Drug-induced liver injury in children: A nationwide cohort study from China.

Background & Aims: Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China. Methods: This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring <6 were included in the analysis. Among them, 460 cases met the EASL biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old). Results: Hepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratios 4.75, p = 0.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (13.7%). For adolescents, the most commonly suspected drugs were antitubercular drugs (22%) and traditional Chinese medicine (23%). Conclusion: Adolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices. Impact and implications: Drug-induced liver injury, a poorly understood yet serious cause of pediatric liver disease, encompasses a spectrum of clinical presentations, ranging from asymptomatic liver enzyme elevation to acute liver failure. This retrospective study, utilizing a large Chinese cohort of pediatric liver injury cases from 308 centers nationwide, characterized the major clinical patterns and suspected drugs in detail, revealing that adolescents are at a greater risk of severe liver injury compared to younger children. Vigilant care and careful surveillance of at-risk pediatric patients are crucial for physicians, researchers, patients, caregivers, and policymakers. Additional multicenter prospective studies are needed to evaluate the risk of hepatotoxicity in outpatients and hospitalized pediatric patients.

Validation of the revised electronic version of RUCAM for diagnosis of DILI in Chinese patients.

BACKGROUND AIMS: The Revised Electronic Causality Assessment Method (RECAM), a computerized update of the Roussel Uclaf Causality Assessment Methodology (RUCAM), was recently proposed. In this study, we validated and compared the utility of the RECAM and RUCAM in Chinese patients with a single conventional or herbal agent-induced liver injury. METHODS: In this retrospective multicenter cohort of well-established DILI and non-DILI patients from 5 centers in China, the diagnostic performance of the RUCAM and RECAM was compared by AUC analysis. The consistency was evaluated by weighted kappa. The major causes of discrepancy were explored. RESULTS: A total of 481 DILI and 100 non-DILI patients were included. In total, 62.6% of the DILI cases were induced by conventional agents, and 37.4% were induced by herbs. The RECAM had relatively higher AUC than RUCAM for overall [0.947 (0.926-0.964) vs. 0.867 (0.836-0.893), p=0.0016], conventional agents [0.923 (0.890-0.949) vs. 0.819 (0.775-0.858), p=0.0185], and herbs [0.972 (0.941-0.989) vs.0.911 (0.866-0.944), p=0.0199]. Latency, scores associated with hepatitis B, and hepatotoxicity information of the insulting drugs were the 3 main causes for the inconsistency between RECAM and RUCAM scores. CONCLUSIONS: The RECAM had relatively better diagnostic performance than RUCAM, with a higher AUC for Chinese DILI patients. Timely updates of the LiverTox category and refinement of serum markers to exclude hepatitis B activity would further improve the applicability of RECAM in areas where the use of herbs and resolution of past HBV infections are common.

Validation of the Nanjing Criteria for Diagnosing Pyrrolizidine Alkaloids-induced Hepatic Sinusoidal Obstruction Syndrome.

BACKGROUND AND AIMS: Hepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury to sinusoidal endothelial cells in the liver. The intake of pyrrolizidine alkaloids (PAs) in some Chinese herbal remedies/plants remains the major etiology for HSOS in China. Recently, new diagnostic criteria for PA-induced HSOS (i.e. PA-HSOS) have been developed; however, the efficacy has not been clinically validated. This study aimed to assess the performance of the Nanjing criteria for PA-HSOS. METHODS: Data obtained from consecutive patients in multiple hospitals, which included 86 PA-HSOS patients and 327 patients with other liver diseases, were retrospectively analyzed. Then, the diagnostic performance of the Nanjing criteria and simplified Nanjing criteria were evaluated and validated. The study is registered in www.chictr.org.cn (ID: ChiCTR1900020784). RESULTS: The Nanjing criteria have a sensitivity and specificity of 95.35% and 100%, respectively, while the simplified Nanjing criteria have a sensitivity and specificity of 96.51% and 96.33%, respectively, for the diagnosis of PA-HSOS. Notably, a proportion of patients with Budd-Chiari syndrome (11/49) was misdiagnosed as PA-HSOS on the basis of the simplified Nanjing criteria, and this was mainly due to the overlapping features in the enhanced computed tomography/magnetic resonance imaging examinations. Furthermore, most of these patients (10/11) had occlusion or thrombosis of the hepatic vein, and communicating vessels in the liver were found in 8/11 patients, which were absent in PA-HSOS patients. CONCLUSIONS: The Nanjing criteria and simplified Nanjing criteria exhibit excellent performance in diagnosing PA-HSOS. Thus, both could be valuable diagnostic tools in clinical practice.

