Developmental toxicity assay of xanthatin in zebrafish embryos.

Xanthatin (XAN), a xanthanolide sesquiterpene lactone, isolated from Chinese herb, Xanthium strumarium L, has various pharmacological activities, such as antitumor activity and anti-inflammatory. However, little is known about its potential toxicity and the mechanism. Here, zebrafish model was used to study the developmental toxicity in vivo. Our results indicated that xanthatin increased the mortality and led to the morphological abnormalities including pericardial edema, yolk sac edema, curved body shape and hatching delay. Furthermore, xanthatin damaged the normal structure and/or function of heart, liver, immune and nervous system. ROS elevation and much more apoptosis cells were observed after xanthatin exposure. Gene expression results showed that oxidative stress-related genes nrf2 was inhibited, while oxidative stress-related genes (keap1 and nqo1) and apoptotic genes (caspase3, caspase9 and p53) were increased after xanthatin exposure. Mitophagy related genes pink1 and parkin, and wnt pathway (ß-catenin, wnt8a and wnt11) were significantly increased after xanthatin exposure. Taken together, our finding indicated that xanthatin induced developmental toxicity, and the ROS elevation, apoptosis activation, dysregulation of mitophagy and wnt pathways were involved in the toxicity caused by xanthatin.

The Chinese keratoconus (CKC) cohort study.

The Chinese keratoconus (CKC) cohort study is a population-based longitudinal prospective cohort study in the Chinese population involving a clinical database and biobanks. This ongoing study focuses on the prevention of KC progression and is the first to involve the effect of gene‒environment interactions on KC progression. The CKC cohort is hospital-based and dynamic and was established in Zhengzhou, China; KC patients (n = 1114) from a large geographical area were enrolled from January 2019 to June 2023, with a mean age of 22.23 years (6‒57 years). Demographic details, socioeconomic characteristics, lifestyle, disease history, surgical history, family history, and visual and social function data are being collected using questionnaires. General physical examination, eye examination, biological specimen collection, and first-degree relative data were collected and analyzed in the present study. The primary focus of the present study was placed on gene, environment and the effect of gene‒environment interactions on KC progression. The follow-up of the CKC cohort study is expected to include data collection at 3 months, 6 months, and 1 year after the initial examination and then at the annual follow-up examinations. The first follow-up of the CKC cohort study was recorded. A total of 918 patients completed the follow-up by June 1, 2023, with a response rate of 82.40%. Aside from the younger age of patients who were followed up, no significant differences were found between patients who were followed up and patients who were not.

Association of Novel Loci With Keratoconus Susceptibility in a Chinese Genome-Wide Association Study.

Purpose: Keratoconus (KC) is a progressive corneal disease that can lead to corneal blindness if not properly managed. The purpose of this study was to identify genetic associations with KC in China and to investigate whether these genetic variants are associated with corneal thickness and corneal curvature in KC cases. Methods: A genome-wide association study was conducted on 853 patients with KC and 6248 controls. The KC cases were genotyped with the Illumina Infinium Human Asian Screening Array BeadChip, and the controls were genotyped with the Illumina Infinium Human Global Screening Array BeadChip. Genetic associations with KC, as well as correlations between the positive variants and corneal parameters including central corneal thickness (CCT) and mean keratometry (Km), were compared using PLINK version 1.90. Results: Our present study identified four single-nucleotide polymorphisms (SNPs) within four risk loci (PTGER3: rs2300163, EYA1: rs1077435, ASS1: rs141365191, and CHTF8: rs3743680) associated with KC in Chinese patients that reached genome-wide significance. Among the identified SNPs with P < 1.00 × 10-4, seven SNPs (FOSL2-PLB1: rs12622211, RXRA-COL5A1: rs3118515, rs3132306, rs1536482, rs3118520, KAT6B: rs192187772, RAP2A-IPO5: rs41361245) were observed to be associated with CCT, and one SNP (USP13: rs6767552) was found to be associated with Km. Conclusions: In the first genome-wide association study of KC with a relatively large study population in China, we identified four SNPs in four risk loci associated with the disease. The findings enriched the understanding of genetic susceptibility to KC and provided new insights into the genetic etiology of the disease.

