Measurement of Hyperfine Structure and the Zemach Radius in

We investigate the 2^{3}S_{1}-2^{3}P_{J} (J=0, 1, 2) transitions in ^{6}Li^{+} using the optical Ramsey technique and achieve the most precise values of the hyperfine splittings of the 2^{3}S_{1} and 2^{3}P_{J} states, with smallest uncertainty of about 10 kHz. The present results reduce the uncertainties of previous experiments by a factor of 5 for the 2^{3}S_{1} state and a factor of 50 for the 2^{3}P_{J} states, and are in better agreement with theoretical values. Combining our measured hyperfine intervals of the 2^{3}S_{1} state with the latest quantum electrodynamic (QED) calculations, the improved Zemach radius of the ^{6}Li nucleus is determined to be 2.44(2) fm, with the uncertainty entirely due to the uncalculated QED effects of order mα^{7}. The result is in sharp disagreement with the value 3.71(16) fm determined from simple models of the nuclear charge and magnetization distribution. We call for a more definitive nuclear physics value of the ^{6}Li Zemach radius.

Precision Calculation of Hyperfine Structure and the Zemach Radii of

The hyperfine structures of the 2^{3}S_{1} states of the ^{6}Li^{+} and ^{7}Li^{+} ions are investigated theoretically to extract the Zemach radii of the ^{6}Li and ^{7}Li nuclei by comparing with precision measurements. The obtained Zemach radii are larger than the previous values of Puchalski and Pachucki [Phys. Rev. Lett. 111, 243001 (2013)PRLTAO0031-900710.1103/PhysRevLett.111.243001] and disagree with them by about 1.5 and 2.2 standard deviations for ^{6}Li and ^{7}Li, respectively. Furthermore, our Zemach radius of ^{6}Li differs significantly from the nuclear physics value, derived from the nuclear charge and magnetic radii [Phys. Rev. A 78, 012513 (2008)PLRAAN1050-294710.1103/PhysRevA.78.012513] by more than 6σ, indicating an anomalous nuclear structure for ^{6}Li. The conclusion that the Zemach radius of ^{7}Li is about 40% larger than that of ^{6}Li is confirmed. The obtained Zemach radii are used to calculate the hyperfine splittings of the 2^{3}P_{J} states of ^{6,7}Li^{+}, where an order of magnitude improvement over the previous theory has been achieved for ^{7}Li^{+}.

Sequential combination therapy with pegylated interferon leads to loss of hepatitis B surface antigen and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B patients receiving long-term entecavir treatment.

Nucleos(t)ide analogues rarely result in a durable off-treatment response in chronic hepatitis B infection, whereas pegylated interferon (Peg-IFN) induces a long-lasting response only in a subset of patients. We assessed the effect of sequential combination therapy with Peg-IFN-α2a and entecavir in hepatitis B e antigen (HBeAg)-positive patients with prior long-term entecavir therapy and investigated the predictors of response to treatment. HBeAg-positive individuals who did not achieve HBeAg seroconversion during previous long-term entecavir therapy, receiving Peg-IFN-α2a added to ongoing entecavir therapy (sequential combination [S-C] therapy; n = 81) for 48 weeks or remaining on entecavir monotherapy (n = 116), were retrospectively included. A matched pair was created at a 1:1 ratio from each treatment group. The primary endpoint was HBeAg seroconversion at week 48. Subgroup analysis of response prediction was conducted for 81 patients with S-C therapy. More patients in the S-C therapy group achieved HBeAg seroconversion than those in the entecavir group (44% versus 6%; P < 0.0001). An HBeAg level of <200 signal-to-cutoff ratio (S/CO) at baseline was a strong predictor for higher HBeAg seroconversion than that achieved when HBeAg was ≥200 S/CO (64.2% versus 17.9%; P < 0.0001). Hepatitis B surface antigen (HBsAg) levels at baseline and the decrease in HBsAg levels predicted HBsAg loss in the S-C therapy group. The combination of baseline HBeAg of <200 S/CO and HBsAg of <1,000 IU/ml and an HBsAg decline at week 12 of ≥0.5 log10 IU/ml provided the highest rate of HBeAg seroconversion (92.31%) and HBsAg loss (83.3%) at week 48. Patients receiving sequential combination therapy have a higher rate of HBeAg seroconversion and are more likely to experience HBsAg clearance than do those continuing entecavir monotherapy. Sequential combination therapy can be guided by baseline HBsAg/HBeAg levels and on-treatment HBsAg dynamics.

ERK5 signalling pathway is essential for fluid shear stress-induced COX-2 gene expression in MC3T3-E1 osteoblast.

