Chondroitin sulfate enhances the barrier function of basement membrane assembled by heparan sulfate.

Glycosaminoglycans are ubiquitously expressed polysaccharides that are attached to proteoglycans. Here, we showed that ablation of the heparan sulfate (HS) polymerase Ext1 in retinal progenitor cells did not affect initial progression of retinal angiogenesis, but it disrupted the pruning of blood vessels and establishment of arterioles and venules. In the absence of retinal HS, blood vessels were also vulnerable to high oxygen tension in early postnatal stages, which could be rescued by exogenous vascular endothelial growth factor (VEGF), consistent with the role of retinal HS in the fine-tuning of VEGF signaling. Furthermore, we observed that the retinal inner limiting membrane (ILM) was disrupted by deletion of Ext1 in a timing-specific manner, suggesting that retinal HS is required for the assembly but not the maintenance of the basement membrane. Lastly, we showed that further deletion of C4st1, a chondroitin sulfate (CS) sulfation enzyme, did not affect the assembly of the ILM but, when combined with Ext1 deletion, it aggravated the retinal permeability by disrupting the retinal glycocalyx. These results demonstrate an important role of CS and HS in establishing the barrier function of the extracellular matrix.

Effects of Bony Pelvic and Prostate Dimensions on Surgical Difficulty of Robot-Assisted Radical Prostatectomy: An Original Study and Meta-analysis.

BACKGROUND: Due to the deep location of the prostate within the pelvic cavity, procedures of robot-assisted radical prostatectomy (RARP) might be challenged by the prostate size and the limited pelvic cavity space. This study aimed to investigate the roles of bony pelvic and prostate dimensions in RARP procedures by an original study coupled with a meta-analysis. METHODS: In the original study, patients undergoing multiport RARP between 2021 and 2022 were consecutively assessed. The associations of anatomic features with operative time (OT), estimated blood loss (EBL), and positive surgical margin (PSM) were evaluated using linear and logistic regression analyses as well as restricted cubic spline (RCS) analysis. Based on machine-learning algorithms, this study established predictive models for surgical difficulty and interpreted the model using SHapley Additive exPlanation (SHAP). In the meta-analysis, three databases were searched for eligible studies. Quantitative syntheses were subsequently performed. RESULTS: Overall, 219 patients were enrolled in the original study. Prostate volume (PV) and the prostate volume-to-pelvic cavity index (PCI) ratio (PV-to-PCI ratio) were significantly associated with longer OT (P < 0.05). In the RCS models, U-shaped associations were observed between the prostate anteroposterior diameter (PAD) and OT, and between the prostate height (PH) and EBL, and an L-shaped association was observed between the anteroposterior diameter of the pelvic inlet (API) and EBL. The XGBoost model was superior to the logistic regression model in predicting prolonged OT. The meta-analysis demonstrated that greater PV was significantly associated with longer OT (ß = 0.20; 95% confidence interval [CI] 0.12-0.27; odds ratio [OR] = 1.05; 95% CI 1.00-1.11), and a smaller PV could increase the risk of PSM (OR = 0.82; 95% CI 0.77-0.88). CONCLUSIONS: A large prostate within a narrow and deep pelvis might suggest increased surgical difficulty of RARP. The size of the pelvic inlet also had a great impact on RARP. For PAD and PH, there seemed to be an optimal range with the lowest surgical difficulty. Machine-learning models based on the XGBoost algorithm could be successfully applied to predict the surgical difficulty of RARP.

Novel scoring system incorporating lipoproteins to predict outcomes of epithelial ovarian cancer patients.

