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This study aimed to investigate the structural and metabolic changes in cumulus cells of underweight women and their effects on oocyte maturation and fertilization. The cytoplasmic ultrastructure was analyzed by electron microscopy, mitochondrial membrane potential by immunofluorescence, and mitochondrial DNA copy number by relative quantitative polymerase chain reaction. The expression of various proteins including the oxidative stress-derived product 4-hydroxynonenal (4-HNE) and autophagy and apoptosis markers such as Vps34, Atg-5, Beclin 1, Lc3-I, II, Bax, and Bcl-2 was assessed and compared between groups. Oocyte maturation and fertilization rates were lower in underweight women (P < 0.05), who presented with cumulus cells showing abnormal mitochondrial morphology and increased cell autophagy. Compared with the mitochondrial DNA copies of the control group, those of the underweight group increased but not significantly. The mitochondrial membrane potential was similar between the groups (P = 0.8). Vps34, Atg-5, Lc3-II, Bax, and Bcl-2 expression and 4-HNE levels were higher in the underweight group compared with the control group (P < 0.01); however, the Bax/Bcl-2 ratio was lower in the underweight group compared with the control group (P = 0.031). Additionally, Beclin 1 protein levels were higher in the underweight group compared with the control group but without statistical significance. In conclusion, malnutrition and other conditions in underweight women may adversely affect ovulation, and the development, and fertilization of oocytes resulting from changes to the intracellular structure of cumulus cells and metabolic processes. These changes may lead to reduced fertility or unsatisfactory reproduction outcomes in women.
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Células do Cúmulo , Magreza , Feminino , Humanos , Proteína X Associada a bcl-2/genética , Magreza/metabolismo , Oócitos , DNA Mitocondrial/metabolismo , Técnicas de Maturação in Vitro de Oócitos/métodosRESUMO
Fibroblast-like synoviocytes (FLS) are the main cell component in the inflamed joints of patients with rheumatoid arthritis (RA). FLS intimately interact with infiltrating T cells. Fibroblasts have potent inhibitory effects on T cells, leading to the resolution of inflammation and immune tolerance. However, this "regulatory" phenotype is defect in RA, and FLS in RA instead act as "proinflammatory" phenotype mediating inflammation perpetuation. Signals that orchestrate fibroblast heterogeneity remain unclear. Here, it is demonstrated that different cytokines can induce distinct phenotypes of FLS. Interferon-gamma (IFN-γ) is pivotal in inducing the regulatory phenotype of FLS (which is termed FLSreg ) characterized by high expressions of several inhibitory molecules. Rapamycin enhances the effect of IFN-γ on FLS. Based on the characteristics of FLSreg , a novel biomimetic therapeutic strategy for RA is designed by coating cell membrane derived from FLSreg induced by IFN-γ and rapamycin on nanoparticles, which is called FIRN. FIRN show good efficacy, stability, and inflammatory joint targeting ability in an RA mouse model. The findings clarify how fibroblast phenotypes are modulated in the inflammatory microenvironment and provide insights into novel therapeutic designs for autoimmune diseases based on regulatory fibroblasts.
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Artrite Reumatoide , Sinoviócitos , Animais , Camundongos , Sinoviócitos/metabolismo , Membrana Sinovial/metabolismo , Células Cultivadas , Artrite Reumatoide/tratamento farmacológico , Inflamação/metabolismo , Interferon gama/metabolismo , Fibroblastos/metabolismo , Membrana Celular/metabolismoRESUMO
Background: Recent studies have proven the existence of distinct monocyte subsets, which play a significant role in the development of some rheumatic diseases such as systemic lupus erythematosus (SLE). This study was performed to define the changes of monocyte subsets in patients with Sjögren's Syndrome (SjS). Methods: Single cell RNA-sequencing (scRNA-seq) data of monocytes from SjS patients and controls were analyzed. The transcriptomic changes in monocyte subsets between SjS and controls were identified and potential key functional pathways involved in SjS development were also explored. Results: A total of 11 monocyte subsets were identified in the scRNA-seq analyses of monocytes. A new monocyte subset characterized by higher expression of VNN2 (GPI-80) and S100A12 (Monocyte cluster 3) was identified, and it was increased in SjS patients. Compared with controls, almost all monocyte subsets from SjS patients had increased expression of TNFSF10 (TRAIL). Moreover, interferon (IFN)-related and neutrophil activation-associated pathways were main up-regulated pathways in the monocytes of SjS patients. Conclusion: This study uncovered the abnormal changes in monocyte subsets and their transcriptomic changes in SjS patients, and identified TNFSF10 high/+ monocytes as a potential key player in SjS pathogenesis and a promising target for SjS treatment.
