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Background/purpose: Oral potentially malignant disorder (OPMD) is an important premalignancy worldwide. MicroRNAs (miRNAs) are endogenously expressed non-coding RNAs that regulate the post-transcriptional levels of targeted mRNAs. MiRNA-375 (miR-375) is markedly downregulated in oral carcinoma tissues and plays an oncogenic role in oral carcinogenesis. We explored the potential of the deregulated salivary miR-375 levels in OPMD patients. Materials and methods: . We analyzed the levels of miR-375 in the saliva of patients with OPMD (n = 45) and healthy controls (n = 24) by quantitative RT-PCR. The cell lysates and supernatants were treated with the miR-375 mimic and inhibitor. Results: Salivary miR-375 levels were decreased markedly in the patients with OPMD, compared with the controls. OPMD patients with non-dysplasia showed a higher abundance of miR-375 in the saliva than dysplasia patients, suggesting that salivary miR-375 is a more sensitive marker for OPMD. Patients with malignant transformation during the follow-up period showed lower expression of saliva miR-375 than the others. MiR-375 expression was markedly decreased by treatment with the miR-375 inhibitor, and the supernatants of both NHOK and SAS cells showed a corresponding decline in miR-375 expression. Conclusion: Our results indicate the potential application of salivary miR-375 as a biomarker for the detection and long-term follow-up of OPMD.

Abstract Background Phlebosclerotic colitis (PC) is a rare form of nonthrombotic colonic ischemia. This retrospective study analyzed the clinical findings and temporal CT changes in 29 PC patients with long-term follow-up. Methods Twenty-nine patients with characteristic CT features of PC collected between 1997 and 2020 were stratified into the acute abdomen group (AA-group) (n = 10), chronic-progressive group (CP-group) (n = 14) and chronic-stable group (CS-group) (n = 5). Clinical and CT changes during follow-up, comorbidities and final outcomes were compared. Results The AA-group exhibited a significantly thicker colonic wall and more involved segments and pericolic inflammation than the CP-group and CS-group on initial CT (p =

Background Carotid artery stenosis (CAS) is a common cause of ischemic stroke, and the early detection of CAS may improve patient outcomes. Carotid Doppler ultrasound is commonly used to diagnose CAS. However, it is costly and may not be practical for regular screening practice. This article presents a novel noninvasive and noncontact detection technique using video‐based motion analysis (VMA) to extract useful information from subtle pulses on the skin surface to screen for CAS. Methods and Results We prospectively enrolled 202 patients with prior carotid Doppler ultrasound data. A short 30‐second video clip of the neck was taken using a commercial mobile device and analyzed by VMA with mathematical quantification of the amplitude of skin motion changes in a blinded manner. The first 40 subjects were used to set up the VMA protocol and define cutoff values, and the following 162 subjects were used for validation. Overall, 54% of the 202 subjects had ultrasound‐confirmed CAS. Using receiver operating characteristic curve analysis, the area under the curve of VMA‐derived discrepancy values to differentiate patients with and without CAS was excellent (area under the curve, 0.914 [95% CI, 0.874–0.954]; P

