Characterization of acute-on-chronic liver diseases: A multicenter prospective cohort study

BACKGROUND Acute-on-chronic liver disease(AoCLD)accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases.AIM To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of AoCLD.METHODS Patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure(ACLF)study cohort were included in this study.The clinical characteristics and outcomes,and the 90-d survival rate associated with each clinical type of AoCLD were analyzed,using the Kaplan-Meier method and the log-rank test.RESULTS A total of 3375 patients with AoCLD were enrolled,including 1679(49.7%)patients with liver cirrhosis acute decompensation(LC-AD),850(25.2%)patients with ACLF,577(17.1%)patients with chronic hepatitis acute exacer-bation(CHAE),and 269(8.0%)patients with liver cirrhosis active phase(LC-A).The most common cause of chronic liver disease(CLD)was HBV infection(71.4%).The most common precipitants of AoCLD was bacterial infection(22.8%).The 90-d mortality rates of each clinical subtype of AoCLD were 43.4%(232/535)for type-C ACLF,36.0%(36/100)for type-B ACLF,27.0%(58/215)for type-A ACLF,9.0%(151/1679)for LC-AD,3.0%(8/269)for LC-A,and 1.2%(7/577)for CHAE.CONCLUSION HBV infection is the main cause of CLD,and bacterial infection is the main precipitant of AoCLD.The most common clinical type of AoCLD is LC-AD.Early diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.

调神益咽针刺对脑梗死后吞咽障碍患者的疗效研究

目的探究调神益咽针刺对脑梗死后吞咽障碍患者的疗效。方法选取2011年1月-2015年1月于四川省成都市第二中医医院收治的122例脑梗死后吞咽障碍患者,采用随机数字表法分为对照组和观察组。两组患者经常规药物和康复治疗,观察组患者加用调神益咽针刺法治疗,对照组患者加用常规针刺治疗。对比两组患者治疗后的临床疗效,治疗前后的标准吞咽功能评定量表(SSA)评分、微型营养评价(MNA)评分及洼田饮水试验结果。结果治疗后观察组和对照组患者的临床总有效率分别为93.43%和80.31%,两组患者比较有差异(P<0.05)。治疗前两组患者的SSA评分和MNA评分比较无差异(P>0.05)。治疗后两组患者SSA评分和MNA评分较治疗前改善(P<0.05),观察组优于对照组。治疗前两组患者的洼田饮水试验结果比较无差异(P>0.05)。治疗后两组患者的洼田饮水试验结果较治疗前改善(P<0.05)。结论给予脑梗死后吞咽障碍患者常规治疗联合调神益咽针刺法治疗能够显著改善患者的吞咽功能,改善营养状态,提高临床疗效,在临床上值得进一步推广和使用。

Combination treatment with comprehensive cryoablation and immunotherapy in metastatic hepatocellular cancer

AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intraand extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up. RESULTS: Median OS was higher following cryo-immu-notherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryoimmunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy.

Prevalence and clinical characteristics of autoimmune liver disease in hospitalized patients with cirrhosis and acute decompensation in China

BACKGROUND Autoimmune liver disease(AILD)has been considered a relatively uncommon disease in China,epidemiological data for AILD in patients with cirrhosis and acute decompensation(AD)is sparse.AIM To investigate the prevalence,outcome and risk factors for AILD in cirrhotic patients complicated with AD in China.METHODS We collected data from patients with cirrhosis and AD from two prospective,multicenter cohorts in hepatitis B virus endemic areas.Patients were regularly followed up at the end of 28-d,90-d and 365-d,or until death or liver transplantation(LT).The primary outcome in this study was 90-d LTfree mortality.Acute-on-chronic liver failure(ACLF)was assessed on admission and during 28-d hospitalization,according to the diagnostic criteria of the European Association for the Study of the Liver(EASL).Risk factors for death were analyzed with logistic regression model.RESULTS In patients with cirrhosis and AD,the overall prevalence of AILD was 9.3%(242/2597).Prevalence of ACLF was significantly lower in AILD cases(14%)than those with all etiology groups with cirrhosis and AD(22.8%)(P<0.001).Among 242 enrolled AILD patients,the prevalence rates of primary biliary cirrhosis(PBC),autoimmune hepatitis(AIH)and PBC-AIH overlap syndrome(PBC/AIH)were 50.8%,28.5%and 12.0%,respectively.In ACLF patients,the proportions of PBC,AIH and PBC/AIH were 41.2%,29.4% and 20.6%.28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF.The etiology of AILD had no significant impact on 28-d,90-d or 365-d LTfree mortality in patients with cirrhosis and AD in both univariate and multivariate analysis.Total bilirubin(TB),hepatic encephalopathy(HE)and blood urea nitrogen(BUN)were independent risk factors for 90-d LT-free mortality in multivariate analysis.The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio.CONCLUSION AILD was not rare in hospitalized patients with cirrhosis and AD in China,among which PBC was the most common etiology.90-d LT-free mortality were independently associated with TB,HE and BUN.

