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Background Both IGF-1R/PI3K/AKT/mTOR and Hippo pathways are crucial for breast cancer stem cells (BCSCs). However, their interplay remains unclear. Methods Four triple negative breast cancer cell lines derived from CSC of two patient-derived xenografts (PDXs), AS-B145, AS-B145-1R, AS-B244, and AS-B244-1R, were used to elucidate the role of YAP in BCSCs. YAP silenced BCSCs were analyzed by cell proliferation, aldehyde dehydrogenase (ALDH) activity, mammosphere formation, and tumorigenesis. The effects of modulating IGF-1R and IGF-1 on YAP expression and localization were evaluated. The clinical correlation of YAP and IGF-1R signaling with the overall survival (OS) of 7830 breast cancer patients was analyzed by KM plotter. Results Knockdown of YAP abates the viability and stemness of BCSCs in vitro and tumorigenicity in vivo. Depletion of IGF-1R by shRNA or specific inhibitor decreases YAP expression. In contrast, IGF-1 addition upregulates YAP and enhances its nuclear localization. YAP overexpression increased the mRNA level of IGF-1, but not IGF-1R. Data mining of clinical breast cancer specimens revealed that basal-like breast cancer patients with higher level of IGF-1 and YAP exhibit significantly shorter OS. Conclusions YAP contributes to stemness features of breast cancer in vitro and in vivo. The expression and localization of YAP was regulated by IGF-1R and YAP expression in turns upregulates IGF-1, but not IGF-1R. Clinically, higher level of YAP and IGF-1 significantly correlated with shorter OS in basal-like breast cancer. Taken together, these findings suggest the clinical relevance of interplay between YAP and IGF-1/IGF-1R pathway in sustaining the properties of BCSCs.

The effect of inhaled corticosteroids (ICS) on the clinical outcomes of patients with coronavirus disease 2019 (COVID-19) was not known. Only phase 2 and 3 randomized clinical trials (RCTs) from electronic databases that investigated ICS in the treatment of COVID-19 patients were included. The outcomes of interest were the resolution of symptoms, risk of hospitalization or urgent medical visit, mortality, and the incidence of adverse events (AEs). Five RCTs involving 1243 patients who received ICS and 1526 patients with placebo or usual care were included. The ICS group had a higher rate of symptom resolution than the control group at day 14 (risk ratio [RR], 1.21; 95% confidence interval [CI], 1.12-1.30, p < 0.00001) and day 28 (RR, 1.12; 95% CI, 1.06-1.18, p < 0.0001). Additionally, the ICS group had a significantly lower risk of needing urgent medical care or hospitalization than the control group (RR, 0.15; 95% CI, 0.05-0.50; I2 = 0, p = 0.002). However, no significant difference in the 28-day mortality rate. In patients with mild-to-moderate COVID-19, ICS therapy improved symptom resolution, and decreased the risk of needing urgent medical care or hospitalization.

Background Anti-interleukin-5 (IL-5) therapy has been proposed as a novel treatment option for patients with chronic obstructive pulmonary disease (COPD). However, its efficacy for preventing COPD exacerbation remains unclear. Methods A literature review was conducted to August 26th 2019. Only randomized controlled trials (RCTs) that investigated the clinical efficacy and adverse effects of anti-IL-5 therapy were included in the meta-analysis. The primary outcome was the risk of COPD exacerbation. Results A total of 3 articles containing 5 RCTs were included in the study. Overall, 2837 and 1442 patients received anti-IL-5 therapy (mepolizumab, n = 865; benralizumab, n = 1972) and placebo, respectively. In the pooled analysis, anti-IL-5 therapy was associated with a lower risk of COPD exacerbation compared with the placebo (rate ratio, 0.92; 95% CI, 0.86–0.97, I2 = 0%). In addition, no significant differences in the changes in SGRQ scores and FEV1 from baseline were found between the anti-IL-5 therapy and placebo (SGRQ, mean difference, −0.86, 95% CI, −1.92 – 0.19, I2 = 0%; FEV1, mean difference, 0.01, 95% CI, −0.01 – 0.03, I2 = 0%). Anti-IL-5 therapy had a similar risk of any adverse event (risk ratio, 1.02; 95% CI, 0.99–1.05), an event leading to treatment discontinuation (risk ratio, 1.04; 95% CI, 0.72–1.48) and any serious adverse events (risk ratio, 0.93; 95% CI, 0.85–1.01) when compared with the placebo. Conclusion Anti-IL-5 therapy was associated with a lower rate of COPD exacerbation compared with placebo. In addition, anti-IL-5 therapy was well tolerated for COPD patients.

In the forensic estimation of bone age, the pelvis is important for identifying the bone age of teenagers. However, studies on this topic remain insufficient as a result of lower accuracy due to the overlapping of pelvic organs in X-ray images. Segmentation networks have been used to automate the location of key pelvic areas and minimize restrictions like doubling images of pelvic organs to increase the accuracy of estimation. This study conducted a retrospective analysis of 2164 pelvis X-ray images of Chinese Han teenagers ranging from 11 to 21 years old. Key areas of the pelvis were detected with a U-Net segmentation network, and the findings were combined with the original X-ray image for regional augmentation. Bone age estimation was conducted with the enhanced and not enhanced pelvis X-ray images by separately using three convolutional neural networks (CNNs). The root mean square errors (RMSE) of the Inception-V3, Inception-ResNet-V2, and VGG19 convolutional neural networks were 0.93 years, 1.12 years, and 1.14 years, respectively, and the mean absolute errors (MAE) of these networks were 0.67 years, 0.77 years, and 0.88 years, respectively. For comparison, a network without segmentation was employed to conduct the estimation, and it was found that the RMSE of the three CNNs above became 1.22 years, 1.25 years, and 1.63 years, respectively, and the MAE became 0.93 years, 0.96 years, and 1.23 years. Bland-Altman plots and attention maps were also generated to provide a visual comparison. The proposed segmentation network can be used to reduce the influence of restrictions like image overlapping of organs and can thus increase the accuracy of pelvic bone age estimation.

Purpose The aim of this meta-analysis is to compare the clinical efficacy and safety of baloxavir with other anti-influenza agents or placebo in the treatment of influenza. Methods PubMed, Embase, Web of Science, Google Scholar, Scopus, CINAHL, Cochrane databases and clinical registration were searched from inception until February 15 2021 for relevant randomized controlled trials (RCTs). Only phase 3 RCTs evaluating the usefulness of baloxavir in the treatment of influenza were included. Results Three RCTs enrolling 3771 patients (baloxavir group, n = 1451; oseltamivir group, n = 1288; placebo group, n = 1032) were included. Compared with oseltamivir, baloxavir had an insignificantly shorter time to the alleviation of symptoms (mean difference [MD], −1.29 h; 95% CI, −6.80 to 4.21; I2 = 0%). In contrast, baloxavir had a significantly shorter time to the alleviation of symptoms than placebo (MD, −26.32 h; 95% CI, −33.78 to −18.86; I2 = 0%). Baloxavir was associated with a significant decline in influenza virus titers and viral RNA load compared to oseltamivir and placebo. Baloxavir was associated with a lower risk of any adverse events than oseltamivir (OR, 0.82; 95% CI, 0.69–0.98; I2 = 0%) and placebo (OR, 0.79; 95% CI, 0.66–0.96; I2 = 0%). Conclusions The findings of this meta-analysis suggested that baloxavir is superior to placebo in the treatment of influenza in both clinical outcome and virological response. Moreover, baloxavir was found to have a better virological response than oseltamivir and to be as effective as oseltamivir clinically. Compared with oseltamivir and placebo, baloxavir appears to be a relatively safe anti-influenza agent.

Background Liver fibrosis is a wound-healing response to chronic injury, featuring with excess accumulation of extracellular matrix secreted by the activated hepatic stellate cells (HSC). Disulfiram (DSF), also known as Antabuse, has been used for the treatment of alcohol addiction and substance abuse. Recently, overwhelming studies had revealed anti-cancer effects of DSF in multiple cancers, including liver cancer. But the actual effects of DSF on liver fibrosis and liver function remain unknown. Methods In this study, we evaluated the effects of low-dose DSF in CCl4- and Bile Duct Ligation (BDL)—induced hepatic fibrosis rat models. Cell proliferation was detected by using the Cell-Light™ EdU Apollo®567 Cell Tracking Kit. Cell apoptosis was analyzed using a TdT-mediated dUTP nick end labeling (TUNEL) kit, viability was measured with Cell Counting Kit-8(CCK8). Relative mRNA expression of pro-fibrogenic was assessed using quantitative RT-PCR. The degree of liver fibrosis, activated HSCs, were separately evaluated through Sirius Red-staining, immunohistochemistry and immunofluorescence. Serum alanine aminotransferase (ALT) and asparagine aminotransferase (AST) activities were detected with ALT and AST detecting kits using an automated analyzer. Results Liver fibrosis was distinctly attenuated while liver functions were moderately ameliorated in the DSF-treated group. Activation and proliferation of primary rat HSCs isolated from rat livers were significantly suppressed by low-dose DSF. DSF also inhibited the viability of in vitro cultured rat or human HSC cells dose-dependently but had no repressive role on human immortalized hepatocyte THLE-2 cells. Interestingly, upon DSF treatment, the viability of LX-2 cells co-cultured with THLE-2 was significantly inhibited, while that of THLE-2 co-cultured with LX-2 was increased. Further study indicated that HSCs apoptosis was increased in DSF/CCl4-treated liver samples. These data indicated that DSF has potent anti-fibrosis effects and protective effects toward hepatocytes and could possibly be repurposed as an anti-fibrosis drug in the clinic. Conclusions DSF attenuated ECM remodeling through suppressing the transformation of quiet HSCs into proliferative, fibrogenic myofibroblasts in hepatic fibrosis rat models. DSF provides a novel approach for the treatment of liver fibrosis.

