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With the development of wireless communication technology and the rapid increase of user data, multi-server key agreement authentication scheme has been widely used. In order to protect users’ privacy and legitimate rights, a two-factor multi-server authentication scheme based on device PUF and users’ biometrics is proposed. The users’ biometrics are combined with the physical characteristics of the Physically Unclonable Functions (PUF) as authentication factors, which not only ensures the security of the scheme, but it also is user-friendly without a password. The proposed scheme can be applied to telemedicine, smart home, Internet of Vehicles and other fields to achieve mutual authentication and key agreement between users and servers. In order to prove the security of the proposed scheme, the widely accepted ROR model and BAN logic are used for formal security analysis. The scheme can effectively resist various security attacks, and the comparison with existing schemes shows that it has better performance in terms of communication cost and computational complexity.

Background. Spinal cord injury (SCI) is known to cause a more robust systemic inflammatory response than general trauma without CNS injury, inducing severe secondary organ damage, especially the lung and liver. Related studies are principally focused on the mechanisms underlying repair and regeneration in the injured spinal cord tissue. However, the specific mechanism of secondary injury after acute SCI is widely overlooked, compared with general trauma. Methods. Two datasets of GSE151371 and GSE45376 related to the blood samples and spinal cord after acute SCI were selected to identify the differentially expressed genes (DEGs). In GSE151371, functional enrichment analysis on specific DEGs of blood samples was performed. And the top 15 specific hub genes were identified from intersectional genes between the specific upregulated DEGs of blood samples in GSE151371 and the upregulated DEGs of the spinal cord in GSE45376. The specific functional enrichment analysis and the drug candidates of the hub genes and the miRNAs-targeted hub genes were also analyzed and predicted. Results. DEGs were identified, and a total of 64 specific genes were the intersection of upregulated genes of the spinal cord in GSE45376 and upregulated genes of human blood samples in GSE151371. The top 15 hub genes including HP, LCN2, DLGAP5, CEP55, HMMR, CDKN3, PRTN3, SKA3, MPO, LTF, CDC25C, MMP9, NEIL3, NUSAP1, and CD163 were calculated from the 64 specific genes. Functional enrichment analysis of the top 15 hub genes revealed inflammation-related pathways. The predicted miRNAs-targeted hub genes and drug candidates of hub genes were also performed to put forward reasonable treatment strategies. Conclusion. The specific hub genes of acute SCI as compared with trauma without CNS injury were identified. The functional enrichment analysis of hub genes showed a specific immune response. Several predicted drugs of hub genes were also obtained. The hub genes and the predicted miRNAs may be potential biomarkers and therapeutic targets and require further validation.

KRAS proto-oncogene, GTPase (KRAS)-mutant metastatic colorectal cancer (mCRC) lacks targeted therapy because the underlying mechanism remains obscure. Based on bioinformatic analysis, this study aims to elucidate a potential gene target for which an approved drug is available , and to further reveal the function as well as the underlying mechanism of the candidate gene. Here, we identified that ryanodine receptor 2 (RyR2) expression was upregulated in KRAS-mutant mCRC, and that this promoted cancer cell metastasis. S107, an approved drug to inhibit calcium release from RyR2 in the clinic, inhibited cancer cell metastasis both in vitro and in vivo. High expression of RyR2 predicts poor survival in our patient cohort. CRC patients with serosa invasion and vascular tumor thrombus are characterized by high RyR2 expression. Analysis of expression profiles upon RyR2 knockdown and inhibition reveals a set of metastasis-related molecules, and identifies BTB domain and CNC homolog 1 (BACH1) as the main transcription factor regulated by RyR2. RyR2 regulates cellular reactive oxygen species (ROS) levels, which activates nuclear factor erythroid 2-related factor 2 (Nrf2; also known as NFE2L2) and HMOX1 expression, and thus BACH1 accumulation. Collectively, this study provides evidence that the RyR2/ROS/BACH1 axis may be a potential target to intervene with CRC metastasis.

