Identification of Somatic Mutations in Plasma Cell-Free DNA from Patients with Metastatic Oral Squamous Cell Carcinoma.

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.

Effects of Psychiatric Disease Severity and Clinical Characteristics on Duration of High Violence Risk: A Perspective on Violence Prevention in the Psychiatric Ward.

Objective: Prevention, de-escalation, and management of violence in the acute psychiatric ward is essential. Few studies have focused on differences in the duration of high-violence risk between different profiles of high-violence risk. This study aimed to analyze the data of high-violence patients and duration of high-violence risk to provide a new perspective on violence prevention, de-escalation and management. Methods: This retrospective observational cohort study included 171 patients who were treated in the acute psychiatric ward of Keelung Chang Gung Memorial Hospital between January 2016 and June 2020, and who were assessed daily as having high violence risk. All patient data were collected from electronic hospital records (eg, age, gender, diagnosis, violence history, self-harm history, and admission condition (involuntary admission, discharged against medical advice). Between-group differences in disease severity, use of antipsychotics and benzodiazepine, and duration of high violence risk were analyzed using regression analysis. Results: Only patients' age was significantly associated with duration of high-violence risk (P = 0.028), making it predictive of longer duration of high-violence risk. In patients with schizophrenia spectrum disorder or bipolar disorder, higher severity was significantly associated with longer duration of high-violence risk (P = 0.007, P = 0.001, respectively). Conclusion: Only age is a predictor of longer duration of violence risk in psychiatric patients, although higher severity is associated with higher violence risk. Study results may help management and healthcare staff better understand how quickly or slowly violence risk will decrease and may improve efficient use of healthcare resources and individualized patient-centered care.

External validation of a risk model for survival prediction in older patients with cancer undergoing elective abdominal surgery: a prospective cohort study.

We previously developed a Chang Gung Memorial Hospital (CGMH) model to predict the 1-year postoperative mortality risk in patients with solid cancer undergoing cancer surgery. This study aimed to externally validate the CGMH score for survival outcome and surgical complication prediction in a prospective patient cohort. A total of 345 consecutive patients aged ≥65 years who underwent elective abdominal surgery for cancer treatment were prospectively enrolled. Patients were categorized into the low, intermediate, high, and very high-risk groups according to the CGMH score for comparison. The postoperative 1-year mortality rate was 12.5% in the entire cohort. The postoperative 1-year mortality rates were 0%, 2.2%, 14.0%, and 31.6% among patients in the low, intermediate, high, and very-high risk groups, respectively. The c-statistic of the CGMH model was 0.82 (95% confidence interval [CI], 0.76-0.88) for predicting the 1-year mortality risk. Hazard ratios for overall survival were 3.73 (95% CI, 2.11-6.57; P<0.001) and 10.1 (95% CI, 5.84-17.6; P<0.001) when comparing the high and very-high risk groups with the low/intermediate risk groups, respectively. Patients in the higher CGMH risk groups had higher risks of adverse surgical outcomes in terms of longer length of hospital stay, major surgical complications, postoperative intensive care unit stay, and in-hospital death. The CGMH model accurately predicted thesurvival probabilityand risk of adverse surgical outcomes in older patients with cancer undergoing elective abdominal surgery. Our study justifies the prospective use of the CGMH model for survival outcome and safety profile predictionfor cancer surgery in older patients.

Exploiting salivary miR-375 as a clinical biomarker of oral potentially malignant disorder.

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.

Droplet digital polymerase chain reaction for detection and quantification of cell-free DNA TP53 target somatic mutations in oral cancer.

BACKGROUND: TP53 mutation is a driver mutation of oral carcinogenesis. This study investigated cancerous and cell-free DNA (cfDNA) in patients with oral squamous cell carcinoma (OSCC) to detect the target hotspot somatic mutation of TP53. OBJECTIVE: TP53 target hotspot mutations were determined in surgically resected primary tumor samples from 107 OSCC patients. METHODS: Cancerous and cfDNA samples were examined for mutations through droplet digital polymerase chain reaction (ddPCR) by using mutation-specific assays. The ddPCR results were evaluated alongside clinicopathological data. RESULTS: In total, 23 cases had target TP53 mutations in varying degrees. We found that OSCC had relatively low cfDNA shedding, and mutations were at low allele frequencies. Of these 23 cases, 13 had target TP53 mutations in their corresponding cfDNA. Target somatic mutations in cancerous DNA and cfDNA are related to cervical lymph node metastasis. The cfDNA concentration is related to primary tumor size, lymph node metastasis, and OSCC stage. CONCLUSIONS: Our results show that the detection of TP53 target somatic mutations in OSCC patients by using ddPCR is technically feasible. Low levels of cfDNA may produce different results between cancerous tissue and cfDNA analyses. Future research on cfDNA may quantify diagnostic biomarkers in the surveillance of OSCC patients.