Metabolomic Analysis Uncovers Energy Supply Disturbance as an Underlying Mechanism of the Development of Alcohol-Associated Liver Cirrhosis.

Alcohol-associated liver disease (ALD) is caused by alcohol metabolism's effects on the liver. The underlying mechanisms from a metabolic view in the development of alcohol-associated liver cirrhosis (ALC) are still elusive. We performed an untargeted serum metabolomic analysis in 14 controls, 16 patients with ALD without cirrhosis (NC), 27 patients with compensated cirrhosis, and 79 patients with decompensated ALC. We identified two metabolic fingerprints associated with ALC development (38 metabolites) and those associated with hepatic decompensation (64 metabolites) in ALC. The cirrhosis-associated fingerprint (eigenmetabolite) showed a better capability to differentiate ALC from NC than the aspartate aminotransferase-to-platelet ratio index score. The eigenmetabolite associated with hepatic decompensation showed an increasing trend during the disease progression and was positively correlated with the Model for End-Stage Liver Disease score. These metabolic fingerprints belong to the metabolites in lipid metabolism, amino acid pathway, and intermediary metabolites in the tricarboxylic acid cycle. Conclusion: The metabolomic fingerprints suggest the disturbance of the metabolites associated with cellular energy supply as an underlying mechanism in the development and progression of alcoholic cirrhosis.

Metabolomic Signatures of Autoimmune Hepatitis in the Development of Cirrhosis.

Objectives: Autoimmune hepatitis (AIH) can progress into severe outcomes, i.e., decompensated cirrhosis, from remarkable and persistent inflammation in the liver. Considering the energy-expending nature of inflammation, we tried to define the metabolomics signatures of AIH to uncover the underlying mechanisms of cirrhosis development and its metabolic biomarkers. Methods: Untargeted metabolomics analysis was performed on sera samples from 79 AIH patients at the stages (phenotypes) of non-cirrhosis (n = 27), compensated cirrhosis (n = 22), and decompensated cirrhosis (n = 30). Pattern recognition was used to find unique metabolite fingerprints of cirrhosis with or without decompensation. Results: Out of the 294 annotated metabolites identified, 2 metabolic fingerprints were found associated with the development of cirrhosis (independent of the decompensated state, 42 metabolites) and the evolution of decompensated cirrhosis (out of 47 metabolites), respectively. The cirrhosis-associated fingerprints (eigenmetabolite) showed better capability to differentiate cirrhosis from non-cirrhosis patients than the aminotransferase-to-platelet ratio index. From the metabolic fingerprints, we found two pairs of metabolites (Mesobilirubinogen/6-Hydroxynicotinic acid and LysoPA(8:0/0:0)/7alpha-Hydroxycholesterol) calculated as ratio of intensities, which revealed robust abilities to identify cirrhosis or predict decompensated patients, respectively. These phenotype-related fingerprint metabolites featured fundamental energy supply disturbance along with the development of AIH cirrhosis and progression to decompensation, which was characterized as increased lipolysis, enhanced proteolysis, and increased glycolysis. Conclusions: Remodeling of metabolism to meet the liver inflammation-related energy supply is one of the key signatures of AIH in the development of cirrhosis and decompensation. Therefore, drug regulation metabolism has great potential in the treatment of AIH.

ABO blood group influence COVID-19 infection: a meta-analysis.

INTRODUCTION: Previous studies have linked the relationship between ABO blood group and COVID-19 infection. However, existing evidence is preliminary and controversial. This meta-analysis sought to identify studies that describe COVID-19 and ABO blood group. METHODOLOGY: A literature search was conducted from PubMed, Web of Science, MedRxiv, BioRxiv and Google Scholar databases. Members of cases and controls were extracted from collected studies. Pooled Odds ratio (OR) and 95% confidence interval (95%CI) were calculated and interpreted from extracted data. Publication bias and sensitivity analysis were also applied to confirm our discovery. RESULTS: Total 13,600 patients and 3,445,047 controls were included in the study. Compared to other ABO blood group, blood group O was associated with a lower risk of COVID-19 infection (OR = 0.76, 95%CI 0.66-0.84), while blood group A and AB was associated with a higher risk (OR = 1.25, 95%CI 1.10-1.41; OR = 1.13, 95%CI 1.04-1.23, respectively). In the subgroup analysis, the relationship between blood group A, O and COVID-19 infection remained stable among Chinese, European and Eastern Mediterranean populations. In American population, blood groups B was linked with increased risk of COVID-19 infection (OR = 1.21, 95%CI 1.09-1.35). CONCLUSIONS: Our data suggested that individuals with blood types A and AB are more susceptible to COVID-19, while people with blood type O are less susceptible to infection. More research is needed to clarify the precise role of the ABO blood group in COVID-19 infection to address the global question.

