RESUMO
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by proliferative vascular remodeling. Abnormal vascular smooth muscle cell (VSMC) phenotype switching is crucial to this process, highlighting the need for VSMC metabolic changes to cover cellular energy demand in CTEPH. We report that elevated Wnt family member 5B (WNT5B) expression is associated with vascular remodeling and promotes VSMC phenotype switching via mitochondrial dynamics regulation in CTEPH. Using primary culture of pulmonary artery smooth muscle cells, we show that high WNT5B expression activates VSMC proliferation and migration and results in mitochondrial fission via noncanonical Wnt signaling in CTEPH. Abnormal VSMC proliferation and migration were abolished by mitochondrial division inhibitor 1, an inhibitor of mitochondrial fission. Secreted frizzled-related protein 2, a soluble scavenger of Wnt signaling, attenuates VSMC proliferation and migration by accelerating mitochondrial fusion. These findings indicate that WNT5B is an essential regulator of mitochondrial dynamics, contributing to VSMC phenotype switching in CTEPH.
Assuntos
Hipertensão Pulmonar , Músculo Liso Vascular , Desdiferenciação Celular , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Humanos , Hipertensão Pulmonar/metabolismo , Dinâmica Mitocondrial/fisiologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Remodelação Vascular/genética , Proteínas Wnt/metabolismoRESUMO
BACKGROUND: The high degree of heterogeneity brought great challenges to the diagnosis and treatment of acute myeloid leukemia (AML). Although several different AML prognostic scoring models have been proposed to assess the prognosis of patients, the accuracy still needs to be improved. As important components of the tumor microenvironment, immune cells played important roles in the physiological functions of tumors and had certain research value. Therefore, whether the tumor immune microenvironment (TIME) can be used to assess the prognosis of AML aroused our great interest. METHODS: The patients' gene expression profile from 7 GEO databases was normalized after removing the batch effect. TIME cell components were explored through Xcell tools and then hierarchically clustered to establish TIME classification. Subsequently, a prognostic model was established by Lasso-Cox. Multiple GEO databases and the Cancer Genome Atlas dataset were employed to validate the prognostic performance of the model. Receiver operating characteristic (ROC) and the concordance index (C-index) were utilized to assess the prognostic efficacy. RESULTS: After analyzing the composition of TIME cells in AML, we found infiltration of ten types of cells with prognostic significance. Then using hierarchical clustering methods, we established a TIME classification system, which clustered all patients into three groups with distinct prognostic characteristics. Using the differential genes between the first and third groups in the TIME classification, we constructed a 121-gene prognostic model. The model successfully divided 1229 patients into the low and high groups which had obvious differences in prognosis. The high group with shorter overall survival had more patients older than 60 years and more poor-risk patients (both P< 0.001). Besides, the model can perform well in multiple datasets and could further stratify the cytogenetically normal AML patients and intermediate-risk AML population. Compared with the European Leukemia Net Risk Stratification System and other AML prognostic models, our model had the highest C-index and the largest AUC of the ROC curve, which demonstrated that our model had the best prognostic efficacy. CONCLUSION: A prognostic model for AML based on the TIME classification was constructed in our study, which may provide a new strategy for precision treatment in AML.
Assuntos
Leucemia Mieloide Aguda , Microambiente Tumoral , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Prognóstico , Curva ROC , TranscriptomaRESUMO
Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and does not have sufficient prognostic indicators. Interferon gamma inducible protein 16 (IFI16) plays a crucial role in B-cell differentiation. Several studies have shown that IFI16 predicted prognosis in many cancers. However, the relationship between MM prognosis and IFI16 expression has not been studied. In our study, we analyzed the prognostic role of IFI16 expression and explored the possible mechanism in MM progression by using 4498 myeloma patients and 52 healthy donors from 13 independent gene expression omnibus (GEO) datasets. The IFI16 expression increased with myeloma progression, ISS stage, 1q21 amplification, and relapse (all P < 0.01). MM patients with higher IFI16 expression had shorter survival in six datasets (all P < 0.05). Furthermore, multivariate analysis indicated that enhanced IFI16 expression was an independent poor prognostic factor for EFS and OS (P = 0.007, 0.009, respectively). And PPI, GO, KEGG, and GSEA also confirmed that IFI16 promoted MM progression by participating in tumor-related pathways. In conclusion, our study confirmed that IFI16 was a poor prognostic biomarker in MM.
