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Targeted protein degradation technology has gained substantial momentum over the past two decades as a revolutionary strategy for eliminating pathogenic proteins that are otherwise refractory to treatment. Among the various approaches developed to harness the body's innate protein homeostasis mechanisms for this purpose, lysosome targeting chimeras (LYTACs) that exploit the lysosomal degradation pathway by coupling the target proteins with lysosome-trafficking receptors represent the latest innovation. These chimeras are uniquely tailored to degrade proteins that are membrane-bound and extracellular, encompassing approximately 40% of all proteome. Several novel LYTAC formulas have been developed recently, providing valuable insights for the design and development of therapeutic degraders. This review delineates the recent progresses of LYTAC technology, its practical applications, and the factors that dictate target degradation efficiency. The potential and emerging trends of this technology are discussed as well. LYTAC technology offers a promising avenue for targeted protein degradation, potentially revolutionizing the therapeutic landscape for numerous diseases., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Objective: This cross-sectional study aimed to determine the epidemiology of olfactory and gustatory dysfunctions related to COVID-19 in China., Methods: This study was conducted by 45 tertiary Grade-A hospitals in China. Online and offline questionnaire data were obtained from patients infected with COVID-19 between December 28, 2022, and February 21, 2023. The collected information included basic demographics, medical history, smoking and drinking history, vaccination history, changes in olfactory and gustatory functions before and after infection, and other postinfection symptoms, as well as the duration and improvement status of olfactory and gustatory disorders., Results: Complete questionnaires were obtained from 35,566 subjects. The overall incidence of olfactory and taste dysfunction was 67.75%. Being female or being a cigarette smoker increased the likelihood of developing olfactory and taste dysfunction. Having received four doses of the vaccine or having good oral health or being a alcohol drinker decreased the risk of such dysfunction. Before infection, the average olfactory and taste VAS scores were 8.41 and 8.51, respectively; after infection, they decreased to 3.69 and 4.29 and recovered to 5.83 and 6.55 by the time of the survey. The median duration of dysosmia and dysgeusia was 15 and 12 days, respectively, with 0.5% of patients having symptoms lasting for more than 28 days. The overall self-reported improvement rate was 59.16%. Recovery was higher in males, never smokers, those who received two or three vaccine doses, and those that had never experienced dental health issues, or chronic accompanying symptoms., Conclusions: The incidence of dysosmia and dysgeusia following infection with the SARS-CoV-2 virus is high in China. Incidence and prognosis are influenced by several factors, including sex, SARS-CoV-2 vaccination, history of head-facial trauma, nasal and oral health status, smoking and drinking history, and the persistence of accompanying symptoms., Competing Interests: Professor Lei Cheng, Hua‐Bin Li, Jian‐Feng Liu, Zhen‐Lin Wang, Chang‐Qing Zhao and Dong‐Dong Zhu are the members of World Journal of Otorhinolaryngology ‐ Head and Neck Surgery editorial board and are not involved in the peer review process of this article. The other authors declare no conflict of interest., (© 2024 The Authors. World Journal of Otorhinolaryngology ‐ Head and Neck Surgery published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.)

Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir., Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development., Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment., Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Dong, Cao, Zhang, Zhao, Shang, Zhang, Ma, Xie, Gui, Zhang, Liu, Shang, Xie, Liu, Zhang, Wang, Zhao and China HepB Related Fibrosis Assessment Research Group.)

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV)., Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment., Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p =0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p =0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p =0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p =0.031)., Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients., Competing Interests: The authors have no conflict of interests related to this publication., (© 2023 Authors.)