The inhibitory effects of NKX3.1 on IGF- 1R expression and its signalling pathway in human prostatic carcinoma PC3 cells

NKX3.1, which is a prostate-specific homeobox gene, plays an important role in prostate cancer and usually functions as a tumour suppressor gene. In this study, we investigated the inhibitory effect of NKX3,1 on insulin-like growth factor （IGF）- 1R expression and its downstream signalling pathway in PC3 cells, PC3 cells were stably transfected with NKX3.1 expression plasmid （pcDNA3.1-NKX3.1） or vector plasmid （pcDNA3.1＋）. The IGF-IR mRNA and protein expression levels were assessed in PC3-NKX3.1 transfectants by reverse transcriptase-polymerase chain reaction （RT-PCR） and Western blotting. The expression and activation of IGF-1/IGF-1R downstream signalling targets were examined by Western blotting and luciferase reporter assay. The cells were subsequently treated with relevant concentrations of IGF-1. The effect of IGF-1 on cell growth was examined by 3-（4,5）-dimethylthiahiazo（-z-yl）-3, 5-diphenytetrazoliumromide （MTT） assay and flow cytometry analysis. A significant suppression of IGF-1R mRNA and protein expression was observed after forced expression of NKX3.1 in PC3 cells. Correspondingly, the forced expression of NKX3.1 decreased IGF-l-induced phosphorylation of extracellular signal-regulated kinase 1/2 （ERK1/2） and protein kinase B （AKT） and activation of the Elk-1 transcription factor and downregulated the expression of the downstream target genes c-fos and cyclin D1. Furthermore, the forced expression of NKX3.1 inhibited IGF-l-induced cell growth. In conclusion, NKX3.1 could downregulate IGF-1R expression and could inhibit IGF-1R-mediated mitogen-activated protein kinase （MAPK）/ERK and AKT signalling pathways, which might partially leads to the inhibition of IGF-l-induced cell growth. This study provides new insights into the molecular mechanisms that NKX3,1 exerts against prostate cancer and ultimately expands the scope of alternative approaches in advanced prostate cancer therapy.

FABRICATION OF SELF-ASSEMBLY DNA-C_(60) MULTILAYER FILMS

Electrostatic layer-by-layer self-assembly multilayer films were successfully fabricated from C-60-ethylenediamine adduct (C-60-EDA) and DNA. Under visible light irradiation, DNA is ready to be cleaved and the films are destroyed.

Synthesis, in vitro and in vivo biological evaluation of novel lappaconitine derivatives as potential anti-inflammatory agents

Lappaconitine(LA),a natural compound with a novel C18-diterpenoid alkaloid skeleton,displayed extensive biological profile.Recent research on LA is focused mainly on its anti-tumor and analgesic effects,and therefore we aimed to investigate its anti-inflammatory potential.A series of novel LA derivatives with various substituents on the 20-N position was designed and synthesized.In the initial screening of LA derivatives against NO production,all the target compounds,except compound E2,exhibited excellent inhibitory ability relative to that of LA.Particularly,compound A4 exhibited the most potent inhibition with IC50 of 12.91 mmol/L.The elementary structureeactivity relationships(SARs)of NO inhibitory activity indicated that replacement of the benzene ring with an electron donating group could improve the anti-inflammatory efficacy.Furthermore,compound A4 shows an anti-inflammatory mechanism by inhibiting NO,PGE2,and TNF-a generation via the suppression of NF-kB and MAPK signaling pathways.Notably,compound A4 could exert a significant therapeutic effect on LPS-induced acute lung injury(ALI)in vivo.Based on the above research,we further investigated the preliminary pharmacokinetic property of A4 in rats.Therefore,compound A4 could be a promising candidate for the development of anti-inflammatory agents in the future.

Advances in the role of helper T cells in autoimmune diseases

Autoimmune diseases are primary immune diseases in which autoreactive antibodies or sensitized lymphocytes destroy and damage tissue and cellular components, resulting in tissue damage and organ dysfunction. Helper T cells may be involved in the pathogenesis of autoimmune diseases under certain conditions. This review summarizes recent research on the role of helper T cells in autoimmune diseases from two aspects, helper T cell-mediated production of autoantibodies by B cells and helper T cell-induced activation of abnormal lymphocytes, and provides ideas for the treatment of autoimmune diseases. The abnormal expression of helper T cells promotes the differentiation of B cells that produce autoantibodies, which leads to the development of different diseases. Among them, abnormal expression of Th2 cells and T follicular helper cells is more likely to cause antibody-mediated autoimmune diseases. In addition, abnormal activation of helper T cells also mediates autoimmune diseases through the production of abnormal cytokines and chemokines. Helper T cells play an essential role in the pathogenesis of autoimmune diseases, and a full understanding of their role in autoimmune diseases is helpful for providing ideas for the treatment of autoimmune diseases.