OBJECTIVE: Epithelial ovarian cancer is the most lethal gynecological malignancy worldwide. While common prognostic factors are identified, the impact of serum lipoproteins remains controversial. This retrospective cohort study aims to investigate the association between specific lipoprotein levels and prognosis. METHODS: Clinical data of 420 participants with epithelial ovarian cancer registered at Women's Hospital, School of Medicine, Zhejiang University, between January 2014 and April 2021 were included. Cox regression analyses and Kaplan-Meier methods were used to assess prognosis, estimated by hazard ratio (HR) with 95% confidence interval (CI). A novel prognostic model incorporating lipoproteins was developed for evaluating the prognosis. Meta-analysis was applied to assess the impact of low density lipoprotein cholesterol (LDL-C) on prognosis. RESULTS: Among 420 patients, those in advanced stages exhibited higher low density lipoprotein cholesterol (LDL-C) (p=0.008) and lower high density lipoprotein cholesterol (HDL-C) levels (p<0.001), with no significant differences in total cholesterol or triglyceride levels. Elevated LDL-C level was significantly associated with worse overall survival (HR 1.72; 95% CI 1.15 to 2.58; p=0.010) and progression free survival (HR 1.94; 95% CI 1.46 to 2.58; p<0.001), whereas higher HDL-C level was linked to better overall survival (HR 0.56; 95% CI 0.37 to 0.85; p=0.004) and progression free survival (HR 0.61; 95% CI 0.46 to 0.81; p<0.001). A novel prognostic model, low density lipoprotein cholesterol-high density lipoprotein cholesterol-fibrinogen-lactate dehydrogenase-prealbumin-Fe-stage (LH-FLPFS), was established to enhance prognostic predictive efficacy. The meta-analysis further suggested that higher LDL-C level was associated with worse overall survival (HR 1.82; 95% CI 1.39 to 2.38; p<0.001). CONCLUSIONS: In this study, preoperative LDL-C and HDL-C levels emerged as potential prognostic factors for ovarian cancer. Establishment of a novel prognostic model, LH-FLPFS, holds promise for significantly improving prognostic predictive efficacy.

Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-ß/SMADs signaling pathway.

Perfluorononanoic acid (PFNA), an acknowledged environmental endocrine disruptor, is increasingly utilized as a substitute for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Despite its growing use, limited research has been conducted to investigate its potential impact on tumorigenesis and progression, and the potential molecular mechanisms. Earlier studies linked perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure to breast and gynecological cancer progression in humans, lacking a clear understanding of the underlying mechanisms, notably in ovarian cancer. Our investigation into PFNA's effects at environmental concentrations (0.25-2 mM) showed no significant impact on cell proliferation but a notable increase in invasion and migration of ovarian cancer cells. This led to alterations in epithelial-mesenchymal transition (EMT) markers, including Claudin1, Vimentin, and Snail. Notably, PFNA exposure activated the TGF-ß/SMADs signaling pathway. Crucially, SMAD7 degradation through the ubiquitin-proteasome system emerged as PFNA's pivotal molecular target for inducing EMT, corroborated in mouse models. In summary, this study presented evidence that environmentally relevant concentrations of PFNA could induce SMAD7 degradation via the proteasome pathway, subsequently activating the TGF-ß/SMADs signaling pathway, and promoting EMT in ovarian cancer. These results illuminated the association between PFNA exposure and metastasis of ovarian cancer.

A retrospective study on the influence of inclination of cusp on implant marginal bone height in patients with periodontal disease.

PURPOSE: To investigate the correlation between the marginal bone height of implants in the posterior maxilla of patients with periodontal disease and the inclination of cusp, providing a theoretical basis for the occlusal design of implant restorations in such patients.  Methods: A total of 80 patients with periodontal disease who underwent implant restoration in the posterior maxilla (55 men and 25 women; mean age 56.66 ± 12.70 years) were selected, with a total of 80 implant restorations (one implant restoration per patient). In addition to recording the main research factor of the inclination of cusp, general patient information, implant characteristics and restoration characteristics were taken, and retrospective analysis of the case data and imaging data of the 80 patients from over 3 years was conducted. Cone beam computed tomography was performed preoperatively and 3 years after implant loading to measure and calculate the marginal bone height of the implants using the One Volume Viewer software. Correlation analysis was performed to determine the relationship between the inclination of the cusp and marginal bone height.  Results: There was a positive correlation between the inclination of cusp and the marginal bone height of the implants, with a correlation coefficient of 0.661 (p < 0.001); the diameter of the implants, implant type and restoration type were negatively correlated with the marginal bone height of the implants, with correlation coefficients of -0.364 (p = 0.001), -0.232 (p = 0.038) and -0.298 (p = 0.007), respectively.  Conclusion: When designing the occlusion of implant restorations in the posterior maxilla of patients with periodontal disease, it is advisable to appropriately reduce the restoration's inclination of cusp.

