SPHK1 Promotes Pancreatic Cancer Lymphangiogenesis Through the Activation of ERK in LECs.

Lymphatic metastasis is related to an unsatisfactory prognosis in pancreatic cancer. Sphingosine kinase 1 (SPHK1) is an oncogene in cancer. However, the potential effect of SPHK1 on the lymphangiogenesis of pancreatic cancer is little known. In this study, the expression level and role of SPHK1 in pancreatic cancer were evaluated to explore the underlying mechanism involved. The expression of SPHK1 and the lymphatic vessel density (LVD) in pancreatic cancer patient tissue were investigated by immunohistochemistry. The role of SPHK1 in lymphangiogenesis was verified in vitro. Elevated expression of SPHK1 was strongly related to high LVD in pancreatic cancer patient tissue. Silencing of SPHK1 in pancreatic cancer cells observably inhibited lymphangiogenesis. Furthermore, the downregulation of SPHK1 markedly attenuated the phosphorylation of extracellular signal-regulated kinase in lymphatic endothelial cells. This study revealed that SPHK1 might play a crucial role in pancreatic cancer lymphangiogenesis.

Common Methods for Phylogenetic Tree Construction and Their Implementation in R.

A phylogenetic tree can reflect the evolutionary relationships between species or gene families, and they play a critical role in modern biological research. In this review, we summarize common methods for constructing phylogenetic trees, including distance methods, maximum parsimony, maximum likelihood, Bayesian inference, and tree-integration methods (supermatrix and supertree). Here we discuss the advantages, shortcomings, and applications of each method and offer relevant codes to construct phylogenetic trees from molecular data using packages and algorithms in R. This review aims to provide comprehensive guidance and reference for researchers seeking to construct phylogenetic trees while also promoting further development and innovation in this field. By offering a clear and concise overview of the different methods available, we hope to enable researchers to select the most appropriate approach for their specific research questions and datasets.

Extended Clopidogrel Monotherapy vs DAPT in Patients With Acute Coronary Syndromes at High Ischemic and Bleeding Risk: The OPT-BIRISK Randomized Clinical Trial.

Importance: Purinergic receptor P2Y12 (P2Y12) inhibitor monotherapy after a certain period of dual antiplatelet therapy (DAPT) may be an attractive option of maintenance antiplatelet treatment for patients undergoing percutaneous coronary intervention (PCI) who are at both high bleeding and ischemic risk (birisk). Objective: To determine if extended P2Y12 inhibitor monotherapy with clopidogrel is superior to ongoing DAPT with aspirin and clopidogrel after 9 to 12 months of DAPT after PCI in birisk patients with acute coronary syndromes (ACS). Design, Setting, and Participants: This was a multicenter, double-blind, placebo-controlled, randomized clinical trial including birisk patients with ACS who had completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months at 101 China centers between February 2018 and December 2020. Study data were analyzed from April 2023 to May 2023. Interventions: Patients were randomized either to clopidogrel plus placebo or clopidogrel plus aspirin for an additional 9 months. Main Outcomes and Measures: The primary end point was Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding 9 months after randomization. The key secondary end point was major adverse cardiac and cerebral events (MACCE; the composite of all-cause death, myocardial infarction, stroke or clinically driven revascularization). The primary end point was tested for superiority, and the MACCE end point was tested for sequential noninferiority and superiority. Results: A total of 7758 patients (mean [SD] age, 64.8 [9.0] years; 4575 male [59.0%]) were included in this study. The primary end point of BARC types 2, 3, or 5 bleeding occurred in 95 of 3873 patients (2.5%) assigned to clopidogrel plus placebo and 127 of 3885 patients (3.3%) assigned to clopidogrel plus aspirin (hazard ratio [HR], 0.75; 95% CI, 0.57-0.97; difference, -0.8%; 95% CI, -1.6% to -0.1%; P = .03). The incidence of MACCE was 2.6% (101 of 3873 patients) in the clopidogrel plus placebo group and 3.5% (136 of 3885 patients) in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96; difference, -0.9%; 95% CI, -1.7% to -0.1%; P < .001 for noninferiority; P = .02 for superiority). Conclusions and Relevance: Among birisk patients with ACS who completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months before randomization, an extended 9-month clopidogrel monotherapy regimen was superior to continuing DAPT with clopidogrel in reducing clinically relevant bleeding without increasing ischemic events. Trial Registration: ClinicalTrials.gov Identifier: NCT03431142.

