Objective:To investigate the clinical symptoms of coronavirus disease 2019(COVID-19)patients with and without B.1.1.7 mutation.Methods:This retrospective observational study included COVID-19 patients who were divided...Objective:To investigate the clinical symptoms of coronavirus disease 2019(COVID-19)patients with and without B.1.1.7 mutation.Methods:This retrospective observational study included COVID-19 patients who were divided into two groups,the mutation and the non-mutation group.Demographics characteristics,clinical characteristics,laboratory parameters,and mortality rates were recorded and compared between the two groups.Results:A total of 196 patients were included in the study.The relationship between the mutant virus status and sex,age,comorbidity,survival status,and disease severity was not significant(P>0.05).No significant differences were found in duration of hospitalization between the mutation and the non-mutation group(P>0.05).However,there was a statistically significant difference between patients with and without mutant viruses in hemoglobin,mean platelet volume,procalcitonin,low density lipoprotein,iron-binding capacity,potassium,calcium,C-reactive protein,folate,creatine kinase myocardial band,D-dimer,and international normalized ratio(P<0.05).Conclusions:No significant difference is found in mortality rate,disease severity or duration of hospitalization between the patients with and without variant B.1.1.7.Careful monitoring of COVID-19 patients is required for all variants.展开更多
目的探讨银杏内酯B通过激活免疫性血小板减少症(ITP)哺乳动物雷帕霉素靶蛋白(mTOR)信号通路调节长链非编码RNA人浆细胞瘤转化迁移基因1(lncRNA PVT1)促进调节性T淋巴细胞/辅助性T淋巴细胞17(Treg/Th17)免疫平衡而抑制炎症反应的机制。...目的探讨银杏内酯B通过激活免疫性血小板减少症(ITP)哺乳动物雷帕霉素靶蛋白(mTOR)信号通路调节长链非编码RNA人浆细胞瘤转化迁移基因1(lncRNA PVT1)促进调节性T淋巴细胞/辅助性T淋巴细胞17(Treg/Th17)免疫平衡而抑制炎症反应的机制。方法选用80只雄性SD小鼠,采用腹腔注射抗小鼠血小板血清方法建立模型,随机分为正常组、模型组、低剂量组、高剂量组,每组20只,连续给药14天。实时荧光定量PCR(qRT-PCR)检测血清lncRNA PVT1表达,流式细胞仪检测Treg/Th17细胞,Western Blot检测磷脂酰肌醇-3-激酶(PI3K)、Akt、mTOR蛋白表达。检测血清白细胞介素-4(IL-4)、干扰素-γ(IFN-γ)和全血血小板计数(PLT)。结果与正常组比较,模型组小鼠血清lncRNA PVT1、Th17、IFN-γ升高,Treg、Treg/Th17、PI3K、Akt、mTOR蛋白、IL-4、PLT降低,差异具有统计学意义(t=2.510~54.899,均P<0.05);与模型组比较,低剂量组、高剂量组lncRNA PVT1(1.99±0.14、1.25±0.11 vs 2.39±0.15)、Th17(1.76%±0.32%、0.87%±0.04%vs 5.28%±1.21%)、IFN-γ(7.65±0.28pg/ml、6.84±0.33pg/ml vs 8.45±0.36 pg/ml)均降低(t_(低剂量组)=8.718、8.782、3.292,t_(高剂量组)=27.408、9.789、6.542),Treg(3.46%±0.43%、4.77%±0.51%vs 2.41%±0.44%)、Treg/Th17(1.98±0.16、4.24±1.02 vs 0.45±0.05)、PI3K(0.88±0.08、1.22±0.21 vs 0.45±0.05)、Akt(0.66±0.07、1.11±0.11 vs 0.21±0.02)、mTOR蛋白(0.70±0.08、1.21±0.13 vs 0.45±0.06)、IL-4(12.28±1.28pg/ml、13.08±1.01pg/ml vs 11.45±1.05pg/ml)、PLT[(526.99±50.34)×10^(9)/L、(880.37±52.78)×10^(9)/L vs(218.58±50.35)×10^(9)/L]均升高(t_(低剂量组)=4.943~27.643,t_(高剂量组)=7.766~40.818),差异具有统计学意义(均P<0.05)。与低剂量组比较,高剂量组lncRNA PVT1、Th17、IFN-γ降低,Treg、Treg/Th17、PI3K、Akt、mTOR蛋白、IL-4、PLT升高,差异具有统计学意义(t=2.411~21.667,均P<0.05)。结论银杏内酯B可通过激活mTOR信号通路,调节lncRNA PVT1促进Treg/Th17免疫平衡,抑制ITP小鼠炎症反应,提升血小板数量。展开更多
间变型弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)是一种罕见的非特指型DLBCL,组织形态学常为窦性或者弥漫生长。该文报道1例,其左侧腋窝淋巴结具有大量多形性的中心母细胞样伴间变特征的细胞和HRS样细胞呈结节状或滤泡...间变型弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)是一种罕见的非特指型DLBCL,组织形态学常为窦性或者弥漫生长。该文报道1例,其左侧腋窝淋巴结具有大量多形性的中心母细胞样伴间变特征的细胞和HRS样细胞呈结节状或滤泡生发中心样生长,符合DLBCL,非特殊类型,间变型。结合相关文献探讨其临床病理学及分子遗传学特征,以提高临床和病理医师对该肿瘤的认识。展开更多
Chronic hepatitis B is a global health problem. The clinical outcomes of chronic hepatitis B infection include asymptomatic carrier state, chronic hepatitis(CH), liver cirrhosis(LC), and hepatocellular carcinoma(HCC)....Chronic hepatitis B is a global health problem. The clinical outcomes of chronic hepatitis B infection include asymptomatic carrier state, chronic hepatitis(CH), liver cirrhosis(LC), and hepatocellular carcinoma(HCC). Because of the spontaneous error rate inherent to viral reverse transcriptase, the hepatitis B virus(HBV) genome evolves during the course of infection under the antiviral pressure of host immunity. The clinical significance of pre-S/S variants has become increasingly recognized in patients with chronic HBV infection. Pre-S/S variants are often identified in hepatitis B carriers with CH, LC, and HCC, which suggests that these naturally occurring pre-S/S variants may contribute to the development of progressive liver damage and hepatocarcinogenesis. This paper reviews the function of the pre-S/S region along with recent findings related to the role of pre-S/S variants in liver diseases. According to the mutation type, five pre-S/S variants have been identified: pre-S deletion, pre-S point mutation, pre-S1 