Applications, challenges, and prospects of induced pluripotent stem cells for vascular disease.

Vascular disease, including heart disease, stroke, and peripheral arterial disease, is one of the leading causes of death and disability and represents a significant global health issue. Since the development of human induced pluripotent stem cells (hiPSCs) in 2007, hiPSCs have provided unique and tremendous opportunities for studying human pathophysiology, disease modeling, and drug discovery in the field of regenerative medicine. In this review, we discuss vascular physiology and related diseases, the current methods for generating vascular cells (eg, endothelial cells, smooth muscle cells, and pericytes) from hiPSCs, and describe the opportunities and challenges to the clinical applications of vascular organoids, tissue-engineered blood vessels, and vessels-on-a-chip. We then explore how hiPSCs can be used to study and treat inherited vascular diseases and discuss the current challenges and future prospects. In the future, it will be essential to develop vascularized organoids or tissues that can simultaneously undergo shear stress and cyclic stretching. This development will not only increase their maturity and function but also enable effective and innovative disease modeling and drug discovery.

Mechano-inhibition of endocytosis sensitizes cancer cells to Fas-induced Apoptosis.

The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.

hMAGEA2 Accelerates the Progression of Prostate Cancer via the EFNA3-Erk1/2 Signaling Pathway.

BACKGROUND/AIM: Human melanoma-associated antigen A2 (hMAGEA2) family members play several roles in many types of cancer and have been explored as potential prognostic markers. In this study, we investigated the molecular mechanism underlying hMAGEA2-mediated tumorigenesis of prostate cancer. MATERIALS AND METHODS: Immunohistochemistry and western blot were used to assess protein expression whereas microarray and quantitative reverse transcription-PCR determined mRNA expression. CCK-8 assay was used to determine cell proliferation. Colony formation assay was used to examine tumorigenesis. Migration and invasion were examined using a transwell assay. Propidium iodide (PI)/Annexin V double staining was performed to measure apoptosis. Transcriptional activity was measured using Dual-luciferase reporter assay. RESULTS: hMAGEA2 was highly over-expressed in human prostate cancer tissues compared to benign prostatic hyperplasia tissues. To elucidate its biological function in prostate cancer, we established two stable hMAGEA2-knockdown prostate cancer cell lines, PC3M and 22RV1, and found that they presented significantly decreased proliferation, anchorage-independent colony formation, migration, and invasion. As hMAGEA2 knockdown suppressed prostate cancer cell growth, we examined its potential influence on tumor apoptosis. hMAGEA2-knockdown cell lines displayed early apoptosis. Moreover, knockdown of hMAGEA2 resulted in the down-regulation of EFNA3 expression. Luciferase assay showed that hMAGEA2 bound to the EFNA promoter region and regulated its transcription. Down-regulation of EFNA3 expression led to decreased Ras/Braf/MEK/Erk1/2 phosphorylation and, consequently, inhibited prostate cancer progression. CONCLUSION: hMAGEA2 promotes prostate cancer growth, metastasis, and tumorigenesis by regulating the EFNA3-Erk1/2 signaling pathway, indicating its potential as a therapeutic marker for prostate cancer.

De Novo Elastin Assembly Alleviates Development of Supravalvular Aortic Stenosis-Brief Report.

BACKGROUND: A series of incurable cardiovascular disorders arise due to improper formation of elastin during development. Supravalvular aortic stenosis (SVAS), resulting from a haploinsufficiency of ELN, is caused by improper stress sensing by medial vascular smooth muscle cells, leading to progressive luminal occlusion and heart failure. SVAS remains incurable, as current therapies do not address the root issue of defective elastin. METHODS: We use SVAS here as a model of vascular proliferative disease using both human induced pluripotent stem cell-derived vascular smooth muscle cells and developmental Eln+/- mouse models to establish de novo elastin assembly as a new therapeutic intervention. RESULTS: We demonstrate mitigation of vascular proliferative abnormalities following de novo extracellular elastin assembly through the addition of the polyphenol epigallocatechin gallate to SVAS human induced pluripotent stem cell-derived vascular smooth muscle cells and in utero to Eln+/- mice. CONCLUSIONS: We demonstrate de novo elastin deposition normalizes SVAS human induced pluripotent stem cell-derived vascular smooth muscle cell hyperproliferation and rescues hypertension and aortic mechanics in Eln+/- mice, providing critical preclinical findings for the future application of epigallocatechin gallate treatment in humans.

