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Objective Osteoarthritis (OA) progression has been shown to increase the expression of inflammatory cytokines in joints, leading to the destruction of cartilage matrix. Interleukin (IL)-1β is a potent inflammatory cytokine associated with osteoarthritic synovial fluid. The protective effects of polysaccharides from Enteromorpha prolifera against acute hepatic injury was reported. Design In this study, we examined the effects of Enteromorpha polysaccharide extracts (EPEs) in the treatment of OA. The effects of the EPEs were assessed using an IL-1β-stimulated SW1353 and SW982 cells. The expression levels of specific mRNA and proteins were evaluated using semi-quantitative reverse transcription polymerase chain reaction (sqRT-PCR) and western immunoblotting. An OA animal study involving C57BL/6J mice was also conducted to assess the effects on tactile sensitivity and anterior cruciate ligament transection (ACLT). Results Acidic polysaccharide extract (APE) was shown to significantly reduce cytokine and chemokine mRNA levels in IL-1β-stimulated SW1353 and SW982 cells and attenuate the expression of proinflammatory cytokines and p38/AP-1 in SW1353 cells. APE was also shown to minimize the effect of osteolytic lesions in the knee joints of ACLT-induced osteoarthritic mice. Conclusions APE is a potent inhibitor of joint degeneration associated with OA.

Neutrophil extracellular traps (NETs) play important roles in sepsis and deep-seated infections, but whether NET formation correlates with clinical outcomes of patients with streptococcal bloodstream infections (BSIs) is unclear.We analyzed serum levels of complexes of myeloperoxidase and DNA (MPO-DNA) in patients with streptococcal-BSIs. In vitro assay of NET induction by serum from BSI patients was performed.MPO-DNA values for the Streptococci-BSI group (n = 59) were significantly higher than those for healthy controls (p 0.00001) and matched control groups (n = 59, p = 0.004). The rate of higher MPO-DNA levels (1.87 μg/mL) were higher in abscess-prone streptococcal groups (streptococcus milleri group) (72.2% vs. 52.5%, p = 0.02). For patients with BSIs due to highly infective endocarditis (IE)-prone pathogens, the values of serum MPO-DNA were also higher in patients diagnosed of IE compared to their counterparts (p = 0.009). Notably, serum from patients with leukopenia could induce higher amounts of in vitro NET formation, despite having low MPO-DNA levels, suggesting that NET formation could be influenced by WBC counts. Therefore, we combined WBC counts with MPO-DNA to predict all-cause 30-day mortality in patients with commensal streptococcal-BSIs. The mortality risk was lowest among patients who had neither high MPO-DNA levels nor abnormal WBC counts (p = 0.058). Furthermore, this group of patients also had a favorable composite outcome consisting of major adverse cardiovascular events (MACE) and all-cause mortality (p = 0.026).Together, these study data suggested that serum MPO-DNA can be a biomarker for predicting a composite outcome consisting of MACE and all-cause mortality in patients with commensal streptococcal-BSIs.

Omipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment.

Metastasis of cancer cells is multi-step process and dissemination is an initial step. Here we report a tamoxifen-controllable Twist1a-ERT2 transgenic zebrafish line as a new animal model for metastasis research, and demonstrate that this model can serve as a novel platform for discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of EGFR) transgenic zebrafish, which develops hepatocellular carcinoma, approximately 80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labeled hepatocytes from the liver to the entire abdomen region and the tail region. The dissemination is accomplished in 5 days through induction of an epithelial-to-mesenchymal transition. Using this model, we conducted in vivo drug screening and identified three hit drugs. One of them, adrenosterone, an inhibitor for hydroxysteroid (11-beta) dehydrogenase 1 (HSD11β1), has a suppressor effect on cell dissemination in this model. Pharmacologic and genetic inhibition of HSD11β1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Through downregulation of Snail and Slug, adrenosterone-treated cells recovered expression of E-cadherin and other epithelial markers and lost partial expression of mesenchymal markers compared with vehicle-treated cells. Taken together, our model offers a useful platform for the discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells.Implications:This study describes a transgenic zebrafish model for liver tumor metastasis and it has been successfully used for identification of some drugs to inhibit metastatic dissemination of human cancer cells.

Figures S1. Liver-specific expression of Twist1a-ERT2 mRNA and increase of mesenchymal marker Vimentin in liver cells in Twist1a-ERT2 transgenic zebrafish. Figure S2. Lack of significant effect of Adrenosterone, Rabeprazole and Olmesartan in primary liver tumor growth, fish survival, liver cell proliferation and apoptosis in Twist1a-ERT2/xmrk double transgenic zebrafish. Figure S3. Effect of Adrenosterone or Rabeprazole on cell viabilities of highly metastatic human cell lines, related to Fig. 4. Figure S4. Expression of mesenchymal markers and appearance E -cad+ cells after adrenosteroneadrenosterone treatment of HCCLM3. Supplementary Table 1. Oligo primers used for cloning, RT-PCR and qPCRPrimer. Supplementary Table S2. The number and frequencies of the fish showing the dissemination patterns in ERT2, Twist1a-ERT2, ERT2/xmrk or Twist1a-ERT2/xmrk double transgenic fish. Supplementary Table S3. Effects of Ki16425 and Y27632 on cell dissemination of Twist1a-ERT2/xmrk double transgenic zebrafish line. Supplementary Table S4. Effects of Adrenosterone, Rabeprazole and Olmesartan on cell dissemination of Twist1a-ERT2/xmrk double transgenic zebrafish line. Supplementary Table S5. Effects of pharmacological and genetic inhibition of HSD11�1 on metastatic dissemination of human cancer cells in zebrafish xenografted models.