Increasingly, individuals and companies adopt a cloud service provider as a primary data and IT infrastructure platform. The remote access of the data inevitably brings the issue of trust. Data encryption is necessary to keep sensitive information secure and private on the cloud. Yet adversaries can still learn valuable information regarding encrypted data by observing data access patterns. To solve such problem, Oblivious RAMs (ORAMs) are proposed to completely hide access patterns. However, most ORAM constructions are expensive and not suitable to deploy in a database for supporting query processing over large data. Furthermore, an ORAM processes queries synchronously, hence, does not provide high throughput for concurrent query processing. In this work, we design a practical oblivious query processing framework to enable efficient query processing over a cloud database. In particular, we focus on processing multiple range and kNN queries asynchronously and concurrently with high throughput. The key idea is to integrate indices into ORAM which leverages a suite of optimization techniques (e.g., oblivious batch processing and caching). The effectiveness and efficiency of our oblivious query processing framework is demonstrated through extensive evaluations over large datasets. Our construction shows an order of magnitude speedup in comparison with other baselines.

As the typical bio-macromolecules, cellulose and its derivates are widely studied due to the fact that they are green and renewable resources in nature. In this work, intelligent temperature-pH sensitive nanohydrogels consisting of nanocellulose, thermal responsive monomer (N-isopropylacrylamide, NIPAM), and pH responsive monomer (acrylic acid, AA; acrylamide, AM) were prepared [NFC-g-(AA/AM)]-g-NIPAM, the [NFC-g-(AA/AM)]-g-NIPAM was characterized by FTIR, scanning electron microscope (SEM), thermogravimetric analysis (TGA) and automatic gas adsorption analysis (BET). The results showed that the copolymerization of AA, AM and NIPAM were carried out successfully. The specific surface area, total pore volume, average pore diameter and thermal stability of the modified nano-cellulose were increased. In addition, the as-prepared nanohydrogels with 5-fluorouracil (5-FU) released more 5-FU at 40 °C and acidic condition compared to the room temperature and neutral pH, showing the characteristics of the temperature-PH dual response functionalization. The [NFC-g-(AA/AM)]-g-NIPAM have been proved to be the promising drug release nanohydrogels towards 5-FU, and the valuable findings might provide an idea for maximizing the potential of the nanocellulose-based nanohydrogels for the application of environmental pollution control.

Environmental chambers are a kind of equipment to simulate various conventional and extreme environments, which are usually applied to create various environmental conditions and conduct various studies related to environmental parameters. Through our review of literature of the past 30 years, environmental chambers have been mainly used in the following four aspects: pollutants’ emission characterization, human thermal comfort research, products and materials development and transformation and the reaction and behaviour of other living bodies such as animals and plants. In this paper, the current application of environmental chambers is summarized based on the research objectives, conditions and technical means. The purpose of this paper is to provide a review of the use of environmental chambers for research and analyze the current application of environmental chambers for the future application of environmental chambers and explore the direction of its future transformation and application.

In this paper, the atomic configuration, electronic structure, and work of adhesion for TiN(111)//B2-NiTi(110) and TiN(111)//B19′-NiTi(010) interfaces were investigated by first-principles calculations based on density functional theory (DFT), which aim to provide a theoretical guidance for analyzing the service reliability of TiN films modified NiTi alloy devices. The results of this paper indicated that a hollow-site stacking structure was formed on the interface when Ti and N were the terminal atoms on two sides. Such interfaces demonstrated a stronger bonding performance and a more stable structure than that with Ni and Ti as the terminal atoms. The work of adhesion of the TiN(111)//B19′-NiTi(010) interface was 17.47 J/m2, which is greater than the work of fracture of TiN(111) (6.73 J/m2), whereas the work of adhesion of the TiN(111)//B2-NiTi(110) interface was found to reach 5.49 J/m2, which is lower than the work of fracture of TiN(111). The models of the work of adhesion between the two interfaces indicate that there are significant bond strength changes in the TiN/NiTi interface, when the NiTi substrate undergoes martensitic transformation. The results of this paper contribute significantly to the service reliability analysis of TiN films coated on NiTi alloy devices.