Neural Radiance Fields-Based 3D Reconstruction of Power Transmission Lines Using Progressive Motion Sequence Images.

To address the fuzzy reconstruction effect on distant objects in unbounded scenes and the difficulty in feature matching caused by the thin structure of power lines in images, this paper proposes a novel image-based method for the reconstruction of power transmission lines (PTLs). The dataset used in this paper comprises PTL progressive motion sequence datasets, constructed by a visual acquisition system carried by a developed Flying-walking Power Line Inspection Robot (FPLIR). This system captures close-distance and continuous images of power lines. The study introduces PL-NeRF, that is, an enhanced method based on the Neural Radiance Fields (NeRF) method for reconstructing PTLs. The highlights of PL-NeRF include (1) compressing the unbounded scene of PTLs by exploiting the spatial compression of normal L∞; (2) encoding the direction and position of the sample points through Integrated Position Encoding (IPE) and Hash Encoding (HE), respectively. Compared to existing methods, the proposed method demonstrates good performance in 3D reconstruction, with fidelity indicators of PSNR = 29, SSIM = 0.871, and LPIPS = 0.087. Experimental results highlight that the combination of PL-NeRF with progressive motion sequence images ensures the integrity and continuity of PTLs, improving the efficiency and accuracy of image-based reconstructions. In the future, this method could be widely applied for efficient and accurate 3D reconstruction and inspection of PTLs, providing a strong foundation for automated monitoring of transmission corridors and digital power engineering.

Hyper-Null Models and Their Applications.

Null models are crucial tools for investigating network topological structures. However, research on null models for higher-order networks is still relatively scarce. In this study, we introduce an innovative method to construct null models for hypergraphs, namely the hyperedge swapping-based method. By preserving certain network properties while altering others, we generate six hyper-null models with various orders and analyze their interrelationships. To validate our approach, we first employ hypergraph entropy to assess the randomness of these null models across four datasets. Furthermore, we examine the differences in important statistical properties between the various null models and the original networks. Lastly, we investigate the impact of hypergraph randomness on network dynamics using the proposed hyper-null models, focusing on dismantling and epidemic contagion. The findings show that our proposed hyper-null models are applicable to various scenarios. By introducing a comprehensive framework for generating and analyzing hyper-null models, this research opens up avenues for further exploration of the intricacies of network structures and their real-world implications.

Neodymium affects the generation of reactive oxygen species via GSK-3ß/Nrf2 signaling in the gill of zebrafish.

Rare earth element neodymium (Nd) is widely used in industry and agriculture, which may result in the pollution of aquatic environment. In this study, we exposed zebrafish with 10, 50, and 100 µg/L Nd for four weeks. The results showed that Nd could be accumulated in fish gill and Nd accumulation affected the equilibrium of nutrient elements. Nd decreased the antioxidant enzymes' activity and gene expression level, but enhanced the generation of reactive oxygen species (ROS). Moreover, various concentration of Nd treatments inhibited Nrf2 signaling in gill. To examine the critical role of GSK-3ß/Nrf2 signaling on ROS generation under Nd stress, we further interfered gsk-3ß gene in zebrafish under 100 µg/L Nd exposure. The result showed that gsk-3ß gene interference induced Nrf2 signaling as well as the expression and activity of antioxidant enzymes in fish gill. In all, Nd could be accumulated in fish gill, and the signaling of GSK-3ß/Nrf2 was involved in regulating ROS generation under Nd treatments.

A case of unexpected death due to primary angiitis of the central nervous system.

