) was used as a feed additive for GIFT. A control group (fed on a diet without APP) and five groups fed on diets supplemented with APP (at 0.05%, 0.1%, 0.2%, 0.4%, or 0.8% of the diet, by weight) were established to investigate the effects of APP on GIFT growth performance and physiological parameters, and on gene expression as determined by transcriptomic analysis. Dietary supplementation with APP at 0.2% promoted GIFT growth, reduced total cholesterol and triacylglycerol levels in the serum and liver, and decreased alanine aminotransferase and aspartate aminotransferase activities in the serum. Gene expression profiles in the liver were compared among the control, 0.2% APP, and 0.8% APP groups, and differentially expressed genes among these groups were identified. Annotation analyses using tools at the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases showed that the differentially expressed genes were mainly involved in the regulation of immunity and fat metabolism. The results showed that excessive supplementation with APP in the diet significantly inhibited the expression of insulin-like growth factor 2 and liver-type fatty acid-binding protein, and stimulated the expression of fatty acid desaturase 2, heat shock protein 90 beta family member 1, and nuclear factor kappa B. This resulted in disordered lipid metabolism and increased pro-inflammatory reactions, which in turn caused liver damage. Therefore, APP has good potential as an environmentally friendly feed additive for GIFT at levels of 0.1%-0.2% in the diet, but excessive amounts can have adverse effects., Competing Interests: The authors declare that they have no competing interests including employment, consultancy, patents, products in development, or marketed products. The commercial affiliation of the authors (HJJ; JWB) to Beijing Yujing Biotechnology Co., Ltd. does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Developing countries still struggle with late detection and mortality from pertussis. A review of clinical case definitions is necessary for early disease detection. This paper aimed to study possible clinical characteristics for earlier pertussis detection in a sporadic setting., Methods: We conducted a retrospective review of medical and laboratory records in a general paediatric ward of a district hospital in a developing country. Inclusion criteria were all children hospitalised with nasopharyngeal swab taken for Bordetella pertussis. We compared sensitivity and specificity of World Health Organization diagnostic criteria with other clinical characteristics. Polymerase chain reaction Bordetella pertussis was the gold standard used., Results: Out of 207 eligible admissions, the study retrieved 128 complete records. Approximately half of the children were less than 3 months old. The World Health Organization diagnostic criteria had a low sensitivity (15%), but high specificity (92%). In comparison, combinations that included paroxysmal cough, ill contact and facial congestion had higher sensitivity. Increasing cough duration improved specificity while compromising sensitivity., Conclusion: Several clinical characteristics such as paroxysmal cough, facial congestion and a history of ill contact have potential for early clinical detection. Conventional emphasis on cough duration may hamper early detection., Competing Interests: The authors have declared that no competing interests exist.

Background: Frozen-thawed embryo transfer (FET) has become a routine procedure in assisted reproductive technology (ART). In FET, although blastocysts cultured from thawed cleavage-stage embryos are associated with better perinatal outcomes. it may increase cycle cancellation due to no suitable embryo to transfer. The overall clinical outcomes following transfer of thawed cleavage-stage FET and blastocysts cultured from thawed cleavage-stage embryos in young and advanced age patients remains unclear. Therefore, we aimed to identify the optimal FET strategy in young and advanced age women who undergo FET., Methods: This retrospective study included 16,387 thaw cycles. We retrospectively analyzed data of couples who had completed the first FET cycle. Two FET strategies were studied: transfer of thawed cleavage-stage embryos (strategy A) or blastocysts cultured from thawed cleavage-stage embryos (strategy B). The clinical and neonatal outcomes of two FET strategies were compared in young (<35 years) and advanced (≥35 years) age women., Results: In young women, the clinical outcomes per transfer cycle were better in strategy B than strategy A. While the clinical pregnancy (59.29%, 52.60%) and live birth rates (49.37%, 43.88%) per thaw cycle were significantly higher in strategy A than in B. In women of advanced age, the clinical outcomes per transfer cycle were still better in strategy B than in A, and the clinical pregnancy (36.44%, 39.66%) and live birth rates (25.70%, 30.00%) per thaw cycle were significantly higher in strategy B than in A., Conclusions: FET of blastocysts cultured from cleavage-stage embryos showed higher efficiency for per transfer cycle whether in younger or advanced age women. Whereas, when cycle cancellations due to no suitable embryo to transfer were considered, cleavage-stage FET was found to be more suitable for younger women, while FET of blastocysts cultured from cleavage-stage embryos was better suited for women of advanced age., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies., Methods: Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients., Results: The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients., Conclusions: This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients., Competing Interests: LW has received fees for serving as a speaker, consultant, and advisory board member for AbbVie, Bristol-Myers Squibb (BMS), Gilead, Johnson & Johnson (J&J), and GlaxoSmithKline (GSK) within the last 3 years. Additional funding for the study was provided to LW by the China National Science and Technology Major Project for Infectious Diseases Control during the 12th Five-Year Plan Period. HW has received grant/research support from Abbott, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, and Siemens, and has received consulting fees and has been an advisory board and speakers’ bureau member for Abbott, AbbVie, Biolex, BMS, Boehringer Ingelheim, Eiger Pharmaceuticals, Falk Foundation, Gilead, IST, J&J/Janssen-Cilag/Janssen TE, Medgenics, Merck/Schering-Plough, Novartis, Novira, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV. Y-FL has served as an advisory board member for Roche. HL-YC has received fees for serving as a speaker and advisory board member for Roche, BMS, Gilead, Novartis, and MSD, and as a speaker for Echosens and GSK, and has received an unrestricted grant for HBV research from Roche. TP has received grant/research support from BMS, Roche, MSD, Novartis, Fibrogen, and Bayer, and has been a member of advisory boards or speakers’ bureaux for BMS, Roche, MSD, Novartis, and GSK. JJ has received fees for serving as a speaker, consultant, and advisory board member for BMS, MSD, Novartis, and Roche within the last 3 years. MRB has been a member of speakers’ bureaux for BMS, Gilead, Roche, and Janssen, and has been a member of advisory boards for AbbVie, Roche, Gilead, and MSD. MD has been a member of speakers’ bureaux for Roche, MSD, AbbVie, BMS, Gilead, and Janssen. SG has received fees as a member of advisory boards and speakers’ bureaux for Roche, BMS, Gilead, Janssen, and MSD. YZ has been a Genentech/Roche employee and has owned Roche stock and options. HH and CW are employees of Roche and declare stock ownership. BS has received fees for serving as a consultant/contract statistician for Roche, through BStats Solutions Ltd, from March 2013 to the present. AJT has received grant funding from AbbVie, Gilead Sciences, BMS, and Merck, has received consultancy fees from AbbVie, Gilead Sciences, BMS, Roche Diagnostics, Merck, and Spring Bank Pharmaceuticals, and has provided sponsored lectures (national or international) for AbbVie, Roche Diagnostics, Gilead Sciences, BMS, and Merck. The China National Science and Technology Major Project for Infectious Diseases Control during the 12th Five-Year Plan Period provided support in the form of salaries to HH, YZ, CW, and BS. This does not alter our adherence to PLOS ONE policies on sharing data and materials. This study was funded in part by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Peginterferon alfa-2a (PEGASYS®) is marketed worldwide by F Hoffmann-la Roche Ltd, Basel, Switzerland.