The KMT1E mutation (H1224A) does not suppress ANXA2 promoter activity in cancer cells.

Cell viability effects of KMT1E in lung cancer.

revised supporting materials and methods

Supplemental Figure Legends

ANXA2 is highly expressed in metastatic cancer cells.

KMT1E expression in 192 lung cancer as evaluated by tissue microarray-based immunohistochemistry

KMT1E DNA binding sequences identified by ChIP-Seq.

Clinicopathological characteristics of patients with lung cancer.

ANXA2 is required for rescue filopodia formation in lung cancer cells.

ANXA2 and SMAD3 promotes F-actin polymerization formation in lung cancer cells.

KMT1E inhibits filopodia formation in sublines cells.

KMT1E modulates ANXA2 expression to suppress cancer cell invasion in lung cancer cells.

Background: It is unknown whether the direct oral anticoagulant edoxaban can reduce leaflet thrombosis and the accompanying cerebral thromboembolic risk after transcatheter aortic valve replacement. In addition, the causal relationship of subclinical leaflet thrombosis with cerebral thromboembolism and neurological or neurocognitive dysfunction remains unclear. Methods: We conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy (aspirin plus clopidogrel) in patients who had undergone successful transcatheter aortic valve replacement and did not have an indication for anticoagulation. The primary end point was an incidence of leaflet thrombosis on 4-dimensional computed tomography at 6 months. Key secondary end points were the number and volume of new cerebral lesions on brain magnetic resonance imaging and the serial changes of neurological and neurocognitive function between 6 months and immediately after transcatheter aortic valve replacement. Results: A total of 229 patients were included in the final intention-to-treat population. There was a trend toward a lower incidence of leaflet thrombosis in the edoxaban group compared with the dual antiplatelet therapy group (9.8% versus 18.4%; absolute difference, −8.5% [95% CI, −17.8% to 0.8%]; P =0.076). The percentage of patients with new cerebral lesions on brain magnetic resonance imaging (edoxaban versus dual antiplatelet therapy, 25.0% versus 20.2%; difference, 4.8%; 95% CI, −6.4% to 16.0%) and median total new lesion number and volume were not different between the 2 groups. In addition, the percentages of patients with worsening of neurological and neurocognitive function were not different between the groups. The incidence of any or major bleeding events was not different between the 2 groups. We found no significant association between the presence or extent of leaflet thrombosis with new cerebral lesions and a change of neurological or neurocognitive function. Conclusions: In patients without an indication for long-term anticoagulation after successful transcatheter aortic valve replacement, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effects on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the 2 groups. Because the study was underpowered, the results should be considered hypothesis generating, highlighting the need for further research. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03284827.

完整的心臟衰竭照護鏈應將流程緊密結合，整合組織內外具有關聯性的服務，並且提供持續性照顧。本院藉由疾病照護品質認證的三大架構，全面審視心衰竭照護實際運作狀況。在團隊推動下，主診斷心衰竭收縮分率≦40%之病人，死亡率由15.1%降低至13.0%；指引用藥RAS與Beta blocker比率由28.5%上升至40.0%，MRA由60.0%上升至68.8%；接受復健比率自9.3%提升到18.60%，有顯著上升。本院透過評鑑過程改善流程，有助於臨床人員將心衰竭照護融入實際照護。 A comprehensive heart failure care chain should contain a tightly interconnected process, integrate related services within and outside an organization, and provide continuous care. Using the three major frameworks of the Heart Failure Disease Care Certification, National Taiwan University Hospital (NTUH) comprehensively examined the status quo of heart failure care operation. After the NTUH medical team implemented the certification, the mortality rate of patients with heart failure with an ejection fraction of ≤40% as their principal diagnosis decreased from 15.1% to 13.0%; the percentage of guideline-directed medical treatment with renin-angiotensin system-acting agents and beta-blockers increased from 28.5% to 40.0%; the percentage of using magnetic resonance angiography increased from 60.0% to 68.8 %; and the percentage of patients receiving rehabilitation increased significantly from 9.3% to 18.60%. NTUH improved the care process through the certification, which helped clinical staff to integrate heart failure care into actual care. &nbsp

Emergency surgery for acute type A aortic dissection (AAAD) was usually avoided or denied in octogenarians because of high surgical mortality. Refined surgical techniques and improved postoperative care have led to an improved in-hospital outcome. However, a significant number of operative survivors suffered from postoperative complications and had compromised quality of life. We sought to assess the clinical outcome of emergency surgery using a standard conservative approach in octogenarians with AAAD.From 2004 to 2021, 123 patients underwent emergency surgery for AAAD by one surgeon using a standard conservative approach with right subclavian artery cannulation, no aortic cross-clamp, selective antegrade cerebral perfusion, moderate systemic hypothermia, reinforced sandwich technique, and a strategy of limited aortic resection. Hospital and late outcomes were assessed in patients with age80 years.Eighteen patients (15%) were octogenarians with seven males (39%) and median age of 82 years (range, 80-89). Hypertension was present in six patients (33%). None had diabetes mellitus, Marfan, or bicuspid aortic valve. Dissection was intramural hematoma in six (33%) and DeBakey type I in 15 patients (83%). Cardiac tamponade with shock was present in seven patients (39%). Ascending aortic grafting was performed in 17 patients, and additional hemiarch replacement in one patient. The hospital mortality rate was 17% (3/18). Fourteen patients (82%) were alive and well at discharge.Emergency surgery for AAAD using a standard conservative approach showed an improved outcome in octogenarians. The majority of patients could return home with an acceptable living.

