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Abstract Background The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI. Methods We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S). Results Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = − 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = − 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p

Summary: Endomucin (EMCN) currently represents the only hematopoietic stem cell (HSC) marker expressed by both murine and human HSCs. Here, we report that EMCN+ long-term repopulating HSCs (LT-HSCs; CD150+CD48−LSK) have a higher long-term multi-lineage repopulating capacity compared to EMCN− LT-HSCs. Cell cycle analyses and transcriptional profiling demonstrated that EMCN+ LT-HSCs were more quiescent compared to EMCN− LT-HSCs. Emcn−/− and Emcn+/+ mice displayed comparable steady-state hematopoiesis, as well as frequencies, transcriptional programs, and long-term multi-lineage repopulating capacity of their LT-HSCs. Complementary functional analyses further revealed increased cell cycle entry upon treatment with 5-fluorouracil and reduced granulocyte colony-stimulating factor (GCSF) mobilization of Emcn−/− LT-HSCs, demonstrating that EMCN expression by LT-HSCs associates with quiescence in response to hematopoietic stress and is indispensable for effective LT-HSC mobilization. Transplantation of wild-type bone marrow cells into Emcn−/− or Emcn+/+ recipients demonstrated that EMCN is essential for endothelial cell-dependent maintenance/self-renewal of the LT-HSC pool and sustained blood cell production post-transplant.

Abstract Osteoporosis is characterized by low bone mass, bone microarchitecture disruption, and collagen loss, leading to increased fracture risk. In the current study, collagen peptides were extracted from milkfish scales (MS) to develop potential therapeutic candidates for osteoporosis. MS was used to synthesize a crude extract of fish scales (FS), collagen liquid (COL), and hydroxyapatite powder (HA). COL samples were further categorized according to the peptide size of total COL (0.1 mg/mL), COL 10 kDa (0.1 mg/mL) to determine it. Semi‐quantitative reverse transcription polymerase chain reaction (sqRT‐PCR) and immunofluorescence labeling were used to assess the expression levels of specific mRNA and proteins in vitro. For in vivo studies, mice ovariectomy (OVX)‐induced postmenopausal osteoporosis were developed, while the sham surgery (Sham) group was treated as a control. Collagen peptides (CP) from MS inhibited osteoclast differentiation in RAW264.7 cells following an insult with nuclear factor kappa‐B ligand (RANKL). CP also enhanced osteoblast proliferation in MG‐63 cells, possibly through downregulating NFATc1 and TRAP mRNA expression and upregulating ALP and OPG mRNA levels. Furthermore, COL1 kDa also inhibited bone density loss in osteoporotic mice. Taken together, CP may reduce RANKL‐induced osteoclast activity while promoting osteoblast synthesis, and therefore may act as a potential therapeutic agent for the prevention and control of osteoporosis.

Background: The European System for Cardiac Operative Risk Evaluation (EuroSCORE II) is a well-established scoring system for predicting mortality in cardiac surgery. This system was derived predominantly from a European patient cohort; however, no validation of this system has been conducted in Taiwan. We sought to assess the performance of EuroSCORE II at a tertiary centre. Methods: The 2161 adult patients receiving cardiac surgery between 2017 and 2020 in our institution were included. Results: Overall, the in-hospital mortality rate was 7.89%. The performance of EuroSCORE II was assessed using the area under the receiver operator curve (AUC) for discrimination and the Hosmer–Lemeshow (H–L) test for calibration. Data were analysed for type of surgery, risk stratification, and status of the operation.EuroSCORE II had good discriminative power (AUC=0.854, 95% Confidence Interval (CI): 0.822–0.885) and good calibration (χ2=5.19, p=0.82) for all types of surgery except ventricular assist devices (AUC=0.618, 95% CI: 0.497–0.738). EuroSCORE II also showed good calibration for most types of surgery except coronary artery bypass surgery (CABG) combined procedure (P=0.033), heart transplantation (HT) (P=0.017), and urgent operation (P=0.041). EuroSCORE II significantly underestimated the risk for CABG combined procedure and urgent operations, and overestimated the risk for HT. Conclusion: EuroSCORE II had satisfactory discrimination and calibration power to predict surgical mortality in Taiwan. However, the model is poorly calibrated for CABG combined procedure, HT, urgent operation, and, likely, lower- and higher-risk patients.