The accurate diagnosis and treatment of oral squamous cell carcinoma (OSCC) requires an understanding of its genomic alterations. Liquid biopsies, especially cell-free DNA (cfDNA) analysis, are a minimally invasive technique used for genomic profiling. We conducted comprehensive whole-exome sequencing (WES) of 50 paired OSCC cell-free plasma with whole blood samples using multiple mutation calling pipelines and filtering criteria. Integrative Genomics Viewer (IGV) was used to validate somatic mutations. Mutation burden and mutant genes were correlated to clinico-pathological parameters. The plasma mutation burden of cfDNA was significantly associated with clinical staging and distant metastasis status. The genes TTN, PLEC, SYNE1, and USH2A were most frequently mutated in OSCC, and known driver genes, including KMT2D, LRP1B, TRRAP, and FLNA, were also significantly and frequently mutated. Additionally, the novel mutated genes CCDC168, HMCN2, STARD9, and CRAMP1 were significantly and frequently present in patients with OSCC. The mutated genes most frequently found in patients with metastatic OSCC were RORC, SLC49A3, and NUMBL. Further analysis revealed that branched-chain amino acid (BCAA) catabolism, extracellular matrix–receptor interaction, and the hypoxia-related pathway were associated with OSCC prognosis. Choline metabolism in cancer, O-glycan biosynthesis, and protein processing in the endoplasmic reticulum pathway were associated with distant metastatic status. About 20% of tumors carried at least one aberrant event in BCAA catabolism signaling that could possibly be targeted by an approved therapeutic agent. We identified molecular-level OSCC that were correlated with etiology and prognosis while defining the landscape of major altered events of the OSCC plasma genome. These findings will be useful in the design of clinical trials for targeted therapies and the stratification of patients with OSCC according to therapeutic efficacy.

Peripheral stent could fracture from cyclic loadings as a result of our blood pressures or daily activities. Fatigue performance has therefore become a key issue for peripheral stent design. A simple yet powerful tapered-strut design concept for fatigue life enhancement was investigated. This concept is to move the stress concentration away from the crown and re-distribute the stresses along the strut by narrowing the strut geometry. Finite element analysis was performed to evaluate the stent fatigue performance under various conditions consistent with the current clinical practice. Thirty stent prototypes were manufactured in-house by laser with a series of post-laser treatments, followed by the validation of bench fatigue tests for proof of concept. FEA simulation results show that the fatigue safety factor of the 40% tapered-strut design increased by 4.2 times that of a standard counterpart, which was validated by bench tests with 6.6-times and 5.9-times fatigue enhancement at room temperature and body temperature, respectively. Bench fatigue test results agreed very well with the increasing trend predicted by FEA simulation. The effects of the tapered-strut design were significant and could be considered as an option for fatigue optimization of future stent designs.

Abstract Exosomes are extracellular vesicles that share components of their parent cells and are attractive in biotechnology and biomedical research as potential disease biomarkers as well as therapeutic agents. Crucial to realizing this potential is the ability to manufacture high‐quality exosomes; however, unlike biologics such as proteins, exosomes lack standardized Good Manufacturing Practices for their processing and characterization. Furthermore, there is a lack of well‐characterized reference exosome materials to aid in selection of methods for exosome isolation, purification, and analysis. This review informs exosome research and technology development by comparing exosome processing and characterization methods and recommending exosome workflows. This review also provides a detailed introduction to exosomes, including their physical and chemical properties, roles in normal biological processes and in disease progression, and summarizes some of the on‐going clinical trials.

Understanding the genomic alterations in oral carcinogenesis remains crucial for the appropriate diagnosis and treatment of oral squamous cell carcinoma (OSCC). To unveil the mutational spectrum, in this study, we conducted whole-exome sequencing (WES), using six mutation calling pipelines and multiple filtering criteria applied to 50 paired OSCC samples. The tumor mutation burden extracted from the data set of somatic variations was significantly associated with age, tumor staging, and survival. Several genes (MUC16, MUC19, KMT2D, TTN, HERC2) with a high frequency of false positive mutations were identified. Moreover, known (TP53, FAT1, EPHA2, NOTCH1, CASP8, and PIK3CA) and novel (HYDIN, ALPK3, ASXL1, USP9X, SKOR2, CPLANE1, STARD9, and NSD2) genes have been found to be significantly and frequently mutated in OSCC. Further analysis of gene alteration status with clinical parameters revealed that canonical pathways, including clathrin-mediated endocytotic signaling, NFκB signaling, PEDF signaling, and calcium signaling were associated with OSCC prognosis. Defining a catalog of targetable genomic alterations showed that 58% of the tumors carried at least one aberrant event that may potentially be targeted by approved therapeutic agents. We found molecular OSCC subgroups which were correlated with etiology and prognosis while defining the landscape of major altered events in the coding regions of OSCC genomes. These findings provide information that will be helpful in the design of clinical trials on targeted therapies and in the stratification of patients with OSCC according to therapeutic efficacy.

