Comprehensive bioinformatics analysis combined with experimental validation to screen biomarkers for malignant transformation of oral leukoplakia.

Oral leukoplakia (OLK) is the most common potentially malignant disorders in the oral cavity. This study aimed to screen the key genes of OLK malignant transformation using the Gene Expression Omnibus (GEO) database and experiments. In this study, the GEO database was employed to screen OLK malignant transformation-related genes, which were subsequently identified with a series of bioinformatic analyses. External validation showed that the model based on LAPTM4B, NR3C1, and COX6A1 had high accuracy in diagnosing OLK malignant transformation. Furthermore, the DMBA-induced potentially malignant disorders and OSCC models in vivo and real-time PCR experiment in vitro further verified the database analysis results. In conclusion, three key genes (LAPTM4B, NR3C1, and COX6A1) were screened as potential biomarkers for the diagnosis and treatment of OLK malignant transformation.

Epidemiological Investigation of Facial Soft Tissue Injury in Chinese Preschool Children.

OBJECTIVE: The aim of this study was to analyze the epidemiological characteristics of pediatric facial soft tissue injuries of Chinese preschool-aged children in Hangzhou Plastic Surgery Hospital. METHODS: Medical records of preschool-aged children's facial injuries, 6 years and younger, from January 2017 to December 2019 were collected. Sex; age; time of injury; length of stay; causes of injury; location, type, length, and depth of wound; anesthesia methods; and treatment and evaluation of postoperative scars were analyzed. RESULTS: There were 10,862 cases (male, 6780 cases; female, 4082 cases) in the group. The ratio of male to female was 1.66:1. Mean age was 3.4 (±1.6) years; the youngest was 1 month old. The time of injury occurred frequently between 9:00 and 13:00 and 16:00 to 21:00, with the most common incident time being between 19:00 and 20:00. Collision injury was the main cause of injury (9822 [90.43%]). The most frequently injured area was the forehead (4874 [44.87%]). The main form of injury was laceration wound (9721 [89.45%]). The depth of injuries was mainly middle layer (adipose or muscular layer) (6299 [57.99%]). The length of injuries was 1.7 (±0.9) cm, ranging from 0.2 to 10.5 cm. Furthermore, 9110 cases were repaired by plastic surgeries and 1 or more antiscar measures. After 6-month to 2-year follow-up, 9 cases of animal scratch or bite, lip penetrating wound, or bumping teeth were infected and 26 cases had scar hyperplasia. The others achieved satisfactory results, and the scars were not obvious. CONCLUSION: Preschool-aged children's facial injuries have predictable patterns of occurrence, and targeted preventive measures can reduce the incidence rates. After facial injury, children should present for timely plastic surgery treatment and accept combined antiscarring measures to minimize postoperative scarring.

Application of External Nasal Skin Stretching in Asian Rhinoplasty.

ABSTRACT: Asian nasal characteristics include a low dorsum, short nose, and thick skin envelope, usually requiring lengthening and elevating the nose during rhinoplasty ( Facial Plast Surg Clin North Am 2007;15(3):293-307, v). The increase in rhinoplasty popularity has resulted in a greater prevalence of complications. In a severely short and contracted nose, an extensively scarred or contracted soft tissue envelope results in weak laxity and extensibility of the nasal skin. For these patients, the essential component of rhinoplasty is to improve skin texture and obtain a sufficient nasal skin soft tissue envelope. Tissue expanders have previously been utilized to expand nasal skin and soft tissue ( Plast Reconstr Surg 2006;118(6):1447-1452; Facial Plast Surg 2019;35(1):68-72). However, nasal anatomical characteristics have limited the clinical application of tissue expanders. This article introduces a simple, noninvasive, and easily adopted method of external nasal skin stretching, which was first proposed by the senior author. This approach has been accepted by rhinoplasty surgeons in China and widely used in clinic. The approach can improve skin laxity, yield extra nasal soft tissue, and create adequate soft tissue coverage of the reconstructed nasal framework to reduce the difficulty of surgery with a reliable clinical effect.

Comprehensive bioinformatics analysis and experimental validation: An anoikis-related gene prognostic model for targeted drug development in head and neck squamous cell carcinoma.

