Background/Aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported. Conclusions 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Antibody-mediated rejection (AMR) is one of the major causes of graft loss after transplantation. Recently, the regulation of B cell differentiation and the prevention of donor-specific antibody (DSA) production have gained increased attention in transplant research. Herein, we established a secondary allogeneic in vivo skin transplant model to study the effects of romidepsin (FK228) on DSA. The survival of grafted skins was monitored daily. The serum levels of DSA and the number of relevant immunocytes in the recipient spleens were evaluated by flow cytometry. Then, we isolated and purified B cells from B6 mouse spleens in vitro by magnetic bead sorting. The B cells were cultured with interleukin-4 (IL-4) and anti-clusters of differentiation 40 (CD40) antibody with or without FK228 treatment. The immunoglobulin G1 (IgG1) and IgM levels in the supernatant were evaluated by enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting were conducted to determine the corresponding levels of messenger RNA (mRNA) and protein expression in cultured cells and the recipient spleens. The results showed that FK228 significantly improved the survival of allogeneic skin grafts. Moreover, FK228 inhibited DSA production in the serum along with the suppression of histone deacetylase 1 (HADC1) and HDAC2 and the upregulation of the acetylation of histones H2A and H3. It also inhibited the differentiation of B cells to plasma cells, decreased the transcription of positive regulatory domain-containing 1 (Prdm1) and X-box-binding protein 1 (Xbp1), and decreased the expression of phosphorylated inositol-requiring enzyme 1 α (p-IRE1α), XBP1, and B lymphocyte-induced maturation protein-1 (Blimp-1). In conclusion, FK228 could decrease the production of antibodies by B cells via inhibition of the IRE1α-XBP1 signaling pathway. Thus, FK228 is considered as a promising therapeutic agent for the clinical treatment of AMR.
Animals ; Depsipeptides ; Endoribonucleases ; Hematopoietic Stem Cell Transplantation ; Histone Deacetylase Inhibitors/pharmacology* ; Mice ; Protein Serine-Threonine Kinases ; Skin Transplantation

Aim To establish the 3D hepatocyte model by selecting the humanized hepatocyte HepG2 cells and 3D cell culture methods, and to establish the 3D hepatocyte cytokinesis-block micronucleus cytome(CBMN-cyt)assay and 3D hepatocyte comet assay by using chemicals of different mode of action.Methods In this study, a scaffold-free culture method was used to successfully establish a 3D HepG2 hepatocyte spheroid model.The appearance of the sphere, the survival rate of cells inside the sphere, the gene expression of phase I and II metabolic enzymes, and the expression of liver-specific biomarkers were selected as the observation indicators to obtain the best culture conditions for the 3D hepatocyte model.The 3D hepatocyte model was combined with in vitro micronucleomics test and in vitro comet test to explore its applicability for genotoxicity test.Results The best culture conditions for the 3D hepatocyte model was 5×103 cells/20 μL /drop inoculation, cultivating for seven days.A 3D hepatocyte CBMN-cyt assay was established using mitomycin C(MMC), a micronucleus positive compound, and the results showed that it could successfully detect the genotoxicity and cytotoxicity of MMC.Compared with the CBMN-cyt results of 2D hepatocyte model, 3D hepatocyte model had higher sensitivity in detecting MN and Nbud.The 3D hepatocyte comet assay methods were established using the known in vivo and in vitro comet assay positive compound methyl methanesulfonate(MMS), and the results showed that MMS could significantly increase the tail DNA% of 3D hepatocytes with low cytotoxicity.The sensitivity of 3D hepatocyte model to MMS genotoxicity detection was higher than that of 2D cells.Conclusions The 3D hepatocyte model established in this study is easy to use and low in cost, and shows good sensitivity and specificity in the in vitro micronucleus test and comet test, suggesting that the 3D hepatocyte genotoxicity test method is used in early drug genotoxicity screening.It has good application prospects in additional experimental research.

In the clinical practice of rheumatic immune diseases in traditional Chinese medicine （TCM），it`s still unclear about the dominant diseases and breakthrough points. It`s urgent missions to formulate TCM diagnosis and treatment guidelines widely recognized and integrated by traditional Chinese medicine and Western medicine. In order to clarify the dominant diseases and breakthrough points in rheumatism，China association of Chinese medicine initiated a research group covering experts in the field of rheumatism of traditional Chinese medicine and Western medicine. Based on questionnaire survey and on-site discussion，experts had reached the following consensus. Evidence-based medicine research using modern medical methods and scientific methods should be carried out to provide objective clinical evidences. "Four mutuality" were put forward as the basis for the work of integrated traditional Chinese and Western medicine，that is the mutual communication using the exchangeable context，the mutual explanation using common theories，the mutual certification using common standards，and the mutual integration using common means. Key works should focus on solving refractory rheumatism in the future. In terms of dominant diseases and breakthrough points，this paper introduces 21 breakthrough points in 6 dominant diseases，including rheumatoid arthritis，ankylosing spondylitis，Sjogren's syndrome，hyperuricemia and gout，systemic lupus erythematosus and fibromyalgia syndrome. Advice on this discussion can provide valuable references for developing the treatment scheme of rheumatism with TCM and integrated Chinese and Western medicine and clinical practice and scientific research.