The impact of the type, purpose, and timing of prior surgery on heart transplantation (HT) remains unclear. This study investigated the influence of conventional cardiac surgery (PCCS) on HT outcomes. This study analyzed HTs performed between 1999 and 2019 at a single institution. Patients were categorized into two groups: those with and without PCCS. Short-term outcomes, including post-transplant complications and mortality rates, were evaluated. Cox proportional and Kaplan–Meier survival analyses were used to identify risk factors for mortality and assess long-term survival, respectively. Of 368 patients, 29% had PCCS. Patients with PCCS had a higher incidence of post-transplant complications. The in-hospital and 1 year mortality rates were higher in the PCCS group. PCCS and cardiopulmonary bypass time were significant risk factors for 1 year mortality (hazard ratios = 2.485 and 1.005, respectively). The long-term survival rates were lower in the PCCS group, particularly in the first year. In sub-analysis, patients with ischemic cardiomyopathy and PCCS had the poorest outcomes. The era of surgery and timing of PCCS in relation to HT did not significantly impact outcomes. In conclusion, PCCS worsen the HT outcomes, especially in patients with ischemic etiology. However, the timing of PCCS and era of HT did not significantly affect this concern.

The study analyzed the long-term survival of 1,482 eligible patients with coronary artery disease who received on-pump coronary artery bypass grafting (ONCAB) between 1997 and 2003 in Taiwan. The cumulative all-cause death rate over 23 years was 21.9%, while the cumulative cardiovascular-specific death (CVD) rate was 2.09%. Patients aged ≥ 70 years had a significantly higher incidence rate ratio (IRR) (IRR, 2.183, 95% confidence interval [CI], 1.742–2.731), but the lower cumulative incidence rate ratio (CIRR) (CIRR, 0.634, 95% CI, 0.524–0.767) for all-cause deaths than those aged < 70 years. There was no significant difference for IRR and CIRR of CVD between 2 groups. Overall survival was influenced by hypertension (hazard ratio [HR], 1.412, 95% CI, 1.104–1.806), dyslipidemia (HR, 1.890, 95% CI, 1.506–2.372), and previous stroke (HR, 0.525, 95% CI, 0.391–0.705) in all patients. Our results suggest that ONCAB may be a viable option for older patients.

The role of secretion chaperone-regulated virulence proteins in the pathogenesis of infective endocarditis (IE) induced by viridans streptococci such as Streptococcus mutans is unclear. In this study, we investigated the contribution of the foldase protein PrsA, a putative parvulin-type peptidyl-prolyl isomerase, to the pathogenesis of S. mutans-induced IE. We found that a prsA-deficient strain had reduced virulence in terms of formation of vegetation on damaged heart valves, as well as reduced autolysis activity, eDNA release and biofilm formation capacity. The secretion and surface exposure of AtlA in vitro was reduced in the prsA-deficient mutant strain, and complementation of recombinant AtlA in the culture medium restored a wild type biofilm phenotype of the prsA-deficient mutant strain. This result suggests that secretion and surface localization of AtlA is regulated by PrsA during biofilm formation. Together, these results demonstrate that S. mutans PrsA could regulate AtlA-mediated eDNA release to contribute to biofilm formation in the pathogenesis of IE.

Background: 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. Methods: 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. Results: MPO-DNA values for the Streptococci-BSI group (n = 59) were significantly higher than those for healthy controls (p 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). Conclusion: 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.

Hydrogels’ exceptional mechanical strength and skin-adhesion characteristics offer significant advantages for various applications, particularly in the fields of tissue adhesion and wearable sensors. Herein, we incorporated a combination of metal-coordination and hydrogen-bonding forces in the design of stretchable and adhesive hydrogels. We synthesized four hydrogels, namely PAID-0, PAID-1, PAID-2, and PAID-3, consisting of acrylamide (AAM), N,N′-methylene-bis-acrylamide (MBA), and methacrylic-modified dopamine (DA). The impact of different ratios of iron (III) ions to DA on each hydrogel’s performance was investigated. Our results demonstrate that the incorporation of iron–dopamine complexes significantly enhances the mechanical strength of the hydrogel. Interestingly, as the DA content increased, we observed a continuous and substantial improvement in both the stretchability and skin adhesiveness of the hydrogel. Among the hydrogels tested, PAID-3, which exhibited optimal mechanical properties, was selected for adhesion testing on various materials. Impressively, PAID-3 demonstrated excellent adhesion to diverse materials and, combined with the low cytotoxicity of PAID hydrogel, holds great promise as an innovative option for biomedical engineering applications.