Peripheral blood mononuclear cell microRNAs are novel biomarkers for diagnosing and monitoring Crohn's disease.

Crohn's disease is a recurrent, progressive, immune-mediated inflammatory disease and merely manifests non-specific symptoms at early stage. In this study, we isolated peripheral blood mononuclear cells (PBMCs) to determine whether PBMC miRNAs are reliable biomarkers for Crohn's disease diagnosing and monitoring. 5 Crohn's disease patients and 5 healthy controls were recruited to find differentially expressed miRNAs by next generation sequencing. Candidate PBMC miRNAs were further validated by qRT-PCR in another cohort consisting of 86 Crohn's disease patients and 39 healthy controls. We found PBMC miR-582-5p could diagnose Crohn's disease with the area under receiver operating characteristic curve (AUROC) of 0.701(95%CI 0.606-0.796, p < .001). While PBMC miR-96-5p was significantly higher in active Crohn's disease and correlated with both clinical (ρ = 0.376, p < .001) and endoscopic activity (ρ = 0.512, p = .015). Furthermore, PBMC miR-96-5p had a better performance in recognizing active Crohn's disease with AUROC of 0.727 (95%CI 0.609-0.844, p = .001) than C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fecal calprotectin. In conclusion, PBMC miR-582-5p may be further utilized as a diagnostic biomarker, while miR-96-5p may be a novel and valuable biomarker in monitoring disease activity.

Low dose PFDA induces DNA damage and DNA repair inhibition by promoting nuclear cGAS accumulation in ovarian epithelial cells.

Per- and polyfluoroalkyl substances (PFAS), the versatile anthropogenic chemicals, are popular with the markets and manufactured in large quantities yearly. Accumulation of PFAS has various adverse health effects on human. Albeit certain members of PFAS were found to have genotoxicity in previous studies, the mechanisms underlying their effects on DNA damage repair remain unclear. Here, we investigated the effects of Perfluorodecanoic acid (PFDA) on DNA damage and DNA damage repair in ovarian epithelial cells through a series of in vivo and in vitro experiments. At environmentally relevant concentration, we firstly found that PFDA can cause DNA damage in primary mouse ovarian epithelial cells and IOSE-80 cells. Moreover, nuclear cGAS increased in PFDA-treated cells, which leaded to the efficiency of DNA homologous recombination (HR) decreased and DNA double-strand breaks perpetuated. In vivo experiments also verified that PFDA can induce more DNA double-strand breaks lesions and nuclear cGAS in ovarian tissue. Taken together, our results unveiled that low dose PFDA can cause deleterious effects on DNA and DNA damage repair (DDR) in ovarian epithelial cells and induce genomic instability.

Toxicogenomics scoring system: TGSS, a novel integrated risk assessment model for chemical carcinogenicity prediction.

BACKGROUND: Given the increasing exposure of humans to environmental chemicals and the limitations of conventional toxicity test, there is an urgent need to develop next-generation risk assessment methods. OBJECTIVES: This study aims to establish a novel computational system named Toxicogenomics Scoring System (TGSS) to predict the carcinogenicity of chemicals coupling chemical-gene interactions with multiple cancer transcriptomic datasets. METHODS: Chemical-related gene signatures were derived from chemical-gene interaction data from the Comparative Toxicogenomics Database (CTD). For each cancer type in TCGA, genes were ranked by their effects on tumorigenesis, which is based on the differential expression between tumor and normal samples. Next, we developed carcinogenicity scores (C-scores) using pre-ranked GSEA to quantify the correlation between chemical-related gene signatures and ranked gene lists. Then we established TGSS by systematically evaluating the C-scores in multiple chemical-tumor pairs. Furthermore, we examined the performance of our approach by ROC curves or prognostic analyses in TCGA and multiple independent cancer cohorts. RESULTS: Forty-six environmental chemicals were finally included in the study. C-score was calculated for each chemical-tumor pair. The C-scores of IARC Group 3 chemicals were significantly lower than those of chemicals in Group 1 (P-value = 0.02) and Group 2 (P-values = 7.49 ×10-5). ROC curves analysis indicated that C-score could distinguish "high-risk chemicals" from the other compounds (AUC = 0.67) with a specificity and sensitivity of 0.86 and 0.57. The results of survival analysis were also in line with the assessed carcinogenicity in TGSS for the chemicals in Group 1. Finally, consistent results were further validated in independent cancer cohorts. CONCLUSION: TGSS highlighted the great potential of integrating chemical-gene interactions with gene-cancer relationships to predict the carcinogenic risk of chemicals, which would be valuable for systems toxicology.

