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OBJECTIVE: This study aims to explore ADH4 expression in hepatocellular carcinoma (HCC), its prognostic impact, and its immune correlation to provide novel insights into HCC prognostication and treatment. METHODS: HCC prognostic marker genes were rigorously selected using GEO database, Lasso regression, GEPIA, Kaplan-Meier and pROC analyses. The expression of interested markers (ADH4, DNASE1L3, RDH16, LCAT, HGFAC) in HCC and adjacent tissues was assessed by Immunohistochemistry (IHC). We observed that ADH4 exhibited low expression levels in liver cancer tissues and high expression levels in normal liver tissues. However, the remaining four genes did not manifest any statistically significant differences between hepatocellular carcinoma (HCC) tissue and adjacent non-cancerous tissue. Consequently, ADH4 became the primary focus of our research. ADH4 expression was validated by signed-rank tests and unpaired Wilcoxon rank sum tests across pan-cancer and HCC datasets. Clinical significance and associations with clinicopathological variables were determined using Kaplan-Meier, logistic regression and Cox analyses on TCGA data. The ADH4-related immune responses were explored by Spearman correlation analysis using TIMER2 data. CD68, CD4, and CD19 protein levels were confirmed by IHC in HCC and non-cancerous tissues. RESULTS: ADH4 showed significant downregulation in various cancers, particularly in HCC. Moreover, low ADH4 expression was associated with clinicopathological variables and served as an independent prognostic marker for HCC patients. Additionally, ADH4 affects a variety of biochemical functions and may influence cancer development, prognosis, and treatment by binding to immune cells. Furthermore, at the immune level, the low expression pattern of ADH4 is TME-specific, indicating that ADH4 has the potential to be used as a target for cancer immunotherapy. CONCLUSION: This study highlights the diagnostic, prognostic and immunomodulatory roles of ADH4 in HCC. ADH4 could serve as a valuable biomarker for HCC diagnosis and prognosis, as well as a potential target for immunotherapeutic interventions.
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Álcool Desidrogenase , Biomarcadores Tumorais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Prognóstico , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Estimativa de Kaplan-MeierRESUMO
OBJECTIVES: First, we retrospectively compared the clinical efficacy of concurrent chemoradiotherapy combined with nimotuzumab vs. chemoradiotherapy alone in patients with nasopharyngeal carcinoma (NPC) and cervical lymph node metastasis. Second, we analyzed the value of Ki-67 as a predictor of nimotuzumab efficacy. METHODS: From January 2012 to December 2019, 1250 patients with cervical lymph node metastasis eligible for enrollment were included, of whom 383 were treated with concurrent chemoradiotherapy combined with nimotuzumab (targeted therapy group), and 867 were treated with concurrent chemoradiotherapy (CRT group). A total of 381 pairs of patients were matched using 1:1 propensity score matching, and differences in clinical prognosis were compared between the two groups. RESULTS: Overall survival (OS) (P = 0.028), disease-free survival (DFS) (P = 0.040), and distant metastasis-free survival (DMFS) (P = 0.040) were better in the targeted therapy compared to the CRT group. Multivariate analysis revealed that clinical staging, chemotherapy, and nimotuzumab therapy were predictors of OS and DFS. In the targeted therapy group, patients with ≥ 50% Ki-67 positivity had better OS and DFS rates than those with < 50% Ki-67 positivity. CONCLUSIONS: In patients with stage N1-3 NPC and lymph node metastasis, the addition of nimotuzumab to concurrent chemoradiotherapy may provide additional survival benefits. Ki-67 is a potential biomarker with clinical predictive value for the efficacy of nimotuzumab combined with chemoradiotherapy.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Metástase Linfática , Estudos Retrospectivos , Antígeno Ki-67 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Estadiamento de NeoplasiasRESUMO
Angiosarcoma is an uncommon, aggressive endothelial-cell tumor that usually affects the skin, and involvement of the skull is rare. Here, we describe a case of skull angiosarcoma associated with a calcified chronic subdural hematoma (CSDH). HIGHLIGHTSA very rare case of skull angiosarcoma associated with a calcified chronic subdural hematoma is presented.An asymptomatic subdural hematoma with an atypical history and radiological features should prompt further investigation.Contrast MRI images should to be obtained early to differentiate a subdural hematoma from other pathologies.