With the development of sensor and communication technologies, the Internet of Things (IoT) subsystem is gradually becoming a crucial part in vehicles. It can effectively enhance functionalities of vehicles. However, new attack types are also emerging. For example, a driver with the smart key in their pocket can push the start button to start a car. At the same time, security issues in the push-to-start scenario are pervasive, such as smart key forgery. In this study, we propose a vehicle Passive Entry Passive Start (PEPS) system that adopts deep learning algorithms to recognize the driver using the electrocardiogram (ECG) signals measured on the driver's smart watch. ECG signals are used for personal identification. Smart watches, serving as new smart keys of the PEPS system, can improve convenience and security. In the experiment, we consider commercial smart watches capable of sensing ECG signals. The sample rate and precision are typically lower than those of a 12-lead ECG used in hospitals. The experimental results show that Long Short-Term Memory (LSTM) models achieve the best accuracy score for identity recognition (91%) when a single ECG cycle is used. However, it takes at least 30 min for training. The training of a personalized Auto Encoder model takes only 5 min for each subject. When 15 continuous ECG cycles are sensed and used, this can achieve 100% identity accuracy. As the personalized Auto Encoder model is an unsupervised learning one-class recognizer, it can be trained using only the driver's ECG signal. This will simplify the management of ECG recordings extremely, as well as the integration of the proposed technology into PEPS vehicles. A FIDO (Fast Identify Online)-like environment for the proposed PEPS system is discussed. Public key cryptography is adopted for communication between the smart watch and the PEPS car. The driver is first verified on the smart watch via local ECG biometric authentication, and then identified by the PEPS car. Phishing attacks, MITM (man in the middle) attacks, and replay attacks can be effectively prevented. [ABSTRACT FROM AUTHOR]

ObjectivesThis study compared transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in terms of short- and long-term effectiveness.MethodsThis retrospective cohort study based on nationwide National Health Insurance claims data and Cause of Death data focused on adult patients (n = 3,643) who received SAVR (79%) or TAVR (21%) between 2015 and 2019. Propensity score overlap weighting was applied to account for selection bias. Primary outcomes included all-cause mortality (ACM), hospitalization for heart failure, and a composite endpoint of major adverse cardiac events (MACE). Secondary outcomes included medical utilization, hospital stay, and total medical costs at index admission for the procedure and in various post-procedure periods. The Cox proportional-hazard model with competing risk was used to investigate survival and incidental health outcomes. Generalized estimation equation (GEE) models were used to estimate differences in the utilization of medical resources and overall costs.ResultsAfter weighting, the mean age of the patients was 77.98 ± 5.86 years in the TAVR group and 77.98 ± 2.55 years in the SAVR group. More than half of the patients were female (53.94%). The incidence of negative outcomes was lower in the TAVR group than in the SAVR group, including 1-year ACM (11.39 vs. 17.98%) and 3-year ACM (15.77 vs. 23.85%). The risk of ACM was lower in the TAVR group (HR [95% CI]: 0.61 [0.44–0.84]; P = 0.002) as was the risk of CV death (HR [95% CI]: 0.47 [0.30–0.74]; P = 0.001) or MACE (HR [95% CI]: 0.66 [0.46–0.96]; P = 0.0274). Total medical costs were significantly higher in the TAVR group than in the SAVR in the first year after the procedure ($1,271.89 ± 4,048.36 vs. $887.20 ± 978.51; P = 0.0266); however, costs were similar in the second and third years after the procedure. The cumulative total medical costs after the procedure were significantly higher in the TAVR group than in the SAVR group (adjusted difference: $420.49 ± 176.48; P = 0.0172).ConclusionIn this real-world cohort of patients with aortic stenosis, TAVR proved superior to SAVR in terms of clinical outcomes and survival with comparable medical utilization after the procedure.