Microvascular invasion (MVI) is a known risk factor for prognosis after R0 liver resection for hepatocellular carcinoma (HCC). The aim of this study was to develop a deep learning prognostic prediction model by incorporating a new factor of MVI area to the other independent risk factors.Consecutive patients with HCC who underwent R0 liver resection from January to December 2016 at the Eastern Hepatobiliary Surgery Hospital were included in this retrospective study. For patients with MVI detected on resected specimens, they were divided into two groups according to the size of the maximal MVI area: the small-MVI group and the large-MVI group.Of 193 patients who had MVI in the 337 HCC patients, 130 patients formed the training cohort and 63 patients formed the validation cohort. The large-MVI group of patients had worse overall survival (OS) when compared with the small-MVI group (p = 0.009). A deep learning model was developed based on the following independent risk factors found in this study: MVI stage, maximal MVI area, presence/absence of cirrhosis, and maximal tumor diameter. The areas under the receiver operating characteristic of the deep learning model for the 1-, 3-, and 5-year predictions of OS were 80.65, 74.04, and 79.44, respectively, which outperformed the traditional COX proportional hazards model.The deep learning model, by incorporating the maximal MVI area as an additional prognostic factor to the other previously known independent risk factors, predicted more accurately postoperative long-term OS for HCC patients with MVI after R0 liver resection.

Endoplasmic reticulum stress (ERS) and long non-coding RNAs (lncRNAs) are important in melanoma development and progression. This study aimed to explore the prognostic value of ERS-associated lncRNA profiles in cutaneous melanoma (CM).The Cancer Genome Atlas (TCGA) provides the raw data of CM. GSEA website was used to obtain ERS-related genes, and mRNA and LncRNA co-expression network were used to obtain ERS-related lncRNAs. A Lasso regression analysis was used to identify a prognostic risk model for the composition of ERS-related lncRNAs. Patients were divided into high- and low-risk groups based on the model's risk score. The researchers then compared the two groups' survival rates, immune infiltration, chemotherapeutic drug sensitivity, and immune checkpoint gene expression.Thirty-nine ERS-related lncRNAs were discovered to be prognostic. A prognostic risk model made up of ten ERS-related lncRNAs was discovered. Patients in the low-risk group had a better prognosis than those in the high-risk group. An examination of tumor microenvironment revealed that risk scores correlated with immune cell infiltration in eight cases. Dacarbazine, paclitaxel, and cisplatin, three chemotherapy drugs, were more sensitive in the low-risk group than in the high-risk group.This study identified a risk model of ten ERS-related lncRNAs that have significant prognostic value in CM and could help guide clinical treatment.

