Longitudinal test of the social cognitive model of well-being among Chinese college students.

Since the social cognitive model of well-being in academic\work settings was proposed, more and more studies have supported its validity. Nevertheless, most studies failed to test the temporal precedence of its core variables related to individual career development. Thus, we aimed to test this model among 1512 Chinese college students with a longitudinal perspective. They completed the Career-related Parental Support Inventory, Career Exploration and Decision Self-Efficacy-Brief Decision Scale, Career Commitment Making Scale, and Multiple Happiness Questionnaire three times being a four-month interval. The result indicated that there were more positive predicting associations between career-related parental support, career decision self-efficacy (CDSE), career commitment making, and well-being. Moreover, the longitudinal mediation analyses indicated that T1 career-related parental support was linked to T3 well-being via T2 career commitment making, and that T1 CDSE was linked to T3 well-being via T2 career commitment making. The implications of these findings for further research, practices, and policy-making were discussed.

Lobster-Inspired Chitosan-Derived Adhesives with a Biomimetic Design.

Polysaccharide-based adhesives, especially chitosan (CS)-derived adhesives, serve as promising sustainable alternatives to traditional adhesives. However, most demonstrate a poor adhesive strength. Inspired by the inherent layered structure of marine arthropods (lobsters), a core-shell structure (SiO2-NH2@OPG) with amine-functionalized silica (SiO2-NH2) as the core and oxidized pyrogallol (OPG) as the shell is prepared in this study. The compound is blended with CS to produce a structural biomimetic wood adhesive (SiO2-NH2@OPG/CS) with excellent performance. In addition to thermocompressive curing, this adhesive exhibits a water-evaporation-induced curing behavior at room temperature. With reference to the design mechanism of the lobster cuticle, this microphase-separated structure consists of clustered nanofibers with varying amounts of SiO2-NH2@OPG particles between the fibers. This intriguing microphase structure and its mechanical effects could offer a powerful solution for improving the functional modification of wood composites.

Generating detailed intercellular communication patterns in psoriasis at the single-cell level using social networking, pattern recognition, and manifold learning methods to optimize treatment strategies.

Psoriasis, a complex and recurrent chronic inflammatory skin disease involving various inflammatory cell types, requires effective cell communication to maintain the homeostatic balance of inflammation. However, patterns of communication at the single-cell level have not been systematically investigated. In this study, we employed social network analysis tools, pattern recognition, and manifold learning to compare molecular communication features between psoriasis cells and normal skin cells. Utilizing a process that facilitates the discovery of cell type-specific regulons, we analyzed internal regulatory networks among different cells in psoriasis. Advanced techniques for the quantitative detection of non-targeted proteins in pathological tissue sections were employed to demonstrate protein expression. Our findings revealed a synergistic interplay among the communication signals of immune cells in psoriasis. B-cells were activated, while Langerhans cells shifted into the primary signaling output mode to fulfill antigen presentation, mediating T-cell immunity. In contrast to normal skin cells, psoriasis cells shut down numerous signaling pathways, influencing the balance of skin cell renewal and differentiation. Additionally, we identified a significant number of active cell type-specific regulons of resident immune cells around the hair follicle. This study unveiled the molecular communication features of the hair follicle cell-psoriasis axis, showcasing its potential for therapeutic targeting at the single-cell level. By elucidating the pattern of immune cell communication in psoriasis and identifying new molecular features of the hair follicle cell-psoriasis axis, our findings present innovative strategies for drug targeting to enhance psoriasis treatment.

Probing the communication patterns of different chondrocyte subtypes in osteoarthritis at the single cell level using pattern recognition and manifold learning.