In this study, the authors first obtained the mitochondrial genome of Somanniathelphusa boyangensis. The results showed that the mitochondrial genome is 17,032bp in length, included 13 protein-coding genes, 2 rRNAs genes, 22 tRNAs genes and 1 putative control region, and it has the characteristics of the metazoan mitochondrial genome A+T bias. All tRNA genes display the typical clover-leaf secondary structure except tRNASer(AGN), which has lost the dihydroxyuridine arm. The GenBank database contains the mitochondrial genomes of representatives of approximately 22 families of Brachyura, comprising 56 species, including 4 species of freshwater crab. The authors established the phylogenetic relationships using the maximum likelihood and Bayesian inference methods. The phylogenetic relationship indicated that the molecular taxonomy of S. boyangensis is consistent with current morphological classification, and Parathelphusidae and Potamidae are derived within the freshwater clade or as part of it. In addition, the authors used the COX1 sequence of Somanniathelphusa in GenBank and the COX1 sequence of S. boyangensis to estimated the divergence time of this genus. The result displayed that the divergence time of Somanniathelphusa qiongshanensis is consistent with the separation of Hainan Island from mainland China in the Beibu Gulf, and the divergence time for Somanniathelphusa taiwanensis and Somanniathelphusa amoyensis is consistent with the separation of Taiwan Province from Mainland China at Fujian Province. These data indicate that geologic events influenced speciation of the genus Somanniathelphusa.

Background: The use of assisted reproductive technology (ART) has been reported to increase the incidence of monozygotic twinning (MZT) compared with the incidence following natural conception. It has been hypothesized that splitting of the inner cell mass (ICM) through a small zona hole may result in MZT. In this study, using a cohort of patients undergoing preimplantation genetic diagnosis/screening (PGD/PGS), we compared the clinical and neonatal outcomes of human 8-shaped blastocysts hatching with ICM incarceration with partially or fully hatched blastocysts, and attempted to verify whether this phenomenon increases the incidence of MZT pregnancy or negatively impact newborns., Methods: This retrospective study included 2059 patients undergoing PGD/PGS between March 1, 2013, and December 31, 2015. Clinical and neonatal outcomes were only collected from patients who received a single blastocyst transfer after PGD/PGS (n = 992). A 25- to 30-μm hole was made in the zona of day 3 embryos by laser. The blastocysts were biopsied and vitrified on day 6. The biopsied trophectoderm (TE) cells were analyzed using different genetic methods. One tested blastocyst was thawed and transferred to each patient in the subsequent frozen embryo transfer cycle. All the biopsied blastocysts were divided into three types: 8-shaped with ICM incarceration (type I), partially hatched without ICM incarceration (type II), and fully hatched (type III). ICM/TE grading, clinical and neonatal outcomes were compared between the groups., Results: The percentage of grade A ICMs in type I blastocysts (22.2%) was comparable to that in type III blastocysts (20.1%) but higher than that in type II blastocysts (4.5%). The percentage of grade A TEs in type I blastocysts (4.2%) was comparable to that in type II (3.6%) but lower than that in type III (13.5%). There were no significant differences in clinical pregnancy, MZT pregnancy, miscarriage, live birth, MZT births, and neonatal outcomes between the groups., Conclusions: Compared to partially and fully hatched blastocysts, 8-shaped blastocysts with ICM incarceration showed relatively higher ICM and lower TE grades. ICM incarceration in 8-shaped blastocysts does not increase the incidence of MZT and has no negative effects on newborns in PGD/PGS patients.

Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury which could be caused by viral, autoimmune, drugs, and so on. Unfortunately, there was no effective therapy available for liver fibrosis in clinic. In this study, we identified the anti-fibrotic effects of 1,7-dihydroxy-3,4,8-trimethoxyxanthone (ZYC-1) on the dimethylnitrosamine (DMN)-induced rat model. ZYC-1 was isolated from Swertia punicea Hemsl and was administrated to DMN-induced rat model. ZYC decreased the hyaluronic acid (HA), type IV collagen (CIV) and hydroxyproline (Hyp) levels and inhibited the expression of α smooth muscle actin (α-SMA) and transforming growth factor beta 1 (TGF-1β). The anti-fibrotic effect of ZYC-1 was also confirmed by Sirius Red staining. Finally, we identified 42 differentially expressed proteins by using proteomics analysis after ZYC-1 treatment, of which 17 were up-regulated and 25 were down-regulated. These Most of the 42 proteins are involved in the oxidative stress pathway, the mitochondrial-mediated apoptotic pathway and the amino acid metabolism pathway. Our study presented the first elucidated mechanisms of xanthone on liver fibrosis in vivo. This study pointed out that ZYC-1 may be used as a lead compound for hepatofibrosis treatment.