This study aims to investigate the prevalence of short-acting β2-agonist (SABA) overuse in asthma and the associated risk of acute exacerbation and mortality in Taiwan. We used the Taiwanese pay-for-performance asthma program database, which included patients aged between 12 and 100 years who were enrolled in the program between 2001 and 2015. Among a total of 218,039 patients, 34,641 (15.9%) patients are classified as SABA over-users. Compared with patients who did not receive inhaled corticosteroids (ICS) and collected ≤2 canisters, SABA over-users had a higher risk of severe exacerbations. SABA over-users had a higher risk of all-cause mortality compared with patients who did not receive ICS and collected ≤2 canisters. The overall prevalence of SABA overuse in Taiwan is 15.9%, and this is even higher in concomitant ICS users. In addition, the overuse of SABA is associated with an increased risk of severe exacerbation and death.

Objectives We performed a systematic review and network meta-analysis of randomized controlled trials (RCTs) to provide updated information regarding the clinical efficacy of remdesivir in treating coronavirus disease 2019 (COVID-19). Methods PubMed, Embase, Cochrane Library, clinical trial registries of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched for relevant articles published up to 18 November 2020. Results Five RCTs, including 13 544 patients, were included in this meta-analysis. Among them, 3839 and 391 patients were assigned to the 10 day and 5 day remdesivir regimens, respectively. Patients receiving 5 day remdesivir therapy presented greater clinical improvement than those in the control group [OR = 1.68 (95% CI 1.18–2.40)], with no significant difference observed between the 10 day and placebo groups [OR = 1.23 (95% CI 0.90–1.68)]. Patients receiving remdesivir revealed a greater likelihood of discharge [10 day remdesivir versus control: OR = 1.32 (95% CI 1.09–1.60); 5 day remdesivir versus control: OR = 1.73 (95% CI 1.28–2.35)] and recovery [10 day remdesivir versus control: OR = 1.29 (95% CI 1.03–1.60); 5 day remdesivir versus control: OR = 1.80 (95% CI 1.31–2.48)] than those in the control group. In contrast, no mortality benefit was observed following remdesivir therapy. Furthermore, no significant association was observed between remdesivir treatment and an increased risk of adverse events. Conclusions Remdesivir can help improve the clinical outcome of hospitalized patients with COVID-19 and a 5 day regimen, instead of a 10 day regimen, may be sufficient for treatment. Moreover, remdesivir appears as tolerable as other comparators or placebo.

Prolactin binding to the prolactin receptor exerts pleiotropic biological effects in vertebrates. The prolactin receptor (PRLR) has multiple isoforms due to alternative splicing. The biological roles and related signaling of the long isoform (PRLR-LF) have been fully elucidated. However, little is known about the short isoform (PRLR-SF), particularly in cancer development and metabolic reprogramming, a core hallmark of cancer. Here, we reveal the role and underlying mechanism of PRLR-SF in pancreatic ductal adenocarcinoma (PDAC). Methods: A human PDAC tissue array was used to investigate the clinical relevance of PRLR in PDAC. The in vivo implications of PRLR-SF in PDAC were examined in a subcutaneous xenograft model and an orthotopic xenograft model. Immunohistochemistry was performed on tumor tissue obtained from genetically engineered KPC (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) mice with spontaneous tumors. 13C-labeled metabolite measures, LC-MS, EdU incorporation assays and seahorse analyses were used to identify the effects of PRLR-SF on the pentose phosphate pathway and glycolysis. We identified the molecular mechanisms by immunofluorescence, coimmunoprecipitation, proximity ligation assays, chromatin immunoprecipitation and promoter luciferase activity. Public databases (TCGA, GEO and GTEx) were used to analyze the expression and survival correlations of the related genes. Results: We demonstrated that PRLR-SF is predominantly expressed in spontaneously forming pancreatic tumors of genetically engineered KPC mice and human PDAC cell lines. PRLR-SF inhibits the proliferation of PDAC cells (AsPC-1 and BxPC-3) in vitro and tumor growth in vivo. We showed that PRLR-SF reduces the expression of genes in the pentose phosphate pathway (PPP) and nucleotide biosynthesis by activating Hippo signaling. TEAD1, a downstream transcription factor of Hippo signaling, directly regulates the expression of G6PD and TKT, which are PPP rate-limiting enzymes. Moreover, NEK9 directly interacts with PRLR-SF and is the intermediator between PRLR and the Hippo pathway. The PRLR expression level is negatively correlated with overall survival and TNM stage in PDAC patients. Additionally, pregnancy and lactation increase the ratio of PRLR-SF:PRLR-LF in the pancreas of wild-type mice and subcutaneous PDAC xenograft tumors. Conclusion: Our characterization of the relationship between PRLR-SF signaling, the NEK9-Hippo pathway, PPP and nucleotide synthesis explains a mechanism for the correlation between PRLR-SF and metabolic reprogramming in PDAC progression. Strategies to alter this pathway might be developed for the treatment or prevention of pancreatic cancer.

Background Existence of breast cancer stem cells (BCSCs) is implicated in disease relapse, metastasis, and resistance of treatment. β1,3-Galactosyltransferase 5 (B3GALT5) has been shown to be a pro-survival marker for BCSCs. However, little is known about the prognostic significance of B3GALT5 in breast cancer. Methods Paired tissues (tumor part and adjacent non-tumor part) from a cohort of 202 women with breast cancer were used to determine the expression levels of B3GALT5 mRNA by qRT-PCR. Kaplan–Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of relapse-free survival (RFS) and overall survival (OS). Both breast cancer cells and cancer stem cells (BCSCs) were used to see the in vitro effects of knockdown or overexpression of B3GALT5 on cell migration, invasion, and epithelial-to-mesenchymal transition (EMT). A patient-derived xenograft (PDX) model was used to see the in vivo effects of knockdown of B3GALT5 in BCSCs on tumor growth and metastasis. Results Higher expression of B3GALT5 in 202 breast cancer tissues, especially in adjacent non-tumor tissue, correlated with poor clinical outcomes including shorter OS and RFS in all patients, especially those with early stage breast cancer. In vitro studies showed B3GALT5 could enhance cell migration, invasion, mammosphere formation, and EMT. Of note, B3GALT5 upregulated the expression of β-catenin and EMT activator zinc finger E-box binding homeobox 1 (ZEB1) pathway in BCSCs. In vivo studies showed B3GALT5 expression in BCSCs is critical for not only tumor growth but also lymph node and lung metastasis in PDX mice. Conclusion Our results demonstrated the value of B3GALT5 as a prognostic marker of breast cancer, especially among the early stage patients, and its crucial roles in regulating EMT, cell migration, and stemness thereby promoting breast cancer progression.

The abnormal expressions of minichromosome maintenance protein 2 (MCM2) are closely related to the development of various kinds of cancers. We aimed to explore the functions and potential molecular mechanisms of MCM2 gene in cholangiocarcinoma (CCA) cell lines (Huh28 and RBE). First, the cell counting kit-8 (CCK-8), plate clone formation, transwell and invasion assays showed that MCM2 promotes the proliferation, migration and invasion of CCA cells. Flow cytometry assays showed that MCM2 significantly promotes the cell cycle, and inhibits the apoptosis of CCA cells. Further, by analyzing the RNA sequencing data of cholangiocarcinoma, we found that MCM2 gene is significantly negatively correlated with p53 signaling pathway. Quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting (WB) assays confirmed that MCM2 in CCA cells significantly down-regulated the mRNA and protein expression levels of p53 and BAX, and up-regulated the mRNA and protein expression levels of BCL2 and CCND1. Flow cytometry, qRT-PCR and WB assays confirmed that MCM2 promotes CCA through p53 pathway. Finally, we found that MCM2 is up-regulated in CCA tissues compared to the matched non-tumor cholangiocarcinoma tissues, and the high expressions of MCM2 are significantly associated with the poor clinical outcomes of CCA patients. In conclusion, this study revealed that MCM2 promotes the development of CCA by reducing the p53 pathway, and its high expression levels predict poor prognosis in CCA patients. These results provide a theoretical basis for the development of new clinical diagnosis and treatment of cholangiocarcinoma in the future.微小染色体维持蛋白2 (minichromosome maintenance protein 2, MCM2)的异常表达与多种恶性肿瘤的发生发展密切相关。为探索MCM2基因对胆管癌细胞肿瘤生物学行为的影响及其潜在的作用机制,本研究首先采用cell counting kit-8 (CCK-8)、平板细胞克隆形成、Transwell和Invasion实验证实,MCM2可促进胆管癌细胞的增殖、迁移和侵袭能力;流式细胞术检测结果显示,MCM2可加快细胞周期进程,抑制细胞凋亡。进一步通过对胆管癌组织RNA测序数据集的分析发现,MCM2基因与p53信号通路的激活显著负相关。采用实时定量PCR (quantitative real time polymerase chain reaction, qRT-PCR)和蛋白质免疫印迹(Western blotting, WB)实验发现,在胆管癌细胞中MCM2可显著下调p53和BAX的mRNA和蛋白表达水平,显著上调BCL2和CCND1的mRNA和蛋白表达水平。采用流式细胞术、qRT-PCR和WB实验进一步证实MCM2基因依赖于p53通路发挥影响胆管癌细胞周期和凋亡的功能。最后,通过分析MCM2的表达水平与胆管癌患者临床预后的相关性发现,MCM2在胆管癌组织中的表达显著高于癌旁组织,且其高表达与患者的不良预后显著相关。综上所述,本研究初步揭示MCM2可能通过抑制p53信号通路促进胆管癌的发生发展,并提示MCM2的高表达与胆管癌的不良预后显著相关,为未来胆管癌新的临床诊治措施的研发提供了理论依据。.