Abstract Background Few systematic methods prioritize the image education in medical students (MS). We hope to develop a checklist of brain computerized tomography (CT) reading in patients with suspected acute ischemic stroke (AIS) for MS and primary care (PC) physicians. Methods Our pilot group generated the items indicating specific structures or signs for the checklist of brain CT reading in suspected AIS patients for MS and PC physicians. These items were used in a modified web-based Delphi process using the online software “SurveyMonkey”. In total 15 panelists including neurologists, neurosurgeons, neuroradiologists, and emergency department physicians participated in the modified Delphi process. Each panelist was encouraged to express feedback, agreement or disagreement on the inclusion of each item using a 9-point Likert scale. Items with median scores of 7–9 were included in our final checklist. Results Fifty-two items were initially provided for the first round of the Delphi process. Of these, 35 achieved general agreement of being an essential item for the MS and PC physicians. The other 17 of the 52 items in this round and another two added items suggested by the panelists were further rated in the next round. Finally, 38 items were included in the essential checklist items of brain CT reading in suspected AIS patients for MS and PC physicians. Conclusions We established a reference regarding the essential items of brain CT reading in suspected AIS patients. We hope this helps to minimize malpractice and a delayed diagnosis, and to improve competency-based medical education for MS and PC physicians.

Abstract Background The survival of OSCC patient needs to be further improved. miR-211 is oncogenic in OSCC and its upregulation is associated with tumor progression and poor patient survival. K14-EGFP-miR-211 transgenic mice also exhibit augmented potential for OSCC induction. Methods Four murine OSCC cell lines, designated MOC-L1 to MOC-L4, are established from tongue tumors induced by 4-nitroquinoline 1-oxide using the K14-EGFP-miR-211 transgenic mouse model. The genetic disruption, in vitro oncogenicity, and the eligibilities of tumorigenesis and metastasis of the cell lines are analyzed. Results All cell lines show green fluorescence and express a range of epithelial markers. The MOC-L1, MOC-L2 and MOC-L3 cells carry missense mutations in the DNA binding domain of the p53 gene. MOC-L1 exhibits a high level of epithelial-mesenchymal transition and has the aggressive characteristics associated with this. MOC-L1 and MOC-L2 are clonogenic in vitro as well as being tumorigenic when implanted into the dermis or tongue of syngeneic recipients. Nonetheless, only MOC-L1 exhibits immense potential for local regional and distal metastasis. Since the expression of miR-196b in MOC-L1 xenografts is drastically decreased on cisplatin treatment, it would seem that targeting of miR-196b might facilitate tumor abrogation. Conclusions As cell lines established in this study originated from the C57BL/6 mouse, the strain most suitable for transgenic engineering, exploring the interplay of these OSCC cells with other genetically modified cells in immune-competent mice would provide important insights into OSCC pathogenesis.

As the incidence and the mortality rate of head and neck squamous cell carcinoma (HNSCC) is increasing worldwide, gaining knowledge about the genomic changes which happen in the carcinogenesis of HNSCC is essential for the diagnosis and therapy of the disease. SMAD4 (DPC4) is a tumor suppressor gene. It is located at chromosome 18q21.1 and a member of the SMAD family. Which mediates the TGF-β signaling pathway, thereby controlling the growth of epithelial cells. In the study presented here, we analyzed tumor samples by multiplex PCR-based next-generation sequencing (NGS) and found deleterious mutations of SMAD4 in 4.1% of the tumors. Knock-down experiments of endogenous and exogenous SMAD4 expression demonstrated that SMAD4 is involved in the migration and invasion of HNSCC cells. Functional analysis of a missense mutation in the MH1 domain of SMAD4 may be responsible for the loss of function in suppressing tumor progression. Missense SMAD4 mutations, therefore, could be useful prognostic determinants for patients affected by HNSCCs. This report is the first study where NGS analysis based on multiplex-PCR is used to demonstrate the imminent occurrence of missense SMAD4 mutations in HNSCC cells. The gene analysis that we performed may support the identification of SMAD4 mutations as a diagnostic marker or even as a potential therapeutic target in head and neck cancer. Moreover, the analytic strategy proposed for the detection of mutations in the SMAD4 gene may be validated as a platform to assist mutation screening.