We analyzed RNA-sequencing (RNA-seq) and clinical data from head and neck squamous cell carcinoma (HNSCC) patients in The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) portal to investigate the prognostic value of anoikis-related genes (ARGs) in HNSCC and develop new targeted drugs. Differentially expressed ARGs were screened using bioinformatics methods; subsequently, a prognostic model including three ARGs (CDKN2A, BIRC5, and PLAU) was constructed. Our results showed that the model-based risk score was a good prognostic indicator, and the potential of the three ARGs in HNSCC prognosis was validated by the TISCH database, the model's accuracy was validated in two independent cohorts of the Gene Expression Omnibus database. Immune correlation analysis and half-maximal inhibitory concentration were also performed to reveal the different landscapes of TIME between risk groups and to predict immuno- and chemo-therapeutic responses. Potential small-molecule drugs for HNSCC were subsequently predicted using the L1000FWD database. Finally, in vitro experiments were used to verify the database findings. The relative ARG mRNA expression levels in HNSCC and surrounding normal tissues remained consistent with the model results. BIRC5 knockdown inhibited anoikis resistance in WSU-HN6 and CAL-27 cells. Molecular docking, real-time PCR, cell counting kit-8 (CCK-8), plate clone, and flow cytometry analyses showed that small-molecule drugs predicted by the database may target the ARGs in the prognostic model, inhibit HNSCC cells survival rate, and promote anoikis in vitro. Therefore, we constructed a new ARG model for HNSCC patients that can predict prognosis and immune activity and identify a potential small-molecule drug for HNSCC, paving the way for clinically targeting anoikis in HNSCC.

Mometasone Furoate Inhibits the Progression of Head and Neck Squamous Cell Carcinoma via Regulating Protein Tyrosine Phosphatase Non-Receptor Type 11.

Mometasone furoate (MF) is a kind of glucocorticoid with extensive pharmacological actions, including inhibiting tumor progression; however, the role of MF in head and neck squamous cell carcinoma (HNSCC) is still unclear. This study aimed to evaluate the inhibitory effect of MF against HNSCC and investigate its underlying mechanisms. Cell viability, colony formation, cell cycle and cell apoptosis were analyzed to explore the effect of MF on HNSCC cells. A xenograft study model was used to investigate the effect of MF on HNSCC in vivo. The core targets of MF for HNSCC were identified using network pharmacology analysis, TCGA database analysis and real-time PCR. Molecular docking was performed to determine the binding energy. Protein tyrosine phosphatase non-receptor type 11 (PTPN11)-overexpressing cells were constructed, and then, the cell viability and the expression levels of proliferation- and apoptosis-related proteins were detected after treatment with MF to explore the role of PTPN11 in the inhibitory effect of MF against HNSCC. After cells were treated with MF, cell viability and the number of colonies were decreased, the cell cycle was arrested and cell apoptosis was increased. The xenograft study results showed that MF could inhibit cell proliferation via promoting cell apoptosis in vivo. PTPN11 was shown to be the core target of MF against HNSCC via network pharmacology analysis, TCGA database analysis and real-time PCR. The molecular docking results revealed that PTPN11 exhibited the strongest ability to bind to MF. Finally, MF could attenuate the effects of increased cell viability and decreased cell apoptosis caused by PTPN11 overexpression, suggesting that MF can inhibit the progression of HNSCC by regulating PTPN11. MF targeted PTPN11, promoting cell cycle arrest and cell apoptosis, and consequently exerting effective anti-tumor activity.

[Variation of irradiance in the arctic pole during the summer].

The variation of irradiance affect the melting rate of the sea ice in the arctic pole, and the research on it is an important component of the global climate change research. The present research was based on the spectrum data collected during the 4th scientific research on the arctic of China in 2010, analyzed the variation of irradiance in the arctic pole during the summer and discussed the reasons for the change. This research shows that many factors lead to the change, among which the weather and the solar elevation angle affect the irradiance directly. The weather factors determine the amount of solar radiation that reached the ground after the absorption and attenuation of the clouds; In high-latitude areas, there is a low solar elevation angle and the attenuation of solar radiation was obvious. Our research shows that the spectrum at shorter wavelength is more sensitive to the changes in altitude of the sun, while the impact of weather on the irradiance increases with wavelength. Moreover, moisture content in the atmosphere also affects the solar radiation reaching the ground and the its impact is in a particular band but not for the entire spectrum range.