Precise Identification of Recurrent Somatic Mutations in Oral Cancer Through Whole-Exome Sequencing Using Multiple Mutation Calling Pipelines.

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.

Association Between Use of Antihyperlipidemic Agents and Chronic Obstructive Pulmonary Disease in Patients with Hyperlipidemia: A Population-Based Retrospective Cohort Study.

Objective: The effect of statins and fibrates on the risk of chronic obstructive pulmonary disease (COPD) remains unclear. The aim of this study was to investigate the effects of statins and fibrates on the risk of COPD in patients with hyperlipidemia. Patients and Methods: This study involved a retrospective cohort with a follow-up period of 6 years. We identified patients who were diagnosed as having hyperlipidemia between 2000 and 2016 from Taiwan's National Health Insurance Research Database. A Cox proportional hazard model was used to estimate the risk of COPD among different groups. The dose-related effects of statins and fibrates on the risk of COPD were evaluated according to the defined daily dose (DDD). Results: Patients with hyperlipidemia not using statins and fibrates (group II) had a significantly higher risk of COPD compared with their comparison group, with an adjusted hazard ratio (HR) of 1.091 [95% confidence interval (CI): 1.034-1.152, p < 0.01]. Dose-dependent reduction in the risk of COPD was observed in patients with hyperlipidemia using statins or fibrates compared with patients not using them. Moreover, with an increase in cumulative exposure, a reduced risk of COPD was observed in patients using more than 361 DDDs, with an adjusted HR of 0.474 (95% CI: 0.401-0.559, p < 0.001). Patients on fibrate monotherapy using more than 541 DDDs were observed to have an adjusted HR of 0.454 (95% CI: 0.226-0.910, p < 0.05) and those on statin monotherapy with over 361 DDDs were noted to have an adjusted HR of 0.583 (95% CI: 0.459-0.740, p < 0.001). Conclusion: This study demonstrated that an increase in the cumulative exposure of statins and fibrates significantly reduced the risk of COPD in patients with hyperlipidemia, and the risk reduction appeared to be significantly dose dependent.

Overexpression of Platelet-Derived Growth Factor and Its Receptor Are Correlated with Oral Tumorigenesis and Poor Prognosis in Oral Squamous Cell Carcinoma.

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.

Effect of prednisolone on glyoxalase 1 in an inbred mouse model of aristolochic acid nephropathy using a proteomics method with fluorogenic derivatization-liquid chromatography-tandem mass spectrometry.

Prednisolone is involved in glucose homeostasis and has been used for treatment for aristolochic acid (AA) nephropathy (AAN), but its effect on glycolysis in kidney has not yet been clarified. This study aims to investigate the effect in terms of altered proteins after prednisolone treatment in a mice model of AAN using a proteomics technique. The six-week C3H/He female mice were administrated AA (0.5 mg/kg/day) for 56 days. AA+P group mice were then given prednisolone (2 mg/kg/day) via oral gavage for the next 14 days, and AA group mice were fed water instead. The tubulointerstitial damage was improved after prednisolone treatment comparing to that of AA group. Kidney homogenates were harvested to perform the proteomics analysis with fluorogenic derivatization-liquid chromatography-tandem mass spectrometry method (FD-LC-MS/MS). On the other hand, urinary methylglyoxal and D-lactate levels were determined by high performance liquid chromatography with fluorescence detection. There were 47 altered peaks and 39 corresponding proteins on day 14 among the groups, and the glycolysis-related proteins, especially glyoxalase 1 (GLO1), fructose-bisphosphate aldolase B (aldolase B), and triosephosphate isomerase (TPI), decreased in the AA+P group. Meanwhile, prednisolone decreased the urinary amount of methylglyoxal (AA+P: 2.004 ± 0.301 µg vs. AA: 2.741 ± 0.630 µg, p < 0.05), which was accompanied with decrease in urinary amount of D-lactate (AA+P: 54.07 ± 5.45 µmol vs. AA: 86.09 ± 8.44 µmol, p < 0.05). Prednisolone thus alleviated inflammation and interstitial renal fibrosis. The renal protective mechanism might be associated with down-regulation of GLO1 via reducing the contents of methylglyoxal derived from glycolysis. With the aid of proteomics analysis and the determination of methylglyoxal and its metabolite-D-lactate, we have demonstrated for the first time the biochemical efficacy of prednisolone, and urinary methylglyoxal and its metabolite-D-lactate might be potential biomarkers for AAN.