BackgroundAlthough the COVID-19 pandemic has accelerated the adoption of telemedicine and virtual consultations worldwide, complex factors that may affect the use of virtual clinics are still unclear. ObjectiveThis study aims to identify factors associated with the utilization of virtual clinics in the experience of virtual clinic service implementation in Taiwan. MethodsWe retrospectively analyzed a total of 187,742 outpatient visits (176,815, 94.2%, in-person visits and 10,927, 5.8%, virtual visits) completed at a large general hospital in Taipei City from May 19 to July 31, 2021, after rapid implementation of virtual outpatient clinic visits due to the COVID-19 pandemic. Data of patients’ demographic characteristics, disease type, physicians’ features, and specialties/departments were collected, and physicians’ opinions regarding virtual clinics were surveyed and evaluated using a 5-point Likert scale. Multilevel analysis was conducted to determine the factors associated with the utilization of virtual clinics. ResultsPatient-/visit-, physician-, and department-level factors accounted for 67.5%, 11.1%, and 21.4% of the total variance in the utilization of virtual clinics, respectively. Female sex (odds ratio [OR] 1.27, 95% CI 1.22-1.33, P50 km, P

Abstract Acinetobacter baumannii-induced nosocomial pneumonia has become a serious clinical problem because of high antibiotic resistance rates. Antimicrobial peptides (AMP) are an ideal alternative strategy due to their broad-spectrum of antimicrobial activity and low incidence of bacterial resistance. However, their application is limited by toxicity and stability in vivo. The present study used a mouse model to directly identify potential AMPs effective for treatment of A. baumannii-induced pneumonia. Fifty-eight AMPs were screened and two identified (SMAP-29 and TP4) to have prophylactic effects which prevented the death of mice with pneumonia. Furthermore, two TP4 derivatives (dN4 and dC4) were found to have therapeutic activity in pneumonia mouse models by peritoneal or intravenous administration. Both dN4 and dC4 also inhibited and/or eliminated A. baumannii biofilms at higher doses. Taken together, these data suggest the AMP derivatives dN4 and dC4 represent a potential treatment strategy for A. baumannii-induced pneumonia.

ObjectiveCurrent guidelines recommend that transcatheter aortic valve replacement (TAVR) for bicuspid aortic valve (BAV) with aortic stenosis (AS) should only be performed in selected patients. However, we consider it even more crucial to identify what the really important factors are while determining long-term outcomes in patients with BAV undergoing TAVR, which is precisely the aim of this study.MethodsWe retrospectively evaluated consecutive patients who underwent TAVR with balloon-expandable Sapien XT or Sapien 3 valves (Edwards Lifesciences, Irvine, CA) for the treatment of severe bicuspid AS. The primary end points were major adverse cardiac and cerebral events (MACCE), that is, mortality, non-fatal myocardial infarction (MI), disabling stroke, valve failure needing reintervention, or clinically relevant valve thrombosis during follow-up.ResultsA total of 56 patients who underwent TAVR with Sapien XT (n = 20) or Sapien 3 (n = 36) were included. The device and procedural success rates were similar between the two TAVR valves; however, the newer-generation Sapien 3 yielded a trend toward better long-term clinical outcomes than the early-generation Sapien XT did (MACCE rates 35 vs. 11%, p = 0.071). In the multivariate Cox proportional hazards analyses, the presence of calcified raphe > 4 mm was the only independent predictor of long-term MACCE (hazard ratio: 6.76; 95% confidence interval: 1.21–37.67, p = 0.029).ConclusionTAVR performed by a skilled heart team, while using newer-generation balloon-expandable Sapien 3 valve, may yield better long-term clinical outcomes compared to TAVR using early-generation Sapien XT valve. Moreover, the presence of calcified raphe >4 mm is an independent determinant of adverse clinical outcomes.

Background. 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 transcatheter mitral valve (MV) in bioprosthetic MV/MV annulopasty ring implantation using the apical approach in 12 patients (pts) with co-existing left atrial appendage (LAA) and/or LA (left atrium) body thrombus, which is considered a contraindication for this procedure. Methods and Results. All pts were severely symptomatic with severe bioprosthetic MV stenosis/regurgitation except one with a previous MV annuloplasty ring and severe native MV stenosis. Thrombus in LAA and/or LA body was noted in all by 2D and 3DTEE. All were at high/prohibitive risk for redo operation and all refused surgery. Utilizing both 2D and 3DTEE, especially 3DTEE, guidewires and the prosthesis deployment system could be manipulated under direct vision into the LA avoiding any contact with the thrombus. The procedure was successful in all with amelioration of symptoms and no embolic or other complications over a mean follow-up of 21 months. Conclusion. Our study demonstrates the feasibility of successfully performing this procedure in pts with thrombus in LAA and/or LA body without any complications.