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Lúpus Eritematoso Sistêmico , Síndrome de Sjogren , Humanos , Interferons , Monócitos , TranscriptomaRESUMO
Tumor necrosis factor-α (TNF-α) inhibitors are the main types of biological conventional synthetic disease-modifying antirheumatic drugs and have efficacy in treating ankylosing spondylitis (AS) which is not sensitive for nonsteroidal anti-inflammatory drug. However, the impact of TNF-α inhibitors on immune cells in patients with AS is still clearly undefined, and the impact of immune cells on treatment response is also largely elusive. This study is aimed at evaluating the longitudinal changes of circulating immune cells after anti-TNF-α therapy and their associations with treatment response in AS patients. Thirty-five AS patients receiving the treatment of anti-TNF-α therapy were included into this prospective observational study. The frequencies of immune cells including Th1, Th2, Th17, regulatory T cell (Treg), T follicular helper cell (Tfh), and regulatory B cell (Breg) in the peripheral blood were measured by flow cytometry at baseline and 4 time points after therapy. The difference in the circulating immune cells between responders and nonresponders was compared. This study suggested that anti-TNF-α therapy could significantly reduce circulating proinflammatory immune cells such as Th17 and Tfh, but significantly increased the percentages of circulating Treg and Breg. Moreover, circulating Breg may be a promising predictor of response to anti-TNF-α therapy in AS patients.
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Linfócitos B Reguladores/imunologia , Linfócitos T CD4-Positivos/imunologia , Espondilite Anquilosante/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Linfócitos B Reguladores/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Contagem de Linfócitos , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/imunologia , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/farmacologiaRESUMO
BACKGROUND AND AIMS: The major cause of Hepatocellular carcinoma (HCC) is acute or chronic infection caused by hepatotropic viruses and HBV infection is the main cause. UHRF2, a ubiquitin-protein ligase E3, is associated with cancer development. This study aimed to investigate the connection and mechanism between UHRF2 and HBV-associated HCC. METHODS: The expression of UHRF2 in human HBV-positive HCC tissues and paracancerous tissues was detected by western blot and tissue microarray. The effects of UHRF2 on invasion, migration and proliferation were detected in HBV-positive hepatoma cell lines. Furthermore, western blot, immunofluorescence, Co-immunoprecipitation and ubiquitination assays were used to explore the relationship and mechanism between UHRF2 and HBV-associated HCC. RESULTS: HBV-positive HCC tissues had higher UHRF2 expression levels than adjacent non-tumor tissues. The HBV-positive HCC patients with a low UHRF2 level in cancer tissues had longer overall and recurrence-free survival compared with those with a high UHRF2 level. UHRF2 induced invasion, migration and proliferation in human HBV-positive HCC cell lines HepG2.2.15 and Hep AD38(-). HBx, an encoding protein of HBV, maintained the stability of UHRF2 by blocking the ubiquitination of UHRF2. HBx up-regulated CDK2 expression through ETS1. UHRF2 bound to CDK2 directly and enhanced UHRF2 phosphorylation at serine 643. CONCLUSIONS: These results suggest that HBx-ETS1-CDK2-UHRF2 pathway plays an important role in the pathogenesis of HBV-associated HCC and represents new therapeutic targets for human HCC. CLINICAL TRIALS REGISTRATION: ChiCTR2000041416.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Vírus da Hepatite B/metabolismo , Humanos , Neoplasias Hepáticas/genética , Fosforilação , Transativadores/genética , Transativadores/metabolismo , Ubiquitina-Proteína Ligases , Ubiquitinação , Regulação para Cima , Proteínas Virais Reguladoras e AcessóriasRESUMO