An Ultrasoft and Flexible PDMS-Based Balloon-Type Implantable Device for Controlled Drug Delivery.

Non-biodegradable implants have undergone extensive investigation as drug delivery devices to enable advanced healthcare toward personalized medicine. However, fibroblast encapsulation is one of the major challenges in all non-biodegradable implants, besides other challenges such as high initial burst, risk of membrane rupture, high onset time, non-conformal contact with tissues, and tissue damage. To tackle such challenges, we propose a novel ultrasoft and flexible balloon-type drug delivery device for unidirectional and long-term controlled release. The ultrasoft balloon-type device (USBD) was fabricated by using selective bonding between 2 polydimethylsiloxane (PDMS) membranes and injecting a fluid into the non-bonded area between them. The balloon acted as a reservoir containing a liquid drug, and at the same time, the membrane of the balloon itself acted as the pathway for release based on diffusion. The release was modulated by tuning the thickness and composition of the PDMS membrane. Regardless of the thickness and composition, all devices exhibited zero-order release behavior. The longest zero-order release and nearly zero-order release were achieved for 30 days and 58 days at a release rate of 1.16 µg/day and 1.68 µg/day, respectively. In vivo evaluation was performed for 35 days in living rats, where the USBD maintained zero-order and nearly zero-order release for 28 days and 35 days, respectively. Thanks to the employment of ultrasoft and flexible membranes and device design, the USBD could achieve minimal tissue damage and foreign body responses. It is expected that the proposed device may provide a novel approach for long-term drug delivery with new therapeutic modalities.

Association Between Atrial Fibrillation Symptoms and Clinical Outcomes: A Prospective Multicenter Registry Study.

The presence of symptoms plays an important role in determining whether to focus on rhythm control or rate control when treating atrial fibrillation (AF). Previous comparative studies on the clinical outcomes of symptomatic and asymptomatic AF have yielded inconsistent results, and a link between AF symptoms and left atrial (LA) remodeling is not established. Patients selected from the COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, which is a prospective, multicenter study consisting of patients with non-valvular AF, were grouped into 2 groups: symptomatic and asymptomatic. The primary outcome was a composite of the following cardiovascular outcomes: all-cause death, ischemic stroke, transient ischemic attack, systemic embolism, myocardial infarction, and heart failure hospitalization. Of 10,210 patients with AF, 4,327 (42%) had symptomatic AF. The asymptomatic group had an older mean age, more men, and more patients with hypertension and diabetes mellitus than the symptomatic group. The asymptomatic group had a larger left atrium (LA) diameter (43.6 vs 42.2 mm, p <0.001) than the symptomatic group. During a median follow-up of 32.9 (29.5 to 36.4) months, the asymptomatic and symptomatic groups showed similar incidences of the primary outcome (1.44 vs 1.45 per 100 person-years; log-rank, p = 0.8). In conclusion, the absence of AF symptoms is associated with increased LA. However, symptomatic and asymptomatic patients with AF have a similar risk of cardiovascular outcomes. This suggests that beneficial treatment for AF may be considered regardless of whether patients have symptomatic or asymptomatic AF.

Boosting Alkaline Hydrogen Oxidation Activity of Ru Single-Atom Through Promoting Hydroxyl Adsorption on Ru/WC1- x Interfaces.

