Fluconazole plus flucytosine is a good alternative therapy for non-HIV and non-transplant-associated cryptococcal meningitis: A retrospective cohort study.

Cryptococcal meningitis (CM) carries a high risk of mortality with increasing incidences in immune competent hosts. Current treatments are not well tolerated, and evaluation of other treatments is needed. Fluconazole and 5-flucytosine in treating immune competent hosts have not been characterised. To evaluate the efficacy of fluconazole and 5-flucytosine in treating non-HIV- and non-transplant-associated CM. We performed a retrospective cohort study of the outcomes in immune competent patients with CM treated with fluconazole and 5-flucytosine or deoxycholate-amphotericin B and 5-flucytosine. The primary outcome was treatment response evaluated at the 12th week after initiation of antifungal therapy. A total of 43 and 47 patients received amphotericin B deoxycholate and 5-flucytosine or fluconazole and 5-flucytosine, respectively. A total of 38 (88.4%) patients cannot tolerate recommended doses of amphotericin B deoxycholate and 5-flucytosine (patients needed dose reduction during the treatment). Patients given fluconazole and 5-flucytosine had higher baseline cryptococcal burdens (median 3632 versus 900 cryptococci/mL, P = 0.008). No significant differences were seen in cryptococcus clearance (74.4% vs 70.2%, P = 0.814), treatment time (39 days, 20-69 days vs 21 days, 7-63 days, P = 0.107) and successful response (including complete and partial responses) rates (69.7% vs 72.3%, P = 0.820). Fluconazole and 5-flucytosine treatment had lower total adverse events (19.1% vs 90.7%, P < 0.001). Fluconazole and 5-flucytosine had relatively high efficacy with few adverse events in treating CM. Fluconazole and 5-flucytosine therapy is promising in patients that do not tolerate or are not suited for amphotericin B deoxycholate treatment.

A genome-wide association study of 23 agronomic traits in Chinese wheat landraces.

Uncovering the genetic basis of agronomic traits in wheat landraces is important for ensuring global food security via the development of improved varieties. Here, 723 wheat landraces from 10 Chinese agro-ecological zones were evaluated for 23 agronomic traits in six environments. All accessions could be clustered into five subgroups based on phenotypic data via discriminant function analysis, which was highly consistent with genotypic classification. A genome-wide association study was conducted for these traits using 52 303 DArT-seq markers to identify marker-trait associations and candidate genes. Using both the general linear model and the mixed linear model, 149 significant markers were identified for 21 agronomic traits based on best linear unbiased prediction values. Considering the linkage disequilibrium decay distance in this study, significant markers within 10 cM were combined as a quantitative trait locus (QTL), with a total of 29 QTL identified for 15 traits. Of these, five QTL for heading date, flag leaf width, peduncle length, and thousand kernel weight had been reported previously. Twenty-five candidate genes associated with significant markers were identified. These included the known vernalization genes VRN-B1 and vrn-B3 and the photoperiod response genes Ppd and PRR. Overall, this study should be helpful in elucidating the underlying genetic mechanisms of complex agronomic traits and performing marker-assisted selection in wheat.

Association of Low Zinc Finger Antiviral Protein Expression with Progression and Poor Survival of Patients with Hepatocellular Carcinoma.

BACKGROUND/AIMS: Zinc finger antiviral protein (ZAP) has been reported to be expressed in hepatocellular carcinoma (HCC), and ZAP expression is associated with apoptotic signaling in cancer cells. This study aimed at investigating the expression of ZAP in HCC cells and its significance in clinical pathology. METHODS: Real-time quantitative PCR and western blot assays were employed to detect ZAP RNA and protein expression in normal human hepatocytes, HCC cells, and five primary HCC cell lines. Immunohistochemistry was performed to detect ZAP expression in 147 paraffin-embedded HCC tissues and adjacent normal tissues. The clinical significance of ZAP expression was analyzed in tissue samples from patients with or without infection by hepatitis B virus (HBV). RESULTS: ZAP expression in HCC cells and human primary HCC cell lines was significantly lower than that of normal human hepatocytes. Among 147 HCC samples, ZAP expression was lower in HCC tissues than in adjacent normal tissues for 107 (77.0%) samples. In patients with HCC and HBV infection, ZAP expression was related to pathological grade (P < 0.05); in HBV-negative patients with HCC, ZAP expression was associated with tumor size (P < 0.05) and clinical stage (P < 0.05). The overall survival time in patients with low ZAP expression was significantly shorter than survival times of those with high ZAP expression (P < 0.05), especially for patients with moderately to well-differentiated HCC (Grade 1-2) and HCC at stage T1 and T2 (P < 0.05). Cox multivariate analysis showed that ZAP expression was an independent predictor of survival of patients with HCC (P < 0.01). CONCLUSION: Low ZAP expression is closely associated with disease progression and poor prognosis for patients with HCC.

