Super-enhancers: Implications in gastric cancer.

Gastric cancer (GC) is the fifth most prevalent malignancy and the third leading cause of cancer-related mortality globally. Despite intensive efforts to enhance the efficiencies of various therapeutics (chemotherapy, surgical interventions, molecular-targeted therapies, immunotherapies), the prognosis for patients with GC remains poor. This might be predominantly due to the limited understanding of the complicated etiology of GC. Importantly, epigenetic modifications and alterations are crucial during GC development. Super-enhancers (SEs) are a large cluster of adjacent enhancers that greatly activate transcription. SEs sustain cell-specific identity by enhancing the transcription of specific oncogenes. In this review, we systematically summarize how SEs are involved in GC development, including the SE landscape in GC, the SE target genes in GC, and the interventions related to SE functions for treating GC.

Correlation Between Anterior Chamber Angle Status and Limbal Stem Cell Deficiency in Primary Angle-Closure Glaucoma.

PURPOSE: To investigate the correlation between the opening and closing states of anterior chamber angle (ACA) and the density of limbal epithelial basal cells (LEBCs) in subjects with primary angle-closure glaucoma (PACG). DESIGN: Cross-sectional observational study. METHODS: A total of 54 eyes of 29 patients diagnosed with PACG were included in the study. Fifty-four eyes from normal subjects were included as control. Automatic evaluation system for ultrasound biomicroscopy images of anterior chamber angle was used to assist ophthalmologists in identifying the opening or closing state of ACA, and the in vivo confocal microscopy (IVCM) was used to evaluate the density of LEBCs in different directions. RESULTS: (1) The average density of LEBCs in the superior, inferior, nasal, and temporal limbus of the eyes in the PACG group was lower than that in the control group, and this pattern did not align with the density distribution observed in the control group. (2) In the early, moderate and advanced PACG, the density of LEBCs corresponding to the closed angle was lower than that in the control group (P < .05). Compared with the density of LEBCs corresponding to the closed angle and the open angle, the closed angle of PACG in the early, moderate and advanced stages was less than that in the open angle (P < .05 in the early and moderate stages; advanced stage P > .05). (3) The basal cell density was processed by dimensionless analysis. In the data calculated by averaging and minimizing, both closed angle dimensionless values were smaller than the open angle (P < .05). (4) Comparative analysis was conducted among the normal, open-angle, and closed-angle conditions in the superior, inferior, nasal, and temporal limbus. In the early stage of PACG, significant differences were observed in 4 limbal regions (P < .05), while in the moderate PACG stage, this difference was noted in 3 limbal regions (P < .05). In advanced PACG, 2 limbal regions exhibited significant differences (P < .05). These findings suggest that during the early PACG stage, angle closure is the predominant influencing factor on LEBCs density, while in the advanced stage, the decrease in density is attributed to a combination of angle closure and the natural progression of the disease. CONCLUSIONS: There is a significant correlation between anterior chamber angle status and LEBCs. Advanced PACG and angle closure should be highly suspected of the occurrence of limbal stem cell deficiency (LSCD).

Genome-wide functional integration identified MAZ-controlled RPS14 dysregulation in hepatocellular carcinoma.

Chronic infection with Hepatitis B virus (HBV) significantly increases the risk of hepatocellular carcinoma (HCC), particularly in Eastern Asia. However, only a subset of individuals with chronic HBV infection develop HCC, suggesting the role for genetic factors in HCC etiology. Despite genome-wide association studies (GWASs) identifying multiple single nucleotide polymorphisms (SNPs) associated with HBV-related HCC susceptibility, the underlying mechanisms and causal genetic polymorphisms remain largely unclear. To address this, we developed The Updated Integrative Functional Genomics Approach (TUIFGA), an methodology that combines data from transcription factor (TF) cistromics, ATAC-seq, DNAase-seq, and the 1000 Genomes Project to identify cancer susceptibility SNPs within TF-binding sites across human genome. Using TUIFGA, we discovered SNP rs13170300 which located in the TF MAZ binding motif of RPS14. The RPS14 rs13170300 was significantly associated with HCC risk in two case-control sets, with the T allele as the protective allele (Shandong discovery set: TT OR = 0.60, 95% CI = 0.49-0.74, P = 1.0 × 10-6; CT OR = 0.69, 95% CI = 0.55-0.86, P = 0.001; Jiangsu validation set: TT OR = 0.70, 95% CI = 0.56-0.87, P = 0.001; CT OR = 0.65, 95% CI = 0.53-0.82, P = 1.6 × 10-4). SNP rs13170300 affected MAZ binding in the RPS14 promoter, resulting in allele-specific changes in gene expression. RPS14 functions as a novel oncogene in HCC, specifically via activating the AKT signaling. Our findings present important insights into the functional genetics underlying HBV-related HCC development and may contribute to personalized approaches for cancer prevention and novel therapeutics.