Potential prognostic value of a eight ferroptosis-related lncRNAs model and the correlative immune activity in oral squamous cell carcinoma.

BACKGROUND: To investigate the prognostic value of ferroptosis-related long noncoding RNAs (lncRNAs) in oral squamous cell carcinoma (OSCC) and to construct a prognostic risk and immune activity model. METHODS: We obtained clinical and RNA-seq information on OSCC patient data in The Cancer Genome Atlas (TCGA) Genome Data Sharing (GDC) portal. Through a combination of a differential analysis, Pearson correlation analysis and Cox regression analysis, ferroptosis-related lncRNAs were identified, and a prognostic model was established based on these ferroptosis-related lncRNAs. The accuracy of the model was evaluated via analyses based on survival curves, receiver operating characteristic (ROC) curves, and clinical decision curve analysis (DCA). Univariate Cox and multivariate Cox regression analyses were performed to evaluate independent prognostic factors. Then, the infiltration and functional enrichment of immune cells in high- and low-risk groups were compared. Finally, certain small-molecule drugs that potentially target OSCC were predicted via use of the L1000FWD database. RESULTS: The prognostic model included 8 ferroptosis-related lncRNAs (FIRRE, LINC01305, AC099850.3, AL512274.1, AC090246.1, MIAT, AC079921.2 and LINC00524). The area under the ROC curve (AUC) was 0.726. The DCA revealed that the risk score based on the prognostic model was a better prognostic indicator than other clinical indicators. The multivariate Cox regression analysis showed that the risk score was an independent prognostic factor for OSCC. There were differences in immune cell infiltration, immune functions, m6A-related gene expression levels, and signal pathway enrichment between the high- and low-risk groups. Subsequently, several small-molecule drugs were predicted for use against differentially expressed ferroptosis-related genes in OSCC. CONCLUSIONS: We constructed a new prognostic model of OSCC based on ferroptosis-related lncRNAs. The model is valuable for prognostic prediction and immune evaluation, laying a foundation for the study of ferroptosis-related lncRNAs in OSCC.

Hydrogel-based patient-friendly photodynamic therapy of oral potentially malignant disorders.

Oral potentially malignant disorders (OPMDs) are precursor lesions with an increased risk of malignant transformation. Topical photodynamic therapy (PDT) mediated by 5-aminolevulinic acid (ALA) (ALA-PDT) is a promising therapeutic method in the treatment of OPMDs. However, the clinical application of topical ALA-PDT is restricted by several limitations, including low delivery efficiency, poor comfort, and easy influence by saliva. Here, we designed a highly adhesion-strength dry polyacrylic acid (PAA)-chitosan (CHI)-ALA interpenetrating network hydrogel (PACA) patch after investigating the spatiotemporal dynamics of ALA drug delivery via diffusion-based finite-element models. The PACA patch could adhere to the moist oral mucosa fast and stably and deliver ALA. PACA hydrogel-mediated PDT (PACA-PDT) effectively improved OPMDs in vitro and in a hamster oral carcinogenesis model. In particular, we conducted a trial to recruit 60 OPMD volunteers to demonstrate the feasibility and comfort of the PACA hydrogel patch. This study provides evidence that PACA hydrogel-mediated PDT could be a patient-friendly treatment modality for OPMDs.

Mechanism and application of fermentation to remove beany flavor from plant-based meat analogs: A mini review.

Over the past few decades, there has been a noticeable surge in the market of plant-based meat analogs (PBMA). Such popularity stems from their environmentally friendly production procedures as well as their positive health effects. In order to meet the market demand, it is necessary to look for plant protein processing techniques that can help them match the quality of conventional meat protein from the aspects of sensory, quality and functionality. Bean proteins are ideal options for PBMA with their easy accessibility, high nutrient-density and reasonable price. However, the high polyunsaturated lipids content of beans inevitably leads to the unpleasant beany flavor of soy protein products, which severely affects the promotion of soy protein-based PBMA. In order to solve this issue, various methods including bleaching, enzyme and fermentation etc. are developed. Among these, fermentation is widely investigated due to its high efficiency, less harm to the protein matrix, targeted performance and low budget. In addition, proper utilization of microbiome during the fermentation process not only reduces the unpleasant beany flavors, but also enhances the aroma profile of the final product. In this review, we provide a thorough and succinct overview of the mechanism underlying the formation and elimination of beany flavor with associated fermentation process. The pros and cons of typical fermentation technologies for removing beany flavors are discussed in alongside with their application scenarios. Additionally, the variations among different methods are compared in terms of the strains, fermentation condition, target functionality, matrix for application, sensory perception etc.