Except the complete literature of , Tianhui medical slips unearthed in Chengdu also include a part of literature document on meridian, which was seriously damaged. Both of them were found in the same box together with . The title of the document chapter was not found in the residual medical slips. By investigated the textual content, it was discovered that such medical slips were different from the Mawangdui silk books, i.e. and , of Zhangjiashan bamboo slips of Han Dynasty, as well as in Tianhui medical slips. But, the sentences in description are similar to the sentences of in (), therefore, this residual slips was named as () by the collator. In the paper, by the comparison of this residual slip chapter with the unearthed literature document on meridian as well as in , the origin and evolution of meridian theory of traditional Chinese medicine in the Qin and Han dynasties were explained. By taking it as an example, the construction process of classical theory of traditional Chinese medicine was explored.
Acupuncture ; history ; Books ; China ; History, Ancient ; Humans ; Medicine, Chinese Traditional ; Meridians

Objective To provide clues for the study on the mechanism of autoimmune liver disease (AILD) by exploring the existence of specific bacteria in liver tissues of AILD patients.Methods From August 2017 to August 2018,at Department of Gastroenterology arnd Hepatology,Tianjin Medical University General Hospital,a total of 12 patients diagnosed as AILD (four autoimmune hepatitis (AIH),four primary biliary cirrhosis (PBC) and four PBC-AIH overlap syndrome (OS)) and four patients with hepatic cyst (control group) were enrolled and all the patients underwent liver biopsy.16S rRNA gene sequencing was carried out in the obtained aseptic liver tissues.Linear discriminant analysis effect size was used to find out the specific bacteria.Spearman correlation analysis was performed to analyze the correlation between the liver microbiota and the disease.The metabolic function of the 16S rRNA gene sequences was also predicted.Results Bacteria were detected in the liver tissues of all the 16 patients.At the species level,the abundance of Planococcus rifietoensis of AIH group was 0.100％,which was higher than those of other three groups (0),and the difference was statistically significant (linear discriminant analysis (LDA) =3.31,P =0.034).The abundance of Anoxybacillus flavithermus of PBC group was 0.200％,which was higher than those of other three groups (0.100％),and the difference was statistically significant (LDA =3.34,P =0.014).The abundance of Pseudomonas aeruginosa PAO1,Bacillus firmus,Brevibacillus agri,Acinetobacter baumannii,Sphingomonas zeae and Salmonella enterica were significantly negatively correlated with serum level of γ-glutamyl transferase (r=-0.68,-0.68,-0.67,-0.68,-0.68 and-0.66,all P ＜0.01).Compared with that of the hepatic cyst group,the lipid metabolism of AILD patients decreased.The levels of serum low density lipoprotein and total cholesterol were significantly negatively correlated with the biosynthesis of unsaturated fatty acids (r =-0.55 and-0.65,both P ＜ 0.05).Conclusions There exist specific bacteria in the liver tissues of AIH and PBC groups.The liver microbiota which is closely related with the pathogenesis of AILD might be a potential therapeutic target and diagnostic biomarker.

Objective To investigate the clinical effect of external ventricular drainage on the prognosis of anterior communicating artery aneurysms.Methods Retrospectively collected and analyzed 96 patients of anterior communicating artery aneurysms who were treated in our hospital from June 2013 to October 2015,and they were divided into the observation group which was given external ventricular drainage treatment and the control group which was not given external ventricular drainage treatment.These patients were followed up for 6 months to 2 years,and the results of the 2 groups were graded according to the analysis of postoperative complications and the Glasgow prognostic score (GOS).Meanwhile,evaluated the general function of the patients according to the KPS score.Results The the incidence rate of complications after treatment in observation group was 54.17％,which was lower than 86.96％ in the control group,and the difference was statistically significant(P ＜ 0.05).The cure rate of observation group was 79.16％,which was higher than 50％ in the control group,and the difference was statistically significant (P ＜ 0.05).The postoperative KPS score in the observation group was (79.68 ± 13.24) points,which was higher than (62.57 ± 12.72) points in the control group,and the differences were statistically significant (P ＜ 0.05).Conclusion External ventricular drainage can reduce the compression injury of the brain tissue to a minimum degree,reduce intracranial pressure,relieve cerebral edema caused by intracranial pressure,reduce complications,and improve the prognosis of patients and the cure rate.