Effects of hepatitis C virus infection on the safety of chemotherapy for breast cancer patients.

PURPOSE: Hepatitis C virus (HCV) is one of the major pathogens of chronic viral hepatitis, and approximately 38 million patients are infected with HCV in China. However, little information is available on the effect of HCV infection during chemotherapy for breast cancer and the impact of HCV infection on the toxicity of chemotherapy and targeted therapy. METHODS: We performed a retrospective survey of 835 patients who were diagnosed with breast cancer between January 2010 and December 2015 at our institution. All patients had been screened for HCV infection at the time of breast cancer diagnosis. We retrospectively investigated the toxicities of chemotherapy and the changes in HCV load based on a review of the medical records. RESULTS: A total of 21 patients with positive anti-HCV antibody tests received chemotherapy. The median patient age was 46.3 ± 11.2 years. Four (19.0%) patients exhibited abnormal liver function at baseline. The morbidity of abnormal liver function at baseline was higher in HCV-infected patients (19.0% vs. 0, P = 0.000). Four patients received trastuzumab therapy. Five (23.8%) patients who received chemotherapy developed hepatitis. No patients presented with HCV reactivation. The morbidity of hepatitis and the rate of disruption of chemotherapy were not significantly different between breast cancer patients without HCV infection and those with HCV infection (23.8 vs. 14.2% P = 0.342, 9.5 vs. 5.0% P = 0.619, respectively). CONCLUSION: HCV infection had no adverse impact on chemotherapy in breast cancer patients. However, consulting a gastroenterologist and closely monitoring liver function during the course of chemotherapy may benefit patients.

ß-Functionalization of Indolin-2-one-Derived Aliphatic Acids for the Divergent Synthesis of Spirooxindole γ-Butyrolactones.

ß-Functionalization of indolin-2-one-derived aliphatic acids has been applied in formal [3 + 2] annualtions for catalyst-free and divergent synthesis of two series of structurally interesting 3,3'-spirooxindole γ-butyrolactones that may be attractive for potential drug discovery. These findings also pave the way for further diversity-oriented synthesis of spirooxindoles starting from indolin-2-one-derived aliphatic acids or their derivatives.

Entecavir Combined With Adefovir Ameliorates Patients With Chronic Hepatitis B Who Fail to Respond to Nucleotide (Acid) Analog Monotherapy.

The aim of this study was to evaluate the efficacy and safety of entecavir (ETV) combined treatment with adefovir (ADV) on chronic hepatitic B (CHB) patients who failed to respond to nucleotide (acid) analog (NA) treatment. On this basis, the possible factors in the combined treatment of these patients will be analyzed. The safety, biochemical index, and the possible factors that might affect the ETV and ADV combined treatment at different points in time were retrospectively analyzed. The biochemical index included the following: virological response, hepatitis B virus (HBV) DNA decline, primary nonresponse, biochemical response, and the hepatitis B virus E antigen/hepatitis B virus E antibody seroconversion rate. There were 94 CHB patients and compensated liver cirrhosis patients who received ETV plus ADV treatment for over 12 weeks after failure of treatment with NAs. The authors have also investigated 76 CHB patients (80.9%) and 18 hepatitis B cirrhosis patients (19.1%) in this study. The HBV DNA baseline was 4.4 ± 1.4 log10 IU/mL, and the positive rate of HBeAg before salvage treatment was 78.7% (74/94). The sample sizes were 94, 78, 42, 10, 6, and 1 for follow-up of 24, 48, 96, 144, 192, and 240 weeks, respectively. The virological responses (HBV DNA < 2 log10 IU/mL) and biochemical responses were 52.1%, 74.3%, and 90.4% and 63.1%, 61.6%, and 81.1%, respectively, at 24, 48, and 96 weeks, which showed significant differences (P < 0.001 and P < 0.005, respectively). The HBV DNA decline was presented as mean ± SEM, which were 1.53 ± 1.23, 1.75 ± 1.37, 2.07 ± 1.54, and 2.39 ± 1.77 log10 IU/mL at 12, 24, 48, and 96 weeks, respectively. They showed significant differences compared with the baseline (χ = 8.084, P < 0.05). The rate of primary nonresponse was 30.9% (29/94), and the primary treatment failure rates were 26.6% (25/94), 24.4% (19/78), and 4.8% (2/42) at 24, 48, and 96 weeks, respectively. They all have statistical difference (P = 0.011 < 0.05). There were 23 patients who experienced virological breakthrough after the HBV DNA levels were undetectable, whereas after follow-up for 12-24 weeks, the HBV DNA levels were back to undetectable again. ETV plus ADV treatment is an efficient and safe treatment for CHB and compensated liver cirrhosis patients who experienced NA treatment failure. The high quantity of baseline HBV DNA level is a risk factor for poor efficacy of salvage treatment.

