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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.

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 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.

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.

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.

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.

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

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

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

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.

Acute myeloid leukemia (AML) is a clonal and heterogeneous disease characterized by proliferation of immature myeloid cells, with impaired differentiation and maturation. Spinster homolog (SPNS) is a widely distributed transmembrane transporter, which assists sphingolipids in playing their roles through the cell membrane. However, the expression and clinical implication of the SPNS family has not been investigated in AML. From the Cancer Genome Atlas database, a total of 155 AML patients with complete clinical characteristics and SPNS1-3 expression data were contained in our study. In patients who received chemotherapy only, high expressions of SPNS2 and SPNS3 had adverse effects on event-free survival (EFS) and overall survival (OS) (all P＜0.05). However, in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) group, we only found a significant difference in OS between the high and low SPNS3 expression groups (P=0.001), while other SPNS members showed no effect on survival. Multivariate analysis indicated that high SPNS2 expression was an independent risk factor for both EFS and OS in chemotherapy patients. The results confirmed that high expression of SPNS2 and SPNS3 were poor prognostic factors, and the effect of SPNS2 can be neutralized by allo-HSCT.

Summary: Ectopic expression of Oct4, Sox2, Klf4, and c-Myc can reprogram differentiated somatic cells into induced pluripotent stem cells (iPSCs). For years, Oct4 has been considered the key reprogramming factor core of the four factors. Here, we challenge this view by reporting a core function of Sox2 and Klf4 in reprogramming. We found that polycistronic expression of Sox2 and Klf4 was sufficient to induce pluripotency in the absence of exogenous Oct4, and the stoichiometry of Sox2 and Klf4 was essential. Sox2 and Klf4 cooperatively bound across the genome, leading to epigenetic remodeling of their targets, including pluripotency genes and gradual activation of the pluripotency network. Interestingly, cells of different germ layer origins, fibroblasts (mesoderm) and neural progenitor cells (ectoderm), showed convergent reprogramming trajectories and similar efficiency. This work demonstrates a core function of Sox2 and Klf4 in pluripotency induction and shows that this mechanism is independent of germ layer origin. : An et al. report that polycistronic Sox2 and Klf4 induced pluripotency in multiple cell types, and the factor stoichiometry and cooperativity are essential for pluripotency network activation. This work demonstrates a core function of Sox2 and Klf4 in pluripotency induction and a mechanism independent of germ layer origin. Keywords: stoichiometry, cooperativity, reprogramming, Sox2, Klf4, pluripotency

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.

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

DOCK family proteins are evolutionarily conserved guanine nucleotide exchange factors for Rho GTPase with different cellular functions. It has been demonstrated that DOCK1 had adverse prognostic effect in acute myeloid leukemia (AML). We first analyzed data of 85 AML patients who were treated with chemotherapy and had available DOCK1 to DOCK11 expression information and found that DOCK1 and DOCK2 had prognostic significance in AML. In view of the known prognosis of DOCK1 in AML, we then explored the prognostic role of DOCK2. One hundred fifty-six AML patients with DOCK2 expression data were extracted from The Cancer Genome Atlas (TCGA) database and enrolled in this study. Patients were divided based on treatment modality into the chemotherapy group and the allogeneic hematopoietic stem cell transplant (allo-HSCT) group. Each group was divided into two groups by the median expression levels of DOCK2. In the chemotherapy group, high DOCK2 expression was associated with longer event-free survival (EFS, P=0.001) and overall survival (OS, P=0.007). In the allo-HSCT group, EFS and OS were not significantly different between high and low DOCK2 expression groups. Multivariate analysis showed that high DOCK2 expression was an independent favorable prognostic factor for both EFS and OS in all patients (all P

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.

Background Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Transducin-like Enhancer of split (TLE) family proteins repress transcription by multiple mechanisms. The prognostic role of TLEs in LUAD is still unclear. Methods We took TCGA dataset to analyze the relationship between the expression of TLEs and LUAD outcome. Results The expression of TLEs were different between 59 normal and 513 tumor samples. High TLE1 and low TLE2 were associated with poor PFS and OS (all p＜0.050). Multivariate analysis demonstrated that high TLE1 and low TLE2 were independent risk factors. Moreover, the combination of TLE1 and TLE2 was a better tool in prognostication. Conclusions High TLE1 and low TLE2 expressions are independent adverse prognostic factors and can be used as prognostic biomarkers in LUAD.

