USP14 regulates heme metabolism and ovarian cancer invasion through BACH1 deubiquitination and stabilization.

The deubiquitinating enzyme USP14 has been established as a crucial regulator in various diseases, including tumors, neurodegenerative diseases, and metabolic diseases, through its ability to stabilize its substrate proteins. Our group has utilized proteomic techniques to identify new potential substrate proteins for USP14, however, the underlying signaling pathways regulated by USP14 remain largely unknown. Here, we demonstrate the key role of USP14 in both heme metabolism and tumor invasion by stabilizing the protein BACH1. The cellular oxidative stress response factor NRF2 regulates antioxidant protein expression through binding to the antioxidant response element (ARE). BACH1 can compete with NRF2 for ARE binding, leading to the inhibition of the expression of antioxidant genes, including HMOX-1. Activated NRF2 also inhibits the degradation of BACH1, promoting cancer cell invasion and metastasis. Our findings showed a positive correlation between USP14 expression and NRF2 expression in various cancer tissues from the TCGA database and normal tissues from the GTEx database. Furthermore, activated NRF2 was found to increase USP14 expression in ovarian cancer (OV) cells. The overexpression of USP14 was observed to inhibit HMOX1 expression, while USP14 knockdown had the opposite effect, suggesting a role for USP14 in regulating heme metabolism. The depletion of BACH1 or inhibition of heme oxygenase 1 (coded by HMOX-1) was also found to significantly impair USP14-dependent OV cell invasion. In conclusion, our results highlight the importance of the NRF2-USP14-BACH1 axis in regulating OV cell invasion and heme metabolism, providing evidence for its potential as a therapeutic target in related diseases.

Surface Fitting for Quasi Scattered Data from Coordinate Measuring Systems.

Non-uniform rational B-spline (NURBS) surface fitting from data points is wildly used in the fields of computer aided design (CAD), medical imaging, cultural relic representation and object-shape detection. Usually, the measured data acquired from coordinate measuring systems is neither gridded nor completely scattered. The distribution of this kind of data is scattered in physical space, but the data points are stored in a way consistent with the order of measurement, so it is named quasi scattered data in this paper. Therefore they can be organized into rows easily but the number of points in each row is random. In order to overcome the difficulty of surface fitting from this kind of data, a new method based on resampling is proposed. It consists of three major steps: (1) NURBS curve fitting for each row, (2) resampling on the fitted curve and (3) surface fitting from the resampled data. Iterative projection optimization scheme is applied in the first and third step to yield advisable parameterization and reduce the time cost of projection. A resampling approach based on parameters, local peaks and contour curvature is proposed to overcome the problems of nodes redundancy and high time consumption in the fitting of this kind of scattered data. Numerical experiments are conducted with both simulation and practical data, and the results show that the proposed method is fast, effective and robust. What's more, by analyzing the fitting results acquired form data with different degrees of scatterness it can be demonstrated that the error introduced by resampling is negligible and therefore it is feasible.

Digital Three-Dimensional Automation of the Modified Huddart and Bodenham Scoring System for Patients With Cleft Lip and Palate.

OBJECTIVE: The modified Huddart and Bodenham scoring system assesses maxillary arch constriction and surgical outcomes in cleft lip and palate. This project automates modified Huddart and Bodenham scoring using three-dimensional digital models. DESIGN: Development of a novel software tool. SETTING: The design, construction, development, and testing of the system was carried out at Dundee Dental Hospital. PATIENTS, PARTICIPANTS: Subjects with cleft lip and palate. INTERVENTIONS: A plug-in has been developed using an open three-dimensional development platform: Rhinoceros, version 5 ( http://www.rhino3d.co.uk ). Users select cusps on mandibular and maxillary teeth on three-dimensional digital models. A three-dimensional cubic spline generates a mandibular curve, and a best-fit horizontal mandibular reference plane is produced using a least-squares method. Horizontal distances projected from the shortest three-dimensional distances were subsequently calculated between the maxillary cusps and the mandibular curve to calculate the modified Huddart and Bodenham score. MAIN OUTCOME MEASURES: Automatic scoring of digital models using the modified Huddart and Bodenham system produces similar results to manual scoring. RESULTS: By standardizing outcome assessment in cleft care, multicenter comparisons for audit and research can be simplified, allowing centers throughout the world to upload three-dimensional digital models or intraoral scans of the dental arches for remote scoring. Thereafter, these data can feed back into the global database on orofacial clefting as part of the World Health Organization's international collaborative "Global Burden of Disease" research project for craniofacial anomalies. CONCLUSIONS: The automated system facilitates quicker and more reliable outcome assessments by minimizing human errors.

