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BACKGROUND: Information on the protein-based severe acute respiratory syndrome (SARS-CoV-2) vaccine-NVX-CoV2373 (Novavax), as a heterologous booster remains limited. We investigated the immunogenicity and adverse events of NVX-CoV2373 as a second booster and compared them with those of mRNA vaccines in healthy adults. METHODS: Healthcare workers who had received an mRNA vaccine (mRNA-1273 or BNT-162b2) as the first booster (third dose) 12 weeks prior were recruited. Participants voluntarily received either NVX-CoV2373 or an mRNA vaccine as a second booster. Participants with a history of SARS-CoV-2 infection were excluded. The primary outcomes included serum anti-SARS-CoV-2 spike protein (SP) and neutralizing antibody titers against B.1.1.7 (Alpha), B.1.1.529 (Omicron) BA2, and BA5 variants on the 28th day after the boost. Secondary outcomes included new SARS-CoV-2 infections and adverse events reported during the study period. RESULTS: A total of 160 participants were enrolled in this study. Compared with the mRNA vaccination group (n = 59), the NVX-CoV2373 vaccination group (n = 101) had significantly lower anti-SARS-CoV-2 SP antibody titers and neutralizing antibody titers against all variants tested after the boost. During the study period, higher rates of new SARS-CoV-2 infections and a lower incidence of adverse events were observed in the NVX-CoV2373 vaccination group. No significant differences in cellular immune responses were observed between the two groups. CONCLUSION: Compared to a homologous mRNA booster vaccination, heterologous boosters with NVX-CoV2373 showed lower antibody responses, a higher incidence of new SARS-CoV-2 infections, and fewer adverse events.
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Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , Vacinas contra COVID-19/efeitos adversos , Vacinas de mRNA , SARS-CoV-2 , COVID-19/prevenção & controle , RNA Mensageiro , Anticorpos Neutralizantes , Anticorpos AntiviraisRESUMO
BACKGROUND/PURPOSE: Healthcare workers (HCWs) are at risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to occupational exposure. We aim to investigate the prevalence and risk factors of SARS-CoV-2 infection among HCWs during epidemic outbreak of omicron variant in Taiwan. METHODS: Sequential reserved serum samples collected from our previous study during December 2021 and July 2022 were tested for antibodies against SARS-CoV-2 nucleocapsid protein (NP). Diagnosis of SARS-CoV-2 infection was defined as positive either of anti-SARS-CoV-2 nucleoprotein, rapid antigen test or polymerase chain reaction. Retrospective chart review and a questionnaire were used to access the symptoms and risk factors for SARS-CoV-2 infection. RESULTS: Totally 300 participants (69.3% female) with a median age of 37.9 years were enrolled. A significant increase incidence of SARS-CoV-2 infection was found before and during community outbreak (11.91 versus 230.93 per 100,000 person-days, P < 0.001), which was a trend paralleling that observed in the general population. For 61 SARS-CoV-2 infected participants, nine (14.8%) were asymptomatic. Multivariate analysis revealed recent contact with a SARS-CoV-2 infected household (odds ratio [OR], 7.01; 95% confidence interval [95% CI], 3.70-13.30; P < 0.001) and co-existed underlying autoimmune diseases (OR, 4.46; 95% CI, 1.28-15.51; P = 0.019) were significant risk factors associated with acquisition of SARS-CoV-2 infection among HCWs. CONCLUSION: Community factors, such as closely contact with SARS-CoV-2 infected individuals and underlying immune suppression status, were significant factors for acquisition of SARS-CoV-2 infection among HCWs. We suggest the application of appropriate infection control measures for HCWs should be maintained to reduce risk of SARS-CoV-2 infection.