Effect of Lycopene on Oral Squamous Cell Carcinoma Cell Growth by Inhibiting IGF1 Pathway.

PURPOSE: Lycopene has produced robust clinical effects and shows a promising chemopreventive in the oral cancer and precancerous lesions. However, much is still unknown about its mechanisms of the carotenoid in protecting against oral squamous cell carcinoma (OSCC). Insulin-like growth factor 1 (IGF1) pathway serves as a key regulatory signal pathway in the tumor microenvironment, which may be associated with the angiogenesis, tumorigenicity, and cancer proliferation. The current study was focused on elucidating the potential pathway played for lycopene to exert its function in treating with OSCC. MATERIALS AND METHODS: Firstly, we explored the dose- and time-response of CAL-27 and WSU-HN6 cells to lycopene. Both cells were incubated with various concentrations of lycopene (0.25, 0.5, 1, 2 µM). The inhibiting rate of cell proliferation was assessed using MTT assay. To observe the regulating effect of lycopene on OSCC, cell migration, apoptosis and tumor formation were detected in vitro and in vivo. The potential signaling pathways of OSCC cells treated with lycopene were analyzed by Affymetrix microarrays. And then, we investigated the changing of IGF1 signaling pathway, on the protein levels of tumor tissue after lycopene. RESULTS: Cell proliferation was inhibited by lycopene in a dose- and time-dependent manner. The optimum inhibition efficiencies for OSCC cells were also found. Further, the results also demonstrated that pre-treatment of OSCC with lycopene drastically induced cell apoptosis suppresses cell migration and tumor growth. Mechanistically, ingenuity pathway analysis further revealed that IGF1 pathway participate in killing effects on OSCC after treatment of lycopene. Lycopene may inhibit the pathway by regulating protein expression of IGF1, IGF binding protein (BP) 1, IGFBP3, transcription factor Jun/AP-1 (JUN), and forkhead box O1 (FOXO1). CONCLUSION: These observations indicate that lycopene regulates OSCC cell growth by inhibiting IGF1 pathway, which may be a promising agent for the treatment of OSCC.

Strontium-Loaded Nanotubes of Ti-24Nb-4Zr-8Sn Alloys for Biomedical Implantation.

Ti-24Nb-4Zr-8Sn (Ti2448) alloys, with a relatively low elastic modulus and unique mechanical properties, are desirable materials for oral implantation. In the current study, a multifaceted strontium-incorporating nanotube coating was fabricated on a Ti2448 alloy (Ti2-NTSr) through anodization and hydrothermal procedures. In vitro, the Ti2-NTSr specimens demonstrated better osteogenic properties and more favorable osteoimmunomodulatory abilities. Moreover, macrophages on Ti2-NTSr specimens could improve the recruitment and osteogenic differentiation of osteoblasts. In vivo, dense clots with highly branched, thin fibrins and small pores existed on the Ti2-NTSr implant in the early stage after surgery. Analysis of the deposition of Ca and P elements, hard tissue slices and the bone-implant contact rate (BIC%) of the Ti2-NTSr implants also showed superior osseointegration. Taken together, these results demonstrate that the Ti2-NTSr coating may maximize the clinical outcomes of Ti2448 alloys for implantation applications.

Supramolecularly enabled pH- triggered drug action at tumor microenvironment potentiates nanomedicine efficacy against glioblastoma.