SMAD4 Somatic Mutations in Head and Neck Carcinoma Are Associated With Tumor Progression.

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-ß 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.

Effect of Etching Depth on Threshold Characteristics of GaSb-Based Middle Infrared Photonic-Crystal Surface-Emitting Lasers.

We study the effect of etching depth on the threshold characteristics of GaSb-based middle infrared (Mid-IR) photonic-crystal surface-emitting lasers (PCSELs) with different lattice periods. The below-threshold emission spectra are measured to identify the bandgap as well as band-edge modes. Moreover, the bandgap separation widens with increasing etching depth as a result of enhanced diffraction feedback coupling. However, the coupling is nearly independent of lattice period. The relationship between threshold gain and Bragg detuning is also experimentally determined for PCSELs and is similar to that calculated theoretically for one-dimensional distributed feedback lasers.

Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/ß-Catenin Signaling Pathway in Glioma Cells.

Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/ß-catenin signaling. After THD treatment, Fzd-1 and GSK3ß-S9 phosphorylation (inactivated form) was reduced to promote ß-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from ß-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/ß-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/ß-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.

PCSEL Performance of Type-I InGaAsSb Double-QWs Laser Structure Prepared by MBE.

This paper discusses the issue of controlling the epitaxial growth of mixed group V alloys to form a type-I InGaAsSb/AlGaAsSb double quantum wells (QWs) structure. We also discuss the run-to-run reproducibility of lattice-matched AlGaAsSb alloys and strained In0.35Ga0.65As0.095Sb0.905 in terms of growth parameters (V/III ratio, Sb2/As2 ratio). Molecular beam epitaxy (MBE) was used to grow two type-I InGaAsSb double-QWs laser structures differing only in the composition of the bottom cladding layer: Al0.85Ga0.15As0.072Sb0.928 (sample A) and Al0.5Ga0.5As0.043Sb0.957 (sample B). Both samples were respectively used in the fabrication of photonic crystal surface-emitting lasers (PCSELs). Sample A presented surface lasing action from circular as well as triangular photonic crystals. Sample B did not present surface lasing due to the deterioration of the active region during the growth of the upper cladding. Our findings underline the importance of temperature in the epitaxial formation of AlxGa1-xAsySb1-y in terms of lasing performance.

Increased Plasma Circulating Cell-Free DNA Could Be a Potential Marker for Oral Cancer.

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.

FAT1 somatic mutations in head and neck carcinoma are associated with tumor progression and survival.

In recent years, the incidence and mortality rates of head and neck squamous cell carcinoma (HNSCC) have increased worldwide. Therefore, understanding genomic alterations in HNSCC carcinogenesis is crucial for appropriate diagnosis and therapy. Protocadherin FAT1, which encodes 4588 amino acid residues, regulates complex mechanisms to promote oncogenesis or suppression of malignancies. Multiplex PCR-based next-generation sequencing (NGS) revealed FAT1 somatic mutations. The clinicopathologic implications of FAT1 in HNSCC were investigated using expression assays, and the functional role of FAT1 in HNSCC pathogenesis was determined using ectopic expression and knockdown experiments. Approximately 29% patients with HNSCC harbored damaging FAT1 mutations. InVEx algorithm identified FAT1 as a significant functional mutation burden. Each type of mutation (missense, nonsense and frameshift) accounted for nearly one-third of deleterious mutations. FAT1 mutations correlated with lower FAT1 expression in tumors. The knockdown of the endogenous expression of FAT1 and exogenous expression of crucial FAT1 domains unequivocally indicated that FAT1 suppressed the migration and invasion capability of HNSCC cells. Functional analysis suggested that nonsense mutations in FAT1 result in the loss of the suppression of tumor progression. FAT1 mutations and downregulation defined nodal involvement, lymphovascular permeation and tumor recurrence. In addition, FAT1 mutations and downregulation are independent predictors of poor disease-free survival in patients with HNSCC. This study is the first to perform multiplex PCR-based NGS to indicate marked non-synonymous FAT1 mutations in HNSCC, which are prognostic indicators. The gene analysis strategy proposed for detecting FAT1 mutations may be a valid method for mutation screening.

Regulatory analysis on the medical use of ephedrine-related products in Taiwan.