The validity and reliability of an automated method of scoring dental arch relationships in unilateral cleft lip and palate using the modified Huddart-Bodenham scoring system.

OBJECTIVE: To evaluate an automated software tool for the assessment of dental arch relationships using the modified Huddart and Bodenham (MHB) index. DESIGN: Cohort of 43 models of subjects aged 9-21 with UCLP and the ten GOSLON reference models sets. METHOD: The 53 sets of plaster models were scored using the MHB index and scanned with a benchtop scanner. The digital models were MHB scored visually using a commercial software program and landmarked for automatic scoring using a software plug-in. Scoring/landmarking was undertaken by three observers and repeated after 1 month. Intra- and inter-observer reproducibility were tested using Cronbach's alpha and intraclass correlation coefficients (ICC) (threshold > 0.9). Bland-Altman plots demonstrated inter-observer agreement for each model format. Random and systematic error with digital landmark identification error were determined using the x, y, and z co-ordinates for 28 models digitized twice 1 month apart using Cronbach's alpha and a t-test, respectively. RESULTS: Intra-operator landmark identification was excellent (Cronbach's alpha = 0.933) with no differences between sessions (P > 0.05). Intra-observer reproducibility was excellent for all examiners (Cronbach's alpha and ICC 0.986-0.988). Inter-observer reproducibility was highest for the software plug-in (0.991), followed by plaster (0.989) and OrthoAnalyzer (0.979) and Bland-Altman plots confirmed no systematic bias and greater consistency of scores with the automated software. CONCLUSION: The automated MHB software tool is valid, reproducible, and the most objective method of assessing maxillary arch constriction for patients with UCLP. CONFLICT OF INTEREST STATEMENT: The authors declare no conflict of interest or financial relationship with any organization or software used within the study.

Analyzing chemical composition of Sargentodoxae caulis water extract and their hypouricemia effect in hyperuricemic mice.

Hyperuricemia (HUA) is a metabolic disease characterized by the increase of serum uric acid (UA) level. Sargentodoxae Caulis (SC) is a commonly used herbal medicine for the treatment of gouty arthritis, traumatic swelling, and rheumatic arthritis in clinic. In this study, a total of fifteen compounds were identified in SC water extract using UHPLC-Q-TOF-MS/MS, including three phenolic acids, seven phenolic glycosides, four organic acids, and one lignan. Then, to study the hypouricemia effect of SC, a HUA mouse model was induced using a combination of PO, HX, and 20% yeast feed. After 14 days of treatment with the SC water extract, the levels of serum UA, creatinine (CRE), blood urea nitrogen (BUN) were reduced significantly, and the organ indexes were restored, the xanthine oxidase (XOD) activity were inhibited as well. Meanwhile, SC water extract could ameliorate the pathological status of kidneys and intestine of HUA mice. Additionally, quantitative real-time PCR (qRT-PCR) and western blotting results showed that SC water extract could increase the expression of ATP binding cassette subfamily G member 2 (ABCG2), organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3), whereas decrease the expression of glucose transporter 9 (GLUT9). This study provided a data support for the clinical application of SC in the treatment of HUA.