miR-455-3p inhibits proliferation, migration and epithelial-mesenchymal transition of ovarian cancer SKOV-3 cells by regulating translipoprotein 4 / 中国肿瘤生物治疗杂志

@#Objective: To investigate the potential effects of miR-455-3p on proliferation, invasion and epithelial-mesenchymal transition (EMT) process of ovarian cancer cells, and explore its molecular mechanism. Methods: The IOSE80, SKOV-3 and A2780 cells were transfected with miR-455-3p mimics and negative controls (NC) by using LipofectamineTM 2000. Quantitative polymerase chain reaction (qPCR) assay was performed to detect the mRNA expressions of miR-455-3p and fatty acid-binding protein 4 (FABP4) in IOSE80, SKOV-3 and A2780 cells. The expression levels of FABP4 and EMT-associated proteins were detected by Wb. CCK-8 assay was applied to measure cell proliferation. Cell migration was analyzed by using Transwell assay. Bioinformatics analysis was used to predict the potential target of miR-455-3p, and the targeting effect of miR-455-3p on FABP4 was verified by the dual-luciferase reporter assay system. Results: The expression of miR-455-3p was declined (all P<0.05), while the expression of FABP4 was elevated (all P< 0.05) in ovarian cancer cells (SKOV-3 and A2780) in comparison with normal ovarian IOSE80 cells. Additionally, over-expression of miR-455-3p obviously inhibited cell proliferation and migration capacity of SKOV-3 cells (all P<0.05). Furthermore, over-expression of miR-455-3p impeded EMT progress by up-regulating E-cadherin expression and down-regulating N-cadherin and vimentin expression (all P<0.05). Importantly, the dual-luciferase reporter system, qPCR and Wb validated that FABP4 was a specific target gene of miR-455-3p, and miR-455-3p showed specific binding with FABP4 3’-UTR and negatively regulated the expression of FABP4 at both mRNA and protein levels. Mechanistically, over-expression of FABP4 apparently reversed the inhibitory effects of miR-455-3p on cell proliferation and migration of SKOV-3 cells (all P<0.05). Conclusion: miR-455-3p, acting as a tumor suppressor protein, can inhibit ovarian cancer cell proliferation, migration and EMT process by targeting FABP4, suggesting that miR-455-3p may be a new potential therapeutic target for ovarian cancer treatment.

Optimization of hepatobiliary phase delay time of Gd-EOB-DTPA-enhanced magnetic resonance imaging for identification of hepatocellular carcinoma in patients with cirrhosis of different degrees of severity.

AIM: To optimize the hepatobiliary phase delay time (HBP-DT) of Gd-EOB-DTPA-enhanced magnetic resonance imaging (GED-MRI) for more efficient identification of hepatocellular carcinoma (HCC) occurring in different degrees of cirrhosis assessed by Child-Pugh (CP) score. METHODS: The liver parenchyma signal intensity (LPSI), the liver parenchyma (LP)/HCC signal ratios, and the visibility of HCC at HBP-DT of 5, 10, 15, 20, and 25 min (i.e., DT-5, DT-10, DT-15, DT-20, and DT-25 ) after injection of Gd-EOB-DTPA were collected and analyzed in 73 patients with cirrhosis of different degrees of severity (including 42 patients suffering from HCC) and 18 healthy adult controls. RESULTS: The LPSI increased with HBP-DT more significantly in the healthy group than in the cirrhosis group (F = 17.361, P < 0.001). The LP/HCC signal ratios had a significant difference (F = 12.453, P < 0.001) among various HBP-DT points, as well as between CP-A and CP-B/C subgroups (F = 9.761, P < 0.001). The constituent ratios of HCC foci identified as obvious hypointensity (+++), moderate hypointensity (++), and mild hypointensity or isointensity (+/-) kept stable from DT-10 to DT-25: 90.6%, 9.4%, and 0.0% in the CP-A subgroup; 50.0%, 50.0%, and 0.0% in the CP-B subgroup; and 0.0%, 0.0%, and 100.0% in the CP-C subgroup, respectively. CONCLUSION: The severity of liver cirrhosis has significant negative influence on the HCC visualization by GED-MRI. DT-10 is more efficient and practical than other HBP-DT points to identify most of HCC foci emerging in CP-A cirrhosis, as well as in CP-B cirrhosis; but an HBP-DT of 15 min or longer seems more appropriate than DT-10 for visualization of HCC in patients with CP-C cirrhosis.