Obstructive sleep apnea (OSA) is a chronic breathing disorder characterized by intermittent sleep state-dependent upper airway (UA) collapse. The tongue comprises the primary UA dilator muscle and plays an essential role in the pathogenesis of OSA. We examined whether tongue stiffness measurement using ultrasound (US) shear wave elastography (SWE) is useful for predicting the existence of OSA. Forty-six participants (20 healthy controls and 26 patients with OSA) underwent transcutaneous submental SWE using a US system. Quantification with a shear modulus of 0-200 kPa was recorded during normal breathing and Muller's maneuver (MM). Polysomnography was used as the reference standard. Mid-sagittal tongue stiffness was significantly higher in awake patients with OSA than in controls during normal breathing and the MM (p < 0.0001). The posterior third of the tongue in patients with OSA had the highest value of shear modulus during the MM (p < 0.001). With cut-offs of 27.6 and 35.2 kPa for the whole tongue and posterior third during the MM, respectively, the sensitivity obtained was 69.2% and 76.9%, and the specificity was 85% and 95%, respectively, for detecting OSA. The corresponding areas under the receiver operating characteristic curve were 0.82 and 0.88, respectively. US SWE may have the potential for non-invasive tongue stiffness measurement in OSA.

Background Chinese populations have been reported higher incidence of all strokes and intracerebral hemorrhage. However, few large-scale studies have evaluated changes of stroke epidemiology in the 21st century. Methods We explored the rates of incidence of all first-ever strokes, subtypes, and 1-month case fatality by using data from the Taiwan National Health Insurance Research Database since 2004. Also, we investigated sex differences in stroke. Time-trend analysis was performed for incidence and case fatality rates of all strokes and subtypes in both sexes. Results The age-adjusted incidence of all strokes per 100,000 person-years decreased by 16%, from 251 (95% confidence interval [CI] 249–253) in 2004 to 210 (95% CI 209–212) in 2011 (p Conclusions In Taiwan, the incidence rate of first-ever stroke decreased in both Chinese men and women in the early 21st century. Men had a higher incidence rate than women. Furthermore, a marked decrease was noted in the incidence of intracerebral hemorrhage, while a slight decrease was noted in that of ischemic stroke; however, the decreased incidence of ischemic stroke was significant in only women.

SynopsisA sugar-lipid molecule called OAcGD2 is a novel marker for breast cancer stem cells. Treatment with anti-OAcGD2 mAb8B6 may have superior anticancer efficacy by targeting cancer stem cells, thereby reducing metastasis and recurrence of cancer.BackgroundCancer stem cells (CSCs) that drive tumor progression and disease recurrence are rare subsets of tumor cells. CSCs are relatively resistant to conventional chemotherapy and radiotherapy. Eradication of CSCs is thus essential to achieve durable responses. GD2 was reported to be a CSC marker in human triple-negative breast cancer, and anti-GD2 immunotherapy showed reduced tumor growth in cell lines. Using a specific anti-OAcGD2 antibody, mAb8D6, we set out to determine whether OAcGD2+ cells exhibit stem cell properties and mAb8D6 can inhibit tumor growth by targeting OAcGD2+CSCs.MethodOAcGD2 expression in patient-derived xenografts (PDXs) of breast cancer was determined by flow cytometric analyses using mAb8D6. The stemness of OAcGD2+ cells isolated by sorting and the effects of mAb8B6 were assessed by CSC growth and mammosphere formation in vitro and tumor growth in vivo using PDX models.ResultWe found that the OAcGD2 expression levels in six PDXs of various molecular subtypes of breast cancer highly correlated with their previously defined CSC markers in these PDXs. The sorted OAcGD2+ cells displayed a greater capacity for mammosphere formation in vitro and tumor initiation in vivo than OAcGD2− cells. In addition, the majority of OAcGD2+ cells were aldehyde dehydrogenase (ALDH+) or CD44hiCD24lo, the known CSC markers in breast cancer. Treatment of PDXs-bearing mice with mAb8B6, but not doxorubicin, suppressed the tumor growth, along with reduced CSCs as assessed by CSC markers and in vivo tumorigenicity. In vitro, mAb8B6 suppressed proliferation and mammosphere formation and induced apoptosis of OAcGD2+ breast cancer cells harvested from PDXs, in a dose-dependent manner. Finally, administration of mAb8B6 in vivo dramatically suppressed tumor growth of OAcGD2+ breast CSCs (BCSCs) with complete tumor abrogation in 3/6 mice.ConclusionOAcGD2 is a novel marker for CSC in various subtypes of breast cancer. Anti-OAcGD2 mAb8B6 directly eradicated OAcGD2+ cells and reduced tumor growth in PDX model. Our data demonstrate the potential of mAb8B6 as a promising immunotherapeutic agent to target BCSCs.

The purpose of the present study was to test whether a new stage classification based on radiographic visibility of the periodontal ligament in lower third molars in a Chinese population can be used for the 18- and 21-year thresholds. A total of 1300 orthopantomograms, including equal numbers of northern Chinese males and females evenly distributed between the ages of 15 and 40 years, were analyzed. The stages were defined according to the visibility of periodontal ligament for the outer parts of lower third molar roots because the visibility status of the periodontal ligament between the roots of lower third molars is none valuable in many Chinese individuals. Stage 0 was first achieved at the age of 17.05 years in males and 17.46 years in females. The earliest appearance of stage 1 was 17.47 years in males and 17.86 years in females. Stage 2 was first observed in males at the age of 21.43 years and in females at the age of 21.96 years. The onset of stage 3 was first observed at the age of 25.83 years in males and 23.14 years in females. Compared with the stage classification of Olze et al., which also considers the mesial parts of the roots, the number of assessable cases could be significantly increased. Therefore, our novel approach is effective for age estimation in the Chinese population.

This study aimed to compare the effect of budesonide/formoterol and fluticasone/salmeterol on the risk and outcomes of sepsis in COPD patients. We conducted this study using the Taiwan National Health Insurance Research Database. We included COPD patients prescribed with budesonide/formoterol or fluticasone/salmeterol between 2004 and 2011. Outcomes including sepsis and mortality were measured. 10,267 COPD patients who received fluticasone/salmeterol and 6,844 patients who received budesonide/formoterol were enrolled into this study and then subsequence were adjusted by propensity score weighting. The incidence of sepsis was 5.74 and 4.99 per 100 person-years for the patients receiving fluticasone/salmeterol and budesonide/formoterol, respectively. Fluticasone/salmeterol was associated with higher risk of sepsis (aHR, 1.15; 95%CI, 1.07-1.24) and septic shock (aHR, 1.14; 95%CI, 1.01-1.29) than budesonide/formoterol. Besides, fluticasone/salmeterol was associated with higher risk of death (aHR, 1.090; 95%CI, 1.01-1.18) than budesonide/formoterol. Patients receiving fluticasone/salmeterol had a significant higher risk of sepsis related respiratory organ dysfunction, lower respiratory tract infection, genitourinary tract infection, bacteremia and skin infection. In conclusion, long-term treatment with budesonide/formoterol was associated with lower rates of sepsis and deaths than fluticasone/salmeterol in patients with COPD.

G protein‐coupled estrogen receptor‐1 (GPER), a member of the G protein‐coupled receptor (GPCR) superfamily, mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non‐BCSCs of three patient‐derived xenografts of ER−/PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER‐mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD‐Ser118 to sustain BCSC characteristics. Transfection with a dominant‐negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs., What's new? G protein‐coupled estrogen receptor‐1 (GPER) mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. However, the role of GPER in breast cancer stem cells (BCSC) biology remains unclear. Here, using patient‐derived xenografts of ER–/PR+ breast cancer, the authors found higher expression of GPER in BCSCs than non‐BCSCs. Moreover, the results indicated that stemness features were sustained via GPER‐mediated PKA/BAD phosphorylation. Stimulation by the GPER ligand tamoxifen enhanced BCSC cell viability and population and BAD phosphorylation. The findings revealed a vital role of GPER‐mediated signaling pathways in BCSC survival, suggesting GPER as a potential therapeutic target for eradicating BCSCs.