Genome-wide association study of drought-related resistance traits in Aegilops tauschii.

The D-genome progenitor of wheat (Triticum aestivum), Aegilops tauschii, possesses numerous genes for resistance to abiotic stresses, including drought. Therefore, information on the genetic architecture of A. tauschii can aid the development of drought-resistant wheat varieties. Here, we evaluated 13 traits in 373 A. tauschii accessions grown under normal and polyethylene glycol-simulated drought stress conditions and performed a genome-wide association study using 7,185 single nucleotide polymorphism (SNP) markers. We identified 208 and 28 SNPs associated with all traits using the general linear model and mixed linear model, respectively, while both models detected 25 significant SNPs with genome-wide distribution. Public database searches revealed several candidate/flanking genes related to drought resistance that were grouped into three categories according to the type of encoded protein (enzyme, storage protein, and drought-induced protein). This study provided essential information for SNPs and genes related to drought resistance in A. tauschii and wheat, and represents a foundation for breeding drought-resistant wheat cultivars using marker-assisted selection.

Genome-wide association study of phosphorus-deficiency-tolerance traits in Aegilops tauschii.

KEY MESSAGE: Using GWAS, 13 significant SNPs distributed on six of the seven Aegilops tauschii chromosomes (all but 5D) were identified, and several candidate P-deficiency-responsive genes were proposed from searches of public databases. Aegilops tauschii, the wheat (Triticum aestivum) D-genome progenitor, possesses numerous genes for stress resistance, including genes for tolerance of phosphorus (P) deficiency. Investigation of the genetic architecture of A. tauschii will help in developing P-deficiency-tolerant varieties of wheat. We evaluated nine traits in a population of 380 A. tauschii specimens under conditions with and without P application, and we performed genome-wide association studies for these traits using single nucleotide polymorphism (SNP) chips containing 7185 markers. Using a general linear model, we identified 119 SNPs that were significantly associated with all nine traits, and a mixed linear model revealed 18 SNPs associated with all traits. Both models detected 13 significant markers distributed on six of the seven A. tauschii chromosomes (all but 5D). Searches of public databases revealed several candidate/flanking genes related to P-deficiency tolerance. These genes were grouped in five categories by the types of proteins they encoded: defense response proteins, enzymes, promoters and transcription factors, storage proteins, or proteins triggered by P deficiency. The identified SNPs and genes contain essential information for cloning genes related to P-deficiency tolerance in A. tauschii and wheat, and they provide a foundation for breeding P-deficiency tolerant wheat cultivars.

[Naturally occurring NS5B variants resistant to non-nucleoside or nucleoside polymerase inhibitors among treatment-naïve hepatitis C patients in south China].