Assuntos
Expressão Gênica/genética , Mieloma Múltiplo/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Mieloma Múltiplo/patologia , PrognósticoRESUMO
The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and the median DDIT4 expression levels. High DDIT4 expressers had shorter overall survival (OS) and event-free survival (EFS) than the low expressers among the chemotherapy-only group (all P < .001); EFS and OS were similar in the high and low DDIT4 expressers of the allogeneic haematopoietic stem cell transplantation (allo-HSCT) group. Furthermore, in the DDIT4high group, patients treated with allo-HSCT had longer EFS and OS than those who received chemotherapy alone (all P < .01). In the DDIT4low group, OS and EFS were similar in different treatment groups. Secondly, we analysed two other cytogenetically normal AML (CN-AML) cohorts derived from the Gene Expression Omnibus database, which confirmed that high DDIT4 expression was associated with poorer survival. Gene Ontology (GO) enrichment analysis showed that the genes related to DDIT4 expression were mainly concentrated in the acute and chronic myeloid leukaemia signalling pathways. Collectively, our study indicates that high DDIT4 expression may serve as a poor prognostic factor for AML, but its prognostic effects could be outweighed by allo-HSCT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Fatores de Transcrição/metabolismo , Terapia Combinada , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Transcrição/genética , Transplante HomólogoRESUMO
BACKGROUND: Venous thromboembolism (VTE) is a life-threatening disease that can affect each hospitalized patient. But the current in-hospital thromboprophylaxis remains suboptimal and there exists a large gap between clinical practice and guideline-recommended care in China. METHODS: To facilitate implementation of guideline recommendations, we conduct a multicenter, adjudicator-blinded, cluster-randomized clinical trial, aiming to assess the effectiveness of a system-wide multifaceted quality improvement (QI) strategy on VTE prophylaxis improvement and thromboembolism reduction in clinical setting. Hospitals are randomized into intervention or control group. In intervention group, hospitals receive the concept of appropriate in-hospital thromboprophylaxis plus a multifaceted QI which encompasses four components: (1) an electronic alert combining computer-based clinical decision support system and electronic reminders, (2) appropriate prophylaxis based on dynamic VTE and bleeding risk assessments, (3) periodical audit and interactive feedback on performance, (4) strengthened training and patient education. In control, hospitals receive the concept of recommended prophylaxis alone without QI. Thromboprophylaxis will be at the discretion of hospitals and conducted as usual. With a final sample size of 5760 hospitalized patients in 32 hospitals on mainland China, this trial will examine the effect of QI on improvement in thromboprophylaxis and patient-centered outcomes. This is an open-label trial that patients and healthcare professionals will know group allocation after enrollment, but endpoint adjudicators and statisticians will be blinded. RCT# NCT04211181 CONCLUSIONS: The system-wide multifaceted QI intervention is expected to facilitate implementation of recommended VTE prophylaxis in hospital, thereafter reducing VTE incidence and relevant adverse events among hospitalized patients in China.
