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A graph is minimally k -(edge)-connected if it is k -connected (respectively, k -edge-connected) and deleting any arbitrary chosen edge always leaves a graph which is not k -connected (respectively, k -edge-connected). What is the maximum (signless Laplacian) spectral radius and what are the corresponding extremal graphs among minimally k -(edge)-connected graphs for k ≥ 2 ? Chen and Guo (2019) gave the answer to k = 2 and characterized the corresponding extremal graphs. In this paper, we first give the answer to k = 3 for minimally 3-connected graphs. For the signless Laplacian spectral radius, we also consider the problem for k = 2 , 3 and characterize the extremal graphs.

Neutrophils are important components of innate immunity in the blood. They are the body's first line of defense against microbial pathogens, especially when suppurative bacteria invade. Since its function can be both beneficial and harmful to the pathogen and the surrounding host tissues, its functions must be tightly regulated. First discovered in red blood cells, the 4.1R protein is a membrane skeleton protein that plays an important role in regulating the deformation and stability of the membrane. Many lines of evidence suggest that 4.1R has the ability to regulate cellular pathways in a variety of immune cells, but its function in neutrophils has not yet been reported. Here, we investigated the function of 4.1R in neutrophils using 4.1R−/−mice. Our results showed that the chemotactic function, phagocytic function, ROS production ability, and the secretion of inflammatory factors were increased in the 4.1R−/−neutrophils. Furthermore, results fromin vivoexperiments demonstrated that 4.1R−/−mice recruited more neutrophils, secreted higher levels of inflammatory cytokines, and had a shorter life-span. Further mechanistic evaluation revealed that the protein phosphorylation of JAK2/STAT3 was increased in the 4.1R knockout neutrophils after their stimulation and activation. In summary, the expression of 4.1R protein has an important negative regulatory effect on neutrophil function, which may be mediated through the JAK2/STAT3 signaling pathway.

Background Colorectal cancer (CRC) is one of the most common malignant tumours. The recurrence and metastasis of CRC seriously affect the survival rate of patients. Angiogenesis is an extremely important cause of tumour growth and metastasis. Circular RNAs (circRNAs) have been emerged as vital regulators for tumour progression. However, the regulatory role, clinical significance and underlying mechanisms still remain largely unknown. Methods High-throughput sequencing was used to analyse differential circRNAs expression in tumour and non-tumour tissues of CRC. In situ hybridization (ISH) and qRT-PCR were used to determine the level of circ3823 in CRC tissues and serum samples. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circ3823 on tumour growth, metastasis and angiogenesis in CRC. Sanger sequencing, RNase R and Actinomycin D assay were used to verify the ring structure of circ3823. Mechanistically, dual luciferase reporter assay, fluorescent in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down experiments were performed to confirm the underlying mechanisms of circ3823. Results Circ3823 was evidently highly expressed in CRC and high circ3823 expression predicted a worse prognosis of CRC patients. Receiver operating characteristic curves (ROCs) indicated that the expression of circ3823 in serum showed high sensitivity and specificity for detecting CRC which means circ3823 have the potential to be used as diagnostic biomarkers. Functional experiments in vitro and in vivo indicated that circ3823 promote CRC cell proliferation, metastasis and angiogenesis. Mechanism analysis showed that circ3823 act as a competing endogenous RNA of miR-30c-5p to relieve the repressive effect of miR-30c-5p on its target TCF7 which upregulates MYC and CCND1, and finally facilitates CRC progression. In addition, we found that N6-methyladenosine (m6A) modification exists on circ3823. And the m6A modification is involved in regulating the degradation of circ3823. Conclusions Our findings suggest that circ3823 promotes CRC growth, metastasis and angiogenesis through circ3823/miR-30c-5p/TCF7 axis and it may serve as a new diagnostic marker or target for treatment of CRC patients. In addition, m6A modification is involved in regulating the degradation of circ3823.

Emerging evidence suggests that childhood maltreatment (CM) alters trajectories of brain development to affect network architecture and is a risk factor for the development and maintenance of depression. The current study aimed to explore the association between CM and depressive severity on the large-scale resting-state networks (RSNs) level in major depressive disorder (MDD) patients and explored the network basis of clinical symptoms. 42 healthy controls without childhood maltreatment, 13 healthy controls with CM, 35 MDD without CM and 50 MDD with CM were included in the study population. Group differences in ten large-scale RSNs, associations between CM and depressive symptom dimensions and network variables were tested. And we explored whether symptom-related networks might discriminate between the four groups. We found one-versus-all-others-network showed an inverted U-shaped curve across groups. Network variables were significantly associated with Hamilton Depression Scale subscores and Childhood Trauma Questionnaire subscores. Different symptoms showed different imaging patterns, and overlapping connections of patterns had better ability to distinguish groups. Our findings suggest that CM could lead to significant changes in both network measures and connections in healthy individuals and MDD. These results deepen our understanding of the neuroimaging mechanisms of CM and MDD.

Robust point set registration is a challenging problem, especially in the cases of noise, outliers, and partial overlapping. Previous methods generally formulate their objective functions based on the mean-square error (MSE) loss and, hence, are only able to register point sets under predefined constraints (e.g., with Gaussian noise). This article proposes a novel objective function based on a bidirectional kernel mean ${p}$ -power error (KMPE) loss, to jointly deal with the above nonideal situations. KMPE is a nonsecond-order similarity measure in kernel space and shows a strong robustness against various noise and outliers. Moreover, a bidirectional measure is applied to judge the registration, which can avoid the ill-posed problem when a lot of points converges to the same point. In particular, we develop two effective optimization methods to deal with the point set registrations with the similarity and the affine transformations, respectively. The experimental results demonstrate the effectiveness of our methods.