What role does the seed coat play during symbiotic seed germination in orchids: an experimental approach with Dendrobium officinale.

BACKGROUND: Orchids require specific mycorrhizal associations for seed germination. During symbiotic germination, the seed coat is the first point of fungal attachment, and whether the seed coat plays a role in the identification of compatible and incompatible fungi is unclear. Here, we compared the effects of compatible and incompatible fungi on seed germination, protocorm formation, seedling development, and colonization patterns in Dendrobium officinale; additionally, two experimental approaches, seeds pretreated with NaClO to change the permeability of the seed coat and fungi incubated with in vitro-produced protocorms, were used to assess the role of seed coat played during symbiotic seed germination. RESULTS: The two compatible fungi, Tulasnella sp. TPYD-2 and Serendipita indica PI could quickly promote D. officinale seed germination to the seedling stage. Sixty-two days after incubation, 67.8 ± 5.23% of seeds developed into seedlings with two leaves in the PI treatment, which was significantly higher than that in the TPYD-2 treatment (37.1 ± 3.55%), and massive pelotons formed inside the basal cells of the protocorm or seedlings in both compatible fungi treatments. In contrast, the incompatible fungus Tulasnella sp. FDd1 did not promote seed germination up to seedlings at 62 days after incubation, and only a few pelotons were occasionally observed inside the protocorms. NaClO seed pretreatment improved seed germination under all three fungal treatments but did not improve seed colonization or promote seedling formation by incompatible fungi. Without the seed coat barrier, the colonization of in vitro-produced protocorms by TPYD-2 and PI was slowed, postponing protocorm development and seedling formation compared to those in intact seeds incubated with the same fungi. Moreover, the incompatible fungus FDd1 was still unable to colonize in vitro-produced protocorms and promote seedling formation. CONCLUSIONS: Compatible fungi could quickly promote seed germination up to the seedling stage accompanied by hyphal colonization of seeds and formation of many pelotons inside cells, while incompatible fungi could not continuously colonize seeds and form enough protocorms to support D. officinale seedling development. The improvement of seed germination by seed pretreatment may result from improving the seed coat hydrophilicity and permeability, but seed pretreatment cannot change the compatibility of a fungus with an orchid. Without a seed coat, the incompatible fungus FDd1 still cannot colonize in vitro-produced protocorms or support seedling development. These results suggest that seed coats are not involved in symbiotic germination in D. officinale.

A novel lncRNA lnc-PPRL promotes pterygium development by activating PI3K/PDK1 signaling pathway.

A sight threatening, pterygium is a common proliferative and degenerative disease of the ocular surface. LncRNAs have been widely studied in the occurrence and development of various diseases, however, the study of lncRNAs in pterygium has just relatively lacking. In the present study, we performed the high-throughput RNA sequencing (HTS) technology to identify differentially expressed lncRNAs in pterygium. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out to forecast the regulatory and functional role of lncRNAs in pterygium. Notably, we identified a novel lncRNA, LOC102724238, which we named pterygium positively-related lncRNA (lnc-PPRL), was up-regulated in pterygium. Lnc-PPRL showed to be preferentially accumulated in cytoplasm, and it can promote cell proliferation, migration and invasion of human pterygium epithelium cells (hPECs). Further study of underlying mechanisms demonstrated that lnc-PPRL may exert its biological effect by activating canonical PI3K/PDK1 pathway, and subsequently promoting the activation of Akt/mTOR signaling pathway and its downstream effectors. Interestingly, lnc-PPRL was also proved to influence YAP nuclear localization. Taken together, our study firstly suggested that the "big molecule" lnc-PPRL have potential as a novel therapeutic target for the prevention and treatment of pterygium.

Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq.

Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon compound, is a carcinogen that causes head and neck cancers. Despite intensive research, the molecular mechanism of BaP in the development of oral squamous cell carcinoma (OSCC) remains largely unknown. In the present study, the SCC-9 human OSCC cell line was cultured in vitro, separated into treatment groups, and treated with dimethyl sulfoxide or BaP at various concentrations. The malignant behavior ascribed to the BaP treatment was investigated by cell proliferation, clony formation assay, and Transwell assays. Furthermore, transcriptome sequencing was performed to detect the differentially expressed genes, followed by quantitative real-time PCR to measure the expression levels of nine of these genes. Moreover, the Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed the biological processes and signaling pathways in which the target genes were involved. Significant effects on SCC-9 cell proliferation, tumorigenicity, cell migration, and invasion were observed after exposure to 8 µM BaP. Additional results revealed that BaP inhibited apoptosis in a dose-dependent manner. The transcriptome sequencing results showed 137 upregulated genes and 135 downregulated genes induced by BaP, associated with tumor-related biological processes and signaling pathways, mainly including transcriptional dysregulation in cancer, the tumor necrosis factor signaling pathway, metabolism of xenobiotics by cytochrome P450, mitogen-activated protein kinase signaling pathway, and so forth. Our study demonstrates that BaP may regulate the expression of certain genes involved in tumor-associated signaling pathways, thereby promoting the proliferative, tumorigenic, and metastatic behaviors of OSCC cells while suppressing their apoptosis.

Arthroscopic reconstruction of anterior cruciate ligaments with allograft: single-tunnel single-bundle versus single-tunnel double-bundle techniques.

PURPOSE: To compare the clinical results of anterior cruciate ligament (ACL) reconstruction using the single-tunnel single-bundle (STSB) technique versus the single-tunnel double-bundle (STDB) technique. METHODS: This was a retrospective, single-center, single-surgeon study based on data collected from March 2012 to June 2013. According to our inclusion/exclusion criteria, a total of 78 patients (64 males, 14 females; mean age, 25.1 years) who underwent arthroscopic ACL reconstruction with anterior tibialis tendon allografts through either the STSB technique (36 cases) or the STDB technique (42 cases) in our department were recruited. The International Knee Documentation Committee (IKDC), Lysholm, and Tegner scores were used to evaluate the subjective function of the knee joint during the postoperative follow-up. The Lachman test and pivot shift test were used to objectively assess the stability of the knee. RESULTS: The average follow-up duration was 24.9 ± 1.8 months in the STSB group and 24.6 ± 1.7 months in the STDB group (P > 0.05). Patients in both groups recovered to the preoperative sports level with few complications. The postoperative Lysholm score (86.1 ± 7.5 vs. 47.7 ± 9.0 in the STSB group; 87.0 ± 7.1 vs. 48.2 ± 8.3 in the STDB group), IKDC score (87.8 ± 7.2 vs. 49.3 ± 6.1 in the STSB group; 88.7 ± 6.6 vs. 49.8 ± 6.3 in the STDB group), Tegner score (6.5 ± 1.3 vs. 2.5 ± 1.3 in the STSB group; 6.6 ± 1.2 vs. 2.6 ± 1.2 in the STDB group), Lachman test positive rate (8.3% vs. 89.9% in the STSB group; 7.1% vs. 85.7% in the STDB group), and pivot shift test positive rate (27.8% vs. 63.9% in the STSB group; 7.1% vs. 69.0% in the STDB group) were significantly improved compared to the preoperative status in both groups (P < 0.05). However, no statistically significant difference was observed between the two groups at the final follow-up (P > 0.05), except for the pivot shift test positive rate in the STDB group versus the STSB group (7.1% vs. 27.8%, P < 0.05). CONCLUSIONS: The STDB technique achieved a satisfactory clinical outcome with better rotational stability compared to the traditional STSB technique and therefore provided an effective option for ACL reconstruction. LEVEL OF EVIDENCE: Case series, Level IV.

Combined procalcitonin and hemogram parameters contribute to early differential diagnosis of Gram-negative/Gram-positive bloodstream infections.