The patterns of communication among different chondrocyte subtypes in human cartilage degeneration and regeneration help us understand the microenvironment of osteoarthritis and optimize cell-targeted therapies. Here, a single-cell transcriptome dataset of chondrocytes is used to explore the synergistic and communicative patterns of different chondrocyte subtypes. We collected 1600 chondrocytes from 10 patients with osteoarthritis and analyzed the active communication patterns for the first time based on network analysis and pattern recognition at the single-cell level. Manifold learning and quantitative contrasts were performed to analyze conserved and specific communication pathways. We found that ProCs (Proliferative chondrocytes), ECs (Effector chondrocytes), preHTCs (Prehypertrophic chondrocytes), HTCs (Hypertrophic chondrocytes), and FCs (Fibrocartilage chondrocytes) are more active in incoming and outgoing signaling patterns, which is consistent with studies on their close functional cooperation. Among them, preHTCs play multiple roles in chondrocyte communication, and ProCs and preHTCs have many overlapping pathways. These two subtypes are the most active among all chondrocyte subtypes. Interestingly, ECs and FCs are a pair of "mutually exclusive" subtypes, of which ECs are predominant in incoming patterns and FCs in outgoing patterns. The active signaling pathways of ECs and FCs largely do not overlap. COLLAGEN and LAMININ are the main pivotal pathways, which means they are very important in the repair and expansion of joint homeostasis. Notably, only preHTCs assume multiple roles (including sender, receiver, mediator, and influencer) and are involved in multiple communication pathways. We have examined their communication patterns from the perspective of cellular interactions, revealed the relationships among different chondrocyte subtypes, and, in particular, identified a number of active subtypes and pathways that are important for targeted therapy in the osteoarthritic microenvironment. Our findings provide a new research paradigm and new insights into understanding chondrocyte activity patterns in the osteoarthritic microenvironment.

Single-cell communication patterns and their intracellular information flow in synovial fibroblastic osteoarthritis and rheumatoid arthritis.

BACKGROUND: Synovial fibroblasts are critical for maintaining homeostasis in major autoimmune diseases involving joint inflammation, including osteoarthritis and rheumatoid arthritis. However, little is known about the interactions among different cell subtypes and the specific sets of signaling pathways and activities that they trigger. METHODS: Using social network analysis, pattern recognition, and manifold learning approaches, we identified patterns of single-cell communication in OA (osteoarthritis) and RA (rheumatoid arthritis). RESULTS: Our results suggest that OA and RA have distinct cellular communication patterns and signaling pathways. The LAMININ (Laminin) and COLLAGEN (Collagen) pathways predominate in osteoarthritis, while the EGF (Epidermal growth factor), NT (Neurotrophin) and CDH5 (Cadherin 5) pathways predominate in rheumatoid arthritis, with a central role for THY1 (Thy-1 cell surface antigen) +CDH11 (Cadherin 11) + cells. The OA opens the PDGF (Platelet-derived growth factors) pathway (driver of bone angiogenesis), the RA opens the EGF pathway (bone formation) and the SEMA3 (Semaphorin 3A) pathway (involved in immune regulation). Interestingly, we found that OA no longer has cell types involved in the MHC complex (Major histocompatibility complex) and their activity, whereas the MHC complex functions primarily in RA in the presentation of inflammatory antigens, and that the complement system in OA has the potential to displace the function of the MHC complex. The specific signaling patterns of THY1+CDH11+ cells and their secreted ligand receptors are more conducive to cell migration and lay the foundation for promoting osteoclastogenesis. This subpopulation may also be involved in the accumulation of lymphocytes, affecting the recruitment of immune cells. Members of the collagen family (COL1A1 (Collagen Type I Alpha 1 Chain), COL6A2 (Collagen Type VI Alpha 2 Chain) and COL6A1 (Collagen Type VI Alpha 1 Chain)) and transforming growth factor (TGFB3) maintain the extracellular matrix in osteoarthritis and mediate cell migration and adhesion in rheumatoid arthritis, including the PTN (Pleiotrophin) / THBS1 (Thrombospondin 1) interaction. CONCLUSION: Increased understanding of the interaction networks between synovial fibroblast subtypes, particularly the shared and unique cellular communication features between osteoarthritis and rheumatoid arthritis and their hub cells, should help inform the design of therapeutic agents for inflammatory joint disease.