Primary angiitis of the central nervous system (PACNS) is a rare and fatal cerebral vasculitis mainly involving the arteriole of the pia mater, cerebral cortex, and spinal cord. It has an insidious onset atypical symptoms. In this paper, we reported an unexpected death due to cerebral hemorrhage caused by PACNS. According to the typical clinical manifestations (headache, dizziness, weakness of the limbs, temporary blurred vision, etc.) and pathological examination (wide degeneration and fibrinoid necrosis of blood vessel walls with inflammatory cell infiltration), as well as hematoxylin-eosin staining, immunohistochemistry for CD15 + and gram staining, we finally determined that the patient died due to cerebral vascular rupture and hemorrhage caused by PACNS. This case illustrates the value and key points of autopsy in evaluating sudden deaths.

CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy.

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.

Computational drug repurposing by exploiting large-scale gene expression data: Strategy, methods and applications.

De novo drug development is an extremely complex, time-consuming and costly task. Urgent needs for therapies of various diseases have greatly accelerated searches for more effective drug development methods. Luckily, drug repurposing provides a new and effective perspective on disease treatment. Rapidly increased large-scale transcriptome data paints a detailed prospect of gene expression during disease onset and thus has received wide attention in the field of computational drug repurposing. However, how to efficiently mine transcriptome data and identify new indications for old drugs remains a critical challenge. This review discussed the irreplaceable role of transcriptome data in computational drug repurposing and summarized some representative databases, tools and strategies. More importantly, it proposed a practical guideline through establishing the correspondence between three gene expression data types and five strategies, which would facilitate researchers to adopt appropriate strategies to deeply mine large-scale transcriptome data and discover more effective therapies.

Identification of Differentially Expressed Genes and Prediction of Expression Regulation Networks in Dysfunctional Endothelium.

The detection of early coronary atherosclerosis (ECA) is still a challenge and the mechanism of endothelial dysfunction remains unclear. In the present study, we aimed to identify differentially expressed genes (DEGs) and the regulatory network of miRNAs as well as TFs in dysfunctional endothelium to elucidate the possible pathogenesis of ECA and find new potential markers. The GSE132651 data set of the GEO database was used for the bioinformatic analysis. Principal component analysis (PCA), the identification of DEGs, correlation analysis between significant DEGs, the prediction of regulatory networks of miRNA and transcription factors (TFs), the validation of the selected significant DEGs, and the receiver operating characteristic (ROC) curve analysis as well as area under the curve (AUC) values were performed. We identified ten genes with significantly upregulated signatures and thirteen genes with significantly downregulated signals. Following this, we found twenty-two miRNAs regulating two or more DEGs based on the miRNA-target gene regulatory network. TFs with targets ≥ 10 were E2F1, RBPJ, SSX3, MMS19, POU3F3, HOXB5, and KLF4. Finally, three significant DEGs (TOX, RasGRP3, TSPAN13) were selected to perform validation experiments. Our study identified TOX, RasGRP3, and TSPAN13 in dysfunctional endothelium and provided potential biomarkers as well as new insights into the possible molecular mechanisms of ECA.

Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p.