The crucial balance of stability in blood-circulation and tumor-specific delivery has been suggested as one of the challenges for effective bench-to-bedside translation of nanomedicines (NMs). Herein, we developed a supramolecularly enabled tumor-extracellular (Tex) pH-triggered NM that can maintain the micellar structure with the entrapped-drug during systemic circulation and progressively release drug in the tumor by rightly sensing heterogeneous tumor-pH. Desacetylvinblastine hydrazide (DAVBNH), a derivative of potent anticancer drug vinblastine, was conjugated to an aliphatic ketone-functionalized poly(ethylene glycol)-b-poly(amino acid) copolymer and the hydrolytic stability of the derived hydrazone bond was efficiently tailored by exploiting the compartmentalized structure of polymer micelle. We confirmed an effective and safe therapeutic application of Tex pH-sensitive DAVBNH-loaded micelle (Tex-micelle) in orthotopic glioblastoma (GBM) models, extending median survival to 1.4 times in GBM xenograft and 2.6 times in GBM syngeneic model, compared to that of the free DAVBNH. The work presented here offers novel chemical insights into the molecular design of smart NMs correctly sensing Tex-pH via programmed functionalities. The practical engineering strategy based on a clinically relevant NM platform, and the encouraging therapeutic application of Tex-micelle in GBM, one of the most lethal human cancers, thus suggests the potential clinical translation of this system against other types of common cancers, including GBM.

Comparison of the osteoblastic activity of low elastic modulus Ti-24Nb-4Zr-8Sn alloy and pure titanium modified by physical and chemical methods.

Ti-24Nb-4Zr-8Sn (Ti2448) alloy is a novel low elastic modulus ß-titanium alloy without toxic elements. It also has the advantage of high strength, so it has potential application prospects for implantation. To develop its osteogenic effects, it can be modified by electrochemical, and physical processes. The main research aim of this study was to explore the bioactivity of Ti2448 alloy modified by sandblasted, large-grit, acid-etched (SLA), micro-arc oxidation (MAO) and anodic oxidation (AO), and to determine which of the three surface modifications is the best way for developing the osteogenesis of bone marrow mesenchymal stem cells (BMMSCs). In vitro studies, the cytoskeleton, focal adhesion and proliferation of BMMSCs showed that both pure titanium and Ti2448 alloy have good biocompatibility. The osteogenic differentiation of BMMSCs with the Ti2448 alloy were examined by detecting alkaline phosphatase (ALP), mineralization nodules and osteogenic proteins and were better than that with pure titanium. These results showed that the Ti2448 alloy treated by SLA has a better effect on osteogenesis than pure titanium, and AO is the best way of three surface treatments to improve osteogenesis in this study.

Polymeric Micelles Loading Proteins through Concurrent Ion Complexation and pH-Cleavable Covalent Bonding for In Vivo Delivery.

Protein drugs have great potential as targeted therapies, yet their application suffers from several drawbacks, such as instability, short half-life, and adverse immune responses. Thus, protein delivery approaches based on stimuli-responsive nanocarriers can provide effective strategies for selectively enhancing the availability and activation of proteins in targeted tissues. Herein, polymeric micelles with the ability of encapsulating proteins are developed via concurrent ion complexation and pH-cleavable covalent bonding between proteins and block copolymers directed to pH-triggered release of the protein payload. Carboxydimethylmaleic anhydride (CDM) is selected as the pH-sensitive moiety, since the CDMamide bond is stable at physiological pH (pH 7.4), while it cleaves at pH 6.5, that is, the pathophysiological pH of tumors and inflammatory tissues. By using poly(ethylene glycol)-poly(l-lysine) block copolymers having 45% CDM addition, different proteins with various sizes and isoelectric points are loaded successfully. By using myoglobin-loaded micelles (myo/m) as a model, the stability of the micelles in physiological conditions and the dissociation and release of functional myoglobin at pH 6.5 are successfully confirmed. Moreover, myo/m shows extended half-life in blood compared to free myoglobin and micelles assembled solely by polyion complex, indicating the potential of this system for in vivo delivery of proteins.

PEG-Poly(1-Methyl-l-Tryptophan)-Based Polymeric Micelles as Enzymatically Activated Inhibitors of Indoleamine 2,3-Dioxygenase.