Targeting mutant p53 stabilization for cancer therapy.

Over 50% cancer bears TP53 mutation, the highly stabilized mutant p53 protein drives the tumorigenesis and progression. Mutation of p53 not only cause loss-of-function and dominant-negative effects (DNE), but also results in the abnormal stability by the regulation of the ubiquitin-proteasome system and molecular chaperones that promote tumorigenesis through gain-of-function effects. The accumulation of mutant p53 is mainly regulated by molecular chaperones, including Hsp40, Hsp70, Hsp90 and other biomolecules such as TRIM21, BAG2 and Stat3. In addition, mutant p53 forms prion-like aggregates or complexes with other protein molecules and result in the accumulation of mutant p53 in tumor cells. Depleting mutant p53 has become one of the strategies to target mutant p53. This review will focus on the mechanism of mutant p53 stabilization and discuss how the strategies to manipulate these interconnected processes for cancer therapy.

Butein inhibits cancer cell growth by rescuing the wild-type thermal stability of mutant p53.

p53 is a transcription factor that activates the expression of various genes involved in the maintenance of genomic stability, and more than 50% of cancers harbor inactivating p53 mutations, which are indicative of highly aggressive cancer and poor prognosis. Pharmacological targeting of mutant p53 to restore the wild-type p53 tumor-suppressing function is a promising strategy for cancer therapy. In this study, we identified a small molecule, Butein, that reactivates mutant p53 activity in tumor cells harboring the R175H or R273H mutation. Butein restored wild-type-like conformation and DNA-binding ability in HT29 and SK-BR-3 cells harboring mutant p53-R175H and mutant p53-R273H, respectively. Moreover, Butein enabled the transactivation of p53 target genes and decreased the interactions of Hsp90 with mutant p53-R175H and mutant p53-R273H proteins, while Hsp90 overexpression reversed targeted p53 gene activation. In addition, Butein induced thermal stabilization of wild-type p53, mutant p53-R273H and mutant p53-R175H, as determined via CETSA. From docking study, we further proved that Butein binding to p53 stabilized the DNA-binding loop-sheet-helix motif of mutant p53-R175H and regulated its DNA-binding activity via an allosteric mechanism, conferring wild-type-like the DNA-binding activity of mutant p53. Collectively, the data suggest that Butein is a potential antitumor agent that restores p53 function in cancers harboring mutant p53-R273H or mutant p53-R175H. SIGNIFICANCE: Butein restores the ability of mutant p53 to bind DNA by reversing its transition to the Loop3 (L3) state, endows p53 mutants with thermal stability and re-establishes their transcriptional activity to induce cancer cell death.

Influence of miosis and laser peripheral iridotomy on intraocular lens power calculation in patients with primary angle closure disease.

OBJECTIVES: To evaluate the effect of miosis and laser peripheral iridotomy (LPI) on intraocular lens (IOL) power prediction and ocular biometry in eyes with primary angle closure disease (PACD). METHODS: In this prospective observational study, primary angle closure suspects (PACS), and subjects classified with primary angle closure (PAC)/primary angle-closure glaucoma (PACG) undergoing LPI were enrolled. Ocular biometric parameters were measured with IOLMaster700 at baseline (T0), one week after pilocarpine instillation (T1), and another week post LPI (T2). Biometric changes and the IOL power predicted for emmetropia using Barrett Universal II, Haigis, Holladay2, Hoffer Q and SRK/T formulae were analysed and compared among different time points. RESULTS: 100 eyes of 50 PACS and 50 PAC/PACG patients were enrolled. Following pilocarpine-induced miosis, lens thickness (LT) increased and anterior chamber depth (ACD) decreased (all groups p < 0.01), while white-to-white diameter decreased and central corneal thickness increased significantly only in the PACS cohort (both p < 0.01). Compared to baseline, LPI induced an increase of ACD and a slight decrease of LT in PACS (both p < 0.01), whereas only axial length changed significantly (p = 0.012) in the PAC/PACG cohort. Regardless of the formula used, no significant difference to the predicted IOL power for emmetropia existed among the three time points in each group (all p > 0.1). CONCLUSION: We report the changes of anterior segment parameters induced by miosis and LPI in PACD. These interventions do not significantly affect the IOL power calculation predicted for emmetropia in Chinese eyes when common third-, fourth-and new generation IOL formulae are used.