Multidrug-resistance hepatitis B virus (MDR HBV), defined as those with mutations resistant to both nucleoside analogs lamivudine/telbivudine/entecavir (LAM/LdT/ETV) and nucleotide analog adefovir (ADV), has potential to cause treatment difficulty. To clarify clinical prevalence and virological features of MDR HBV, we investigated serum samples from 28,236 chronic HBV-infected patients with treatment of nucleoside/nucleotide analogs. All patients underwent resistance testing in the Fifth Medical Center of Chinese PLA General Hospital between 2007 and 2019. MDR mutations were screened by direct sequencing; MDR strains (with mutations co-located on the same viral genome) were verified by clonal sequencing (≥20 clones/sample) and subjected to phenotypic analysis if necessary. MDR mutations were detected in 0.81% (229/28,236) patients. MDR strains were verified in 83.0% (190/229) of MDR mutation-positive patients. As ETV-resistance mutation (ETVr) had additional mutation(s) on LAMr conferring more resistance, MDR mutations fell into LAMr + ADVr and ETVr + ADVr subsets. Sixteen mutation patterns of MDR strains were verified, including eight with LAMr + ADVr and eight with ETVr + ADVr. Refractory to sequential therapies of LAM/LdT/ETV and ADV were closely linked with MDR HBV development. Ten representative MDR strains (five LAMr + ADVr and five ETVr + ADVr) tested all had decrease in replication capacity compared to wild-type strains and decrease extent was positively related with the number of primary resistance on viral genome. Compared to ADV + ETV, TDF/TDF + ETV showed higher inhibitory rates on MDR HBV, especially for the five ETVr + ADVr strains (74.5%-97.6% vs. 60.2%-79.5%, all P < 0.05). This study significantly extends the knowledge on MDR HBV and has clinical implications for resistance management.
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Farmacorresistência Viral Múltipla , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Mutação , Nucleosídeos/uso terapêutico , Nucleotídeos/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Antivirais/uso terapêutico , Estudos de Coortes , DNA Viral , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/virologia , Humanos , Lamivudina/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Filogenia , Telbivudina/uso terapêutico , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
INTRODUCTION: Adefovir plus entecavir (ADV+ETV) rescue therapy in ETV-resistant patients with chronic hepatitis B virus (HBV) infection is suboptimal in some patients. This study aims to elucidate the evolutionary characteristics of drug-resistant HBV mutants and their association with clinical responses in such patients. METHODOLOGY: Thirty-seven ETV-resistant patients were enrolled, among whom twelve had an inadequate virological response to ADV+ETV rescue therapy. The clonal sequence (³ 20 clones/sample) of HBV reverse transcriptase gene was performed to identify the resistance mutations. Phenotypic analysis was performed to evaluate the replication capacity and drug susceptibility of the mutants. RESULTS: ETV-resistant mutants were continuously detected in 10 of the 12 patients, and multidrug-resistant (MDR) mutants, including a novel strain (rtL180M+A181V+T184A+S202G+M204V), were detected in two patients. Seven of the 12 patients who subsequently received tenofovir (TDF)-based therapy for 38 (23-60) months all achieved undetectable HBV DNA after treatment, and ETV-resistant mutants converted to wild-type in the four patients' samples. In contrast, the other five patients who did not achieve an adequate virological response had remaining of ETV-resistant mutants. The novel MDR strain exhibited multiple resistances to LAM, ADV, and ETV, and 11.2-fold lower susceptibility to TDF. CONCLUSIONS: This study is the first to demonstrate that MDR HBV mutations may contribute to the poor efficacy of ADV+ETV combination therapy in ETV-resistant patients. Moreover, a novel MDR HBV strain was identified. Our results indicate that a TDF-based rescue therapy would be effective for the treatment of the refractory cases.