Alteration of ghrelin/obestatin ratio in adolescence with polycystic ovarian syndrome.

Ghrelin, an endoggenous for the growth hormone secretagogue receptor, has been shown to participate in the regulation of energy homeostasis and pituitary hormone secretion. Obestatin, encoded by the same gene as ghrelin, is described as a physiological opponent of ghrelin. Ghrelin and obestatin are altered in polycystic ovary syndrome (PCOS), which is characterized by insulin resistance and pituitary hormone secretion disorder. The aim of this study was to evaluate ghrelin/obestatin imbalance in relation to insulin resistance and pituitary hormone in adolescence with PCOS. This restrospective case-control study included 33 adolescence with PCOS and 38 control adolescence. Ghrelin and obestatin concentrations in serum were determined by RIA, and the serum fasting glucose and Insulin were determined by the glucose oxidase color method and INS-EASIA. The serum LH and FSH were measured by highly specific hemiluminescence immunoassays. We found that the serum ghrelin levels and ghrelin/obestatin ratio were significant lower in PCOS group than in control group, and the serum obestatin levels were significant higher in PCOS group than in control group. The ghrelin/obestatin ratios were negatively correlation with LH/FSH ratio and insulin resistant index in PCOS group. The findings of this study suggest that ghrelin/obestatin imbalance may play a role in pathogenesis of adolescent PCOS.

CSH guidelines for the diagnosis and treatment of drug-induced liver injury.

Drug-induced liver injury (DILI) is an important clinical problem, which has received more attention in recent decades. It can be induced by small chemical molecules, biological agents, traditional Chinese medicines (TCM), natural medicines (NM), health products (HP), and dietary supplements (DS). Idiosyncratic DILI is far more common than intrinsic DILI clinically and can be classified into hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the types of injured target cells. The CSH guidelines summarized the epidemiology, pathogenesis, pathology, and clinical manifestation and gives 16 evidence-based recommendations on diagnosis, differential diagnosis, treatment, and prevention of DILI.

Antiviral efficacy of entecavir for hepatitis B virus rtA181V/T mutants.

BACKGROUND: The amino acid substitution at position 181 of the Hepatitis B virus (HBV) polymerase is a multi-drug resistance affecting both the L-nucleoside and acyclic phosphonate nucleotide groups. Data is limited on the efficacy of entecavir (ETV) rescuing chronic hepatitis B (CHB) patients with rtA181T/V mutation. METHODS: Thirty-one patients with rtA181T/V mutation and 25 patients with rtA181T/V and rtN236T mutation were enrolled. Virological, serological and biochemical outcomes of ETV rescue therapy over 12 months in CHB patients with rtA181T/V mutation strains were investigated. All patients were treated with ETV 0.5 mg/day for 12 months and scheduled follow-up every 3 months. Patients' characteristics, laboratory tests results and clinical outcomes were collected and compared. RESULTS: After emergence of rtA181T/V mutant, serum HBV DNA levels increased over 4 log10 IU/mL, but the total bilirubin, alanine aminotransferase (ALT) levels raised moderately. No significant difference in baseline characteristics was observed between the rtA181T/V group and rtA181T/V + rtN236T group. After 12 months rescue therapy, total 85.7% (48/56) patients achieved HBV DNA undetectable. No significant difference in the mean reduction of serum HBV DNA and biochemical response was observed between both groups (3.59 ± 1.85 vs. 3.76 ± 2.15 log10 IU/ml; P = 0.756 and 90.3 vs. 80.0%; P = 0.272, respectively). The mean HBV DNA reduction, HBsAg and ALT levels were also similar between different rtA181T/sW172 mutations (P > 0.05). HBV DNA level is the only predictor of 12 months antiviral outcomes (odds ratio 6.723, P = 0.022). CONCLUSIONS: The results of the present study suggested that ETV is efficient in rescuing rtA181T/V mutation CHB patients. HBV DNA level could predict viral clearance at the 12th month.