CD 4+, CD 8+ and CD 19+cell surface antigen and abnormal mitochondria ultrastructure of peripheral blood P-type atypical lymphocytes in patients with schizophrenia.

OBJECTIVE: P-type atypical lymphocytes may play important roles in the aetiology and therapy of schizophrenia. However, there is merely a direct immunological characterisation of it. The aim of this study is to explore the surface antigens of these cells and their comparative ultrastructure in schizophrenia. METHODS: We recruited 25 age-and gender-matched patients with unmedicated schizophrenia, other mental diseases and healthy individuals. Peripheral venous blood was smeared and stained. CD4+, CD8+ and CD19+ cell surface antigen- positive lymphocytes were purified using magnetic beads and prepared for light microscopy and electron microscopy. RESULTS: The percentages of P-type atypical lymphocytes (34.53% ± 9.92%) were significantly higher (p < 0.0001) in schizophrenia than that of other mental diseases (9.79% ± 3.45%). These cells could present CD4+, CD8+ and CD19+ surface antigens. Their relative ultrastructure differed from that of normal lymphocytes, especially in mitochondria, which showed abundant, aggregated and quite irregular mitochondria; for example, slight dilation of the foci, swelling, degeneration, and even cavity. CONCLUSIONS: P-type atypical lymphocytes could be found among CD4+, CD8+, and CD19 + lymphocytes with schizophrenia. Their abnormal ultrastructure of mitochondria implied that energy metabolism might play an important role in the aetiology of schizophrenia.

Outcomes of combined phacoemulsification, anterior vitrectomy, and sclerectomy in nanophthalmic eyes with glaucoma.

OBJECTIVES: To compare the long-term efficacy and safety of combined phacoemulsification, anterior vitrectomy, and sclerectomy (triple procedure surgery, TS); combined phacoemulsification and anterior vitrectomy (double procedure surgery, DS); and filtering surgery (FS) in nanophthalmos with angle-closure glaucoma (NACG). METHODS: Retrospective cohort study. Forty patients (44 eyes) diagnosed with NACG who underwent TS, DS, and FS were included. All eyes in the TS group and seven (47%) eyes in the DS group also underwent goniosynechialysis during the surgery. The main outcome measures (intraocular pressure [IOP], best-corrected visual acuity, complications, and second surgeries) were recorded at the early- (within 1 week) and late-stage (>3 months) follow-up. RESULTS: The late-stage IOP was significantly lower in the TS (mean ± standard deviation: 13.29 ± 2.49 mm Hg) than in the DS (19.69 ± 6.97 mm Hg) and FS groups (27.57 ± 12.26 mm Hg, p < 0.001). More visual improvements were observed in the TS and DS groups than in the FS group at late-stage follow-up (p = 0.04). The complication rates in the TS, DS, and FS groups were 26%, 33%, and 70%, respectively (p = 0.046); the second surgery rates were 0%, 33%, and 60%, respectively (p < 0.001). In total, one, three, and six severe complications were observed in the TS, DS, and FS groups, respectively. The mean follow-up durations in the TS, DS, and FS groups were 18.89, 20.02, and 25.75 months, respectively. CONCLUSIONS: NACG management remains challenging. TS presented relatively good clinical efficacy and safety with better postoperative IOP outcomes, lower complications, and second surgery rates among the three groups in eyes with NACG.