Splicing factor hnRNPA1 regulates alternative splicing of LOXL2 to enhance production of LOXL2Δ13.

Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family and has the ability to catalyze the cross-linking of extracellular matrix collagen and elastin. High expression of LOXL2 is related to tumor cell proliferation, invasion and metastasis. LOXL2 contains 14 exons. Previous studies have found that LOXL2 has abnormal alternative splicing and exon skipping in a variety of tissues and cells, resulting in a new alternatively-spliced isoform denoted LOXL2Δ13. LOXL2Δ13 lacks LOXL2WT exon 13, but its encoded protein has greater ability to induce tumor cell proliferation, invasion and metastasis. However, the molecular events that produce LOXL2Δ13 are still unclear. In this study, we found that overexpression of the splicing factor hnRNPA1 in cells can regulate the alternative splicing of LOXL2 and increase the expression of LOXL2Δ13. The exonic splicing silencer (ESS) exists at the 3' splice site (3' SS) and 5' splice site (5' SS) of LOXL2 exon 13. HnRNPA1 can bind to the ESS and inhibit the inclusion of exon 13. The RRM domain of hnRNPA1 and phosphorylation of hnRNPA1 at S91 and S95 are important for the regulation of LOXL2 alternative splicing. These results show that hnRNPA1 is a splicing factor that enhances the production of LOXL2Δ13.

Long non-coding RNA-NONMMMUT004552.2 regulates the unloading-induced bone loss through the miRNA-15b-5p/Syne1 in mice.

Exercise-induced mechanical loading can increase bone strength whilst mechanical unloading enhances bone-loss. Here, we investigated the role of lncRNA NONMMUT004552.2 in unloading-induced bone-loss. Knockout of lncRNA NONMMUT004552.2 in hindlimb-unloaded mice caused an increase in the bone formation and osteoblast activity. The silencing of lncRNA NONMMUT004552.2 also decreased the osteoblast apoptosis and expression of Bax and cleaved caspase-3, increased Bcl-2 protein expression in MC3T3-E1 cells. Mechanistic investigations demonstrated that NONMMUT004552.2 functions as a competing endogenous RNA (ceRNA) to facilitate the protein expression of spectrin repeat containing, nuclear envelope 1 (Syne1) by competitively binding miR-15b-5p and subsequently inhibits the osteoblast differentiation and bone formation in the microgravity unloading environment. These data highlight the importance of the lncRNA NONMMUT004552.2/miR-15b-5p/Syne1 axis for the treatment of osteoporosis.

Construction and validation of classification models for predicting the response to concurrent chemo-radiotherapy of patients with esophageal squamous cell carcinoma based on multi-omics data.

BACKGROUND: Concurrent chemo-radiotherapy (CCRT) is the preferred non-surgical treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Unfortunately, some patients respond poorly, which leads to inappropriate or excessive treatment and affects patient survival. To accurately predict the response of ESCC patients to CCRT, we developed classification models based on the clinical, serum proteomic and radiomic data. METHODS: A total of 138 ESCC patients receiving CCRT were enrolled in this study and randomly split into a training cohort (n = 92) and a test cohort (n = 46). All patients were classified into either complete response (CR) or incomplete response (non-CR) groups according to RECIST1.1. Radiomic features were extracted by 3Dslicer. Serum proteomic data was obtained by Olink proximity extension assay. The logistic regression model with elastic-net penalty and the R-package "rms" v6.2-0 were applied to construct classification and nomogram models, respectively. The area under the receiver operating characteristic curves (AUC) was used to evaluate the predictive performance of the models. RESULTS: Seven classification models based on multi-omics data were constructed, of which Model-COR, which integrates five clinical, five serum proteomic, and seven radiomic features, achieved the best predictive performance on the test cohort (AUC = 0.8357, 95 % CI: 0.7158-0.9556). Meanwhile, patients predicted to be CR by Model-COR showed significantly longer overall survival than those predicted to be non-CR in both cohorts (Log-rank P = 0.0014 and 0.027, respectively). Furthermore, two nomogram models based on multi-omics data also performed well in predicting response to CCRT (AUC = 0.8398 and 0.8483, respectively). CONCLUSION: We developed and validated a multi-omics based classification model and two nomogram models for predicting the response of ESCC patients to CCRT, which achieved the best prediction performance by integrating clinical, serum Olink proteomic, and radiomic data. These models could be useful for personalized treatment decisions and more precise clinical radiotherapy and chemotherapy for ESCC patients.

KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Fascin - F-actin interaction studied by molecular dynamics simulation and protein network analysis.

Actin bundles are an important component of cellular cytoskeleton and participate in the movement of cells. The formation of actin bundles requires the participation of many actin binding proteins (ABPs). Fascin is a member of ABPs, which plays a key role in bundling filamentous actin (F-actin) to bundles. However, the detailed interactions between fascin and F-actin are unclear. In this study, we construct an atomic-level structure of fascin - F-actin complex based on a rather poor cryo-EM data with resolution of 20 nm. We first optimized the geometries of the complex by molecular dynamics (MD) simulation and analyzed the binding site and pose of fascin which bundles two F-actin chains. Next, binding free energy of fascin was calculated by MM/GBSA method. Finally, protein structure network analysis (PSNs) was performed to analyze the key residues for fascin binding. Our results show that residues of K22, E27, E29, K41, K43, R110, R149, K358, R408 and K471 on fascin are important for its bundling, which are in good agreement with the experimental data. On the other hand, the consistent results indicate that the atomic-level model of fascin - F-actin complex is reliable. In short, this model can be used to understand the detailed interactions between fascin and F-actin, and to develop novel potential drugs targeting fascin.Communicated by Ramaswamy H. Sarma.

Machine learning analysis with the comprehensive index of corneal tomographic and biomechanical parameters in detecting pediatric subclinical keratoconus.

Background: Keratoconus (KC) occurs at puberty but diagnosis is focused on adults. The early diagnosis of pediatric KC can prevent its progression and improve the quality of life of patients. This study aimed to evaluate the ability of corneal tomographic and biomechanical variables through machine learning analysis to detect subclinical keratoconus (SKC) in a pediatric population. Methods: Fifty-two KC, 52 SKC, and 52 control pediatric eyes matched by age and gender were recruited in a case-control study. The corneal tomographic and biomechanical parameters were measured by professionals. A linear mixed-effects test was used to compare the differences among the three groups and a least significant difference analysis was used to conduct pairwise comparisons. The receiver operating characteristic (ROC) curve and the Delong test were used to evaluate diagnostic ability. Variables were used in a multivariate logistic regression in the machine learning analysis, using a stepwise variable selection to decrease overfitting, and comprehensive indices for detecting pediatric SKC eyes were produced in each step. Results: PE, BAD-D, and TBI had the highest area under the curve (AUC) values in identifying pediatric KC eyes, and the corresponding cutoff values were 12 µm, 2.48, and 0.6, respectively. For discriminating SKC eyes, the highest AUC (95% CI) was found in SP A1 with a value of 0.84 (0.765, 0.915), and BAD-D was the best parameter among the corneal tomographic parameters with an AUC (95% CI) value of 0.817 (0.729, 0.886). Three models were generated in the machine learning analysis, and Model 3 (y = 0.400*PE + 1.982* DA ratio max [2 mm]-0.072 * SP A1-3.245) had the highest AUC (95% CI) value, with 90.4% sensitivity and 76.9% specificity, and the cutoff value providing the best Youden index was 0.19. Conclusion: The criteria of parameters for diagnosing pediatric KC and SKC eyes were inconsistent with the adult population. Combined corneal tomographic and biomechanical parameters could enhance the early diagnosis of young patients and improve the inadequate representation of pediatric KC research.