Stroke is the second leading cause of death in the world. Ischemic stroke, caused by the blockage of intracranial arteries, accounts for approximately 80% of strokes. Among this proportion, acute ischemic stroke, usually caused by the sudden formation of blood clots, can cause fatal blockages in arteries. We proposed a unique blood clot retriever for the treatment of acute ischemic stroke, and conducted a series of tasks, including design, computer simulation, prototyping, and bench testing, for the proof of concept. Unlike most blood clot retrievers used today, our novel design deviates from traditional stent-like blood clot retrievers and uses large closed cells, irregular spikes, and strut protrusions to achieve maximum entanglement for better retrieval performance. Experimental results showed that the retrieval rate of our blood clot retriever was 79%, which demonstrated the feasibility of our new design concept.

Absorbable magnesium stents have become alternatives for treating restenosis owing to their better mechanical properties than those of bioabsorbable polymer stents. However, without modification, magnesium alloys cannot provide the proper degradation rate required to match the vascular reform speed. Gallic acid is a phenolic acid with attractive biological functions, including anti-inflammation, promotion of endothelial cell proliferation, and inhibition of smooth muscle cell growth. Thus, in the present work, a small-molecule eluting coating is designed using a sandwich-like configuration with a gallic acid layer enclosed between poly (d,l-lactide-co-glycolide) layers. This coating was deposited on ZK60 substrate, a magnesium alloy that is used to fabricate bioresorbable coronary artery stents. Electrochemical analysis showed that the corrosion rate of the specimen was ~2000 times lower than that of the bare counterpart. The released gallic acid molecules from sandwich coating inhibit oxidation by capturing free radicals, selectively promote the proliferation of endothelial cells, and inhibit smooth muscle cell growth. In a cell migration assay, sandwich coating delayed wound closure in smooth muscle cells. The sandwich coating not only improved the corrosion resistance but also promoted endothelialization, and it thus has great potential for the development of functional vascular stents that prevent late-stent restenosis.

Oral squamous cell carcinoma (OSCC) is a cancerous disease with poor prognosis. According to the statistics, the 5-year survival rate has not improved significantly over the past 20 years. The platelet-derived growth factor (PDGF) and its signaling pathway is a key regulator of angiogenesis and tumorigenesis. High level of PDGF and its receptor (PDGFR) have been reported in several types of malignancies. In this study, we investigated the relationship of the molecular expression levels of PDGF and PDGFR with clinicopathological parameters in OSCC. To this end, we measured the mRNA and protein levels of PDGF and PDGFR by real-time quantitative PCR (qRT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA), respectively. We found positive correlations of the mRNA levels of PDGFA, PDGFB, and PDGFRB with lymph node metastasis and poor overall survival (OS). High expression of PDGF, PDGFRA, and PDGFRB were remarkably associated with lymph node metastasis and poor OS, as determined by immunohistochemistry. Preoperative serum levels of PDGF-AA and PDGF-BB had a positive correlation with preoperative platelet count. Elevated serum levels of PDGF-AA. PDGF-BB, and platelet count correlated with lymph node metastasis and an unfavorable outcome. In multivariate Cox regression analysis, PDGFA mRNA, PDGFB mRNA, PDGFRB mRNA, PDGF immunoexpression, PDGFRB immunoexpression, serum PDGF-AA, serum PDGF-BB, and platelet count emerged as significant independent prognostic factors for OS. In vitro, we found that elevated PDGF promotes colony formation, migration, and invasiveness of SAS and OECM-1 cancer cell lines. Our results suggest that the expression level of serum PDGF has the potential to become a useful diagnostic marker for the prognosis of OSCC. In addition, PDGFR should be considered as a potential therapeutic target for OSCC. Furthermore, research should be undertaken to elucidate the role of PDGF and PDGFR regarding the behavior of tumor cells in OSCC.