Osteoarthritis (OA) progression has been shown to increase the expression of inflammatory cytokines in joints, leading to the destruction of cartilage matrix. Interleukin (IL)-1β is a potent inflammatory cytokine associated with osteoarthritic synovial fluid. The protective effects of polysaccharides from Enteromorpha prolifera against acute hepatic injury was reported.In this study, we examined the effects of Enteromorpha polysaccharide extracts (EPEs) in the treatment of OA. The effects of the EPEs were assessed using an IL-1β-stimulated SW1353 and SW982 cells. The expression levels of specific mRNA and proteins were evaluated using semi-quantitative reverse transcription polymerase chain reaction (sqRT-PCR) and western immunoblotting. An OA animal study involving C57BL/6J mice was also conducted to assess the effects on tactile sensitivity and anterior cruciate ligament transection (ACLT).Acidic polysaccharide extract (APE) was shown to significantly reduce cytokine and chemokine mRNA levels in IL-1β-stimulated SW1353 and SW982 cells and attenuate the expression of proinflammatory cytokines and p38/AP-1 in SW1353 cells. APE was also shown to minimize the effect of osteolytic lesions in the knee joints of ACLT-induced osteoarthritic mice.APE is a potent inhibitor of joint degeneration associated with OA.

AIMS AND OBJECTIVES To investigate the characteristics and prevalence of demoralisation syndrome among heart transplantation patients in Taiwan. BACKGROUND Patients with end-stage heart failure who have undergone cardiac transplantation are at risk of demoralisation syndrome. Demoralisation syndrome has been studied in cancer populations, but our understanding of the syndrome among heart transplant recipients is limited. DESIGN AND METHODS The study adopted a cross-sectional design and analysed the baseline data from a longitudinal study with cardiac transplant patients at a heart centre in northern Taiwan. A structured questionnaire, namely the Demoralization Scale-Mandarin Version (DS-MV), was used to assess demoralisation syndrome. Hierarchical regression was applied to determine the predictors of demoralisation. Reporting was consistent with the STROBE checklist. RESULTS There were a total of 84 participants with an average age of 51.9 years and a time since heart transplantation of around 4.1 years. Among them, the prevalence of demoralisation syndrome was 35.8%, and 57.1% coped well with stress. In addition, on the DS-MV, participants tended to choose sentences with positive rather than negative wording. Our data showed that cardiac transplant recipients with stress have higher possibility suffering from demoralisation syndrome; poor renal function and those who cannot relive from stress are predictors for loss of meaning. CONCLUSIONS Chinese individuals tend to hide their weaknesses; nevertheless, demoralisation syndrome among cardiac transplant recipients, as related to stress status and kidney function, is still remarkable. RELEVANCE TO CLINICAL PRACTICE Since demoralisation is preventable, further research on this phenomenon in the cardiac transplant population is warranted and needs to be developed.

Background. The presence of thrombus in the left atrial appendage (LAA) and/or LA body has so far been considered a contraindication to the transcatheter mitral valve (MV) in bioprosthetic MV/ MV annuloplasty ring implantation. Objective. The aim of this study is to describe, for the first time to our knowledge, the utilization of both two-dimensional (2D) and three-dimensional (3D) transesophageal echocardiography (TEE) in successfully performing without any embolic or other complications transcatheter MV in bioprosthetic MV/ mitral ring implantation using the apical approach in a group of 12 patients (pts) with co-existing LAA and/or LA body thrombus. Patients, Methods and Results. All pts were severely symptomatic with severe bioprosthetic MV stenosis in 9, severe native MV stenosis with a previous surgically inserted MV annuloplasty ring in 1 and severe MV regurgitation secondary to bioprosthetic cusp rupture in 2 pts. Thrombus in the LAA and/ or LA body was noted in all pts by 2D and 3DTEE. All pts were at high or prohibitive risk for surgery and all refused surgery. Utilizing both 2D and 3DTEE, especially 3DTEE, the guidewires and the prosthesis deployment system could be manipulated under direct vision through the MV bioprosthesis into the LA and left superior pulmonary vein bypassing and avoiding any contact with the thrombus. The transcatheter procedure was successfully accomplished in all patients with relief of stenosis/ regurgitation and amelioration of symptoms with no embolic or other complications during the procedure and over a mean follow-up period of 21 months. Conclusion. Our small study demonstrates the feasibility of successfully performing transcatheter MV in bioprosthetic MV/ MV annuloplasty ring procedure in pts with thrombus in LAA and/or LA body without any embolic or other complications.