LINC00921 reduces lung cancer radiosensitivity by destabilizing NUDT21 and driving aberrant MED23 alternative polyadenylation.

Alternative polyadenylation (APA) plays a major role in controlling transcriptome diversity and therapeutic resistance of cancers. However, long non-coding RNAs (lncRNAs) involved in pathological APA remain poorly defined. Here, we functionally characterize LINC00921, a MED13L/P300-induced oncogenic lncRNA, and show that it is required for global regulation of APA in non-small cell lung cancer (NSCLC). LINC00921 shows significant potential for reducing NSCLC radiosensitivity, and high LINC00921 levels are associated with a poor prognosis for patients with NSCLC treated with radiotherapy. LINC00921 controls NUDT21 stability by facilitating binding of NUDT21 with the E3 ligase TRIP12. LINC00921-induced destabilization of NUDT21 promotes 3' UTR shortening of MED23 mRNA via APA, which, in turn, leads to elevated MED23 protein levels in cancer cells and nuclear translocation of ß-catenin and thereby activates expression of multiple ß-catenin/T cell factor (TCF)/lymphoid enhancer-binding factor (LEF)-regulated core oncogenes (c-Myc, CCND1, and BMP4). These findings highlight the importance of functionally annotating lncRNAs controlling APA and suggest the clinical potential of therapeutics for advanced NSCLC.

The ASH1L-AS1-ASH1L axis controls NME1-mediated activation of the RAS signaling in gastric cancer.

Gastric cancer (GC) is one of the most leading cause of malignancies. However, the molecular mechanisms underlying stomach carcinogenesis remain incompletely understood. Dysregulated genetic and epigenetic alternations significantly contribute to GC development. Here, we report that ASH1L and its antisense lncRNA ASH1L-AS1, which are transcribed from the most significant GC-risk signal at 1q22, act as novel oncogenes. The high levels of ASH1L or lncRNA ASH1L-AS1 expression in GC specimens are associated with worse prognosis of patients. In line with this, ASH1L and ASH1L-AS1 are functionally important in promoting GC disease progression. LncRNA ASH1L-AS1 up-regulates ASH1L transcription, increases histone methyltransferase ASH1L expression and elevates genome-wide H3K4me3 modification levels in GC cells. Furthermore, ASH1L-AS1 directly interacts with transcription factor NME1 protein to form the ASH1L-AS1-NME1 ribonucleoprotein, which transcriptionally promotes expression of ASH1L, ASH1L-AS1, KRAS and RAF1, and activates the RAS signaling pathway in GC cells. Taken together, our data demonstrated that the ASH1L-AS1-ASH1L regulatory axis controls histone modification reprogram and activation of the RAS signaling in cancers. Thus, ASH1L-AS1 might be a novel targets of GC therapeutics and diagnosis in the clinic.

Deep Learning-Based Model for Automatic Assessment of Anterior Angle Chamber in Ultrasound Biomicroscopy.