Proximal pulmonary artery masses are exceedingly rare, and their diagnosis and therapy are important and challenging for clinicians. This study reviews our experience exploring the value of a combination of transthoracic echocardiography and contrast echocardiography for the differential diagnosis of proximal pulmonary artery masses. Between January 2018 and June 2021, 44 patients diagnosed with a mass attached to the major pulmonary artery and straddling the bilateral pulmonary arteries or pulmonary valve on transthoracic echocardiography were referred to this study. Contrast echocardiography was performed in 17 patients. Masses were diagnosed based on their site of attachment, shape, size, mobility, hemodynamic consequences on transthoracic echocardiography, and tissue perfusion on contrast echocardiographic perfusion imaging. Pathological data were collected from medical records and analyzed. The most frequent location of proximal pulmonary artery masses was the major pulmonary artery trunk. Twelve patients underwent complete mass resection, whereas nine patients underwent percutaneous pulmonary artery biopsy puncture and had a pathological diagnosis. Another 24 patients were confirmed with the validation methods. Contrast echocardiography has good sensitivity and specificity for differentiating thrombi from pulmonary artery sarcomas (PAS). The mass types were distributed as follows: thrombi (19, 43%), PAS (15, 34%), metastatic tumors (6, 14%), vegetations (3, 7%), and primary benign lesions (1, 2%). The majority of proximal pulmonary artery masses were thrombi or PAS. A combination of transthoracic echocardiography and contrast echocardiography offers advantages in the early identification of proximal pulmonary masses and provides clinically important information about the characteristics of masses, especially for differentiating thrombi from PAS., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The identification of ecological sources and corridors plays an important role in the construction of ecological security pattern. However, previous studies mainly concentrated on the optimal path selection of species migration and diffusion rather than the random path selection of the species, which makes most conclusions fail to objectively reveal the process of species migration and diffusion. Taking the downtown area of Hengyang City as an example, we selected the ecological sources and ecological corridors with the habitat quality analysis module of InVEST and Circuitscape 4.0 and evaluated the importance and connectivity of relevant ecological elements with the Linkage Mapper, with the aim to construct the ecological security pattern and delimitate the regions prior to ecological restoration. The results showed that there were 85 ecological sources dominated by woodland and grassland, together with a small number of ponds and beaches, which mainly distributed in the southwest of Zhengxiang District, the west of Yanfeng District, the northeast and south central of Zhuhui District, with a total area of 11.8 km 2 . There were 60 ecological sources with centrality greater than 100, accounting for 70.6% of the total. There were 217 ecological corridors and five potential ecological corridors mainly composed of forest land, among which the proportion of shrubbery and sparse forest land was higher. The corridors with higher importance were mainly distributed in the west of the studied area. After removing the barriers, the regional connectivity had been significantly improved, with the highest extent of 54.9%. The priority areas of ecological restoration were classified into three levels according to the value of cumulative current, namely, the high-grade area, the middle-grade area and the low-grade area. The high-grade area covered 4.3 km 2 of barriers, mainly distributed in the southwest of Zhengxiang District, northeast and south central of Zhuhui District. The middle-grade area was dominated by pinch area and ecological source area with centrality less than 100, covering an area of about 12.9 km 2 , mainly distributed in the central part of Zhengxiang District, northeast and south central of Zhuhui District. The low-level area was mainly distributed in south central of Zhuhui District, with 51.8 km 2 of residual ecological sources. By coupling InVEST habitat quality analysis module and circuit theory, the ecological security pattern for biological protection was constructed, which provides scientific reference for biological protection.

Background: Transthoracic intervention for isolated congenital heart disease (CHD) has been well tested for its technological feasibility and is increasingly used in clinical practice. We aimed to present our experience in simultaneous transthoracic intervention for multiple cardiac lesions in a series of pediatric patients., Methods: Between March 2015 and December 2019, 20 patients with multiple CHD were referred to this study; mean age was 18.8±8.6 (range, 4-36) months. The transthoracic echocardiography (TTE) diagnosis was atrial septal defect (ASD) and perimembranous ventricular septal defect (pmVSD) in 7 patients, patent ductus arteriosus (PDA) and ASD in 6, pmVSD and PDA in 2, pmVSD and valvular pulmonary stenosis (PS) in 2, ASD and PS in 2, and doubly committed subarterial VSD (dcsVSD) and PS in 1 patient. These patients underwent simultaneous transthoracic interventions with transesophageal echocardiography guidance. The procedure sequence was PS→VSD→PDA→ASD. Electrocardiography and TTE were scheduled at discharge and follow-ups., Results: All patients were occluded successfully without any thoracotomy conversion. Operation time was 56-120 (mean, 75±13) minutes. A 1.5-2.0-cm median sternum incision was performed in 6 ASD&PDAs, 2 ASD&PSs, and 1 dcsVSD&PS. In 11 other patients, a 1.5-2.0-cm incision in the inferior sternum was made and the chest closed with a drain. There were no serious complications before discharge and at follow-up., Conclusions: Simultaneous transthoracic intervention for multiple cardiac defects in children is feasible with good short-term outcomes. For different lesions, the appropriate surgical incision and operational sequence can render the intervention minimally invasive and safer., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tp-20-202). The authors have no conflicts of interest to declare., (2021 Translational Pediatrics. All rights reserved.)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-717). The authors have no conflicts of interest to declare.

A novel three-dimensional aluminum sludge/polyvinyl alcohol/sodium alginate(AS/PA/SA) gel spheres were designed and prepared for uranium(VI) adsorption, and it overcomes the shortcomings of poor recycling of powdery aluminum sludge adsorbent and poor stability of sodium alginate. Experiments show that the P-S-AS has a good pH range for removal of uranium (4-5). Fitting experimental data with pseudo-first-order kinetic model and pseudo-second-order kinetic model shows that the adsorption of U(VI) by P-S-AS is a chemical action. The fit of the Langmuir isotherm model and Freundlich isotherm model to the experimental data found that the P-S-AS adsorbed U(VI) to a single layer. Thermodynamic analysis shows that the adsorption occurs spontaneously, and an increase in temperature is favorable for the adsorption of uranium by the P-S-AS. Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS) analysis of the P-S-AS before and after adsorption showed that the main adsorption mechanism was the complexation reaction between functional groups and U(VI), the bonding reaction between metal oxides and U(VI).