INTRODUCTION: Neuroendocrine differentiation (NED) in colorectal cancer (CRC) cells has been known for decades, and our previous meta-analysis indicated that CRC patients with neuroendocrine differentiation have a lower 5-year survival rate. In recent years, an increasing number of studies have found that exosome-derived long non-coding RNAs (lncRNAs) play important roles in cancer progression and metastasis. However, the functions and mechanism of exosome-derived lncRNAs in CRC with neuroendocrine differentiation are not yet fully clear. MATERIALS AND METHODS: The clinical significance of NED was assessed in a retrospective study of 105 patients. Next-generation sequencing and bioinformatics analysis were conducted to select lnc-HOXB8-1:2 for further study. Using immunohistochemistry, qRT-PCR, western blot, transwell assay, immunofluorescence assay, fluorescence in situ hybridization assay and dual-luciferase reporter assay, the oncogenic role of exosome-derived lnc-HOXB8-1:2 was determined in CRC with NED. The mechanism underlying the lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was also explored. RESULTS: NED was a risk factor for the progression and mortality of CRC. lnc-HOXB8-1:2, derived from exosomes secreted by neuroendocrine differentiated colon cancer cells, was identified in our study. The proportion of M2 macrophages and the migration and invasion capacities of tumor-associated macrophages (TAMs) markedly increased after the addition of neuroendocrine differentiated CRC cell-derived exosomes. More excitingly, the expression of lnc-HOXB8-1:2 and the protein level of CXCR3 were also upregulated in TAMs. The lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was predicted via miRanda software and confirmed by the dual-luciferase reporter assay. Furthermore, the increased expression of lnc-HOXB8-1:2 was accompanied by downregulation of hsa-miR-6825-5p expression and upregulation of CXCR3 protein levels. Overexpression of hsa-miR-6825-5p also reduced CXCR3 expression. CONCLUSION: lnc-HOXB8-1:2 in exosomes derived from neuroendocrine differentiated CRC cells acted as a ceRNA competitively binding hsa-miR-6825-5p to upregulate CXCR3 expression and leading to TAM infiltration and M2 polarization, which promotes neuroendocrine differentiated CRC progression.

A Novel Auto-Synthesis Dataset Approach for Fitting Recognition Using Prior Series Data.

To address power transmission line (PTL) traversing complex environments leading to data collection being difficult and costly, we propose a novel auto-synthesis dataset approach for fitting recognition using prior series data. The approach mainly includes three steps: (1) formulates synthesis rules by the prior series data; (2) renders 2D images based on the synthesis rules utilizing advanced virtual 3D techniques; (3) generates the synthetic dataset with images and annotations obtained by processing images using the OpenCV. The trained model using the synthetic dataset was tested by the real dataset (including images and annotations) with a mean average precision (mAP) of 0.98, verifying the feasibility and effectiveness of the proposed approach. The recognition accuracy by the test is comparable with training by real samples and the cost is greatly reduced to generate synthetic datasets. The proposed approach improves the efficiency of establishing a dataset, providing a training data basis for deep learning (DL) of fitting recognition.

Methylated septin 9 gene is an important prognostic marker in stage II and stage III colorectal cancer for evaluating local recurrence or distant metastasis after surgery.

BACKGROUND: Abnormal hypermethylation of the septin 9 gene was an inchoate incident in some cancers. Though latest several researches had paid attention to its value in prognosis, the consequences were not distinctly, especially in colorectal cancer (CRC) with stage II and stage III. PURPOSE: The aim of this research was to pick up the prognostic value of the methylated septin 9 gene (mSEPT9) in CRC patients, particularly in TNM stage II-III. METHODS: Blood samples before surgery were obtained from 144 CRC patients, of which there were 94 with stage II and stage III. mSEPT9 was considered positive when the cycle number of the peak reaction (Ct) was lower than the threshold value (41.0) for two times during three times PCR test. mSEPT9 and other relative factors of prognosis were estimated by survival analysis. The level of septin 9 in tissues was tested by immunohistochemical (IHC). RESULTS: Stage II and stage III patients with mSEPT9 positive (mSEPT9+) had a lower disease-free survival (DFS) rate than those with mSEPT9 negative (mSEPT9-) (2-year DFS rates, 52.1% vs 73.9%, P = 0.014). In multivariate regression analysis, mSEPT9 was also an independent predictor of prognosis (HR = 2.741, P = 0.009). The risk of local recurrence or distant metastasis in CRC patients after surgery was mSEPT9+ with stage III, mSEPT9- with stage III/mSEPT9+ with stage II, and mSEPT9- with stage II (P = 0.001), from highest to lowest. In addition, mSEPT9 was strongly associated with TNM staging, tumor immersion depth, distant metastasis, differentiation degree, vascular invasion and microsatellite. When we explored the associations between septin 9 protein level revealed by IHC and other elements, recurrence/progression (R = - 0.523, P = 0.001), mSEPT9 status (R = - 0.451, P = 0.004) and T stage (R = - 0.375, P = 0.017) showed significant correlations. CONCLUSIONS: Positive mSEPT9 is a poor prognostic marker for CRC patients in stage II and III. It is also a powerful complement to TNM staging in predicting postoperative DFS of CRC patients of stage II and III.