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COVID-19 , Humanos , Feminino , Adulto , Masculino , COVID-19/epidemiologia , COVID-19/prevenção & controle , SARS-CoV-2 , Estudos Retrospectivos , Taiwan/epidemiologia , Surtos de Doenças/prevenção & controle , Pessoal de Saúde , VacinaçãoRESUMO
Mutations may ultimately change the local conformation of proteins; however, little attention has been paid to alterations in protein function caused by the incidence of cis-peptide bonds (ICPB) in mammalian cells. In this study, a statistical approach, coimmunoprecipitation, and immunofluorescence staining have been used to confirm that S246âY and S246âW missense mutations, which help increase the ICPB in Xaa246-P247 (Xaa is any amino acid) in human ß-catenin, can reduce the interactions between ß-catenin and adenomatous polyposis coli (APC) and between ß-catenin and Ca2+-dependent cell adhesion molecule family in epithelial tissue (E-cadherin), eventually leading to increased nuclear migration of ß-catenin in the HepG2 cell line (an immortalized cell line consisting of human liver carcinoma cells). Conversely, S246âL and S246âM missense mutations, which reduce the ICPB in Xaa246-P247 in human ß-catenin, can enhance interactions between ß-catenin and APC and between ß-catenin and E-cadherin, leading to decreased nuclear migration of ß-catenin. These results not only indicate that a change in the ICPB may be an important cause of functional protein changes but also provide a new basis for the study of genetic disease prediction, gene diagnosis, individualized treatment, and protein modification at the gene level for clinicians and other professionals.-Yu, S., Zhang, Y., Wu, Y., Yang, H., Chen, Y., Yang, Y., Zhang, Z. Subcellular localization of mutated ß-catenins with different incidences of cis-peptide bonds at the Xaa246-P247 site in HepG2 cells.
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Antígenos CD/metabolismo , Caderinas/metabolismo , Núcleo Celular/metabolismo , Mutação de Sentido Incorreto , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular/genética , Substituição de Aminoácidos , Antígenos CD/genética , Caderinas/genética , Núcleo Celular/genética , Células Hep G2 , Humanos , beta Catenina/genéticaRESUMO
This study aimed to investigate the potential effects of gold nanoparticles (Au-NPs) on rat cortical neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R) and to elucidate the corresponding mechanisms. Primary rat cortical neurons were exposed to OGD/R, which is commonly used in vitro to mimic ischemic injury, and then treated with 5- or 20-nm Au-NPs. We then evaluated cell viability, apoptosis, oxidative stress, and mitochondrial respiration in these neurons. We found that 20-nm Au-NPs increased cell viability, alleviated neuronal apoptosis and oxidative stress, and improved mitochondrial respiration after OGD/R injury, while opposite effects were observed for 5-nm Au-NPs. In terms of the underlying mechanisms, we found that Au-NPs could regulate Akt signaling. Taken together, these results show that 20-nm Au-NPs can protect primary cortical neurons against OGD/R injury, possibly by decreasing apoptosis and oxidative stress, while activating Akt signaling and mitochondrial pathways. Our results suggest that Au-NPs may be potential therapeutic agents for ischemic stroke.
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Glucose/metabolismo , Ouro/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Oxigênio/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/efeitos adversos , Antioxidantes/química , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Ouro/efeitos adversos , Ouro/química , Inflamação/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas Metálicas/efeitos adversos , Nanopartículas Metálicas/química , Mitocôndrias/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND This study was to investigate the correlation between osteoporosis and serum uric acid in ankylosing spondylitis (AS) patients, and to further identify potential factors that might be associated with osteoporosis in AS patients. MATERIAL AND METHODS We included 182 AS patients, consisted of 143 male patients and 39 female patients, who visited our hospital from January 1, 2014 to December 31, 2018. We used dual-energy x-ray absorptiometry to measure bone mineral density (BMD) of orthotopic lumbar vertebrae in patients with AS. The gender, age, disease duration, BMD, T-score, Z-score, uric acid, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood platelet (PLT), and status of treatment with biologics of the patients were collected. Then, the Spearman correlation coefficient and multivariate liner regression analysis were applied to identify the relationship between the factors and BMD, T-score, and Z-score in AS patients. RESULTS Male AS patients between the ages of 16 and 30 years old had a higher risk of osteoporosis (P<0.05). AS patients with uric acid value between 300-360 µmol/L had the highest BMD, T-score, and Z-score. The BMD had a positive correlation with age and disease duration (P<0.01) while had a negative correlation with PLT (P<0.05). BMD in AS patients with elevated ESR was significantly (P<0.05) lower than in AS patients with normal ESR. There were no significant differences in BMD between AS patients with elevated CRP and the patients with normal CRP and PLT. Treatment with TNFi (tumor necrosis factor alpha inhibitor) did not improve BMD in AS patients. CONCLUSIONS The relationship between uric acid and BMD in AS patients was observed as inverted "U"-type. Keeping uric acid within 300-360 µmol/L might be helpful in preventing AS patients from developing osteoporosis.