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Hemangiossarcoma , Hematoma Subdural Crônico , Humanos , Hematoma Subdural Crônico/complicações , Hematoma Subdural Crônico/diagnóstico por imagem , Hemangiossarcoma/complicações , Hemangiossarcoma/diagnóstico por imagem , Hemangiossarcoma/cirurgia , Crânio , Cabeça , RadiografiaRESUMO
AIMS: The aim of this study is to investigate the expression profiles of cell cycle related proteins in nasal extranodal NK/T cell lymphoma, nasal type (ENKTCL). METHODS: The expression profiles of cell cycle related proteins were assessed with a cell cycle antibody array and validated by immunohistochemistry. Correlations between the expression levels of proteins and clinical outcomes of patients with nasal ENKTCL were evaluated. RESULTS: The expression of full length ataxia telangiectasia mutated (ATM) in nasal ENKTCL significantly decreased compared with that in nasal benign lymphoid proliferative disease (NBLPD), but the expression levels of p-ATM, CHK2 and RAD51 significantly increased in nasal ENKTCL compared with that in NBLPD. Kaplan-Meier analysis showed that the expression levels of p-ATM and CHK2 in nasal ENKTCL were inversely related to overall survival (p=0.011 and p=0.025, respectively). CONCLUSION: Abnormalities in the ATM pathway may play a crucial role in the oncogenesis and chemoradiotherapy resistance of nasal ENKTCL.
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Proteínas Mutadas de Ataxia Telangiectasia/análise , Biomarcadores Tumorais/análise , Quinase do Ponto de Checagem 2/análise , Linfoma Extranodal de Células T-NK/enzimologia , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Imuno-Histoquímica , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/terapia , Gradação de Tumores , Fosforilação , Rad51 Recombinase/análise , Tolerância a Radiação , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para CimaRESUMO
Nasopharyngeal carcinoma (NPC) is an EBV associated carcinoma showing prevalence in southeast China. Distant metastasis is the major cause of death. Herein, we investigated the expressions of microRNA-3182 (miR-3182) and EBV-miR-BART8-3p in 89 cases of NPC and evaluated their correlation with clinical outcomes. Fifty-one percent of NPC showed high level expression of miR-3182. Its expression was significantly correlated with distant metastasis (P=0.005). Fifty-two percent of NPC demonstrated high level expression of EBV-miR-BART8-3p and its expression was significantly correlated with distant metastasis (P=0.006). The overall survival was influenced by the expression of miR-3182 and EBV-miR-BART8-3p. The patients with a high-level expression of miR-3182 and EBV-miR-BART8-3p had worse overall survival (P=0.005 and P=0.007). Multivariable analysis demonstrated that EBV-miR-BART8-3p was an independent prognostic factor for overall survival (P=0.018). The expression of miR-3182 was significantly correlated with EBV-miR-BART8-3p (P=0.045). In conclusion, this is the first study examining the potential clinical utility of miR-3182 and EBV-miR-BART8-3p as prognostic biomarkers in NPC. EBV infection may promote NPC progression by disrupting the expression of miR-3182.
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The present study aimed to determine the association between changes in Zbtb7a expression levels and heterogeneity of nasopharyngeal carcinoma (NPC) CNE3 sublines. CNE3 sublines were established by screening of serial dilution and continuous passage. Proliferative ability and tumorigenicity of the sublines were analyzed separately by soft-agar colony formation and mouse studies. The NPC tissues from mice were analyzed by histological evaluation and immunohistochemistry. The expression levels of Zbtb7a mRNA and protein were analyzed separately by quantitative reverse transcription polymerase chain reaction and western blotting. According to findings from the soft-agar colony formation and mouse studies, two sublines with increased tumorigenicity compared with other sublines were transfected transiently with Zbtb7a short hairpin RNA (shRNA) recombinant plasmid. The changes in viability, migration and invasion abilities were evaluated separately by MTT, colorimetric focus-formation, Transwell migration and invasion assays. The sublines CNE3-GX6 and CNE3-GX11 were selected for subsequent study due to increased tumorigenicity and increased Zbtb7a expression levels compared with the other sublines. High metastatic potency was not observed in all of the sublines. Zbtb7a expression levels were positively associated with tumorigenic degree of the sublines. The growth, migration and invasion abilities of the sublines transfected with Zbtb7a shRNA plasmid were decreased compared with the cells transfected with empty vector in the negative control group. The findings suggest Zbtb7a expression levels may be associated with heterogeneity of CNE3 sublines. Therefore, Zbtb7a may have an important role in the regulatory mechanism of NPC heterogeneity.