Open-heart patients often experience sleep problems postoperatively. This cross-sectional study is aimed to investigate open-heart patients’ sleep quality and its influencing factors during intensive care. A consecutive sample of 117 eligible open-heart patients was recruited from an intensive care unit (ICU) of a general hospital. Data were collected using questionnaires. The respondents were 22–88 years, with a median age of 60.25 (13.51). Seventy-nine (67.5%) respondents were male. Most respondents reported a low-to-moderate postoperative pain level (average pain score = 2.02; range: 0–10). The average anxiety score was 4.68 (standard deviation [SD] = 4.2), and the average depression score was 6.91 (SD = 4.52; range: 0–21). The average sleep efficiency index was 70.4% (SD = 10.74%). Most (95.7%) respondents had a sleep efficiency index below 85%, indicating that most patients did not sleep well in the ICU. Linear regression analysis showed that the key predictors of the sleep quality of open-heart patients in the ICU were wound pain (β = −1.9) and noise disturbance (β = −1.86). These results provide information on sleep quality and the factors affecting postoperative patients in the ICU. These findings can be used as a reference for developing relevant interventions.

Complete blood cell (CBC) counting has played a vital role in general medical examination. Common approaches, such as traditional manual counting and automated analyzers, were heavily influenced by the operation of medical professionals. In recent years, computer-aided object detection using deep learning algorithms has been successfully applied in many different visual tasks. In this paper, we propose a deep neural network-based architecture to accurately detect and count blood cells on blood smear images. A public BCCD (Blood Cell Count and Detection) dataset is used for the performance evaluation of our architecture. It is not uncommon that blood smear images are in low resolution, and blood cells on them are blurry and overlapping. The original images were preprocessed, including image augmentation, enlargement, sharpening, and blurring. With different settings in the proposed architecture, five models are constructed herein. We compare their performance on red blood cells (RBC), white blood cells (WBC), and platelet detection and deeply investigate the factors related to their performance. The experiment results show that our models can recognize blood cells accurately when blood cells are not heavily overlapping.

Purpose: In this study, transapical transcatheter mitral valve-in-valve implantation (TAMVI) was compared with surgical redo mitral valve replacement (SRMVR) in terms of clinical outcomes.Methods: We retrospectively identified patients with degenerated mitral bioprosthesis or failed annuloplasty rings who underwent redo SRMVR or TAMVI at our medical center. Clinical outcomes were based on echocardiography results.Results: We retrospectively identified patients with symptomatic mitral bioprosthetic valve dysfunction (n = 58) and failed annuloplasty rings (n = 14) who underwent redo SRMVR (n = 36) or TAMVI (n = 36). The Society of Thoracic Surgeons Predicted Risk of Mortality scores were higher in the TAMVI group (median: 9.52) than in the SRMVR group (median: 5.59) (p-value = 0.02). TAMVI patients were more severe in New York Heart Association (p-value = 0.04). The total procedure time (skin to skin) and length of stay after procedures were significantly shorter in the TAMVI group, and no significant difference in mortality was noted after adjustment for confounding factors (p-value = 0.11). The overall mean mitral valve pressure gradient was lower in the TAMVI group than in the SRMVR group at 24 months (p < 0.01). Both groups presented a decrease in the severity of mitral and tricuspid regurgitation at 3–24 months.Conclusions: In conclusion, the statistical analysis is still not robust enough to make a claim that TAMVI is an appropriate alternative. The outcome of the patient appears only to be related to the patient's pre-operative STS score. Additional multi-center, longitudinal studies are warranted to adequately assess the effect of TAMVI.