splice variant, C-terminus S point mutation, and pre-S/S nonsense mutation. Their associations with HBV genotype and the possible pathogenesis of pre-S/S variants are discussed. Different pre-S/S variants cause liver diseases through different mechanisms. Most cause the intracellular retention of HBV envelope proteins and induction of endoplasmic reticulum stress, which results in liver diseases. Pre-S/S variants should be routinely determined in HBV carriers to help identify individuals who may be at a high risk of less favorable liver disease progression. Additional investigations are required to explore the molecular mechanisms of the pre-S/S variants involved in the pathogenesis of each stage of liver disease.展开更多
The appearance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant Omicron(B.1.1.529)has caused panic responses around the world because of its high transmission rate and number of mutations.This rev...The appearance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant Omicron(B.1.1.529)has caused panic responses around the world because of its high transmission rate and number of mutations.This review summarizes the highly mutated regions,the essential infectivity,transmission,vaccine breakthrough and antibody resistance of the Omicron variant of SARSCoV-2.The Omicron is highly transmissible and is spreading faster than any previous variant,but may cause less severe symptoms than previous variants.The Omicron is able to escape the immune system’s defenses and coronavirus disease 2019 vaccines are less effective against the Omicron variant.Early careful preventive steps including vaccination will always be key for the suppression of the Omicron variant.展开更多
Molecular virology methods including polymerase chain reaction, cloning and sequencing have revolutionised our understanding of viral genome variation. In the case of hepatitis B virus (HBV), sequencing studies have i...Molecular virology methods including polymerase chain reaction, cloning and sequencing have revolutionised our understanding of viral genome variation. In the case of hepatitis B virus (HBV), sequencing studies have identified a number of virus variants normally found during the natural course of chronic infection. The appearance of the precore stop codon (with G-for-A substitution at position 1896) and basal core promoter (BCP) (with A-for-T and G-for-A, at positions 1762 and 1764, respectively) variants which reduce or abrogate hepatitis B e antigen (HBeAg) production, heralds the initiation of the seroconversion phase from HBeAg to anti-HBe positivity. The gradual removal of the tolerogenic effect of HBeAg leads to the awakening of the immune response (immune clearance phase). Most patients after HBeAg seroconversion become “inactive HBsAg carriers”. However during the course of infection precore and/or BCP variants may emerge and be selected leading to HBeAg negative chronic hepatitis B (CHB) with high viremia levels (reactivation phase). The prevalence of HBeAg negative CHB has been increasing over the last few decades and has become the commonest type of HBV infection in many countries of the world. This probably reflects the aging of existing HBV carriers and the effective prevention measures restricting new HBV infections. Frequent acute exacerbations accompanied by high viral replication, elevated alanine aminotransferase levels and histological activity are a common feature of HBeAg negative CHB leading to cirrhosis much faster than in HBeAg positive CHB patients.展开更多
Objective: To analyse the emergence of YMDD motif(tyrosine-methionine-aspartate-aspartate) variants inpatients with hepatitis B treated with lamivudine.Methods: The amino acid substitution from methio-nine or isoleuci...Objective: To analyse the emergence of YMDD motif(tyrosine-methionine-aspartate-aspartate) variants inpatients with hepatitis B treated with lamivudine.Methods: The amino acid substitution from methio-nine or isoleucine at the YMDD motif at the HBVpolymerase gene is a main mutation resistant to lami-vudine treatment. Generated from a fragment of do-main C of the polymerase gene, patients HBV DNA,which had been positive previously became positive a-gain ever since it had been negative during lamivudi-ne therapy. Variants were detected by cleavage of theproducts of the three PCRs with following enzymes:FokI, SspI, Alw441. The results of PCR-RELP wereanalysed by 8. 4% polypropylene acidemide gel elec-trophoresis. PCR-RFLP assay was compared to di-rect sequencing.Results: HBV DNA was positive again in 33 patientsand positive for one year in 2 patients. YMDD vari-ants were detected in serum 14 of 35 patients, YIDDvariants in 4, YVDD variants in 6, and YI/MDD va-riants in 1; all were in concordance with the resultsof direct sequencing. The samples of other 3 patientsshowed YI/VDD mutations, as shown by direct se-quencing. The results of PCR-RFLP assay of themixed sera of YIDD and YVDD variants were similarto those sera of YI/VDD variants.Conclusion: PCR-RFLP is suitable for rapid detec-tion of YMDD variants of viral polymerase in hepati-tis B virus patients treated with lamivudine.展开更多