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Povo Asiático , Osteoporose/sangue , Osteoporose/complicações , Espondilite Anquilosante/sangue , Espondilite Anquilosante/complicações , Ácido Úrico/sangue , Adolescente , Adulto , Antirreumáticos/uso terapêutico , Plaquetas/metabolismo , Sedimentação Sanguínea , Densidade Óssea , Proteína C-Reativa/metabolismo , Feminino , Humanos , Inflamação/sangue , Inflamação/patologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Osteoporose/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/fisiopatologia , Adulto JovemRESUMO
Previous studies have indicated that heparanase (Hpa) might represent a candidate universal tumor-associated antigen. However, vaccine therapy targeting only one cytotoxic T lymphocyte (CTL) epitope is suboptimal in preventing cancer. In the present study, we designed heparanase multi-epitope vaccines to increase the immune response to standard single heparanase epitopes. The results showed that multi-epitope vaccines Hpa525 + 277 + 405 + 16 and Hpa8 + 310 + 315 + 363 induced higher Hpa-specific lysis of various cancer cells from different tissues in a HLA-A2-restricted and heparanase-specific manner compared with the single epitope vaccines Hpa525, Hpa277, Hpa405, Hpa16, Hpa8, Hpa310, Hpa315 and Hpa363, both in vitro and ex vivo. Heparanase multi-epitope vaccines not only induced the heparanase-specific CTL to lyse tumor cells but also increased CTL secretion of interferon-γ. However, these heparanase-specific CTL did not lyse heparanase-expressing autologous lymphocytes and dendritic cells, which confirms the safety of these multi-epitope vaccines. Therefore, the present study provides theoretical evidence for the use of heparanase multi-epitope vaccines for clinical application.
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Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Heparina Liase/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Epitopos/imunologia , Antígeno HLA-A2/imunologia , Células Hep G2 , Humanos , Interferon gama/imunologia , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T Citotóxicos/imunologiaRESUMO
Background: Urosepsis is a common disease in urology, which is characterized by high treatment costs and high mortality. In the treatment of sepsis, anti-infection therapy is the most important means. However, the effect of empirical anti-infection therapy is often not ideal. Therefore, it is necessary to continuously monitor the prevalence of bacterial isolates in the blood culture of patients with urinary sepsis and their sensitivity to antibacterial drugs. This is of great significance to improve the efficacy of empirical antibiotic therapy for urosepsis. Objective: To elucidate the landscape of prevailing bacterial profiles and their antimicrobial susceptibilities in urosepsis cases, and to furnish robust clinical evidence to underpin the timely initiation of empirical antibiotic treatment. Methods: Collect the basic information and blood culture results of patients with urosepsis hospitalized from 2017 to 2020. Retrospective analysis of bacterial species and antimicrobial susceptibility in urosepsis and changes over 4 years. Results: Gram-negative bacteria (178 isolates, 75.11%) constituted the main pathogens causing urosepsis, followed by Gram-positive bacteria (46 isolates, 19.41%) and fungus (13 isolates, 5.48%). The sensitivity of ertapenem, meropenem, amikacin, and imipenem to Gram-negative bacteria all exceeded 85%. The sensitivity rates of levofloxacin, gentamicin, and ciprofloxacin are decreasing every year (p < 0.05). Tigecycline, vancomycin, and linezolid exhibited excellent sensitivity against Gram-positive bacteria. Among fungi, fluconazole demonstrated universal sensitivity, while itraconazole-resistant isolates have been found, and amphotericin B is still effective. Conclusion: Analysis of blood culture results of patients more accurately reflected the etiology of urosepsis, mainly Escherichia coli, Enterococcus, and Klebsiella pneumoniae. If there are no definitive blood culture results, empiric treatment of urosepsis should not include fluoroquinolone antibiotics. Cefepime, cefoxitin, and ceftazidime are the most sensitive antibiotics to Gram-negative bacteria besides carbapenem antibiotics. In addition, the current situation regarding extended-spectrum ß-lactamase-producing bacteria and carbapenem-resistant Enterobacteriaceae bacteria resistance is extremely concerning with limited therapeutic options available. Strengthening antibiotic management practices and exploring novel antibacterial agents can help mitigate this issue.