Multi-objective optimization of water resources allocation in Han River basin (China) integrating efficiency, equity and sustainability.

The hydrological cycle, affected by climate change and rapid urbanization in recent decades, has been altered to some extent and further poses great challenges to three key factors of water resources allocation (i.e., efficiency, equity and sustainability). However, previous studies usually focused on one or two aspects without considering their underlying interconnections, which are insufficient for interaction cognition between hydrology and social systems. This study aims at reinforcing water management by considering all factors simultaneously. The efficiency represents the total economic interests of domesticity, industry and agriculture sectors, and the Gini coefficient is introduced to measure the allocation equity. A multi-objective water resources allocation model was developed for efficiency and equity optimization, with sustainability (the river ecological flow) as a constraint. The Non-dominated sorting genetic algorithm II (NSGA-II) was employed to derive the Pareto front of such a water resources allocation system, which enabled decision-makers to make a scientific and practical policy in water resources planning and management. The proposed model was demonstrated in the middle and lower Han River basin, China. The results indicate that the Pareto front can reflect the conflicting relationship of efficiency and equity in water resources allocation, and the best alternative chosen by cost performance method may provide rich information as references in integrated water resources planning and management.

The genomic history of southwestern Chinese populations demonstrated massive population migration and admixture among proto-Hmong-Mien speakers and incoming migrants.

Southwest China was the crossroad for the initial settler people of East Asia, which shows the highest diversity in languages and genetics. This region played a significant role in the formation of the genetic makeup of the proto-Hmong-Mien-speaking people and in the north-to-south human expansion during the Neolithic-to-historic transformation. Their genetic history covering migration events and the admixture processes still needs to be further explored. Therefore, in the current study, we have generated genome-wide data from three genomic aspects covering autosomal, mitochondrial and Y-chromosomal regions in 260 Hmong-Mien, Tibeto-Burman, and Sinitic people from 29 different southwestern Chinese groups, and further analyzed them with 2676 published modern and ancient Eurasian genomes. Here, we have noticed a new southwestern East Asian genetic cline composed of the Hmong-Mien-specific ancestry enriched in modern Hmong and Pathen. This newly identified southern inland East Asian lineage contributed to a great extent of the gene pool in the modern southern East Asians. We also have observed genetic substructure among Hmong-Mien-speaking populations. The southern Hmong-Mien-speaking people showed more genetic affinity with modern Tai-Kadai/Austroasiatic people, while the northern Hmong-Mien speakers expressed a closer genetic connection with the Neolithic-to-modern northern East Asians. Moreover, southwestern Sinitic populations had a strong genomic affinity with the adjacent Hmong-Mien-speaking populations and the lowlander Tibeto-Burman-speaking populations, which suggested the large-scale genetic admixture occurred between them. Allele-sharing-based qpAdm/qpGraph results further confirmed that all included southwestern Chinese populations could be modeled as a mixed result of the major ancestry component from the northern millet farmers in the Yellow River basin and the minor ancestry component from the southern rice farmers in the Yangtze River basin. Usually, this newly identified Hmong-Mien-associated southern East Asian ancestry could improve our understanding of the full-scale genetic landscape of the evolutionary and admixture history of southwestern East Asians. Further ancient genomic studies from southeastern China are required to shed deeper light on our established phylogeny context.