Background Possible sarcopenia, aortic valve stenosis, and malnutrition are important issues that afflict older adults. Objective The aims of this study were to compare the differences in nutritional status and family support in older adults with possible sarcopenia and those without sarcopenia after undergoing transcatheter aortic valve implantation (TAVI) and to identify the predictors of malnutrition and demonstrate changes in heart function over time after undergoing TAVI. Methods A case-control design was conducted. Possible sarcopenia was identified by measuring calf circumference, grip strength, and gait speed. The Mini Nutritional Assessment-Short Form and numerical family support rating scale were used to collect data. Left ventricular ejection fraction and New York Heart Association (NYHA) functional class were assessed at 5 time points to evaluate heart function. Results Eighty-one participants were categorized into those without sarcopenia (34) and those with possible sarcopenia (47). Logistic linear regression showed albumin and possible sarcopenia to be predictors of malnutrition (odds ratio, 5.5; 95% confidence interval, 1.02-30.19). Family support was associated with nutrition status (P = .019). For patient heart function, the results of NYHA functional class and left ventricular ejection fraction improved over time after TAVI. The improvement in NYHA functional class at T2 was significantly different between the 2 groups compared with that at T0. Conclusions The nutrition level was higher among participants without sarcopenia than those with possible sarcopenia. Approximately 90% of the participants indicated that they had high family support. Demographic factors and albumin levels could be used to evaluate risk of malnutrition. Patients without possible sarcopenia showed greater improvement in NYHA class.

Background Hepatitis C increases the mortality and morbidity of patients after heart transplant. Direct-acting antivirals (DAAs) are the primary drugs for hepatitis C treatment. However, such drugs are expensive and frequently unaffordable for patients. In DAA treatment, the assessment of drug interaction is crucial. Methods We investigated a retrospective case series study from January 2017 to December 2019. Sustained virologic response 12 (SVR12) was used to assess the effectiveness of DAA treatment. Data on patients’ demographic information, timing of hepatitis C virus (HCV) infection (before or after heart transplant), HCV genotypes and viral loads, DAAs used (branded drugs or generic drugs), and drug interaction assessments were collected. Results Fifteen heart transplant patients received hepatitis C treatments during the study period, 11 of whom were infected because their donors had hepatitis C. After DAA treatment, HCV was undetectable in all patients, and 93.3% of them achieved SVR12. Nine patients used the generic sofosbuvir/velpatasvir, and 88.9% of them achieved SVR12. A total of 256 drugs were used with DAAs; 51 records of drug interactions were noted, 3 of which were contraindications, and the remaining records were potential interactions. Patients who used sofosbuvir or elbasvir/grazoprevir experienced fewer drug interactions. Conclusions DAA treatment is effective for hepatitis C treatment in patients after heart transplant. Patients who cannot afford branded drugs because of their prices can use generic drugs as an alternative. Drug interactions must be surveyed during DAA treatment.

The crosstalk between tumors and their local microenvironment has been well studied, whereas the effect of tumors on distant tissues remains understudied. Studying how tumors affect other tissues is important for understanding the systemic effect of tumors and for improving the overall health of cancer patients. In this study, we focused on the changes in the intestine during liver tumor progression, using a previously established liver tumor model through inducible expression of the oncogene

Active bloodstream infection (BSI) is a contraindication for heart transplantation (HT). However, some critical patients with BSI may undergo HT as a life-saving procedure. We aimed to investigate the impact of pre-transplant BSI on the clinical outcomes after HT.We enrolled 511 consecutive patients who underwent HT between 1999 and 2019. Patients were divided into two groups based on the presence of BSI within 30 days preoperatively. Forty-three patients (8.4%) with BSI who were clinically stable and had no metastatic infection were considered for HT on an individual basis. In-hospital mortality, incidence of early postoperative BSI, length of postoperative hospital stays, and long-term survival were compared between the groups. Logistic and Cox regression analyses were performed to identify risk factors for in-hospital and 1-year mortality.Patients with pre-transplant BSI had a high incidence of previous cardiopulmonary resuscitation, pre-transplant ventilator use, mechanical circulatory support use, renal replacement therapy, United Network for Organ Sharing status 1A, and a prolonged preoperative hospital waiting period. The in-hospital mortality rate was higher in patients with pre-transplant BSI (21% vs. 12%, p = .081), and the mortality rate was very high (33.3%) for those with BSI 0-15 days before HT. In addition, patients with pre-transplant BSI had a significantly longer postoperative hospital stay than patients in the control group. However, long-term survival was similar in both groups.Although pre-transplant BSI was associated with higher in-hospital mortality and prolonged postoperative hospital stay, patients who survived the early period had a similar long-term prognosis.

Granular cell tumours are usually benign with a 1–2% incidence of malignancy. They are less sensitive to radiotherapy and chemotherapy and are treated by surgical excision. We report a case of a malignant granular cell tumour located at the interventricular septum.