The increased atmospheric temperatures resulting from the increased concentration of atmospheric carbon dioxide (CO2) have had a profound influence on global rice production. China serves as an important area for producing and consuming rice. Therefore, exploring the effects of the simultaneously rising levels of atmospheric CO2 and temperatures on rice growth and quality in the future is very important. The present study was designed to measure the most important aspects of variation for rice-related physiological, ecological and quality indices in different growing periods under a simultaneous increase of CO2 and temperature, through simulation experiments in climate-controlled growth chambers, with southern rice as the study object. The results indicated that the ecological indices, rice phenology, and leaf area would decrease under a simultaneous increase of CO2 and temperature. For the physiological indices, Malondialdehyde (MDA) levels increased significantly in the seedling period. However, it showed the trend of increase and subsequent decrease in the heading and filling periods. In addition, the decomposition of soluble protein (SP) and soluble sugar (SS) accelerated in filling period. The rice quality index of the Head Rice Rate showed the decreasing trend and subsequent increase, but the Chalky Rice Rate and Protein Content indices gradually decreased while the Gel Consistency gradually increased.

The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. The present study aims to evaluate the role of age on treatments and outcome of HCC patients. 1530 patients firstly diagnosed with HCC were retrospectively included and classified as older (≥65 years, n = 318, 21%) and younger patients (<65 years, n = 1212, 79%). The two groups were compared with clinical characteristics, tumor burden, Barcelona Clinics Liver Cancer (BCLC) stage, treatments and long-term prognosis. Elderly patients were more HCV infected, had more diabetes, poorer performance status, and were less aggressively treated. The proportion of HCC within BCLC stage 0-A, B or C was similar between the two groups, but elderly patients were more presented with BCLC stage D. The overall survival of older patients was poorer compared to younger patients before and after propensity score matching. However, elderly patients were less often effectively treated with surgery and loco-regional therapies across different BCLC stages. After stratified by BCLC stages or treatments, older patients showed comparable long-term outcome to younger patients. Performance status, BCLC stages and effective treatments, rather than age, was independent factors determining prognosis in the whole cohort and only elderly patients by multivariate analysis. In conclusion, older could have comparable survival to younger patients within the same tumor stage or after similar treatments. Thus, equally active treatments should be encouraged to elderly patients.

Background: Stroke is a devastating and potentially preventable complication of cardiac surgery. Tranexamic acid (TXA) is a commonly antifibrinolytic agent in cardiac surgeries with cardiopulmonary bypass (CPB), however, there is concern that it might increase incidence of stroke after cardiac surgery. In this retrospective study, we investigated whether TXA usage could increase postoperative stroke in cardiac surgery., Methods: A retrospective study was conducted from January 1, 2010, to December 31, 2015, in 2,016 patients undergoing cardiac surgery, 664 patients received intravenous TXA infusion and 1,352 patients did not receive any antifibrinolytic agent. Univariate and propensity-weighted multivariate regression analysis were applied for data analysis., Results: Intraoperative TXA administration was associated with postoperative stroke (1.7% vs. 0.5%; adjusted OR, 4.11; 95% CI, 1.33 to 12.71; p = 0.014) and coma (adjusted OR, 2.77; 95% CI, 1.06 to 7.26; p = 0.038) in cardiac surgery. As subtype analysis was performed, TXA administration was still associated with postoperative stroke (1.7% vs. 0.3%; adjusted OR, 5.78; 95% CI, 1.34 to 27.89; p = 0.018) in patients undergoing valve surgery or multi-valve surgery only, but was not associated with postoperative stroke (1.7% vs. 1.3%; adjusted OR, 5.21; 95% CI, 0.27 to 101.17; p = 0.276) in patients undergoing CABG surgery only. However, TXA administration was not associated with postoperative mortality (adjusted OR, 1.31; 95% CI, 0.56 to 3.71; p = 0.451), seizure (adjusted OR, 1.13; 95% CI, 0.42 to 3.04; p = 0.816), continuous renal replacement therapy (adjusted OR, 1.36; 95% CI, 0.56 to 3.28; p = 0.495) and resternotomy for postoperative bleeding (adjusted OR, 1.55; 95% CI, 0.55 to 4.30; p = 0.405). No difference was found in postoperative ventilation time (adjusted B, -1.45; SE, 2.33; p = 0.535), length of intensive care unit stay (adjusted B, -0.12; SE, 0.25; p = 0.633) and length of hospital stay (adjusted B, 0.48; SE, 0.58; p = 0.408)., Conclusions: Based on the 5-year experience of TXA administration in cardiac surgery with CPB, we found that postoperative stroke was associated with intraoperative TXA administration in patients undergoing cardiac surgery, especially in those undergoing valve surgeries only. This study may suggest that TXA should be administrated according to clear indications after evaluating the bleeding risk in patients undergoing cardiac surgery, especially in those with high stroke risk.

Arrhythmogenesis in acute myocardial infarction (MI) is associated with depolarization of resting membraine potential (RMP) and decrease of inward rectifier potassium current (IK1) in cardiomyocytes. However, clinical anti-arrhythmic agents that primarily act on RMP by enhancing the IK1 channel are not currently available. We hypothesized that zacopride, a selective and moderate agonist of the IK1/Kir2.1 channels, prevents and cures acute ischemic arrhythmias. To test this viewpoint, adult Sprague-Dawley (SD) rats were subjected to MI by ligating the left main coronary artery. The antiarrhythmic effects of zacopride (i.v. infusion) were observed in the settings of pre-treatment (zacopride given 3 min prior to coronary occlusion), post-treatment (zacopride given 3 min after coronary occlusion) and therapeutic treatment (zacopride given 30 s after the onset of the first sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) post MI). In all the three treatment modes, zacopride (15 μg/kg) inhibited MI-induced ventricular tachyarrhythmias, as shown by significant decreases in the premature ventricular contraction (PVC) and the duration and incidence of VT or VF. In Langendorff perfused rat hearts, the antiarrhythmic effect of 1 μmol/L zacopride were reversed by 1 μmol/L BaCl2, a blocker of IK1 channel. Patch clamp results in freshly isolated rat ventricular myocytes indicated that zacopride activated the IK1 channel and thereby reversed hypoxia-induced RMP depolarization and action potential duration (APD) prolongation. In addition, zacopride (1 μmol/L) suppressed hypoxia- or isoproterenol- induced delayed afterdepolarizations (DADs). In Kir2.x transfected Chinese hamster ovary (CHO) cells, zacopride activated the Kir2.1 homomeric channel but not the Kir2.2 or Kir2.3 channels. These results support our hypothesis that moderately enhancing IK1/Kir2.1 currents as by zacopride rescues ischemia- and hypoxia- induced RMP depolarization, and thereby prevents and cures acute ischemic arrhythmias. This study brings a new viewpoint to antiarrhythmic theories and provides a promising target for the treatment of acute ischemic arrhythmias.