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), resulting in the change of the nucleolar localization signal into a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus causes downregulation of the HOXA genes, leading to the speculation that NPM1c directly regulates their transcription. Here, we show that NPM1c binds to a subset of active gene promoters marked with high levels of H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts, including well-known leukemia-driving genes such as posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets IRX5. The binding of NPM1c on chromatin sustains active transcription of key target genes by maintaining high local-concentration of transcriptional complexes, including RNA Pol2, the Super Elongation Complex (SEC) and Menin/MLL1. We also find NPM1c induce this maintenance of high local concentration of transcription complex by multivalent heterotypic interactions. We also found NPM1c could only hijack and amplify the pre-existing active transcription using a NPM1c knock-in HOXB8-immortalized hematopoietic progenitor cell line. Besides the direct modulation of transcription, we found NPM1c also maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Depletion of NPM1c causes histone deacetylation and the silencing of key leukemic genes, leading to cell differentiation and growth arrest. We also found the export protein XPO1 plays a key role by tethering NPM1c onto chromatin. The combination of XPO1 inhibitors (e.g., Selinexor and Eltanexor) with the Menin inhibitor MI-3454 has a synergistic effect on inducing differentiation in both NPM1-mutated leukemia cell lines and PDX model. Together, these findings reveal paradigm-shifting mechanistic insights into NPM1c mediated gene control and open up potential avenues for therapeutic intervention. Citation Format: Xue Qing David Wang, Dandan Fan, Yiman Liu, Hongzhi Miao, Dong Chen, Xinyu Wang, Haley Gore, Pamela Himadewi, Gerd Pfeifer, Tomasz Cierpicki, Jolanta Su, Liling Wan, Xiaotian Zhang. Mutant NPM1 hijacks active transcriptional machinery to maintain pathogenic gene programs in AML [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A34.

Defocus blur detection (DBD), which has been widely applied to various fields, aims to detect the out-of-focus or in-focus pixels from a single image. Despite the fact that the deep learning based methods applied to DBD have outperformed the hand-crafted feature based methods, the performance cannot still meet our requirement. In this paper, a novel network is established for DBD. Unlike existing methods which only learn the projection from the in-focus part to the ground-truth, both in-focus and out-of-focus pixels, which are completely and symmetrically complementary, are taken into account. Specifically, two symmetric branches are designed to jointly estimate the probability of focus and defocus pixels, respectively. Due to their complementary constraint, each layer in a branch is affected by an attention obtained from another branch, effectively learning the detailed information which may be ignored in one branch. The feature maps from these two branches are then passed through a unique fusion block to simultaneously get the two-channel output measured by a complementary loss. Additionally, instead of estimating only one binary map from a specific layer, each layer is encouraged to estimate the ground truth to guide the binary map estimation in its linked shallower layer followed by a top-to-bottom combination strategy, gradually exploiting the global and local information. Experimental results on released datasets demonstrate that our proposed method remarkably outperforms state-of-the-art algorithms.

In this study, differentially expressed genes (DEGs) and signaling pathways involved in diquat (DQ) and paraquat (PQ) poisoning were identified via bioinformatics analysis, in order to inform the development of novel clinical treatments.Raw data from GSE153959 were downloaded from the Gene Expression Omnibus database. DEGs of the DQ vs. control (CON) and PQ vs. CON comparison groups were identified using R, and DEGs shared by the two groups were identified using TBtools. Subsequently, the shared DEGs were searched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, using the Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction (PPI) network was constructed, and hub genes were identified using the cytoHubba plug-in in Cytoscape software. Finally, circos and contrast plots showing the DEGs shared between mouse and human chromosomes were constructed using TBtools.Thirty-one DEGs shared by the DQ and PQ groups were identified. Enriched biological process terms included positive regulation of cell proliferation and translation. Enriched cellular component terms included extracellular region, intracellular membrane-bounded organelle and mitochondrion. Enriched molecular function terms included transcription factor activity and sequence-specific double-stranded DNA binding. Enriched KEGG pathways included the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and human T-cell leukemia virus 1 infection. The top 10 hub genes in the PPI network were prostaglandin-endoperoxide synthase 2 (These pathways and DEGs may serve as targets for gene therapy.

The relationships among cerebral blood flow (CBF), functional connectivity (FC) and suicidal ideation (SI) in major depressive disorder (MDD) patients have remained elusive. In this study, we characterized the changes in CBF and FC among 175 individuals including 47 MDD without SI (MDDNSI), 59 MDD with SI (MDDSI), and 69 healthy control (HC) who underwent arterial spin labeling and resting-state functional MRI scans. Then the voxel-wise CBF, seed-based FC and partial correlation analyses were measured. Mediation analysis was carried out to reveal the effects of FC on the association between CBF and behavioral performances in both subgroups. Results showed that CBF was higher in MDDSI patients in the bilateral precuneus compared to HC and MDDNSI participants. MDDSI patients exhibited enhanced FC in the prefrontal-limbic system and decreased FC in the sensorimotor cortex (SMC) relative to MDDNSI patients. CBF and FC were significantly correlated with clinical variables. More importantly, exploratory mediation analyses identified that abnormal FC can mediate the association between regional CBF and behavioral performances. These results highlight the potential role of precuneus gyrus, prefrontal-limbic system as well as SMC in the process of suicide and provide new insights into the neural mechanism underlying suicide in MDD patients.