Cisplatin is one of the most common therapeutics used in treatments of several types of cancers. To enhance cisplatin lipophilicity and reduce resistance and side effects, a polyfluorinated bipyridine-modified cisplatin analogue, dichloro[4,4’-bis(2,2,3,3-tetrafluoropropoxy)methyl)-2,2’-bipryridine] platinum (TFBPC), was synthesized and therapeutic assessments were performed. TFBPC displayed superior effects in inhibiting the proliferation of several cisplatin-resistant human cancer cell lines, including MDA-MB-231 breast cancers, COLO205 colon cancers and SK-OV-3 ovarian cancers. TFBPC bound to DNA and formed DNA crosslinks that resulted in DNA degradation, triggering the cell death program through the PARP/Bax/Bcl-2 apoptosis and LC3-related autophagy pathway. Moreover, TFBPC significantly inhibited tumor growth in both animal models which include a cell line-derived xenograft model (CDX) of cisplatin-resistant MDA-MB-231, and a patient-derived xenograft (PDX) model of triple-negative breast cancers (TNBCs). Furthermore, the biopsy specimen from TFBPC-treated xenografts revealed decreased expressions of P53, Ki-67 and PD-L1 coupled with higher expression of cleaved caspase 3, suggesting TFBPC treatment was effective and resulted in good prognostic indications. No significant pathological changes were observed in hematological and biochemistry tests in blood and histological examinations from the specimen of major organs. Therefore, TFBPC is a potential candidate for treatments of patients suffering from TNBCs as well as other cisplatin-resistant cancers.

RNA interference (RNAi) is an emerging therapeutic modality for tumors. However, lack of a safe and efficient small interfering RNA (siRNA) delivery system limits its clinical application. Here, we report a bioreducible and less-cationic siRNA delivery carrier by conjugating Zn(II)-dipicolylamine complexes (Zn-DPA) onto hyaluronic acid (HA) via a redox-sensitive disulfide (-SS-) linker. Such polymer conjugates can formulate stable siRNA nanomedicines via coordination between zinc ions of DPA and the anionic phosphate of siRNA. After the conjugates are taken up by cells, intracellular reduction stimulus subsequently triggers the release of siRNAs and elucidates the desired RNAi effect. Our studies showed the formulated siRNA nanomedicines can be efficiently delivered into tumor cells/tissues and mediates less cytotoxicities both in vitro and in vivo. More importantly, when applied in a xenograft glioblastoma tumor model, this siRNA nanomedicine demonstrated significantly enhanced antitumor ability comparing to naked siRNA. This work demonstrates that such bioreducible Zn-DPA-functionalized HA conjugates without using cationic material as a siRNA carrier represents a promising direction for RNAi-based cancer therapy.

Almond is an extendible open-source virtual assistant designed to help people access Internet services and IoT (Internet of Things) devices. Both are referred to as skills here. Service providers can easily enable their devices for Almond by defining proper APIs (Application Programming Interfaces) for ThingTalk in Thingpedia. ThingTalk is a virtual assistant programming language, and Thingpedia is an application encyclopedia. Almond uses a large neural network to translate user commands in natural language into ThingTalk programs. To obtain enough data for the training of the neural network, Genie was developed to synthesize pairs of user commands and corresponding ThingTalk programs based on a natural language template approach. In this work, we extended Genie to support Chinese. For 107 devices and 261 functions registered in Thingpedia, 649 Chinese primitive templates and 292 Chinese construct templates were analyzed and developed. Two models, seq2seq (sequence-to-sequence) and MQAN (multiple question answer network), were trained to translate user commands in Chinese into ThingTalk programs. Both models were evaluated, and the experiment results showed that MQAN outperformed seq2seq. The exact match, BLEU, and F1 token accuracy of MQAN were 0.7, 0.82, and 0.88, respectively. As a result, users could use Chinese in Almond to access Internet services and IoT devices registered in Thingpedia.

Blue carbon ecosystems (BCEs) are a promising resource for the mitigation of global warming; however, climate spectrums and anthropogenic activities could influence the fragile balance of BCEs as carbon sinks or sources. We assess how oyster farming affects dissolved inorganic carbon (DIC) and total alkalinity (TA) on CO

Gouty arthritis is the one of the most painful arthritis and is caused by an inflammatory reaction. This study investigated whether astaxanthin (AXT), which has documented anti-inflammatory and antioxidant properties, exhibits protective effects against monosodium urate (MSU) crystal-induced inflammation. Cell viability of J774A.1 murine macrophages was assessed by AXT dose-dependent incubation by MTT assays, and expression levels of iNOS and COX-2 proteins as well as secretion of IL-1β were also analyzed under MSU crystals stimulation with or without AXT treatment. The production of inflammatory mediators was found to significantly decrease with AXT treatment, and the formation of the inflammasome complex was also attenuated when cells were co-stimulated with MSU crystals and AXT. Furthermore, we found that expression of the MAPK pathway was downregulated in J774A.1 cells. AXT also inhibited the induction of COX-2 and IL-6 in human chondrocytes and synovial fibroblasts by western blots. Finally, an MSU crystal intra-articular injection rat model for gouty arthritis was utilized in which treatment groups received 5-daily intraperitoneal injections of AXT prior to MSU crystal stimulation, or once intra-articular injections of AXT following MSU crystal stimulation for 6 hours. Results of synovitis score analysis revealed that inflammation was significantly attenuated in the group which received intraperitoneal AXT injection prior to MSU crystal stimulation compared to the group which received MSU only. These results indicate that AXT attenuates the effects of MSU crystal-induced inflammation by suppressing the production of pro-inflammatory cytokines and inflammatory mediators. Our findings that the anti-inflammatory activities of AXT may be beneficial in the treatment of MSU crystal-induced arthritis.