ß-catenin/TCF4-induced SCUBE3 upregulation promotes ovarian cancer development via HIF-1 signaling pathway.

The precise involvement and mechanistic role of the signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) in ovarian cancer (OV) remain poorly understood. Here, leveraging comprehensive data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we unveil the selective overexpression of SCUBE3 in ovarian cancer tissues and cells. Intriguingly, elevated SCUBE3 expression levels correlate with an unfavorable prognosis in patients. Through meticulous manipulation of SCUBE3 expression, we elucidate its consequential impact on in vitro proliferation and invasion of ovarian cancer cells, as well as in vivo tumor growth in mice. Our multifaceted investigations, encompassing luciferase reporter assays, chromatin immunoprecipitation (ChIP) experiments, and mining of public databases, successfully identify SCUBE3 as a direct downstream target gene of TCF4-a pivotal positive regulator within the ß-catenin/TCF4 complex. Furthermore, utilizing a recessive mutant mouse line (kta41) harboring a functionally impaired point mutation at position 882 in the SCUBE3 gene, we uncover SCUBE3's involvement in the intricate regulation of angiogenesis and epithelial-mesenchymal transition (EMT). Strikingly, Spearman correlation coefficient analysis unveils a close association between SCUBE3 and HIF1A in OV, with SCUBE3 exerting tight control over HIF1A mRNA expression. Moreover, functional inhibition of HIF1A significantly impedes the pro-proliferative and invasive capabilities of SCUBE3-overexpressing ovarian cancer cells. Collectively, our findings underscore the pivotal role of SCUBE3 in driving ovarian cancer progression, shedding light on its intricate molecular mechanisms and establishing it as a potential therapeutic target for this devastating disease.

CENPK orchestrates ovarian cancer progression via GOLPH3-Mediated activation of mTOR signaling.

Ovarian cancer stands as a formidable clinical challenge, with limited therapeutic options. This investigation delves into the intricate molecular mechanisms governing ovarian cancer progression and uncovers Centromere Protein K (CENPK) as a central figure in disease pathogenesis. Elevated CENPK levels within ovarian cancer tissues conspicuously align with adverse clinical outcomes, positioning CENPK as a promising prognostic biomarker. Deeper exploration reveals a direct transcriptional connection between CENPK and the E2F1 transcription factor and clearly establishes E2F1's role as the master regulator of CENPK expression in ovarian cancer. Our inquiry revealing a suppression of tumor-promoting signaling pathways, most notably the mTOR pathway, upon CENPK silencing. Intriguingly, CENPK renders ovarian cancer cells more responsive to the mTOR inhibitor rapamycin, introducing a promising avenue for therapeutic intervention. In summation, our study unravels the multifaceted role of CENPK in ovarian cancer progression. It emerges as a prognostic indicator, a pivotal mediator of cell proliferation and tumorigenicity, and a regulator of the mTOR pathway, shedding light on potential therapeutic avenues for this formidable disease.

FBXO5-mediated RNF183 degradation prevents endoplasmic reticulum stress-induced apoptosis and promotes colon cancer progression.

Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), and prolonged ER stress leads to cell apoptosis. Despite increasing research in this area, the underlying molecular mechanisms remain unclear. Here, we discover that ER stress upregulates the UPR signaling pathway while downregulating E2F target gene expression and inhibiting the G2/M phase transition. Prolonged ER stress decreases the mRNA levels of E2F2, which specifically regulates the expression of F-Box Protein 5(FBXO5), an F-box protein that functions as an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex. Depletion of FBXO5 results in increased ER stress-induced apoptosis and decreased expression of proteins related to PERK/IRE1α/ATF6 signaling. Overexpression of FBXO5 wild-type (not its ΔF-box mutant) alleviates apoptosis and the expression of the C/EBP Homologous Protein (CHOP)/ATF. Mechanistically, we find that FBXO5 directly binds to and promotes the ubiquitin-dependent degradation of RNF183, which acts as a ubiquitin E3 ligase in regulating ER stress-induced apoptosis. Reversal of the apoptosis defects caused by FBXO5 deficiency in colorectal cancer cells can be achieved by knocking down RNF183 in FBXO5-deficient cells. Functionally, we observed significant upregulation of FBXO5 in colon cancer tissues, and its silencing suppresses tumor occurrence in vivo. Therefore, our study highlights the critical role of the FBXO5/RNF183 axis in ER stress regulation and identifies a potential therapeutic target for colon cancer treatment.