Acute myocardial infarction can be caused by ischemia/reperfusion (I/R) injury; however, the mechanism underlying I/R is not completely understood. The present study investigated the functions and mechanisms underlying microRNA (miR)‑494 in I/R‑induced cardiomyocyte apoptosis and autophagy. Hypoxia/reoxygenation (H/R)‑treated H9c2 rat myocardial cells were used as an in vitro I/R injury model. Apoptosis and autophagy were analyzed by Cell Counting Kit‑8 assay, Lactic dehydrogenase and superoxide dismutase assay, flow cytometry, TUNEL staining and western blotting. Reverse transcription‑quantitative PCR demonstrated that, H9c2 cells treated with 12 h hypoxia and 3 h reoxygenation displayed significantly downregulated miR‑494 expression levels compared with control cells. Compared with the corresponding negative control (NC) groups, miR‑494 mimic reduced H/R‑induced cell apoptosis and autophagy, whereas miR‑494 inhibitor displayed the opposite effects. Silent information regulator 1 (SIRT1) was identified as a target gene of miR‑494. Furthermore, miR‑494 inhibitor‑mediated effects on H/R‑induced cardiomyocyte apoptosis and autophagy were partially reversed by SIRT1 knockdown. Moreover, compared with si‑NC, SIRT1 knockdown significantly increased the phosphorylation levels of PI3K, AKT and mTOR in H/R‑treated and miR‑494 inhibitor‑transfected H9c2 cells. Collectively, the results indicated that miR‑494 served a protective role against H/R‑induced cardiomyocyte apoptosis and autophagy by directly targeting SIRT1, suggesting that miR‑494 may serve as a novel therapeutic target for myocardial I/R injury.

Background Recent studies have validated and confirmed the great potential of nanoscale metal-organic framework (NMOF) in the biomedical field, especially in improving the efficiency of cancer diagnosis and therapy. However, most previous studies only utilized either the metal cluster or the organic ligand of the NMOF for cancer treatments and merely reported limited theranostic functions, which may not be optimized. As a highly designable and easily functionalized material, prospective rational design offers a powerful way to extract the maximum benefit from NMOF for cancer theranostic applications. Materials and methods A NMOF based on hafnium (Hf) cluster and Mn(III)-porphyrin ligand was rational designed and synthesized as a high-performance multifunctional theranostic agent. The folic acid (FA) was modified on the NMOF surface to enhance the cancer targeting efficacy. The proposed "all-in-one" FA-Hf-Mn-NMOF (fHMNM) was characterized and identified using various analytical techniques. Then, in vitro and in vivo studies were performed to further explore the effects of fHMNM both as the magnetic resonance imaging (MRI)/computed tomography (CT)/photoacoustic imaging (PAI) contrast agent and as the photothermal therapy (PTT)/radiotherapy (RT) agent. Results A tumour targeting multifunctional fHMNM was successfully synthesized with high performance for MRI/CT/PAI enhancements and image-guided PTT/RT synergistic therapy properties. Compared with the current clinical CT and MR contrast agents, the X-ray attenuation and T1 relaxation rate of this integrated nanosystem increased 1.7-fold and 3-5-fold, respectively. More importantly, the catalase-like Mn(III)-porphyrin ligand can decompose H2O2 into O2 in tumour microenvironments to improve the synergistic treatment efficiency of PTT and RT. Significant tumour growth inhibition was achieved in mouse cancer models without obvious damage to the other organs. Conclusion This work highlights the potential of fHMNM as an easily designable material for biomedical applications, could be an effective tool for in vivo detection and subsequent treatment of tumour.

How does the sharing economy affect the retail industry? This study investigates the impact of service sharing on the decisions and profits of two profit modes in the Online-to-Offline (O2O) retail market. We find that service sharing always improves the profit of the brand supplier as a service demander in both two profit modes, and improves the profit of the offline franchisee as a service provider in the profit-sharing mode under certain circumstances, but always reduces its profit in the non-profit-sharing mode. This is associated with the double marginalisation effect of the non-profit-sharing mode which leads to channel conflicts. Thus, a service-cost sharing mechanism is introduced to coordinate conflicts and achieve a win-win strategy, thereby improving the performance of the entire O2O supply chain.

The neural mechanisms underlying the polygenic effects of the endocytosis pathway on the brain function of Alzheimer's Disease (AD) remain unclear, especially in the prodromal stages of AD from early mild cognitive impairment (EMCI) to late mild cognitive impairment (LMCI). We used an imaging genetic approach to investigate the polygenic effects of the endocytosis pathway on the hippocampal network across the prodromal stages of AD. The subjects' data were selected from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal volumes were examined in subjects of cognitive normal (CN), EMCI and LMCI groups. Multivariate linear regression analysis was employed to measure the effects of disease and endocytosis-based multilocus genetic risk scores (MGRS) on the hippocampal network which was constructed using the bilateral hippocampal regions. We identified hippocampal volumes in LMCI group were smaller than those in CN and EMCI groups. Endocytosis-based MGRS was widely influenced the neural structures within the hippocampal network, especially in the prefrontal-occipital regions and striatum. Compared to low endocytosis-based MGRS carriers, high MGRS carriers showed the opposite trajectory of hippocampal network functional connectivity (FC) across the prodromal stages of AD. Further, a model composed of selected hippocampal FCs and hippocampal volume yielded strong classification powers of EMCI and LMCI. These findings expand our understanding of the pathophysiology of polygenic effects underlying brain network in the prodromal stages of AD.

