The application of zebrafish model in the study of cleft lip and palate development: A systematic review.

Objective: Craniofacial growth and development are more than a scientific curiosity; it is of tremendous interest to clinicians. Insights into the genetic etiology of cleft lip and palate development are essential for improving diagnosis and treatment planning. The purpose of this systematic review was to utilize a zebrafish model to highlight the role of the IRF6 gene in cleft lip and palate development in humans. Data: This review adhered to the guidelines outlined in the PRISMA statement. Nine studies were included in the analysis. Sources: This study used major scientific databases such as MEDLINE, EMBASE, Web of Science, and the Zebrafish Information Network and yielded 1275 articles. Two reviewers performed the screening using COVIDENCE™ independently, and a third reviewer resolved any conflicts. Study selection: After applying the inclusion and exclusion criteria and screening, nine studies were included in the analysis. The Systematic Review Center for Laboratory Animal Experimentation's (SYRCLE's) risk-of-bias tool was used to assess the quality of the included studies. Results: The main outcome supports the role of the IRF6 gene in zebrafish periderm development and embryogenesis, and IRF6 variations result in cleft lip and palate development. The overall SYRCLE risk of bias was low-medium. Conclusion: In conclusion, this review indicated the critical role of the IRF6 gene and its downstream genes (GRHL3, KLF17, and ESRP1/2) in the development of cleft lip and palate in zebrafish models. Genetic mutation zebrafish models provide a high level of insights into zebrafish craniofacial development. Clinical relevance: this review provides a productive avenue for understanding the powerful and conserved zebrafish model for investigating the pathogenesis of human cleft lip and palate.

Students' perception of the educational environment at King Saud bin Abdulaziz University for health sciences using DREEM tool.

BACKGROUND: Students' learning results are influenced by the educational environment. The best learning environment is created when students are involved in the evaluation process of their education. The purpose of this study was to evaluate students' perceptions of their learning environment at King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) in Riyadh using the Dundee Ready Education Environment Measure (DREEM) instrument. METHODS: This observational cross-sectional study was conducted through an online questionnaire using the Arabic version of the DREEM tool. Students from six colleges at KSAU-HS Riyadh campus were asked to complete the questionnaire through emails. The study was carried out between November 2021 and April 2022. Descriptive statistics and inferential statistics were performed for DREEM as both a continuous (two-way ANOVA test) and categorical variable (Chi-squared and Monte-Carlo test). RESULTS: A total of 370 students completed the questionnaire. The overall DREEM score for the study was 125.88/200, with a standard deviation of 58.79. SSP items received the highest scores, while SAP items earned the lowest scores. The college and the academic level showed statistically significant differences in the DREEM overall score and the five subscales, whereas gender showed no significant difference. The college of pharmacy scored the highest total DREEM score (140.35 ± 27.75), and scored higher among the five subscales than both colleges of dentistry (114.13 ± 29.74) and medicine (113.87 ± 33.03). Students in their third year had the greatest overall DREEM score (132.23 ± 29.76), and scored higher in SPL, SPA and SSP compared to students in their sixth year, in which the total DREEM score was (111.65 ± 27.58). CONCLUSIONS: Students of KSAU-HS generally perceived the educational environment as having more positive than negative. The educational level and college differed significantly in the overall DREEM score and the five subscales. Junior students had better perception of the educational environment and they differed significantly in the SPL and SPA subscales. The faculty of pharmacy had higher scores in the overall DREEM and the five subsequent scales than colleges of dentistry and medicine. Further research is needed in order to optimize the educational environment by investigating different solutions.

Comparative efficacy of mandibular advancement devices in obstructive sleep apnea: a network meta-analysis.

PURPOSE: To analyze relative efficacies of mandibular advancement devices (MAD) in sleep apnea treatment. METHODS: From eligible randomized controlled trials (RCT), MADs were classified based on their mechanistic designs. Data on apnea-hypopnea index (AHI), Epworth sleepiness scale (ESS), nadir oxygen saturation (minSaO2), and sleep efficiency (SE%) from RCTs were then analyzed in network meta-analyses, and relative ranking of different MADs was computed based on P scores (a method of ranking similar to SUCRA). Similar analyses were conducted based on the different brands of MADs. RESULTS: There were no statistically significant differences between MADs in any of the outcomes analyzed. However, the P-scores, based on the point estimates and standard errors of the network estimates, ranked some MADs higher than others in some of the outcomes. Of the different mechanistic designs, the highest P scores were achieved for attached midline traction (P score = 0.84) and unattached bilateral interlocking (P score = 0.78) devices for AHI reduction, attached bilateral traction (P score = 0.78) and unattached bilateral interlocking (P score = 0.76) for ESS, monobloc (P score = 0.91) and unattached bilateral interlocking (P score = 0.64) for minSaO2, and unattached bilateral interlocking (P score = 0.82) and attached bilateral traction (P score = 0.77) for SE%. Notable findings in the network meta-analyses based on MAD brands, of the limited number of studies that specified them were the effects of SomnoDent Flex™, TAP™, and IST® in their effects on AHI reduction, with P scores of 0.94, 0.83, and 0.82, respectively. Monobloc decreased supine-AHI the most (- 44.46 [- 62.55; - 26.36], P score = 0.99), and unattached bilateral interlocking had the greatest effect on REM-AHI (- 11.10 [- 17.10; - 5.10], P score = 0.87). CONCLUSIONS: Findings from this study show clinically (but not statistically) significant differences between MADs in terms of their relative efficacy when analyzed for different sleep apnea treatment outcomes and sleep apnea phenotypes.