Assuntos
Anticoagulantes/uso terapêutico , Fidelidade a Diretrizes , Hospitais , Melhoria de Qualidade , Tromboembolia Venosa/prevenção & controle , Adulto , Anticoagulantes/efeitos adversos , China , Sistemas de Apoio a Decisões Clínicas , Hemorragia/induzido quimicamente , Humanos , Análise de Intenção de Tratamento , Educação de Pacientes como Assunto , Guias de Prática Clínica como Assunto , Modelos de Riscos Proporcionais , Medição de Risco , Método Simples-CegoRESUMO
The prognosis role of CCT3 in MM and the possible pathways it involved were studied in our research. By analyzing ten independent datasets (including 48 healthy donors, 2220 MM, 73 MGUS, and 6 PCL), CCT3 was found to express higher in MM than healthy donors, and the expression level was gradually increased from MGUS, SMM, MM to PCL (all P < 0.01). By analyzing three independent datasets (GSE24080, GSE2658, and GSE4204), we found that CCT3 was a significant indicator of poor prognosis (all P < 0.01). KEGG and GSEA analysis showed that CCT3 expression was associated with JAK-STAT3 pathway, Hippo signaling pathway, and WNT signaling pathway. In addition, different expressed genes analysis revealed MYC, which was one of the downstream genes regulated by JAK-STAT3 pathway, was upregulated in MM. This confirms that JAK-STAT3 signaling pathway may promote the progress of disease which was regulated by CCT3 expression. Our study revealed that CCT3 may play a supporting role at the diagnosis of myeloid, and high expression of CCT3 suggested poor prognosis in MM. CCT3 expression may promote the progression of MM mainly by regulating MYC through JAK-STAT3 signaling pathway.
Assuntos
Chaperonina com TCP-1/biossíntese , Chaperonina com TCP-1/genética , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Adulto , Idoso , Bases de Dados Genéticas/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Prognóstico , Taxa de Sobrevida/tendênciasRESUMO
Acute myeloid leukemia (AML) is a malignant disease of myeloid hematopoietic stem or progenitor cells characterized by abnormal proliferation of primary and immature myeloid cells in bone marrow and peripheral blood. Gene mutation and expression profiles can be used as prognosis predictors for different prognostic subgroups. Secretory carrier-associated membrane proteins (SCAMPs) are a multigenic family with five members and act as cell surface vectors in the post-Golgi recycling pathways in mammals. Nevertheless, the prognostic and clinical influence of SCAMP family has hardly ever been illustrated in AML. In our study, expression patterns of SCAMP family (SCAMP1-5) were analyzed in 155 AML patients which were extracted from the Cancer Genome Atlas database. In chemotherapy, only subgroup, higher SCAMP1 level was significantly associated with longer EFS and OS (all P = 0.002), and SCAMP1 was confirmed to be an independent favorable factor in un-transplanted patients by Multivariate analysis (all P < 0.05). Nevertheless, in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) treatment subgroup, none of the SCAMP genes had any effect on the clinical survival. Our study found that high expression level of SCAMP1 is a favorable prognostic factor in AML, but allo-HSCT may neutralize its prognostic effect.
Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas de Transporte Vesicular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Bases de Dados Genéticas/tendências , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
Background: Lymphopenia is common in respiratory viral infection. However, no studies elucidated the impact of prolonged lymphopenia on worse outcome in the way of quantitative risk. Methods: Adult patients with laboratory-confirmed respiratory virus infection (influenza, SARS-CoV-2, and other viruses) between January 1st, 2016, and February 1st, 2023 were enrolled in this retrospective cohort study. Serial data of laboratory examination during hospitalization were acquired. The primary outcome was in-hospital all-cause death, and all information was obtained from the electronic medical records system. Legendre orthogonal polynomials (LOP), restricted cubic splines, and multivariable logistic regression were performed. Results: Finally, 2388 inpatients were involved in this study, including 436 patients with influenza, 1397 with SARS-CoV-2, and 319 with other respiratory virus infections. After being adjusted for age, corticosteroids, chronic kidney disease, chronic respiratory disease, cardiovascular disease, lymphopenia on admission and length of hospital stay, prolonged lymphopenia was significantly associated with death in influenza (OR 7.20, 95 % CI 2.27-22.77, p = 0. 0008 for lasting for 3-7 days; OR 17.80, 95 % CI 5.21-60.82, p < 0.0001 for lasting for more than 7 days) and SARS-CoV-2 (OR 3.07, 95 % CI 1.89-5.01, p < 0.0001 for lasting for 3-7 days; OR 6.28, 95 % CI 3.53-11.18, p < 0.0001 for lasting for more than 7 days), compared with a transient lymphopenia of 1-2 days, while no significant association was found in other respiratory viruses. Prolonged lymphopenia was also associated with multi-organ damage in influenza and SARS-CoV-2 infections. Conclusions: Prolonged lymphopenia was significantly associated with worse clinical prognoses in influenza and SARS-CoV-2 infections, but not in other respiratory virus infections.