OBJECTIVE: The goal of the work described here was to develop and assess a deep learning-based model that could automatically segment anterior chamber angle (ACA) tissues; classify iris curvature (I-Curv), iris root insertion (IRI), and angle closure (AC); automatically locate scleral spur; and measure ACA parameters in ultrasound biomicroscopy (UBM) images. METHODS: A total of 11,006 UBM images were obtained from 1538 patients with primary angle-closure glaucoma who were admitted to the Eye Center of Renmin Hospital of Wuhan University (Wuhan, China) to develop an imaging database. The UNet++ network was used to segment ACA tissues automatically. In addition, two support vector machine (SVM) algorithms were developed to classify I-Curv and AC, and a logistic regression (LR) algorithm was developed to classify IRI. Meanwhile, an algorithm was developed to automatically locate the scleral spur and measure ACA parameters. An external data set of 1,658 images from Huangshi Aier Eye Hospital was used to evaluate the performance of the model under different conditions. An additional 439 images were collected to compare the performance of the model with experts. RESULTS: The model achieved accuracies of 95.2%, 88.9% and 85.6% in classification of AC, I-Curv and IRI, respectively. Compared with ophthalmologists, the model achieved an accuracy of 0.765 in classifying AC, I-Curv and IRI, indicating that its high accuracy was as high as that of the ophthalmologists (p > 0.05). The average relative errors (AREs) of ACA parameters were smaller than 15% in the internal data sets. Intraclass correlation coefficients (ICCs) of all the angle-related parameters were greater than 0.911. ICC values of all iris thickness parameters were greater than 0.884. The accurate measurement of ACA parameters partly depended on accurate localization of the scleral spur (p < 0.001). CONCLUSION: The model could effectively and accurately evaluate the ACA automatically based on fully automated analysis of UBM images, and it can potentially be a promising tool to assist ophthalmologists. The present study suggested that the deep learning model can be extensively applied to the evaluation of ACA and AC-related biometric risk factors, and it may broaden the application of UBM imaging in the clinical research of primary angle-closure glaucoma.

Inflammatory cytokine-regulated LNCPTCTS suppresses thyroid cancer progression via enhancing Snail nuclear export.

Lymph node metastases are commonly observed in diverse malignancies where they promote cancer progression and poor outcomes, although the molecular basis is incompletely understood. Thyroid cancer is the most prevalent endocrine neoplasm characterized by high frequency of lymph node metastases. Here, we uncover an inflammatory cytokines-controlled epigenetic program during thyroid cancer progression. LNCPTCTS acts as a novel tumor suppressive lncRNA with remarkably decreased expression in thyroid cancer specimens, especially in metastatic lymph nodes. Inflammatory cytokines TNFα or CXCL10, which are released from tumor microenvironment (TME), impair binding capabilities of the transcription factor (TF) EGR1 to the LNCPTCTS promoter and reduce the lncRNA expression in cells. Notably, LNCPTCTS binds to eEF1A2 protein and facilitates the interaction between eEF1A2 and Snail, which promotes Snail nucleus export via the RanGTP-Exp5-aa-tRNA-eEF1A2 complex. Loss of LNCPTCTS in tumors leads to accumulation of Snail in the nucleus, suppressed transcription of E-cadherin and PEBP1, reduced E-cadherin and PEBP1 protein levels, and activated epithelial-mesenchymal transition and MAPK signaling. Our results reveal what we believe to be a novel paradigm between TME and epigenetic reprogram in cancer cells which drives lymph node metastases, therefore illuminating the suitability of LNCPTCTS as a targetable vulnerability in thyroid cancer.

Noncoding RNAs: an emerging modulator of drug resistance in pancreatic cancer.

Pancreatic cancer is the eighth leading cause of cancer-related deaths worldwide. Chemotherapy including gemcitabine, 5-fluorouracil, adriamycin and cisplatin, immunotherapy with immune checkpoint inhibitors and targeted therapy have been demonstrated to significantly improve prognosis of pancreatic cancer patients with advanced diseases. However, most patients developed drug resistance to these therapeutic agents, which leading to shortened patient survival. The detailed molecular mechanisms contributing to pancreatic cancer drug resistance remain largely unclear. The growing evidences have shown that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in pancreatic cancer pathogenesis and development of drug resistance. In the present review, we systematically summarized the new insight on of various miRNAs, lncRNAs and circRNAs on drug resistance of pancreatic cancer. These results demonstrated that targeting the tumor-specific ncRNA may provide novel options for pancreatic cancer treatments.