Chih-Cheng Lai,1 Cheng-Hsin Chen,2 Charlotte Yu Hsuan Lin,3 Cheng-Yi Wang,2 Ya-Hui Wang41Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 2Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, USA; 4Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, TaiwanBackground: This study aims to compare the effects of single inhaler triple therapy comprised of inhaled corticosteroids (ICSs), long-acting β2-agonists (LABAs), and long-acting muscarinic receptor antagonists (LAMAs) with dual therapies comprised of either LABA/LAMA, ICS/LABA or separate ICS/LABA plus LAMA triple therapy.Methods: The Pubmed, Embase, and Cochrane databases were searched up to October 31st 2018. Only randomized controlled trials were included in the meta-analysis. The primary outcome was the rate of moderate-to-severe chronic obstructive pulmonary disease (COPD) exacerbations.Results: Seven studies fulfilling the inclusion criteria were included in the meta-analysis. Single inhaler triple therapy was associated with a significantly lower risk of COPD exacerbation compared with LABA/LAMA (rate ratio, 0.69; 95% confidence interval [CI] 0.55 to 0.87, I2=85%), and ICS/LABA (rate ratio, 0.81; 95% CI 0.73 to 0.89, I2=29%) dual therapy. Single inhaler triple therapy led to a more significant improvement in lung function and quality of life compared with LABA/LAMA and ICS/LABA dual therapy. Single inhaler triple therapy was associated with a higher risk of pneumonia compared with LABA/LAMA (risk ratio, 1.38, 95% CI 1.14 to 1.67, I2=0) dual therapy.Conclusions: The use of single inhaler triple therapy for COPD patients can result in lower rates of moderate or severe exacerbations of COPD as well as improved lung function and quality of life compared with dual therapy with LABA/LAMA or ICS/LABA.Keywords: COPD, triple therapy, randomized controlled trials, single inhaler

Acetyl-CoA synthetase 2 (ACSS2) generates acetyl-CoA from acetate is important for histone acetylation and gene expression. ACSS2 fulfills distinct functions depending on its cellular location in tumor cells. The role and cellular localization of ACSS2 in hepatocellular carcinoma (HCC) remains to be studied. Herein, we identified that the alternative transcription start site selection of ACSS2 was significantly different between HCC and corresponding adjacent tissues. Alternative transcription start site selection produced two different ACSS2 transcripts, ACSS2-S1 and ACSS2-S2. The two isoforms of ACSS2 had different subcellular localization and different functions. Overexpression of ACSS2-S2 promoted cell proliferation and invasion, but ACSS2-S1 did not. The ACSS2-S1 was mainly present in cytoplasm, and ACSS2-S2 was distributed in both nucleus and cytoplasm. Finally, we demonstrated that alternative transcription start site selection of ACSS2 correlates ribosome biogenesis in HCC. Our findings reveal an oncogenic role of ACSS2-S2 in HCC progression via increase of ribosome biogenesis, and suggest ACSS2-S2 might be a potential therapeutic target against the HCC.

Background Hepatic fibrosis is caused by chronic liver injury and may progress toward liver cirrhosis, and even hepatocellular carcinoma. However, current treatment is not satisfactory. Therefore, there is a mandate to find novel therapeutic targets to improve therapy, and biomarkers to monitor therapeutic response. Methods Liver fibrosis was induced by carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild type (WT) or CTHRC1−/− mice, followed by immunofluorescence and immunohistochemical analyses. CTHRC1 monoclonal antibody (mAb) was used to abrogate the effect of CTHRC1 in vitro and in vivo. Results Here, we reported that collagen triple helix repeat containing 1 (CTHRC1), a secreted protein derived from hepatic stellate cells (HSCs), was significantly up-regulated in fibrotic liver tissues. CTHRC1 promoted HSCs transformation from a quiescent to an activated state, and enhanced migratory or contractile capacities of HSCs by activating TGF-β signaling. Meanwhile, CTHRC1 competitively bound to Wnt noncononical receptor and promoted the contractility but not activation of HSCs. CCl4 or TAA-induced liver fibrosis was attenuated in CTHRC−/− mice compared with littermate control, while a monoclonal antibody of CTHRC1 suppressed liver fibrosis in WT mice treated with CCl4 or TAA. Interpretation We demonstrated that CTHRC1 is a new regulator of liver fibrosis by modulating TGF-β signaling. Targeting CTHRC1 could be a promising therapeutic approach, which can suppress TGF-β signaling and avoid the side effects caused by directly targeting TGF-β. CTHRC1 could also be a potential biomarker for monitoring response to anti-fibrotic therapy. Fund This study was supported by the National Natural Science Foundation of China (ID 81672358, 81871923, 81872242, 81802890), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (ID 20181708), the Natural Science Foundation of Shanghai (ID 17ZR1428300, 18ZR1436900), and Shanghai Municipal Health Bureau (ID 2018BR32). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript.

Background Lysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). However, the role of LOXL4 in HCC progression remains largely unclear. In this study, we investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC. Methods LOXL4 expression was measured in HCC tissues and cell lines. Overexpression, shRNA-mediated knockdown, recombinant human LOXL4 (rhLOXL4), and deletion mutants were applied to study the function of LOXL4 in HCC. Exosomes derived from HCC cell lines were assessed for the ability to promote cancer progression in standard assays. The effects of LOXL4 on the FAK/Src pathway were examined by western blotting. Results LOXL4 was commonly upregulated in HCC tissues and predicted a poor prognosis. Elevated LOXL4 was associated with tumor differentiation, vascular invasion, and tumor-node-metastasis (TNM) stage. Overexpression of LOXL4 promoted, whereas knockdown of LOXL4 inhibited cell migration and invasion of HCC in vitro, and overexpressed LOXL4 promoted intrahepatic and pulmonary metastases of HCC in vivo. Most interestingly, we found that HCC-derived exosomes transferred LOXL4 between HCC cells, and intracellular but not extracellular LOXL4 promoted cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. In addition, HCC-derived exosomes transferred LOXL4 to human umbilical vein endothelial cells (HUVECs) though a paracrine mechanism to promote angiogenesis. Conclusions Taken together, our data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in HCC. Electronic supplementary material The online version of this article (10.1186/s12943-019-0948-8) contains supplementary material, which is available to authorized users.

Background Accumulating evidence has revealed the pivotal role of epigenetic regulation in the pathogenesis of liver disease. However, the epigenetic mechanism that accounts for hepatic stellate cells (HSCs) activation in liver fibrosis remains largely unknown. Methods Primary HSCs were used to screen the differentially expressed histone H3 lysine methyltransferases and demethylases during HSC activation. Loss-of-function experiments were applied to determine the cellular functions of KDM4D in HSCs. Transcriptome analysis was applied to explore the downstream targets of KDM4D. Real-time qPCR, western blotting, immunohistochemical staining, and chromatin immunoprecipitation were performed to uncover the underlying mechanism concerning KDM4D during liver fibrogenesis. Findings KDM4D was identified as a remarkable up-regulated histone H3 demethylase during HSC activation. The overexpression profile of KDM4D was confirmed in three fibrosis animal models and human fibrotic liver tissues. In vitro Kdm4d knockdown impaired the collagen gel contraction and migration capacity of primary HSCs. In established CCl4-induced mice model, Kdm4d knockdown inhibited fibrosis progression, and promoted fibrosis reversal, with enhanced thinning and splitting of fibrotic septa, as well as a dramatic decrease in collagen area. Whole gene transcriptome analysis showed the regulatory role of KDM4D in Toll-Like Receptor (TLR) signaling pathway. Mechanistically, KDM4D catalyzed histone 3 on lysine 9 (H3K9) di-, and tri-demethylation, which promoted TLR4 expression, and subsequently prompted liver fibrogenesis by activating NF-κB signaling pathways. Interpretation KDM4D facilitates TLR4 transcription through demethylation of H3K9, thus activating TLR4/NF-κB signaling pathways in HSCs, contributing to HSC activation and collagen crosslinking, further, hepatic fibrosis progression. Fund Shanghai New Hundred Talents Program, Shanghai Municipal Commission of Health and Family Planning, Key Developing Disciplines Program, Shanghai Key disciplines program of Health and Family Planning and Shanghai Sailing Program.