Indoleamine 2,3-dioxygenase (IDO) is an immunomodulating enzyme that is overexpressed in many cancers with poor prognosis. IDO suppresses T cell immunity by catabolizing tryptophan into kynurenine (KYN), which induces apoptosis in T effector cells and enhances T regulatory cells, providing a powerful immunosuppressive mechanism in tumors. Thus, major efforts for developing IDO inhibitors have been undertaken. Among them, 1-Methyl-l-Tryptophan (MLT) and 1-Methyl-d-Tryptophan (MDT) effectively inhibit IDO in preclinical tumor models and the latter is under clinical evaluation. However, both MLT and MDT present poor pharmacokinetics, with the maximum serum concentration being below their 50% inhibitory concentration value. Herein, we have developed polymeric IDO inhibitors based on MLT, which can release active MLT after enzymatic degradation, toward establishing superior antitumor immunotherapies. These polymers were prepared by ring opening polymerization of an N-phenyl carbamate (NPC) derivative of MLT that was synthesized by carbamylation with diphenyl carbonate. By using ω-amino-poly(ethylene glycol) (PEG-NH2) as the macroinitiator, we prepared amphiphilic PEG-poly(MLT) block copolymers, which self-assembled into polymeric micelles in aqueous conditions. The PEG-poly(MLT) block copolymers could be readily degraded by chymotrypsin and the micelles were able to reduce the levels of KYN in activated macrophages. These results provide a strong rationale for pursuing MLT-based polymeric micelles as tumor-targeted prodrug systems.

Proteasome Inhibitor-Loaded Micelles Enhance Antitumor Activity Through Macrophage Reprogramming by NF-κB Inhibition.

Macrophage reprogramming toward a tumor-attacking phenotype is a promising treatment strategy, yet such strategies are scarce and it is not clear how to combine them with cytotoxic therapies that are often used to treat solid tumors. Here, we evaluate whether a micelle-encapsulated proteasome inhibitor, that is, the peptide aldehyde drug MG132, which is cytotoxic to cancer cells, can reprogram macrophages to attack the tumor. Through in vitro studies, we demonstrated that the proteasome inhibition reduces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-a known promoter of tumor-supporting macrophages and chemoresistance-in both cancer cells and macrophages. In in vivo studies, we showed that, although free MG132 did not affect the macrophage phenotype in tumors even at its maximum tolerated dose, the micellar formulation of MG132 safely achieved simultaneous cancer cell killing and macrophage reprogramming, thereby enhancing the antitumor efficacy in a syngeneic, orthotopic breast cancer model.

Biologically responsive carrier-mediated anti-angiogenesis shRNA delivery for tumor treatment.

Small interfering RNA (siRNA) has increased the hope for highly-efficient treatment of gene-related diseases. However, the stable and efficient delivery of therapeutic nucleic acids is a prerequisite for the successful clinical translation of RNA interfering therapy. To achieve this, we condensed the low molecular weight polyethyleneimine (PEI, Mw < 2000) with 2,6-pyridinedicarboxaldehyde (PDA) to synthesize a biologically responsive and degradable cationic polymer (abbreviated to PDAPEI) which was utilized as a gene vector for the delivery of a VEGF-A shRNA expression plasmid DNA (pDNA). The resulting electrostatic interaction between PDAPEI and pDNA led to the self-assembly of nanoscale polyplexes with suitable particle size and stable zeta potential. The PDAPEI/pDNA polyplexes demonstrated an outstanding gene transfection and silencing efficiency at 30 w/w ratio, as well as negligible cytotoxicity. Also, the designed polymer showed no stimulation to the innate immune system. Moreover, compared with PEI 25 KDa, the polyplexes accomplished comparatively better anti-angiogenesis efficacy, which resulted in the inhibition of tumor growth in subcutaneous tumor mice models. In conclusion, PDAPEI has great potential to be a gene delivery vector for cancer therapy.

Long-acting preparations of exenatide.

Exenatide has been widely used for the treatment of type 2 diabetes mellitus. However, its short plasma half-life of 2.4 hours has limited its clinical application. The exenatide products on the market, twice-daily Byetta™ and once-weekly Bydureon™ (both Amylin Pharmaceuticals, San Diego, CA, USA), are still not perfect. Many researchers have attempted to prolong the acting time of exenatide by preparing sustained-release dosage forms, modifying its structure, gene therapies, and other means. This review summarizes recent advances in long-acting exenatide preparations.