Objective To investigate the clinical efficacy of small bone-flap decompression of posterior fossa through neuroendoscopy in the treatment of ChiariⅠmalformation.Methods Retrospectively analyzed the clinical data of 44 cases of ChiariⅠdeformity/syringomyelia who were admitted into affiliated hospital of Xuzhou medical university from January 2013 to December 2016.And divided these patients into the observation group ( n=22,treated with small bone-flap decompression of posterior fossa through neuroendoscopy ) and the control group ( n=22,treated with posterior fossa decompression/tonsillectomy) according to surgical methods .The recovery time and the postoperative com-plications of the two groups were analyzed ,and the long-term efficacy and changes in spinal cord cavity were observed through the follow-up of 1 to 20 months.Results There was no death case in both of the two groups .The effective rate of the two groups were 86.36％and 86.36％respectively.The complication rate of the observation group was 27.35％, which was significantly lower than 77.3％of the control group with statistical significance(P<0.05).There was no significant differences in the recovery time ,postoperative curative effect and spinal cord cavi-ty changes between the two groups (P>0.05).Conclusion The treatment of Chiari Ⅰmalformation with small bone-flap decompression of posterior fossa through neuroendoscopy is a new surgical procedure with less trauma ,shorter hospital stay ,less complication and less effective compared with traditional method .

Purpose To investigate the clinicopathologic features and differential diagnosis of oncocytic variant of medullary thyroid carcinoma (MTC).Methods Morphological,immunohistochemical findings on 3 oncocytic variant of MTC cases and electron microscopic findings on 2 of these 3 cases were studied,with review of the relevant literatures.Results The cytoplasm was abundant,eosinophilic and granular with defined margins.The nuclei were enlarged,round to oval.Prominent nucleoli were identified in some cells.Tumor cells formed sheets,trabeculae or follicles with infiltrative pattern.Immunohistochemically,thyroglobulin (TG) was negative in all 3 cases.Calcitonin was positive in 2 cases and negative in 1 case.Ultrastructurally,a large number of mitochondria and various neuroendocrine granules were found in the 2nd and 3rd cases.Conclusion Oncocytic variant of MTC is very rare with variable histopathologic appearances.It should be considered in diagnosing oncocytic lesions of thyroid.A definite diagnosis can be rendered based on comprehensive findings of the immunohistochemistry,serology study and electron microscopy.It needs to avoid misdiagnosis and missed diagnosis.

This study aims to investigate the function of two SNPs (rs8904C > T and rs696G >A) in 3' untranslated region (3'UTR) of NFKBIA gene by constructing luciferase reporter gene. A patient's genomic DNA with rs8904 CC and rs696 GA genotype was used as the PCR template. Full-length 3'UTR of NFKBIA gene was amplified by different primers. After sequencing validation, these fragments were inserted to the luciferase reporter vector, pGL3-promoter to construct recombinant plasmids containing four kinds of haplotypes, pGL3-rs8904C/rs696G, pGL3-rs8904C/rs696A, pGL3-rs8904T/rs696G and pGL3-rs8904T/rs696A. Then these plasmids were transfected into LS174T cells and the luciferase activity was detected. Compared with pGL3-vector transfected cells (negative control), the luciferase activity of the four kinds of recombinant plasmids was significantly decreased (P < 0.001). For rs696G > A, the luciferase activity of the recombinant plasmids containing A allele (pGL3-rs8904C/rs696A and pGL3-rs8904T/rs696A) was about 45.1% (P < 0.05) and 56.1% (P < 0.001) lower than those containing G allele (pGL3-rs8904C/rs696G and pGL3-rs8904T/rs696G), respectively. For rs8904C > T, there were no significant differences in the luciferase activity between the recombinant plasmids containing T allele and those with C allele. Together, the luciferase reporter gene vectors containing SNPs in NFKBIA gene 3'UTR were constructed successfully and rs696G > A could decrease the luciferase activity while rs8904C >T didn't have much effect on the luciferase activity.
3' Untranslated Regions ; Genes, Reporter ; Genetic Vectors ; Humans ; I-kappa B Proteins ; genetics ; Luciferases ; NF-KappaB Inhibitor alpha ; Plasmids ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Transfection