OBJECTIVE: To determine the prevalence of mutations in the non-structural protein 5B (NS5B) of the hepatitis C virus (HCV),which are associated with natural resistance to non-nucleoside and nucleoside polymerase inhibitors (PIs),in treatment-naive hepatitis C patients in south China. METHODS: A nested PCR protocol that amplified three different regions of NS5B was used to detect the naturally occurring drag-resistant substitutions.Direct PCR sequencing was performed to analyze the sequences. RESULTS: NS5B mutations known to confer resistance to nucleoside PIs,such as A15G,S96T and S282T,were mainly detected in HCV genotype 6a (20/88,22.73%).Of the NS5B mutations known to confer resistance to non-nucleoside PIs,C316N and S365A were detected in HCV genotype lb (60/60,100% and 2/60,3.33%, respectively) and I482L and V499A were mainly detected in HCV genotype 2a (9/9,100% and 4/4,100%, respectively) and HCV genotype 6a (9/9,100% and 4/4,100%, respectively).Other NS5B mutations found in the study population included A1 5S,S365F,S365P,S368A and S368L;although none of these has been previously shown to confer resistance to PIs. CONCLUSION: Naturally occurring dominant PI resistance mutations in NS5B exist in treatment-na(i)ve hepatitis C patients in south China and may be related to the virus genotype.

Finite versus Indefinite Nucleos(t)ide Analogue Therapy of Patients with Chronic Hepatitis B Exhibiting Negative HBsAg Levels after Treatment.

Aim: To determine whether a decrease in HBsAg to <0.05 IU/mL could be a criterion for cessation of finite nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). Methods: This was a retrospective analysis of 6715 patients with CHB between January 1998 and May 2016. Patients were followed up every 12-24 weeks. Among 104 patients achieving HBsAg levels < 0.05 IU/mL, 71 were eligible for inclusion in the analysis: 31 received finite NUC therapy, and 40 received indefinite NUC therapy. In the finite therapy group, 9 patients received no NUC consolidation therapy, 6 received short-term (<1 year) consolidation, and 16 received long-term (>1 year) consolidation. The outcome measures were alanine aminotransferase (ALT), total bilirubin, albumin, hepatitis B virus DNA, and HBsAg levels. Results: Baseline parameters and characteristics at the time when HBsAg levels had fallen to <0.05 IU/mL were similar between the finite and indefinite therapy groups. No patients experienced viral breakthrough/relapse during a median follow-up of 120 weeks. There were little or no differences in long-term outcomes between the finite and indefinite therapy groups and between the short-term and long-term consolidation groups. Conclusions: Discontinuation of NUCs may be acceptable in patients whose HBsAg levels fall to <0.05 IU/mL. Consolidation therapy lasting <1 year appears adequate to prevent poor long-term prognosis.

Analgesic and neuroprotective effects of Baimai Ointment on diabetic peripheral neuropathy.

ETHNOPHARMACOLOGY RELEVANCE: Baimai (BM) ointment, a traditional Tibetan medicine, has been widely used to treat "white vein" disease, paralysis, hemiplegia and claudication caused by trauma, because of its great effects on muscle stretching and collateral activation. As one of the most terrible complications in diabetes patients, diabetes peripheral neuropathy (DPN) is mainly manifested as abnormal pain or numbness in extremities. However, whether BM ointment is a potential drug for DPN treatment is unclear. AIMS OF THE STUDY: The aim of this study was to investigate the therapeutic effects of BM on DPN in a high-fat diet/low-dose of streptozotocin induced type 2 diabetes rat model and explore underlying mechanisms. METHODS: The chemical components of BM were determined by high performance liquid chromatography (HPLC), and the possible targets and related pathways candidates involved in the effects of BM on DPN were predicted using network pharmacology methods. Next, the effects of different doses (1.5, 3.0 and 6.0 g/kg) of BM on physiological changes, pain behaviors, motor nerve conduction velocity (MNCV) in DPN rats were assessed and compared with placebo- and mecobalamine (Meco)-treated DPN controls. Then, the effects of BM on the expression of pain associated genes as well as the phosphorylation of PI3K/AKT and MAPKs pathways in DRG of DPN rats were examined. RESULTS: Through HPLC analysis, curcumin was identified as one of the primary contents of BM. The information from network pharmacology indicated a series of target candidates for BM including IL6, IL10, TNF, CCL2, CXCL12, EGF, VEGFA, BDNF, TGFß1 and TNF, as well as PI3K-AKT and MAPK signaling pathways. Topical treatment of BM significantly improved the hypersensitivity of mechanical and thermal pain, MNCV and the morphological changes and demyelination of sciatic nerve fibers, without affecting the body weight, serum metabolism or blood glucose. The up-regulated levels of neuropeptides Cgrp, Sst, Sp and chemokines Ccl2 and Ccl3 along with the abnormal expression of p-P38, p-ERK and p-AKT in the DRG of DPN rats were alleviated by BM application. CONCLUSION: BM ointment has great activities in relieving pain hypersensitivity, neuroprotecting peripheral nerves damage caused by DPN, which may be related to the inhibition of related neuropeptide (Cgrp, Sst, Sp) and chemokine (Ccl2, Ccl3) expression and the regulation of PI3K/AKT and MAPKs signaling pathways in DRG.