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Epigenomic imbalance drives abnormal transcriptional processes, promoting the onset and progression of cancer. Although defective gene regulation generally affects carcinogenesis and tumor suppression networks, tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes, which may have significant implications for the development and application of epigenetic therapy, cancer immunotherapy, and their combinations. Herein, we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes, DNA methylation, histone post-translational modification, and chromatin structure in tumor immunogenicity, and introduce these epigenetic research methods. We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immunotherapy through the complex interaction between cancer epigenetics and cancer immunology.
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Resistance to anoikis, the subtype of apoptosis induced by lack of matrix adhesion, contributes to malignant transformation and development of metastasis. MicroRNAs play key regulatory roles in tumorigenesis and metastasis. In this study, we described that miR-26a, which is usually downregulated in tumor cells, is involved in the acquisition of anoikis-resistance of human esophageal adenocarcinoma (EA) cells. Results of qRT-PCR in clinical samples showed that downregulated miR-26a expression is related to tumorigenesis and metastasis of EA. In vitro experiments determined that miR-26a directly participates in the regulation of cell cycle and anoikis of human EA OE33 cells. Further, we identified that Rb1 is the direct functional target of miR-26a, and revealed that the reduction of miR-26a expression leads to increased Rb1 protein level and thus inhibits the function of E2F1, by which it influences the phenotypes of cell cycle and anoikis. The findings we reported here presented the evidence that miR-26a may be involved in regulation of anoikis-resistance of EA cells. Targeting miR-26a may provide a novel strategy to inhibit metastasis.
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Adenocarcinoma/metabolismo , Anoikis , Fator de Transcrição E2F1/metabolismo , Neoplasias Esofágicas/metabolismo , MicroRNAs/fisiologia , Proteína do Retinoblastoma/genética , Regiões 3' não Traduzidas , Adenocarcinoma/secundário , Animais , Sequência de Bases , Sítios de Ligação , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação para Baixo , Neoplasias Esofágicas/patologia , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Camundongos , Camundongos Nus , Transplante de Neoplasias , Interferência de RNA , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Transcrição GênicaRESUMO
OBJECTIVES: Identification of m6A- related lncRNAs associated with BC diagnosis and prognosis. METHODS: From the TCGA database, we obtained transcriptome data and corresponding clinical information (including histopathological and CT imaging data) for 408 patients. And bioinformatics, computational histopathology, and radiomics were used to identify and analyze diagnostic and prognostic biomarkers of m6A-related lncRNAs in BC. RESULTS: 3 significantly high-expressed m6A-related lncRNAs were significantly associated with the prognosis of BC. The BC samples were divided into two subgroups based on the expression of the 3 lncRNAs. The overall survival of patients in cluster 2 was significantly lower than that in cluster 1. The immune landscape results showed that the expression of PD-L1, T cells follicular helper, NK cells resting, and mast cells activated in cluster 2 were significantly higher, and naive B cells, plasma cells, T cells regulatory (Tregs), and mast cells resting were significantly lower. Computational histopathology results showed a significantly higher percentage of tumor-infiltrating lymphocytes (TILs) in cluster 2. The radiomics results show that the 3 eigenvalues of diagnostics image-original minimum, diagnostics image-original maximum, and original GLCM inverse variance are significantly higher in cluster 2. High expression of 2 bridge genes in the PPI network of 30 key immune genes predicts poorer disease-free survival, while immunohistochemistry showed that their expression levels were significantly higher in high-grade BC than in low-grade BC and normal tissue. CONCLUSION: Based on the results of immune landscape, computational histopathology, and radiomics, these 3 m6A-related lncRNAs may be diagnostic and prognostic biomarkers for BC.
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Urosepsis is sepsis caused by urogenital tract infection and is one of the most common critical illnesses in urology. If urosepsis is not diagnosed early, it can rapidly progress and worsen, leading to increased mortality. In recent years, with the increase of urinary tract surgery, the incidence of urosepsis continues to rise, posing a serious threat to patients. Early diagnosis of urosepsis, timely and effective treatment can greatly reduce the mortality of patients. Biomarkers such as WBC, NLR, PCT, IL-6, CRP, lactate, and LncRNA all play specific roles in the early diagnosis or prognosis of urosepsis. In addition to the abnormal increase of WBC, we should be more alert to the rapid decline of WBC. NLR values were superior to WBC counts alone in predicting infection severity. Compared with several other biomarkers, PCT values can differentiate between bacterial and non-bacterial sepsis. IL-6 always has high sensitivity and specificity for the diagnosis of sepsis, and CRP also has high sensitivity and specificity for the diagnosis of urosepsis. Lactic acid is closely related to the prognosis of patients with urosepsis. LncRNAs may be potential biomarkers of urosepsis. This article summarizes the main biomarkers, hoping to provide a reference for the timely diagnosis and evaluation of urosepsis.