Maternal serum ratio of ghrelin to obestatin decreased in preeclampsia.

OBJECTIVE: Ghrelin, an endogenous for the growth hormone secretagogue receptor, has been shown to participate in blood pressure regulation. Obestatin, encoded by the same gene as ghrelin, is described as a physiological opponent of ghrelin. We hypothesized that ghrelin/obestatin imbalance played a role in the pathogenesis. This study was designed to determine the alterations of ghrelin and obestatin concentrations and ghrelin/obestatin ratio in maternal serum in preeclampsia. METHOD: This retrospective case-control study included 31 preeclampsia and 31 gestational week-matched normal pregnancies. Ghrelin and obestatin concentrations in maternal serum were determined by radioimmunoassay, and the ghrelin/obestatin ratio was calculated. RESULTS: The ghrelin concentration and ghrelin/obestatin ratio in maternal serum were significantly lower in preeclampsia than in normal pregnancies (214.34±14.27pg/mL vs 251.49±16.15pg/mL, P=0.041, 1.07±0.09 vs 0.82±0.08, P=0.023). The obestatin concentration in maternal serum was significantly higher in preeclampsia than in normal pregnancies (276.35±15.38pg/mL vs 223.53±18.61pg/mL, P=0.019). The systolic blood pressure in preeclampsia was negatively correlated with ghrelin concentration and ghrelin/obestatin ratio (r=-0.549, P=0.003; r=-0.491, P=0.004) and was positively correlated with obestatin concentrations in preeclampsia (r=0.388, P=0.013). CONCLUSIONS: The findings of this study suggested disturbance of ghrelin and obestatin in maternal serum in preeclampsia, and ghrelin/obestatin imbalance might play a role in the pathogenesis of preeclampsia.

Management of hepatitis C virus infection in hemodialysis patients.

The prevalence of hepatitis C virus (HCV) infection in patients on maintenance hemodialysis (MHD) is relatively higher than those without MHD. Chronic HCV infection detrimentally affects the life quality and expectancy, leads to renal transplant rejection, and increases the mortality of MHD patients. With the application of erythropoietin to improve uremic anemia and avoid blood transfusion, the new HCV infections during MHD in recent years are mainly caused by the lack of stringent universal precautions. Strict implementation of universal precautions for HCV transmission has led to markedly decreased HCV infections in many hemodialysis units, but physicians still should be alert for the anti-HCV negative HCV infection and occult HCV infection in MHD patients. Standard interferon alpha and pegylated interferon alpha monotherapies at a reduced dose are currently the main treatment strategies for MHD patients with active HCV replication, but how to increase the sustained virological response and decrease the side effects is the key problem. IFNα-free treatments with two or three direct-acting antivirals without ribavirin in MHD patients are waiting for future investigations.

SDF-1/CXCR7 axis enhances ovarian cancer cell invasion by MMP-9 expression through p38 MAPK pathway.

Ovarian cancer is an aggressive gynecological malignancy with high metastatic potential. Recently, the CXC receptor (CXCR7) has been identified as a new receptor for stromal-derived factor-1 (SDF-1), and exerts important roles in cancer development. However, its effect on ovarian cancer and the underlying mechanism remain unknown. In this study, we detected abundant CXCR7 expression in ovarian cancer tissues and cells. Moreover, SDF-1 induced dramatically upregulation of CXCR7 mRNA and protein levels, indicating that the SDF-1/CXCR7 axis existed in ovarian cancer. Further analysis confirmed that SDF-1 enhanced cell adhesion and subsequent invasion, which were significantly attenuated when pretreated with CXCR7 small interference RNA (siRNA), indicating the critical function of SDF-1/CXCR7 in cell invasion. Further mechanistic analysis indicated that SDF-1/CXCR7 enhanced cell invasion by matrix metalloproteinase (MMP)-9, as pretreatment with MMP-9 siRNA significantly abrogated a number of invading cells. Additionally, SDF-1/CXCR7 induced phosphorylation of the p38 MAPK pathway, which was accounted for MMP-9 expression as preconditioning with the p38 MAPK inhibitor SB203580 obviously decreased MMP-9 expression. Together, our data implied that SDF-1/CXCR7 enhanced ovarian cancer cell invasion by MMP-9 expression through the p38 MAPK pathway. Thus, these findings confirmed the critical role of SDF-1/CXCR7 during the pathological processes of ovarian cancer and supported its potential targets for further development of antiovarian cancer therapy.