Genetic abnormalities are more frequently viewed as prognostic markers in acute myeloid leukemia (AML) in recent years. Fucosylation, catalyzed by fucosyltransferases (FUTs), is a post-translational modification that widely exists in cancer cells. However, the expression and clinical implication of the FUT family (FUT1-11) in AML has not been investigated. From the Cancer Genome Atlas database, a total of 155 AML patients with complete clinical characteristics and FUT1-11 expression data were included in our study. In patients who received chemotherapy alone showed that high expression levels of FUT3, FUT6, and FUT7 had adverse effects on event-free survival (EFS) and overall survival (OS) (all P

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., Graphical abstract Unlabelled Image

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

ObjectivesCarotid artery geometry influences blood flow disturbances and is thus an important risk factor for carotid atherosclerosis. Extracellular matrix (ECM) and yes-associated protein (YAP) expression may play essential roles in the pathophysiology of carotid artery stenosis, but the effect of blood flow disturbances of carotid bifurcation location on the ECM is unknown. We hypothesized that carotid artery anatomy and geometry are independently associated with the ECM and YAP expression.MethodsIn this cross-sectional study, 193 patients were divided into two groups: an asymptomatic group (n = 111) and a symptomatic group (n = 82), symptomatic patients presenting with ischemic attack, amaurosis fugax, or minor non-disabling stroke. For all subjects before surgery, carotid bifurcation angle and internal artery angle were measured with computed tomography angiography (CTA), and laminar shear stress was measured with ultrasonography. After surgery, pathology of all plaque specimens was analyzed using hematoxylin and eosin (HE) staining and Movat special staining. Immunohistochemistry was performed to detect expression of YAP in a subset of 30 specimens.ResultsSymptomatic patients had increased carotid bifurcation angle and laminar shear stress compared to asymptomatic patients (P < 0.05), although asymptomatic patients had increased internal carotid angle compared to symptomatic patients (P < 0.001). Relative higher bifurcation angles were correlated with increased carotid bifurcation, decreased internal angle, and decreased laminar shear stress. For each change in intervertebral space or one-third of vertebral body height, carotid bifurcation angle changed 4.76°, internal carotid angle changed 6.91°, and laminar shear stress changed 0.57 dynes/cm2. Pathology showed that average fibrous cap thickness and average narrowest fibrous cap thickness were greater in asymptomatic patients than symptomatic patients (P < 0.05). Expression of proteoglycan and YAP protein in symptomatic patients was higher than in asymptomatic patients (P < 0.001), while collagen expression was lower in symptomatic patients than asymptomatic patients (P < 0.05).ConclusionGeometry of the carotid artery and position relative to cervical spine might be associated with ECM and YAP protein expression, which could contribute to carotid artery stenosis.

Irritable bowel syndrome (IBS) is a common gastrointestinal dysfunctional disease. The pathophysiology of IBS is, however, largely unknown. This study aimed to determine whether evaluation of fecal metabolite and microbiota profiles may offer an opportunity to identify a novel pathophysiological target for IBS, and to reveal possible gut microbe–metabolite associations. By using gas chromatography coupled to time-of-flight mass spectrometry (GC-TOFMS) and 16S rRNA gene sequencing, we measured fecal metabolites and microbiota of the control and water avoidance stress (WAS)-induced IBS rats. We found a significantly differential metabolite profile between the IBS and control groups; a cluster of metabolites was also found to be significantly associated with the amount of defecations. Moreover, the WAS group exhibited a decreased alpha diversity of the microbial population as compared to the control group. However, the characteristics of gut microbiota could not differentiate the IBS group from the control group. Correlation of the metabolite level with the number of microbial genera showed no significant association between the control and IBS groups. This study provides a global perspective on metabolomics and microbiota profiling in WAS-induced IBS model and a theoretical basis for research on the pathophysiology of IBS.