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Although accumulating evidence has highlighted the molecular mechanisms by which hTERT promotes tumour cell invasion and metastasis, the molecular mechanisms of the properties enabling hTERT to contribute to invasion and metastasis have not been clearly illustrated. Here, we report that hTERT promotes gastric cancer invasion and metastasis by recruiting p50 to synergistically inhibit PLEKHA7 expression. We observed that the expression of PLEKHA7 in gastric cancer was significantly negatively associated with the TNM stage and lymphatic metastasis and that decreased PLEKHA7 expression dramatically increased invasion and metastasis in gastric cancer cells. Further mechanistic research showed that hTERT directly regulates PLEKHA7 expression by binding p50 and recruiting the hTERT/p50 complex to the PLEKHA7 promoter. Increased hTERT dramatically decreased PLEKHA7 expression and promoted invasion and metastasis in gastric cancer cells. The hTERT-mediated invasion/metastasis properties at least partially depended on PLEKHA7. Our work uncovers a novel molecular mechanism underlying invasion/metastasis in gastric cancer orchestrated by hTERT and p50.
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Proteínas de Transporte , Neoplasias Gástricas , Telomerase , Humanos , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Metástase Linfática , Invasividade Neoplásica , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Telomerase/genética , Telomerase/metabolismoRESUMO
The development of peptide vaccines aimed at enhancing immune responses against tumor cells is becoming a promising area of research. Human telomerase reverse transcriptase (hTERT) is an ideal universal target for novel immunotherapies against cancers. The aim of this work was to verify whether the multiple antigen peptides (MAP) based on HLA-A0201-restricted CTL epitopes of hTERT could trigger a better and more sustained CTL response and kill multiple types of hTERT-positive tumor cells in vitro and ex vivo. Dendritic cells (DC) pulsed with MAP based on HLA-A0201-restricted CTL epitopes of hTERT (hTERT-540, hTERT-865 and hTERT-572Y) were used to evaluate immune responses against various tumors and were compared to the immune responses resulting from the use of corresponding linear epitopes and a recombinant adenovirus-hTERT vector. A 4-h standard (51) Cr-release assay and an ELISPOT assay were used for both in vitro and ex vivo analyses. Results demonstrated that targeting hTERT with an adenovector was the most effective way to stimulate a CD8(+) T cell response. When compared with linear hTERT epitopes, MAP could trigger stronger hTERT-specific CTL responses against tumor cells expressing hTERT and HLA-A0201. In contrast, the activated CTL could neither kill the hTERT-negative tumor cells, such as U2OS cells, nor kill HLA-A0201 negative cells, such as HepG2 cells. We also found that these peptide-specific CTL could not kill autologous lymphocytes and DC with low telomerase activity. Our results indicate that MAP from hTERT can be exploited for cancer immunotherapy.
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Antineoplásicos/farmacologia , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/imunologia , Neoplasias/terapia , Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Telomerase/imunologia , Animais , Antineoplásicos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Vetores Genéticos/imunologia , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Peptídeos/farmacologia , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
BACKGROUND: Telomerase is commonly recognized as an effective anticancer target. The human telomerase reverse transcriptase (hTERT), the rate-limiting component of telomerase, is expressed in most malignant tumors, but it is not found in most normal somatic cells. Here, we report a real-time and noninvasive method to monitor tumor response to a lentivirus-based hTERT-conditional suicidal gene therapy. METHODS: In this study, we constructed a lentivirus system in which an optimized hTERT promoter was used to drive the expression of the cytosine deaminase (CD) gene, one of the suicide genes, and a green fluorescent protein (GFP) reporter gene (pLenti-CD/GFP). The lentivirus was used to infect telomerase-positive or telomerase-negative cell lines. In vitro and in vivo experiments were conducted to analyze the dynamic processes of exogenous gene expression noninvasively in cell culture and living animals in real time via optical imaging. RESULTS: The lentivirus was able to express the CD gene and GFP in telomerase-positive tumor cells and significantly decrease cell proliferation after the use of prodrug 5-flucytosine. However, it could not express GFP and CD in telomerase-negative cell lines, nor could it induce any suicidal effect in those cells. The in vivo study showed that telomerase-positive tumors can be visualized after intratumor injection of the lentivirus in tumor-bearing nude mice via an optical imaging system. Significant tumor growth suppression was observed in telomerase-positive tumors. CONCLUSIONS: Collectively, this technology provides a valuable, noninvasive method to evaluate the real-time therapeutic response of tumors in vivo.