Hongxuan Wu,* Pingxiu He,* Dong Xie, Jianqiao Wang, Chuan Wan Department of Dermatology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chuan Wan, Department of Dermatology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China, Tel +86-791-88692799, Email chuanwan@ncu.edu.cnPurpose: The long non-coding RNA (lncRNA) anti-differentiation noncoding RNA (ANCR) is closely related to the occurrence and development of various malignancies. However, its expression and potential role in basal cell carcinoma (BCC) have not been established. In this study, we characterized the effects of ANCR in BCC and its underlying mechanism.Methods: The expression of ANCR in BCC tissues and cells was detected by qRT-PCR. Proliferation, invasion, migration and apoptosis of ANCR overexpressed or knock down TE354.T and A431 cells were examined by CCK8, transwell assay, wound healing assay and flow cytometry analysis, respectively. Western blot was performed to measure the expression of apoptosis-related proteins (BAX, BCL2 and Cleaved-caspase3), epithelial-mesenchymal transformation-related proteins (E-cadherin, N-cadherin, vimentin and β-catenin), and Hedgehog-pathway-related proteins (PTCH, GLI1 and SMO). RNA pull-down assay was used to analyze the relationship between ANCR and PTCH. The effect of ANCR on BCC growth in vivo was analyzed using xenograft model. TUNEL assay was used to determine the cell apoptosis.Results: ANCR and Hedgehog pathway were more highly expressed in BCC tissues than in adjacent normal tissues. ANCR overexpression substantially promoted BCC cell proliferation, invasion, and migration, inhibited apoptosis, and up-regulated BCL2 and decreased the expression of BAX and Cleaved-caspase3 proteins. Additionally, the upregulation of N-cadherin, vimentin, β-catenin, PTCH, GLI1, and SMO expression, and downregulation of E-cadherin expression were observed after ANCR overexpression. Moreover, ANCR knockdown had the opposite effects. An RNA pull-down assay further revealed that ANCR is specifically bound to PTCH. In vivo experiments also showed that ANCR overexpression significantly increased tumor growth and decreased apoptosis, which was reversed by cyclopamine, a specific inhibitor of the Hedgehog signaling pathway.Conclusion: ANCR activates the Hedgehog signaling pathway by binding to PTCH, thereby promoting BCC progression; accordingly, ANCR could be a candidate therapeutic target in BCC.Keywords: anti-differentiation noncoding RNA, basal cell carcinoma, Hedgehog signaling pathway, PTCH, epithelial–mesenchymal transition

There has been an increasing demand for real-time data analytics. Approximate Query Processing (AQP) is a popular option for that because it can use random sampling to trade some accuracy for lower query latency. However, the state-of-the-art AQP system either relies on scan-based sampling algorithms to draw samples, which can still incur a non-trivial cost of table scan, or creates samples of the database in a preprocessing step, which are hard to update. The alternative is to use the aggregate B-tree indexes to support both random sampling and updates in database with logarithmic time. However, to the best of our knowledge, it is unknown how to design an aggregate B-tree to support highly concurrent random sampling and updates, due to the difficulty of maintaining the aggregate weights correctly and efficiently with concurrency. In this work, we identify the key challenges to achieve high concurrency and present AB-tree, an index for highly concurrent random sampling and update operations. We also conduct extensive experiments to show its efficiency and efficacy in a variety of workloads.

BACKGROUND: Radiomics based on computed tomography (CT) images is potential in promoting individualized treatment of non-small cell lung cancer (NSCLC), however, its role in immunotherapy needs further exploration. The aim of this study was to develop a CT-based radiomics score to predict the efficacy of immune checkpoint inhibitor (ICI) monotherapy in patients with advanced NSCLC. METHODS: Two hundred and thirty-six ICI-treated patients were retrospectively included and divided into a training cohort (n=188) and testing cohort (n=48) at a ratio of 8 to 2. The efficacy outcomes of ICI were evaluated based on overall survival (OS) and progression-free survival (PFS). We designed a survival network and combined it with a Cox regression model to obtain patients’ OS risk score (OSRS) and PFS risk score (PFSRS). RESULTS: Based on OSRS and PFSRS, patients were divided into high- and low-risk groups in the training cohort and the test cohort with distinctly different [training cohort, log-rank P

In this article, we propose a novel semicentralized deep deterministic policy gradient (SCDDPG) algorithm for cooperative multiagent games. Specifically, we design a two-level actor-critic structure to help the agents with interactions and cooperation in the StarCraft combat. The local actor-critic structure is established for each kind of agents with partially observable information received from the environment. Then, the global actor-critic structure is built to provide the local design an overall view of the combat based on the limited centralized information, such as the health value. These two structures work together to generate the optimal control action for each agent and to achieve better cooperation in the games. Comparing with the fully centralized methods, this design can reduce the communication burden by only sending limited information to the global level during the learning process. Furthermore, the reward functions are also designed for both local and global structures based on the agents' attributes to further improve the learning performance in the stochastic environment. The developed method has been demonstrated on several scenarios in a real-time strategy game, i.e., StarCraft. The simulation results show that the agents can effectively cooperate with their teammates and defeat the enemies in various StarCraft scenarios.