A score of DNA damage repair pathway with the predictive ability for chemotherapy and immunotherapy is strongly associated with immune signaling pathway in pan-cancer.

DNA damage repair (DDR) is critical in maintaining normal cellular function and genome integrity and is associated with cancer risk, progression, and therapeutic response. However, there is still a lack of a thorough understanding of the effects of DDR genes' expression level in cancer progression and therapeutic resistance. Therefore, we defined a tumor-related DDR score (TR-DDR score), utilizing the expression levels of 20 genes, to quantify the tumor signature of DNA damage repair pathways in tumors and explore the possible function and mechanism for the score among different cancers. The TR-DDR score has remarkably predictive power for tumor tissues. It is a more accurate indicator for the response of chemotherapy or immunotherapy combined with the tumor-infiltrating lymphocyte (TIL) and G2M checkpoint score than the pre-existing predictors (CD8 or PD-L1). This study points out that the TR-DDR score generally has positive correlations with patients of advanced-stage, genome-instability, and cell proliferation signature, while negative correlations with inflammatory response, apoptosis, and p53 pathway signature. In the context of tumor immune response, the TR-DDR score strongly positively correlates with the number of T cells (CD4+ activated memory cells, CD8+ cells, T regs, Tfh) and macrophages M1 polarization. In addition, by difference analysis and correlation analysis, COL2A1, MAGEA4, FCRL4, and ZIC1 are screened out as the potential modulating factors for the TR-DDR score. In summary, we light on a new biomarker for DNA damage repair pathways and explore its possible mechanism to guide therapeutic strategies and drug response prediction.

Anterior Lens Curvature Matters in the Course of Primary Angle Closure: An Analysis Based on Ultrasound Biomicroscopic Imaging.

PURPOSE: To evaluate the effect of anterior lens curvature in primary angle closure (PAC) and find additional anatomical features of crystalline lens that may predispose primary angle closure to the acute course. METHODS: 435 eyes (263 subjects) were enrolled in this study. Four groups of eyes were included based on angle configurations and clinical features: (i) acute primary angle closure (APAC, 140 eyes); (ii) chronic primary angle closure (CPAC, 116 eyes); (iii) primary angle closure suspect (PACS, 84 eyes); and (iv) normal controls (95 eyes). All patients underwent thorough ophthalmic exams including applanation tonometry, gonioscopy, low-coherence interferometry, and ultrasound biomicroscopic imaging. Based on the panoramic anterior segment images from ultrasound biomicroscopic imaging measurements, the radius of anterior lens curvature (ALR) was calculated using the least-squares curve fitting technique. ALR, in addition to axial length (AL), anterior chamber depth (ACD), and lens thickness (LT), was compared among different groups using univariate and multivariate analysis with mixed effects linear model. RESULTS: APAC, CPAC, and PACS groups all had steeper ALR, shorter AL, shallower ACD, and thicker LT than normal control group. ACD and LT further differ between APAC and CPAC or PACS eyes. Moreover, a steeper ALR was also found in the APAC group as compared to CPAC, PACS, and normal control groups. CONCLUSIONS: A steeper ALR may predispose the acute attack of PAC. In addition to the relative lens position and size, lens curvature is another variable that contributes to the pathophysiological mechanisms of primary angle closure.

Performance of human papillomavirus (HPV) mRNA testing and HPV 16 and 18/45 genotyping combined with age stratification in the triaging of women with ASC-US cytology.