Saccharomyces cerevisiae responds to changes in extracellular inorganic phosphate (Pi) availability by regulating the activity of the phosphate-responsive (PHO) signaling pathway, enabling cells to maintain intracellular levels of the essential nutrient Pi. Pi-limitation induces upregulation of inositol heptakisphosphate (IP7) synthesized by the inositol hexakisphosphate kinase Vip1, triggering inhibition of the Pho80/Pho85 cyclin-cyclin dependent kinase (CDK) complex by the CDK inhibitor Pho81, which upregulates the PHO regulon through the CDK target and transcription factor Pho4. To identify genes that are involved in signaling upstream of the Pho80/Pho85/Pho81 complex and how they interact with each other to regulate the PHO pathway, we performed genome-wide screens with the synthetic genetic array method. We identified more than 300 mutants with defects in signaling upstream of the Pho80/Pho85/Pho81 complex, including AAH1, which encodes an adenine deaminase that negatively regulates the PHO pathway in a Vip1-dependent manner. Furthermore, we showed that even in the absence of VIP1, the PHO pathway can be activated under prolonged periods of Pi starvation, suggesting complexity in the mechanisms by which the PHO pathway is regulated.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Human WW domain-containing oxidoreductase (WWOX) gene has been identified as a tumor suppressor gene in multiple cancers. We hypothesize that genetic variations in WWOX are associated with HCC risk., Methodology/principal Findings: Five single-nucleotide polymorphisms (SNPs) of the WWOX gene were evaluated from 708 normal controls and 354 patients with HCC. We identified a significant association between a WWOX single nucleotide polymorphism (SNP), rs73569323, and decreased risk of HCC. After adjustment for potential confounders, patients with at least one T allele at rs11545028 of WWOX may have a significantly smaller tumor size, reduced levels of α-fetoprotein and alanine aminotransferase (ALT). Moreover, the A allele at SNP rs12918952 in WWOX conferred higher risk of vascular invasion. Additional in silico analysis also suggests that WWOX rs12918952 polymorphism tends to affect WWOX expression, which in turn contributes to tumor vascular invasion., Conclusions: In conclusion, genetic variations in WWOX may be a significant predictor of early HCC occurrence and a reliable biomarker for disease progression.

Background: We identified rs17071138 T/C, rs3744941 C/T, and rs8089104 T/C gene polymorphisms of SERPINB5 (mammary serine protease inhibitor) that are specific to patients with oral cancer susceptibility and their clinicopathological status., Methodology/principal Findings: In total, 1342 participants, including 601 healthy controls and 741 patients with oral cancer, were recruited for this study. Allelic discrimination of rs17071138 T/C, rs3744941 C/T, and rs8089104 T/C of the SERPINB5 gene was assessed by a real-time PCR with a TaqMan assay. We found that individuals carrying the polymorphic rs17071138 and rs8089104 are more susceptible to oral cancer (OR, 1.57; 95% CI, 1.07~2.31 and OR, 1.58; 95% CI, 1.04~2.39, respectively). Among oral cancer-related risk factor exposures, the individuals carrying the polymorphic rs17071138 had 4.26- (95% CI: 1.65~11.01; p = 0.002), 2.34- (95% CI: 1.19~4.61; p = 0.01), and 2.34-fold (95% CI: 1.38~3.96; p = 0.001) higher risks of developing oral cancer., Conclusions: Heterozygous TC of the SERPINB5 rs17071138 polymorphism may be a factor that increases susceptibility to oral cancer. Interactions of gene-to-gene and gene-to-oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development.

The Jiangxi Province of China has numerous native domestic chicken breeds, including some black skin breeds. The genetic diversity of Jiangxi native chickens is largely unknown, and specifically, the genetic contribution of the grey junglefowl to black skin chickens is not well understood. To address these questions, the complete D-loop region of the mitochondrial DNA (mtDNA) and beta-carotene dioxygenase 2(BCDO2)gene was sequenced in a total of 209 chickens representing seven Jiangxi native breeds. Thirty-one polymorphic sites were identified across the complete mtDNA D-loop region sequence. Twenty-three haplotypes were observed in the seven breeds, which belonged to four distinct mitochondrial clades (A, B, C and E). Clade A and B were dominant in the chickens with a frequency of approximately 67.9%. There were five SNPs that defined two haplotypes, W and Y in BCDO2. Four breeds had one haplotype and three breeds had two. We conclude that Jiangxi native chicken breeds have relatively low genetic diversity and likely share four common maternal lineages from two different maternal ancestors of junglefowl. Furthermore, some Jiangxi chicken populations may have been mixed with chickens with exotic lineage. Further research should be established to protect these domestic chicken resources.

Background: ADAMTS14 is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), which are proteolytic enzymes with a variety of further ancillary domain in the C-terminal region for substrate specificity and enzyme localization via extracellular matrix association. However, whether ADAMTS14 genetic variants play a role in hepatocellular carcinoma (HCC) susceptibility remains unknown., Methodology/principal Findings: Four non-synonymous single-nucleotide polymorphisms (nsSNPs) of the ADAMTS14 gene were examined from 680 controls and 340 patients with HCC. Among 141 HCC patients with smoking behaviour, we found significant associations of the rs12774070 (CC+AA vs CC) and rs61573157 (CT+TT vs CC) variants with a clinical stage of HCC (OR: 2.500 and 2.767; 95% CI: 1.148-5.446 and 1.096-6.483; P = 0.019 and 0.026, respectively) and tumour size (OR: 2.387 and 2.659; 95% CI: 1.098-5.188 and 1.055-6.704; P = 0.026 and 0.034, respectively), but not with lymph node metastasis or other clinical statuses. Moreover, an additional integrated in silico analysis proposed that rs12774070 and rs61573157 affected essential post-translation O-glycosylation site within the 3rd thrombospondin type 1 repeat and a novel proline-rich region embedded within the C-terminal extension, respectively., Conclusions: Taken together, our results suggest an involvement of ADAMTS14 SNP rs12774070 and rs61573157 in the liver tumorigenesis and implicate the ADAMTS14 gene polymorphism as a predict factor during the progression of HCC.