CCL2 Potentiates Inflammation Pain and Related Anxiety-Like Behavior Through NMDA Signaling in Anterior Cingulate Cortex.

Previous studies have shown that the C-C motif chemokine ligand 2 (CCL2) is widely expressed in the nervous system and involved in regulating the development of chronic pain and related anxiety-like behaviors, but its precise mechanism is still unclear. This paper provides an in-depth examination of the involvement of CCL2-CCR2 signaling in the anterior cingulate cortex (ACC) in intraplantar injection of complete Freund's adjuvant (CFA) leading to inflammatory pain and its concomitant anxiety-like behaviors by modulation of glutamatergic N-methyl-D-aspartate receptor (NMDAR). Our findings suggest that local bilateral injection of CCR2 antagonist in the ACC inhibits CFA-induced inflammatory pain and anxiety-like behavior. Meanwhile, the expression of CCR2 and CCL2 was significantly increased in ACC after 14 days of intraplantar injection of CFA, and CCR2 was mainly expressed in excitatory neurons. Whole-cell patch-clamp recordings showed that the CCR2 inhibitor RS504393 reduced the frequency of miniature excitatory postsynaptic currents (mEPSC) in ACC, and CCL2 was involved in the regulation of NMDAR-induced current in ACC neurons in the pathological state. In addition, local injection of the NR2B inhibitor of NMDAR subunits, Ro 25-6981, attenuated the effects of CCL2-induced hyperalgesia and anxiety-like behavior in the ACC. In summary, CCL2 acts on CCR2 in ACC excitatory neurons and participates in the regulation of CFA-induced pain and related anxiety-like behaviors through upregulation of NR2B. CCR2 in the ACC neuron may be a potential target for the treatment of chronic inflammatory pain and pain-related anxiety.

Improved photoacoustic images via wavefront shaping modulation based on the scattering structure: retraction.

The referenced article [Opt. Express30, 36489 (2022)10.1364/OE.470330] has been retracted by the authors.

Elevated serum creatinine levels and risk of cognitive impairment in older adults with diabetes: a NHANES study from 2011-2014.

Background: The brain and kidney have similar microvascular structure, which makes them susceptible to certain common pathophysiological processes. In this study, we examined several indicators of kidney injury/function associated with cognitive function in older diabetic patients in the hope of finding effective markers for detecting cognitive impairment (CI). Methods: A total of 2209 older participants (aged ≥60 years) from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) were analyzed for the association between diabetes and CI using a multiple linear regression analysis model. Using the same approach, we also analyzed the relationship between indicators of kidney injury/function and cognitive function (Animal Fluency Test, Digit Symbol Substitution Test) in the diabetic population. Results: Diabetes was associated with CI. In age-adjusted model, older diabetics performed significantly poorer on tests of cognitive function compared to normoglycaemic individuals (1.145 points lower on the Animal Fluency Test (P = 0.005) and 7.868 points reduced on the Digit Symbol Substitution Test (P < 0.001)). In diabetics, we found elevated serum creatinine (SCr) (especially at SCr≥300uM) was associated with lower scores on cognitive function tests after strict adjustment for potential influences on cognitive function. While, albumin/creatinine ratio (ACR) was only associated with Digit Symbol Substitution score (DSS) not Animal Fluency score (AFS), and estimated glomerular filtration rate (eGFR) was only associated with CI (AFS and DSS) at the end-stage renal disease. Conclusion: SCr, as a sensitive indicator of kidney injury, was significantly associated with CI and can potentially be used as an effective marker for screening CI in older diabetics.

Mitochondrial DNA heteroplasmy analysis in keratoconus patients from China.