Evaluation of a computer-aided diagnostic model for corneal diseases by analyzing in vivo confocal microscopy images.

Objective: In order to automatically and rapidly recognize the layers of corneal images using in vivo confocal microscopy (IVCM) and classify them into normal and abnormal images, a computer-aided diagnostic model was developed and tested based on deep learning to reduce physicians' workload. Methods: A total of 19,612 corneal images were retrospectively collected from 423 patients who underwent IVCM between January 2021 and August 2022 from Renmin Hospital of Wuhan University (Wuhan, China) and Zhongnan Hospital of Wuhan University (Wuhan, China). Images were then reviewed and categorized by three corneal specialists before training and testing the models, including the layer recognition model (epithelium, bowman's membrane, stroma, and endothelium) and diagnostic model, to identify the layers of corneal images and distinguish normal images from abnormal images. Totally, 580 database-independent IVCM images were used in a human-machine competition to assess the speed and accuracy of image recognition by 4 ophthalmologists and artificial intelligence (AI). To evaluate the efficacy of the model, 8 trainees were employed to recognize these 580 images both with and without model assistance, and the results of the two evaluations were analyzed to explore the effects of model assistance. Results: The accuracy of the model reached 0.914, 0.957, 0.967, and 0.950 for the recognition of 4 layers of epithelium, bowman's membrane, stroma, and endothelium in the internal test dataset, respectively, and it was 0.961, 0.932, 0.945, and 0.959 for the recognition of normal/abnormal images at each layer, respectively. In the external test dataset, the accuracy of the recognition of corneal layers was 0.960, 0.965, 0.966, and 0.964, respectively, and the accuracy of normal/abnormal image recognition was 0.983, 0.972, 0.940, and 0.982, respectively. In the human-machine competition, the model achieved an accuracy of 0.929, which was similar to that of specialists and higher than that of senior physicians, and the recognition speed was 237 times faster than that of specialists. With model assistance, the accuracy of trainees increased from 0.712 to 0.886. Conclusion: A computer-aided diagnostic model was developed for IVCM images based on deep learning, which rapidly recognized the layers of corneal images and classified them as normal and abnormal. This model can increase the efficacy of clinical diagnosis and assist physicians in training and learning for clinical purposes.

The Allelic Expression of RNA Editing Gene ADARB1 in Hepatocellular Carcinoma Treated with Transarterial Chemoembolization.

Introduction: Transarterial chemoembolization (TACE) is the commonly used therapy of unresectable hepatocellular carcinoma (HCC), though the prognosis of different TACE-treated HCC patients varies, which may be due to the heterogeneity of HCC tumors caused by genetic variants and epigenetic changes such as RNA editing. There is dysregulated RNA adenosine-to-inosine (A-to-I) editing in HCC and RNA-edited genes are involved in the epigenetic process. It remains unclear how genetic variants of RNA editing genes affect the prognosis of HCC cases treated by TACE. Methods: In this study, we examined 28 potentially functional single-nucleotide polymorphisms (SNPs) of four RNA editing genes (ADARB1, ADAR, ADARB2 and AIMP2) in two independent TACE patient cohorts. Results: We found that ADARB1 rs1051367 and rs2253763 polymorphisms were markedly associated with the prognosis of HCC cases who received TACE in both cohorts. In HCC cells, the rs2253763 C-to-T change in ADARB1 3'-untranslated region attenuated its binding with miR-542-3p and allele-specifically elevated ADARB1 levels. Consistent with this, patients carrying the rs2253763 C allele showed reduced ADARB1 expression in cancer tissues and notably shorter survival after TACE therapy in comparison with individuals with the T allele. Ectopic ADARB1 profoundly enhanced the efficacy of oxaliplatin, one of the common TACE chemotherapeutic drugs. Discussion: Our findings highlighted the value of ADARB1 polymorphisms as prognostic markers in TACE therapy for HCC patients. Notably, our findings revealed that targeting the ADARB1 enzyme may be a promising therapeutic strategy in combination with TACE for HCC cases.

The Epigenetic Regulation of RNA N6-Methyladenosine Methylation in Glycolipid Metabolism.