Formation of intravenous catheter-related thrombosis leads to central venous stenosis in patients requiring renal replacement therapy or chemotherapy infusion, yet the triggers or mechanisms remain unclear, especially in patients without symptoms of infection. In this study, we found that neutrophil extracellular traps (NETs) could be detected in the fibrin sheaths from dialysis patients without clinical manifestations of infection. Confocal microscopy revealed bacteria imbedded in NETs in the fibrin sheaths. Thirty-nine of 50 (78%) fibrin sheath specimens contained bacteria detectable by 16S ribosomal RNA genome typing with a predominance of Staphylococcus aureus (69%). In rat models, transient bacteremia of S. aureus induced NETs in enlarged fibrin sheaths, and treatment with DNase I alone significantly reduced both NET and fibrin sheath formation surrounding the catheter. Therefore, transient bacteremia could be a silent trigger that induces NET-related immunothrombosis enhancing catheter-related central venous stenosis.

The poor prognosis of patients diagnosed with hepatocellular carcinoma (HCC) is directly associated with the multi-step process of tumor metastasis. TWIST1, a basic helix-loop-helix (bHLH) transcription factor, is the most important epithelial-mesenchymal transition (EMT) gene involved in embryonic development, tumor progression, and metastasis. However, the role that TWIST1 gene plays in the process of liver tumor metastasis in vivo is still not well understood. Zebrafish can serve as a powerful model for cancer research. Thus, in this study, we crossed twist1a+ and kras+ transgenic zebrafish, which, respectively, express hepatocyte-specific mCherry and enhanced green fluorescent protein (EGFP); they also drive overexpression of their respective transcription factors. This was found to exacerbate the development of metastatic HCC. Fluorescence of mCherry and EGFP-labeled hepatocytes revealed that approximately 37.5% to 45.5% of the twist1a+/kras+ double transgenic zebrafish exhibited spontaneous tumor metastasis from the liver to the abdomen and tail areas, respectively. We also investigated the inflammatory effects of lipopolysaccharides (LPS) on the hepatocyte-specific co-expression of twist1a+ and kras+ in double transgenic zebrafish. Following LPS exposure, co-expression of twist1a+ and kras+ was found to increase tumor metastasis by 57.8%, likely due to crosstalk with the EMT pathway. Our results confirm that twist1a and kras are important mediators in the development of metastatic HCC. Taken together, our in-vivo model demonstrated that co-expression of twist1a+/kras+ in conjunction with exposure to LPS enhanced metastatic HCC offers a useful platform for the study of tumor initiation and metastasis in liver cancer.

End stage renal disease (ESRD) is a contraindication to isolated heart transplantation (HT). However, heart candidates with cardiogenic shock may experience acute kidney injury and require renal replacement therapy (RRT) and isolated HT as a life-saving operation. The outcomes, including survival and renal function, are rarely reported. We enrolled 569 patients undergoing isolated HT from 1989 to 2018. Among them, 66 patients required RRT before HT (34 transient and 32 persistent). The survival was worse in patients with RRT than those without (65.2% vs 84.7%; 27.3% vs 51.1% at 1- and 10-year, p < 0.001 and p = 0.012, respectively). Multivariate Cox analysis identified pre-transplant hyperbilirubinemia (Hazard ratio (HR) 2.534, 95% confidence interval (CI) 1.098–5.853, p = 0.029), post-transplant RRT (HR 5.551, 95%CI 1.280–24.068, p = 0.022) and post-transplant early bloodstream infection (HR 3.014, 95%CI 1.270–7.152, p = 0.012) as independent risk factors of 1-year mortality. The majority of operative survivors (98%) displayed renal recovery after HT. Although patients with persistent or transient RRT before HT had a similar long-term survival, patients with persistent RRT developed a high incidence (49.2%) of dialysis-dependent ESRD at 10 years. In transplant candidates with pretransplant RRT, hyperbilirubinemia should be carefully re-evaluated for the eligibility of HT whereas prevention and management of bloodstream infection after HT improve survival.

Computed tomography (CT)-determined skeletal muscle measures have been used for predicting postoperative outcomes in patients undergoing transcatheter aortic valve implantation (TAVI). We investigated the impact of CT-determined muscle quantity (measured as psoas muscle area [PMA] and psoas muscle index [PMI]) and quality (measured as psoas muscle density [PMD]) on hospital length of stay (LOS) after TAVI.We retrospectively identified 182 consecutive patients who underwent TAVI between March 2013 and August 2017 with adequate preprocedural CT imaging. Baseline demographic and clinical data, the Society of Thoracic Surgeons score, the essential frailty toolset (EFT) frailty rating, and precontrast PMD, PMA, and PMI were obtained in all study patients. The primary outcome was prolonged postoperative LOS defined as greater than 14 days.Patients with prolonged LOS had a significantly higher Society of Thoracic Surgeons score (p0.001) and significantly lower PMD (p0.001) than those with LOS ≤14 days. More patients with prolonged LOS had concomitant peripheral vascular disease (p = 0.001), had undergone percutaneous coronary interventions (p = 0.022), and had an EFT score ≥4 (p0.001) compared to those without prolonged LOS. Neither PMA (p = 0.123) nor PMI (p = 0.271) were associated with prolonged LOS. Multivariate analysis identified EFT score ≥4, the presence of peripheral vascular disease, and PMD as independent predictors of prolonged LOS.The precontrast CT-determined muscle quality measurement PMD is a simple and objective predictor of prolonged LOS after TAVI.