Background: Mitochondrial DNA (mtDNA) variants have been implicated in keratoconus (KC). The present study aimed to characterize the mtDNA heteroplasmy profile in KC and explore the association of mitochondrial heteroplasmic levels with KC. Methods: Mitochondrial sequencing of peripheral blood samples and corneal tomography were conducted in 300 KC cases and 300 matched controls. The number of heteroplasmic and homoplasmic variants was calculated across the mitochondrial genome. Spearman's correlation was used to analyze the correlation between the number of heteroplasmic variants and age. The association of mtDNA heteroplasmic level with KC was analyzed by logistic regression analysis. Moreover, the relationship between mitochondrial heteroplasmic levels and clinical parameters was determined by linear regression analysis. Results: The distribution of mtDNA heteroplasmic variants showed the highest number of heteroplasmic variants in the non-coding region, while the COX3 gene exhibited the highest number in protein-coding genes. Comparisons of the number of heteroplasmic and homoplasmic non-synonymous variants in protein-coding genes revealed no significant differences between KC cases and controls (all p > 0.05). In addition, the number of heteroplasmic variants was positively associated with age in all subjects (r = 0.085, p = 0.037). The logistic regression analyses indicated that the heteroplasmic levels of m.16180_16181delAA was associated with KC (p < 0.005). Linear regression analyses demonstrated that the heteroplasmic levels of m.16180_16181delAA and m.302A>C were not correlated with thinnest corneal thickness (TCT), steep keratometry (Ks), and flat keratometry (Kf) (all p > 0.05) in KC cases and controls separately. Conclusion: The current study characterized the mtDNA heteroplasmy profile in KC, and revealed that the heteroplasmic levels of m.16180_16181delAA were associated with KC.

A high body mass index strengthens the association between the time of eye rubbing and keratoconus in a Chinese population: a case control study.

BACKGROUND: Although body mass index (BMI) and eye rubbing are linked to an increased risk of keratoconus (KC), the interactive effect of eye rubbing and BMI on KC is largely unknown. This study aimed to evaluate the independent and interactive effects of BMI and eye rubbing on KC and to further explore the role of environmental factors on the occurrence of KC. METHODS: A total of 621 individuals (291 KC patients and 330 control individuals) were enrolled in this hospital­based study on KC patients in Central China after individuals missing BMI data were excluded. BMI was calculated as weight in kilograms divided by the square of height in meters. Data on eye rubbing was recorded through face-to-face interviews. Generalized linear regression models were used to analyze associations among BMI, eye rubbing and KC. Interaction plots were used to describe the interactive effects of BMI and eye rubbing on KC. RESULTS: The ß and 95% confidence interval (CI) were 0.923 (0.112, 1.733) (p = 0.026) and 3.356 (1.953, 4.759) (p < 0.001), respectively, for the effect of each 10 kg/m2 increase in BMI and each 1 min increase in eye rubbing on KC. The interaction of BMI and eye rubbing were positively correlated with KC (p < 0.001). CONCLUSION: These findings suggested that a high BMI aggravated the negative effect of eye rubbing on KC, implying that individuals with a high BMI may be more susceptible to exposure to eye rubbing, which is related to an increased risk of KC.

Multiple functions and dual characteristics of RAB11A in cancers.

Vesicle trafficking is an unceasing and elaborate cellular process that functions in material transport and information delivery. Recent studies have identified the small GTPase, Ras-related protein in brain 11A (RAB11A), as a key regulator in this process. Aberrant RAB11A expression has been reported in several types of cancers, suggesting the important functions and characteristics of RAB11A in cancer. These discoveries are of great significance because therapeutic strategies based on the physiological and pathological status of RAB11A might make cancer treatment more effective, as the molecular mechanisms of cancer development have not been completely revealed. However, these studies on RAB11A have not been reviewed and discussed specifically. Therefore, we summarize and discuss the recent findings of RAB11A involvement in different biological processes, including endocytic recycling regulation, receptors and adhesion molecules recycling, exosome secretion, phagophore formation and cytokinesis, as well as regulatory mechanisms in several tumor types. Moreover, contradictory effects of RAB11A have also been observed in different types of cancers, implying the dual characteristics of RAB11A in cancer, which are either oncogenic or tumor-suppressive. This review on the functions and characteristics of RAB11A highlights the value of RAB11A in inducing multiple important phenotypes based on vesicle trafficking and therefore will offer insights for future studies to reveal the molecular mechanisms, clinical significance, and therapeutic targeting of RAB11A in different cancers.