Osteoporosis is characterized by low bone mass, bone microarchitecture disruption, and collagen loss, leading to increased fracture risk. In the current study, collagen peptides were extracted from milkfish scales (MS) to develop potential therapeutic candidates for osteoporosis. MS was used to synthesize a crude extract of fish scales (FS), collagen liquid (COL), and hydroxyapatite powder (HA). COL samples were further categorized according to the peptide size of total COL (0.1 mg/mL), COL < 1 kDa (0.1 mg/mL), COL: 1–10 kDa (0.1 mg/mL), and COL > 10 kDa (0.1 mg/mL) to determine it. Semi‐quantitative reverse transcription polymerase chain reaction (sqRT‐PCR) and immunofluorescence labeling were used to assess the expression levels of specific mRNA and proteins in vitro. For in vivo studies, mice ovariectomy (OVX)‐induced postmenopausal osteoporosis were developed, while the sham surgery (Sham) group was treated as a control. Collagen peptides (CP) from MS inhibited osteoclast differentiation in RAW264.7 cells following an insult with nuclear factor kappa‐B ligand (RANKL). CP also enhanced osteoblast proliferation in MG‐63 cells, possibly through downregulating NFATc1 and TRAP mRNA expression and upregulating ALP and OPG mRNA levels. Furthermore, COL1 kDa also inhibited bone density loss in osteoporotic mice. Taken together, CP may reduce RANKL‐induced osteoclast activity while promoting osteoblast synthesis, and therefore may act as a potential therapeutic agent for the prevention and control of osteoporosis. [ABSTRACT FROM AUTHOR]

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 xmrk in zebrafish. Progressive disruption of intestinal structure was found in the tumor fish, displaying villus damage, thinning of bowel wall, increase in goblet cell number, decrease in goblet cell size and infiltration of eosinophils, most of which were observed phenotypes of an inflammatory intestine. Intestinal epithelial cell renewal was also disrupted, with decreased cell proliferation and increased cell death. Analysis of intestinal gene expression through RNA-seq suggested deregulation of genes related to intestinal function, epithelial barrier and homeostasis and activation of pathways in inflammation, epithelial mesenchymal transition, extracellular matrix organization, as well as hemostasis. Gene set enrichment analysis showed common gene signatures between the intestine of liver tumor fish and human inflammatory bowel disease, the association of which with cancer has been recently noticed. Overall, this study represented the first systematic characterization of the disruption of intestine under the liver tumor condition and suggested targeting intestinal inflammation as a potential approach for managing cancer cachexia.

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.

Tumor hypoxia is a hallmark of solid tumors and emerged as the therapeutic target for cancer treatments, such as a prodrug Tirapazamine (TPZ) activated in hypoxia. To increase tumor accumulation, gold nanoparticles (GNPs) were selected to conjugate with TPZ. In this study, we successfully formulated and assessed the biochemical and therapeutic roles of the conjugated gold nanoparticles–Tirapazamine (GNPs–TPZ) on therapeutic assessments of MKN45-induced xenograft animal model. The results indicated that GNPs–TPZ was a potential nanomedicine for selectively targeting hypoxia tumors coupled with decreased side effects on healthy tissue or organs. TPZ significantly reduced cell viability of hypoxic gastric cancer MKN45 cells, but not in cells incubated in normoxia condition. For improving tumor targeting efficiency, furthermore, the GNPs drug carrier was conjugated to TPZ via biding mediator bovine serum albumin (BSA), and we demonstrated that this conjugated GNPs–TPZ retained the unique characteristics of hypoxic toxin and possessed the adequate feature of systemic bio-distributions in animals. GNPs–TPZ nanoparticles revealed their superior affinity to hypoxia tumors in the MKN45 xenograft. Moreover, GNPs–TPZ treatments did not significantly alter the biochemical parameters of blood samples acquired from animals. Taken together, TPZ, a prodrug activated by hypoxia, was conjugated with GNPs, whereas BSA severed as an excellent binding agent for preparing the conjugated GNPs–TPZ nanomedicines. We demonstrated that GNPs–TPZ enhanced tumor targeting, resulting in higher therapeutic efficacy compared to TPZ. We suggest that it may sever as an adjuvant treatment or combined therapy with other chemotherapeutics for the treatment of cancer patients in the future.

KRAS mutations are a major risk factor in colorectal cancers. In particular, a point mutation of KRAS of amino acid 12, such as KRAS V12, renders it stable activity in oncogenesis. We found that krasV12 promotes intestinal carcinogenesis by generating a transgenic zebrafish line with inducible krasV12 expression in the intestine, Tg(ifabp:EGFP-krasV12). The transgenic fish generated exhibited significant increases in the rates of intestinal epithelial outgrowth, proliferation, and cross talk in the active Ras signaling pathway involving in epithelial-mesenchymal transition (EMT). These results provide in vivo evidence of Ras pathway activation via krasV12 overexpression. Long-term transgenic expression of krasV12 resulted in enteritis, epithelial hyperplasia, and tubular adenoma in adult fish. This was accompanied by increased levels of the signaling proteins p-Erk and p-Akt and by downregulation of the EMT marker E-cadherin. Furthermore, we also observed a synergistic effect of krasV12 expression and dextran sodium sulfate treatment to enhance intestinal tumor in zebrafish. Our results demonstrate that krasV12 overexpression induces intestinal tumorigenesis in zebrafish, which mimics intestinal tumor formation in humans. Thus, our transgenic zebrafish may provide a valuable in vivo platform that can be used to investigate tumor initiation and anticancer drugs for gastrointestinal cancers.