[Meta-analysis of magnesium isoglycyrrhizinate combined with nucleoside analogues in patients with chronic hepatitis B].

OBJECTIVE: To evaluate the efficacy and safety of the magnesium isoglycyrrhizinate plus nucleoside analogues (MGL + NA) combination therapy in patients with chronic hepatitis B using a meta-analysis approach. METHODS: The Chinese Biochemical literature on Disc (CBMDisc) and the Chinese Scientific Journal database, CNKI, were searched for randomized controlled trials (RCTs) of MGL+NA in patients with chronic hepatitis B published between 1995 and 2013. Data related to treatment type (combination therapy vs. mono-therapy) and outcome (markers of efficacy and safety, including levels of hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)). Weighted mean differences (WMD) were calculated and the Peto method was used to determine the relative risk (RR), both with 95% confidence intervals (CIs). RESULTS: Meta-analysis of the six included RCTs of MGL + NA, representing a 704 patients with chronic hepatitis B, showed WMDs for ALT of -12.98 (95% CI: -18.24 to -7.71, P less than 0.01) and for AST of -9.49 (95% CI: -14.53 to -4.45, P = 0.0002) and RRs for HBeAg of 1.79 (95% CI: 1.17 to 2.76, P = 0.008) and for HBV DNA of 1.35 (95% CI: 1.05 to 1.74, P = 0.02). The therapeutic efficacy of MGL+NA combination therapy was better than that of NA mono-therapy (P less than 0.01). CONCLUSION: For patients with chronic hepatitis B, MGL combination therapy may enhance the antiviral efficacy of NA treatment and help to improve liver function during treatment.

[RUCAM scale-based diagnosis, clinical features and prognosis of 140 cases of drug-induced liver injury].

OBJECTIVE: To analyze the etiology, clinical features and prognosis of liver injuries caused by different drugs. METHODS: The types of suspected drugs related to liver injury, clinical manifestations, liver biochemical parameters, clinical outcomes and other associated data were retrospectively assessed for 140 patients with drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method (RUCAM) was used to assess the causality between drugs and liver injury. RESULTS: The most prevalent agents inducing DILI were Chinese traditional drugs (62.1%), followed by antipyretic analgesic drugs (10%) and antibiotics (5%). The ratio of male to female patients in the study cohort was 1:1.69, with 71 of the total patients (50.7%) being between the ages of 40 and 60 years-old. The RUCAM scale was not less than 3 points for any of the patients.In general, the clinical manifestations and biochemical results were not specific. The percentages of hepatocellular injury type, cholestatic injury type and mixed injury type were 51.4%, 30.7% and 17.9% respectively. The median age of patients with cholestatic liver injury was 55.6 years, which was older than that of patients with hepatocellular injury (47.1 years) or mixed injury (49.9 years). CONCLUSION: Although antipyretic analgesics and antibiotics are considered as common drugs that can induce DILI, Chinese traditional drugs have emerged as another important group of liver injurious agents. Cholestatic DILI was found to occur more often in elderly patients than in younger patients.

Loss of HBsAg and antiviral treatment: from basics to clinical significance.

Accurate prediction of the sustained virological response (SVR) to antiviral therapy against chronic hepatitis B (CHB) is still a crucial problem needing profound investigation. In recent years, quantification of hepatitis B surface antigen (HBsAg), a reliable predictor of SVR and an ideal endpoint of treatment, has attracted increasing attention. Serum HBsAg titer may reflect the level of intrahepatic hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in most patients, and vary with natural phases of chronic HBV infection, genotypes and variants, antiviral therapy, and other related factors. Serum HBsAg <200 IU/mL or yearly reduction ≥0.5 log10IU/mL may be the optimum cut-off values for prediction of the chance of spontaneous seroclearance of HBsAg. Serum HBsAg <1,000 IU/mL with HBV DNA <2,000 IU/mL may identify most of the inactive HBV carriers from active HBeAg(-) hepatitis. Interferon-based therapy can lead to more significant HBsAg decline than therapy based on nucleoside and/or nucleotide analogues. Different patterns or kinetics of HBsAg decline during therapy are related to different probabilities of SVR. A low HBsAg level, <3,000 IU/mL at baseline, or HBsAg level, <1,500 IU/mL at week 12, or a rapid on-treatment HBsAg decline of ≥0.5 log10IU/mL at week 12, may predict higher probability of SVR. However these cut-off values must be further validated for larger cohort of patients across genotypes worldwide. Incorporation of serum HBsAg level, HBeAg status, HBV DNA load, HBV genotypes, and other related factors might help establish new concept of more practical "response-guided treatment (RGT)" rules for antiviral therapy.