RESUMO
BACKGROUNDS: Ovarian cancer (OC) is the second most common gynecological tumor with the highest mortality rate worldwide. High FAM111B expression has been reported as a predictor of poor prognosis in other cancers, but its correlation with OC has not been reported. METHODS: Immunohistochemistry of tissue microarrays was performed to detect FAM111B expression levels in 141 OC patient tissues. The prognostic value of FAM111B was determined by Kaplan-Meier survival analysis, and correlations between FAM111B expression and clinicopathologic features were investigated by the Clu-square test. The significance of FAM111B expression was verified bioinformatically using the Gene Expression Omnibus database. Protein-protein interaction were performed to explore downstream mechanisms of FAM111B in OC. RESULTS: Among 141 OC patients, FAM111B was positively expressed in 87.23%, 58.16%, and 87.94%; and highly expressed in 8.51%, 17.02%, and 19.86%, as evaluated by cytoplasmic, nuclear, and combined cytoplasmic/nuclear staining. FAM111B expression was positively correlated with the expression of tumor protein markers KI67, EGFR, and PDL-1. Patients with high FAM111B expression had aggressive clinicopathologic features and shorter overall survival (P value 0.0428, 0.0050, 0.0029) and progression-free survival (P value 0.0251, 0.012, 0.0596) compared to the low FAM111B expression group for cytoplasmic, nuclear, and combined cytoplasmic/nuclear groups, respectively. These results were verified using patient data from the Gene Expression Omnibus. Seventeen genes co-expressed with FAM111B were primarily involved in "negative regulation of histone modification", "hippo signaling" and "inner ear receptor cell differentiation". CONCLUSIONS: High FAM111B expression may serve as a novel prognostic predictor and molecular therapeutic target for OC.
RESUMO
BACKGROUND: Exercise, as the cornerstone of pulmonary rehabilitation, is recommended to chronic obstructive pulmonary disease (COPD) patients. The underlying molecular basis and metabolic process were not fully elucidated. METHODS: Sprague-Dawley rats were classified into five groups: non-COPD/rest ( n â=â8), non-COPD/exercise ( n â=â7), COPD/rest ( n â=â7), COPD/medium exercise ( n â=â10), and COPD/intensive exercise ( n â=â10). COPD animals were exposed to cigarette smoke and lipopolysaccharide instillation for 90 days, while the non-COPD control animals were exposed to room air. Non-COPD/exercise and COPD/medium exercise animals were trained on a treadmill at a decline of 5° and a speed of 15 m/min while animals in the COPD/intensive exercise group were trained at a decline of 5° and a speed of 18 m/min. After eight weeks of exercise/rest, we used ultrasonography, immunohistochemistry, transmission electron microscopy, oxidative capacity of mitochondria, airflow-assisted desorption electrospray ionization-mass spectrometry imaging (AFADESI-MSI), and transcriptomics analyses to assess rectal femoris (RF). RESULTS: At the end of 90 days, COPD rats' weight gain was smaller than control by 59.48â±â15.33âg ( P â=â0.0005). The oxidative muscle fibers proportion was lower ( P â<â0.0001). At the end of additional eight weeks of exercise/rest, compared to COPD/rest, COPD/medium exercise group showed advantages in weight gain, femoral artery peak flow velocity (Δ58.22 mm/s, 95% CI: 13.85-102.60 mm/s, P â=â0.0104), RF diameters (Δ0.16âmm, 95% CI: 0.04-0.28âmm, P â=â0.0093), myofibrils diameter (Δ0.06 µm, 95% CI: 0.02-0.10âµm, P â=â0.006), oxidative muscle fiber percentage (Δ4.84%, 95% CI: 0.15-9.53%, P â=â0.0434), mitochondria oxidative phosphorylate capacity ( P â<â0.0001). Biomolecules spatial distribution in situ and bioinformatic analyses of transcriptomics suggested COPD-related alteration in metabolites and gene expression, which can be impacted by exercise. CONCLUSION: COPD rat model had multi-level structure and function impairment, which can be mitigated by exercise.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Ratos , Animais , Ratos Sprague-Dawley , Doença Pulmonar Obstrutiva Crônica/metabolismo , Pulmão/metabolismo , Mitocôndrias Musculares/metabolismo , MetabolomaRESUMO