Bacterial extracellular DNA (eDNA) and activated platelets have been found to contribute to biofilm formation by Streptococcus mutans on injured heart valves to induce infective endocarditis (IE), yet the bacterial component directly responsible for biofilm formation or platelet adhesion remains unclear. Using in vivo survival assays coupled with microarray analysis, the present study identified a LiaR-regulated PspC domain-containing protein (PCP) in S. mutans that mediates bacterial biofilm formation in vivo. Reverse transcriptase- and chromatin immunoprecipitation-polymerase chain reaction assays confirmed the regulation of pcp by LiaR, while PCP is well-preserved among streptococcal pathogens. Deficiency of pcp reduced in vitro and in vivo biofilm formation and released the eDNA inside bacteria floe along with reduced bacterial platelet adhesion capacity in a fibrinogen-dependent manner. Therefore, LiaR-regulated PCP alone could determine release of bacterial eDNA and binding to platelets, thus contributing to biofilm formation in S. mutans-induced IE.

Introduction Optimal antithrombotic strategy following transcatheter aortic valve replacement (TAVR) is still unknown. We hypothesised that the direct factor Xa inhibitor edoxaban can potentially prevent subclinical leaflet thrombosis and cerebral embolisation compared with conventional dual antiplatelet therapy (DAPT) in patients undergoing TAVR.Methods and analysis The ADAPT-TAVR trial is an international, multicentre, randomised, open-label, superiority trial comparing edoxaban-based strategy and DAPT strategy in patients without an indication for oral anticoagulation who underwent successful TAVR. A total of 220 patients are randomised (1:1 ratio), 1–7 days after successful TAVR, to receive either edoxaban (60 mg daily or 30 mg daily if patients had dose-reduction criteria) or DAPT using aspirin (100 mg daily) plus clopidogrel (75 mg daily) for 6 months. The primary endpoint was an incidence of leaflet thrombosis on four-dimensional, volume-rendered cardiac CT imaging at 6 months post-TAVR. The key secondary endpoints were the number of new lesions and new lesion volume on brain diffusion-weighted MRI and the changes in neurological and neurocognitive function assessment between immediate post-TAVR and 6 months of study drug administration. Detailed clinical information on thromboembolic and bleeding events were also assessed.Ethics and dissemination Ethic approval has been obtained from the Ethics Committee/Institutional Review Board of Asan Medical Center (approval number: 2017–1317) and this trial is also approved by National Institute of Food and Drug Safety Evaluation of Republic of Korea (approval number: 31511). Results of this study will be disseminated in scientific publication in reputed journals.Trial registration number NCT03284827.

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.

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.

Fractional flow reserve (FFR)-guided percutaneous coronary intervention has shown favorable long-term clinical outcomes. However, limited data exist evaluating the FFR assessment among the chronic kidney disease (CKD) population. The aim of this study was to evaluate the long-term clinical outcomes of FFR-guided coronary revascularization in patients with CKD. A total of 242 CKD patients who underwent FFR assessment were retrospectively analyzed. Patients were divided into two groups: revascularization (FFR ≤ 0.80) and non-revascularization (FFR > 0.80). The primary endpoint was the composite of cardiac death, non-fatal myocardial infarction, and target vessel failure (TVF). The key secondary endpoint was TVF. The Cox regression model was used for risk evaluation. With 91% of the ischemic vessels revascularized, the revascularization group had higher risks for both the primary endpoint (adjusted hazard ratio [aHR]: 2.06; 95% confidence interval [CI], 1.07–3.97; p = 0.030) and key secondary endpoint (aHR: 2.19, 95% CI: 1.10–4.37; p = 0.026), during a median follow-up of 2.9 years. This result was consistent among different CKD severities. In patients with CKD, functional ischemia in coronary artery stenosis was associated with poor clinical outcomes despite coronary revascularization.