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Sistemas Computacionais , Citosina Desaminase/metabolismo , Monitoramento de Medicamentos/métodos , Terapia Genética/métodos , Neoplasias/terapia , Telomerase/genética , Animais , Linhagem Celular Tumoral , Citosina Desaminase/genética , Flucitosina , Genes Reporter , Genes Transgênicos Suicidas , Proteínas de Fluorescência Verde/genética , Humanos , Lentivirus/genética , Camundongos , Camundongos Nus , Neoplasias/genética , Regiões Promotoras Genéticas , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The SDF-1/CXCR4 axis is critical for inducing stem cell mobilization into the circulation, for homing stem cells to the site of injury, and for stem cell participation in the regeneration of liver tissue. In this study, we have gained insight into the molecular mechanisms involved in regulating the expression of SDF-1α by miRNAs. Using microarray and bioinformatics approaches, we identified six miRNAs with differential expression in damaged liver tissue (21 days after liver injury) compared to normal C57BL/6 murine liver tissue and further confirmed these observations by qPCR; miR-23a, which was identified by other researchers, was also included for comparative purposes. We found that miR-23a, miR-27a and miR-27b expression was significantly lower in the damaged liver than in the normal liver (p<0.05). We further confirmed that miR-27b could directly interact with the 3'UTR of SDF-1α to suppress SDF-1α protein expression using a luciferase reporter assay and Western blot analysis. In addition, we found that the over-expression of miR-27b significantly reduced the directional migration of primary cultured CRCX4-positive murine mesenchymal stem cells (mMSCs) in vitro using a transwell assay. These results suggest that miR-27b may be a unique signature of the stem cell niche in the damaged mouse liver and that mir-27b can suppress the directional migration of mMSCs by down-regulating SDF-1α expression by binding directly to the SDF-1α 3'UTR.
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Movimento Celular , Quimiocina CXCL12/biossíntese , Fígado/fisiologia , Células-Tronco Mesenquimais/fisiologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Animais , Células Cultivadas , Quimiocina CXCL12/genética , Regulação para Baixo , Fígado/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genéticaRESUMO
Gastric cancer is one of the most common malignant tumors of the digestive tract, with a high degree of malignancy and poor prognosis. With advancements in disease research, the role of epigenetic changes in its pathogenesis has become a research focus. The known epigenetic changes mainly include DNA methylation, histone modification, and regulation of chromatin structure. This article details the effects of these changes that would result in gastric cancer. Using next-generation sequencing methods and bioinformatics analysis, we can determine the epigenetic changes in abnormal tissues of the digestive tract that facilitate the early diagnosis and treatment of gastric cancer patients. In this article, we summarize how epigenetic changes determine gastric cancer and the new technologies used in research on cancer to benefit gastric cancer patients.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Epigênese Genética , Metilação de DNA , Epigenômica , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
The incidence of kidney stones averages 10%, and the recurrence rate of kidney stones is approximately 10% at 1 year, 35% at 5 years, 50% at 10 years, and 75% at 20 years. However, there is currently a lack of good medicines for the prevention and treatment of kidney stones. Osteopontin (OPN) is an important protein in kidney stone formation, but its role is controversial, with some studies suggesting that it inhibits stone formation, while other studies suggest that it can promote stone formation. OPN is a highly phosphorylated protein, and with the deepening of research, there is growing evidence that it promotes stone formation, and the phosphorylated protein is believed to have adhesion effect, promote stone aggregation and nucleation. In addition, OPN is closely related to immune cell infiltration, such as OPN as a pro-inflammatory factor, which can activate mast cells (degranulate to release various inflammatory factors), macrophages (differentiated into M1 macrophages), and T cells (differentiated into T1 cells) etc., and these inflammatory cells play a role in kidney damage and stone formation. In short, OPN mainly exists in the phosphorylated form in kidney stones, plays an important role in the formation of stones, and may be an important target for drug therapy of kidney stones.