Background: To explore the feasibility and effectiveness of multifaceted quality improvement intervention based on the clinical decision support system (CDSS) in VTE prophylaxis in hospitalized patients. Methods: A randomized, department-based clinical trial was conducted in the department of respiratory and critical care medicine, orthopedic, and general surgery wards. Patients aged ≥18 years, without VTE in admission, were allocated to the intervention group and received regular care combined with multifaceted quality improvement intervention based on CDSS during hospitalization. VTE prophylaxis rate and the occurrence of hospital-associated VTE events were analyzed as primary and secondary outcomes. Results: A total of 3644 eligible residents were enrolled in this trial. With the implementation of the multifaceted quality improvement intervention based on the CDSS, the VTE prophylaxis rate of the intervention group increased from 22.93% to 34.56% (p < 0.001), and the incidence of HA-VTE events increased from 0.49% to 1.00% (p = 0.366). In the nonintervention group, the VTE prophylaxis rate increased from 24.49% to 27.90% (p = 0.091), and the incidence of HA-VTE events increased from 0.47% to 2.02% (p = 0.001). Conclusions: Multifaceted quality improvement intervention based on the CDSS strategy is feasible and expected to facilitate implementation of the recommended VTE prophylaxis strategies and reduce the incidence of HA-VTE in hospital. However, it is necessary to conduct more multicenter clinical trials in the future to provide more reliable real-world evidence.
RESUMO
BACKGROUND: Treponema pallidum subspecies pallidum (T. pallidum) infection induces significant immune responses, resulting in tissue damage. Gene expression plays an essential role in regulating the progression of syphilis infection. However, little is known about the regulatory role of microRNAs (miRNAs) in the immune response to T. pallidum infection. Here, we analyze the differential expression of miRNAs in peripheral blood mononuclear cells (PBMCs) between untreated secondary syphilis patients and healthy controls and study the correlation between miRNA expression and clinical features with bioinformatics. METHODS: The expression profile of miRNAs was measured by microarray analysis in PBMCs of untreated secondary syphilis patients and healthy controls. Weighted Gene Coexpression Network Analysis (WGCNA) was used to construct the expression of miRNAs and the clinical data of secondary syphilis patients. Gene ontology (GO) and KEGG enrichment analyses were performed on target genes of miR-142-3p. RESULTS: 244 miRNAs exhibited at least 1.0-fold differential expression between secondary syphilis patients and healthy controls. The miRNAs were divided into three modules by WGCNA. The blue module was positively correlated with TPHA, TRUST, duration of disease, and erythema. And in the blue module, the expression of miR-142-3p was significantly higher in secondary syphilis patients than in healthy controls (p = 0.02), which is also close to the clinical features of secondary syphilis. GO and KEGG pathway analyses showed that these target genes of miR-142-3p are correlated with endocytosis and positive regulation of the apoptotic process. CONCLUSION: The elevated miR-142-3p expression in PBMCs may play an important role in the immune response to T. pallidum infection and may be a potential biomarker for secondary syphilis.