Background: Few data are available regarding the progression of liver disease and therapeutic efficacy in chronic hepatitis B virus (HBV) carriers infected by mother-to-child transmission (MTCT). This study aimed to investigate these two aspects by comparing the adult chronic HBV carriers in MTCT group with those in horizontal transmission group., Methods: The 683 adult chronic HBV patients qualified for liver biopsy including 191 with MTCT and 492 with horizontal transmission entered the multi-center prospective study from October 2013 to May 2016. Biopsy results from 217 patients at baseline and 78 weeks post antiviral therapy were collected., Results: Patients infected by MTCT were more likely to have e antigen positive (68.6% vs. 58.2%, χ = -2.491, P = 0.012) than those with horizontal transmission. However, in patients with MTCT, levels of alkaline phosphatase (ALP) (P = 0.031), Fibroscan (P = 0.013), N-terminal propeptide of Type III procollagen (PIIINP) (P = 0.014), and Laminin (LN) (P = 0.006) were high, in contrast to the patients with horizontal transmission for whom the levels of albumin (ALB) (P = 0.041), matrix metalloproteinase-3 (MMP-3) (P = 0.001) were high. The 47.2% of patients with MTCT and 36.8% of those with horizontal transmission had significant liver fibrosis (P = 0.013). Following antiviral therapy for 78 weeks, 21.2% and 38.0% patients with MTCT and horizontal transmission acquired hepatitis B e antigen (HBeAg) clearance, respectively (P = 0.043), and the virological response rates were 54.7% and 74.1% in the MTCT and horizontal groups, respectively (P = 0.005). MTCT was a risk factor for HBeAg clearance and virological response., Conclusion: Adult patients with MTCT were more prone to severe liver diseases, and the therapeutic efficacy was relatively poor, which underlined the importance of earlier, long-term treatment and interrupting perinatal transmission., Trial Registration: NCT01962155; https://clinicaltrials.gov.

In the original version of this Data Descriptor the word "Gulf" was incorrectly spelled in the affiliation "Ocean College, Beibu Gulf University, Qinzhou, 535011, Guangxi, China". This has now been corrected in both the HTML and PDF versions.

It has generally been assumed that the immobilization of U(VI) via polyphosphate accumulating microorganisms may present a sink for uranium, but the potential mechanisms of the process and the stability of precipitated uranium under aerobic conditions remain elusive. This study seeks to explore the mechanism, capacity, and stability of uranium precipitation under aerobic conditions by a purified indigenous bacteria isolated from acidic tailings (pH 6.5) in China. The results show that over the treatment ranges investigated, maximum removal of U(VI) from aqueous solution was 99.82% when the initial concentration of U(VI) was 42 μM, pH was 3.5, and the temperature was with 30 °C much higher than that of other reported microorganisms. The adsorption mechanism was elucidated via the use of SEM-EDS, XPS and FTIR. SEM-EDS showed two peaks of uranium on the surface. A plausible explanation for this, supported by FTIR, is that uranium precipitated on the biosorbent surfaces. XPS measurements indicated that the uranium product is most likely a mixture of 13% U(VI) and 87% U(IV). Notably, the reoxidation experiment found that the uranium precipitates were stable in the presence of Ca 2+ and Mg 2+ , however, U(IV) is oxidized to U(VI) in the presence of NO 3 - and Na + ions, resulting in rapid dissolution. It implies that the synthesized Leifsonia sp. coated biochar could be utilized as a green and effective biosorbent. However, it may not a good choice for in-situ remediation due to the subsequent re-oxidation under aerobic conditions. These observations can be of some guiding significance to the application of the bioremediation technology in surface environments., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The shells of Chinese chestnuts (Castanea mollissima) are an agricultural residue. This work aimed to evaluate this feasibility of using steam explosion to modify this residue for Cu(II) biosorption from aqueous solutions. Equilibrium, kinetic and thermodynamic parameters were evaluated. The steam-explosion pretreatment increased the surface area of the chestnut shell and exposed more hydroxyl and carboxyl groups, which are binding sites for Cu(II). It changed the sorption from a spontaneous process driven by enthalpy to a nonspontaneous one driven by entropy. It increased the Cu(II) sorption capacity at higher temperatures while it decreased the capacity at lower ones. Compared with untreated chestnut shell, the steam-exploded shell is preferable for Cu(II) sorption at higher temperatures.

This study was conducted to (1) characterize coagulation cascade and complement system in systemic lupus erythematosus (SLE); (2) evaluate the associations between coagulation cascade, complement system, inflammatory response and SLE disease severity; (3) test the diagnostic value of a combination of D-dimer and C4 for lupus activity. Transcriptomics, proteomics and metabolomics were performed in 24 SLE patients and 24 healthy controls. The levels of ten coagulations, seven complements and three cytokines were measured in 112 SLE patients. Clinical data were collected from 2025 SLE patients. The analysis of multi-omics data revealed the common links for the components of coagulation cascade and complement system. The results of ELISA showed coagulation cascade and complement system had an interaction effect on SLE disease severity, this effect was pronounced among patients with excess inflammation. The analysis of clinical data revealed a combination of D-dimer and C4 provided good diagnostic performance for lupus activity. This study suggested that coagulation cascade and complement system become 'partners in crime', contributing to SLE disease severity and identified the diagnostic value of D-dimer combined with C4for lupus activity., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interests.