BACKGROUND: Hemogram parameters and procalcitonin (PCT) play auxiliary roles in the diagnosis and outcome of sepsis. However, it is not clear whether these indicators can quickly distinguish bacterial classification or guide the choice of empirical antibiotics. METHODS: We retrospectively enrolled 381 patients with bloodstream infections (BSI), divided into Gram-positive bloodstream infections (GP-BSI) and Gram-negative bloodstream infections (GN-BSI). Demographic parameters, hemogram parameters, and PCT were recorded and compared between the two groups. RESULTS: The mean platelet volume (MPV), platelet distribution width (PDW), and PCT in the GN-BSI group were significantly higher than those in the GP-BSI group, while the platelet count (PLT), plateletcrit, platelet count-to-white blood cell count ratio (PWR), platelet count-to-neutrophil count ratio (PNR), platelet count-to-PCT ratio (PLT/PCT), and mean platelet volume-to-PCT ratio (MPV/PCT) were significantly lower in the GN-BSI group. Multivariate stepwise logistic regression analysis revealed that the independent predictors of GN-BSI were MPV, PWR, and PCT. The areas under the curve (AUC) for this prediction model was 0.79, with sensitivity =0.75 and specificity =0.71. CONCLUSIONS: There were significant differences in terms of PCT, platelet parameters, and platelet-related index-PCT ratio between GN-BSI and GP-BSI. Combined PCT and hemogram parameters are more conducive to the early differential diagnosis of bacterial classification of BSI.

Mid-Term Follow-Up of Transcatheter Closure for Coronary Cameral Fistula in Pediatrics.

BACKGROUND: Coronary cameral fistula (CCF), a rare abnormal coronary communication to cardiac chambers, may lead to coronary steal phenomenon and increase cardiac overload. We investigated the clinical and cardiovascular characteristics in children before and after transcatheter closure. METHODS: We retrospectively reviewed pediatric patients with CCFs diagnosed by echocardiography in a tertiary medical center between 1998 and 2019. Basic information, echocardiogram, catheterization and interventional procedures were obtained from medical charts. RESULTS: A total of 12 pediatric subjects were included. The median ages at diagnosis and catheterization were 0.2 and 2.8 years, respectively. All CCFs were unilateral and single with varying degrees of coronary artery dilatation and aneurysm formation and diagnosed by echocardiography. The median follow-up periods before and after catheterization were 2.5 and 7.3 years, respectively. Seven of the CCFs originated from the left side. The drainage sites were all right hearts. Before catheterization, the median size of the proximal end of the fistula was 3.1 mm, concomitant with enlargement of conduit coronary arteries. Eleven of the 12 patients underwent transcatheter closure using coils in six and vascular plugs in five. Only one patient had a significant increase in pulmonary-to-systemic flow ratio. The size of conduit coronary artery gradually decreased and the size of ipsilateral coronary branch increased after closure. CONCLUSIONS: Transcatheter occlusion for CCFs in children is safe and effective. The morphology of CCFs varies with the degrees of dilation, tortuosity, and aneurysmal formation. After occlusion, alterations in the size of coronary arteries may be a prognostic indicator.

Long noncoding RNA SNHG12 modulated by human papillomavirus 16 E6/E7 promotes cervical cancer progression via ERK/Slug pathway.

Recently, long noncoding RNA SNHG12 has been reported to be dysregulated in various types of cancer. This study investigated its biological function and the underlying molecular mechanism in cervical squamous cell carcinoma (CSCC). We found that SNHG12 was significantly overexpressed in CSCC tissues. Further evidence showed that human papillomavirus (HPV) type 16 E6 and E7 might regulate the expression level of SNHG12 by modulating transcription factor c-Myc. Functional experiments suggested that SNHG12 knockdown dramatically repressed CSCC cells proliferation, migration, and invasion while induced apoptosis in vitro as well as suppressed tumor growth in vivo. In addition, SNHG12 could facilitate epithelial-mesenchymal transition through ERK/Slug/E-cadherin pathway at least in part. Our findings highlight SNHG12 functions as an oncogenic long noncoding RNA in malignant phenotype and tumorigenesis of CSCC, which implicate it may be a potential target for CSCC treatment.

Flexible inorganic CsPbI3 perovskite nanocrystal-PMMA composite films with enhanced stability in air and water for white light-emitting diodes.