Activated Hepatic Stellate Cells Induce Infiltration and Formation of CD163+ Macrophages via CCL2/CCR2 Pathway.

Background: Activated hepatic stellate cells (aHSCs) regulate the function of immune cells during liver fibrosis. As major innate cells in the liver, macrophages have inducible plasticity. Nevertheless, the mechanisms through which aHSCs regulate macrophages' phenotype and function during liver fibrosis and cirrhosis remain unclear. In this study, we examined the immunoregulatory function of aHSCs during liver fibrosis and explored their role in regulating macrophage phenotype and function. Methods: A total of 96 patients with different stages of chronic hepatitis B-related liver fibrosis were recruited in the study. Metavir score system was used to evaluate the degree of fibrosis. The expression of hepatic CCL2 and M2 phenotype macrophage marker CD163 were detected by immunohistochemistry, and the relationship among hepatic CD163, CCL2, and fibrosis scores were also explored. In the in vitro model, the aHSCs isolated from human liver tissues and THP-1-derived M0-type macrophages (M0MΦ) were co-cultured to observe whether and how aHSCs regulate the phenotype and function of macrophages. To explore whether CCL2/CCR2 axis has a crucial role in macrophage phenotypic changes during liver fibrosis, we treated the M0MΦ with recombinant human CCL2 or its specific receptor antagonist INCB-3284. Furthermore, we used LX2 and TGF-ß-activated LX2 to mimic the different activation statuses of aHSCs to further confirm our results. Results: In patients, the infiltration of M2 macrophages increased during the progression of liver fibrosis. Intriguingly, as a key molecule for aHSC chemotactic macrophage aggregation, CCL2 markedly up-regulated the expression of CD163 and CD206 on the macrophages, which was further confirmed by adding the CCR2 antagonist (INCB 3284) into the cell culture system. In addition, the TGF-ß stimulated LX2 further confirmed that aHSCs up-regulate the expression of CD163 and CD206 on macrophages. LX2 stimulated with TGF-ß could produce more CCL2 and up-regulate other M2 phenotype macrophage-specific markers, including IL-10, ARG-1, and CCR2 besides CD163 and CD206 at the gene level, indicating that the different activation status of aHSCs might affect the final phenotype and function of macrophages. Conclusions: The expression of the M2 macrophage marker increases during liver fibrosis progression and is associated with fibrosis severity. AHSCs can recruit macrophages through the CCL2/CCR2 pathway and induce M2 phenotypic transformation.

Dysregulation of Circulating FGF19 and Bile Acids in Primary Biliary Cholangitis-Autoimmune Hepatitis Overlap Syndrome.

BACKGROUND: Primary biliary cholangitis-autoimmune hepatitis overlap syndrome (PBC-AIH OS), which exhibits features between autoimmune hepatitis and cholestasis, is a common condition and usually shows a progressive course toward cirrhosis and liver failure without adequate treatment. Synthesis of bile acids (BAs) plays an important role in liver injury in cholestasis, and the process is regulated by fibroblast growth factor 19 (FGF19). The overall role of circulating FGF19 in BA synthesis and PBC-AIH OS requires further investigation. METHODS: We analyzed BA synthesis and correlated clinical parameters with serum BAs and FGF19 in 35 patients with PBC-AIH OS. Serum concentrations of 7alpha-hydroxycholest-4-en-3-one (C4) were used to quantify the synthesis of BA directly. RESULTS: Serum FGF19 levels were higher, while C4 levels were substantially lower in PBC-AIH OS patients than those in healthy controls. Circulating FGF19 levels strongly correlated with C4 (r = -0.695, p < 0.0001), direct bilirubin (r = 0.598, p = 0.0001), and total bile acids (r = 0.595, p = 0.002). Moreover, circulating FGF19 levels strongly correlated with the model for end-stage liver disease score (r = 0.574, p = 0.0005) and Mayo risk score (r = 0.578, p = 0.001). CONCLUSIONS: Serum FGF19 is significantly increased in patients with PBC-AIH OS, while BA synthesis is suppressed. Circulating FGF19 primarily controls the regulation of BA synthesis in response to cholestasis and under cholestatic conditions. Therefore, modulation of circulating FGF19 could provide a promising targeted therapy for patients with PBC-AIH OS.