ObjectiveEarly identifying arteriosclerosis in newly diagnosed type 2 diabetes (T2D) patients could contribute to choosing proper subjects for early prevention. Here, we aimed to investigate whether radiomic intermuscular adipose tissue (IMAT) analysis could be used as a novel marker to indicate arteriosclerosis in newly diagnosed T2D patients.MethodsA total of 549 patients with newly diagnosed T2D were included in this study. The clinical information of the patients was recorded and the carotid plaque burden was used to indicate arteriosclerosis. Three models were constructed to evaluate the risk of arteriosclerosis: a clinical model, a radiomics model (a model based on IMAT analysis proceeded on chest CT images), and a clinical-radiomics combined model (a model that integrated clinical-radiological features). The performance of the three models were compared using the area under the curve (AUC) and DeLong test. Nomograms were constructed to indicate arteriosclerosis presence and severity. Calibration curves and decision curves were plotted to evaluate the clinical benefit of using the optimal model.ResultsThe AUC for indicating arteriosclerosis of the clinical-radiomics combined model was higher than that of the clinical model [0.934 (0.909, 0.959) vs. 0.687 (0.634, 0.730), P < 0.001 in the training set, 0.933 (0.898, 0.969) vs. 0.721 (0.642, 0.799), P < 0.001 in the validation set]. Similar indicative efficacies were found between the clinical-radiomics combined model and radiomics model (P = 0.5694). The AUC for indicating the severity of arteriosclerosis of the combined clinical-radiomics model was higher than that of both the clinical model and radiomics model [0.824 (0.765, 0.882) vs. 0.755 (0.683, 0.826) and 0.734 (0.663, 0.805), P < 0.001 in the training set, 0.717 (0.604, 0.830) vs. 0.620 (0.490, 0.750) and 0.698 (0.582, 0.814), P < 0.001 in the validation set, respectively]. The decision curve showed that the clinical-radiomics combined model and radiomics model indicated a better performance than the clinical model in indicating arteriosclerosis. However, in indicating severe arteriosclerosis, the clinical-radiomics combined model had higher efficacy than the other two models.ConclusionRadiomics IMAT analysis could be a novel marker for indicating arteriosclerosis in patients with newly diagnosed T2D. The constructed nomograms provide a quantitative and intuitive way to assess the risk of arteriosclerosis, which may help clinicians comprehensively analyse radiomics characteristics and clinical risk factors more confidently.

Somatic embryogenesis (SE) is a key regeneration pathway in various biotechnology approaches to crop improvement, especially for economically important perennial woody crops like citrus. However, maintenance of SE capability has long been a challenge and becomes a bottleneck in biotechnology-facilitated plant improvement. In the embryogenic callus (EC) of citrus, we identified two csi-miR171c targeted SCARECROW-LIKE genes CsSCL2 and CsSCL3 (CsSCL2/3), which exert positive feedback regulation on csi-miR171c expression. Suppression of CsSCL2 expression by RNA interference (RNAi) enhanced SE in citrus callus. A thioredoxin superfamily protein CsClot was identified as an interactive protein of CsSCL2/3. Overexpression of CsClot disturbed reactive oxygen species (ROS) homeostasis in EC and enhanced SE. ChIP-Seq and RNA-Seq identified 660 genes directly suppressed by CsSCL2 that were enriched in biological processes including development related processes, auxin signaling pathway and cell wall organization. CsSCL2/3 bound to the promoters of regeneration-related genes, such as WUSCHEL-RELATED HOMEOBOX 2 (CsWOX2), CsWOX13 and Lateral Organ Boundaries Domain 40 (LBD40), and repressed their expression. Overall, CsSCL2/3 modulate ROS homeostasis through the interactive protein CsClot and directly suppress the expression of regeneration-related genes, thus regulating SE in citrus. We uncovered a regulatory pathway of miR171c-targeted CsSCL2/3 in SE, which shed light on the mechanism of SE and regeneration capability maintenance in citrus.