Assuntos
Regulação da Expressão Gênica , Genoma Humano , Leucócitos Mononucleares/metabolismo , MicroRNAs/genética , Sífilis/sangue , Sífilis/genética , Adolescente , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Imunidade/genética , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Fenótipo , Mapas de Interação de Proteínas/genética , Sífilis/imunologia , Adulto JovemRESUMO
BACKGROUND: Lung cancer claims more lives than any other cancer worldwide. Lung adenocarcinoma (LUAD) accounts for approximately 40% of all lung cancers. Members of the Transducin-like Enhancer of split (TLE) protein family repress transcription through multiple mechanisms; however, their prognostic value in LUAD is still unclear. METHODS: A dataset from The Cancer Genome Atlas was used to analyze the relationship between the expression of TLE family members and outcomes of LUAD. The expression of TLE family members in 59 normal and 513 tumor samples in the TCGA dataset was selected. For paired analysis, 57 normal and 57 tumor paired tissues were selected. Gene Ontology (GO) term and Reactome pathway enrichment analyses of the TLE family members were performed. Progression-free survival (PFS) and overall survival (OS) served as endpoints in this study. All statistical analyses were performed with R 3.6.0. RESULTS: The expression levels of TLE family proteins differed between 59 normal and 513 tumor samples. High TLE1 and low TLE2 levels were associated with poor progression-free and OS (all P<0.050). Multivariate analysis demonstrated that high TLE1 expression and low TLE2 expression were independent risk factors for a poor outcome in LUAD. Moreover, the combined expression of these two proteins was a good tool for prognostication. CONCLUSIONS: High TLE1 expression and low TLE2 are independent adverse prognostic factors in LUAD and can serve as prognostic biomarkers.
RESUMO
Objective: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of the proximal pulmonary arteries, which result in vascular remodeling of the distal pulmonary artery. While the cellular and molecular mechanisms underlying CTEPH pathogenesis remain incompletely understood, recent evidence implicates vascular remodeling. Here, we identify the molecular mechanisms that contribute to vascular remodeling in CTEPH. Methods: Microarray data (GSE130391) for patients with CTEPH and healthy controls were downloaded from the Gene Expression Omnibus (GEO) and screened for differentially expressed genes (DEGs). DEGs were functionally annotated using Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A protein-protein interaction (PPI) network was constructed to identify hub genes. Finally, pulmonary artery samples were harvested from patients with CTEPH (n = 10) and from controls (n = 10) and primary vascular smooth muscle cells (VSMCs) were cultured. Effects of the proto-oncogene FOS on VSMC proliferation and migration were assessed using expression and knockdown studies. Results: We detected a total of 292 DEGs, including 151 upregulated and 141 downregulated genes. GO analysis revealed enrichment of DEGs in biological processes of signal transduction, response to lipopolysaccharide, signal transduction, and myeloid dendritic cell differentiation. Molecular function analysis revealed enrichment in tumor necrosis factor (TNF)-activated receptor activity, transcriptional activator activity, and protein homodimerization activity. The expression of TNF-α and its receptor (sTNFR1 and sTNFR2) were significantly higher in CTEPH group, compared with control group. KEGG pathway analysis revealed enrichment in salmonella infection, pathways in cancer, osteoclast differentiation, and cytokine-cytokine receptor interaction. Hub genes in the PPI included FOS, suggesting an important role for this gene in vascular remodeling in CTEPH. Primary VSMCs derived from patients with CTEPH showed increased FOS expression and high proliferation and migration, which was attenuated by FOS inhibition. In control VSMCs, TNF-α treatment increased proliferation and migration, which FOS inhibition likewise attenuated. Conclusion: TNF-α drives CTEPH pathogenesis by promoting VSMC proliferation and migration via increased FOS expression. These results advance our understanding of the molecular mechanisms of vascular remodeling in CTEPH, and may inform the development of new therapeutic targets.