Bone cells respond to various mechanical stimuli including fluid shear stress (FSS) in vitro. Induction of cyclooxygenase-2 (COX-2) is thought to be important for the anabolic effects of mechanical loading. Recently, extracellular-signal-regulated kinase 5 (ERK5) has been found to be involved in multiple cellular processes. However, the relationship between ERK5 and the induction of COX-2 is still unknown. Here, we investigated the potential involvement of ERK5 in the response of pre-osteoblastic MC3T3-E1 cells upon FSS. MC3T3-E1 cells were subjected to 12 dyn/cm(2) FSS. Then, we established a ERK5 small interfering RNA (siRNA) transfected cell line using the MC3T3-E1 cells. After the successful transfection confirmed by real-time reverse transcription-polymerase chain reaction and Western blotting, the expression of COX-2, cAMP response element-binding protein (CREB), and nuclear factor kappa B cells (NF-κB) were assayed for downstream effectors of activated ERK5 under FSS by Western blotting. Our results showed that FSS could stimulate COX-2 activity, and induce the phosphorylation of ERK5, CREB, and NF-κB. When the MC3T3-E1 cells were transfected using siRNA before exposure to FSS, COX-2 activity was suppressed, and the phosphorylation of CREB and NF-κB was significantly downregulated. In summary, we demonstrated that ERK5 pathway is essential in the induction of COX-2 gene.

The MEK5/ERK5 pathway mediates fluid shear stress promoted osteoblast differentiation.

The aim of this study was to determine the role of the mitogen-activated protein kinase kinase (MEK) 5/extracellular signal-regulated kinase (ERK) 5 pathway in osteoblast differentiation promoted by intermittent fluid shear stress (FSS). MC3T3-E1 osteoblastic cells were subjected to 12 dyn/cm(2) intermittent FSS, and the phenotypic markers for osteoblast differentiation, such as alkaline phosphatase (ALP) activity and expression of osteopontin (OPN) and osteocalcin (OCN), were then examined. The results showed that intermittent FSS could stimulate ERK5 phosphorylation, ALP activity and the expression of OPN and OCN. When the MEK5/ERK5 pathway was selectively inhibited by BIX02189, ALP activity was suppressed, and the expression of OPN and OCN was downregulated. Intermittent FSS induce the expression of Runt-related transcription factor-2 (Runx-2), which is involved in osteoblast differentiation by promoting the transcription of the above genes. Furthermore, the expression of Runx-2 was also reduced after treatment with BIX02189. Finally, we found that intermittent FSS was a more intense stimulus than steady FSS for promoting osteoblast differentiation. In summary, our results suggest that the MEK5/ERK5 pathway mediates osteoblast differentiation promoted by intermittent FSS, which was more effective than steady FSS in the differentiation process. The MEK5/ERK5 pathway also mediates FSS-induced Runx-2 expression in osteoblast differentiation.

Secondary prophylaxis of variceal bleeding for cirrhotic patients: a multiple-treatments meta-analysis.

OBJECTIVE: To evaluate comprehensively the effects of 12 prophylaxis interventions for secondary prophylaxis of variceal bleeding using multiple-treatments meta-analysis. METHODS: PubMed, EMBASE and the Cochrane Library were searched prior to November 2011. Randomized controlled trials (RCTs) comparing the interventions for secondary prophylaxis of variceal bleeding. The primary study outcomes were variceal rebleeding, mortality due to rebleeding and mortality due to all causes. RESULTS: We systematically reviewed 51 RCTs. Transjugular intrahepatic portosystemic shunt (TIPS), ß-blockers combined with endoscopic injection sclerotherapy (EIS) and endoscopic banding ligation (EBL) combined with EIS were superior to ß-blockers [odds ratios (OR) 0·13, 0·23 and 0·13, respectively] and EIS (0·19, 0·34 and 0·18, respectively) in reducing the rate of rebleeding. To reduce the mortality rate due to rebleeding, TIPS was more efficacious than ß-blockers (0·11), EBL (0·13), EIS (0·19), ß-blockers combined with isosorbide-5-mononitrate (5-ISMN) (0·16) and ß-blockers combined with EIS (0·14). In addition, ß-blockers combined with 5-ISMN were significantly more efficacious than ß-blockers (0·56) and EBL (0·64) to reduce the mortality rate due to all causes. EBL combined with argon plasma coagulation showed the best profile of reduction in rebleeding rate and mortality rate due to all causes. To reduce the mortality rate due to rebleeding, TIPS had the highest probability. EBL combined with EIS was the best choice according to the cumulative probabilities of being among the three most efficacious interventions for the three outcomes. CONCLUSIONS: Endoscopic banding ligation combined with EIS might be the first choice in the secondary prophylaxis of varices bleeding.