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Adenina/análogos & derivados , Antivirais/uso terapêutico , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/uso terapêutico , Tenofovir/uso terapêutico , Adenina/uso terapêutico , Adulto , Idoso , DNA Viral , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Genótipo , Guanina/uso terapêutico , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , DNA Polimerase Dirigida por RNA/genética , Carga Viral , Replicação ViralRESUMO
BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for bone and mineral metabolism disorder. Bone and mineral metabolism disorder develop gradually with the progression of renal failure. Various abnormalities include elevated fibroblast growth factor-23, decreased levels of 1,25-Dihydroxy Vitamin D (1,25-(OH)2D), and secondary hyperparathyroidism. This study aimed to evaluate the biomarkers and inflammation indexes of CKD-mineral and bone disorder (MBD), and to examine the associations of serum alkaline phosphatase (ALP) levels with serum C-reactive protein (CRP) levels and leukocyte count, in patients with end-stage renal disease (ESRD). METHODS: ESRD patients who were yet to initiate dialysis were enrolled as the study subjects. All CKD patients who were discharged from our hospital between January 1, 2013, and December 31, 2017, were screened. Based on quartiles of serum ALP, all subjects were categorized into four subgroups. The clinical characteristics of patients in the four subgroups were investigated. The prevalence of hypocalcemia, hyperphosphatemia, elevated intact parathyroid hormone (iPTH), and elevated CRP level was calculated in the four subgroups. The association between serum ALP and inflammation indexes was examined using regression analysis. RESULTS: Based on the inclusion criteria and exclusion criteria, 256 cases with ESRD were included in our study. The overall prevalence of hypocalcemia and hyperphosphatemia was 57.81% and 89.84%, respectively. Of the patients with ESRD, 174 (68.75%) had an elevated iPTH level >2 times of the upper limit of normal value), and 40 (15.63%) had an elevated iPTH level >9 times of the upper limit of normal value Discrepancies between serum ALP and iPTH levels were found in 29 patients. In the adjusted model, log-transformed CRP, log-transformed iPTH, and leukocyte count were significantly associated with log-transformed ALP. CONCLUSIONS: Hypocalcemia, hyperphosphatemia, and increased levels of iPTH and CRP were found to be extremely common in ESRD patients. Discrepancies between serum ALP and iPTH were also observed. Our results also indicate that serum ALP level is associated with the levels of iPTH and CRP, as well as leukocyte count.
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Distúrbio Mineral e Ósseo na Doença Renal Crônica , Falência Renal Crônica , Biomarcadores , Humanos , Inflamação , MineraisRESUMO
Background: Increased platelet count has been reported in ankylosing spondylitis (AS) patients, but its clinical significance is still largely elusive. The objective of this study was to evaluate the clinical role of platelet count in AS patients, especially its impact on treatment outcomes. Methods: A case-control study containing 35 AS patients receiving anti-tumor necrosis factor-α (anti-TNF-α) therapy and 45 healthy controls was performed, and AS patients were followed at least 6 months after anti-TNF-α therapy. A systematic review and meta-analysis of studies containing relevant data on outcomes of interest was also performed. Results: AS patients had significantly higher platelet count than controls (p = 0.0001), and the significantly increased platelet count in AS patients was confirmed in a meta-analysis of 14 studies involving 1,223 AS patients and 913 controls (mean difference = 39.61, 95% CI 27.89-51.34, p < 0.001). Besides, platelet count was significantly correlated with ESR (p < 0.001) and was moderately correlated with ASDAS-CRP score (p = 0.002). Moreover, anti-TNF-α therapy could reduce platelet count in AS patients at the first month and the effect was maintained through the treatment duration. In the prospective follow-up study of those 35 AS patients, those responders to anti-TNF-α therapy had significantly lower platelet count than nonresponders (p = 0.015). Logistic regression analysis suggested that lower platelet count was associated with higher possibility of achieving good response to anti-TNF-α therapy in AS patients (odds ratio = 2.26; 95% CI = 1.06-4.82; p = 0.035). Conclusion: This study suggested that platelet count was associated with inflammation severity and treatment outcomes in AS patients, and elevated platelet count was a promising biomarker of poorer response to anti-TNF-α therapy. The findings above need to be validated in more future studies.