This network meta-analysis compared the clinical efficacy and safety of anti-viral agents for the prevention of disease progression among non-hospitalized patients with COVID-19. PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched from their inception to 28 May 2022. Only randomized controlled trials (RCTs) that investigated the clinical efficacy of anti-viral agents for non-hospitalized patients with COVID-19 were included. Three RCTs involving 4241 patients were included. Overall, anti-viral agents were associated with a significantly lower risk of COVID-19 related hospitalization or death compared with the placebo (OR, 0.23; 95% CI: 0.06–0.96; p = 0.04). Compared with the placebo, patients receiving nirmatrelvir plus ritonavir had the lowest risk of hospitalization or death (OR, 0.12; 95% CI: 0.06–0.24), followed by remdesivir (OR, 0.13; 95% CI: 0.03–0.57) and then molnupiravir (OR, 0.67; 95% CI: 0.46–0.99). The rank probability for each treatment calculated using the P-score revealed that nirmatrelvir plus ritonavir was the best anti-viral treatment, followed by remdesivir and then molnupiravir. Finally, anti-viral agents were not associated with an increased risk of adverse events compared with the placebo. For non-hospitalized patients with COVID-19 who are at risk of disease progression, the currently recommended three anti-viral agents, nirmatrelvir plus ritonavir, molnupiravir and remdesivir, should continue to be recommended for the prevention of disease progression. Among them, oral nirmatrelvir plus ritonavir and intravenous remdesivir seem to be the better choice, followed by molnupiravir, as determined by this network meta-analysis. Additionally, these three anti-viral agents were shown to be as tolerable as the placebo in this clinical setting.

IntroductionStudies based on health claims data (HCD) have been increasingly adopted in medical research for their strengths in large sample size and abundant information, and the Taiwan National Health Insurance Research Database (NHIRD) has been widely used in medical research across disciplines, including dementia. How the diagnostic codes are applied to define the diseases/conditions of interest is pivotal in HCD-related research, but the consensus on the issue that diagnostic codes most appropriately define dementias in the NHIRD is lacking. The objectives of this scoping review are (1) to investigate the relevant characteristics in the published reports targeting dementias based on the NHIRD, and (2) to address the diversity by a case study.Methods and analysisThis scoping review protocol follows the methodological framework of the Joanna Briggs Institute Reviewer’s Manual and the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. The review will be performed between 1 March and 31 December 2022 in five stages, including identifying the relevant studies, developing search strategies, individually screening and selecting evidence, collecting and extracting data, and summarising and reporting the results. The electronic databases of MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO, Airiti Library Academic Database, the National Health Insurance Administration’s repository, and Taiwan Government Research Bulletin will be searched. We will perform narrative syntheses of the results to address research questions and will analyse the prevalence across the included individual studies as a case study.Ethics and disseminationOur scoping review is a review of the published reports and ethical approval is not required. The results will provide a panorama of the dementia studies based on the NHIRD. We will disseminate our findings through peer-reviewed journals and conferences, and share with stakeholders by distributing the summaries in social media and emails.

Overuse of short-acting β-agonists (SABAs) could be associated with increased acute exacerbations and mortality in patients with asthma. However, the role of SABAs in sepsis has not been well studied.We sought to investigate the association between the overuse of SABAs and sepsis in patients with asthma.Between 2001 and 2013, patients with asthma were identified from Taiwan asthma pay-for-performance program database, but patients with prior sepsis were excluded. The overuse of SABAs was defined as the use of 3 or more canisters annually.A total of 28,033 patients were found to have overused SABAs (overuse group), and 155,453 patients had acceptable use of SABAs (control group). Using propensity score matching method with 1:1 ratio, we had 2 subgroups with similar baseline characteristic and each group had 20,542 patients. The incidence of sepsis during the follow-up period was 1.26 per 100 person-years in the SABA overuse group, which was higher than in the control group (0.94 per 100 person-years). The crude and adjusted hazard ratios were 1.35 (95% CI, 1.26-1.44) and 1.33 (95% CI, 1.24-1.43), respectively. The SABA overuse group also had a higher risk of sepsis within 1 year than the control group (adjusted odds ratio, 1.34; 95% CI, 1.09-1.64). The incidence of septic shock during the follow-up period was 0.44 per 100 person-years in the SABA overuse group, which was higher than in the control group (0.33 per 100 person-years). The crude and adjusted hazard ratios were 1.32 (95% CI, 1.17-1.48) and 1.28 (95% CI, 1.14-1.44), respectively. Subgroup analysis consistently revealed a higher incidence of sepsis in the SABA overuse group than in the control group in all age and male groups before and after propensity score matching.The overuse of SABA could be associated with an increased risk of sepsis and septic shock in the patient with asthma in Taiwan.

Studies on use of inhaled corticosteroids (ICS) and the risk of nontuberculous mycobacterial lung disease (NTM-LD) are limited and have some conflicting results. We recruited 1235 NTM-LD patients and found that ICS use within 1 year was associated with increased NTM-LD, and the risk increased with elevated ICS dose and cumulative duration. Discontinuation of ICS use for more than 120 days could reduce the risk of NTM-LD to an insignificant level. For NTM species, the development of NTM-LD by ICS was highest for Mycobacterium kansasii lung disease. The pooled results of the meta-analysis showed that ICS use might increase the risk of NTM-LD with dose response in medium and high dose of daily ICS. In addition, budesonide had a smaller impact on the risk of NTM-LD than other ICS medications. The present study and meta-analysis provide evidence for ICS adjustment, including dose, discontinuation effect, and medications to possibly reduce the risk of NTM-LD.

Introduction Nintedanib can inhibit processes involved in the progression of fibrosis and can reduce the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF) and fibrotic-interstitial lung disease (fibrotic-ILDs). Although the adverse events associated with nintedanib in IPF patients are well known, its safety in other fibrotic-ILD patients remained unclear. Methods We searched PubMed, EMBASE, Cochrane CENTRAL and Cochrane CDSR for randomized controlled studies which compared nintedanib with a placebo in ILD patients. We estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs) for adverse events using the DerSimonian–Laird random-effects model. Results Six studies with a total of 2,583 patients were included in the meta-analysis. The pooled estimates showed that patients treated with nintedanib had a significantly higher likelihood of having any adverse events (OR = 2.39; 95% CI = 1.71–3.36) or adverse events leading to treatment discontinuation (OR = 1.73; 95% CI = 1.34–2.25). However, they had trend to lower likelihood of having fatal adverse events (OR = 0.69; 95% CI = 0.41–1.14) compared with the placebo group. Use of nintedanib was positively associated with diarrhea (OR = 5.96; 95% CI = 4.35–8.16), nausea (OR = 3.00; 95% CI = 1.93–4.66), vomiting (OR = 3.22; 95% CI = 2.17–4.76) and weight loss (OR = 3.38; 95% CI = 1.1.76–6.47). Whereas, patients treated with nintedanib were less likely to have a cough (OR = 0.73; 95% CI = 0.56–0.96) and dyspnea (OR = 0.70; 95% CI = 0.53–0.94). Conclusions Compared to a placebo, nintedanib was associated with a higher risk of adverse events, especially for diarrhea, nausea, vomiting and weight loss, but it was also associated with a lower risk of cough and dyspnea in IPF and fibrotic-ILD patients.

Endometrial cancer (EC) is becoming one of the most common gynecologic malignancies. Lipid metabolism is a hallmark feature of cancers. The molecular mechanisms underlying lipid metabolism in EC remain unclear. In this study, we revealed that many lipid metabolism-related genes were aberrantly expressed in endometrial cancer tissues, especially ACLY. Upregulated ACLY promoted EC cell proliferation and colony formation, and attenuated apoptosis. Mechanistically, cotreatment with obesity-related factors (estradiol, insulin and leptin) promoted nuclear translocation of ACLY through Akt-mediated phosphorylation of ACLY at Ser455. Nuclear-localized ACLY increased histone acetylation levels, thus resulting in upregulation of pyrimidine metabolism genes, such as DHODH. Moreover, STAT3 altered the ACLY expression at the transcriptional level via directly binding to its promoter region. In conclusion, our findings clarify the roles and mechanisms of ACLY in endometrial cancer and ACLY could link obesity risk factors to the regulation of histone acetylation. We believe that novel therapeutic strategies for EC can be designed by targeting the ACLY axis.

Metastasis is a major cause of cancer-related deaths. Tumor-intrinsic properties can determine whether tumor metastasis occurs or not. Here, by comparing the gene expression patterns in primary colorectal cancer (CRC) patients with or without metastasis, we found that Collagen Triple Helix Repeat Containing 1 (CTHRC1) in primary CRC served as a metastasis-associated gene. Animal experiments verified that CTHRC1 secreted by CRC cells promoted hepatic metastasis, which was closely correlated with macrophage infiltration. Depletion of macrophages by liposomal clodronate largely abolished the promoting effect of CTHRC1 on CRC liver metastasis. Furthermore, we demonstrated that CTHRC1 modulated macrophage polarization to M2 phenotypes through TGF-β signaling. A mechanistic study revealed that CTHRC1 bound directly to TGF-β receptor II and TGF-β receptor III, stabilized the TGF-β receptor complex, and activated TGF-β signaling. The combination treatment of CTHRC1 monoclonal antibody and anti-PD-1 blocking antibody effectively suppressed CRC hepatic metastasis. Taken together, our data demonstrated that CTHRC1 is an intrinsic marker of CRC metastasis and further revealed that CTHRC1 promoted CRC liver metastasis by reshaping infiltrated macrophages through TGF-β signaling, suggesting that CTHRC1 could be a potential biomarker for the early prediction of and a therapeutic target of CRC hepatic metastasis.