Metastasis of cancer cells is multi-step process and dissemination is an initial step. Here we report a tamoxifen-controllable Twist1a-ERT2 transgenic zebrafish line as a new animal model for metastasis research, and demonstrate that this model can serve as a novel platform for discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells. By crossing Twist1a-ERT2 with xmrk (a homolog of hyperactive form of EGFR) transgenic zebrafish, which develops hepatocellular carcinoma, approximately 80% of the double transgenic zebrafish showed spontaneous cell dissemination of mCherry-labeled hepatocytes from the liver to the entire abdomen region and the tail region. The dissemination is accomplished in 5 days through induction of an epithelial-to-mesenchymal transition. Using this model, we conducted in vivo drug screening and identified three hit drugs. One of them, adrenosterone, an inhibitor for hydroxysteroid (11-beta) dehydrogenase 1 (HSD11β1), has a suppressor effect on cell dissemination in this model. Pharmacologic and genetic inhibition of HSD11β1 suppressed metastatic dissemination of highly metastatic human cell lines in a zebrafish xenotransplantation model. Through downregulation of Snail and Slug, adrenosterone-treated cells recovered expression of E-cadherin and other epithelial markers and lost partial expression of mesenchymal markers compared with vehicle-treated cells. Taken together, our model offers a useful platform for the discovery of antimetastasis drugs targeting metastatic dissemination of cancer cells. Implications: This study describes a transgenic zebrafish model for liver tumor metastasis and it has been successfully used for identification of some drugs to inhibit metastatic dissemination of human cancer cells.

Tuberculosis (TB) has been one of top 10 leading causes of death. A computer-aided diagnosis system to accelerate TB diagnosis is crucial. In this paper, we apply convolutional neural network and deep learning to classify the images of TB culture test—the gold standard of TB diagnostic test. Since the dataset is small and imbalanced, a transfer learning approach is applied. Moreover, as the recall of non-negative class is an important metric for this application, we propose a two-stage classification method to boost the results. The experiment results on a real dataset of TB culture test (1727 samples with 16,503 images from Tao-Yuan General Hospital, Taiwan) show that the proposed method can achieve 99% precision and 98% recall on the non-negative class.

Background/Aim: Casein kinase 1 epsilon (CK1ε) is a member of the casein kinase 1 family, which includes highly conserved and ubiquitous serine/threonine protein kinases. Recent research has revealed that CK1ε plays an important role in a variety of human cancer types; however, its role in human melanoma remains unclear. The aim of this study was to elucidate the clinical role of CK1ε in patients with melanoma. Patients and Methods: Samples from 34 patients with melanoma were analyzed by immunohistochemical staining. Formalin-fixed paraffin-embedded tissue microarrays were also examined by two histopathologists to assess CK1ε protein expression in humans. Results: Cytoplasmic CK1ε protein expression was significantly lower in tumor tissue than in normal tissue. Lack of cytoplasmic CK1ε protein was significantly correlated with distant metastasis (p=0.022) and poorer survival (p=0.030). However, Kaplan-Meier survival analysis revealed that elevated expression of cytoplasmic CK1ε protein was not significantly associated with the overall survival of patients with melanoma. Univariate and multivariate analyses demonstrated that lack of cytoplasmic CK1ε protein expression was related to distant metastasis (p

Background Systemic lupus erythematosus (SLE) is associated with a higher risk of cardiovascular disease. However, it is not clear whether or not SLE is associated with poor outcomes after acute myocardial infarction (AMI). Methods and results Using the Taiwan National Health Insurance Database, we identified the SLE group as patients with AMI who have a concurrent discharge diagnosis of SLE. We also selected an age-, sex-, hospital level-, and admission calendar year-matched non-SLE group at a ratio of 1:3 from the total non-SLE group. One hundred fifty-one patients with SLE, 113,791 patients without SLE, and 453 matched patients without SLE were admitted with a diagnosis of AMI. Patients with SLE were significantly younger, predominantly female, and more likely to have chronic kidney disease than those without SLE. The in-hospital mortality rates were 12.6%, 9.0%, and 4.2% in the SLE, total non-SLE, and matched non-SLE groups, respectively. The in-hospital mortality was significantly higher in the SLE group than in the total non-SLE group (OR = 1.98; 95% CI = 1.2–3.26) and the matched non-SLE group (mortality OR = 2.20; 95% CI = 1.06–4.58). In addition, the SLE group was associated with a borderline significant risk of prolonged hospitalization when compared with the non-SLE group. Conclusion SLE is associated with a higher risk of in-hospital mortality and a borderline significantly higher risk of prolonged hospitalization after AMI.

Zika virus (ZIKV) is an emerging vector-borne virus that is associated with severe congenital cerebral anomalies in fetuses and paralytic Guillain-Barre syndrome in adults. In the current global health crisis, there are no vaccines or therapeutics available for the treatment of ZIKV infection. In the present study, we evaluated the efficacy of the protoberberine alkaloid, palmatine, in inhibiting ZIKV and Japanese encephalitis virus (JEV). Palmatine was shown to bind to restricted viruses, inhibit ZIKV infection, and resist ZIKV-induced cytopathic effects. Palmatine was also shown to inhibit JEV infection in multiple cell lines. Overall, the effects of palmatine in disrupting ZIKV binding, entry, and stability indicate that this small molecule would be a good starting point for the development of treatments aimed at inhibiting ZIKV infection.