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Background: Exposure to Epstein-Barr virus (EBV) infection has been hypothesized to be an important risk factor for multiple rheumatic diseases, but the serological evidence so far for its role in Sjögren's syndrome (SjS) is not clearly established yet. This study aimed to assess the seroepidemiological associations of antibodies to EBV with SjS. Methods: A seroepidemiological study containing 119 patients with SjS and 65 healthy controls was first performed, in which the associations of SjS with four commonly studied EBV antibodies including IgM-anti-viral capsid antigen (anti-VCA) antibody, IgG-anti-VCA antibody, IgG-anti-early antigen (anti-EA) antibody, and IgG-anti-EBV nuclear antigen 1 (anti-EBNA1) antibody were evaluated. A systematic review and meta-analysis of eligible seroepidemiological studies was also carried out, and data syntheses were performed using random-effect meta-analysis. Results: In the case-control study, the patients with SjS had both a significantly higher prevalence of IgG-anti-EA antibody positivity (31.9% vs. 3.1%, P < 0.001) and high titers of IgG-anti-EA antibody (P < 0.001) than healthy controls. The titer of IgG-anti-VCA antibody was significantly increased in the patients with SjS compared with healthy controls (P < 0.001). IgG-anti-EA antibody seropositive patients with SjS had lower levels of both C3 (P = 0.002) and C4 (P = 0.02), and the titer of IgG-anti-EA antibody was inversely related to the levels of both C3 (r = -0.31, P < 0.001) and C4 (r = -0.20, P = 0.03). A total of 14 eligible studies on the serological associations between EBV infection and SjS were finally included into the meta-analysis, which suggested obvious associations of SjS with IgM-anti-VCA antibody [Odds ratio (OR) = 5.77, 95%CI 1.73-19.25, P = 0.004] and IgG-anti-EA antibody (OR = 9.97, 95%CI 4.58-21.67, P < 0.00001). Conclusions: The findings from this study provide strong serological evidence for the association between EBV infection and SjS. SjS has obvious associations with IgM-anti-VCA antibody and IgG-anti-EA antibody. IgG-anti-EA antibody is linked to low levels of C3 and C4 in the patients with SjS, the significance of which needs to be addressed in further studies.
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Infecções por Vírus Epstein-Barr , Síndrome de Sjogren , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Estudos de Casos e Controles , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Estudos Soroepidemiológicos , Síndrome de Sjogren/sangue , Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/imunologiaRESUMO
BACKGROUND: It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen (HBsAg) are associated with nucleoside/nucleotide analog resistance. AIM: To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations. METHODS: In total, 19440 patients with chronic hepatitis B virus infection, who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017, were enrolled. As determined by sequence analysis, 6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations. Phenotypic analyses were performed to evaluate HBsAg production, replication capacity, and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V. RESULTS: The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations. In particular, these mutations were sQ101H/K/R, sS114A/L/T, sT118A/K/M/R/S/V, sP120A/L/Q/S/T, sT/I126A/N/P/S, sM133I/L/T, sC137W/Y, sG145A/R, and sA159G/V. Among these, sA159V was detected in 1.95% (136/6982) of patients with resistance mutations and 1.08% (134/12,458) of patients lacking resistance mutations (P < 0.05). The coexistence of sA159V with lamivudine (LAM) and entecavir (ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance. HBsAg production was significantly lower and the replication capacity was significantly higher, without a significant difference in LAM/ETV susceptibility, in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts. CONCLUSION: In summary, we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations. sA159V might increase the fitness of LAM/ETV-resistant mutants under environmental pressure in some cases.