Mortality from hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) is high due to limited treatment options. Preclinical and clinical investigations have proved that treatment with mesenchymal stromal cells (MSCs) is beneficial for recovery from liver injury. We hypothesized that the outcome of HBV-related ACLF would be improved by MSC treatment. From 2010 to 2013, 110 patients with HBV-related ACLF were enrolled in this open-label, nonblinded randomized controlled study. The control group (n = 54) was treated with standard medical therapy (SMT) only. The experimental group (n = 56) was infused weekly for 4 weeks with 1.0 to 10 × 10 5 cells/kg allogeneic bone marrow-derived MSCs and then followed for 24 weeks. The cumulated survival rate of the MSC group was 73.2% (95% confidence interval 61.6%-84.8%) versus 55.6% (95% confidence interval 42.3%-68.9%) for the SMT group (P = 0.03). There were no infusion-related side effects, but fever was more frequent in MSC compared to SMT patients during weeks 5-24 of follow-up. No carcinoma occurred in any trial patient in either group. Compared with the control group, allogeneic bone marrow-derived MSC treatment markedly improved clinical laboratory measurements, including serum total bilirubin and Model for End-Stage Liver Disease scores. The incidence of severe infection in the MSC group was much lower than that in the SMT group (16.1% versus 33.3%, P = 0.04). Mortality from multiple organ failure and severe infection was higher in the SMT group than in the MSC group (37.0% versus 17.9%, P = 0.02)., Conclusion: Peripheral infusion of allogeneic bone marrow-derived MSCs is safe and convenient for patients with HBV-related ACLF and significantly increases the 24-week survival rate by improving liver function and decreasing the incidence of severe infections. (Hepatology 2017;66:209-219)., (© 2017 by the American Association for the Study of Liver Diseases.)

Background: The filamentous fungus Penicillium oxalicum is a potential alternative to Trichoderma reesei for industrial production of a complete cellulolytic enzyme system for a bio-refinery. Comparative omics approaches can support rational genetic engineering and/or breeding of filamentous fungi with improved cellulase production capacity. In this study, comparative genomic, transcriptomic and secretomic profiling of P. oxalicum HP7-1 and its cellulase and xylanase hyper-producing mutant EU2106 were employed to screen for novel regulators of cellulase and xylanase gene expression., Results: The 30.62 Mb P. oxalicum HP7-1 genome was sequenced, and 9834 protein-coding genes were annotated. Re-sequencing of the mutant EU2106 genome identified 274 single nucleotide variations and 12 insertion/deletions. Comparative genomic, transcriptomic and secretomic profiling of HP7-1 and EU2106 revealed four candidate regulators of cellulase and xylanase gene expression. Deletion of these candidate genes and measurement of the enzymatic activity of the resultant mutants confirmed the identity of three regulatory genes. POX02484 and POX08522, encoding a putative Zn(II)2Cys6 DNA-binding domain and forkhead protein, respectively, were found to be novel, while PoxClrB is an ortholog of ClrB, a key transcriptional regulator of cellulolytic enzyme gene expression in filamentous fungi. ΔPOX02484 and ΔPOX08522 mutants exhibited significantly reduced β-glucosidase activity, increased carboxymethylcellulose cellulase and xylanase activities, and altered transcription level of cellulase and xylanase genes compared with the parent strain ΔPoxKu70, with Avicel as the sole carbon source., Conclusions: Two novel genes, POX02484 and POX08522, were found and characterized to regulate the expression of cellulase and xylanase genes in P. oxalicum. These findings are important for engineering filamentous fungi to improve cellulase and xylanase production.

Previous studies of small cohorts have implicated several circulating cytokines with progression of chronic hepatitis B (CHB). However, to date there have been no reliable biomarkers for assessing histological liver damage in CHB patients with normal or mildly elevated alanine aminotransferase (ALT). The aim of the present study was to investigate the association between circulating cytokines and histological liver damage in a large cohort. Also, this study was designed to assess the utility of circulating cytokines in diagnosing liver inflammation and fibrosis in CHB patients with ALT less than 2 times the upper limit of normal range (ULN). A total of 227 CHB patients were prospectively enrolled. All patients underwent liver biopsy and staging by Ishak system. Patients with at least moderate inflammation showed significantly higher levels of CXCL-11, CXCL-10, and interleukin (IL)-2 receptor (R) than patients with less than moderate inflammation (P < 0.001). Patients with significant fibrosis had higher levels of IL-8 (P = 0.027), transforming growth factor alpha (TGF-α) (P = 0.011), IL-2R (P = 0.002), and CXCL-11 (P = 0.032) than the group without significant fibrosis. In addition, 31.8% and 29.1% of 151 patients with ALT < 2 × ULN had at least moderate inflammation and significant fibrosis, respectively. Multivariate analysis demonstrated that CXCL-11 was independently associated with at least moderate inflammation, and TGF-α and IL-2R independently correlated with significant fibrosis in patients with ALT < 2 × ULN. Based on certain cytokines and clinical parameters, an inflammation-index and fib-index were developed, which showed areas under the receiver operating characteristics curve (AUROC) of 0.75 (95% CI 0.66-0.84) for at least moderate inflammation and 0.82 (95% CI 0.75-0.90) for significant fibrosis, correspondingly. Compared to existing scores, fib-index was significantly superior to aspartate aminotransferase (AST) to platelet ratio index (APRI) and FIB-4 score for significant fibrosis. In conclusion, CXCL-11 was independently associated with at least moderate inflammation, whereas IL-2R and TGF-α were independent indicators of significant fibrosis in both, total CHB patients and patients with normal or mildly elevated ALT. An IL-2R and TGF-α based score (fib-index) was superior to APRI and FIB-4 for the diagnosis of significant fibrosis in patients with normal or mildly elevated ALT.