Expression Pattern of Cytokines in Patients with Chronic Hepatitis B Receiving PEGinterferon Therapy.

Purpose: Chronic hepatitis B virus (CHB) infection is a worldwide health problem. Polyethylene glycol (PEG)ylated interferon (PEG-IFN) is an available therapy for CHB that has antiviral and immunomodulatory effects. However, PEG-IFN therapy is limited by the fact that only a subset of patients show a sustained response, its severe side effects, and high cost. The aim of this study was to explore novel biomarkers for the early prediction of PEG-IFN treatment response and to uncover its underlying mechanism. Patients and Methods: We enrolled 10 paired patients with Hepatitis B e antigen (HBeAg)-positive CHB who received PEG-IFN-α2a monotherapy. Patient serum samples were collected at 0, 4, 12, 24, and 48 weeks and serum samples were collected from eight healthy people as healthy controls. For confirmation, we enrolled 27 patients with HBeAg-positive CHB receiving PEG-IFN therapy and serum samples at 0 and 12 weeks were obtained. Serum samples were analyzed using Luminex technology. Results: Among 27 assessed cytokines, 10 cytokines were identified to have high expression levels. Among them, six cytokines had significant differences in their levels between the patients with HBeAg-positive CHB and the healthy controls (P < 0.05). Potentially, treatment response could be predicted using the early time points of 4, 12, and 24 weeks. Moreover, after 12 weeks of PEG-IFN treatment, increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines were observed. The fold change of IP-10 between 12 weeks and 0 weeks correlated with the decrease in ALT levels from 0 to 12 weeks (r = 0.2675, P = 0.0024). Conclusion: In patients with CHB, we observed a certain pattern in the levels of cytokines during treatment with PEG-IFN, and the cytokine IP-10 might be a potential biomarker for treatment response.

RON in hepatobiliary and pancreatic cancers: Pathogenesis and potential therapeutic targets.

The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family. Research has shown that RON has a role in cancer pathogenesis, which places RON on the frontline of the development of novel cancer therapeutic strategies. Hepatobiliary and pancreatic (HBP) cancers have a poor prognosis, being reported as having higher rates of cancer-related death. Therefore, to combat these malignant diseases, the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis, and the development of RON as a drug target for therapeutic intervention should be investigated. Abnormal RON expression and signaling have been identified in HBP cancers, and also act as tumorigenic determinants for HBP cancer malignant behaviors. In addition, RON is emerging as an important mediator of the clinical prognosis of HBP cancers. Thus, not only is RON significant in HBP cancers, but also RON-targeted therapeutics could be developed to treat these cancers, for example, therapeutic monoclonal antibodies and small-molecule inhibitors. Among them, antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials.

Histological outcome for chronic hepatitis B patients treated with entecavir vs lamivudine-based therapy.

AIM: To compare the histological outcome of chronic hepatitis B (CHB) patients treated with entecavir (ETV) or lamivudine (LAM)-based therapy. METHODS: We conducted a retrospective analysis of data from 42 CHB patients with advanced fibrosis (baseline Ishak score ≥ 2) or cirrhosis who were treated with ETV or LAM-based therapy in Beilun People's Hospital, Ningbo between January 2005 and May 2012. The patients enrolled were more than 16 years of age and underwent a minimum of 12 mo of antiviral therapy. We collected data on the baseline characteristics of each patient and obtained paired liver biopsies pre- and post-treatment. The Knodell scoring system and Ishak fibrosis scores were used to evaluate each example. An improvement or worsening of necroinflammation was defined as ≥ 2-point change in the Knodell inflammatory score. The progression or regression of fibrosis was defined as ≥ 1-point change in the Ishak fibrosis score. The continuous variables were compared using t-test or Mann-Whitney test, and the binary variables were compared using χ(2) test or Fisher's exact test. The results of paired liver biopsies were compared with a Wilcoxon signed rank test. RESULTS: Nineteen patients were treated with ETV and 23 patients were treated with LAM therapy for a mean duration of 39 and 42 mo, respectively. After long-term antiviral treatment, 94.74% (18/19) of the patients in the ETV arm and 95.65% (22/23) in the LAM arm achieved an HBV DNA level less than 1000 IU/mL. The majority of the patients (94.74% in the ETV arm and 73.91% in the LAM arm) had normalized ALT levels. The median Knodell necroinflammatory score decreased from 11 to 0 in the patients receiving ETV, and the median Knodell score decreased from 9 to 3 in the patients receiving LAM (P = 0.0002 and < 0.0001, respectively). The median Ishak fibrosis score showed a 1-point reduction in ETV-treated patients and a 2-point reduction in LAM-treated patients (P = 0.0019 and 0.0205, respectively). The patients receiving ETV showed a more significant improvement in necroinflammation than the LAM-treated patients (P = 0.0003). However, there was no significant difference in fibrotic improvement between the two arms. Furthermore, two patients in each arm achieved a fibrosis score of 0 post-treatment, which indicates a full reversion of fibrosis after antiviral therapy. CONCLUSION: CHB patients with advanced fibrosis or cirrhosis benefit from antiviral treatment. ETV is superior to LAM therapy in improving necroinflammatory but not fibrotic outcome.