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Antivirais , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral/genética , Farmacorresistência Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Humanos , Lamivudina/uso terapêutico , MutaçãoRESUMO
Though macrophages and neutrophils are considered to be the principal immune cells involved in gout inflammation, recent studies highlight an emerging role of T cell subsets in the pathogenesis of gout. Some studies found that abnormal functions of several T cell subsets and aberrant expressions of their signature cytokines existed in gouty arthritis. Additionally, recent studies also suggested that therapeutic strategies by targeting pro-inflammatory T cell subsets or their related cytokines could ameliorate monosodium urate (MSU) crystals-induced arthritis in mice. The important role of T cells in gouty arthritis may provide some explanation for the absence of acute gout attacks among individuals with severe hyperuricemia or clinical evidence of MSU crystals deposition. Nevertheless, the molecular mechanisms underlying the role of those T cell subsets in gouty arthritis and their role in the initiation, progression and resolution of gouty arthritis are largely elusive, which need to be elaborated in future research. Uncovering the role of those T cell subsets in gout may transform our understanding of gout and facilitate new promising preventive or therapeutic strategies for gouty arthritis.
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Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/etiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Artrite Gotosa/imunologia , Doenças Autoimunes/imunologia , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Ácido Úrico/efeitos adversosRESUMO
BACKGROUND: Occult HBV infection (OBI) is of great concern due to their complicated diagnosis and potential for public transmission. OBJECTIVE: The study aimed to determine the clinical prevalence of OBI and if viral immune escape-associated mutations contribute to the occurrence of OBI. STUDY DESIGN: A total of 91,037 HBV-infected patients with different related illnesses who were admitted to the Fifth Medical Center of Chinese PLA General Hospital from January 2005 to December 2017 were tested for OBI. Serum samples from 62 patients with OBI manifestations (OBI patients) and 124 matched non-OBI patients were sequenced for possible immune escape-associated mutations within the major hydrophilic region of HBV S protein. HBsAg and HBV DNA levels in representative viral strains were measured. RESULTS: Of the 91,037 tested patients, 487 (0.53 %) were negative for HBsAg but positive for HBV DNA and were defined as OBI patients. The prevalence in different illness categories varied. Immune escape-associated mutations were more frequently detected in OBI patients than in non-OBI patients (59.68 % vs. 35.48 %, P < 0.01), as did the coexistence of multiple mutations (43.55 % vs. 22.58 %, P < 0.01). Specifically, the prevalence rates of sT118â¯K, sK122R, and sV168A were increased in OBI patients. Strains with sK122R mutants (sK122R, sK122Râ¯+â¯D144E, sK122Râ¯+â¯C121Râ¯+â¯D144E, and sK122Râ¯+â¯F134Lâ¯+â¯D144E) from a follow-up OBI patient all showed significantly lower levels of HBsAg production than a wild-type strain. CONCLUSIONS: The study clarified the clinical prevalence of OBI, verified the influence of immune escape-associated mutations, and identified the role of the sK122R mutation in multiple OBI patients.
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Vírus da Hepatite B , Hepatite B , China/epidemiologia , DNA Viral/genética , Hepatite B/epidemiologia , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Humanos , MutaçãoRESUMO
The study aimed to characterize the prevalence and virological features of the rtA181S + T184I + M204I mutant in a large cohort of patients with chronic HBV infection. In total, 22,009 nucleoside/nucleotide analog-treated patients who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between 2007 and 2016 were enrolled. Serum samples were collected for HBV reverse-transcriptase gene sequencing. Phenotypic analysis of the viral replication capacity and drug susceptibility was performed. The rtA181S mutation was detected in 0.82% (180/22,009) of samples. rtA181S-positive patients had significantly higher lamivudine (LAM), adefovir (ADV), and entecavir (ETV) exposure than rtA181S-negative patients. Of 180 rtA181S-positive patients, 42 had no coexistent resistance mutations, 34 had coexisting LAM-resistance mutation (LAMr), 17 had coexisting ADV-resistance mutation (ADVr), and 86 had coexisting ETV-resistance mutation (ETVr), and one had ADVr + ETVr. rtA181S + T184I + M204I occurred in 79.1% (68/86) of patients with rtA181S + ETVr and 37.8% (68/180) of all rtA181S-positive patients. Longitudinal analysis of the clinical course of resistant mutant evolution for four representative cases showed that rtA181S + T184I + M204I developed in all patients who had received LAM/telbivudine ± ADV and was receiving ETV or ADV + ETV. Compared with wild-type, the rtA181S + T184I + M204I mutant had 53.7% lower replication capacity and >1000-, 3.9-, and 383.3-fold greater LAM, ADV, and ETV resistance, respectively, but remained sensitive to tenofovir. Artificial elimination of rtA181S from the rtA181S + T184I + M204I mutant restored viral susceptibility to ADV but decreased viral replication capacity. Our study presented the first evidence that HBV rtA181S + T184I + M204I mutation had features of multidrug-resistance that contributed to resistance to both nucleoside and nucleotide analogs.