AIM: To investigate the mechanism of endoplasmic reticulum(ER) stress induction by an occult infection related hepatitis B virus S surface antigen(HBsAg)variant.METHODS: We used an HBsAg variant with lower secretion c...AIM: To investigate the mechanism of endoplasmic reticulum(ER) stress induction by an occult infection related hepatitis B virus S surface antigen(HBsAg)variant.METHODS: We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western blot.RESULTS: Confocal microscopy indicated that the KD variant had higher levels of co-localization with ER than the wild-type HBsAg. The KD variant upregulated ER stress-related proteins and induced reactive oxygen species(ROS) compared to the wildtype via an increase in calcium. The KD variant also down-regulated anti-oxidant proteins(HO-1, catalase and SOD) compared to the wild-type, which indicates positive amplification loops of the ER-ROS axis. The KD variant also induced apoptotic cell death via the upregulation of caspase proteins(caspase 6, 9 and 12).Furthermore, the KD variant induced a higher level of nitric oxide than wild-type HBsAg via the up-regulation of the iNOS protein.CONCLUSION: Our data indicate that occult infection related HBsAg variants can lead to ER-derived oxidative stress and liver cell death in HuH-7 cells.展开更多
During the two-year pandemic of coronavirus disease 2019(COVID-19), its causative agent, severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has been evolving. SARS-CoV-2 Delta, a variant of concern, has beco...During the two-year pandemic of coronavirus disease 2019(COVID-19), its causative agent, severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has been evolving. SARS-CoV-2 Delta, a variant of concern, has become the dominant circulating strain worldwide within just a few months. Here, we performed a comprehensive analysis of a new B.1.617.2 Delta strain(Delta630) compared with the early WIV04 strain(WIV04) in vitro and in vivo, in terms of replication, infectivity, pathogenicity, and transmission in hamsters. When inoculated intranasally, Delta630 led to more pronounced weight loss and more severe disease in hamsters. Moreover, 40%mortality occurred about one week after infection with 10^(4)PFU of Delta630, whereas no deaths occurred even after infection with 10^(5)PFU of WIV04 or other strains belonging to the Delta variant. Moreover, Delta630outgrew over WIV04 in the competitive aerosol transmission experiment. Taken together, the Delta630 strain showed increased replication ability, pathogenicity, and transmissibility over WIV04 in hamsters. To our knowledge, this is the first SARS-CoV-2 strain that causes death in a hamster model, which could be an asset for the efficacy evaluation of vaccines and antivirals against infections of SARS-CoV-2 Delta strains. The underlying molecular mechanisms of increased virulence and transmission await further analysis.展开更多
BACKGROUND Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters.Herein,we firstly pro...BACKGROUND Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters.Herein,we firstly provide the evidence that a nonsense variant of ATP8B1 gene(c.1558A>T)in heterozygous form is involved in BRIC pathogenesis.CASE SUMMARY A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase.Acute and chronic liver diseases with viral,metabolic and autoimmune etiology were excluded.Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance.Liver biopsy showed:Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment,Kupffer’s cell activation/hyperplasia and preserved biliary ducts.Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria,ATP8B1 and ABCB11 gene analysis was performed.Surprisingly,we found a novel nonsense variant of ATP8B1 gene(c.1558A>T)in heterozygosis.The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation,showing a maternal inheritance.Immunohistochemistry confirmed a significant reduction of mutated gene related protein(familial intrahepatic cholestasis 1).The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo.CONCLUSION A genetic abnormality,different from those already known,could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition,thus encouraging further mutation detection in this field.展开更多