Stromal cell-derived factor-1 (SDF-1) enhances cells invasion by αvß6 integrin-mediated signaling in ovarian cancer.

Ovarian carcinoma is a common gynecological malignancy and a great threat to health as a result of metastasis. The chemokine stromal-derived factor (SDF-1) plays multiple roles in tumor pathogenesis. However, the precise molecular mechanism underlying SDF-1-induced ovarian cancer cell invasion is still undefined. αvß6 integrin is an important factor in tumor progression. Therefore, we speculate that SDF-1-enhanced ovarian cancer cell invasion is related to αvß6 integrin-mediated signaling. After culturing with SDF-1, an obvious time- and dose-dependent increase in αvß6 integrin was demonstrated. Furthermore, CXC receptor 4 (CXCR4) was responsible for SDF-1-induced αvß6 integrin expression. Simultaneously, SDF-1 was found to dramatically enhance extracellular matrix degradation via urokinase-type plasminogen activator (uPA) expression and cell invasion by αvß6 integrin expression; these reinforce failed to be increased when pretreatment was performed with the CXCR4 inhibitor AMD3100 or anti-αvß6 integrin antibody, respectively. In addition, αvß6 integrin induced the phosphorylation of p38 MAPK and PI3 K/Akt, contributing to the up-regulation of uPA, as treatment with the specific inhibitor for p38 mitogen-activated protein kinases (MAPK) (SB203580) or phosphatidylinositol 3-kinase (PI3 K)/Akt (LY294002) strikingly abrogated uPA expression. Taken together, these results demonstrated that SDF-1 enhanced ovarian cancer cell invasion through αvß6 integrin-mediated uPA expression via the p38 MAPK and PI3 K/Akt pathway. Consequently, our findings will provide a new explanation about how SDF-1 aggravates the pathogenesis of ovarian cancer.

Stromal cell-derived factor-1 (SDF-1)/CXCR4 axis enhances cellular invasion in ovarian carcinoma cells via integrin ß1 and ß3 expressions.

Accumulating evidence has showed that stromal cell-derived factor-1 (SDF-1/CXCR4 axis played important roles in cancer metastases, but the detailed function in ovarian cancer is still largely unknown. In the present study, we determined the location of CXCR4 and lipid rafts, a specialized structure on cell membrane, in ovarian cancer tissues and ovarian cancer cell line SKOV3 cells by immunofluorescence. To analyze the role of SDF-1/CXCR4 and lipid rafts in tumor cell migration and invasion, Transwell assay and wound healing assay were also performed. Cytoflowmetry was carried out to determine the participation of integrins. Our data showed that CXCR4 and GM1 (marker of lipid rafts) were expressed in both ovarian cancer tissue and SKOV3 cells, and SDF-1 promoted the invasion and migration of SKOV3 cells, which was mediated by complete lipid rafts. Further studies uncovered that SDF-1 upregulated the expression of integrin ß1 and ß3, two molecules closely related with cancer metastasis. These results indicated that SDF-1 might promote the invasion and metastasis of ovarian cancer by regulating these two integrin molecules.

Regularization path for ν-support vector classification.

The v-support vector classification (v-SVC) proposed by Schölkopf has the advantage of using a regularization parameter v for controlling the number of support vectors and margin errors. However, compared to C-SVC, its formulation is more complicated, and to date there are no effective methods for computing its regularization path. In this paper, we propose a new regularization path algorithm, which is designed on the basis of a modified formulation of v-SVC and traces the solution path with respect to the parameter v. Through theoretical analysis and confirmatory experiments, we show that our algorithm can avoid the infeasible updating path under several assumptions (i.e., Assumptions 1 and 2), and fit the entire solution path in a finite number of steps. When the regularization path of v-SVC is available, a novel approach proposed by Yang and Ong can be applied to obtain the global optimal solution of common validation functions for v-SVC, and the computation for the whole process is minimal. Numerical experiments show that it is more efficient than various kinds of grid search methods for selecting the optimal regularization parameter v.