A reliable tool for detecting 7-dehydrocholesterol and cholesterol in human plasma and its use in diagnosis of Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome is a birth defect caused by the deficiency of 7-dehydrocholesterol reductase in cholesterol biosynthesis pathway, which leads to accumulation of 7-dehydrocholesterol and reduction of cholesterol in body fluids. To effectively diagnose Smith-Lemli-Opitz syndrome and monitor therapy, a reliable method for simultaneous detection of 7-dehydrocholesterol and cholesterol is needed. METHODS: In the presence of antioxidants (2,6-ditert-butyl-4-methylphenol and triphenylphosphine), 50 µL of human plasma were hydrolyzed at 70℃ for 40 min with 1 M potassium hydroxide in 90% ethanol, and then 7-dehydrocholesterol and cholesterol were extracted by 600 µL of n-hexane for three times. After microwave-assisted derivatization with 70 µL of N,O-bis(trimethylsilyl)trifluoroacetamide at 460 W for 3 min, the analytes were measured by gas chromatography-mass spectrometry. RESULTS: The limits of detection were 100 ng/mL for 7-dehydrocholesterol and 300 ng/mL for cholesterol. Good linearity was obtained in the range of 1-600 µg/mL for 7-dehydrocholesterol and 10-600 µg/mL for cholesterol, which completely covered the biochemical levels of Smith-Lemli-Opitz syndrome patients that have been reported. CONCLUSION: A time-saving and accurate gas chromatography with mass spectrometry based method was developed for the determination of 7-dehydrocholesterol and cholesterol in human plasma, which also serves as a useful tool for Smith-Lemli-Opitz syndrome diagnosis, treatment, and research.

Circular RNA circHERC4 as a novel oncogenic driver to promote tumor metastasis via the miR-556-5p/CTBP2/E-cadherin axis in colorectal cancer.

BACKGROUND: The main cause of death in colorectal cancer patients is metastasis. Accumulating evidences suggest that circRNA plays pivotal roles in cancer initiation and development. However, the underlying molecular mechanisms of circRNAs that orchestrate cancer metastasis remain vague and need further clarification. METHODS: Two paired CRC and adjacent normal tissues were used to screen the upregulated circRNAs by circRNA-seq; then, cell invasion assay was applied to confirm the functional invasion-related circRNAs. According to the above methods, circHERC4 (hsa_circ_0007113) was selected for further research. Next, we investigated the clinical significance of circHERC4 in a large cohort of patients with CRC. The oncogenic activity of circHERC4 was investigated in both CRC cell lines and animal xenograft studies. Finally, we explored the molecular mechanisms underlying circHERC4 as a malignant driver. RESULTS: We demonstrated that circHERC4 was aberrantly elevated in CRC tissues (P < 0.001), and was positively associated with lymph node metastasis and advanced tumor grade (P < 0.01). Notably, the expression of circHERC4 was associated with worse survival in patients with CRC. Silencing of circHERC4 significantly inhibited the proliferation and migration of two highly aggressive CRC cell lines and reduced liver and lung metastasis in vivo. Mechanistically, we revealed that circHERC4 inactivated the tumor suppressor, miR-556-5p, leading to the activation of CTBP2/E-cadherin pathway which promotes tumor metastasis in CRC. CONCLUSIONS: CircHERC4 exerts critical roles in promoting tumor aggressiveness through miR-556-5p/CTBP2/E-cadherin pathway and is a prognostic biomarker of the disease, suggesting that circHERC4 may serve as an exploitable therapeutic target for patients with CRC.

DNA Methylation Regulator-Meditated Modification Patterns Define the Distinct Tumor Microenvironment in Lung Adenocarcinoma.

BACKGROUND: Epigenetic changes of lung adenocarcinoma (LUAD) have been reported to be a relevant factor in tumorigenesis and cancer progression. However, the molecular mechanisms responsible for DNA methylation patterns in the tumor immune-infiltrating microenvironment and in cancer immunotherapy remain unclear. METHODS: We conducted a global analysis of the DNA methylation modification pattern (DMP) and immune cell-infiltrating characteristics of LUAD patients based on 21 DNA methylation regulators. A DNA methylation score (DMS) system was constructed to quantify the DMP model in each patient and estimate their potential benefit from immunotherapy. RESULTS: Two DNA methylation modification patterns able to distinctly characterize the immune microenvironment characterization were identified among 513 LUAD samples. A lower DMS, characterized by increased CTLA-4/PD-1/L1 gene expression, greater methylation modifications, and tumor mutation burden, characterized a noninflamed phenotype with worse survival. A higher DMS, characterized by decreased methylation modification, a greater stromal-relevant response, and immune hyperactivation, characterized an inflamed phenotype with better prognosis. Moreover, a lower DMS indicated an increased mutation load and exhibited a poor immunotherapeutic response in the anti-CTLA-4/PD-1/PD-L1 cohort. CONCLUSION: Evaluating the DNA methylation modification pattern of LUAD patients could enhance our understanding of the features of tumor microenvironment characterization and may promote more favorable immunotherapy strategies.