LPS pretreatment ameliorates D-galactosamine/lipopolysaccharide-induced acute liver failure in rat.

Acute liver failure (ALF) remains an extremely poor prognosis and high mortality; with no effective treatments. The endotoxin tolerance (ET) phenotype has been reported to exhibit protective activities in several sepsis models. We now investigated the effects and underlying intraperitoneal injection of the same volume of pyrogen-free 0.9% sodium chloride instead of LPS for five consecutive days before D-GalN/LPS injection in rats. The serum levels of TNF-α, IL-6, ALT, AST and TBiL from ET + ALF group and ALF group were measured at different time points. Our results showed that ET + ALF group markedly reduced the serum levels of TNF-α, IL-6, ALT, AST and TBiL and histological features in the ET + ALF group were improved significantly. Furthermore, LPS pre-treatment inhibited D-GalN/LPS-induced NF-κB activation, Bax activation, signal transducer and activator of transcription-1 (STAT1) and signal transducer and activator of transcription-3 (STAT3) activities. LPS pre-treatment also significantly enhance the expression of suppressors of cytokine signaling 1 (SOCS1) and suppressors of cytokine signaling 3 (SOCS3). Our experimental data indicated that ET might alleviate D-GalN/LPS-induced ALF by inhibiting the inflammatory response, inactivation of STAT1 and STAT3 and up-regulation of SOCS1 and SOCS3.

A new strategy for treatment of liver fibrosis: letting MicroRNAs do the job.

MicroRNAs (miRNAs) are short, endogenous, noncoding RNA molecules that regulate gene expression at a post-translational level. MiRNAs have been recognized in the regulation of physiological conditions. Moreover, awareness of the association between dysregulated miRNAs and human diseases is increasing, which consequently brings miRNAs to the frontline in the development of novel therapeutic strategies. We review the latest advances in our knowledge of the involvement of miRNAs in fibrosis with particular emphasis on hepatic fibrosis and the possibilities in the near future for miRNA-based therapy for targeted treatment of liver fibrosis. With recent advances in our understanding of the important role of senescence in the resolution of activated hepatic stellate cells (HSCs), we suggested the therapeutic potential of inducing activated HSCs into senescence by an miRNA-based strategy.

Bone morphogenetic protein 7 suppresses the progression of hepatic fibrosis and regulates the expression of gremlin and transforming growth factor ß1.

Bone morphogenetic protein 7 (BMP-7), a member of the transforming growth factor (TGF)-ß superfamily, counteracts the effect of TGF-ß through different signaling pathways, and gremlin is considered as one of the antagonists of BMP-7. The aim of this study was to investigate the antifibrotic effect of BMP-7, and to clarify the expression patterns of gremlin and TGF-ß1 in the progression of hepatic fibrosis after treatment with BMP-7. A mouse liver fibrosis model was induced by hypodermic injection of CCL4 and all the liver and blood samples were preserved for further study. Reverse transcription-polymerase chain reaction was used for detecting mRNA expression, and protein levels and localization were measured by western blotting and immunohistochemistry, respectively. The improvement of liver function and the regression of hepatic fibrosis were demonstrated by the parameters of a liver test and a histopathological assay, owing to the downregulated expression of COL-I, α-SMA, TIMP-2 and upregulated MMP-2. Moreover, exogenous BMP-7 appeared to suppress the expression of TGF-ß1 and increase the levels of gremlin. In conclusion, hepatic fibrosis was ameliorated by the administration of BMP-7, and the expression of gremlin and TGF-ß1 were regulated by BMP-7. The identification of the dynamic expression pattern of gremlin may yield a novel biomarker for assessing the degree of hepatic fibrosis.

An unprecedented double-bridging interpenetrating α-Po network based on a new heterometallic cluster {Cu4Mo6}.

A new coordination polymer of polyoxomolybdate, {[Cu(4)(bbp)(5)Mo(6)O(22)]·(H(2)O)(4)}(∞) (bbp = 1,4-bis(benzoimidazol-1-yl)phenyl), has been synthesized under solvothermal reaction, which represents a double-bridging interpenetrating α-Po network based on the bimetallic cluster {Cu(4)Mo(6)}. The thermogravimetric and electrochemical behaviors have also been studied.