Matrine, one of the main extract components of Sophora flavescens, has been shown to exhibit inhibitory effects on some tumors through autophagy. However, the mechanism underlying the effect of matrine remains unclear. The cultured human hepatocellular carcinoma cell line HepG2 and SMMC‑7721 were treated with matrine. Signal transduction and gene expression profile were determined. Matrine stimulated autophagy in SMMC‑7721 cells in a mammalian target of rapamycin (mTOR)-dependent manner, but in an mTOR-independent manner in HepG2 cells. Next, in HepG2 cells, autophagy induced by matrine was regulated by p53 inactivation through AMP-activated protein kinase (AMPK) signaling transduction, then AMPK suppression switched autophagy to apoptosis. Furthermore, the interferon (IFN)-inducible genes, including interferon α-inducible protein 27 (IFI27) and interferon induced transmembrane protein 1 (IFITM1), which are downstream effector of p53, might be modulated by matrine-induced autophagy. In addition, we found that the p53 protein isoforms, p53β, p53γ, ∆133p53, and ∆133p53γ, due to alternative splicing of intron 9, might be regulated by the p53-mediated autophagy. These results show that matrine induces autophagy in human hepatoma cells through a novel mechanism, which is p53/AMPK signaling pathway involvement in matrine-promoted autophagy.

Purpose: The present study was done to establish an objective, sensitive prognostic scoring system and to determine the applicability of this model in predicting the 3-month mortality of patients with acute-on-chronic liver failure in hepatitis B (ACLFB)., Methods: We developed a novel prognostic scoring system, calculated from six clinical indices including serum total bilirubin, prothrombin activity, serum creatinine, hepatic encephalopathy, infections, and the depth of ascites from 499 patients with ACLFB. Differences in the sensitivity, specificity, and practicality of a Novel prognostic scoring system and the model of end-stage liver disease (MELD) were analyzed., Results: The areas under the receiver operating characteristic curve (ROC) for the Novel scoring systems and MELD scoring systems were 0.967 (95% CI, 0.956-0.977) and 0.900 (95% CI, 0.878-0.922), respectively. The analysis of the ROC curve indicated that the Novel scoring systems were an exact, pertinent, and objective prognostic model with greater accuracy than the MELD. In the Novel scoring systems, the survival rate of these patients whose scores ranged from 2 to 6 was 98.80%, while for those whose scores point at 7 and 15, the mortality rates were 8.70% (2/23) and 95.45% (21/22), respectively, and the mortality rate of these patients whose scores were 16 and above was 100.00%. However, in the MELD prognostic scoring systems, there were no score ranges with 100.00% survival rate., Conclusions: We developed an objective, pertinent, and sensitive prognostic scoring system that predicted the 3-month mortality of patients with ACLFB with greater accuracy than the MELD.

Purpose: The purpose of the current study was to establish an objective, simple, and sensitive prognostic scoring system for estimating the severity of acute-on-chronic liver failure in hepatitis B (ACLFB)., Methods: A novel prognostic scoring system was calculated from six clinical indices including total bilirubin (TB), prothrombin activity (PTA), creatinine (Cr), hepatic encephalopathy (HE), infections, and the depth of ascites from 726 patients with ACLFB. Indices were scored from 1 to 4 according to their severity. Groups of the same patients were scored with three-indices (TB, PTA and Cr), four-indices (TB, PTA, Cr and HE), five-indices (TB, PTA, Cr, HE and the depth of ascites) or six-indices (TB, PTA, Cr, HE, the depth of ascites, and infections). The differences in the sensitivity and specificity of four scoring systems were analyzed., Results: The demarcation points of the three-, four-, five- and six-indices scoring systems were 4.62, 6.12, 7.88 and 9.57, respectively. The analysis of the areas under the receiver operating characteristic (ROC) curve indicated that the four-, five- and six-indices scoring systems were more exact, and objective than the three-indices prognostic scoring system. In the six-indices scoring system, the survival rates of patients with scores from 2 to 6 was 98.31% (233/237), and the mortality rate of patients with scores of 16 and above was 100.00% (140/140), while the mortality rates were 8.33% (3/36) and 96.43% (27/28) for those with scores from 7 to 15, respectively., Conclusion: A six-indices scoring system is an objective, pertinent, and sensitive system, and may be useful for the prognostic evaluation of ACLFB.