Background: DNA methylation is an epigenetic mechanism essential for gene regulation and vital for mammalian development. 5-hydroxymethylcytosine (5hmC) is the first oxidative product of the TET-mediated 5-methylcytosine (5mC) demethylation pathway. Aside from being a key intermediate in cytosine demethylation, 5hmC may have potential regulatory functions with emerging importance in mammalian biology., Methods: Here, we investigate the global 5hmC enrichment in five brain structures, including cerebellum, cerebral cortex, hippocampus, hypothalamus and thalamus, as well as liver tissues from female and male adult mice by using chemical capture-based technique coupled with next-generation sequencing. At the same time, we carried out total RNA sequencing (RNA-seq) to analyze the transcriptomes of brain regions and liver tissues., Results: Our results reveal preferential 5hmC enrichment in the gene bodies of expressed genes, and 5hmC levels of many protein-coding genes are positively correlated with RNA expression intensity. However, more than 75% of genes with low or no 5hmC enrichment are genes encode for mitochondrial proteins and ribosomal proteins despite being actively transcribed, implying different transcriptional regulation mechanisms of these housekeeping genes. Brain regions developed from the same embryonic structures have more similar 5hmC profiles. Also, the genic 5hmC enrichment pattern is highly tissue-specific, and 5hmC marks genes involving in tissue-specific biological processes. Sex chromosomes are mostly depleted of 5hmC, and the X inactive specific transcript (Xist) gene located on the X chromosome is the only gene to show sex-specific 5hmC enrichment., Conclusions: This is the first report of the whole-genome 5hmC methylome of five major brain structures and liver tissues in mice of both sexes. This study offers a comprehensive resource for future work of mammalian cytosine methylation dynamics. Our findings offer additional evidence that suggests 5hmC is an active epigenetic mark stably maintained after the global reprogramming event during early embryonic development., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: Liver computed tomography and dynamic magnetic resonance imaging play an important role in the early detection of hepatocellular carcinoma. However, the American Association for the Study of Liver Diseases (AASLD) recommend the use of applied imaging studies for HCC diagnosis only in cirrhotic patients. This study aimed to comprehensively compare liver CT and dynamic MRI for HCC diagnosis before surgical resection over years in clinical practice, and also to compare the diagnostic differences between liver CT and dynamic MRI in HCCs with varying degrees of fibrosis., Methods: 841 patients with liver tumor who had liver CT or dynamic MRI examinations followed by surgical resection were included in the study. We defined typical HCC imaging characteristics as early enhancement in the artery phase and early washout in the venous phase. The tumor size was recorded based on pathological examination after surgery. The pathologic fibrosis score was verified by the METAVIR scoring classification., Results: Among the 841 patients, 756 underwent liver CT and 204 underwent dynamic liver MRI before surgery. The etiologies of chronic liver disease included hepatitis B virus, hepatitis C virus, hepatitis B and C virus, and non-hepatitis B or C virus. The sensitivity and accuracy of liver CT or MRI for HCC diagnosis was approximately 80%~90%. Liver CT had a diagnostic accuracy for HCC similar to that of dynamic MRI, and liver fibrosis stage did not influence their diagnostic efficacies., Conclusions: The application of 4-phase dynamic CT and MRI exhibit similar diagnostic accuracy for hepatocellular carcinoma, in tumors of sizes 1 to 2 cm and >2 cm. Liver fibrosis status did not affect the diagnostic accuracy of liver CT or MRI for HCC. The AASLD and EASL restrictions of dynamic imaging studies for HCC diagnosis to cirrhotic patients alone are unnecessary., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The aim of this study was to determine the effects of diagnostic discordance with or without a thoracolumbar spine lateral view X-ray in patients with osteoporosis., Methods: We randomly enrolled 368 women over 65 years old (74.3 ± 6.0 years) from Tianliao Township in 2009 (response rate: 75.7%). A diagnosis of osteoporosis was confirmed using one of these criteria: (1) a history of non-traumatic fracture, (2) vertebral fractures based on a thoracolumbar spine lateral view X-ray, or (3) a bone mineral density T-score ≤ -2.5 for the total hip, the femoral neck, the lumbar spine, or all 3 sites. The prevalence of osteoporosis in three groups was compared based on Model I (criteria 1+2) vs. Model II (criteria 1+3) vs. Model III (criteria 1+2+3). The role of thoracolumbar X-ray reflected by the diagnostic discordance of osteoporosis between Models II and III was evaluated., Results: The overall prevalence of osteoporosis was 78.3% (Model III, age-standardized 78.1%). The diagnostic discordance was 17.4% in the 368 participants. A logistic regression model showed that age was negatively associated with diagnostic discordance (odds ratio [OR] = 0.93, 95% confidence interval [CI]: 0.88-0.98, p < 0.05), but body mass index was positively associated (OR = 1.07, 95% CI: 1.00-1.15, p < 0.05)., Conclusions: A thoracolumbar spine lateral view X-ray should be added for women ≥ 65 years old or with a body mass index ≥ 25 kg/m2 to minimize the diagnostic discordance in osteoporosis, especially in highly endemic regions., Competing Interests: The authors have declared that no competing interests exist.

Background: Oral cancer is a common malignancy that is shown to be causally associated with hereditary and acquired factors. ADAMTS14 is a member of the ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin motifs) metalloproteinase family that plays an important role in extracellular matrix (ECM) assembly and degradation. Elevation or deficiency of certain ADAMTS proteinases has been known to be implicated in a wide range of pathological processes including atherosclerosis, arthritis, and cancer. The present study aimed to explore the impact of ADAMTS14 gene polymorphisms, combined with environmental risks on the susceptibility to oral tumorigenesis., Methodology/principal Findings: Four single-nucleotide polymorphisms (SNPs) of the ADAMTS14 gene, including rs10823607, rs12774070, rs4747096, and rs61573157 were evaluated from 1200 normal controls and 850 patients with oral cancer. We failed to detect a significant association of four individual SNPs with oral cancer between case and control group. However, while considering behavioral exposure of environmental carcinogens, the presence of four ADAMTS14 SNPs, combined with betel nut chewing and/or smoking, profoundly leveraged the risk of oral cancer. Moreover, we observed a significant association of rs12774070, which is predicted to alter the expression and function of ADAMTS14 by in silico and bioinformatics analyses, with poor tumor cell differentiation (AOR: 0.59; 95% CI: 0.38-0.92; p = 0.02) in patients who chewed betel nuts., Conclusions: These results implicate the interaction between ADAMTS14 gene polymorphisms and environmental mutagens as a risk factor of oral tumorigenesis and suggest a correlation of rs12774070 with the degree of oral tumor cell differentiation.

