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Background and Aims: Hepatitis B virus (HBV) vaccination programs in Taiwan are one of the earliest programs in the world and have largely reduced the prevalence of HBV infection. We aimed to demonstrate the vaccination efficacy after 35 years and identify gaps toward HBV elimination., Methods: A total of 4717 individuals aged 1-60 years were recruited from four administrative regions based on the proportion of population distribution. Serum levels of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were assessed. HBV viral load, genotypes and HBsAg 'ɑ' determinant variants were evaluated if indicated., Results: After 35 years of vaccination, the overall seropositivity rates for HBsAg and anti-HBc in Taiwan were 4.05% and 21.3%, respectively. The vaccinated birth cohorts exhibited significantly lower seropositivity rates for both markers compared to the unvaccinated birth cohorts (HBsAg: 0.64% vs. 9.78%; anti-HBc: 2.1% vs. 53.55%, respectively; p < 0.0001). Maternal transmission was identified as the main route of HBV infection in breakthrough cases. Additionally, increased prevalences of genotype C and HBsAg escape mutants were observed., Conclusion: The 35-year universal HBV vaccination program effectively reduced the burden of HBV infection, but complete eradication of HBV infection has not yet been achieved. In addition to immunization, comprehensive screening and antiviral therapy for infected individuals, especially for pregnant women, are crucial strategies to eliminate HBV., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: The immunologic features involved in the immune-tolerant phase of chronic hepatitis B (CHB) virus (HBV) infection are unclear. The hepatitis B virus X (HBx) protein disrupts IFN-β induction by downregulating MAVS and may destroy subsequent HBV-specific adaptive immunity. We aimed to analyse the impacts of genetic variability of HBx in CHB patients on the immune-tolerant phase during long-term follow-up., Methods: Children with CHB in the immune-tolerant phase were recruited and followed longitudinally. HBx gene sequencing of infecting HBV strains was performed, and the effects of HBx mutations on the immune-tolerant phase were assessed. Restoration of the host immune response to end the immune-tolerant phase was investigated by immunoblotting, immunostaining, ELISA and reporter assays of MAVS/IFN-β signalling in liver cell lines, patient liver tissues and the HBV plasmid replication system., Results: A total of 173 children (median age, 6.92 years) were recruited. Patients carrying HBx R87G, I127V and R87G + I127V double mutations exhibited higher cumulative incidences of immune-tolerant phase breakthrough (p = .011, p = .006 and p = .017 respectively). Cells transfected with HBx R87G and I127V mutants and pHBV1.3-B6.3 replicons containing the HBx R87G and I127V mutations exhibited statistically increased levels of IFN-β, especially under poly(I:C) stimulation or Flag-MAVS cotransfection. HA-HBx wild-type interacted with Flag-MAVS and enhanced its ubiquitination, but this ability was diminished in the R87G and I127V mutants., Conclusions: HBx suppresses IFN-β induction. R87G and I127V mutation restored IFN-β production by preventing MAVS degradation, contributing to curtailing the HBV immune-tolerant phase in CHB patients., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mindin is important in broad spectrum of immune responses. On the other hand, we previously reported that mindin attenuated human colon cancer development by blocking angiogenesis through Egr-1-mediated regulation. However, the mice original mindin directly suppressed the syngenic colorectal cancer (CRC) growth in our recent study and we aimed to further define the role of mindin during CRC development in mice. We established the mouse syngeneic CRC CMT93 and CT26 WT cell lines with stable mindin knock-down or overexpression. These cells were also subcutaneously injected into C57BL/6 and BALB/c mice as well as established a colitis-associated colorectal cancer (CAC) mouse model treated with lentiviral-based overexpression and knocked-down