Objective： Our previous study has showed that △DNMT3B is the predominant form of DNMT3B in non-small cell lung cancer （NSCLC）. In this study, we aimed to explore the expression patterns of the △DNMT3B variants in...Objective： Our previous study has showed that △DNMT3B is the predominant form of DNMT3B in non-small cell lung cancer （NSCLC）. In this study, we aimed to explore the expression patterns of the △DNMT3B variants in breast cancer and to identify whether the pattern was similar to that in NSCLC or not and its clinical significance. Methods： Expression of seven △DNMT3B variants in 59 breast cancer and the corresponding normal tissue was measured using RT-PCR. The correlations between the expressions of △DNMT3B variants and the clinical parameters including ER/PR status, clincopathologic feature and survivals were analyzed. Results： There were significant differences in the expression ratios of △DNMT3B1-7 variants between breast cancer tissues and normal tissues （P〈0.001）. The positive ratio of △DNMT3B1-7 variants were 66%, 71%, 17%, 51%, 76.2%, 50% and 61% in tumor tissue, respectively; while 16%, 8.4%, 3.38%, 3.38%, 11.8%, 13.5% and 5.08% in the corresponding normal tissue, which was different from the pattern of △DNMT3B1-7 expression in NSCLC （62%, 76%, 2.5%, 46%, 18%, 27% and 16% in tumor tissue, respectively; while 18%, 11%, 0%, 3.3%, 0%, 0% and 0% in normal lung tissue, respectively; P〈0.0001）. Expressions of △DNMT3B2, 3B4 and 3B7 were higher in the patients with negative estrogen receptor （ER） than those with positive estrogen receptor （P=0.035, P=0.0141 and P=0.0219, respectively）. △DNMT3B7 expression was higher for the patients with negative progestogen receptor （PR） compared to those with positive progestogen receptor （P=0.0379）. Expression ratio of △DNMT3B5 in stage Ⅲ tumors is lower than that in stage Ⅰ/Ⅱ ones （P= 0.041）. But we did not find any relation between the △DNMT3B variants and the patients＇ survival. Conclusion： The pattern of △DNMT3B variants in breast cancer is different from that in NSCLC. Expressions of △DNMT3B2, 3B4 and 3B7 are associated with estrogen receptors status. While △DNMT3B7 is associated with progestogen receptor. No relation between the △DNMT3B variants and the patients＇ survival were found.展开更多
BACKGROUND The B.1.617.2(delta)variant of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first discovered in Maharashtra in late 2020 and has rapidly expanded across India and worldwide.It took only 2 ...BACKGROUND The B.1.617.2(delta)variant of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first discovered in Maharashtra in late 2020 and has rapidly expanded across India and worldwide.It took only 2 mo for this variant to spread in Indonesia,making the country the new epicenter of the delta variant as of July 2021.Despite efforts made by accelerating massive rollouts of current vaccines to protect against infection,cases of fully-vaccinated people infected with the delta variant have been reported.AIM To describe the demographic statistics and clinical presentation of the delta variant infection after the second dose of vaccine in Indonesia.METHODS A retrospective,single-centre case series of the general consecutive population that worked or studied at Faculty of Medicine,Universitas Indonesia with confirmed Delta Variant Infection after a second dose of vaccine from 24 June and 25 June 2021.Cases were collected retrospectively based on a combination of author recall,reverse transcription-polymerase chain reaction(RT-PCR),and whole genome sequencing results from the Clinical Microbiology Laboratory,Faculty of Medicine,Universitas Indonesia.RESULTS Between 24 June and 25 June 2021,15 subjects were confirmed with the B.1.617.2(delta)variant infection after a second dose of the vaccine.Fourteen subjects were vaccinated with CoronaVac(Sinovac)and one subject with ChAdOx1 nCoV-19(Oxford-AstraZeneca).All of the subjects remained in home isolation,with fever being the most common symptom at the onset of illness(n=10,66.67%).The mean duration of symptoms was 7.73 d(±5.444).The mean time that elapsed from the first positive swab to a negative RT-PCR test for SARS-CoV-2 was 17.93 d(±6.3464).The median time that elapsed from the second dose of vaccine to the first positive swab was 87 d(interquartile range:86-128).CONCLUSION Although this case shows that after two doses of vaccine,subjects are still susceptible to the delta variant infection,currently available vaccines remain the most effective protection.They reduce clinical manifestations of COVID-19,decrease recovery time from the first positive swab to negative swab,and lower the probability of hospitalization and mortality rate compared to unvaccinated individuals.展开更多