Lactobacillus acidophilus species are well-known probiotics with the beneficial activity of regulating cholesterol levels. In this study, we showed that L. acidophilus K301 reduced the level of cholesterol through reverse transport in macrophages. L. acidophilus K301 upregulated the mRNA and protein levels of genes such as ATP-binding cassette A1 (ABCA1) and ATP-binding cassette G1 (ABCG1) under the control of liver X receptor (LXR), resulting in increased apoA-I-dependent cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells. L. acidophilus K301 induced both ABCA1 and ABCG1 through the endogenous LXR agonist 24(S), 25-epoxcycholesterol, which is synthesized by intracellular cholesterol synthetic pathways. In vivo studies using L. acidophilus K301-treated ApoE-/- mice showed reduced accumulation of lipoproteins in the arterial lumen. The inhibitory effects of L. acidophilus K301 on accumulation of lipoprotein in atherosclerotic plaques were mediated by the induction of squalene reductase (SQLE) and oxidosqualene cyclase (OSC) and resulted in ABCA1-mediated cholesterol efflux. Taken together, our findings revealed that Lactobacillus acidophilus K301 regulates the expression of genes related to cholesterol reverse transport via the induction of endogenous LXR agonist, suggesting the therapeutic potential of Lactobacillus acidophilus K301 as an anti-atherosclerotic agent.

Past studies have shown that personal subjective happiness is associated with various macro- and micro-level background factors, including environmental conditions, such as weather and the economic situation, and personal health behaviors, such as smoking and exercise. We contribute to this literature of happiness studies by using a geospatial approach to examine both macro and micro links to personal happiness. Our geospatial approach incorporates two major global datasets: representative national survey data from the International Social Survey Program (ISSP) and corresponding world weather data from the National Oceanic and Atmospheric Administration (NOAA). After processing and filtering 55,081 records of ISSP 2011 survey data from 32 countries, we extracted 5,420 records from China and 25,441 records from 28 other countries. Sensitivity analyses of different intervals for average weather variables showed that macro-level conditions, including temperature, wind speed, elevation, and GDP, are positively correlated with happiness. To distinguish the effects of weather conditions on happiness in different seasons, we also adopted climate zone and seasonal variables. The micro-level analysis indicated that better health status and eating more vegetables or fruits are highly associated with happiness. Never engaging in physical activity appears to make people less happy. The findings suggest that weather conditions, economic situations, and personal health behaviors are all correlated with levels of happiness.

Kelch proteins are implicated in the pathogenesis of many human diseases, including cancer. Nasopharyngeal carcinoma (NPC) is a rare malignancy in most countries, but prevalent in southern China and certain areas of Southeast Asia. In this study, we identified Kelch Domain Containing 4 (KLHDC4), an orphan member of the kelch repeat superfamily, as a prognosis marker for NPC. We examined the expression of KLHDC4 in 168 NPC cases by immunohistochemical staining and found a substantially higher level of KLHDC4 in NPC biopsies compared to adjacent normal nasopharyngeal mucosa. KLHDC4 expression was significantly related to the T classification (P <0.05), N classification (P <0.05) and total staging (P <0.01) in NPC, and patients with higher KLHDC4 expression had poorer overall (P <0.01) and metastasis-free survival (P <0.05) rates. Knockout (KO) of KLHDC4 via CRISPR/Cas9-mediated gene editing in NPC cell line dramatically inhibited cell proliferation, colony formation in soft agar and tumor formation in nude mice. In addition, cell migration and invasion were also impaired by KLHDC4 depletion as revealed by wound healing and Transwell assay. Mechanically, loss of KLHDC4 markedly induced spontaneous apoptosis in NPC cells, as evidenced by increased levels of cleaved caspase-3 and cleaved PARP. Consistently, KLHDC4 knockout cell-derived xenografts also showed elevated cleaved caspase-3 and PARP but reduced Ki-67 staining. In conclusion, our results suggest that KLHDC4 promotes NPC oncogenesis by suppressing cellular apoptosis. Thus, KLHDC4 may serve as a prognosis biomarker and a potential therapeutic target for NPC.

Background & Aims: Current hepatocellular carcinoma (HCC) staging systems only use baseline characteristics to predict outcome. We aimed to explore modifiable factors of the prognosis in HCC cases had undergone non-surgical treatment., Methods: All HCC cases in Kaohsiung Chang Gung Memorial hospital in southern Taiwan from 2002 to 2012 must met all below criteria: (1) met international diagnostic guidelines, (2) underwent the initial treatments in our hospital (3) treated by non-surgical treatment modalities and (4) survived more than two years, with follow-up time longer than five years., Results: A total 698 patients were enrolled: 451 (24.6%, group A) survivied between 2 to 5 years, and 247 (13.5%, group B) had survived > 5 years. Aside from liver function reserve and BCLC stages, four interventional factors: initial treatment modality, outcomes of 1st or 2nd treatment, and anti-viral therapy to chronic viral hepatitis were associated with prognosis. After propensity score matching, multiple logistic regression of 223 well-matched pairs showed that recurrence within one year after 1st treatment (OR: 2.17, 95% CI: 1.35-3.48), incomplete 2nd treatment (2.01, 1.27-3.17) and absence of anti-viral agents (1.68, 1.09-2.59) were independent poor prognostic factors., Conclusion: Complete treatment and anti-viral agents to chronic hepatitis were both independent modifiable prognostic factors of HCC patients had undergone non-surgical treatment. Based on these findings, timely treatment to achieve maximal locoregional control and anti-viral treatment should be provided as possible.