HIF1A-dependent overexpression of MTFP1 promotes lung squamous cell carcinoma development by activating the glycolysis pathway.

Introduction: Mitochondrial fission process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein implicated in the development and progression of various tumors, particularly lung squamous cell carcinoma (LUSC). This study aims to provide a more theoretical basis for the treatment of LUSC. Methods: Through bioinformatics analysis, MTFP1 was identified as a novel target gene of HIF1A. MTFP1 expression in LUSC was examined using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Proteomics Data Commons (PDC) databases. The Kaplan-Meier plotter (KM plotter) database was utilized to evaluate its correlation with patient survival. Western blot and chromatin immunoprecipitation (ChIP) assays were employed to confirm the regulatory relationship between MTFP1 and HIF1A. Additionally, cell proliferation, colony formation, and migration assays were conducted to investigate the mechanism by which MTFP1 enhances LUSC cell proliferation and metastasis. Results: Our findings revealed that MTFP1 overexpression correlated with poor prognosis in LUSC patients(P < 0.05). Moreover, MTFP1 was closely associated with hypoxia and glycolysis in LUSC (R = 0.203; P < 0.001, R = 0.391; P < 0.001). HIF1A was identified as a positive regulator of MTFP1. Functional enrichment analysis demonstrated that MTFP1 played a role in controlling LUSC cell proliferation. Cell proliferation, colony formation, and migration assays indicated that MTFP1 promoted LUSC cell proliferation and metastasis by activating the glycolytic pathway (P < 0.05). Conclusions: This study establishes MTFP1 as a novel HIF1A target gene that promotes LUSC growth by activating the glycolytic pathway. Investigating MTFP1 may contribute to the development of effective therapies for LUSC patients, particularly those lacking targeted oncogene therapies.

FOXP4-mediated induction of PTK7 activates the Wnt/ß-catenin pathway and promotes ovarian cancer development.

Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4's function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

The atypical ubiquitin ligase RNF31 stabilizes c-Myc via epigenetic inactivation of FBXO32 and promotes cancer development.

RNF31, an atypical E3 ubiquitin ligase of the RING-between-RING protein family, is one of the important components of the linear ubiquitin chain complex LUBAC. It plays a carcinogenic role in a variety of cancers by promoting cell proliferation, invasion and inhibiting apoptosis. However, the specific molecular mechanism by which RNF31 exerts its cancer-promoting effects is still unclear. By analyzing the expression profile of RNF31-depleted cancer cells, we found that loss of RNF31 significantly resulted in the inactivation of the c-Myc pathway. We further showed that RNF31 played an important role in the maintenance of c-Myc protein levels in cancer cells by extending the half-life of c-Myc protein and reducing its ubiquitination. c-Myc protein levels are tightly regulated by the ubiquitin proteasome, in which the E3 ligase FBXO32 is required to mediate its ubiquitin-dependent degradation. We found that RNF31 inhibited the transcription of FBXO32 through EZH2-mediated trimethylation of histone H3K27 in the FBXO32 promoter region, leading to the stabilization and activation of c-Myc protein. Under this circumstance, the expression of FBXO32 was significantly increased in RNF31-deficient cells, promoting the degradation of c-Myc protein, inhibiting cell proliferation and invasion, increasing cell apoptosis, and ultimately blocking the progression of tumors. Consistent with these results, the reduced malignancy phenotype caused by RNF31 deficiency could be partially reversed by overexpression of c-Myc or further knockdown of FBXO32. Together, our results reveal a key association between RNF31 and epigenetic inactivation of FBXO32 in cancer cells, and suggest that RNF31 may be a promising target for cancer therapy.