Uncontrolled hepatic immunoactivation is regarded as the primary pathological mechanism of fulminant hepatic failure (FHF). The major acute-phase mediators associated with FHF, including IL-1β, IL-6, and TNF-α, impair the regeneration of liver cells and stem cell grafts. Amniotic-fluid-derived mesenchymal stem cells (AF-MSCs) have the capacity, under specific conditions, to differentiate into hepatocytes. Interleukin-1-receptor antagonist (IL-1Ra) plays an anti-inflammatory and anti-apoptotic role in acute and chronic inflammation, and has been used in many experimental and clinical applications. In the present study, we implanted IL-1Ra-expressing AF-MSCs into injured liver via the portal vein, using D-galactosamine-induced FHF in a rat model. IL-1Ra expression, hepatic injury, liver regeneration, cytokines (IL-1β, IL-6), and animal survival were assessed after cell transplantation. Our results showed that AF-MSCs over-expressing IL-1Ra prevented liver failure and reduced mortality in rats with FHF. These animals also exhibited improved liver function and increased survival rates after injection with these cells. Using green fluorescent protein as a marker, we demonstrated that the engrafted cells and their progeny were incorporated into injured livers and produced albumin. This study suggests that AF-MSCs genetically modified to over-express IL-1Ra can be implanted into the injured liver to provide a novel therapeutic approach to the treatment of FHF.

Background: The accurate assessment of the degree of hepatic fibrosis plays a critical role in guiding the diagnosis, treatment and prognostic assessment of chronic liver diseases. Liver biopsy is currently the most reliable method to evaluate the severity of hepatic fibrosis. However, liver biopsy is an invasive procedure associated with morbidity and mortality, and has several limitations in patients with decompensated cirrhosis. There is no report on the collagen proportionate area (CPA) of liver tissue in the decompensated stage of cirrhosis. This study aimed to determine the CPA of resected liver tissue samples from patients with HBV-related decompensated cirrhosis using digital image analysis, and to analyze the relationship between the CPA and liver functional reserve., Methods: Fifty-three resected liver tissue samples from liver transplant patients with chronic hepatitis B-induced decompensated cirrhosis were stained with Masson's trichrome, and the CPA in these samples was quantitatively determined using digital image analysis. The values of relevant liver function just before liver transplantation, the CPA in liver tissue, and their correlation were analyzed., Results: The mean CPA at the decompensated stage of cirrhosis was 35.93+/-14.42% (11.24%-63.41%). The correlation coefficients of the CPA with a model for end-stage liver disease score, serum total bilirubin and international standard ratio of prothrombin B were 0.553, 0.519 and 0.533, respectively (P<0.001). With increasing CPA values, the three indices reflecting liver functional reserve also changed significantly., Conclusions: The degree of fibrosis may be correlated with the functional reserve. With the advancement of fibrosis, the liver functional reserve is attenuated accordingly.

Hepatitis B virus (HBV) DNA levels and liver histological necroinflammation grades are correlated with the antiviral efficacy. It is necessary to clarify the relationship between HBV replication levels apportioned by the same hepatic parenchyma cell volume and severity of liver histological necroinflammation grades in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B. The serum HBV DNA levels apportioned by the same hepatic parenchyma cell volume were compared between HBeAg-positive and HBeAg-negative chronic hepatitis B as well as among liver histological necroinflammation grades 1, 2, 3 and 4, respectively. There were no differences in the serum HBV DNA levels between HBeAg-positive and HBeAg-negative chronic hepatitis B as well as among liver histological necroinflammation grades 1, 2, 3 and 4. However, there were differences in the serum HBV DNA levels apportioned by the same hepatic parenchyma cell volume among liver histological necroinflammation grades 1, 2, 3 and 4 in both HBeAg-positive and HBeAg-negative chronic hepatitis B, respectively. There were no differences in HBV DNA levels with the same liver histological necroinflammation grade activated by HBV wild-type and variant strains. After the differences in hepatic parenchyma cell volume for HBV replication of the same liver histological necroinflammation grade accompanied by different hepatic fibrosis stages were adjusted, the serum HBV DNA level apportioned by the same hepatic parenchyma cell volume was correlated with the severity of liver histological necroinflammation grade., (© 2011 Blackwell Publishing Ltd.)

The oncoprotein inhibitory member of the ASPP family (iASPP) is a key inhibitor of the p53 tumor suppressor and is upregulated in patients with acute leukemia and breast carcinoma. To investigate the effect of iASPP inhibition on the proliferation of hepatocellular carcinoma cells, a recombinant lentivirus vector expressing a small interfering RNA (siRNA) against iASPP gene expression was constructed and used to infect human hepatocellular carcinoma cells (HepG2 and Hep3B). The results showed that iASPP mRNA and protein levels were significantly down-regulated in both cells infected with the siRNA against iASPP. siRNA-mediated down-regulation of iASPP repressed tumor cell proliferation and colony formation in vitro and induced a growth delay of the tumor in vivo, suggesting that iASPP plays an important role in the proliferation of hepatocellular carcinoma cells. iASPP may be a valuable candidate target gene in hepatocellular carcinoma therapy.