Masked Graph Neural Networks for Unsupervised Anomaly Detection in Multivariate Time Series.

Anomaly detection has been widely used in grid operation and maintenance, machine fault detection, and so on. In these applications, the multivariate time-series data from multiple sensors with latent relationships are always high-dimensional, which makes multivariate time-series anomaly detection particularly challenging. In existing unsupervised anomaly detection methods for multivariate time series, it is difficult to capture the complex associations among multiple sensors. Graph neural networks (GNNs) can model complex relations in the form of a graph, but the observed time-series data from multiple sensors lack explicit graph structures. GNNs cannot automatically learn the complex correlations in the multivariate time-series data or make good use of the latent relationships among time-series data. In this paper, we propose a new method-masked graph neural networks for unsupervised anomaly detection (MGUAD). MGUAD can learn the structure of the unobserved causality among sensors to detect anomalies. To robustly learn the temporal context from adjacent time points of time-series data from the same sensor, MGUAD randomly masks some points of the time-series data from the sensor and reconstructs the masked time points. Similarly, to robustly learn the graph-level context from adjacent nodes or edges in the relation graph of multivariate time series, MGUAD masks some nodes or edges in the graph under the framework of a GNN. Comprehensive experiments are conducted on three public datasets. According to the experimental findings, MGUAD outperforms state-of-the-art anomaly detection methods.

A protein complex of LCN2, LOXL2 and MMP9 facilitates tumour metastasis in oesophageal cancer.

During malignant tumour development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodelling. In this study, protein-protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of oesophageal squamous cell carcinoma (ESCC) cells, as well as tumour growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumour growth. Co-overexpression of LCN2, LOXL2 and MMP9 enhanced the ability of tumour cells to degrade fibronectin and Matrigel, increased the formation and extension of filopodia, and promoted the rearrangement of microfilaments through upregulation of profilin 1. In addition, the LCN2/LOXL2/MMP9 ternary complex promoted the expression of testican-1 (SPOCK1), and abnormally activated the FAK/AKT/GSK3ß signalling pathway. In summary, the LCN2/LOXL2/MMP9 ternary complex promoted the migration and invasion of cancer cells and malignant tumour progression through multiple mechanisms and could be a potential therapeutic target.

Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation.

BACKGROUND: As one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma and adenocarcinoma, arising from distinct cells-of-origin. Distinguishing cell-type-specific molecular features from cancer-specific characteristics is challenging. RESULTS: We analyze whole-genome bisulfite sequencing data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both methylation level and genomic distribution of PMDs across tumor samples. We identify subtype-specific PMDs that are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie genomic distribution of PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor HNF4A maintains the binding sites that it generates in normal cells, while establishing new binding sites cooperatively with novel partners such as FOSL1 in esophageal adenocarcinoma. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of cell-type-specific PMDs and DMRs identified here in esophageal cancer are actually markers that co-occur in other cancers originating from related cell types. CONCLUSIONS: These findings advance our understanding of DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations.

The Expression Pattern and Clinical Significance of Lysyl Oxidase Family in Gliomas.

LOX (Lysyl oxidase) family participates in the catalysis of collagen and elastin to maintain ECM homeostasis. Glioma is the most common primary brain tumor and LOX family has not been systemic studied in glioma. In this study, we found LOX family members are upregulated expressed in gliomas samples. A protein-protein interaction network (PPIN) was construct to visualize and understand the differential expression pattern, as well as functional annotation, for LOX family and their interacting proteins, which involved in collagen fibril organization and MAPK signaling pathway. Through subcellular localization distribution, the LOX family members distribute both intracellular and extracellular. All five LOX members are consistently significantly correlate with dendritic cell both in immune infiltrate of GBM and LGG. Survival analysis showed that high expression of LOX family is associated with a poor prognosis of gliomas patients. These analyses provide important clues to identify the potential biological roles for LOX family in gliomas, which might serve as diagnosis markers.