of mindin. Furthermore, we generated mindin knockout mice using a CRISPR-Cas9 system with CAC model. Our data showed that overexpression of mindin suppressed cell proliferation in both of CMT93 and CT26 WT colon cancer cell lines, while the silencing of mindin promoted in vitro cell proliferation via the ERK and c-Fos pathways and cell cycle control. Moreover, the overexpression of mindin significantly suppressed in vivo tumour growth in both the subcutaneous transplantation and the AOM/DSS-induced CAC models. Consistently, the silencing of mindin reversed these in vivo observations. Expectedly, the tumour growth was promoted in the CAC model on mindin-deficient mice. Thus, mindin plays a direct tumour suppressive function during colon cancer progression and suggesting that mindin might be exploited as a therapeutic target for CRC., (© 2020 Zhongshan Hospital affiliated to Xiamen University, China. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

G-quadruplexes form folded structures because of tandem repeats of guanine sequences in DNA or RNA. They adopt a variety of conformations, depending on many factors, including the type of loops and cations, the nucleotide strand number, and the main strand polarity of the G-quadruplex. Meanwhile, the different conformations of G-quadruplexes have certain influences on their biological functions, such as the inhibition of transcription, translation, and DNA replication. In addition, G-quadruplex binding proteins also affect the structure and function of G-quadruplexes. Some chemically synthesized G-quadruplex sequences have been shown to have biological activities. For example, bimolecular G-quadruplexes of AS1411 act as targets of exogenous drugs that inhibit the proliferation of malignant tumours. G-quadruplexes are also used as vehicles to deliver nanoparticles. Thus, it is important to identify the factors that influence G-quadruplex structures and maintain the stability of G-quadruplexes. Herein, we mainly discuss the factors influencing G-quadruplexes and the synthetic G-quadruplex, AS1411. SIGNIFICANCE OF THE STUDY: This review summarizes the factors that influence G-quadruplexes and the functions of the synthetic G-quadruplex, AS1411. It also discusses the use of G-quadruplexes for drug delivery in tumour therapy., (© 2020 The Authors. Cell Biochemistry and Function published by John Wiley & Sons Ltd.)

Background: Maternal anti-viral treatment prevents mother-to-infant transmission of hepatitis B virus (HBV), but the role of neonatal viremia on subsequent HBV infection is not clear., Aims: To investigate the effect of maternal anti-viral treatment on neonatal serum HBV DNA and hepatitis B surface antigen (HBsAg) in infants born to highly viremic mothers and the roles of neonatal markers in predicting chronic HBV infection in children., Methods: Serum HBV DNA and HBsAg were tested in children. Of the 201 pregnant mothers, 110 received tenofovir during the third trimester. Chronic infection in children was defined by HBsAg seropositivity at 6 or 12 months lasting more than 6 months., Results: The maternal HBV viral loads from baseline to delivery were 8.25 ± 0.48 to 4.29 ± 0.98 log 10  IU/mL; and 8.29 ± 0.49 to 8.12 ± 0.68 log 10  IU/mL in the tenofovir and control group respectively. Of the 208 children, those in the tenofovir group had a lower rate of neonatal HBV DNA seropositivity at birth (5.22% vs 30.11%, P < 0.0001) and HBsAg seropositivity at 6 months (1.74% vs 11.83%, P = 0.003) and 12 months (1.74% vs 10.75%, P = 0.007). In a first multivariate analysis, maternal HBV DNA level at delivery (odds ratio = 1.70, P = 0.0172) and neonatal HBsAg positivity (odds ratio = 19.37, P < 0.0001) were significantly associated with children's chronic HBV infection. In a second model, neonatal HBV DNA positivity was a strong independent influence variable (odds ratio = 61.89, P = 0.0002)., Conclusions: Maternal tenofovir therapy decreased maternal viral load and neonatal viremia. Positive neonatal HBV DNA was highly correlated with chronic HBV infection in children. Clinical Trial Identifier: NCT01312012., (© 2019 John Wiley & Sons Ltd.)