RESUMO
BACKGROUND: CPNEs are significant biomarkers which can affect the progression and prognosis of various tumor diseases. However, the prognosis role of CPNEs in multiple myeloma (MM) is still unclear. OBJECTIVES: To investigate the prognosis role of CPNEs in MM. METHODS: Seven hundred and thirty-five samples from two independent data sets were involved to analyze the clinical and molecular characteristics, and prognosis role of the expression of CPNE1-9 in MM. RESULTS: MM patients with higher expressions of CPNE5 and CPNE9 had longer event-free survival (EFS) and overall survival (OS) compared with CPNE5low and CPNE9low expression groups (EFS: P= 0.0054, 0.0065; OS: P= 0.015, 0.016, respectively). Multivariate regression analysis showed that CPNE5 was an independent favorable predictor for EFS and OS (EFS: P= 0.005; OS: P= 0.006), and CPNE9 was an independent positive indicator for EFS (P= 0.002). Moreover, the survival probability and the cumulative event of EFS and OS in CPNE5highCPNE9high group were significantly longer than other groups. CONCLUSIONS: High expressions of CPNE5 and CPNE9 might be used as positive indicators for MM, and their combination was a better predictor for the survival of MM patients.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mieloma Múltiplo/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Immune and stromal component evaluation is necessary to establish accurate prognostic markers for the prediction of clinical outcomes in lung adenocarcinoma (LUAD). We aimed to develop a gene signature based on the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE)-stromal-immune score in LUAD. METHODS: The transcriptomic profiles of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA), and the immune and stromal scores were derived using the ESTIMATE algorithm. The prognostic signature genes were selected from the differentially expressed genes (DEGs) using the robust partial likelihood-based cox proportional hazards regression method. The negative log-likelihood and the Akaike Information Criterion (AIC) were used to identify the optimal gene signature. The validation was carried out in 2 independent datasets from the Gene Expression Omnibus (GSE68571 and GSE72094). RESULTS: Patients with high ESTIMATE, stromal, and immune scores had better overall survivals (P=0.0035, P=0.066, and P=0.0077). The expression of thirty-seven genes was related to ESTIMATE-stromal-immune score. A risk stratification model was developed based on a gene signature containing CD74, JCHAIN, and PTGDS. The ESTIMATE-stromal-immune risk score was revealed to be a prognostic factor (P=0.009) after multivariate analysis. Four groups were classified based on this risk stratification model, yielding increasing survival outcomes (log-rank test, P=0.0051). This risk stratification model and other clinicopathological factors were combined to generate a nomogram. The calibration curves showed perfect agreement between the nomogram-predicted outcomes and those actually observed. Similar observations were made in 2 independent cohorts. CONCLUSIONS: The gene signature based on the ESTIMATE-stromal-immune score could predict the prognosis of patients with LUAD.
RESUMO
BACKGROUND: Early-stage female lung adenocarcinoma is the most common type of lung cancer encountered in thoracic surgery departments. Tumor-node-metastasis (TNM) staging does not adequately explain a significant stratification phenomenon in the prognosis of patients with stage I lung adenocarcinoma. We aimed to investigate the contributory role of miR-940 in the prognosis prediction. METHODS: We analyzed the microRNA (miRNA) expression level in tumor tissues (high-risk group vs. low-risk group) from 12 non-smoking female patients with stage I lung adenocarcinoma using miRNA array. Bioinformatic analyses of miR-940 were also carried out based on the public database. Then, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) tests of the tissue samples were further validated. And miR-940's function was analyzed and potential target genes were predicted. RESULTS: In all, 24 miRNAs were found to be significantly different between the high-risk group and low-risk group. The expression level of miR-940 was lower in tumor tissue (P=0.011), and the survival rate in the high miR-940 group was higher [hazard ratio (HR) =0.688; P=0.011]. Gene Ontology (GO) analysis showed that the assembly functions of targets regulated by miR-940 were mainly enriched in regulation of myeloid cell differentiation, G1/S transition of mitotic cell cycle, and cellular response to environmental stimulus. miR-940 is involved in transforming growth factor-beta (TGF-beta) signaling pathway; TNF signaling pathway; and estrogen signaling pathway. The number of lung adenocarcinoma cells (A549) was significantly decreased after miR-940 was transfected. Ten epithelial-to-mesenchymal-transition (EMT)-associated genes (MMP9, ZEB1, CDH1, KRT8, KRT18 KET19, TWIST1, VIM, SNAI1, and SNAI2) were found to be significantly related to miR-940. CONCLUSIONS: The present study showed that miR-940 might be a protective factor for positive prognosis in early stage nonsmoking female lung adenocarcinoma, with transforming growth factor-beta (TGF-beta) pathway, TNF pathway, and matrix metalloprotein (MMP9) being potential targets.