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Cell-mediated immunity is critical to the clearance of Mycobacterium tuberculosis due to the primarily intracellular niche of this pathogen. Adoptive transfer of M. tuberculosis-specific effector T cells has been shown to confer immunity to M. tuberculosis-infected recipients resulting in M. tuberculosis clearance. However, it is difficult to generate sufficient numbers of M. tuberculosis antigen-specific T cells in a short time. Recent studies have developed T cell receptor (TCR) gene-modified T cells that allow for the rapid generation of large numbers of antigen-specific T cells. Many TCRs that target various tumor and viral antigens have now been isolated and shown to have functional activity. Nevertheless, TCRs specific for intracellular bacterial antigens (including M. tuberculosis antigens) have yet to be isolated and their functionality confirmed. We isolated M. tuberculosis 38-kDa antigen-specific HLA class I and class II-restricted TCRs and modified the TCR gene C regions by substituting nine amino acids with their murine TCR homologs (minimal murinization). Results showed that both wild-type and minimal murinized TCR genes were successfully cloned into retroviral vectors and transduced into primary CD4(+) and CD8(+) T cells and displayed anti-M. tuberculosis activity. As expected, minimal murinized TCRs displayed higher cell surface expression levels and stronger anti-M. tuberculosis activity than wild-type TCRs. To the best of our knowledge, this is the first report describing TCRs targeting M. tuberculosis antigens and this investigation provides the basis for future TCR gene-based immunotherapies that can be designed for the treatment of immunocompromised M. tuberculosis-infected patients.
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Antígenos de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Lipoproteínas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Substituição de Aminoácidos , Animais , Sequência de Bases , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Citocinas/metabolismo , Citotoxicidade Imunológica , Epitopos/genética , Epitopos/imunologia , Regulação da Expressão Gênica/imunologia , Engenharia Genética , Vetores Genéticos/genética , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Células Th1/imunologiaRESUMO
We investigated the influence of tumor tissue differentiation on the diversity of TCR repertoire. CDR3 spectratypes of CD4(+) and CD8(+) T cell subsets were analyzed from 27 patients with gastrointestinal tract tumors exhibiting varying degrees of differentiation. A CDR3 spectratype complexity scoring system was used to quantify the diversity of TCR repertoire. Each patient was matched with an age-matched healthy group to control for age variability. Results show that the complexity scores (TCR repertoire diversity) have a significant correlation with the degree of tumor differentiation, which provides useful information for understanding immune response in cancer patients.
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Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Neoplasias Retais/imunologia , Neoplasias Retais/patologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Transformação Celular Neoplásica , Feminino , Citometria de Fluxo , Humanos , Imunidade Celular , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologiaRESUMO
To investigate the correlation between normalization of T cell receptor (TCR) repertoire and remission of advanced colorectal cancer. Forty-one patients were randomly assigned to receive either folinic acid/fluorouracil/irinotecan alone (n = 20) or folinic acid/fluorouracil/irinotecan in combination with recombinant human endostatin (n = 21). Efficacy and toxicity were evaluated, and changes in TCR repertoire diversity were assessed by detecting the spectratypes of TCR complementarity-determining region three before and after several cycles of therapy. A scoring system was used to quantify changes in the TCR repertoire over time. The results demonstrated that the TCR repertoire exhibited a higher degree of normalization among patients undergoing remission relative to patients experiencing tumor progression. The results of the current study showed a positive correlation between TCR repertoire normalization and remission of colorectal cancer, suggesting that dynamic monitoring of TCR repertoire diversity may have potential prognostic value in the clinical setting.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/metabolismo , Adenocarcinoma/secundário , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Endostatinas/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Recombinantes/uso terapêutico , Indução de RemissãoRESUMO
In the present study, either modified IFL regimen (modified irinotecan, fluorouracil and leucovorin, mIFL) alone or in combination with bevacizumab was used to treat patients with metastatic colorectal cancer (CRC). Treatment efficacy was assessed using coupled tomography imaging diagnosis. The toxicity accompany with treatment was evaluated, as well as T cell receptor (TCR) repertoire before and several cycles after therapy was dynamically monitored by analyzing the complementarity-determining region 3 (CDR3) length distribution within CD4(+) and CD8(+) T cell subsets. The degrees of normalization of the T cell repertoire in CRC patients treated with the two methods were compared. The results showed that mIFL combined with bevacizumab was more effective in treating patients with metastatic CRC, and was accompanied by an increase in side effects such as proteinuria and hematuria. An even more restricted CDR3 profile in patients with metastatic CRC compared with healthy control has been detected. A prominent usage of TCR beta chain variable (BV) gene BV12 and BV16 families within the CD4(+) T cell subset and BV19 and BV21 families within the CD8(+) T cell subset have been found before treatment. Moreover, CD8(+) T cells showed more restricted patterns than CD4(+) T cells, especially in patients before treatment. For patients with stable disease (SD) or partial remission (PR) after treatment, a less restricted CDR3 profile in post-treatment compared with pre-treatment has been found, but the opposite result was observed for patients with progressive disease (PD). The less restricted CDR3 pattern suggested a trend toward normalization of the TCR repertoire. The normalization of TCR repertoire significantly increased in patients treated with mIFL in combination with bevacizumab, but slightly in patients treated with mIFL alone. The results demonstrate a positive correlation between post-therapy TCR repertoire normalization and remission of metastatic CRC.