Background and Aims: Despite the success of universal infant immunization initiated in Taiwan in 1984, occult hepatitis B virus infection (OBI) and circulating surface antigen mutants remain potential obstacles for eventual eradication of HBV infection., Methods: From 3299 apparently healthy, neonatally-vaccinated subjects (<30 years of age ) enrolled during 2014 serosurvey, we recruited all HBsAg-positive (n = 17), all HBsAg-negative but anti-HBc-positive (n = 132) and randomly selected HBsAg-negative and anti-HBc-negative subjects (n = 411). These recruited subjects and 81 HBsAg-negative children with various forms of hepatitis and multiple transfusions were analysed for serum HBV DNA., Results: In healthy, HBsAg-negative subjects, OBI frequency was higher in anti-HBc-positive than anti-HBc-negative individuals (8/90[8.9%] vs 8/301[2.7%], P = 0.0192) aged <18-years, but was not different between anti-HBc-positive and anti-HBc-negative individuals (0/11[0%] vs 3/110[2.7%], P > 0.05) aged 18 to 30 years. OBI occurred more frequently in children of HBsAg-positive mothers than in children of HBsAg-negative mothers (10/101 [9.9%] vs 1/75 [1.3%], P = 0.025). The prevalence of surface 'a' determinant (aa110-160) mutants was 13.3% (2/15) in OBI subjects compared to 36.4% (4/11) in HBsAg-positive subjects (P > 0.05). OBI was found in 30% (3/10) of serologic 'non-A to E' viral hepatitis, 14.3% (3/21) of chronic hepatitis C and 2.0% (1/50) of multitransfused, thalassemic children., Conclusions: In this highly immunized population, surface antigen mutant infection is uncommon and has low contribution to OBI development. HBsAg screening plus highly sensitive HBV DNA assays are needed for assurance of blood supply safety. Multiple transfusions from HBsAg-negative blood donors rarely result in persistent HBV infection. HBV might be related to some of serologic 'non-A to E' viral hepatitis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mindin has a broad spectrum of roles in the innate immune system, including in macrophage migration, antigen phagocytosis and cytokine production. Mindin functions as a pattern-recognition molecule for microbial pathogens. However, the underlying mechanisms of mindin-mediated phagocytosis and its exact membrane receptors are not well established. Herein, we generated mindin-deficient mice using the CRISPR-Cas9 system and show that peritoneal macrophages from mindin-deficient mice were severely defective in their ability to phagocytize E  coli. Phagocytosis was enhanced when E  coli or fluorescent particles were pre-incubated with mindin, indicating that mindin binds directly to bacteria or non-pathogen particles and promotes phagocytosis. We defined that 131 I-labelled mindin binds with integrin Mac-1 (CD11b/CD18), the F-spondin (FS)-fragment of mindin binds with the α M -I domain of Mac-1 and that mindin serves as a novel ligand of Mac-1. Blockade of the α M -I domain of Mac-1 using either a neutralizing antibody or si-Mac-1 efficiently blocked mindin-induced phagocytosis. Furthermore, mindin activated the Syk and MAPK signalling pathways and promoted NF-κB entry into the nucleus. Our data indicate that mindin binds with the integrin Mac-1 to promote macrophage phagocytosis through Syk activation and NF-κB p65 translocation, suggesting that the mindin/Mac-1 axis plays a critical role during innate immune responses., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: Treatment for laryngopharyngeal reflux disease (LPRD) is challenging because of delays in recognition and poor responsiveness to proton-pump inhibitor therapy. The aim of this study was to determine the efficacy and safety of liquid alginate suspension for treating LPRD., Methods: A double-blind, placebo-controlled, prospective study comparing 8 weeks of treatment with Alginos Oral Suspension (TTY Biopharm Co. Ltd., Taipei, Taiwan) (sodium alginate 1,000 mg three times daily) with a placebo was conducted on patients who fulfilled the criteria of at least one symptom consistent with LPRD, a total reflux symptom index (RSI) score of > 10, and a total reflux finding score (RFS) of > 5. Those with erosive gastroesophageal reflux disease, as evidenced through screened transnasal upper gastrointestinal endoscopy, were excluded. Efficacy was assessed by RSI, RFS, and ambulatory multichannel intraluminal impedance and pH (MII-pH) monitoring., Results: A total of 80 patients aged 22 to 72 years were enrolled. Compared with