Testicular exosomes disturb the immunosuppressive phenotype of testicular macrophages mediated by miR-155-5p in uropathogenic Escherichia coli-induced orchitis

Male reproductive infections are known to shape the immunological homeostasis of the testes,leading to male infertility.However,the specific pathogenesis of these changes remains poorly understood.Exosomes released in the inflammatory microenvironment are important in communication between the local microenvironment and recipient cells.Here,we aim to identify the immunomodulatory properties of inflammatory testes-derived exosomes(IT-exos)and explore their underlying mechanisms in orchitis.IT-exos were isolated using a uropathogenic Escherichia coli(UPEC)-induced orchitis model and confirmed that IT-exos promoted proinflammatory M1 activation with increasing expression of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and interleukin-6(IL-6)in vitro.We further used small RNA sequencing to identify the differential miRNA profiles in exosomes and primary testicular macrophages(TMs)from normal and UPEC-infected testes,respectively,and identified that miR-155-5p was highly enriched in IT-exos and TMs from inflammatory testes.Further study of bone marrow derived macrophages(BMDMs)transfected with miR-155-5p mimic showed that macrophages polarized to proinflammatory phenotype.In addition,the mice that were administrated IT-exos showed remarkable activation of TM1-like macrophages;however,IT-exos with silencing miR-155-5p showed a decrease in proinflammatory responses.Overall,we demonstrate that miR-155-5p delivered by IT-exos plays an important role in the activation of TM1 in UPEC-induced orchitis.Our study provides a new perspective on the immunological mechanisms underlying inflammation-related male infertility.

Prokineticin 2 overexpression induces spermatocyte apoptosis in varicocele in rats

Varicocele is one of the most important causes of male infertility,as this condition leads to a decline in sperm quality.It is generally believed that the presence of varicocele induces an increase in reactive oxygen species levels,leading to oxidative stress and sperm apoptosis;however,the specific pathogenic mechanisms affecting spermatogenesis remain elusive.Prokineticin 2(PK2),a secretory protein,is associated with multiple biological processes,including cell migration,proliferation,and apoptosis.In the testis,PK2 is expressed in spermatocytes under normal physiological conditions.To investigate the role of PK2 in varicocele,a rat varicocele model was established to locate and quantify the expression of PK2 and its receptor,prokineticin receptor 1(PKR1),by immunohistochemistry and quantitative real-time PCR assays(qPCR).Moreover,H2O2 was applied to mimic the oxidative stress state of varicocele through coculturing with a spermatocyte-derived cell line(GC-2)in vitro,and the apoptosis rate was detected by flow cytometry.Here,we illustrated that the expression levels of PK2 and PKR1 were upregulated in the spermatocytes of the rat model.Administration of H202 stimulated the overexpression of PK2 in GC-2.Transfection of recombinant pCMV-HA-PK2 into GC-2 cells promoted apoptosis by upregulating cleaved-caspase-3,caspase-8,and B cell lymphoma 2-associated X;downregulating B cell lymphoma 2;and promoting the accumulation of intracellular calcium.Overall,we revealed that the varicocele-induced oxidative stress stimulated the overexpression of PK2,leading to apoptosis of spermatocytes.Our study provides new insight into the mechanisms underlying oxidative stress-associated male infertility and suggests a novel therapeutic target for male infertility.

Nickel-Catalyzed Cross-Electrophile Vinyl–Vinyl Coupling:An Approach to Structurally Versatile Dienylboronates

Cross C–C bond formation of two vinyl electrophiles is a long-standing challenge in synthetic chemistry.Herein,we report a nickel-catalyzed reductive vinyl–vinyl coupling between vinyl triflates and boron-substituted vinyl bromides.This new protocol offers facile access to dienylboronates with high structural complexity and molecular diversity.The reaction proceeds with a broad substrate scope under very mild conditions.The synthetic utility of the method is highlighted by its gram-scale reaction,modification of complex molecules,and diverse transformation of the products.

Seminal plasma S100A8/A9 as a potential biomarker of genital tract inflammation

Infections and inflammatory reactions in the male genital tract are the leading causes of male infertility with a prevalence of 6%-10%,primarily affecting testicular and epididymal function and ultimately compromising sperm quality.However,most infertile patients with genital infection/inflammation are asymptomatic and easily overlooked.Traditional indicators,including white blood cells,elastase,and other components in semen,can reflect inflammation of the genital tract,but there is still a lack of a uniform standard method of detection.Therefore,it is necessary to explore reliable markers in semen that reflect the inflammatory status of the genital tract.Using the experimental autoimmune orchitis(EAO)model to simulate noninfectious chronic orchitis,we successfully collected ejaculated seminal fluid from EAO rats using optimized electrical stimulation devices.Proteomic analysis was performed using isobaric tags for relative and absolute quantification(iTRAQ).Compared to the control group,55 upregulated and 105 downregulated proteins were identified in seminal plasma samples from the EAO group.In a preliminary screening,the inflammation-related protein S100A8/A9 was upregulated.We further verified that S100A8/A9 was increased in seminal plasma and highly expressed in testicular macrophages of the EAO model.In patients with oligoasthenospermia and genital tract infections,we also found that S100A8/A9 levels were remarkably increased in seminal plasma and testicular macrophages.S100A8/A9 in semen may be a potential biomarker for chronic genital inflammation.Our study provides a new potential biomarker for early diagnosis and further understanding of male infertility caused by genital inflammation.