Long non-coding (lnc) RNA serves a vital role in the cellular processes of carcinoma. This study aimed to explore the accurate mechanism underlying lncRNA small nucleolar RNA host gene 8 (SNHG8) in melanoma. In this study, lncRNA SNHG8 expression were upregulated in melanoma tissues and cells, and lncRNA SNHG8 knockdown reduced melanoma cell viability, migration and invasion. Moreover, lncRNA SNHG8 expression could be induced by transcription factor YY1. In addition, we found that miR-656 could directly bind to lncRNA SNHG8 and SERPINE1 mRNA binding protein 1 (SERBP1). Rescue assays indicated that miR-656 overexpression inhibited the aforementioned cellular activities in melanoma cells, which were reversed by SERBP1 overexpression. In conclusion, this work elucidated that YY1-induced upregulation of lncRNA SNHG8 boosted the development of melanoma via the miR-656-3p/SERBP1 axis, providing a novel therapeutic strategy for melanoma treatment.

Nowadays, about 30% of magnetic resonance imaging (MRI) exams need contrast agents (CAs) to improve the sensitivity and quality of the images for accurate diagnosis. Here, a multifunctional nano-agent with ring-like vortex-domain iron oxide as core and gadolinium oxide as shell (vortex nanoring Fe

The disability rate of spinal cord injury (SCI) is extremely high, and stem cell inhibition is one of the most effective schemes in treating the spinal cord, but the survival rate is extremely low after stem cell transplantation, so it cannot be widely used in clinic. Studies have revealed that loading stem cells with biological scaffolds can effectively improve the survival rate and effect after stem cell transplantation. Therefore, this research was devised to analyze the repair effect of thiolated chitosan nanocarriers scaffold carrying de-epithelized human amniotic epithelial cells (HAECs) on SCI. And we used thiolated chitosan as nanocarriers, aiming to provide a reliable theoretical basis for future clinical practice. Through experiments, we concluded that the Tarlov and BBB scores of rats with SCI were raised under the intervention of thiolated chitosan carrying HAECs, while the inflammatory factors in serum, oxidative stress reaction in spinal cord tissue, apoptosis rate of nerve cells, and autophagy protein expression were all suppressed. Thus, the thiolated chitosan carrying HAECs may be applied to treat SCI by suppressing autophagy protein expression, oxidative stress response, and release of inflammatory factors in spinal cord tissue, which may be a new clinical therapy for SCI in the future. Even though we cannot understand exactly the therapeutic mechanism of thiolated chitosan carrying HAECs for SCI, the real clinical application of thiolated chitosan carrying HAECs needs to be confirmed by human experiments.

Tumour therapy has entered the era of immunotherapy. Monoclonal antibodies (mAb), immune checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T), cytokine-induced killer (CIK), tumour-infiltrating lymphocytes (TILs) and other cellular immunotherapies have become the focus of current research. The CD47/SIRPα target is becoming another popular tumour immunotherapy target following the PDCD1/CD247(PD1/PD-L1) checkpoint inhibitor. In recent years, a large number of CD47/SIRPα mAbs, fusion proteins, and CD47/SIRPα-based bispecific antibodies (BsAbs) are undergoing preclinical and clinical trials and have good curative effects in the treatment of haematological tumours and solid tumours. They bring new vitality and hope for the treatment of patients with advanced tumours. This review summarizes the research progress of CD47/SIRPα-based BsAbs with different targets for tumour treatment. There are 12 and 9 BsAbs in clinical trials and pre-clinical research, respectively. We report on the mechanism of 15 BsAb molecules with different target and analyse the efficacy and safety of preclinical and clinical trials, discuss the issues that may be faced in the development of CD47-based BsAbs, and dual-target molecules, and summarize their development prospects. This review provides a reference for the safety and effectiveness of BsAbs in clinical application and in the future development of antibodies.

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of functions including ribosome biogenesis, mRNA processing, and maintenance of genomic stability. In acute myeloid leukemia (AML), the terminal exon of NPM1 is often mutated (~30% of adult AMLs), changing the nucleolar localization signal into a nuclear export signal, which results in a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have an aberrant expression of the HOXA genes, whose overexpression leads to leukemogenic transformation. The gene regulatory role of NPM1c has long been an enigma. Recently, it was shown that depletion or re-localization of the NPM1c protein into the nucleus [PG1] causes downregulation of the HOXA genes, leading to the speculation that NPM1c modulates transcription of HOXA genes. Here, we found NPM1c binds to chromatin and is located genome-wide at gene promoters and colocalized at active regions marked by H3K27ac in NPM1c leukemia cell lines and primary leukemia blasts. NPM1c clearly binds to known leukemia-driving genes - posterior HOXA, HOXB, and MEIS1/PBX3 genes as well as novel targets -IRX5 and NKX2-3. After PROTAC degradation of NPM1c, we observed a significant RNA polymerase II elongation defect genome-wide. The dramatic elongation defect is caused by the loss of the Super Elongation Complex (SEC) chromatin binding. Further tests suggest that loss of NPM1c leads to disruption of RNA polymerase II condensates as well as other direct transcriptional regulators of HOX genes - Menin and AFF4 through IDR interactions. We found that pulse PROTAC degradation of NPM1c leads to sustained differentiation with the loss of histone acetylation at NPM1c target loci. Further, NPM1c maintains the active chromatin state of target genes by antagonizing HDAC activity. Additionally, we found that NPM1c’s activation of the leukemia driving genes depends on the pre-established active chromatin state in the transformed hematopoietic stem and progenitor cells. NPM1c alone is not sufficient to activate these leukemia driving genes with heterochromatin marks accumulated. We also found that NPM1c binds to genomic regions that have been pre-bound by its export partner, XPO1. The XPO1 inhibitors Selinexor and Eltanexor can displace NPM1c from chromatin. The combination of clinical-grade XPO1 inhibitor eltanexor and Menin inhibitor MI-3454 displayed a strong synergy in inducing differentiation and reducing leukemia driving gene expression in the NPM1 mutated leukemia cell lines and PDX model, which promises to be an effective combination therapy for NPM1c leukemia patients. Citation Format: Xue Qing Wang, Dandan Fan, Yiman Liu, Qinyu Han, Jolanta Grembecka, Tomasz Cierpicki, Jianzhong Su, Shasha Chong, Liling Wan, Xiaotian Zhang. Mutant NPM1 hijacks transcriptional hub to maintain pathogenic gene programs and block differentiation in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR001.