Association between Circulating Growth Differentiation Factor 15 and Cirrhotic Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a common condition that usually shows a progressive course towards cirrhosis without adequate treatment. Growth differentiation factor 15 (GDF15) plays multiple roles in various pathological conditions. The overall role of circulating GDF15 in cirrhotic PBC requires further investigation. Twenty patients with cirrhotic PBC, 26 with non-cirrhotic PBC, and 10 healthy subjects were enrolled between 2014 and 2018, and the serum levels of GDF15 were measured via enzyme immunoassay. The correlations between serum GDF15, weight, biochemical parameters, and the prognosis were analysed. Serum levels of GDF15 were significantly higher in cirrhotic PBC patients than in non-cirrhotic PBC patients or healthy controls (p = 0.009 and p < 0.001, respectively). The circulating GDF15 levels strongly correlated with weight changes (r = -0.541, p = 0.0138), albumin (r = -0.775, p < 0.0001), direct bilirubin (r = -0.786, p < 0.0001), total bile acids (r = 0.585, p = 0.007), and C-reactive protein (r = 0.718, p = 0.0005). Moreover, circulating GDF15 levels strongly correlated with the Mayo risk score (r = 0.685, p = 0.0009) and Model for End-stage Liver Disease score (r = 0.687, p = 0.0008). Determined by the area under the receiver operating characteristic curves, the overall diagnostic accuracies of GDF15 were as follows: cirrhosis = 0.725 (>3646.55 pg/mL, sensitivity: 70.0%, specificity: 69.2%), decompensated cirrhosis = 0.956 (>4073.30 pg/mL, sensitivity: 84.62%, specificity: 100%), and cirrhotic biochemical non-responders = 0.835 (>3479.20 pg/mL, sensitivity: 71.43%, specificity: 92.31%). GDF15 may be a useful and integrated biochemical marker to evaluate not only the disease severity and prognosis but also the nutrition and response to treatment of cirrhotic PBC patients, and its overall performance is satisfactory. Therapy targeting GDF15 is likely to benefit cirrhotic PBC patients and is worth further research.

UV-Induced Photodegradation of Naproxen Using a Nano γ-FeOOH Composite: Degradation Kinetics and Photocatalytic Mechanism.

Naproxen (NPX) is one of the most common pharmaceutical and personal care products found in surface water, which is recalcitrant to degradation by biological treatment or complete removal via traditional sewage treatment processes. In this study, nanoscale γ-FeOOH was synthesized and characterized by X-ray diffraction, scanning electron microscopy, surface analysis, and analysis of the forbidden bandwidth. Under UV irradiation, γ-FeOOH had the capacity to rapidly photodegrade NPX. The photodegradation rate of NPX was dependent on the concentration of γ-FeOOH in solution, initial NPX concentration, and pH. By increasing the concentration of γ-FeOOH, the NPX photodegradation rate was increased and then remained stable. Furthermore, the highest photodegradation rate for NPX was observed under acidic conditions. Through the analysis of the active substances (such as h+, e-, OH, 1O2, and O 2 · - ) by electron spin resonance, the photocatalytic mechanism of NPX degradation on γ-FeOOH was determined to be semiconductor photocatalysis.

Efficacy of tenofovir disoproxil fumarate switch therapy in chronic hepatitis B patients with suboptimal response to adefovir-based combination therapy.