Background: The aim of this study was to analyze the combination with long-term, low-dose hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogs as prophylaxis for hepatitis B virus (HBV) recurrence and to assess the risk factors of HBV recurrence after orthotopic liver transplantation (OLT)., Methods: One hundred sixty patients undergoing OLT with HBV-related liver disease make up the cohort studied. Long-term, low dosage of HBIG in combination with nucleos(t)ide analogs were used as prophylaxis for HBV recurrence after OLT. Patient preoperative data were collected by a retrospective method, and the rate and risk factors of HBV recurrence post-OLT after a long-term follow-up were analyzed., Results: Nineteen patients developed hepatitis B recurrence for a rate of recurrence of 11.88% (19/160). There was no significant correlation between HBV recurrence after OLT and the level of HBV DNA, HBeAg state pre-OLT, or the use of nucleoside analog drug therapy pre-OLT (P>0.05). Of 19 patients with HBV recurrence, 17 patients used Lamivudine, and HBV YMDD mutants were detected in nine cases. The HBV-YMDD mutation was the major reason for recurrence of HBV in our study (P<0.001)., Conclusions: Long-term use of combination prophylaxis with nucleoside analogs and low-dose HBIG can effectively prevent hepatitis B recurrence after OLT, and that a positive preoperative serum HBV DNA status did not affect the recurrence rate of HBV post-OLT. Preoperative nucleoside analogs therapy is unlikely to be obligatory if the patients received effective combination prophylaxis postoperatively. HBV YMDD mutation is the primary reason for HBV recurrence in patients treated with Lamivudine after OLT.

Our objective was to investigate the effect of various reimmunization schemes for hepatitis B in adults with low or undetectable anti-HBs titers. Over 2 years, 10 μg of Saccharomyces cerevisiae-recombinant hepatitis B virus (HBV) vaccine (synthesized in China) was used in at least one standardized scheme to immunize 2,310 healthy male and nonpregnant female adults. Of these, 240 subjects tested negative for hepatitis B markers. These 240 subjects were equally divided into 4 groups. The first group, designated Engerix-40, was revaccinated with 40 μg Engerix-B; the second, Engerix-20, was revaccinated with 20 μg Engerix-B; the third, Chinese-20, was revaccinated with 20 μg Chinese-made yeast-recombinant vaccine; and the last group, Chinese-10, was revaccinated with 10 μg Chinese-made yeast-recombinant vaccine. Blood samples were collected before and 1, 2, 8, and 12 months after the first injection. The anti-HBs-positive conversion rates of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than that of the Chinese-10 group (P < 0.01). Over time, the anti-HBs conversion rate increased in all groups, but values were significantly different from those for the other groups only in the Chinese-10 group (P < 0.001). The anti-HBs geometric mean titers (GMTs) of the Engerix-40, Engerix-20, and Chinese-20 groups were higher than in the Chinese-10 group (P < 0.05). Increased doses raise and maintain anti-HBs titers in subjects with low or undetectable titers after HBV vaccination.

Biosorption of uranium (VI) ions by immobilized Aspergillus fumigatus beads was investigated in a batch system. The influences of solution pH, biosorbent dose, U (VI) concentration, and contact time on U (VI) biosorption were studied. The results indicated that the adsorption capacity was strongly affected by the solution pH, the biosorbent dose and initial U (VI) concentration. Optimum biosorption was observed at pH 5.0, biosrobent dose (w/v) 2.5%, initial U (VI) concentration 60 mg L(-1). Biosorption equilibrium was established in 120 min. The adsorption process conformed to the Freunlich and Temkin isothermal adsorption models. The dynamic adsorption model conformed to pseudo-second order model., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

During the initial phase of chronic hepatitis B virus (HBV) infection, serum HBV DNA levels are high. Contrarily, fibrosis, cirrhosis and hepatocellular carcinoma have been found in patients with lower serum HBV DNA levels. The aim of this study is to clarify HBV DNA level dynamics of serum apportioned by the same hepatic parenchyma cell volume (HPCV) in hepatic fibrosis stages 1-4 during the natural history of chronic hepatitis B. Serum HBV DNA levels were evaluated by real-time polymerase chain reaction. Further, serum HBV DNA levels were apportioned by and compared with the same HPCV in hepatic fibrosis stages 1-4, respectively. Serum HBV DNA levels were 8.91 x 10(6) +/- 4.37 x 10(1), 8.13 x 10(6) +/- 7.41 x 10(1), 9.55 x 10(5) +/- 1.02 x 10(2), and 4.07 x 10(5) +/- 7.24 x 10(1) copies/ml, respectively; there were differences among hepatic fibrosis stages 1-4 (p < 0.021-0.000). However, serum HBV DNA levels apportioned by the same volume of hepatic parenchyma cells in hepatic fibrosis stages 1-4 were 3.47 x 10(10) +/- 8.71 x 10(2), 1.02 x 10(11) +/- 9.55 x 10(2), 1.41 x 10(10) +/- 2.57 x 10(3), and 3.72 x 10(10) +/- 3.02 x 10(3) with HPCV proportions 65.9, 62.7, 58.9, and 53.3%, respectively; there were no differences among hepatic fibrosis stages 1-4 (p > 0.203-0.967).Following the progression of hepatic fibrosis from stage 1 to 4, ongoing decline of HPCV is responsible for a declining trend of serum HBV DNA levels., (Copyright 2008 S. Karger AG, Basel.)