The immune microenvironment has profound impacts on the initiation and progression of colorectal cancer (CRC). Therefore, the goal of this article is to identify two robust immune subtypes in CRC, further provide novel insights for the underlying mechanisms and clinical management. In this study, two CRC immune subtypes were identified using the consensus clustering of immune-related gene expression profiles in the meta-GEO dataset (n = 1,198), and their reproducibility was further verified in the TCGA-CRC dataset (n = 638). Subsequently, we characterized the immune escape mechanisms, gene alterations, and clinical features of two immune subtypes. Cluster 1 (C1) was defined as the “immune cold subtype” with immune cell depletion and deficiency, while cluster 2 (C2) was designed as the “immune hot subtype”, with abundant immune cell infiltration and matrix activation. We also underlined the potential immune escape mechanisms: lack of MHC molecules and defective tumor antigen presentation capacity in C1, increased immunosuppressive molecules in C2. The prognosis and sensitivity to 5-FU, Cisplatin and immunotherapy differed between two subtypes. According to the two immune subtypes, we developed a prognosis associated risk score (PARS) with the accurate performance for predicting the prognosis. Additionally, two nomograms for overall survival (OS) and disease-free survival (DFS) were further constructed to facilitate clinical management. Overall, our research provides new references and insights for understanding and refining the CRC.

Tumor blood vessels provide oxygen and necessary nutrients for the tumor, which provides the basis for tumor metastasis. Therefore, tumor angiogenesis plays a very important role in tumor growth and metastasis. In contrast to linear RNAs, circRNAs represent a type of closed-loop RNA with diverse biological functions. At the same time, circRNAs have strong stability, timeliness, tissue specificity and disease specificity. With the rapid development of next-generation sequencing and bioinformatics, there have been an increasing number of studies on circRNAs. At present, a large number of studies have reported that circRNAs regulate tumor growth, invasion, metastasis, tumor metabolism, tumor immunity and other biological functions. Increasing evidence has shown that circRNAs also play an important role in tumor angiogenesis. In this review, we briefly introduced tumor angiogenesis and circRNAs and outlined the main ways that circRNAs affect tumor angiogenesis from multiple aspects. Finally, we further explored the potential clinical application value of circRNAs in the context of tumor angiogenesis. This article is protected by copyright. All rights reserved.

Objective: Dyslipidemia is a controversial risk for Alzheimer's disease (AD) with unknown mechanisms. This study aimed to investigate polygenic effects of the lipid metabolic pathway on cerebrospinal fluid (CSF) core biomarkers, cognition, and default mode network (DMN). Methods: Cross-sectional data on serum lipids, CSF core biomarkers, and functional MRI findings for 113 participants (25 cognitively normal, 20 with subjective cognitive decline, 24 early amnestic, 23 with late mild cognitive impairment, and 21 with AD) from the Alzheimer's Disease Neuroimaging Initiative were included. Different cognitive stages were categorized based on neuropsychological assessments. Multivariable linear regression analyses were conducted to investigate the polygenic and interactive effects on the DMN. The correlations of lipid-related polygenes and serum lipids with cognitive performance were also studied via regression analyses. Results: The polygenic scores were significantly correlated with CSF levels of core biomarkers (P

M2 macrophages are crucial components of the tumour microenvironment and have been shown to be closely related to tumour progression. Co-culture with 4.1R-/- M2 macrophages enhances the malignancy of colon cancer (CC), but the mechanism remains unclear. Here, we report that protein 4.1R knockout reduced the phagocytosis of M2 macrophages (M-CSF/IL-4-treated bone marrow cells) and promoted MC38 colon cancer cell proliferation, migration, invasion, tumour formation and epithelial-mesenchymal transition (EMT), which are regulated by M2 macrophages. Further mechanistic dissection revealed that the 4.1R knockout upregulated vascular endothelial growth factor A (VEGFA) secreted by M2 macrophages and promoted colon cancer progression by activating the PI3K/AKT signalling pathway. In summary, our present study identified that 4.1R downregulates VEGFA secretion in M2 macrophages and delays the malignant potential of colon cancer by inhibiting the PI3K/AKT signalling pathway.

Childhood maltreatment (CM) is a major risk factor for developing the major depressive disorder (MDD), however, the neurobiological mechanism linking CM and MDD remains unclear. We recruited 34 healthy controls (HCs) and 44 MDD patients to complete the childhood maltreatment experience assessment with Childhood Trauma Questionnaire (CTQ) and resting-state fMRI scan. Multivariate linear regression analysis was employed to identify the main effects of CM and depressive symptoms total and subfactors scores on bilateral anterior and posterior insula functional connectivity (IFC) networks, respectively. Mediation analysis was performed to investigate whether IFC strength mediates the association between CM and depressive symptoms. MDD patients showed significantly decreased connectivity in the dorsal medial prefrontal cortex and increased connectivity in the medial frontal gyrus in the bipartite IFC networks, compared to HCs. The main effects of CM and depressive symptoms showed a large discrepancy on the anterior and posterior IFC networks, which primarily located in the frontal-limbic system. Further, conjunction analysis identified the overlapping regions linking CM and depressive symptoms were mainly implicated in self-regulation and cognitive processing circuits. More important, these IFC strengths could mediate the association between different types of CM, especially for childhood abuse and childhood neglect, and depressive symptoms in those overlapping regions. We demonstrated that early exposure to CM may increase the vulnerability to depression by influencing brain’s self-regulating and cognitive processing circuitry. These findings provide new insight into the understanding of pathological mechanism underlying CM-induced depressive symptoms.