In the present study, the efficacy and safety of tenofovir disoproxil fumarate (TDF) switch therapy were assessed in patients with chronic hepatitis B exhibiting a suboptimal response to adefovir (ADV)-based combination therapy. First, the efficacy of the TDF switch therapy was retrospectively evaluated in 50 patients with chronic hepatitis B who failed to respond to ADV-based combination treatment. Among those, 48 patients with a median age of 35 years were hepatitis B e antigen (HBeAg)-positive and 17, 14 and 19 patients were previously treated with lamivudine (LAM) plus ADV, telbivudine plus ADV and entecavir (ETV) plus ADV, respectively. A total of 41 patients were treated with TDF alone and 9 with TDF plus ETV. The median time of follow-up was 102 weeks. The primary end-point was the cumulative probability of achieving a complete virologic response (CVR). The secondary end-points were the rate of alanine aminotransferase (ALT) normalization, HBeAg seroconversion in HBeAg-positive patients, and the plasma levels of creatinine and creatine kinase. The mean serum hepatitis B virus DNA levels prior to initiation of the TDF switch therapy were 4.8±1.6 log10IU/ml. The cumulative probability of achieving a VR at 24, 48, 96 and 108 weeks was 52.0, 76.0, 89.8 and 94.9%, respectively. The cumulative probability of normalization of ALT at 12, 24, 36, 48, 60,72, 84, 96, 108, 120 and 132 weeks was 34, 44, 50, 58, 66, 70, 74, 80, 90, 92 and 94%, respectively. HBeAg seroconversion was achieved in 5 patients. During the follow-up, 6 patients suffered from a virologic breakthrough, 3 patients failed to respond to the TDF treatment and the remaining patients were able to obtain VR following the continuation of TDF treatment. Slightly elevated serum levels of creatinine were observed in one patient, whereas creatine kinase activity did not increase in any of the subjects. In conclusion, TDF switch therapy is efficient and safe for patients with chronic hepatitis B with a suboptimal response to ADV-based combination therapy.

Efficacy of long-term treatment with tenofovir in Chinese nucleos(t)ide-naïve chronic hepatitis B patients regardless of baseline viral load.

The aim of the present study was to analyze the efficacy and safety of tenofovir (TDF) treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B (CHB) patients, particularly those with a high viral load, a in real-life scenario. A total of 144 nucleos(t)ide-naïve CHB patients who received TDF monotherapy for at least 3 months were retrospectively analyzed. The primary endpoint measure was the achievement of virological response (VR; undetectable serum HBV DNA, <100 IU/ml). The secondary endpoints were alanine aminotransferase (ALT) normalization (ALT < upper limit of normal), hepatitis B e antigen (HBeAg) seroconversion and safety. The median follow-up period was 120 weeks (range, 12-264 weeks). In total, 144, 130, 114, 78, 67, 40 and 13 patients were followed up for at least 12, 24, 48, 96, 144, 192 and 240 weeks, respectively. An incremental trend was observed in the rate of VR: 73.1, 91.3, 98.1, 100, 100 and 100% of the patients exhibited VR at 24, 48, 96, 144, 192 and 240 weeks, respectively. Furthermore, 29 patients with hepatitis B virus (HBV) DNA ≥8 log10 IU/ml at baseline achieved VR during the follow-up period. The proportions of patients achieving normal ALT levels were 72.1, 78.6, 91.2, 95, 96 and 100%, at 24, 48, 96, 144, 192 and 240 weeks, respectively. The rate of HBeAg loss reached 35.6% at week 240. Among the 130 patients, HBV DNA was detectable [partial VR (PVR)] in 35 patients at 24 weeks of follow-up, and 30 of those 35 patients (85.7%) required >24 weeks of further TDF therapy to achieve VR. No serious adverse events were reported. In conclusion, long-term TDF treatment of nucleos(t)ide-naïve chronic hepatitis B patients, regardless of high viral load at baseline, was effective and safe in a real-life scenario. Adjustment of TDF monotherapy may be unnecessary in nucleos(t)ide-naïve patients with PVR at 24 weeks.

Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis.