Objectives To investigate the incidence of active tuberculosis (TB) among COPD patients using fluticasone/salmeterol or budesonide/formoterol, and to identify any differences between these two groups of patients. Methods The study enrolled COPD patients from Taiwan NHIRD who received treatment with fluticasone/salmeterol or budesonide/formoterol for > 90 days between 2004 and 2011. The incidence of active TB was the primary outcome. Results Among the intention-to-treat population prior to matching, the incidence rates of active TB were 0.94 and 0.61% in the fluticasone/salmeterol and budesonide/formoterol groups, respectively. After matching, the fluticasone/salmeterol group had significantly higher rates of active TB (adjusted HR, 1.41, 95% CI, 1.17–1.70) compared with the budesonide/formoterol group. The significant difference between these two groups remained after a competing risk analysis (HR, 1.45, 95% CI, 1.21–1.74). Following propensity score matching, the fluticasone/salmeterol group had significantly higher rates of active TB compared with the budesonide/formoterol group (adjusted HR, 1.45, 95% CI, 1.14–1.85). A similar trend was observed after a competing risk analysis (HR, 1.44, 95% CI, 1.19–1.75). A higher risk of active TB was observed in the fluticasone/salmeterol group compared with the budesonide/formoterol group across all subgroups, but some differences did not reach statistical significance. Conclusion Fluticasone/salmeterol carried a higher risk of active TB compared with budesonide/formoterol among COPD patients.

Aerobic glycolysis, also known as the Warburg effect, is emerged as a hallmark of most cancer cells. Increased aerobic glycolysis is closely associated with tumor aggressiveness and predicts a poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent genomic aberrations and increased glycolytic phenotype. However, the detailed molecular events implicated in aerobic glycolysis of PDAC are not well understood. In this study, we performed a comprehensive molecular characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis of 89 informative PDAC tumors identified substantial copy number variations (MYC, GATA6, FGFR1, IDO1, and SMAD4) and mutations (KRAS, SMAD4, and RNF43) related to aerobic glycolysis. Moreover, integrated analysis of transcriptional profiles revealed many differentially expressed long non-coding RNAs involved in PDAC aerobic glycolysis. Loss-of-function studies showed that LINC01559 and UNC5B-AS1 knockdown significantly inhibited the glycolytic capacity of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate. Moreover, genetic silencing of LINC01559 and UNC5B-AS1 suppressed tumor growth and resulted in alterations in several signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, and transcriptional misregulation in cancer. Notably, high expression of LINC01559 and UNC5B-AS1 predicted poor patient prognosis and correlated with the maximum standard uptakevalue (SUVmax) in PDAC patients who received preoperative 18F-FDG PET/CT. Taken together, our results decipher the glycolysis-associated copy number variations, mutations, and lncRNA landscapes in PDAC. These findings improve our knowledge of the molecular mechanism of PDAC aerobic glycolysis and may have practical implications for precision cancer therapy.

Tongue deformation during whole-night natural sleep in adult patients with obstructive sleep apnea has not been well evaluated. Through simultaneous ultrasonography and polysomnography during whole-night sleep, we examined the prevalence and patterns of tongue depth changes and their relationship with the severity of obstructive sleep apnea. Sixty consecutive eligible adults presenting with symptoms suggesting obstructive sleep apnea were enrolled. We observed that 88.4% (38/43) of patients with obstructive sleep apnea exhibited a significant increase in the maximum ultrasonographic tongue depth when hypopnea or apnea occurred during sleep. A mixed-model analysis of variance demonstrated that compared with patients with primary snoring or mild obstructive sleep apnea, those with moderate to severe obstructive sleep apnea have significantly greater maximum ultrasonographic tongue depth during respiratory events (p = .0047). We identified three different ultrasonographic patterns of tongue deformation, namely en bloc, tongue body and tongue base. Approximately 82% (27/33) of patients with moderate to severe obstructive sleep apnea demonstrated an en bloc tongue deformation. By contrast, 70% (19/27) of primary snorers or patients with mild obstructive sleep apnea showed a tongue body obstruction. Recognizing the prevalence and patterns of tongue deformation during sleep may provide insights into pathogenesis and treatment decisions in patients with obstructive sleep apnea. Future studies are warranted to verify the treatment results of various tongue procedures by using this approach.

Highlights • As of 29 Feb. 2020, COVID-19 has affected 85 403 patients in 57 countries/territories and caused 2924 deaths in 9 countries. • The incidence (per 1 000 000 people) ranged from 61.4 in Republic of Korea to 0.0002 in India. • Daily cumulative index (DCI) of COVID-19 (cumulative cases/no. of days between first reported case and 29 Feb. 2020) was greatest in China (1320.85). • High DCIs were also seen in the Republic of Korea (78.78), Iran (43.11) and Italy (30.62). • The incidence and mortality were correlated with the DCI., It has been 2 months since the first case of coronavirus disease 2019 (COVID-19) was reported in Wuhan, China. So far, COVID-19 has affected 85 403 patients in 57 countries/territories and has caused 2924 deaths in 9 countries. However, epidemiological data differ between countries. Although China had higher morbidity and mortality than other sites, the number of new daily cases in China has been lower than outside of China since 26 February 2020. The incidence ranged from 61.44 per 1 000 000 people in the Republic of Korea to 0.0002 per 1 000 000 people in India. The daily cumulative index (DCI) of COVID-19 (cumulative cases/no. of days between the first reported case and 29 February 2020) was greatest in China (1320.85), followed by the Republic of Korea (78.78), Iran (43.11) and Italy (30.62). However, the DCIs in other countries/territories were

Objective The aim of this study is to examine the effect of taking Clostridium butyricum (Miyarisan BM) orally for 4 weeks since the 32+0 weeks of gestation on preventing Group B Streptococcus colonization. Materials and methods We retrospectively collected data on the pregnancy outcomes of 1602 women between October 2017 and August 2019. The control group received standard antenatal care, and the intervention group received standard antenatal care with a daily oral dose of probiotics since the 32+0 weeks of gestation. The daily dose was one pack of C. butyricum (Miyarisan BM) once or twice a day. A vaginal Group B Streptococcus swab was collected between 36+0 and 36+6 weeks of gestation. Results After applying the designated exclusion criteria, the total number of participants was 1576. The Group B Streptococcus colonization rate was significantly decreased in the intervention group (P = 0.0338; adjusted OR: 0.66 (0.45–0.97)). Conclusion Probiotics can reduce the colonization rate of Group B Streptococcus in the vagina and rectum under three conditions: (1) intervention of adequate length, (2) sufficient probiotic dose, and (3) effective probiotics.

Accumulating evidence has pointed out that metastasis is the leading cause of death in several malignant tumor, including CRC. During CRC, metastatic capacity is closely correlated with reprogrammed energy metabolism. Mitochondrial Pyruvate Carrier 1 (MPC1), as the carrier of transporting pyruvate into mitochondria, linked the glycolysis and TCA cycle, which would affect the energy production. However, the specific role of MPC1 on tumor metastasis in CRC remains unexplored. Here, by data mining of genes involved in pyruvate metabolism using the TCGA dataset, we found that MPC1 was significantly downregulated in CRC compared to nontumor tissues. Similar MPC1 expression pattern was also found in multiple GEO datasets. IHC staining in both human sample and AOM/DSS induced mouse CRC model revealed significant downregulation of MPC1. What is more, we found that MPC1 expression was gradually decreased in normal tissue, primary CRC, and metastasis CRC. Additionally, poor prognosis emerged in the MPC1 low expression patients, especially in patients with metastasis. Following, functional tests showed that MPC1 overexpression inhibited the motility of CRC cells in vitro and MPC1 silencing enhanced liver metastases in vivo. Furthermore, we uncovered that decreased MPC1 activated the Wnt/β-catenin pathway by promoting nuclear translocation of β-catenin to mediate the expression of MMP7, E-cadherin, Snail1, and myc. Collectively, our data suggest that MPC1 has the potential to be served as a promising biomarker for diagnosis and a therapeutic target in CRC.

Aims To investigate a partnership intervention of the community-based and hospital-based home visit to improve patients' satisfaction. Methods A time series quasi-experimental quantitative design was used. The experimental group had “partnership intervention”, while the control group maintained routine home visits. Patient satisfaction was measured pre-intervention, six months and 12 months after the partnership intervention. Results Six and 12 months after partnership intervention, in the experimental group, items related to stabilizing disease conditions, improving daily living abilities, enhancing communication ability and providing relevant resources were significantly higher than pre-intervention. However, 12 months after the intervention, the influence of the intervention became weaken. Conclusions The partnership intervention can significantly improve patients' satisfaction with home visit service.