The highly conserved and dynamically reversible N6-methyladenine (m6A) modification has emerged as a critical gene expression regulator by affecting RNA splicing, translation efficiency, and stability at the post-transcriptional level, which has been established to be involved in various physiological and pathological processes, including glycolipid metabolism and the development of glycolipid metabolic disease (GLMD). Hence, accumulating studies have focused on the effects and regulatory mechanisms of m6A modification on glucose metabolism, lipid metabolism, and GLMD. This review summarizes the underlying mechanism of how m6A modification regulates glucose and lipid metabolism-related enzymes, transcription factors, and signaling pathways and the advances of m6A regulatory mechanisms in GLMD in order to deepen the understanding of the association of m6A modification with glycolipid metabolism and GLMD.

Circular RNA circRNF169 functions as a miR-30c-5p sponge to promote cellular senescence.

Circular RNAs (circRNAs), characterized as single-stranded closed circular RNA molecules, have been established to exert pivotal functions in various biological or pathological processes. Nonetheless, the effects and underlying mechanisms concerning circRNAs on the aging and aging-related diseases remain elusive. We herein compared the expression patterns of circRNAs in young and senescent mouse embryonic fibroblasts (MEFs), and uncovered that circRNF169 was dramatically up-regulated in senescent MEFs compared with that in young MEFs. Therefore, we further digged into the role and potential mechanisms of circRNF169 in the senescence of MEFs. The results of senescence-associate-ß-galactosidase staining and BrdU incorporation assay showed that silencing of circRNF169 significantly delayed MEFs senescence and promoted cell proliferation, while ectopic expression of circRNF169 exhibited the opposite effects. Moreover, the dual-luciferase reporter assay confirmed that circRNF169 acted as an endogenous miR-30c-5p sponge, which accelerated cellular senescence by sequestering and inhibiting miR-30c-5p activity. Taken together, our results suggested that circRNF169 exerted a crucial role in cellular senescence through sponging miR-30c-5p and represented a promising target for aging intervention.

Limbal Stem Cell Deficiency After Glaucoma Surgery.

PURPOSE: To characterize the clinical presentation of limbal stem cell deficiency (LSCD) associated with glaucoma surgeries. METHODS: This is a retrospective cross-sectional study of patients with LSCD and glaucoma who presented to the Stein Eye Institute at the University of California, Los Angeles, between 2009 and 2018. Patients who underwent trabeculectomy and/or aqueous shunt surgery were included. The severity of LSCD was staged using global consensus guidelines and a clinical scoring system, and basal epithelial cell density was measured by in vivo confocal microscopy. Anatomic locations of glaucoma and non-glaucoma surgeries, locations of LSCD, and severity of LSCD were compared. RESULTS: Fifty-one eyes of 41 patients with LSCD associated with glaucoma surgery were included in this study. LSCD in these patients uniquely featured sectoral replacement of corneal epithelium by conjunctival epithelium, without corneal neovascularization or pannus. The sites of glaucoma surgery strongly correlated with the locations of LSCD (P = 0.002). There was a trend toward increased severity of LSCD in eyes with 2 or more glaucoma surgeries as compared to eyes with 1 glaucoma surgery, although the difference did not reach statistical significance (P = 0.3). Use of topical glaucoma medications correlated with LSCD severity, while the impact of antimetabolites did not reach statistical significance. The location of glaucoma drainage surgery is correlated with the location of LSCD. CONCLUSIONS: LSCD associated with glaucoma surgery has clinical features distinct from LSCD resulting from other etiologies. Further study is required to delineate the full impact of glaucoma surgery on limbal stem cell function and survival.

Optical Quality and Related Factors in Ocular Hypertension: Preliminary Study.