VHL-HIF-2α axis-induced SEMA6A upregulation stabilized ß-catenin to drive clear cell renal cell carcinoma progression.

SEMA6A is a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role of SEMA6A in clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report that SEMA6A is a novel target gene of the VHL-HIF-2α axis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed that HIF-2α directly activated SEMA6A transcription in hypoxic ccRCC cells. Wnt/ß-catenin pathway activation is correlated with the expression of SEMA6A in ccRCC; the latter physically interacted with SEC62 and promoted ccRCC progression through SEC62-dependent ß-catenin stabilization and activation. Depletion of SEMA6A impaired HIF-2α-induced Wnt/ß-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo. SEMA6A overexpression promoted the malignant phenotypes of ccRCC, which was reversed by SEC62 depletion. Collectively, this study revealed a potential role for VHL-HIF-2α-SEMA6A-SEC62 axis in the activation of Wnt/ß-catenin pathway. Thus, SEMA6A may act as a potential therapeutic target, especially in VHL-deficient ccRCC.

Comparison of High-flow Nasal Cannula (HFNC) and Conventional Oxygen Therapy in Obese Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: High-flow nasal cannula (HFNC), a new method for postoperative oxygenation, has increasingly received attention during postoperative care. However, its importance for obese patients undergoing cardiac surgery remains controversial. This systematic review and meta-analysis compared and evaluated HFNC and conventional oxygen therapy (COT) in this patient group. MATERIALS AND METHODS: Literature was retrieved by searching eight public databases. Randomized controlled trials (RCTs) were selected. RevMan 5.3 was used to analyze the results and any potential bias. The primary outcome included atelectasis score at 24 h postoperatively. The secondary outcomes included PaO2/FiO2 (ratio), dyspnea score at 24 h postoperatively, intensive care unit (ICU) length of stay, and reintubation. RESULTS: The search strategy yielded 382 studies after duplicates were removed. Finally, 3 RCTs with a total of 526 patients were included in the present study. Compared with COT, there was no significant difference in atelectasis score, dyspnea score, reintubation, and ICU length of stay. CONCLUSION: For obese patients undergoing cardiac surgery, postoperative use of HFNC can maintain patient's oxygenation. Additional clinical studies are needed to investigate the role of HFNC in this patient group.

A 3D cephalometric protocol for the accurate quantification of the craniofacial symmetry and facial growth.

BACKGROUND: Cephalometric analysis is used to evaluate facial growth, to study the anatomical relationships within the face. Cephalometric assessment is based on 2D radiographic images, either the sagittal or coronal planes and is an inherently inaccurate methodology. The wide availability of 3D imaging techniques, such as computed tomography and magnetic resonance imaging make routine 3D analysis of facial morphology feasible. 3D cephalometry may not only provide a more accurate quantification of the craniofacial morphology and longitudinal growth, but also the differentiation of subtle changes in occlusion. However, a reliable protocol for the computation of craniofacial symmetry and quantification of craniofacial morphology is still a topic of extensive research. Here, a protocol for 3D cephalometric analysis for both the identification of the natural head position (NHP) and the accurate quantification of facial growth and facial asymmetry is proposed and evaluated. A phantom study was conducted to assess the performance of the protocol and to quantify the ability to repeatedly and reliably align skulls with the NHP and quantify the degree of accuracy with which facial growth and facial asymmetry can be measured. RESULTS: The results obtained show that the protocol allows consistent alignment with the NHP, with an overall average error (and standard deviation) of just 0.17 (9.10e-6) mm, with variations of 0.21 (2.77e-17) mm in the frontonasal suture and 0.30 (5.55e-17) mm in the most prominent point in the chin. The average errors associated with simulated facial growth ranged from 1.83 to 3.75% for 2 years' growth and from - 9.57 to 14.69% for 4 years, while the error in the quantification of facial asymmetry ranged from - 11.38 to 9.31%. CONCLUSIONS: The protocol for 3D skull alignment produces accurate and landmark free estimation of the true symmetry of the head. It allows a reliable alignment of the skull in the NHP independently of user-defined landmarks, as well as an accurate quantification of facial growth and asymmetry.