Photothermal/magnetothermal-based hyperthermia cancer therapy techniques have been widely investigated, and associated nanotechnology-assisted treatments have shown promising clinical potentials. However, each method has some limitations, which have impeded extensive applications. For example, the penetration ability of the photothermal is not satisfactory, while the heating efficiency of the magnetothermal is very poor. In this study, a novel magnetite vortex nanoring nanoparticle-coated with polypyrrole (denoted as nanoring Fe3O4@PPy-PEG) was first synthesized and well-characterized. By combining photothermal and magnetothermal effects, the performance of the dual-enhanced hyperthermia was significantly improved, and was thoroughly examined in this study. Benefiting from the magnetite vortex nanoring and polypyrrole, Fe3O4@PPy-PEG showed excellent hyperthermia effects (SAR = 1,648 Wg–1) when simultaneously exposed to the alternating magnetic field (300 kHz, 45 A) and near-infrared (808 nm, 1 W cm–2) laser. What is more, nanoring Fe3O4@PPy-PEG showed a much faster heating rate, which can further augment the antitumor effect by incurring vascular disorder. Besides, Fe3O4@PPy-PEG exhibited a high transverse relaxation rate [60.61 mM–1 S–1 (Fe)] at a very low B0 field (0.35 T) and good photoacoustic effect. We believe that the results obtained herein can significantly promote the development of multifunctional nanoparticle-mediated magnetic and photo induced efficient hyperthermia therapy.

The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment., The role of regulatory cis-elements in carcinogenesis and metastasis in esophageal squamous cell carcinoma remains crucial. Here the authors investigate H3K27ac-marked active enhancer profiles and transcriptomes in different types of esophageal tissues and identify oncogenic events and potential therapeutic targets.

Background Objective biomarkers are crucial for overcoming the clinical dilemma in major depressive disorder (MDD), and the individualized diagnosis is essential to facilitate the precise medicine for MDD. Methods Sleep disturbance-related magnetic resonance imaging (MRI) features was identified in the internal dataset (92 MDD patients) using the relevance vector regression algorithm, which was further verified in 460 MDD patients of an independent, multicenter dataset. Subsequently, using these MRI features, the eXtreme Gradient Boosting classification model was constructed in the current multicenter dataset (460 MDD patients and 470 normal controls). Meanwhile, the association between classification outputs and the severity of depressive symptoms was also investigated. Results In MDD patients, the combination of gray matter density and fractional amplitude of low-frequency fluctuation can accurately predict individual sleep disturbance score that was calculated by the sum of item 4 score, item 5 score, and item 6 score of the 17-Item Hamilton Rating Scale for Depression (HAMD-17) (R2 = 0.158 in the internal dataset; R2 = 0.110 in multicenter dataset). Furthermore, the classification model based on these MRI features distinguished MDD patients from normal controls with 86.3% accuracy (area under the curve = 0.937). Importantly, the classification outputs significantly correlated with HAMD-17 scores in MDD patients. Limitation Lacking some specialized tools to assess the personal sleep quality, e.g. Pittsburgh Sleep Quality Index. Conclusion Neuroimaging features can reflect accurately individual sleep disturbance manifestation and serve as potential diagnostic biomarkers of MDD.

Suppose that the vertex set of a connected graph G is $$V(G)=\{v_1,\ldots ,v_n\}$$ . Then we denote by $$Tr_{G}(v_i)$$ the sum of distances between $$v_i$$ and all other vertices of G. Let Tr(G) be the $$n\times n$$ diagonal matrix with its (i, i)-entry equal to $$Tr_{G}(v_{i})$$ and D(G) be the distance matrix of G. Then $$Q_{D}(G)=Tr(G)+D(G)$$ is the distance signless Laplacian matrix of G. The largest eigenvalues of $$Q_D(G)$$ is called distance signless Laplacian spectral radius of G. In this paper we give some graft transformations on distance signless Laplacian spectral radius of the graphs and use them to characterize the graphs with the minimum and maximal distance signless Laplacian spectral radius among non-starlike and non-caterpillar trees.

Eye diseases are remarkably common and encompass a large and diverse range of morbidities that affect different components of the visual system and visual function. With advances in omics technology of eye disorders, genome-scale datasets have been rapidly accumulated in genetics and epigenetics field. However, the efficient collection and comprehensive analysis of different kinds of omics data are lacking. Herein, we developed EyeDiseases (https://eyediseases.bio-data.cn/), the first database for multi-omics data integration and interpretation of human eyes diseases. It contains 1344 disease-associated genes with genetic variation, 1774 transcription files of bulk cell expression and single-cell RNA-seq, 105 epigenomics data across 185 kinds of human eye diseases. Using EyeDiseases, we investigated SARS-CoV-2 potential tropism in eye infection and found that the SARS-CoV-2 entry factors, ACE2 and TMPRSS2 are highly correlated with cornea and keratoconus, suggest that ocular surface cells are susceptible to infection by SARS-CoV-2. Additionally, integrating analysis of Age-related macular degeneration (AMD) GWAS loci and co-expression data revealed 9 associated genes involved in HIF-1 signaling pathway and voltage-gate potassium channel complex. The EyeDiseases provides a valuable resource for accelerating the discovery and validation of candidate loci and genes contributed to the molecular diagnosis and therapeutic vulnerabilities with various eyes diseases.