PURPOSE This study evaluates the feasibility of our previously developed Respiratory Motion Compensation System (RMCS) combined with the Phase Lead Compensator (PLC) to eliminate system delays during the compensation of respiration-induced tumor motion. The study objective is to improve the compensation effect of RMCS and the efficay of radiation therapy to reduce its side effects to the patients. MATERIAL AND METHODS In this study, LabVIEW was used to develop the proposed software for calculating real-time adaptive control parameters, combined with PLC and RMCS for the compensation of total system delay time. Experiments of respiratory motion compensation were performed using 6 pre-recorded human respiration patterns and 7 sets of different sine waves. During the experiments, a respiratory simulation device, Respiratory Motion Simulation System (RMSS), was placed on the RMCS, and the detected target motion signals by the Ultrasound Image Tracking Algorithm (UITA) were transmitted to the RMCS, and the compensation of respiration induced motion was started. Finally, the tracking error of the system is obtained by comparing the encoder signals bwtween RMSS and RMCS. The compensation efficacy is verified by the root mean squared error (RMSE) and the system compensation rate (CR). RESULTS The experimental results show that the calcuated CR with the simulated respiration patterns is between 42.85% ∼3.53% and 33.76% ∼2.62% in the Right-Left (RL) and Superior-Inferior (SI), respectively, after the RMCS compensation of using the adaptive control parameters in PLC. For the compensation results of human respiration patterns, the CR is between 58.95% ∼8.56% and 62.87% ∼9.05% in RL and SI, respectively. CONCLUSIONS During the respiratory motion compensation, the influence of the delay time of the entire system (RMCS+RMSS+UITA) on the compensation effect was improved by adding an adaptive control PLC, which reduces compensation error and helps improve efficacy of radiation therapy.

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive deterioration of articular cartilage. There have been reports that small molecule inhibitors have anti-osteoarthritis effects; however, the effects of 3-(4-chloro-2-fluorophenyl)-6-(2,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Cm-02) and 6-(2,4-difluorophenyl)-3-(3,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Ck-02), small molecule inhibitors which share many structural similarities with quercetin (a potent anti-inflammatory flavonoid), remain unclear. In this study, TNF-α-stimulated porcine and human chondrocyte models were used to investigate the inhibitory effects of Cm-02 and Ck-02 on the molecular mechanisms underlying the anti-OA effects. TNF-α was used to stimulate porcine and human chondrocytes to mimic immunomodulatory potency in-vitro. Anti-osteoarthritic effects were characterized in terms of protein and mRNA levels associated with the pathogenesis of OA. We also examined (1) the inducible nitric oxide synthase (iNOS)-nitric oxide (NO) system in cultured chondrocytes, (2) matrix metalloproteinases (MMPs) in cultured chondrocytes, and (3) aggrecan degradation in cartilage explants. Finally, we tested the activation of nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), and activate the protein-1 (AP-1), and we tested the signal transduction and activation of transcription-3 (STAT-3). Our results indicate that, in chondrocytes, Cm-02 and Ck-02 inhibit TNF-α induced NO production, iNOS, MMP, the expression of disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the enzyme activity of MMP-13. Furthermore, both Cm-02 and Ck-02 were found to stimulate TNF-α, which has been shown to suppress the activation of several transcription factors, including NF-κB, STAT-3, and IRF-1 in porcine and human chondrocytes. Cm-02 and Ck-02 were also found to help prevent the release of proteoglycans from cartilage explants. Our findings demonstrate that both Cm-02 and Ck-02 have potent anti-inflammatory activities and the ability to protect cartilage in an OA cell model. These findings indicate that Cm-02 and Ck-02 have the potential to be further developed for the therapeutic treatment of OA.

The identification of prognostic markers for colorectal cancer (CRC) has important clinical implications. However, the association between meningioma 1 (MN1) expression and clinical outcomes of CRC has not been fully investigated. The aim of this study was to investigate the expression of MN1 in the clinical context of CRC. We first used immunohistochemistry (IHC) staining to examine and compare MN1 expression between multiple human cancer tissues and normal tissues. Initial screening revealed that the expression of MN1 proteins was significantly higher in tumor tissues of the breast, colon, and liver than in normal tissues. In further testing conducted on 59 paired CRC samples, we observed that the expression of MN1 in CRC tissue samples was significantly higher than in adjacent normal tissues. Moreover, high MN1 expression was not significantly associated with clinicopathological characteristics. Kaplan-Meier survival analysis revealed that high expression of MN1 mRNA or MN1 protein was significantly associated with poor CRC prognosis. Furthermore, univariate Cox analysis revealed that a high MN1 score was significantly associated with prognostic factors. Multivariate Cox analysis further indicated that gender, histologic grade, tumor-node-metastasis (TNM) stage, and a high MN1 score were independent factors of overall CRC survival rates. Finally, MN1 and PCNA protein levels were positively correlated, which suggests that MN1 may be involved in the cell proliferation process during CRC formation. Our results, which confirm those of other studies, indicate that (1) high levels of MN1 expression contribute to poor CRC prognosis and (2) MN1 can serve as a novel potential biomarker in predicting the prognosis of CRC patients.