Stem cell surface markers may facilitate a better understanding of stem cell biology through molecular function studies or serve as tools to monitor the differentiation status and behavior of stem cells in culture or tissue. Thus, it is important to identify additional novel stem cell markers. We used glycoproteomics to discover surface glycoproteins on human embryonic stem cells (hESCs) that may be useful stem cell markers. We found that a surface glycoprotein, leucine-rich repeat neuronal protein 1 (LRRN1), is expressed abundantly on the surface of hESCs before differentiation into embryoid bodies (EBs). Silencing of LRRN1 with short hairpin RNA (shLRRN1) in hESCs resulted in decreased capacity of self-renewal, and skewed differentiation toward endoderm/mesoderm lineages in vitro and in vivo. Meanwhile, the protein expression levels of the pluripotency factors OCT4, NANOG, and SOX2 were reduced. Interestingly, the mRNA levels of these pluripotency factors were not affected in LRRN1 silenced cells, but protein half-lives were substantially shortened. Furthermore, we found LRRN1 silencing led to nuclear export and proteasomal degradation of all three pluripotency factors. In addition, the effects on nuclear export were mediated by AKT phosphorylation. These results suggest that LRRN1 plays an important role in maintaining the protein stability of pluripotency factors through AKT phosphorylation, thus maintaining hESC self-renewal capacity and pluripotency. Overall, we found that LRRN1 contributes to pluripotency of hESC by preventing translocation of OCT4, NANOG, and SOX2 from nucleus to cytoplasm, thereby lessening their post-translational modification and degradation.

High-risk human papillomavirus oncoproteins E6 and E7 are the major etiological factors of cervical cancer but are insufficient for malignant transformation of cervical cancer. Dysregulated alternative splicing, mainly ascribed to aberrant splicing factor levels and activities, contributes to most cancer hallmarks. However, do E6 and E7 regulate the expression of splicing factors? Does alternative splicing acts as an "accomplice" of E6E7 to promote cervical cancer progression? Here, we identified that the splicing factor SRSF10, which promotes tumorigenesis of cervix, was upregulated by E6E7 via E2F1 transcriptional activation. SRSF10 modulates the alternate terminator of interleukin-1 receptor accessory protein exon 13 to increase production of the membrane form of interleukin-1 receptor accessory protein. SRSF10-mediated mIL1RAP upregulates the expression of the "don't eat me" signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-κB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes. Altogether, these data reveal a close relationship among HPV infection, alternative splicing and tumor immune evasion, and also suggests that the SRSF10-mIL1RAP-CD47 axis could be an attractive therapeutic target for the treatment of cervical cancer.

Background Infective endocarditis (IE) is uncommon in childhood. Its associated epidemiological characteristics in patients with congenital heart disease (CHD) remain unclear. Methods The study population included children born in Taiwan during the years 1997 to 2005 who were diagnosed as having CHD before 3years of age. All children were followed up until the end year of 2010, the diagnosis of infective endocarditis, or death. The demographic characteristics of patients with and without IE, the invasive procedures performed during 6months before the index date, the prophylactic antibiotics related to dental procedures, and in-hospital mortality were collected. Results Information of 24,729 children with CHD were retrieved for our analysis and 237 patients with newly diagnosed IE were identified. The incidence rate of IE in all CHD lesions was 11.13 per 10,000person-years. Taking ASD for reference, the following CHD lesions were at risk for IE: cyanotic CHD (adjusted OR, 9.58; 95% confidence interval, 5.38–17.05), endocardial cushion defect (ECD) (8.01; 2.73–23.50), Left-sided lesions (4.36; 1.90–10.01) and VSD (2.93; 1.64–5.23). Patients who underwent procedures have a higher risk of acquiring IE which include central venous catheter (CVC) insertion (3.17; 2.36–4.27), cardiac catheterization (3.74; 2.67–5.22), open-heart surgery (2.47; 1.61–3.77), valve surgery (3.20; 1.70–6.02), and shunt surgery (7.43; 2.36–23.41). However, dental procedures did not increase the risk of IE, irrespective of antibiotic usage. Conclusions The risk of IE varies markedly among CHD lesions in our study. Invasive heart procedures but not dental procedures, are more significantly associated with IE among children with CHD.

Yueh Lan Huang,1 Chih-Cheng Lai,2 Ya-Hui Wang,3 Cheng-Yi Wang,1 Jen-Yu Wang,1 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 2Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, 3Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan Background: There is conflicting information regarding the effects of selective and nonselective beta-blocker treatment in patients with COPD.Participants and methods: This nested case–control study used the Taiwan National Health Insurance Research Database. We included COPD patients who used inhalation steroid and beta-blockers between 1998 and 2010. From this cohort, there were 16,067 patients with severe exacerbations included in the analysis and 55,970 controls matched on age, sex, COPD diagnosis year, and beta-blockers treatment duration by risk set sampling.Results: For the selective beta-blocker users, the current users had a lower risk of severe exacerbations than the nonusers (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.85–0.96). In contrast, for the nonselective beta-blocker users, the current users had a higher risk of severe acute exacerbations than the nonusers (OR, 1.21; 95% CI, 1.14–1.27). A higher risk of severe exacerbation during increasing mean daily dose or within about the initial 300days was found in nonselective beta-blockers, but not in selective beta-blockers. One selective beta-blocker, betaxolol, had a significantly lower risk of severe exacerbations (OR, 0.75; 95% CI, 0.60–0.95). Two nonselective beta-blockers (labetalol and propranolol) were associated with a significantly higher risk of exacerbations (OR, 1.49; 95% CI, 1.32–1.67 for labetalol; OR, 1.16; 95% CI, 1.10–1.23 for propranolol).Conclusion: Selective beta-blockers can be cautiously prescribed for patients with COPD and cardiovascular disease (CVD), however, nonselective beta-blockers should not be prescribed for patients with COPD. Betaxolol may be the preferred choice of suitable selective beta-blocker for patients with COPD, however, labetalol and propranolol should be avoided for patients with COPD. Keywords: beta-blocker, COPD, selective, nonselective

Hsi-Hsing Yang,1,2 Chih-Cheng Lai,3 Ya-Hui Wang,4 Wei-Chih Yang,5 Cheng-Yi Wang,4,* Hao-Chien Wang,6,* Likwang Chen,5 Chong-Jen Yu6 On behalf of Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan, 2Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, 3Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, 4Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, 6Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan *These authors contributed equally to this work Background: It remains unclear whether severe exacerbation and pneumonia of COPD differs between patients treated with budesonide/formoterol and those treated with fluticasone/salmeterol. Therefore, we conducted a comparative study of those who used budesonide/formoterol and those treated with fluticasone/salmeterol for COPD.Methods: Subjects in this population-based cohort study comprised patients with COPD who were treated with a fixed combination of budesonide/formoterol or fluticasone/salmeterol. All patients were recruited from the Taiwan National Health Insurance database. The outcomes including severe exacerbations, pneumonia, and pneumonia requiring mechanical ventilation (MV) were measured.Results: During the study period, 11,519 COPD patients receiving fluticasone/salmeterol and 7,437 patients receiving budesonide/formoterol were enrolled in the study. Pairwise matching (1:1) of fluticasone/salmeterol and budesonide/formoterol populations resulted in to two similar subgroups comprising each 7,295 patients. Patients receiving fluticasone/salmeterol had higher annual rate and higher risk of severe exacerbation than patients receiving budesonide/formoterol (1.2219/year vs 1.1237/year, adjusted rate ratio, 1.08; 95% CI, 1.07–1.10). In addition, patients receiving fluticasone/salmeterol had higher incidence rate and higher risk of pneumonia than patients receiving budesonide/formoterol (12.11 per 100 person-years vs 10.65 per 100 person-years, adjusted hazard ratio [aHR], 1.13; 95% CI, 1.08–1.20). Finally, patients receiving fluticasone/salmeterol had higher incidence rate and higher risk of pneumonia requiring MV than patients receiving budesonide/formoterol (3.94 per 100 person-years vs 3.47 per 100 person-years, aHR, 1.14; 95% CI, 1.05–1.24). A similar trend was seen before and after propensity score matching analysis, intention-to-treat, and as-treated analysis with and without competing risk.Conclusions: Based on this retrospective observational study, long-term treatment with fixed combination budesonide/formoterol was associated with fewer severe exacerbations, pneumonia, and pneumonia requiring MV than fluticasone/salmeterol in COPD patients. Keywords: COPD, ICS/LABA, exacerbation, pneumonia

// Yuh-Jin Liang 1 , Chen-Yu Wang 2 , I-An Wang 1 , Yi-Wen Chen 1 , Li-Tzu Li 1 , Chuang-Yu Lin 1 , Ming-Yi Ho 1 , Tsung-Lung Chou 1 , Ya-Hui Wang 1 , Shih-Pin Chiou 1 , Yu-Ju Lin 1 and John Yu 1, 3 1 Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan 2 Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan 3 Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan Correspondence to: John Yu, email: johnyu@gate.sinica.edu.tw Yuh-Jin Liang, email: yuh.jin.liang@gmail.com Keywords: glycosphingolipid, ganglioside, breast cancer stem cell, GD3 synthase, glycosyltransferase Received: January 06, 2017 Accepted: April 19, 2017 Published: May 07, 2017 ABSTRACT Many studies have suggested that disialogangliosides, GD2 and GD3, are involved in the development of various tumor types. However, the functional relationships between ganglioside expression and cancer development or aggressiveness are not fully described. GD3 is upregulated in approximately half of all invasive ductal breast carcinoma cases, and enhanced expression of GD3 synthase (GD3S, alpha-N-acetylneuraminide alpha-2,8-sialyltransferase) in estrogen receptor-negative breast tumors, was shown to correlate with reduced overall patient survival. We previously found that GD2 and GD3, together with their common upstream glycosyltransferases, GD3S and GD2/GM2 synthase, maintain a stem cell phenotype in breast cancer stem cells (CSCs). In the current study, we demonstrate that GD3S alone can sustain CSC properties and also promote malignant cancer properties. Using MALDI-MS and flow cytometry, we found that breast cancer cell lines, of various subtypes with or without ectopic GD3S-expression, exhibited distinct GD2/GD3 expression profiles. Furthermore, we found that GD3 was associated with EGFR and activated EGFR signaling in both breast CSCs and breast cancer cell lines. In addition, GD3S knockdown enhanced cytotoxicity of the EGFR-inhibitor gefitinib in resistant MDA-MB468 cells, both in vitro and in vivo . Based on this evidence, we propose that GD3S contributes to gefitinib-resistance in EGFR-positive breast cancer cells and may be an effective therapeutic target in drug-resistant breast cancers.