In this paper we consider a dual-channel supply chain which consists of an online store and multiple independent retail stores. In this system, customer shift induces inventory competition while transshipment brings inventory cooperation, both of which inuences inventory optimization and control. Therefore we respectively construct inventory optimization models under the two situations: customer shift and inventory transshipment. Specifically, unilateral customer shift and inventory transshipment are considered, and a one-for-one replenishment strategy is applied. We first solve the equilibrium state probability of on-hand inventory through Markov chain theory, then optimize performance measure (i.e., the total costs) to obtain the optimal basic inventory level. Finally, we analyze the impact of customer shift rate and inventory transshipment rate on the inventory strategies through numerical simulation, and further compare the differences in inventory decisions between the above two situations, which prove that inventory cooperation brought by inventory transshipment is not necessarily better than inventory competition brought by customer shift. In addition, we discuss several insights that are evident from the parametric analysis of the model.

With the growing demand for hand hygiene and convenience of use, palmprint recognition with touchless manner made a great development recently, providing an effective solution for person identification. Despite many efforts that have been devoted to this area, it is still uncertain about the discriminative ability of the contactless palmprint, especially for large-scale datasets. To tackle the problem, in this paper, we build a large-scale touchless palmprint dataset containing 2334 palms from 1167 individuals. To our best knowledge, it is the largest contactless palmprint image benchmark ever collected with regard to the number of individuals and palms. Besides, we propose a novel deep learning framework for touchless palmprint recognition named 3DCPN (3D Convolution Palmprint recognition Network) which leverages 3D convolution to dynamically integrate multiple Gabor features. In 3DCPN, a novel variant of Gabor filter is embedded into the first layer for enhancement of curve feature extraction. With a well-designed ensemble scheme,low-level 3D features are then convolved to extract high-level features. Finally on the top, we set a region-based loss function to strengthen the discriminative ability of both global and local descriptors. To demonstrate the superiority of our method, extensive experiments are conducted on our dataset and other popular databases TongJi and IITD, where the results show the proposed 3DCPN achieves state-of-the-art or comparable performances.

Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. SMO, a gene encodes Smoothened protein, which is an important signal converter in Sonic Hedgehog (SHH) signal pathway. Studies have shown that CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring SMO mutation, suggested that SMO may be related to immune microenvironment and tumor immunity, but the association between SMO mutation and TMB or survival in metastatic Colorectal Cancer(mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs were retrieved from publicly accessible data (Pancancer.Samstein2018.NGS.1661) and the association between SMO mutation overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. The association between SMO mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 149 patients with Rectum Adenocarcinoma (READ) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and SMO mutation status was further analyzed by CIBERSORT. Statistical significance was set at p=0.05. Results: 7.3% (8/109) patients in the clinical cohort harbored SMO mutation. Survival analysis in the public cohort demonstrated that SMO mutation resulted in significantly longer OS (10.5 vs 8 months; HR, 0; p=0.035) in mCRC patients treated with ICIs. Moreover, SMO mutation is associated with higher TMB in public cohort (p Conclusions: This study shows that SMO mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages, CD8 T cells, as well as the Gamma Delta T cells may be another potential mechanism for the better efficacy of ICIs in patients with SMO mutation. Citation Format: Jinlin Cai, Dandan Fan, Yaoxu Chen, Mengli Huang. SMO as a predicted biomarker on immunotherapy and correlated with immune infiltrates in mCRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5253.

Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including atezolizumab, pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that Tumor Mutation Burden (TMB) was significantly (p < 0.001) associated with mutations in genes like GRIN2A in Non-Small Cell Lung Cancer (NSCLC), which means that the mutation of GRIN2A gene may be related to the efficacy of immunotherapy in patients with NSCLC, but the association between GRIN2A mutation and TMB or survival in melanoma is unknown. Methods: The association between GRIN2A mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Miao2018.Pancancer.249.WES, which worked as training cohort while the validation cohort was retrieved from Melanoma.Allen2015.WES.110. Wilcoxon test was used for the comparison of TMB and Tumor Neoantigen Burden (TNB). Progress Free Survival (PFS):Overall survival (OS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p=0.05. Results: In the training cohort, 33.8% (51/151) melanoma patients harbored GRIN2A mutation. GRIN2A mutation is associated with higher TMB (p Conclusions: This study shows that GRIN2A mutation is correlated with higher TMB and TNB in melanoma and serve as a predictive biomarker of ICI benefit in melanoma. Citation Format: Ling Ye, Dandan Fan, Yaoxu Chen, Mengli Huang. GRIN2A mutations as potential positive predictor for response of immune checkpoint inhibitors in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5251.

Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients and research exploring the association between gene mutation and clinical benefit is limited. USP6 (Ubiquitin-specific protease 6) mutation rate is high in melanoma. Studies have shown that USP6 functions as a tumor suppressor in Ewing Sarcoma through the activation of NK cells and macrophages, which indicates that USP6 activity may create a "hot" tumor microenvironment in immunotherapy. The association between USP6 mutation and survival in melanoma is unknown. Methods: The association between USP6 mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Melanoma.Allen2015.WES.110, which worked as training cohort while another cohort called Melanoma.Hugo2016.WES.38 worked as validation cohort. Wilcoxon test was used for the comparison of TMB. OS (Overall survival) analysis were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. In addition, the genomic and immune cell infiltration data of 466 patients with Skin Cutaneous Melanoma was obtained from TCGA and the correlation analysis was further analyzed by CIBERSORT. Statistical significance was set at p=0.05. Results: In the training cohort, 10.9% (12/110) melanoma patients harbored USP6 mutation. USP6 mutation is associated with higher TMB (p=0.0007) and results in significantly longer OS (21.3 vs 8.1 months; HR, 0.44; p=0.049).Meanwhile, the validation cohort shows that USP6 mutation results in higher TMB without significant difference (p=0.08) and significantly longer OS (31.5 vs 14.4 months; HR, 0.14; p=0.0026).Furthermore, the correlation analysis between immune infiltration and USP6 mutation status in melanoma shows that both M1 macrophages and follicular helper T cells increased significantly (p=0.02, p=0.033), while differential neutrophil decreased significantly (p=0.048). Conclusions: This study shows that USP6 mutation may serve as a potential positive biomarker of ICIs in melanoma since it correlated with higher TMB, the up regulation of M1 macrophages, follicular helper T cells and the down regulation of differential neutrophil. Citation Format: De Long, Dandan Fan, Yaoxu Chen, Mengli Huang. Association of USP6 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5254.