Omicron,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant that is now spreading across the world,is the most altered version to emerge so far,with mutations comparable to changes reported in earli...Omicron,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant that is now spreading across the world,is the most altered version to emerge so far,with mutations comparable to changes reported in earlier variants of concern linked with increased transmissibility and partial resistance to vaccineinduced immunity.This article provides an overview of the SARS-CoV-2 variant Omicron(B.1.1.529)by reviewing the literature from major scientific databases.Although clear immunological and clinical data are not yet available,we extrapolated from what is known about mutations present in the Omicron variant of SARS-CoV-2 and offer preliminary indications on transmissibility,severity,and immune escape through existing research and databases.展开更多
目的探讨胃肠道原发梭形细胞变异型弥漫性大B细胞淋巴瘤(spindle cell variant of diffuse large B-cell lymphoma,SV-DLBCL)的临床病理特点、诊断与鉴别诊断。方法收集4例胃肠道原发SV-DLBCL临床资料,行免疫组化染色及EBER原位杂交检测...目的探讨胃肠道原发梭形细胞变异型弥漫性大B细胞淋巴瘤(spindle cell variant of diffuse large B-cell lymphoma,SV-DLBCL)的临床病理特点、诊断与鉴别诊断。方法收集4例胃肠道原发SV-DLBCL临床资料,行免疫组化染色及EBER原位杂交检测,并结合相关文献分析其临床病理学特征。结果4例患者年龄49~91岁,发生于胃1例,小肠2例,结肠1例。临床表现以腹痛及肠梗阻症状为主。镜下示肿瘤细胞呈弥漫性分布,主要由梭形细胞构成,被胶原束分隔成条索状,细胞中等偏大、可见核仁,核分裂易见。免疫表型:肿瘤细胞表达CD20、PAX5等B细胞标志物,4例中3例为non-GCB型、1例为GCB型,CD30和原位杂交EBER均阴性,Ki67增殖指数均>80%。FISH检测结果显示其中1例BCL6基因断裂信号阳性,其他3例均阴性;4例MYC基因和BCL2基因断裂信号均阴性。结论胃肠道原发的SV-DLBCL较为罕见,需与胃肠道发生的其他梭形细胞肿瘤相鉴别,诊断时需结合HE形态及免疫组化标记等综合判断。展开更多
文摘Objective:To investigate the clinical symptoms of coronavirus disease 2019(COVID-19)patients with and without B.1.1.7 mutation.Methods:This retrospective observational study included COVID-19 patients who were divided into two groups,the mutation and the non-mutation group.Demographics characteristics,clinical characteristics,laboratory parameters,and mortality rates were recorded and compared between the two groups.Results:A total of 196 patients were included in the study.The relationship between the mutant virus status and sex,age,comorbidity,survival status,and disease severity was not significant(P>0.05).No significant differences were found in duration of hospitalization between the mutation and the non-mutation group(P>0.05).However,there was a statistically significant difference between patients with and without mutant viruses in hemoglobin,mean platelet volume,procalcitonin,low density lipoprotein,iron-binding capacity,potassium,calcium,C-reactive protein,folate,creatine kinase myocardial band,D-dimer,and international normalized ratio(P<0.05).Conclusions:No significant difference is found in mortality rate,disease severity or duration of hospitalization between the patients with and without variant B.1.1.7.Careful monitoring of COVID-19 patients is required for all variants.
文摘目的探讨银杏内酯B通过激活免疫性血小板减少症(ITP)哺乳动物雷帕霉素靶蛋白(mTOR)信号通路调节长链非编码RNA人浆细胞瘤转化迁移基因1(lncRNA PVT1)促进调节性T淋巴细胞/辅助性T淋巴细胞17(Treg/Th17)免疫平衡而抑制炎症反应的机制。方法选用80只雄性SD小鼠,采用腹腔注射抗小鼠血小板血清方法建立模型,随机分为正常组、模型组、低剂量组、高剂量组,每组20只,连续给药14天。实时荧光定量PCR(qRT-PCR)检测血清lncRNA PVT1表达,流式细胞仪检测Treg/Th17细胞,Western Blot检测磷脂酰肌醇-3-激酶(PI3K)、Akt、mTOR蛋白表达。检测血清白细胞介素-4(IL-4)、干扰素-γ(IFN-γ)和全血血小板计数(PLT)。结果与正常组比较,模型组小鼠血清lncRNA PVT1、Th17、IFN-γ升高,Treg、Treg/Th17、PI3K、Akt、mTOR蛋白、IL-4、PLT降低,差异具有统计学意义(t=2.510~54.899,均P<0.05);与模型组比较,低剂量组、高剂量组lncRNA PVT1(1.99±0.14、1.25±0.11 vs 2.39±0.15)、Th17(1.76%±0.32%、0.87%±0.04%vs 5.28%±1.21%)、IFN-γ(7.65±0.28pg/ml、6.84±0.33pg/ml vs 8.45±0.36 pg/ml)均降低(t_(低剂量组)=8.718、8.782、3.292,t_(高剂量组)=27.408、9.789、6.542),Treg(3.46%±0.43%、4.77%±0.51%vs 2.41%±0.44%)、Treg/Th17(1.98±0.16、4.24±1.02 vs 0.45±0.05)、PI3K(0.88±0.08、1.22±0.21 vs 0.45±0.05)、Akt(0.66±0.07、1.11±0.11 vs 0.21±0.02)、mTOR蛋白(0.70±0.08、1.21±0.13 vs 0.45±0.06)、IL-4(12.28±1.28pg/ml、13.08±1.01pg/ml vs 11.45±1.05pg/ml)、PLT[(526.99±50.34)×10^(9)/L、(880.37±52.78)×10^(9)/L vs(218.58±50.35)×10^(9)/L]均升高(t_(低剂量组)=4.943~27.643,t_(高剂量组)=7.766~40.818),差异具有统计学意义(均P<0.05)。与低剂量组比较,高剂量组lncRNA PVT1、Th17、IFN-γ降低,Treg、Treg/Th17、PI3K、Akt、mTOR蛋白、IL-4、PLT升高,差异具有统计学意义(t=2.411~21.667,均P<0.05)。结论银杏内酯B可通过激活mTOR信号通路,调节lncRNA PVT1促进Treg/Th17免疫平衡,抑制ITP小鼠炎症反应,提升血小板数量。