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Antivirais/farmacologia , Farmacorresistência Viral Múltipla/genética , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/epidemiologia , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Antivirais/uso terapêutico , Povo Asiático , Pequim/epidemiologia , Estudos de Coortes , DNA Viral/genética , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Organofosfonatos/uso terapêutico , PrevalênciaRESUMO
Objective: Clinical characteristics of immune thrombocytopenia (ITP) associated with primary Sjögren's syndrome (pSS) have not been clearly defined. This study aimed to evaluate the prevalence and clinical characteristics of secondary ITP in patients with pSS. Methods: 291 pSS patients in our hospital were retrospectively analyzed. Clinical manifestations and laboratory findings were compared between pSS patients with and without ITP. Results: The prevalence of secondary ITP in pSS patients was 12.03%. Compared to pSS patients without ITP, pSS patients with ITP were younger and had higher disease activity. The prevalence of interstitial lung diseases (ILD) was significantly lower in pSS patients with ITP (30.43 vs. 54.95%; P = 0.029), and it was the same with arthritis (17.14 vs. 3.9.11%; P = 0.014) and dry eye (33.33 vs. 54.17%, P = 0.027) compared with those without ITP. Serum creatinine level was lower in pSS patients with ITP (P = 0.009), while positivity of anti-histone autoantibodies was higher in pSS patients with ITP (P = 0.025). Conclusion: This study is an initial report describing clinical features of ITP in pSS. The lower incidence of ILD and arthritis among pSS patients with ITP indicated potential active roles of platelets in the pathogenesis of fibrosis or inflammatory arthritis, which may open the way for further experimental and clinical work.
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Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases. Although the progress made with current clinical use of biologic disease-modifying antirheumatic drugs (bioDMARDs), the response rate of RA treatment remains ungratified, primarily due to intricacy interactions of multiple inflammatory cytokines and the awkward drug delivery. Thus, it is of great importance to neutralize cytokines and actively deliver therapeutic agents to RA joints for the purpose of promoting in situ activity. Herein, we proposed and validated a nanoparticle-based broad-spectrum anti-inflammatory strategy for RA management by fusing TRAIL-anchored cell membranes onto drug-loaded polymeric cores (TU-NPs), which makes them ideal decoys of inflamed macrophage-targeted biological molecules. Upon intravenous injection of TU-NPs into collagen-induced arthritic mice, the fluorescence/photoacoustic dual-modal imaging revealed higher accumulations and longer retention of TU-NPs in inflamed joints. In vivo therapeutic evaluations suggested that these nanoparticles could neutralize cytokines, suppress synovial inflammation, and provide strong chondroprotection against joint damage by targeting and deep penetration into the inflamed tissues. Overall, our work provides a novel strategy to treat RA with a strong potential for clinical translation.