e15559 Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, the research exploring the association between gene mutation and clinical benefit is limited. Studies have shown that EPHB1 mutation in the NK cell-related pathway involved in the anti-cancer immune response and associated with survival of NSCLC patients, suggested that EPHB1 may be related to immune microenvironment and tumor immunity. However, the association between EPHB1 mutation and TMB or survival in metastatic Colorectal Cancer (mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs was retrieved from publicly accessible data(Pancancer.Samstein2018.NGS.1661),the association between EPHB1 mutation and overall survival(OS) was analyzed using Kaplan-Meier curves and log-rank tests. At the same time，the association between EPHB1 mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, genome and immune cell infiltration data of 149 patients with Colon Adenocarcinoma (COAD) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and EPHB1 mutation status was further analyzed by CIBERSORT-ABS. Statistical significance was set at p = 0.05. Results: 7.3%(8/109) patients in the clinical cohort harbored EPHB1 mutation. Survival analysis in the public cohort demonstrated that EPHB1 mutation resulted in significantly longer OS (14 vs 8 months; HR, 0; p = 0.03) in mCRC patients treated with ICIs. Moreover, EPHB1 mutation was associated with higher TMB in public cohort (p = 0.0004). Furthermore, the correlation analysis between immune infiltration and EPHB1 mutation status in mCRC showed that CD8+T cells, activated memorial CD4+T Cell, M1 macrophages increased significantly in EPHB1 mutation patients(p = 0.023, p = 0.0079, p = 0.034). Conclusions: EPHB1 mutation may serve as a potential positive biomarker of ICIs in mCRC since it relatively correlated with higher TMB. In addition, the up regulation of CD8+T cells, activated Memorial CD4+T Cell as well as the M1 macrophages may be a potential mechanism for the better efficacy of ICIs in patients with EPHB1 mutation.

Bensulfuron-methyl (BSM) residues in soil threaten the rotation of BSM-sensitive crops. Microbial biofilms formed on crop roots could improve the ability of microbes to survive and protect crop roots. However, the research on biofilms with the purpose of mitigating or even eliminating BSM damage to sensitive crops is very limited. In this study, one BSM-degrading bacterium, Hansschlegelia zhihuaiae S113, colonized maize roots by forming a biofilm. Root exudates were associated with increased BSM degradation efficiency with strain S113 in rhizosphere soil relative to bulk soil, so the interactions among BSM degradation, root exudates, and biofilms may provide a new approach for the BSM-contaminated soil bioremediation. Root exudates and their constituent organic acids, including fumaric acid, tartaric acid, and l -malic acid, enhanced biofilm formation with 13.0–22.2% increases, owing to the regulation of genes encoding proteins responsible for cell motility/chemotaxis (fla/che cluster) and materials metabolism, thus promoting S113 population increases. Additionally, root exudates were also able to induce exopolysaccharide production to promote mature biofilm formation. Complete BSM degradation and healthy maize growth were found in BSM-contaminated rhizosphere soil treated with wild strain S113, compared to that treated with loss-of-function mutants ΔcheA-S113 (89.3%, without biofilm formation ability) and ΔsulE-S113 (22.1%, without degradation ability) or sterile water (10.7%, control). Furthermore, the biofilm mediated by organic acids, such as l -malic acid, exhibited a more favorable effect on BSM degradation and maize growth. These results showed that root exudates and their components (such as organic acids) can induce the biosynthesis of the biofilm to promote BSM degradation, emphasizing the contribution of root biofilm in reducing BSM damage to maize.

Trimethylation of histone H3 lysine 27 trimethylation (H3K27me3) may be recruited by repressive Polycomb complexes to mediate gene silencing, which is critical for maintaining embryonic stem cell pluripotency and differentiation. However, the roles of aberrant H3K27me3 patterns in tumorigenesis are not fully understood. Here, we discovered that grand silencer domains (breadth > 50 kb) for H3K27me3 were significantly associated with epithelial cell differentiation and exhibited high gene essentiality and conservation in human esophageal epithelial cells. These grand H3K27me3 domains exhibited high modification signals involved in gene silencing, and preferentially occupied the entirety of topologically associating domains and interact with each other. We found that widespread loss of the grand H3K27me3 domains in of esophageal squamous cell carcinomas (ESCCs) were enriched in genes involved in epithelium and endothelium differentiation, which were significantly associated with overexpression with increase of active modifications of H3K4me3, H3K4me1, and H3K27ac marks, as well as DNA hypermethylation in the gene bodies. A total of 208 activated genes with loss of grand H3K27me3 domains in ESCC were identified, where the higher expression and mutation of T-box transcription factor 20 (TBX20) were associated with worse patients’ outcomes. Our results showed that knockdown of TBX20 may have led to a striking defect in esophageal cancer cell growth and carcinogenesis-related pathway, including cell cycle and homologous recombination. Together, our results reveal that loss of grand H3K27me3 domains represent a catalog of remarkable activating regulators involved in carcinogenesis.