RESUMO
Multiple myeloma (MM) is a hematologic tumor with monoclonal proliferation of malignant plasma cells in the bone marrow. Fascin (FSCN) is an actin-binding protein that plays a crucial role in cell migration and invasion, contributing to tumor metastasis. There are three members (FSCN1-3) in FSCN family. However, the prognostic role of FSCN family in MM remains unclear. In this study, we used four independent Gene Expression Omnibus (GEO) datasets to explore the relationships between FSCN1-3 expression profiles and patient survival in MM. We found that FSCN1 was dramatically down-regulated in MM compared to normal donors (p < 0.001) and monoclonal gammopathy of undetermined significance (MGUS) (p = 0.032). Patients with high expression of FSCN1 and FSCN2 had significantly longer OS (p = 0.023 and 0.028, respectively). Univariate and multivariate analysis showed that FSCN1 (p = 0.003, 0.002) and FSCN2 (p = 0.018, 0.013) were independent favorable prognostic factors for OS in MM. Moreover, the combination of high expression of FSCN1 and FSCN2 could effectively predict both longer EFS (p = 0.046) and OS (p = 0.015). Our study suggested that FSCN1 and FSCN2 can be used as favorable biomarkers for predicting clinical outcomes in MM.
RESUMO
Multiple myeloma (MM) is a plasma cell malignancy. The minichromosome maintenance (MCM) family involve in DNA replication and is vital in limiting replication in cell cycle. The prognostic role of MCMs in MM is still unclear. We took four independent GEO datasets to analyze the relationship between the expression of MCMs and myeloma progression and survival. The expression of MCMs showed an upward trend with myeloma progression in 205 patients. High MCM2/3/4/6/8 expression was associated with both poor EFS and OS (all p < 0.050). Multivariate analysis demonstrated that high MCM2 expression, B2M, and LDH were independent risk factors. Moreover, the combination of MCM2/B2M and MCM2/LDH was a better tool in prognostication. In conclusion, high MCM2 expression is an independent adverse prognostic factor and could be used as a prognostic biomarker in MM.
Assuntos
Biomarcadores Tumorais/metabolismo , Mieloma Múltiplo/genética , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , PrognósticoRESUMO
Background: Multiple myeloma (MM) is the second most common hematologic malignancy worldwide and does not have sufficient prognostic indicators. FCER1G (Fc fragment Of IgE receptor Ig) is located on chromosome 1q23.3 and is involved in the innate immunity. Early studies have shown that FCER1G participates in many immune-related pathways encompassing multiple cell types. Meanwhile, it is associated with many malignancies. However, the relationship between MM and FCER1G has not been studied. Methods: In this study, we integrated nine independent gene expression omnibus (GEO) datasets and analyzed the associations of FCER1G expression and myeloma progression, ISS stage, 1q21 amplification and survival in 2296 myeloma patients and 48 healthy donors. Results: The expression of FCER1G showed a decreasing trend with the advance of myeloma. As ISS stage and 1q21 amplification level increased, the expression of FCER1G decreased (P = 0.0012 and 0.0036, respectively). MM patients with high FCER1G expression consistently had longer EFS and OS across three large sample datasets (EFS: P = 0.0057, 0.0049, OS: P = 0.0014, 0.00065, 0.0019 and 0.0029, respectively). Meanwhile, univariate and multivariate analysis indicated that high FCER1G expression was an independent favorable prognostic factor for EFS and OS in MM patients (EFS: P = 0.006, 0.027, OS: P =0.002,0.025, respectively). Conclusions: The expression level of FCER1G negatively correlated with myeloma progression, and high FCER1G expression may be applied as a favorable biomarker in MM patients.