Cytoplasmic male sterility (CMS) has long been used to produce seedless fruits in perennial woody crops like citrus. A male sterile somatic cybrid citrus (G1+HBP) was generated from protoplast fusion between a CMS callus parent ‘Guoqing No. 1’ Satsuma mandarin (Citrus unshiu, G1) and a fertile mesophyll parent Hirado Buntan pummelo (Citrus grandis, HBP). To uncover the male sterile mechanism of G1+HBP, we compared the transcriptome profiles of stamen organ and cell types at five stages between G1+HBP and HBP, including the initial stamen primordia, enlarged stamen primordia, pollen mother cells, tetrads and microspores captured by laser microdissection (LMD). The stamen organ and cell types showed distinct gene expression profiles. A majority of genes involved in stamen development were differentially expressed, especially CgAP3.2 that was downregulated in enlarged stamen primordia and upregulated in tetrads of G1+HBP compared with HBP. The jasmonic acid (JA) and auxin related biological processes were enriched among the differential expression genes (DEGs) of stamen primordia, and the content of JA biosynthesis metabolites was higher in flower buds and anthers of G1+HBP. In contrast, the content of auxin biosynthesis metabolites was lower in G1+HBP. The mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) processes were enriched among the DEGs in stamen primordia, meiocytes and microspores, indicating the dysfunction of mitochondria in stamen organ and cell types of G1+HBP. Taken together, the malfunction of mitochondria-nuclear interaction might cause disorder in stamen development, and thus lead to male sterility in the citrus cybrid.

Purpose. Albuvirtide (ABT) is the first long-acting HIV fusion inhibitor originally developed in China, blocking the invasion of HIV-1 virus into target cells. This study aimed to compare the pharmacokinetics, tolerability, and safety of ABT following a single intravenous (IV) bolus injection or intravenous drip in healthy Chinese subjects.Methods. A single-center, randomized, open-label, single-period, parallel phase I clinical trial was conducted. 30 subjects were randomly divided into 3 groups in a ratio of 1:1:1. After an overnight fast, all subjects received a single dose administration of 320 mg ABT by intravenous drip for 45 min (Group A) or bolus injection for 0.5 min (Group B) or bolus injection for 3 min (Group C). ABT plasma concentrations were analyzed using validated enzyme-linked immunosorbent assay. Noncompartmental analysis was used to evaluate PK parameters.Results. The median value of time to reach maximum concentration was 0.75 h in group A and 0.16 h in both group B and C, elimination half-life, mean residence time, apparent clearance and apparent volume of distribution was similar among three groups. The 90% confidence intervals of geometric mean ratios of PK parameters for group B and C relative to group C are mainly within 85–120%. All AEs in this study were mild, according to the CTCAE guidelines and the study investigator’s judgement.Conclusion. ABT bolus injection for 0.5 min and 3 min are expected well tolerated and to have similar pharmacokinetic characteristics as IV drip for 45 min, thus offering potential clinical benefits.