文摘间变型弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)是一种罕见的非特指型DLBCL,组织形态学常为窦性或者弥漫生长。该文报道1例,其左侧腋窝淋巴结具有大量多形性的中心母细胞样伴间变特征的细胞和HRS样细胞呈结节状或滤泡生发中心样生长,符合DLBCL,非特殊类型,间变型。结合相关文献探讨其临床病理学及分子遗传学特征,以提高临床和病理医师对该肿瘤的认识。
基金Supported by the grant from the National Science Council(NSC 96-2320-B-030-004-MY3),Executive Yuan,Taiwan
文摘Chronic hepatitis B is a global health problem. The clinical outcomes of chronic hepatitis B infection include asymptomatic carrier state, chronic hepatitis(CH), liver cirrhosis(LC), and hepatocellular carcinoma(HCC). Because of the spontaneous error rate inherent to viral reverse transcriptase, the hepatitis B virus(HBV) genome evolves during the course of infection under the antiviral pressure of host immunity. The clinical significance of pre-S/S variants has become increasingly recognized in patients with chronic HBV infection. Pre-S/S variants are often identified in hepatitis B carriers with CH, LC, and HCC, which suggests that these naturally occurring pre-S/S variants may contribute to the development of progressive liver damage and hepatocarcinogenesis. This paper reviews the function of the pre-S/S region along with recent findings related to the role of pre-S/S variants in liver diseases. According to the mutation type, five pre-S/S variants have been identified: pre-S deletion, pre-S point mutation, pre-S1 splice variant, C-terminus S point mutation, and pre-S/S nonsense mutation. Their associations with HBV genotype and the possible pathogenesis of pre-S/S variants are discussed. Different pre-S/S variants cause liver diseases through different mechanisms. Most cause the intracellular retention of HBV envelope proteins and induction of endoplasmic reticulum stress, which results in liver diseases. Pre-S/S variants should be routinely determined in HBV carriers to help identify individuals who may be at a high risk of less favorable liver disease progression. Additional investigations are required to explore the molecular mechanisms of the pre-S/S variants involved in the pathogenesis of each stage of liver disease.
文摘The appearance of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant Omicron(B.1.1.529)has caused panic responses around the world because of its high transmission rate and number of mutations.This review summarizes the highly mutated regions,the essential infectivity,transmission,vaccine breakthrough and antibody resistance of the Omicron variant of SARSCoV-2.The Omicron is highly transmissible and is spreading faster than any previous variant,but may cause less severe symptoms than previous variants.The Omicron is able to escape the immune system’s defenses and coronavirus disease 2019 vaccines are less effective against the Omicron variant.Early careful preventive steps including vaccination will always be key for the suppression of the Omicron variant.
文摘Molecular virology methods including polymerase chain reaction, cloning and sequencing have revolutionised our understanding of viral genome variation. In the case of hepatitis B virus (HBV), sequencing studies have identified a number of virus variants normally found during the natural course of chronic infection. The appearance of the precore stop codon (with G-for-A substitution at position 1896) and basal core promoter (BCP) (with A-for-T and G-for-A, at positions 1762 and 1764, respectively) variants which reduce or abrogate hepatitis B e antigen (HBeAg) production, heralds the initiation of the seroconversion phase from HBeAg to anti-HBe positivity. The gradual removal of the tolerogenic effect of HBeAg leads to the awakening of the immune response (immune clearance phase). Most patients after HBeAg seroconversion become “inactive HBsAg carriers”. However during the course of infection precore and/or BCP variants may emerge and be selected leading to HBeAg negative chronic hepatitis B (CHB) with high viremia levels (reactivation phase). The prevalence of HBeAg negative CHB has been increasing over the last few decades and has become the commonest type of HBV infection in many countries of the world. This probably reflects the aging of existing HBV carriers and the effective prevention measures restricting new HBV infections. Frequent acute exacerbations accompanied by high viral replication, elevated alanine aminotransferase levels and histological activity are a common feature of HBeAg negative CHB leading to cirrhosis much faster than in HBeAg positive CHB patients.