OBJECTIVES: This study aimed to assess the clinical performance of an HPV E6/E7 mRNA assay (Aptima HPV, AHPV) and AHPV 16 18/45 genotype assay (AHPV-GT) combined with age stratification for triaging women with atypical squamous cells of undetermined significance (ASC-US) cytology. METHODS: In total, 3052 women >21 years old with ASC-US cytology underwent AHPV testing, and AHPV-positive samples were reflex-tested with the AHPV-GT test. All women were referred for colposcopy and then biopsy if indicated. The AHPV and AHPV-GT test performances and risk estimates by hrHPV status with age stratification were calculated. RESULTS: Overall, 1599 women (52.4%) tested AHPV positive; of these women, 225 (7.4%), 101 (3.3%) and 1273 (41.7%) tested HPV 16+, HPV 18/45+ and other hrHPV-genotype-positive. When identifying CIN3+, the AHPV test had a 93.2% sensitivity and achieved a higher NPV (99.7% vs. 98.5%, P < 0.001) but a lower PPV (4.3% vs. 10.4%, P < 0.001) than the AHPV-GT test. The immediate risks of CIN3+ in AHPV+, other hrHPV+, and AHPV-GT+ women were 4.3%, 2.7%, and 10.4%, respectively. In the 21-24-year-old group, the immediate risks were 1.6%, 2.0% and 0.0%, which were below the 4.0% threshold for immediate colposcopy. The immediate colposcopy referral rate for AHPV-positive/ASC-US women 25 years or older was reduced from 51.7% to 10.5% by the AHPV-GT risk stratification method. CONCLUSIONS: AHPV testing with age stratification is effective for triaging women with ASC-US cytology. AHPV-GT testing may be a proper risk stratification method for women with AHPV-positive ASC-US cytology.

Etiologies and clinical characteristics of young patients with angle-closure glaucoma: a 15-year single-center retrospective study.

PURPOSE: To investigate the etiologies and the clinical characteristics of angle-closure glaucoma (ACG) patients younger than 40 years old in Chinese. METHODS: Inpatients with diagnosis of ACG and diagnosed age younger than or equal to 40 years old, who were admitted in Eye, Ear, Nose, and Throat Hospital Fudan University from 2002 to 2017, were included in this retrospective non-comparative case series. The underlying causes and clinical features for all the patients were analyzed by comprehensive review of medical charts. RESULTS: A total of 298 patients (463 eyes) met the criteria, including 153 females (51.3%) and 145 males (48.7%); the mean age was 25.6 ± 13.0 years. Primary angle-closure glaucoma (PACG), uveitis, and anterior segment dysgenesis (ASD) were the top three etiologies in our patients, which accounted for 32.6%, 20.3%, and 15.1% of the total patients respectively. PACG mainly occurs after 30 years of age and ASD is the top reason of ACG in patients younger than 20 years old. Other known etiologies include iridocorneal endothelial syndrome, neovascular glaucoma, nanophthalmos, retinitis pigmentosa, spherophakia, bestrophinopathy, persistent fetal vasculature, iridociliary cysts, congenital retinoschisis, Marfan's syndrome, retinopathy of prematurity, familial exudative vitreoretinopathy, congenital retinal folds, Coat's disease, and neurofibromatosis. CONCLUSIONS: We described the uncommon presentation of ACG in Chinese young patients. Although unusual, most of the etiologies could be identified. Therefore, more careful and comprehensive examinations are needed for early detection and timely treatment for young ACG patients.

Identification of aberrantly expressed circular RNAs in hyperlipidemia-induced retinal vascular dysfunction in mice.

Hyperlipidemia-induced retinal vascular dysfunction is a complex pathological process. circRNAs are important regulators of biological processes and disease progression. However, the expression pattern of circRNAs in hyperlipidemia-induced retinal vascular dysfunction remains unclear. Herein, we used a murine model of hyperlipidemia and identified 317 differentially expressed circRNAs between hyperlipidemic retinas and normolipidemic retinas by circRNA microarrays. GO analysis indicated that the host genes of dysregulated circRNAs were targeted to cell differentiation (ontology: biological process), cytoplasm (ontology: cellular component), and protein binding (ontology: molecular function). Pathway analysis revealed that circRNAs-mediated network was mostly enriched in focal adhesion signaling. Notably, circLDB1 was significantly up-regulated in the serum of coronary artery disease patients and aqueous humor of age-related macular degeneration patients. circLDB1 regulated endothelial cell viability, proliferation, and apoptosis in vitro. Thus, circRNAs are the promising targets for the prediction and diagnosis of hyperlipidemia-induced vascular diseases.