Aim: To select valuable ultrasonographic predictors for the evaluation of hepatic inflammation and fibrosis degree in chronic hepatitis, and to study the value of ultrasonography in the evaluation of liver fibrosis and compensated liver cirrhosis in comparison with serology and histology., Methods: Forty-four ultrasonographic variables were analyzed and screened using color Doppler ultrasound system in 225 patients with chronic viral hepatitis and compensated liver cirrhosis. The valuable ultrasonographic predictors were selected on the basis of a comparison with histopathological findings. The value of ultrasonography and serology in the evaluation of liver fibrosis degree and the diagnosis of compensated liver cirrhosis was also studied and compared. Meanwhile, the influencing factors on ultrasonographic diagnosis of compensated liver cirrhosis were also analyzed., Results: By statistical analysis, the maximum velocity of portal vein and the degree of gall-bladder wall smoothness were selected as the valuable predictors for the inflammation grade (G), while liver surface, hepatic parenchymal echo pattern, and the wall thickness of gall-bladder were selected as the valuable predictors for the fibrosis stage (S). Three S-related independent ultrasonographyic predictors and three routine serum fibrosis markers (HA, HPCIII and CIV) were used to discriminate variables for the comparison of ultrasonography with serology. The diagnostic accuracy of ultrasonography in moderate fibrosis was higher than that of serology (P<0.01), while there were no significant differences in the general diagnostic accuracy of fibrosis as well as between mild and severe fibrosis (P<0.05). There were no significant differences between ultrasonography and serology in the diagnosis of compensated liver cirrhosis. However, the diagnostic accuracy of ultrasonography was higher in inactive liver cirrhosis and lower in active cirrhosis than that of serology (both P<0.05). False positive and false negative results where found when the diagnosis of compensated liver cirrhosis was made by ultrasonography., Conclusion: There are different ultrasonographic predictors for the evaluation of hepatic inflammation grade and fibrosis stage of chronic hepatitis. Both ultrasonography and serology have their own advantages and disadvantages in the evaluation of liver fibrosis and compensated liver cirrhosis. Combined application of the two methods is hopeful to improve the diagnostic accuracy.

Objective: To assess the significance of serum hyaluronic acid (HA), procollagen type III (PCIII), collagen type IV (CIV) in the histological diagnosis of liver fibrosis., Methods: The concentrations of serum HA, PCIII, CIV in 253 patients with chronic liver diseases were measured by radioimmunoassay. Liver biopsies were performed in all patients at the same time. The liver was pathologically evaluated by a pathologist according to a scoring system. Combined with the results of liver pathological diagnosis, the accuracy of serum HA, PCIII, CIV in diagnosing patients with hepatic fibrosis (staging >/=S2) or cirrhosis (S4) was assessed using the receiver operating curve (ROC)., Results: The cutoff values of serum HA, PCIII and CIV for identifying patients with hepatic fibrosis (>/=S2) or cirrhosis (S4) were determined. The cutoff values of serum HA, PCIII and CIV for detecting patients with fibrosis (stage >/=S2) were 90 micrograms/L, 90 micrograms/L, 75 micrograms/L, respectively; their sensitivity (Se) was 80.4%, 82%, 63.1%; their specificity (Spe) was 70.2%, 60.8%, 83.8%; their positive predictive values (PPV) were 86.7%, 83.5%, 90.4%; their negative predictive values (NPV) were 59.8%, 58.4%, 48.4%, respectively. The cutoff values for detecting patients with liver cirrhosis were 210 micrograms/L for HA, 96.2% for Se, 85.3% for Spe, 65.4% for PPV, 98.8% for NPV; 150 micrograms/L for PCIII, 76.4% for Se, 68.7% for Spe, 40.4% for PPV, 91.3% for NPV; 90 micrograms/L for CIV, 80% for Se, 75.8% for Spe, 47.8% for PPV, 93.2% for NPV, respectively., Conclusions: Serum HA, PCIII and CIV can be determined for an accurate diagnosis of hepatic fibrosis in various stages. HA is the best for screening liver cirrhosis.

Objective: To study the relationship between the serum levels of hyaluronic acid (HA), procollagen type III (PCIII), collagen type IV (CIV) and the histological degree of hepatic fibrosis evaluated by image analysis, and the clinical significance of serum HA, PCIII, CIV in the diagnosis of hepatic fibrosis in patients with chronic viral hepatitis., Methods: The concentrations of serum HA, PCIII, CIV in 151 patients with chronic viral hepatitis were measured by radioimmunoassay. Liver biopsies were performed in all the patients. Histological sections of 4 microm thickness were stained with Masson's trichrome for fibrosis assessment. Morphometric quantitative measurements for hepatic fibrosis assessment in the 4 microm sections were performed using a fully automated image analysis system. Serum levels of HA, PCIII, and CIV were analyzed at different stages of liver pathology and compared with the morphometric quantitative measurements of hepatic fibrosis., Results: The serum levels of HA, PCIII, CIV all elevated gradually with the progression of the disease, and all reached the highest in patients with liver cirrhosis. There was a significant difference in the levels of these 3 components between liver cirrhosis group and the other groups (P<0.05). They all increased steadily with the histological stages of hepatic fibrosis, and reached the highest levels in stage IV. The serum levels of HA, PCIII, CIV were all positively correlated with the histological stages of liver sections and the morphometric measurement (P<0.001). The coefficients with stages were 0.694, 0.493, 0.552 (P<0.001), respectively and with surface density of total collagen on liver biopsy sections by image analysis were 0.715, 0.595, 0.573 (P<0.001), respectively., Conclusion: The serum levels of HA, PCIII, CIV were in consistent with the degree of hepatic fibrosis, and the determination of these marks is valuable for detecting hepatic fibrosis.