baseline, both Alginos (TTY Biopharm Co. Ltd.) and the placebo significantly reduced the total RSI (P < 0.001) and the total number of reflux episodes shown by MII-pH monitoring (P < 0.05) after 8 weeks of treatment. However, liquid alginate suspension was unable to show superiority over the placebo. The incidence of various adverse events from Alginos (TTY Biopharm Co. Ltd.) was relatively low (7.7%) and mild., Conclusion: This study showed that liquid alginate suspension was well tolerated by LPRD patients. It effectively improved symptoms and reflux numbers but was unable to show superiority over placebo. As observed in previous studies, a great placebo effect was present. The importance of lifestyle modification could not be overlooked., Level of Evidence: 2. Laryngoscope, 128:2252-2260, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Aims: Remote ischemic conditionings, such as pre- and per-conditioning, are known to provide cardioprotection in animal models of ischemia. However, little is known about the neuroprotection effect of postconditioning after cerebral ischemia. In this study, we aim to evaluate the motor function rescuing effect of remote limb ischemic postconditioning (RIPostC) in a rat model of acute cerebral stroke., Methods: Left middle cerebral artery occlusion (MCAO) was performed to generate the rat model of ischemic stroke, followed by daily RIPostC treatment for maximum 21 days. The motor function after RIPostC was assessed with foot fault test and balance beam test. Local infarct volume was measured through MRI scanning. Neuronal status was evaluated with Nissl's, HE, and MAP2 immunostaining. Lectin immunostaining was performed to evaluate the microvessel density and area., Results: Daily RIPostC for more than 21 days promoted motor function recovery and provided long-lasting neuroprotection after MCAO. Reduced infarct volume, rescued neuronal loss, and enhanced microvessel density and size in the injured areas were observed. In addition, the RIPostC effect was associated with the up-regulation of endogenous tissue kallikrein (TK) level in circulating blood and local ischemic brain regions. A TK receptor antagonist HOE-140 partially reversed RIPostC-induced improvements, indicating the specificity of endogenous TK mediating the neuroprotection effect of RIPostC., Conclusion: Our study demonstrates RIPostC treatment as an effective rehabilitation therapy to provide motor function recovery and alleviate brain impairment in a rat model of acute cerebral ischemia. We also for the first time provide evidence showing that the up-regulation of endogenous TK from remote conditioning regions underlies the observed effects of RIPostC., (© 2018 John Wiley & Sons Ltd.)

Background: Biliary atresia (BA) is a paediatric cholestatic disease characterized by a progressive fibro-inflammation of the biliary tree. Current treatment of choice is to establish good bile flow via the Kasai operation., Aims: We aimed to identify outcome-predictive serum biomarkers in BA infant., Methods: Thirty-three BA children recruited from 1986 to 2007 served as the baseline-study group. An additional 11 children recruited from 2008 to 2011 served as the validation group. Serum samples were collected immediately before and 6 months after the Kasai operation for the assessment of serum cytokines, including tumour necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-10, IL-12p40 and IL-12p70 as the candidate biomarkers., Results: Increased serum TGF-β levels indicated a lower Knodell hepatitis activity index at Kasai operation. The serum TGF-β levels declined after the operation. Serum IL-12p40 levels before the Kasai operation were higher in the subjects with a 3-month jaundice-free status than in others (P = 0.001). A serum pre-operative IL-12p40 level of 33 pg/ml was predictive of a 3-month jaundice-free status after surgery (positive predictive value=81.0%; negative predictive value=83.3%). This biomarker was also predictive of a better outcome, in terms of 3-year survival with native liver (risk ratio [RR = 4.00]; P < 0.001), and 3-year jaundice-free survival with native liver (RR = 12.00; P < 0.001). We confirmed the predictive power of a high pre-operative IL-12p40 level on 3-month jaundice-free status in the validation group., Conclusions: The pre-operative IL-12p40 level was a good predictive biomarker of clinical outcome in children with BA undergoing the Kasai operation., (© 2012 John Wiley & Sons A/S.)