ObjectHospital sewage have been associated with incorporation of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) into microbes, which is considered as a key indicator for the spread of antimicrobial resistance (AMR). The compositions of dental waste water (DWW) contain heavy metals, the evolution of AMR and its effects on the water environment in the context of heavy metal environment have not been seriously investigated. Thus, our major aims were to elucidate the evolution of AMR in DWW.MethodsDWW samples were collected from a major dental department. The presence of microbial communities, ARGs, and MGEs in untreated and treated (by filter membrane and ozone) samples were analyzed using metagenomics and bioinformatic methods.ResultsDWW-associated resistomes included 1,208 types of ARGs, belonging to 29 antibiotic types/subtypes. The most abundant types/subtypes were ARGs of multidrug resistance and of antibiotics that were frequently used in the clinical practice. Pseudomonas putida, Pseudomonas aeruginosa, Chryseobacterium indologenes, Sphingomonas laterariae were the main bacteria which hosted these ARGs. Mobilomes in DWW consisted of 93 MGE subtypes which belonged to 8 MGE types. Transposases were the most frequently detected MGEs which formed networks of communications. For example, ISCrsp1 and tnpA.5/4/11 were the main transposases located in the central hubs of a network. These significant associations between ARGs and MGEs revealed the strong potential of ARGs transmission towards development of antimicrobial-resistant (AMR) bacteria. On the other hand, treatment of DWW using membranes and ozone was only effective in removing minor species of bacteria and types of ARGs and MGEs.ConclusionDWW contained abundant ARGs, and MGEs, which contributed to the occurrence and spread of AMR bacteria. Consequently, DWW would seriously increase environmental health concerns which may be different but have been well-documented from hospital waste waters.

Background Colorectal cancer (CRC) is one of the most prevalent types of malignant tumours. Metastasis is the leading cause of cancer-related mortality, with lung metastases accounting for 32.9% of all metastatic CRCs. However, since the biological mechanism of lung metastatic CRC is poorly understood, limited therapeutic targets are available. In the present study, we aimed to identify the key genes and molecular processes involved in CRC lung metastasis. Methods The differentially expressed genes (DEGs) between primary and lung metastatic CRC patients were obtained from the Gene Expression Omnibus (GEO) database via the GEO2R tool. The enriched biological processes and pathways modulated by the DEGs were determined with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome Gene Sets analyses. The search tool Retrieval of Interacting Genes (STRING) and Cytoscape were used to construct a protein–protein interaction (PPI) network among DEGs. Results The DEGs were enriched in surfactant metabolism, cell–cell communication and chemokine signaling pathways. The defined hub genes were included CLU, SFTPD, CCL18, SPP1, APOE, BGN and MMP3. Among them, CLU, SFTPD and CCL18 might be associated with the specific lung tropism metastasis in CRC. In addition, the expression and prognostic values of the hub genes in CRC patients were verified in database of The Cancer Genome Atlas (TCGA) and GEO. Moreover, the protein levels of the hub genes were detected in primary and lung metastatic CRC cells, serum or tissues. Furthermore, SFTPD was confirmed to facilitate cellular proliferation and lung metastasis in CRC. Conclusion This bioinformatics study may provide a better understanding of the candidate therapeutic targets and molecular mechanisms for CRC lung metastasis.

The illustration of STAT3/ERR-α signaling pathway.

STAT3 is constitutively activated in many malignant tumor types and plays an important role in multiple aspects of cancer aggressiveness. In this study, we found that estrogen-related receptor α (ERR-α) correlating with STAT3 was highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues, which was associated with both the pathologic stage and prognosis of patients with TNBC. In vitro studies showed that ERR-α promoted TNBC cell migration and invasion, which was regulated by STAT3. Phosphorylated STAT3 (p-STAT3, Tyr 705) could bind to the promotor of ERR-α, and activate its transcription, which was suggested by luciferase assay and chromatin immunoprecipitation assay. We also found that ERR-α was the key target gene regulated by STAT3 in promoting epithelial–mesenchymal transition (EMT), migration, and invasion. ERR-α upregulated the expression of ZEB1, N-cadherin, and vimentin while downregulated the expression of E-cadherin. Furthermore, in vivo studies showed that ERR-α could increase the metastasis ability of TNBC. Our finding demonstrated that ERR-α was a direct regulatory gene target of p-STAT3, which was enriched for processes involving invasion and metastasis in TNBC and provided insight into TNBC pathogenesis, as well as a potential therapeutic option against TNBC metastasis.Implications:Our research first showed that p-STAT3 (Tyr 705) could bind to the promotor region of ERR-α and promote EMT in TNBC by ZEB1 pathways, thus providing a potential clinical target for TNBC.

Primers of Ch-IP (P1-P11)