Background. To evaluate the optical quality and related factors in patients with ocular hypertension (OHT). Methods. This was a prospective case-control study. A total of 12 eyes with OHT and 20 control eyes underwent testing with Optical Quality Analysis System II (OQAS II) to evaluate the modulation transfer function cut off frequency (MTF cutoff), the Strehl 2D ratio (SR), objective scatter index (OSI), tear-film mean OSI (TFOSI), and the OQAS values (OV100%,OV20%, and OV9%). Results. The optical quality of patients with OHT declined, with lower MTF cutoff (OHT 36.86 ± 7.11 cpd , controls 48.50 ± 4.04 cpd, t = -4.60, P < 0.05), lower SR (OHT 0.22 ± 0.04, controls 0.27 ± 0.05, t = -2.72, P < 0.05), lower OV100% (OHT 1.26 ± 0.25, controls 1.61 ± 0.14, t = -4.03, P < 0.05), lower OV20% (OHT 1.27 ± 0.27, controls 1.72 ± 0.20, t = -4.00, P < 0.05), and lower OV9% (OHT 1.30 ± 0.25, controls 1.69 ± 0.32, t = -2.28, P < 0.05). There were not any statistically significant differences in OSI and TFOSI. The MTF cutoff in patients with OHT was correlated significantly with age (r = -0.59, P < 0.05). Conclusions. Optical quality of patients with OHT is reduced, with lower MTF cutoff, SR, OV100%, OV20%, and OV9%. MTF cutoff is negatively related to age.

PTHrP Nuclear Localization and Carboxyl Terminus Sequences Modulate Dental and Mandibular Development in Part via the Action of p27.

To determine whether the action of the PTHrP nuclear localization sequence and C terminus is mediated through p27 in modulating dental and mandibular development, compound mutant mice, which are homozygous for both p27 deletion and the PTHrP1-84 knock-in mutation (p27(-/-)Pthrp(KI/KI)), were generated. Their teeth and mandibular phenotypes were compared with those of p27(-/-), Pthrp(KI/KI), and wild-type mice. At 2 weeks of age, the mandibular mineral density, alveolar bone volume, osteoblast numbers, and dental volume, dentin sialoprotein-immunopositive areas in the first molar were increased significantly in p27(-/-) mice and decreased dramatically in both Pthrp(KI/KI) and p27(-/-) Pthrp(KI/KI) mice compared with wild-type mice; however, these parameters were partly rescued in p27(-/-) Pthrp(KI/KI) mice compared with Pthrp(KI/KI) mice. These data demonstrate that the deletion of p27 in Pthrp(KI/KI) mice can partially rescue defects in dental and mandibular development. Furthermore, we found that deletion of p27 in Pthrp(KI/KI) mice partially corrected the dental and mandibular phenotype by modulating cell cyclin-regulating molecules and antioxidant enzymes. This study therefore indicates that the p27 pathway may function downstream in the action of PTHrP nuclear localization sequence to regulate dental and mandibular development.

[The change of the level of the vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma before and after anterior retinal cryotherapy].

OBJECTIVE: To compare the change of the level of the vascular endothelial growth factor (VEGF) in aqueous humor of patients with neovascular glaucoma (NVG) before and after anterior retinal cryotherapy and investigate the effects of the fluctuation of VEGF on the neovascularization of iris. METHODS: 28 patients with neovascular glaucoma were undergone iris fluorescent angiography to identify the area and amount of new vessels before and after anterior retinal cryotherapy. The neovascularization of iris was observed from 7 to 14 days by iris fluorescent angiography to confirm the regression of new vessels in iris before trabeculectomy. Samples of aqueous humor were obtained before anterior retinal cryotherapy and trabeculectomy, and 30 samples of aqueous humor from patients with senile cataract were collected as normal group. The concentrations of VEGF were measured using enzyme linked immunosorbent assay. RESULTS: the concentration of VEGF (2.096 +/- 0.512) ng/ml in aqueous humor from patients with NVG were much higher than the specimen from the patients pre-trabeculectomy (0.478 +/- 0.312) ng/ml, There was a significant difference between the two groups (t = 17.994, P < 0.01). The mean VEGF concentration of the aqueous humor from patients with senile cataract was (0.198 +/- 0.045) ng/ml which was much lower compared with the samples from patients of pre-trabeculectomy (t = 18.453, P < 0.01). CONCLUSIONS: The concentration of VEGF decline after the regression of new vessels in iris. The results suggest that VEGF play an important role in formation of iris neovascularization. Blockage the release of VEGF might reduce the occurrence of neovascular glaucoma.