ß-Catenin/CBP inhibition alters epidermal growth factor receptor fucosylation status in oral squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) is a major driver of head and neck cancer, a devastating malignancy with a major sub-site in the oral cavity manifesting as oral squamous cell carcinoma (OSCC). EGFR is a glycoprotein receptor tyrosine kinase (RTK) whose activity is upregulated in >80% OSCC. Current anti-EGFR therapy relies on the use of cetuximab, a monoclonal antibody against EGFR, although it has had only a limited response in patients. Here, we uncover a novel mechanism regulating EGFR activity, identifying a role of the nuclear branch of the Wnt/ß-catenin signaling pathway, the ß-catenin/CBP axis, in control of post-translational modification of N-glycans on the EGFR. Genomic and structural analyses reveal that ß-catenin/CBP signaling represses fucosylation on the antennae of N-linked glycans on EGFR. By employing nUPLC-MS/MS, we determined that malignant human OSCC cells harbor EGFR with a paucity of N-glycan antennary fucosylation, while indolent cells display higher levels of fucosylation at sites N420 and N579. Additionally, treatment with either ICG-001 or E7386, which are both small molecule inhibitors of ß-catenin/CBP signaling, leads to increased transcriptional expression of fucosyltransferases FUT2 and FUT3, with a concomitant increase in EGFR N-glycan antennary fucosylation. In order to discover which fucosylated glycan epitopes are involved in the observed effect, we performed in-depth characterization of multiply-fucosylated N-glycans via tandem mass spectrometry analysis of the EGFR tryptic glycopeptides. Data are available via ProteomeXchange with identifier PXD017060. We propose that ß-catenin/CBP signaling promotes EGFR oncogenic activity in OSCC by inhibiting its N-glycan antennary fucosylation through transcriptional repression of FUT2 and FUT3.

Functional and genomic analyses reveal therapeutic potential of targeting ß-catenin/CBP activity in head and neck cancer.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and molecular alterations associated with HNSCC have been identified, they have had limited impact on the clinical management of this disease. To date, few targeted therapies are available for HNSCC, and only a small fraction of patients have benefited from these treatments. A frequent feature of HNSCC is the inappropriate activation of ß-catenin that has been implicated in cell survival and in the maintenance and expansion of stem cell-like populations, thought to be the underlying cause of tumor recurrence and resistance to treatment. However, the therapeutic value of targeting ß-catenin activity in HNSCC has not been explored. METHODS: We utilized a combination of computational and experimental profiling approaches to examine the effects of blocking the interaction between ß-catenin and cAMP-responsive element binding (CREB)-binding protein (CBP) using the small molecule inhibitor ICG-001. We generated and annotated in vitro treatment gene expression signatures of HNSCC cells, derived from human oral squamous cell carcinomas (OSCCs), using microarrays. We validated the anti-tumorigenic activity of ICG-001 in vivo using SCC-derived tumor xenografts in murine models, as well as embryonic zebrafish-based screens of sorted stem cell-like subpopulations. Additionally, ICG-001-inhibition signatures were overlaid with RNA-sequencing data from The Cancer Genome Atlas (TCGA) for human OSCCs to evaluate its association with tumor progression and prognosis. RESULTS: ICG-001 inhibited HNSCC cell proliferation and tumor growth in cellular and murine models, respectively, while promoting intercellular adhesion and loss of invasive phenotypes. Furthermore, ICG-001 preferentially targeted the ability of subpopulations of stem-like cells to establish metastatic tumors in zebrafish. Significantly, interrogation of the ICG-001 inhibition-associated gene expression signature in the TCGA OSCC human cohort indicated that the targeted ß-catenin/CBP transcriptional activity tracked with tumor status, advanced tumor grade, and poor overall patient survival. CONCLUSIONS: Collectively, our results identify ß-catenin/CBP interaction as a novel target for anti-HNSCC therapy and provide evidence that derivatives of ICG-001 with enhanced inhibitory activity may serve as an effective strategy to interfere with aggressive features of HNSCC.