Towards additive manufacturing oriented geometric modeling using implicit functions.

Surface-based geometric modeling has many advantages in terms of visualization and traditional subtractive manufacturing using computer-numerical-control cutting-machine tools. However, it is not an ideal solution for additive manufacturing because to digitally print a surface-represented geometric object using a certain additive manufacturing technology, the object has to be converted into a solid representation. However, converting a known surface-based geometric representation into a printable representation is essentially a redesign process, and this is especially the case, when its interior material structure needs to be considered. To specify a 3D geometric object that is ready to be digitally manufactured, its representation has to be in a certain volumetric form. In this research, we show how some of the difficulties experienced in additive manufacturing can be easily solved by using implicitly represented geometric objects. Like surface-based geometric representation is subtractive manufacturing-friendly, implicitly described geometric objects are additive manufacturing-friendly: implicit shapes are 3D printing ready. The implicit geometric representation allows to combine a geometric shape, material colors, an interior material structure, and other required attributes in one single description as a set of implicit functions, and no conversion is needed. In addition, as implicit objects are typically specified procedurally, very little data is used in their specifications, which makes them particularly useful for design and visualization with modern cloud-based mobile devices, which usually do not have very big storage spaces. Finally, implicit modeling is a design procedure that is parallel computing-friendly, as the design of a complex geometric object can be divided into a set of simple shape-designing tasks, owing to the availability of shape-preserving implicit blending operations.

Selenium nanocomposites as multifunctional nanoplatform for imaging guiding synergistic chemo-photothermal therapy.

A multifunctional selenium nanocomposite (selenium@silica core-shell nanoshperes for loading indocyanine green(ICG)/Doxorubicin(DOX)) was fabricated to reach visible and efficient cancer treatment. The Se@SiO2-ICG nanocomposites could be used not only as excellent photothermal agents but also as carriers for DOX delivery. In addition, the Se@SiO2-ICG/DOX nanocomposites exhibited excellent fluorescence imaging and infrared imaging performance. Tumor could be effectively inhibited by Se@SiO2-ICG/DOX due to the triple treatment of photothermal effect and chemotherapy of selenium and DOX. Thus, the Se@SiO2-ICG/DOX nanocomposites have a great potential in imaging guiding synergistic treatment of cancer.

Immune response mechanism of mouse monocytes/macrophages treated with κ-carrageenan polysaccharide.

This study investigated the function of κ-carrageenan polysaccharide in immune regulation. The immune response of RAW 264.7 cells treated with κ-carrageenan polysaccharide was explored by MTT assay, general morphological observation, neutral red phagocytosis assay, Griess method, fluorescence method, and enzyme-linked immunosorbent assay. In addition, TLR4 blocking experiment and double-fluorescence immunostaining were performed on cells to demonstrate their immune response mechanism. Results show that κ-carrageenan polysaccharide not only promotes cell proliferation but also activates RAW 264.7 cells, thereby improving the cells' phagocytic capability, NO production, and tumor necrosis factor-α (TNF-α) secretion. In addition, the use of TLR4-specific inhibitors can significantly mediate the increased TNF-α secretion induced by κ-carrageenan polysaccharide. The RAW 264.7 cells treated with κ-carrageenan polysaccharide show upregulated TLR4 expression, and the main subunit of NF-κB (p65) is translocated. These results support the immunomodulatory function of κ-carrageenan polysaccharide in RAW 264.7 cells.