Assuntos
Antirreumáticos , Artrite Reumatoide , Animais , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Membrana Celular , Sistemas de Liberação de Medicamentos , CamundongosRESUMO
BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that commonly affects the kidneys. Research into markers that can predict the prognosis of tubulointerstitial lupus nephritis (LN) has been impeded by the lack of well-designed studies. METHODS: In this study, we selected and merged 3 sets of renal biopsy tubulointerstitial data from GSE32591, GSE69438, and GSE127797, including 95 LN and 15 living healthy donors. CIBERSORTx was utilized for differentially infiltrating immune cell (DIIC) analysis. Weighted Gene Co-Expression network analysis (WGCNA) was employed to explore differentially expressed gene (DEG) related modules. Combined WGCNA hub genes and protein-protein interaction (PPI) validation was used for immune marker identification. Lastly, unsupervised clustering was carried out to validate the correlation between these markers and clinical characteristics. RESULTS: Our findings unveiled TYROBP, C1QB, LAPTM5, CTSS, PTPRC as the 5 immune markers, which were negatively correlated with glomerular filtration rate (GFR). Specifically, the expression levels of TYROBP and C1QB were significantly different between proliferative LN (PLN) and membranous LN (MLN). Unsupervised clustering could aggregate LN by these immune marker expression spectrums. CONCLUSIONS: This study is the first to identify infiltrating immune cells and associated molecular patterns in the tubulointerstitium of LN by utilizing bioinformatics methods. These findings contribute to a better understanding of the mechanisms behind LN, and promote more precise diagnosis.
RESUMO
This study aimed to investigate clinical occurrence and significance of the rtS78T/sC69* mutation of hepatitis B virus (HBV). A total of 22,009 consecutive chronic HBV-infected patients who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital (Original name Beijing 302 Hospital) from 2007 to 2016 were enrolled. Serum samples were collected for sequence analysis of HBV reverse-transcriptase (RT) and S regions. Phenotypic analysis was performed to evaluate the viral replication capacity and drug susceptibility. The rtS78T mutation was detected in 0.83% (182/22,009) of the patients' samples. All mutations simultaneously created a stop codon at sC69 (sC69*). The prevalence of rtS78T/sC69* did not differ significantly between the patients with and without entecavir/tenofovir treatment. Of the 182 mutation-positive samples, 41 (22.5%) were detected with signature drug-resistance mutations to adefovir (n = 26), lamivudine (n = 11), entecavir (n = 3), and lamivudine plus adefovir (n = 1). The HBV DNA and RNA levels of the rtS78T/sC69* mutant were significantly increased compared to the wild-type; while the mutant had undetectable secreted and intracellular HBsAg, and its half maximal effective concentration to lamivudine, adefovir, entecavir, and tenofovir were 3.73-, 1.61-, 4.76-, and 3.71-fold of the wild-type, respectively. Artificial elimination of the rtS78T mutation had a limited effect on the drug susceptibilities. The data obtained in the present study suggested that the emergence of the rtS78T/sC69* mutation was not closely related to entecavir/tenofovir treatment and itself appeared insufficient to confer drug resistance unless it coexisted with signature drug-resistance mutations.
Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Mutação , Adulto , Estudos de Coortes , DNA Viral , Farmacorresistência Viral Múltipla/genética , Feminino , Genótipo , Guanina/análogos & derivados , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Nucleosídeos/uso terapêutico , DNA Polimerase Dirigida por RNA/genética , Tenofovir/uso terapêutico , Proteínas Virais/genéticaRESUMO
As the open reading frames of hepatitis B virus (HBV) genomes are overlapping, resistance mutations (MTs) in HBV polymerase may result in stop codon MTs in hepatitis B surface proteins, which are usually detected as a mixed population with wild-type (WT) HBV. The question was raised how the coexistence of nucleos(t)ide analogs (NAs) resistance MTs and WT sequences affects HBV replication. In the present study, HBV genomes with frequently detected reverse transcriptase (RT)/surface truncation MTs, rtA181T/sW172*, rtV191I/sW182* and rtM204I/sW196*, were phenotypically characterized alone or together with their WT counterparts in different ratios by transient transfection in the absence or presence of NAs. In the absence of NAs, RT/surface truncation MTs impaired the expression and secretion of HBV surface proteins, and had a dose-dependent negative effect on WT HBV virion secretion. However, in the presence of NAs, coexistence of MTs with WT maintained viral replication, and the presence of WT was able to rescue the production of MT HBV virions. Our findings reveal that complementation of WT and MT HBV genomes is highly effective under drug treatment.