Background: Oral squamous cell carcinoma (OSCC) is a disease that affects patients worldwide. DNA of dead cells is released into the blood stream and may be isolated from plasma or serum samples. This DNA is termed cell-free DNA (cfDNA). cfDNA is increased in several types of malignancies. We investigated if there was a correlation between cfDNA levels and the progression of OSCC. Methods: Using quantitative spectrometry, we measured plasma cfDNA in 121 patients with OSCC and 50 matched controls. Mann Whitney and Wilcoxon tests were used to compare differences among various clinical variants. Receiver operating characteristic (ROC) analysis was used to obtain levels suitable for the separation of the clinical subsets. Kaplan-Meier analysis was used to assess correlation with survival. Results: Plasma cfDNA was significantly elevated in patients with OSCC relative to controls. Plasma cfDNA levels correlated with larger tumor size, cervical lymph node metastasis and late stage. Higher plasma cfDNA levels were associated with a poor prognosis of OSCC, which is a new finding. Conclusion: Plasma cfDNA could serve as a novel and easily accessible biomarker in OSCC, providing diagnostic and prognostic value.

Gut microbes is a crucial factor in the pathogenesis of type 1 diabetes (T1D). However, it is still unclear which gut microbiota are the key factors affecting T1D and their influence on the development and progression of the disease. To fill these knowledge gaps, we constructed a model to find biomarker from gut microbiota in patients with T1D. We first identified microbial markers using Linear discriminant analysis Effect Size (LEfSe) and random forest (RF) methods. Furthermore, by constructing co-occurrence networks for gut microbes in T1D, we aimed to reveal all gut microbial interactions as well as major beneficial and pathogenic bacteria in healthy populations and type 1 diabetic patients. Finally, PICRUST2 was used to predict Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathways and KO gene levels of microbial markers to investigate the biological role. Our study revealed that 21 identified microbial genera are important biomarker for T1D. Their AUC values are 0.962 and 0.745 on discovery set and validation set. Functional analysis showed that 10 microbial genera were significantly positively associated with D-arginine and D-ornithine metabolism, spliceosome in transcription, steroid hormone biosynthesis and glycosaminoglycan degradation. These genera were significantly negatively correlated with steroid biosynthesis, cyanoamino acid metabolism and drug metabolism. The other 11 genera displayed an inverse correlation. In summary, our research identified a comprehensive set of T1D gut biomarkers with universal applicability and have revealed the biological consequences of alterations in gut microbiota and their interplay. These findings offer significant prospects for individualized management and treatment of T1D. [ABSTRACT FROM AUTHOR]

Recently, National Geographic published a special bookazine titled Nature's Best Remedies. This bookazine reorganized nature's remedies as a therapeutic table for treating ailments. The table provides considerable knowledge but is inconvenient to use. This study converts the therapeutic table into a therapeutic sphere by using optimization techniques. In the therapeutic sphere, similar ailments are clustered together, and remedies related to specified ailments are allocated on the sphere. Two surveys demonstrated that, compared with the therapeutic table, the therapeutic sphere is more convenient to use, more efficient for making queries, and more useful for healthcare as well as more intuitive. The proposed therapeutic sphere system can be accessed at http://140.113.73.198/gbball/examples/medeng2.aspx. [ABSTRACT FROM AUTHOR]

Polynomial discrete programming problems are commonly faced but hard to solve. Treating the nonconvex cross-product terms is the key. State-of-the-art methods usually convert such a problem into a 0-1 mixedinteger [...]