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Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Regiões Determinantes de Complementaridade/análise , Receptores de Antígenos de Linfócitos T/análise , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Hematúria/diagnóstico , Hematúria/etiologia , Humanos , Irinotecano , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteinúria/diagnóstico , Proteinúria/etiologia , Subpopulações de Linfócitos T/imunologia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Tumour necrosis factor (TNF-a) is a pro-inflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma, and which has recently been highlighted as potentially important in refractory asthma. To study the feasibility of local treatment of asthma with recombinant adenovirus vector carrying soluble extra-cellular region of TNF receptor I-IgGFc (sTNFRI-IgGFc) fusion protein, The sTNFRI-IgGFc gene was subcloned into the adenovirus shuttle plasmid pDC316, the products were co-transfected into HEK293 cell line with helper plasmid pBHGloxDeltaE1,3Cre. The recombinant adenovirus (Ad-sTNFRI-IgGFc) was produced by homologous recombination of above 2 plasmids in HEK293 cells. After identification with PCR, Ad-sTNFRI-IgGFc was amplified and purified, its titer was measured by TCID50 assay. The transcription and expression of sTNFRI-IgGFc gene in transfected human airway smooth muscle cells (HASMCs) was detected by RT-PCR, ELISA and immunological histochemistry. The anti-TNF activity assay of transfected HASMCs culture supernatant was measured by MTT. Ad-sTNFRI-IgGFc was successfully constructed with the titer of 3x10(10) TCID50/mL. Ad-sTNFRI-IgGFc can transfect HASMC with high efficacy. The transcription of sTNFRI-IgGFc mRNA and the expression of protein were confirmed in the transfected HASMCs. Moreover, the product in 100 microL expression supernatant could completely antagonize the cytolytic effect of 2ng TNFa on L929 cells, even at 1/64 dilution. This study forms the basement of the experiment study on local treatment of asthma with adenovirus expressing sTNFRI-IgGFc.
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Adenoviridae/metabolismo , Fragmentos Fc das Imunoglobulinas/biossíntese , Imunoglobulina G/biossíntese , Miócitos de Músculo Liso/metabolismo , Receptores do Fator de Necrose Tumoral/biossíntese , Adenoviridae/genética , Asma/terapia , Brônquios/citologia , Células Cultivadas , Vetores Genéticos/genética , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulina G/genética , Miócitos de Músculo Liso/citologia , Receptores do Fator de Necrose Tumoral/genética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Transfecção , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVE: To construct a recombinant adenovirus vector carrying soluble extracellular region of tumor necrosis factor alpha receptor I-IgGFc (sTNFRI-IgGFc) and express the fusion protein in human bronchial epithelial HBE135-E6E7 cells. METHODS: sTNFRI-IgGFc fusion gene was subcloned into the adenovirus shuttle plasmid pDC316, which was co-transfected with helper plasmid pBHGloxPE1,3Cre into HEK293 cells. The recombinant adenovirus (Ad-sTNFRI-IgGFc) was generated by homologous recombination of the 2 plasmids in HEK293 cells. After identification with PCR, Ad-sTNFRI-IgGFc was amplified and purified, and its titer measured using TCID50 assay. The transcription and expression of sTNFRI-IgGFc gene in the transfected HBE135-E6E7 were detected by RT-PCR and immunohistochemistry. RESULTS: Ad-sTNFRI-IgGFc was successfully constructed with a viral titer of 3 x 10(10) TCID50/ml. The expression of sTNFRI-IgGFc mRNA and protein was confirmed in the transfected HBE135-E6E7 cells. CONCLUSION: The constructed Ad-sTNFRI-IgGFc can effectively infect HBE135-E6E7 cells for efficient expression of sTNFRI-IgGFc protein, which antagonizes the cytolytic effect of TNFalpha in L929 cells, suggesting the potential of adenovirus expressing sTNFRI-IgGFc for local treatment of asthma.