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OBJECTIVES: To investigate the inhibitory effect of ketotifen fumarate (KFA), a mast cell membrane stabilizer, on renal calcium oxalate stone (CaOx) formation and its possible molecular mechanism. METHODS: We used the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database for functional and pathway enrichment analyses of osteopontin (OPN), CD44 and fibronectin (FN). Blood biochemistry, reactive oxygen species ratio (ROS), mast cells, proteins (CD44, OPN and FN) and OPN receptor integrin family genes were detected by ELISA, flow cytometry, immunohistochemistry and RT-QPCR, respectively. RESULTS: The crystal area of CaOx in the KFA and Control group was significantly smaller than that in the Model group. The number of activated mast cells, the expression levels of OPN and CD44 in the Control and KFA groups were significantly lower than those in the Model group, and the percentage of ROS in the KFA group was also significantly lower than that in the Model group. The mRNA expression levels of ITGB1, ITGA9, ITGAV and ITGA4 genes in the prominent OPN receptor integrin family increased significantly in the Model group. CONCLUSIONS: Ketotifen can effectively inhibit the crystal formation of CaOx and reduce the inflammatory response of tissue in SD rats. The mechanism may be to reduce the infiltration and activation of mast cells in renal tissue and down-regulate the expression of OPN, CD44 and FN in renal tubules and renal interstitium. And affect the synthesis of integrins (ITGA9, ITGA4, ITGAV, ITGB1, ITGB3 and ITGB5) and ROS.
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Oxalato de Cálcio , Cetotifeno , Animais , Oxalato de Cálcio/metabolismo , Integrinas/metabolismo , Cetotifeno/farmacologia , Rim , Osteopontina/genética , Osteopontina/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION: Manipulation under anesthesia (MUA) is often used for frozen shoulder treatment, but controversy still exists regarding MUA compared with conservative treatment. This research was conducted to compare the outcome between MUA and celecoxib (CLX) in secondary frozen shoulder. METHODS: Patients with secondary frozen shoulder were randomized into two groups, an MUA plus exercise (EX) group and a CLX plus EX group. Clinical outcomes were documented at baseline and at 1 day, 2, 4, and 12 weeks after intervention, including Constant-Murley Score (CMS) for function, Pain Rating Index (PRI) and Present Pain Intensity (PPI) for pain, passive range of motion (ROM) measurements including external rotation, internal rotation, forward flexion, and abduction. Primary outcome was CMS. Secondary outcomes were PRI, PPI, and passive ROM. RESULTS: Sixty-seven patients out of 68 in the MUA group and 66 out of 68 in the CLX group finished the entire study period. There were no significant differences in basic properties of the two groups before intervention. As the primary outcome, CMS changes in the MUA group improved faster than the CLX group. Secondary outcomes, passive ROM, and pain PPI were faster and significant in the MUA group from 1 day after intervention compared with CLX (P < 0.05). At 12 weeks, a statistically significant difference was not observed in the PPI (P > 0.05). A statistically significant difference was not observed in the PRI between groups in 1 day (P > 0.05). For the primary outcome, from 0 to 12 weeks the mean changes in CMS were 44.00 for MUA plus EX (95% CI 43.07-44.93, P < 0.001) and 27.09 for CLX plus EX (26.20-27.98, P < 0.001). The significant difference in improvement appeared from 2 weeks. CONCLUSION: To treat secondary frozen shoulder with MUA, this treatment could achieve better therapeutic effects on improvement of function, pain, and passive ROM than CLX did. CLINICAL TRIAL REGISTRATION: The trial was registered at www.chictr.org.cn , identifier ChiCTR2200060269.
RESUMO
Following the publication of this article, an interested reader drew to the authors' attention that two images in Fig. 1B (the a and d panels) appeared to represent the same clone, albeit with different intensities and the panels were cropped differently. The authors were able to confirm that Figs. 1B(a) and B(d) were inadvertently selected from the same set of images but with different exposure times: Owing to an error in data handling, a wrong image was chosen during the grouping the figures. The corrected version of Fig. 1 is shown on the next page, featuring the correct image for Fig. 1B(d). The authors regret that this error was not picked up upon before the paper was sent to press, although the error did not affect the major conclusions reported in the paper. The authors thank the Editor of International Journal of Oncology for allowing them the opportunity to publish a Corrigendum. and regret any inconvenience caused to the readership. [the origional article was published on International Journal of Oncology 40: 16011609, 2012; DOI: 10.3892/ijo.2012.1338].