High throughput screening is a powerful tool to identify the potential candidate molecules involved during disease progression. However, analysis of complicated data is one of the most challenging steps on the way to obtaining useful results from this approach. Previously, we showed that a specific miRNA, miR-196a, could ameliorate the pathological phenotypes of Huntington's disease (HD) in different models, and performed high throughput screening by using the striatum of transgenic mice. In this study, we further tried to identify the potential regulatory mechanisms using different bioinformatic tools, including Database for Annotation, Visualization and Integrated Discovery (DAVID), Molecular Signatures Database (MSigDB), TargetScan and MetaCore. The results showed that miR-196a dominantly altered "ABC transporters", "RIG-I-like receptor signaling pathway", immune system", "adaptive immune system","tissue remodeling and wound repair" and "cytoskeleton remodeling". In addition, miR-196a also changed the expression of several well-defined pathways of HD, such as apoptosis and cell adhesion. Since these analyses showed the regulatory pathways are highly related to the modification of the cytoskeleton, we further confirmed that miR-196a could enhance the neurite outgrowth in neuroblastoma cells, suggesting miR-196a might provide beneficial functions through the alteration of cytoskeleton structures. Since impairment of the cytoskeleton has been reported in several neuronal diseases, this study will provide not only the potential working mechanisms of miR-196a but also insights for therapeutic strategies for use with different neuronal diseases.

The lymphatic endothelium plays an important role in the maintenance of tissue fluid homeostasis. It also participates in the pathogenesis of several inflammatory diseases. However, little is known about the underlying mechanisms by which lymphatic endothelial cell responds to inflammatory stimuli. In this study, we explored the mechanisms by which lipopolysaccharide (LPS) induces cyclooxygenase (COX)-2 expression in murine lymphatic endothelial cells (SV-LECs). LPS caused increases in cox-2 mRNA and protein levels, as well as in COX-2 promoter luciferase activity in SV-LECs. These actions were associated with protein phosphatase 2A (PP2A), apoptosis signal-regulating kinase 1 (ASK1), JNK1/2 and p38MAPK activation, and NF-κB subunit p65 and C/EBPβ phosphorylation. PP2A-ASK1 signaling blockade reduced LPS-induced JNK1/2, p38MAPK, p65 and C/EBPβ phosphorylation. Transfection with PP2A siRNA reduced LPS's effects on p65 and C/EBPβ binding to the COX-2 promoter region. Transfected with the NF-κB or C/EBPβ site deletion of COX-2 reporter construct also abrogated LPS's enhancing effect on COX-2 promoter luciferase activity in SV-LECs. Taken together, the induction of COX-2 in SV-LECs exposed to LPS may involve PP2A-ASK1-JNK and/or p38MAPK-NF-κB and/or C/EBPβ cascade.

Stromal cell-derived factor-1 (SDF-1) has been confirmed to participate in the formation of choroidal neovascularization (CNV) via its two receptors: CXC chemokine receptors 4 (CXCR4) and CXCR7. Previous studies have indicated that the activation of Toll-like receptors (TLRs) by lipopolysaccharide (LPS) might elevate CXCR4 and/or CXCR7 expression in tumor cells, enhancing the response to SDF-1 to promote invasion and cell dissemination. However, the impact of LPS on the CXCR4 and CXCR7 expression in endothelial cells and subsequent pathological angiogenesis formation remains to be elucidated. The present study shows that LPS enhanced the CXCR4 and CXCR7 expression via activation of the TLR4 pathway in choroid-retinal endothelial (RF/6A) cells. In addition, the transcriptional regulation of CXCR4 and CXCR7 by LPS was found to be mediated by phosphorylation of the extracellular signal-related kinase (ERK) 1/2 and activation of nuclear factor kappa B (NF-κB) signaling pathways, which were blocked by ERK- or NF-κB-specific inhibitors. Furthermore, the increased CXCR4 and CXCR7 expression resulted in increased SDF-1-induced RF/6A cells proliferation, migration and tube formation. In vivo, LPS-treated rat had significantly higher mRNA levels of CXCR4 and CXCR7 expression and lager laser-induced CNV area than vehicle-treated rat. SDF-1 blockade with a neutralizing antibody attenuated the progression of CNV in LPS-treated rat after a single intravitreal injection. Altogether, these results demonstrated that LPS might influence CNV formation by enhancing CXCR7 and CXCR7 expression in endothelial cells, possibly providing a new perspective for the treatment of CNV-associated diseases.

Pleural spread is difficult to treat in malignancies, especially in lung cancer and thymoma. Monotherapy with surgery fails to have a better survival benefit than palliative chemotherapy, the currently accepted treatment. Photodynamic therapy utilizes a photosensitizer to target the tumor site, and the tumor is exposed to light after performing a pleurectomy and tumor resection. However, the benefits of this procedure to lung cancer or thymoma patients are unknown. We retrospectively reviewed the clinical characteristics and treatment outcomes of patients with lung cancer or thymoma with pleural seeding who underwent pleural photodynamic therapy and surgery between 2005 and 2013. Eighteen patients enrolled in this study. The mean patient age was 52.9 ± 12.2 years. Lung cancer was the inciting cancer of pleural dissemination in 10 patients (55.6%), and thymoma in 8 (44.4%). There was no procedure-related mortality. Using Kaplan-Meier survival analysis, the 3-year survival rate and the 5-year survival rate were 68.9% and 57.4%, respectively. We compared the PDT lung cancer patients with those receiving chemotherapy or target therapy (n = 51) and found that the PDT group had better survival than non-PDT patients (mean survival time: 39.0 versus 17.6 months; P = .047). With proper patient selection, radical surgical resection combined with intrapleural photodynamic therapy for pleural spread in patients with non-small cell lung cancer or thymoma is feasible and may provide a survival benefit.