Background and Aims: This cohort study investigated the long-term effect of maternal hepatitis B virus (HBV) sero-status on the spontaneous HBeAg seroconversion in offspring with chronic HBV infection., Methods: A total of 185 HBeAg-positive chronic HBV-infected children, with maternal HBV seromarkers checked, were enrolled. The median age at enrolment and follow-up duration was 5.7 years (range, neonate to 16.5 years) and 20.2 years (range, 4.2-31.0 years) respectively. These children were grouped according to the initial maternal HBsAg and HBeAg status: (i) children of non-carrier mothers (n=48); (ii) children of HBeAg-negative chronic HBV-infected mothers (n=57); (iii) children of HBeAg-positive chronic HBV-infected mothers (n=80). HBV seromarkers and liver function profiles of these children were performed at 6-month intervals., Results: One hundred and twenty-one (65.4%) subjects had achieved spontaneous HBeAg seroconversion at the end of this follow-up study. Spontaneous HBeAg seroconversion was achieved in 83.3% of children with non-carrier mothers, 73.7% of children with HBeAg-negative chronic HBV-infected mothers and 48.8% of children with HBeAg-positive mothers during similar duration (P<0.001). Positive maternal HBeAg and genotype C were associated with delayed spontaneous HBeAg seroconversion in multivariate analysis (P=0.01 and P=0.002 respectively). In children of HBeAg-positive chronic HBV-infected mothers, persistent presence of maternal HBeAg showed a trend of association with delayed HBeAg seroconversion in their offspring (P=0.06). Children of late maternal HBeAg seroconversion (>40 years old) had delayed HBeAg seroconversion compared with those of early HBeAg seroconversion mothers (P=0.06)., Conclusions: Persistence of maternal HBeAg is an important risk factor for delayed spontaneous HBeAg seroconversion in children with chronic HBV infection., (© 2011 John Wiley & Sons A/S.)

The asymmetric unit of the title compound, C(8)H(9)Cl(2)NO, contains two crystallographically independent mol-ecules which are connected via an N-H⋯O hydrogen bond . There is aromatic π-π stacking in the crystal, with a centroid-centroid distance between benzene rings of 3.48 (2)Å. The crystal packing is stabilized by intermolecular hydrogen bonds.

Background: This study aimed to investigate the roles of tumour necrosis factor-α (TNF-α) gene polymorphisms in the spontaneous clearance of HBsAg after a hepatitis B virus (HBV) infection., Methods: Polymorphisms in the TNF-α (-1031 T to C, -863 C to A, -857 C to T, -308 G to A and -238 G to A transition) gene were evaluated in 274 chronic HBV-infected patients and 194 patients with resolved HBV infection. The peripheral blood mononuclear cells (PBMC) isolated from 77 (28%) of the 274 chronic HBV-infected patients with negative HBeAg and positive antibody to HBeAg were stimulated with HBcAg. Data on TNF-α genotypes and phenotypes in subjects with/without the A allele at the TNF-α-863 promoter single nucleotide polymorphism (rs1800630) were compared., Results: The A allele in the -863 promoter region of the TNF-α gene was present in 154 (56.2%) chronic HBV-infected patients and 87 (44.8%) patients who recovered from HBV infection (odds ratio 1.58; P<0.01). The TNF-α-863 A allele genotype predicted lower TNF-α production by PBMC after in vitro HBcAg stimulation (P<0.02)., Conclusions: The A allele at the -863 locus of the promoter region of the TNF-α gene predicts lower HBcAg-inducible TNF-α secretion. It is also associated with chronicity of HBV infection., (© 2010 John Wiley & Sons A/S.)