文摘Objective: To analyse the emergence of YMDD motif(tyrosine-methionine-aspartate-aspartate) variants inpatients with hepatitis B treated with lamivudine.Methods: The amino acid substitution from methio-nine or isoleucine at the YMDD motif at the HBVpolymerase gene is a main mutation resistant to lami-vudine treatment. Generated from a fragment of do-main C of the polymerase gene, patients HBV DNA,which had been positive previously became positive a-gain ever since it had been negative during lamivudi-ne therapy. Variants were detected by cleavage of theproducts of the three PCRs with following enzymes:FokI, SspI, Alw441. The results of PCR-RELP wereanalysed by 8. 4% polypropylene acidemide gel elec-trophoresis. PCR-RFLP assay was compared to di-rect sequencing.Results: HBV DNA was positive again in 33 patientsand positive for one year in 2 patients. YMDD vari-ants were detected in serum 14 of 35 patients, YIDDvariants in 4, YVDD variants in 6, and YI/MDD va-riants in 1; all were in concordance with the resultsof direct sequencing. The samples of other 3 patientsshowed YI/VDD mutations, as shown by direct se-quencing. The results of PCR-RFLP assay of themixed sera of YIDD and YVDD variants were similarto those sera of YI/VDD variants.Conclusion: PCR-RFLP is suitable for rapid detec-tion of YMDD variants of viral polymerase in hepati-tis B virus patients treated with lamivudine.
基金Supported by National Research Foundation of Korea grant funded by the Korea government(MEST),No.2013-005810
文摘AIM: To investigate the mechanism of endoplasmic reticulum(ER) stress induction by an occult infection related hepatitis B virus S surface antigen(HBsAg)variant.METHODS: We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western blot.RESULTS: Confocal microscopy indicated that the KD variant had higher levels of co-localization with ER than the wild-type HBsAg. The KD variant upregulated ER stress-related proteins and induced reactive oxygen species(ROS) compared to the wildtype via an increase in calcium. The KD variant also down-regulated anti-oxidant proteins(HO-1, catalase and SOD) compared to the wild-type, which indicates positive amplification loops of the ER-ROS axis. The KD variant also induced apoptotic cell death via the upregulation of caspase proteins(caspase 6, 9 and 12).Furthermore, the KD variant induced a higher level of nitric oxide than wild-type HBsAg via the up-regulation of the iNOS protein.CONCLUSION: Our data indicate that occult infection related HBsAg variants can lead to ER-derived oxidative stress and liver cell death in HuH-7 cells.
基金supported by China Natural Science Foundation (82150201)
文摘During the two-year pandemic of coronavirus disease 2019(COVID-19), its causative agent, severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has been evolving. SARS-CoV-2 Delta, a variant of concern, has become the dominant circulating strain worldwide within just a few months. Here, we performed a comprehensive analysis of a new B.1.617.2 Delta strain(Delta630) compared with the early WIV04 strain(WIV04) in vitro and in vivo, in terms of replication, infectivity, pathogenicity, and transmission in hamsters. When inoculated intranasally, Delta630 led to more pronounced weight loss and more severe disease in hamsters. Moreover, 40%mortality occurred about one week after infection with 10^(4)PFU of Delta630, whereas no deaths occurred even after infection with 10^(5)PFU of WIV04 or other strains belonging to the Delta variant. Moreover, Delta630outgrew over WIV04 in the competitive aerosol transmission experiment. Taken together, the Delta630 strain showed increased replication ability, pathogenicity, and transmissibility over WIV04 in hamsters. To our knowledge, this is the first SARS-CoV-2 strain that causes death in a hamster model, which could be an asset for the efficacy evaluation of vaccines and antivirals against infections of SARS-CoV-2 Delta strains. The underlying molecular mechanisms of increased virulence and transmission await further analysis.
文摘BACKGROUND Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters.Herein,we firstly provide the evidence that a nonsense variant of ATP8B1 gene(c.1558A>T)in heterozygous form is involved in BRIC pathogenesis.CASE SUMMARY A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase.Acute and chronic liver diseases with viral,metabolic and autoimmune etiology were excluded.Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance.Liver biopsy showed:Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment,Kupffer’s cell activation/hyperplasia and preserved biliary ducts.Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria,ATP8B1 and ABCB11 gene analysis was performed.Surprisingly,we found a novel nonsense variant of ATP8B1 gene(c.1558A>T)in heterozygosis.The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation,showing a maternal inheritance.Immunohistochemistry confirmed a significant reduction of mutated gene related protein(familial intrahepatic cholestasis 1).The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo.CONCLUSION A genetic abnormality,different from those already known,could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition,thus encouraging further mutation detection in this field.