Differential Effects of TGF-ß2 on the Low-Density Lipoprotein Receptor Expression in Three Types of Human Subconjunctival Fibroblasts.

Purpose: To investigate whether TGF-ß2 had a different effect on the expression levels of low-density lipoprotein receptor (LDLr) in the subconjunctival fibroblasts from glaucoma patients who underwent a reoperation (RGSFs) compared with those from glaucoma patients who underwent first filtering surgery (GSFs) and control patients with cataracts (HSFs). Methods: Human subconjunctival fibroblasts were obtained from the three groups of patients. Different concentrations of TGF-ß2 were added to the fibroblasts for 1, 3, and 5 days. The proliferation of the fibroblasts was determined by CCK-8 assays. Real-time PCR and western blotting were performed to analyze the mRNA and protein levels of LDLr. The uptake of DiI-labeled LDL was determined by confocal microscopy. Results: The results revealed that under TGF-ß2 exposure, fibroblast proliferation was positively correlated with LDLr expression (all p < .001). The LDLr mRNA and protein levels were affected by TGF-ß2 in a concentration-dependent and time-dependent manner in the RGSFs, GSFs and HSFs. The maximal expression of LDLr after TGF-ß2 stimulation was consistent with the peak uptake of DiI-LDL, which was obviously highest in the RGSFs, followed by the GSFs, and then the HSFs (all p < .05). All 3 groups took up DiI-LDL in a similar time-dependent manner, with maximal uptake at 6 h following DiI-LDL incubation (all p < .05). In addition, there were significant differences in the LDLr protein levels in the subconjunctival tissues isolated from the glaucoma patients during reoperation, the glaucoma patients during first filtering surgery and the control patients at day 3 (p < .05). The highest protein expression of LDLr was observed in the RG group. Conclusion: These data suggested that the RGSFs had the highest LDLr expression and the highest peak uptake of LDL among three groups. The LDLr-drug-LDL delivery system could potentially be used for targeted delivery of antimetabolite agents in anti-scarring therapy for glaucoma patients after filtering surgery.

Circular RNA Expression Profiling Identifies Glaucoma-Related Circular RNAs in Various Chronic Ocular Hypertension Rat Models.

Circular RNAs are characterized as a class of covalently closed circular RNA transcripts and are associated with a variety of cellular processes and neurological diseases by sponging microRNAs. Expression profiling of circular RNAs in glaucoma, which is a form of optic neuropathy, has not been performed to date. The most common characteristic of all forms of glaucoma is the loss of retinal ganglion cells. While the pathogenesis of glaucoma is not fully understood, intraocular pressure is unquestionably the only proven modifiable factor which makes chronic ocular hypertension (COH) animals the classical glaucoma models. Based on these findings, we completed the first in-depth study of rat retinal circular RNA expression profiling to identify probable biomarkers for the diagnosis of glaucoma. Two ocular hypertension models were induced by episcleral vein ligation (EVL) and microbead injection in rats. Overall, 15,819 circular RNA were detected. Furthermore, 3,502 differentially expressed circular RNAs verified in both COH rats were identified, of which 691 were upregulated and 2,811 were downregulated. Seven significantly downregulated (both log2FoldChange < -2.5 and adjusted P < 0.001) and seven significantly upregulated (both log2FoldChange > 2.5 and adjusted P < 0.001) circular RNAs were shown. Six target microRNAs aligned with the top 14 circular RNAs were identified. According to the construction of the circular RNA-microRNA network and circBase information, only RNO_CIRCpedia_1775 had the homologous hsa_circ_0023826 in the human genome. The hsa_circ_0023826 and mRNA of the host gene TENM4 (teneurin transmembrane protein 4) were validated in aqueous humor samples of five glaucoma patients and five cataract control patients. The expression of hsa_circ_0023826 showed a significant decrease in glaucoma patients, while TENM4 mRNA showed no significant difference compared to cataract patients (P = 0.024 and P = 0.294, respectively). The results of this study comprehensively characterized the expression profiles of circular RNA in glaucoma-affected eyes, as verified by two different ocular hypertension rat models. Together with the target microRNAs underlying the top differentially expressed circular RNAs, a new target of hsa_circ_0023826 and its host gene TENM4 were identified and further verified in the aqueous humor of glaucoma patients, indicating a promising biomarker for the disease.