BACKGROUND AND AIM: Bile acid (BA) synthesis in the liver is regulated by Fibroblast Growth Factor 19 (FGF19) secreted from the ileum as an enterohepatic feedback mechanism. Although FGF19 mRNA is absent in normal liver, FGF19 gene expression was reported to increase in response to both extrahepatic and intrahepatic cholestasis. The impact of upregulated FGF19 expression on BA synthesis is unclear and the overall role of circulating FGF19 and BA synthesis under cholestatic conditions needs to be further investigated. METHODS: BA synthesis was directly quantified by measuring serum concentrations of 7alpha-hydroxycholest-4-en-3-one (C4), along with serum FGF19 and other parameters, in 44 patients with primary biliary cirrhosis (PBC) and 10 healthy subjects. RESULTS: Serum C4 were substantially lower, while those of FGF19 were higher, in cirrhotic PBC patients, as compared to those of either healthy or non-cirrhotic PBC patients. Analyses of the relationships between circulating FGF19, BA synthesis and cholestasis revealed that circulating FGF19 was strongly correlated with BA synthesis (r = -0.735, p<0.0001) and the severity of cholestasis (r = 0.590, p<0.001). Moreover, BA synthesis was found to be strongly correlated with the degree of cholestasis (r = 0.522, p = 0.0005). CONCLUSION: These findings demonstrate that the regulation of BA synthesis in response to cholestasis is primarily controlled by circulating FGF19 and that under cholestatic conditions, the FGF19-BA synthesis feedback mechanism remains intact. Administering FGF19, or suitable mimetic, as a pharmacological intervention to increase circulating levels of FGF19 and suppress BA synthesis by inhibiting CYP7A1 gene expression is likely to provide therapeutic benefits for many PBC patients.

Naturally occurring drug resistance associated variants to hepatitis C virus direct-acting antiviral agents in treatment-naive HCV genotype 1b-infected patients in China.

The direct-acting antiviral agents (DAAs) have drastically improved the prognosis of hepatitis C virus (HCV) patients. However, the resistance-associated variants (RAVs) to DAAs may hamper treatment. There was a lack of data on the prevalence of pre-exist RAVs in Chinese HCV-infected patients. We performed nested PCR assays on 74 HCV genotype 1b-infected patients to amplify HCV viral regions of NS3, NS5A, and NS5B to investigate the prevalence of RAVs to DAAs in treatment-naive HCV genotype1b-infected patients in China. The mutations A156S, T54S, and D168Y of the NS3/4A region were found in 18.33% (11/60), 6.67% (4/60), and 1.67% (1/60) of the successfully amplified cases. Mutations Q30R, L31M, and H58P of the NS5A region were confirmed in 57.63% (34/59), 1.69%(1/59), and 86.44% (51/59) of the cases. Mutations C316N, S365A, M414L, M423I, Y448H, I482T, I482 V, V494L, P495S, and V499A of the NS5B region were detected in 100% (60/60), 3.33% (2/60), 5.88% (3/51), 1.96% (1/51), 1.96% (1/51), 5.88% (3/51), 1.96% (1/51), 3.92% (2/51), 5.88% (3/51), and 15.69% (8/51) of cases, respectively. Naturally occurring RAVs to DAAs pre-exist in treatment-naive Chinese HCV genotype 1b-infected patients and the characteristic is different from that in Europe and the United States. Clinicians should consider RAVs upon the introduction of DAA-based antiviral therapy.

Liver toxicity of chemotherapy and targeted therapy for breast cancer patients with hepatitis virus infection.

BACKGROUND: Chemotherapy has greatly improved the prognosis of breast cancer patients. However, it may also result in undesirable side effects such as hepatitis virus reactivation. Little information is available on the liver toxicity of chemotherapy and targeted therapy for breast cancer patients with hepatitis virus (HBV/HCV) infection. METHODS: We performed a retrospective survey of 835 patients diagnosed with breast cancer between January 2010 and December 2015 at our institution. All patients had been screened for HBV/HCV infection at the time of breast cancer diagnosis. We retrospectively investigated the toxicity of chemotherapy and the changes in HBV/HCV load based on a medical record review. RESULTS: 52 patients with positive anti-HBV antibody test and 21 patients with positive anti-HCV antibody tests received chemotherapy. 762 patients without HBV and HCV infection served as the control group. The morbidity of liver toxicity and disruptions in chemotherapy attributable to liver toxicity were not significantly different among control group, HBV group and HCV groups (27.7% vs 34.6% vs 42.9%, P = 0.189 and 5.0% vs 9.6% vs 9.5%, P = 0.173, respectively). No patients presented with HBV/HCV reactivation. CONCLUSION: Breast cancer patients with HCV can be treated with chemotherapy and targeted therapy with trastuzumab. Breast cancer patients with HBV who accept antiviral therapy can be treated with chemotherapy and targeted therapy with trastuzumab and patients can benefit from prophylactic antiviral therapy before chemotherapy. However, a multidisciplinary cooperation and closely monitoring liver function during the course of chemotherapy may benefit patients.