Background: Diabetic nephropathy (DN) is one of the microvascular complications of diabetes mellitus. Proteinuria is the most important clinical feature of DN and an independent risk factor for the progression of DN. Therefore, reducing urinary protein is the primary goal of DN treatment. Traditional Chinese medicine (TCM) has long been widely used in the treatment of DN. Therefore, this paper conducted a meta-analysis of the clinical efficacy of TCM in the treatment of DN proteinuria, to comprehensively analyze the role of TCM in the treatment of DN. Methods: We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet, Nature, Science online and China Journal Full-text Database, China Biomedical Literature CD-ROM Database, and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to September 2019. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of DN proteinuria. Trial registration number: PROSPERO CRD42019139707.

This study investigated the predominant skin cancer subtype among organ transplant recipients, patients on chronic dialysis, and patients with chronic kidney disease in Asian subjects. Among 23,644 patients with skin cancer, identified from Taiwan Cancer Registry Database, 53 were organ transplant recipients, 255 were on chronic dialysis, 1,792 had chronic kidney disease, and 21,544 were in the control group. The proportions of squamous cell carcinoma were 52.8%, 47.8%, 40.1%, and 33.5%, respectively. Compared with the control group, organ transplant recipients (1.99-fold) and patients on chronic dialysis (1.25-fold) were at higher risk of developing squamous cell carcinoma than other skin cancers after adjustment for potential confounders. Subgroups or covariates associated with increased squamous cell carcinoma compared with other skin cancer risk included patients with chronic kidney disease aged < 70 years (vs. control group; 1.3-fold), old age (vs. young age; 2.8-fold), male sex (vs. female sex; 1.1-fold), and south Taiwan residency (vs. north Taiwan residency; 1.1-fold). Organ transplant recipients and patients on chronic dialysis had immune dysregulation, resulting in a higher risk of squamous cell carcinomas.

Background Gastric cancer is one of the deadliest malignant tumours, with a high incidence in China, and is regulated by aberrantly overexpressed oncogenes. However, existing therapies are insufficient to meet patients’ needs; thus, the identification of additional therapeutic targets and exploration of the underlying mechanism are urgently needed. GPAA1 is the subunit of the GPI transamidase that transfers the GPI anchor to proteins within the ER. The functional impacts of increased expression levels of GPAA1 in human cancers are not well understood. Methods Data mining was performed to determine the pattern of GPAA1 expression and the reason for its overexpression in tumour and adjacent normal tissues. In vitro and in vivo experiments evaluating proliferation and metastasis were performed using cells with stable deletion or overexpression of GPAA1. A tissue microarray established by the Ren Ji Hospital was utilized to analyse the expression profile of GPAA1 and its correlation with prognosis. Western blotting, an in situ proximity ligation assay, and co-immunoprecipitation (co-IP) were performed to reveal the mechanism of GPAA1 in gastric cancer. Results GPAA1 was a markedly upregulated oncogene in gastric cancer due to chromosomal amplification. GPAA1 overexpression was confirmed in specimens from the Ren Ji cohort and was associated with ERBB2 expression, predicting unsatisfactory patient outcomes. Aberrantly upregulated GPAA1 dramatically contributed to cancer growth and metastasis in in vitro and in vivo studies. Mechanistically, GPAA1 enhanced the levels of metastasis-associated GPI-anchored proteins to increase tumour metastasis and intensified lipid raft formation, which consequently promoted the interaction between EGFR and ERBB2 as well as downstream pro-proliferative signalling. Conclusions GPAA1 facilitates the expression of cancer-related GPI-anchored proteins and supplies a more robust platform—the lipid raft—to promote EGFR-ERBB2 dimerization, which further contributes to tumour growth and metastasis and to cancer progression. GPAA1 could be a promising diagnostic biomarker and therapeutic target for gastric cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1218-8) contains supplementary material, which is available to authorized users.

This report describes our experience providing nursing care between 7th October and 7th November 2016 to a homosexual male who repeatedly engaged in stress-related suicide attempts and self-harm. Information was collected using comprehensive nursing assessment, observation, and interviews and the health problems of ineffective coping and disabled family coping were identified. Because of affection-related distress and the lack of recognition of his gender orientation by his family, the client engaged repeatedly in self-harm and attempted suicide on several occasions in order to cope with the self-perceived unbearable stress and stressful situations. The authors provided nursing care based on Watson's theory of human caring. We fulfilled the nature of caring, prompted respect and acceptance, and established a therapeutic, interpersonal relationship. We also adopted the concept of suicide intervention, and used the protective factors as the main coping strategies. These approaches allowed the client to acknowledge the events and reactions that may trigger his suicidal ideas, to develop better self-reflection and impulse control, and to mitigate the ideas and behaviors related to suicide and self-harm. Because constant conflicts between the client and his parents hampered a harmonious family relationship, we adopted family-centered care in order to enhance family resilience, which created room for mutual learning and development and reconstructed a healthy family relationship. Our successful results with this case encouraged our writing this paper in order to share this nursing experience with caregivers facing similar client situations and needs.運用Watson關懷理論於男同性戀者降低反覆自殺行為之護理經驗.本文描述一位男同性戀者，反覆出現自殺自傷行為之護理經驗。護理期間為2016年10月7日至2016年11月7日，藉由整體性護理評估、觀察、會談收集資料，確立健康問題有：無效性因應能力、家庭因應能力失調。個案因感情受挫及家人尚無法接受其性向，無法調適情緒壓力，反覆以自殺自傷行為因應壓力情境，筆者運用Watson關懷理論十項照護因素於護理措施之中，發揮關懷本質尊重與接納，建立治療性人際關係，並以自殺防治概念之保護因子做為因應策略，辨識可能引發個人自殺想法的事件與反應，協助自我覺察、增加控制力，降低自殺自傷想法與行為。個案和父母衝突不斷，原本和諧的家庭關係受到衝擊，故以家庭為中心之照護，促進家庭復原力，讓雙方共同發展更多學習與成長空間，重建和諧健康的家庭，期望藉此照護經驗以供臨床參考。.

To observe the associations between single nucleotide polymorphisms (SNPs) of nicotinamide N-methyltransferase (NNMT) gene and sport performance and to analyse genotype associations of the associated SNPs with sport performance and relative maximal oxygen uptake ([Formula: see text]). Participants were selected from 685 Chinese Han male college students. The completion times of a 1000-m run and a 50-m run were used to reflect sport performance, respectively. Nineteen tagSNPs were genotyped with Polymerase chain reaction-ligase detection reaction. Relative [Formula: see text] was directly determined with a cardiopulmonary function analyser. A significant association was found between rs2256292 and 1000-m run performance, but no significant association was found between any tagSNPs and 50-m run performance. The genotype associations of rs2256292 with 1000-m run performance and with relative [Formula: see text] were both significant under the recessive model (CC vs. CG + GG). No tagSNP in NNMT is significantly associated with 50-m run performance but rs2256292 is significantly associated with 1000-m run performance. The genotype associations of rs2256292 with sport performance are significant under recessive model, and a higher relative [Formula: see text] may be the physiological reason for minor homozygote CC carriers being of the better 1000-m runners.

BACKGROUND An increasing number of studies have demonstrated that Streptococcus bovis and its concomitant inflammatory factors concentrate in the intestine in colorectal cancer (CRC). However, the molecular mechanism of S. bovis on colorectal tumorigenesis remains unclear. This study aimed to explore the role of S. bovis in carcinogenesis and its potential mechanism in CRC of mice orally pretreated with S. bovis. MATERIAL AND METHODS The colons of experimental mice were collected and evaluated for the extent of neoplasm. In addition, comparative feces DNA sequencing was adopted to verify the abundance change of S. bovis during the progression of CRC in patients. RESULTS The results of this study found that S. bovis is more likely to be present at higher levels in patients with progressive colorectal carcinoma compared to those adenoma patients and healthy volunteers (P