The mechanisms of colorectal cancer cell mesenchymal-epithelial transition induced by hepatocyte exosome-derived miR-203a-3p.

BACKGROUND: Liver metastasis is the most common cause of death in patients with colorectal cancer (CRC). Phosphatase of regenerating liver-3 induces CRC metastasis by epithelial-to-mesenchymal transition, which promotes CRC cell liver metastasis. Mesenchymal-to-epithelial transition (MET), the opposite of epithelial-to-mesenchymal transition, has been proposed as a mechanism for the establishment of metastatic neoplasms. However, the molecular mechanism of MET remains unclear. METHODS: Using Immunohistochemistry, western blotting, invasion assays, real-time quantitative PCR, chromatin immunoprecipitation, luciferase reporter assays, human miRNA arrays, and xenograft mouse model, we determined the role of hepatocyte exosome-derived miR-203a-3p in CRC MET. RESULTS: In our study, we found that miR-203a-3p derived from hepatocyte exosomes increased colorectal cancer cells E-cadherin expression, inhibited Src expression, and reduced activity. In this way miR-203a-3p induced the decreased invasion rate of CRC cells. COCLUSION: MiR-203a-3p derived from hepatocyte exosomes plays an important role of CRC cells to colonize in liver.

Identification of a 3-gene signature for predicting the prognosis of stage II colon cancer based on microsatellite status.

BACKGROUND: Though colon cancer (CC) is one of the most malignant tumors across the world, CC patients with microsatellite instability-high (MSI-H) in stage II seem to have a better prognosis. However, the molecular mechanisms underlying the phenomena haven't been elucidated yet. METHODS: This study enrolled 322 CCs with known microsatellite status from GSE143985, GSE39582 and GSE92921 in the Gene Expression Omnibus (GEO) database. Robust rank aggregation (RRA) analysis, univariate Cox regression analysis and multivariate Cox stepwise regression analysis were performed to identify genes and construct risk score signature. Kaplan-Meier and receiver operating characteristic (ROC) curves analyses were used to evaluate the prognostic value of the signature. The potential mechanisms underlying this signature were assessed in the Metascape database, gene set enrichment analysis (GSEA) and immune infiltration analysis. RESULTS: RRA analysis identified 40 differently expressed genes (DEGs). A 3-gene risk score signature (MKQ signature) associated with disease-free survival (DFS) was generated. DFS was significantly longer in CC patients with lower than higher scores (P=0.0046). The areas under curves (AUCs) of the time-dependent ROC curves of MKQ signature at 1-, 3- and 5-year DFS were 1, 0.963 and 0.961 respectively. Recurrence-free survival (RFS) was significantly longer in patients in GSE39582 with lower than higher risk scores (P=0.032). The AUCs for 1-, 3- and 5-year RFS in GSE39582 were 0.63, 0.618 and 0.583, respectively, validating the value of the MKQ signature. Functional annotation and GSEA revealed that the MKQ signature was associated with multiple immune-related pathways. Immune cell infiltration was found to differ in patients differing in the MKQ signature. CONCLUSIONS: Gene expression and microsatellite status identified a 3-gene signature (MKQ signature) that could facilitate risk-stratified management in patients with stage II CC. Dysregulation of MSMB, KRT23, and QPRT can serve as prognostic markers in stage II CC.