基金supported by the grants from the National Natural Science Foundation of China (No.30572104,30772472)
文摘Objective： Our previous study has showed that △DNMT3B is the predominant form of DNMT3B in non-small cell lung cancer （NSCLC）. In this study, we aimed to explore the expression patterns of the △DNMT3B variants in breast cancer and to identify whether the pattern was similar to that in NSCLC or not and its clinical significance. Methods： Expression of seven △DNMT3B variants in 59 breast cancer and the corresponding normal tissue was measured using RT-PCR. The correlations between the expressions of △DNMT3B variants and the clinical parameters including ER/PR status, clincopathologic feature and survivals were analyzed. Results： There were significant differences in the expression ratios of △DNMT3B1-7 variants between breast cancer tissues and normal tissues （P〈0.001）. The positive ratio of △DNMT3B1-7 variants were 66%, 71%, 17%, 51%, 76.2%, 50% and 61% in tumor tissue, respectively; while 16%, 8.4%, 3.38%, 3.38%, 11.8%, 13.5% and 5.08% in the corresponding normal tissue, which was different from the pattern of △DNMT3B1-7 expression in NSCLC （62%, 76%, 2.5%, 46%, 18%, 27% and 16% in tumor tissue, respectively; while 18%, 11%, 0%, 3.3%, 0%, 0% and 0% in normal lung tissue, respectively; P〈0.0001）. Expressions of △DNMT3B2, 3B4 and 3B7 were higher in the patients with negative estrogen receptor （ER） than those with positive estrogen receptor （P=0.035, P=0.0141 and P=0.0219, respectively）. △DNMT3B7 expression was higher for the patients with negative progestogen receptor （PR） compared to those with positive progestogen receptor （P=0.0379）. Expression ratio of △DNMT3B5 in stage Ⅲ tumors is lower than that in stage Ⅰ/Ⅱ ones （P= 0.041）. But we did not find any relation between the △DNMT3B variants and the patients＇ survival. Conclusion： The pattern of △DNMT3B variants in breast cancer is different from that in NSCLC. Expressions of △DNMT3B2, 3B4 and 3B7 are associated with estrogen receptors status. While △DNMT3B7 is associated with progestogen receptor. No relation between the △DNMT3B variants and the patients＇ survival were found.
文摘BACKGROUND The B.1.617.2(delta)variant of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first discovered in Maharashtra in late 2020 and has rapidly expanded across India and worldwide.It took only 2 mo for this variant to spread in Indonesia,making the country the new epicenter of the delta variant as of July 2021.Despite efforts made by accelerating massive rollouts of current vaccines to protect against infection,cases of fully-vaccinated people infected with the delta variant have been reported.AIM To describe the demographic statistics and clinical presentation of the delta variant infection after the second dose of vaccine in Indonesia.METHODS A retrospective,single-centre case series of the general consecutive population that worked or studied at Faculty of Medicine,Universitas Indonesia with confirmed Delta Variant Infection after a second dose of vaccine from 24 June and 25 June 2021.Cases were collected retrospectively based on a combination of author recall,reverse transcription-polymerase chain reaction(RT-PCR),and whole genome sequencing results from the Clinical Microbiology Laboratory,Faculty of Medicine,Universitas Indonesia.RESULTS Between 24 June and 25 June 2021,15 subjects were confirmed with the B.1.617.2(delta)variant infection after a second dose of the vaccine.Fourteen subjects were vaccinated with CoronaVac(Sinovac)and one subject with ChAdOx1 nCoV-19(Oxford-AstraZeneca).All of the subjects remained in home isolation,with fever being the most common symptom at the onset of illness(n=10,66.67%).The mean duration of symptoms was 7.73 d(±5.444).The mean time that elapsed from the first positive swab to a negative RT-PCR test for SARS-CoV-2 was 17.93 d(±6.3464).The median time that elapsed from the second dose of vaccine to the first positive swab was 87 d(interquartile range:86-128).CONCLUSION Although this case shows that after two doses of vaccine,subjects are still susceptible to the delta variant infection,currently available vaccines remain the most effective protection.They reduce clinical manifestations of COVID-19,decrease recovery time from the first positive swab to negative swab,and lower the probability of hospitalization and mortality rate compared to unvaccinated individuals.
文摘Omicron,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variant that is now spreading across the world,is the most altered version to emerge so far,with mutations comparable to changes reported in earlier variants of concern linked with increased transmissibility and partial resistance to vaccineinduced immunity.This article provides an overview of the SARS-CoV-2 variant Omicron(B.1.1.529)by reviewing the literature from major scientific databases.Although clear immunological and clinical data are not yet available,we extrapolated from what is known about mutations present in the Omicron variant of SARS-CoV-2 and offer preliminary indications on transmissibility,severity,and immune escape through existing research and databases.
文摘目的探讨胃肠道原发梭形细胞变异型弥漫性大B细胞淋巴瘤(spindle cell variant of diffuse large B-cell lymphoma,SV-DLBCL)的临床病理特点、诊断与鉴别诊断。方法收集4例胃肠道原发SV-DLBCL临床资料,行免疫组化染色及EBER原位杂交检测,并结合相关文献分析其临床病理学特征。结果4例患者年龄49~91岁,发生于胃1例,小肠2例,结肠1例。临床表现以腹痛及肠梗阻症状为主。镜下示肿瘤细胞呈弥漫性分布,主要由梭形细胞构成,被胶原束分隔成条索状,细胞中等偏大、可见核仁,核分裂易见。免疫表型:肿瘤细胞表达CD20、PAX5等B细胞标志物,4例中3例为non-GCB型、1例为GCB型,CD30和原位杂交EBER均阴性,Ki67增殖指数均>80%。FISH检测结果显示其中1例BCL6基因断裂信号阳性,其他3例均阴性;4例MYC基因和BCL2基因断裂信号均阴性。结论胃肠道原发的SV-DLBCL较为罕见,需与胃肠道发生的其他梭形细胞肿瘤相鉴别,诊断时需结合HE形态及免疫组化标记等综合判断。