To prevent ephedrine-related products from being misused to produce amphetamine and/or its analogs, there's a need for more effective and achievable regulatory mechanisms for the health, police, investigational, prosecution and judiciary authorities in Taiwan. This review was conducted to evaluate the international and Taiwan's regulatory policies and management of medical ephedrine-related products through the corresponding information collected from international and Taiwan government agency authorities. The combat of illegal drugs should involve both supply and demand sides to be successful. Health authorities in Taiwan do not have the investigational power to manage the forbidden transformation, abusing and manufacture of the illegal drugs from ephedrine-related products. Take the judicial interventions in the United States and in Japan as the examples, the organizational cooperation in Taiwan can be one of the main key strategies to combat against illegal drugs from ephedrine-related products. It is necessary to integrate the judicial, police and health agencies to prevent the production of illegal drugs from the ephedrine-related products in Taiwan. The efforts and regulatory control measures should be integrated to speed up the collaboration between different government authorities. It might be achieved through reorganization involving Taiwan Food and Drug Administration.

Moderate to high intensity statin in dialysis patients after acute myocardial infarction: A national cohort study in Asia.

BACKGROUND AND AIMS: Statin is not beneficial for dialysis patients but moderate to high intensity statin is beneficial for patients after acute myocardial infarction (MI). The aim of this study was to evaluate the effect of moderate to high intensity statin on mortality, cardiovascular outcomes in dialysis patients after acute MI. METHODS: Data on dialysis patients were retrieved from the National Health Insurance Research Database in Taiwan. Dialysis patients admitted for MI were selected and divided into two groups according to statin prescription or not after MI. All-cause mortality and cardiovascular outcomes after a 4-year follow-up were analyzed after propensity score matching (PSM). RESULTS: We identified 790 patients who received moderate to high intensity statin therapy and 1788 patients who did not receive any statins after acute MI and clinical outcomes were analyzed after 1:1 PSM. The benefit of statin on mortality therapy appeared from 1 year to the end of the 4-year follow-up period after hospitalization (statin group versus non-statin group: 22.9% vs. 31.1% at 1 year (HR: 0.70; 95% CI: 0.58-0.85); 48.0% vs. 55.1% at the end of the 4 years (HR: 0.76; 95% CI: 0.67-0.88)). In addition, the impact of statin therapy was stronger in patients with shock at admission (p = 0.035). There were no differences in any individual cardiovascular outcome or adverse event. CONCLUSIONS: Moderate to high intensity statin therapy might lower all-cause mortality in dialysis patients after acute MI, especially those with shock, but not influence cardiovascular outcomes and any adverse events.

NEAP/DUSP26 suppresses receptor tyrosine kinases and regulates neuronal development in zebrafish.

Expression of neuroendocrine-associated phosphatase (NEAP, also named as dual specificity phosphatase 26, [DUSP26]) is restricted to neuroendocrine tissues. We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells upon NGF stimulation. Conversely, suppressing NEAP expression by RNA interference enhanced TrkA and FGFR1 phosphorylation. NEAP was capable of de-phosphorylating TrkA and FGFR1 directly in vitro. NEAP-orthologous gene existed in zebrafish. Morpholino (MO) suppression of NEAP in zebrafish resulted in hyper-phosphorylation of TrkA and FGFR1 as well as abnormal body postures and small eyes. Differentiation of retina in zebrafishes with NEAP MO treatment was severely defective, so were cranial motor neurons. Taken together, our data indicated that NEAP/DUSP26 have a critical role in regulating TrkA and FGFR1 signaling as well as proper development of retina and neuronal system in zebrafish.

Editor's Highlight: Periodic Exposure to Smartphone-Mimic Low-Luminance Blue Light Induces Retina Damage Through Bcl-2/BAX-Dependent Apoptosis.

Blue light-induced phototoxicity plays an important role in retinal degeneration and might cause damage as a consequence of smartphone dependency. Here, we investigated the effects of periodic exposure to blue light-emitting diode in a cell model and a rat retinal damage model. Retinal pigment epithelium (RPE) cells were subjected to blue light in vitro and the effects of blue light on activation of key apoptotic pathways were examined by measuring the levels of Bcl-2, Bax, Fas ligand (FasL), Fas-associated protein with death domain (FADD), and caspase-3 protein. Blue light treatment of RPE cells increased Bax, cleaved caspase-3, FasL, and FADD expression, inhibited Bcl-2 and Bcl-xL accumulation, and inhibited Bcl-2/Bax association. A rat model of retinal damage was developed with or without continuous or periodic exposure to blue light for 28 days. In this rat model of retinal damage, periodic blue light exposure caused fundus damage, decreased total retinal thickness, caused atrophy of photoreceptors, and injured neuron transduction in the retina.