miR-587 promotes cervical cancer by repressing interferon regulatory factor 6.

BACKGROUND: Interferon regulatory factor 6 (IRF6) exhibits tumor-suppressive functions in several cancer types. In the present study, the antitumor properties and related pathway mechanism of IRF6 were investigated in cervical cancer. METHODS: Forty-one pairs of cervical cancer specimens and para-carcinoma tissues were collected to evaluate IRF6 expression using immunohistochemical staining and miR-587. The effects of miR-587 and IRF6 on cervical cancer cell growth were explored by MTT assays and in a HeLa tumor xenograft mouse model. The migration and invasion of cervical cancer cells were monitored using transwell assays. RESULTS: IRF6 expression in cervical cancer specimens and cell lines was significantly reduced compared to that in the corresponding control group. In addition, IRF6 expression was negatively correlated with miR-587 in cervical cancer tissues. Bioinformatics algorithms and luciferase assays revealed that IRF6 is a potential target of miR-587, and miR-587 mimic transfection led to a significant repression of IRF6 protein levels in cervical cancer cells. We also discovered that the antineoplastic properties of IRF6 could be reversed by overexpressing miR-587 in cervical cancer cells. The up-regulation of miR-587 was correlated with poor overall survival in cervical cancer. In an in vivo experiment, miR-587 silencing induced HeLa tumor growth inhibition, which was associated with the up-regulation of IRF6 protein in the tumor. CONCLUSIONS: miR-587 post-transcriptionally represses IRF6 protein expression to abrogate the antineoplastic activity of IRF6. The miR-587/IRF6 signaling pathway plays a crucial role in the progression of cervical cancer and serves as a potential therapeutic target for the treatment of cervical cancer.

B-cell lymphoma 2 family genes show a molecular pattern of spatiotemporal heterogeneity in gynaecologic and breast cancer.

OBJECTIVES: BCL2 family proteins have been widely studied over the past decade due to their essential roles in apoptosis, oncogenesis and anti-cancer therapy. However, the similarities and differences in the spatial pattern of the BCL2 gene family within the context of chromatin have not been well characterized. We sought to fill this knowledge gap by assessing correlations between gene alteration, gene expression, chromatin accessibility, and clinical outcomes in gynaecologic and breast cancer. MATERIALS AND METHODS: In this study, the molecular characteristics of the BCL2 gene family in gynaecologic cancer were systematically analysed by integrating multi-omics datasets, including transcriptomics, chromatin accessibility, copy number variation, methylomics and clinical outcome. RESULTS: We evaluated spatiotemporal associations between long-range regulation peaks and tumour heterogeneity. Differential expression of the BCL2 family was coupled with widespread chromatin accessibility changes in gynaecologic cancer, accompanied by highly heterogeneous distal non-coding accessibility surrounding the BCL2L1 gene loci. A relationship was also identified between gene expression, gene amplification, enhancer signatures, DNA methylation and overall patient survival. Prognostic analysis implied clinical correlations with BAD, BIK and BAK1. A shared protein regulatory network was established in which the co-mutation signature of TP53 and PIK3CA was linked to the BCL2L1 gene. CONCLUSIONS: Our results provide the first systematic identification of the molecular features of the BCL2 family under the spatial pattern of chromatin in gynaecologic and breast cancer. These findings broaden the therapeutic scope of the BCL2 family to the non-coding region by including a significantly conserved distal region overlaying an enhancer.