Perovskite nanocrystals are a new type of fluorescent material with the advantages of facile preparation process, bright tunable color with high quantum yield. They are ideal candidates for optoelectronic devices such as light-emitting diode (LED) and display. However, for practical applications of iodine-based perovskite nanocrystals, the photostability remains a great challenge because of their sensitivity to environmental factors such as oxygen, humidity etc. In this paper, we improve the photostability of CsPbI3 by introducing the polymethyl methacrylate (PMMA) as a matrix to form flexible perovskite/PMMA composite films. The composite films maintain good photoluminescence quantum yield for 25 d in air and 4 d in water. Furthermore, these films are flexible and can sustain multiple bending and folding while maintaining their photoluminescence properties. This photostability against mechanical deformation allows for the development of flexible devices. As an example, flexible white light-emitting diodes (WLED) were produced with chromaticity coordination (0.31, 0.32), color temperature 6735 K and good stability over time.

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer.

OBJECTIVE: To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6. DESIGN: We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo. Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novoby virtual screening in 4855 FDA-approved drugs and its antitumour effects were evaluated in vitroand in vivo. RESULTS: SRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a ß2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity. CONCLUSIONS: SRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6. ACCESSION NUMBERS: The accession numbers for sequencing data are SRP111763 and SRP111797.

Mutations of key driver genes in colorectal cancer progression and metastasis.

The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis. A meta-analysis showed that KRAS mutations (combined OR 1.18, 95% CI 1.05-1.33) and p53 mutations (combined OR 1.49, 95% CI 1.23-1.80) were associated with CRC metastasis, including lymphatic and distant metastases. Moreover, CRC patients with a KRAS mutation (combined OR 1.29, 95% CI 1.13-1.47), p53 mutation (combined OR 1.35, 95% CI 1.06-1.72) or SMAD4 mutation (combined OR 2.04, 95% CI 1.41-2.95) were at a higher risk of distant metastasis. Subgroup analysis stratified by ethnic populations indicated that the BRAF mutation was related to CRC metastasis (combined OR 1.42, 95% CI 1.18-1.71) and distant metastasis (combined OR 1.51, 95% CI 1.20-1.91) in an Asian population. No significant association was found between mutations of APC or PIK3CA and CRC metastasis. In conclusion, mutations of KRAS, p53, SMAD4 and BRAF play significant roles in CRC metastasis and may be both potential biomarkers of CRC metastasis as well as therapeutic targets.

Myricetin inhibits NLRP3 inflammasome activation via reduction of ROS-dependent ubiquitination of ASC and promotion of ROS-independent NLRP3 ubiquitination.

Myricetin is a plant-derived flavonoid that exhibits diverse pharmacological properties. The NLRP3 (NLR family, pyrin domain-containing 3 protein) inflammasome is a cytosolic multiprotein complex that plays a critical role in the innate immune response and pathogenesis of multiple inflammatory disorders. The present study found that myricetin inhibited NLRP3 inflammasome assembly via promotion of reactive oxygen species (ROS)-independent ubiquitination of NLRP3 and reduction of ROS-dependent ubiquitination of ASC (apoptosis-associated speck-like protein containing a CARD), which disrupted the interaction between ASC and NLRP3 and inhibited ASC oligomerization. This effect was further confirmed in vivo using mouse models of lipopolysaccharide (LPS)-induced sepsis and alum-induced peritonitis. These results suggest the therapeutic value of myricetin by targeting NLRP3-driven inflammatory diseases.

Advancements in MAPK signaling pathways and MAPK-targeted therapies for ameloblastoma: A review.

Numerous signal transduction pathways are closely associated with the occurrence, development, and prognosis of ameloblastoma (AM). Mitogen-activated protein kinase (MAPK) is a serine/threonine-specific protein kinase that transduces intracellular signals in critical cellular phenomena. A number of recent analyses have reported that the MAPK signaling pathway contributes significantly to AM. High-throughput DNA sequencing methods, such as next-generation sequencing using Illumina have yielded advancements in studies on MAPK signaling pathways and their association with AM; in particular, BRAF V600E is mediated by the activation of the Ras/Raf/MAPK pathway. This review discusses advancements in studies on MAPK signaling pathways and MAPK-targeted inhibitors or antibodies, along with the merits and demerits of MAPK-targeted therapies, finally followed by a discussion regarding more efficient potential MAPK-targeted therapies to treat AM with few side effects, thereby providing novel insights into targeted therapy for AM.