Macrophage proliferation and migration are important for many facets of immune response. Here we showed that stimulation of macrophages with type B CpG oligodeoxynucleotides (CpG-B ODNs) such as CpG-ODN 1668 increased the production of anti-inflammatory cytokine interleukin 1 receptor antagonist (IL-1Ra) in a TLR9- and MyD88-dependent manner. The CpG-B ODNs-induced IL-1Ra increased macrophage migration and promoted macrophage proliferation by down-regulating the expression of a cell cycle negative regulator, p27 to increase cell population in the S phase. The induction of IL-1Ra by CpG-B ODNs was F-spondin dependent. Knockdown of F-spondin and IL-1Ra decreased CpG-B ODNs-induced macrophage migration whereas overexpression of IL-1Ra increased migration of those cells. These findings demonstrated novel roles for F-spondin and IL-1Ra in CpG-B ODNs-mediated cell proliferation and migration of macrophages.

Objective: The definite prognostic role of p-STAT3 has not been well defined. We performed a meta-analysis evaluating the prognostic role of p-STAT3 expression in patients with digestive system cancers., Methods: We searched the available articles reporting the prognostic value of p-STAT3 in patients with cancers of the digestive system, mainly including colorectal cancer, gastric cancer, hepatocellular carcinoma, esophagus cancer and pancreatic cancer. The pooled hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) of overall survival (OS) and disease-free survival (DFS) were used to assess the prognostic role of p-STAT3 expression level in cancer tissues. And the association between p-STAT3 expression and clinicopathological characteristics was evaluated., Results: A total of 22 studies with 3585 patients were finally enrolled in the meta-analysis. The results showed that elevated p-STAT3 expression level predicted inferior OS (HR = 1.809, 95% CI: 1.442-2.270, P < 0.001) and DFS (HR = 1.481, 95% CI: 1.028-2.133, P = 0.035) in patients with malignant cancers of the digestive system. Increased expression of p-STAT3 is significantly related with tumor cell differentiation (Odds ratio (OR) = 1.895, 95% CI: 1.364-2.632, P < 0.001) and lymph node metastases (OR = 2.108, 95% CI: 1.104-4.024, P = 0.024). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Funnel plots and Egger's tests revealed there was no significant publication bias in the meta-analysis., Conclusion: Phospho-STAT3 might be a prognostic factor of patients with digestive system cancers. More well designed studies with adequate follow-up are needed to gain a thorough understanding of the prognostic role of p-STAT3.

The roots of the perennial herb Gentiana macrophylla Pall. (GM) are known as Qinjiao, which has been used for centuries to treat systemic lupus erythematosus (SLE). However, little is known about the effects of GM on cholesterol-aggravated cardiac abnormalities in SLE, and the mechanisms thereof. This study investigates whether GM exhibits anti-apoptotic effects, focusing on the left ventricle (LV) of NZB/W F1 mice fed with high-cholesterol diet. The morphology and apoptotic status of ventricular tissues were determined by microscopy and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Levels of apoptotic biomarkers were determined by immunoblotting. The results thus obtained revealed that GM significantly reduced the cholesterol-aggravated apoptosis of LV in NZB/W F1 mice by suppressing both intrinsic and extrinsic apoptotic pathways. Additionally, GM significantly increased the cardiac insulin-like growth factors (IGF)-1 survival signaling and anti-apoptotic proteins in LV tissues. Accordingly, GM is considered to be beneficial in alleviating cholesterol-aggravated cardiac damage in SLE, and therefore constitute an alternative treatment for SLE patients with cardiac abnormalities.

Objective: Hepatocellular carcinoma (HCC) and its recurrence are major problems in living donor liver transplantation (LDLT). Several biomarkers have been used to investigate this event. We conducted a prospective controlled study to determine the activities of the basic fibroblast growth factor (FGF-2), survivin, Ki67, endostatin, and vascular endothelial growth factor (VEGF) in different conditions before, early after, and late after LDLT with and without HCC recurrence., Methods: Fifty patients with virus-related HCC who underwent LDLT were enrolled in this 2-year cross-sectional study. During the study period, recurrent HCC was identified in 9 patients (study group, n = 9) and 41 patients (control group, n = 41) had no recurrence after LDLT. The mean time to HCC recurrence was 587.11 ± 398.64 days (range, 90-1352 days). Microvascular invasion (MVI) was found in 66.7% (6/9) of the recipients, as determined on pathological examination. The serum biomarkers were investigated by using enzyme-linked immunosorbent assay at the different LDLT stages., Results: The serum levels of the biomarkers significantly correlated with LDLT and HCC recurrence in the repeated-measures analysis (F = 31.676, P = 0.000). Significant differences were observed in the effects of all biomarkers (F = 85.313, P = 0.000) and the time to HCC recurrence after LDLT (F = 3.178, P = 0.046). The biomarkers, ordered by the observed power of the test for HCC recurrence after LDLT, were FGF-2 (1.000) > survivin (0.999) > Ki67 (0.949) > endostatin (0.411) > VEGF (0.305)., Conclusions: Different biomarker activities may be implicated in the pathogenesis of HCC recurrence after LDLT. Oncogenes may not exist in the new graft but may still be present in the peripheral blood. The timing of HCC recurrence and impact of MVI in the explanted liver requires confirmation in larger studies with a longer follow-up.

Background: To investigate the relationships among regional activity abnormalities, clinical disease severity, and prognosis in cirrhotic patients with overt hepatic encephalopathy (OHE) using resting-state functional magnetic resonance imaging (rs-fMRI)., Methods: Regional homogeneity (ReHo) values of 12 cirrhotic patients with OHE and 12 age- and sex-matched healthy volunteers were calculated from rs-fMRI. Two-sample t-test was performed on individual ReHo maps between the two groups. The relationships between ReHo variation, disease severity, and prognosis were analyzed., Results: Cirrhotic patients with OHE had significantly low ReHo values in the left middle cingulum, bilateral superior temporal, left inferior orbito-frontal, right calcarine, left inferior frontal gyrus, left post-central, left inferior temporal, and left lingual areas, and high ReHo in the right superior frontal, right inferior temporal, right caudate, and cerebellum. There was significant group difference in the right superior temporal lobe (p=0.016) and crus1 of the left cerebellum (p=0.015) between survivors and non-survivors in the OHE group. Worse Glasgow Coma Scale was associated with increased local connectivity in the left cerebellar crus I (r=-0.868, p=0.001)., Conclusions: Information on the functional activity of cirrhotic patients with OHE suggests the use of rs-fMRI with ReHo analysis as a non-invasive prognosticating modality.