The sluggish kinetics of the hydrogen oxidation reaction (HOR) in alkaline conditions continue to pose a significant challenge for the practical implementation of anion-exchange membrane fuel cells. Developing single-atom catalysts can accelerate the pace of new HOR catalyst discovery for highly cost-effective and active HOR performance. However, single-atom catalysts (SACs) for the alkaline HOR have rarely been reported, and fundamental studies on the rational design of SACs are still required. Herein, the design of Ru SAC supported on the tungsten carbide (Ru SA/WC1- x ) via in situ high-temperature annealing strategy is reported. The resulting Ru SA/WC1- x catalyst exhibits remarkably enhanced HOR performance in alkaline media, a level of activity that can not be achieved with carbon-supported Ru SAC. Electrochemical results and density functional theory demonstrate that promoting the hydroxyl adsorption on Ru SA/WC1- x interfaces, which is derived from the low potential of zero charge of WC1- x support, has a significant effect on enhancing the HOR performance of SACs. This enhancement leads to 5.8 and 60.1 times higher Ru mass activity of Ru SA/WC1- x than Ru nanoparticles on carbon and Ru single-atom on N-doped carbon, respectively. This work provides new insights into the design of highly active SACs for alkaline HOR.

Decreased SMP30 Expression Is Related With EMT in the Kidneys of Two Siberian Tigers With CKD.

BACKGROUND/AIM: Chronic kidney disease (CKD) is one of the most common causes of mortality in wild non-domestic felidae. The molecular mechanism regulating renal fibrosis in nephropathy is not fully understood especially in the felidae. This study aimed to elucidate senescence marker protein 30 (SMP30) expression patterns and its relationship with epithelial-mesenchymal transition (EMT) by immunostaining in two necropsied Siberian tigers (Panthera tigris altaica) with CKD. MATERIALS AND METHODS: Two kidney samples from male Siberian tigers were fixed and tissue sections were stained for histopathological assay. RESULTS: In CKD, renal tubular epithelial cells lost their tubular structures surrounded by severe interstitial fibrosis and were detached from the basement membrane. These damaged cells resembled the morphology of mesenchymal cells and showed much lower SMP30 expression compared with intact tubular epithelial cells. These cells also expressed vimentin, which is specifically expressed by mesenchymal cells, and through double staining, it was observed that vimentin was expressed in the tubular epithelial cells where SMP30 was not expressed. In addition, double-positive expression of pan-cytokeratin (pan-CK) and vimentin was found in damaged epithelial cells with mesenchymal features. CONCLUSION: We demonstrated possible evidence to understand the role of SMP30 as a new pivotal factor and the possibility of decreased SMP30 as a potential indicator of EMT at the end stage of CKD.

Electrocardiography score based on the Minnesota code classification system predicts cardiovascular mortality in an asymptomatic low-risk population.

BACKGROUND: The use of a single abnormal finding on electrocardiography (ECG) is not recommended for stratifying the risk of cardiovascular (CV) events in low-risk general populations because of its low discriminative power. However, the value of a scoring system containing multiple abnormal ECG findings for predicting CV death has not been sufficiently evaluated. METHODS: In a prospective community-based cohort study, 8417 participants without atherosclerotic CV diseases (ASCVDs) and any related symptoms were followed for 18 years. The standard 12-lead ECGs were recorded at baseline and the ECG findings were categorized using the Minnesota code classification. CV deaths were defined as death from myocardial infarction (MI), chronic ischemic heart disease, heart failure, fatal arrhythmia, cerebrovascular event, pulmonary thromboembolism, peripheral vascular disease and sudden cardiac arrest and identified using the Korean National Statistical Office (KOSTAT) database. RESULTS: In a multivariate Cox proportional hazard (CPH) model, major and minor ST-T wave abnormalities, atrial fibrillation (AF), Q waves in the anterior leads, the lack of Q waves in the posterior leads, high amplitudes of the left and right precordial leads, left axis deviation and sinus tachycardia were associated with higher risks of CV deaths. The ECG score consisted of these findings showed modest predictive values represented by C-statistics that ranged from 0.632 to 760 during the follow-up and performed better in the early follow-up period. The ECG score independently predicted CV death after adjustment for relevant covariates in a multivariate model, and improved the predictive performance of the 10-year ASCVD risk estimator and a model of conventional risk factors including age, diabetes and current smoking. The combined ECG score (Harrell's C-index: 0.852, 95% confidence interval [CI], 0.828-0.876) composed of the ECG score and the conventional risk factors outperformed the 10-year ASCVD risk estimator (Harrell's C-index: 0.806; 95% CI, 0.780-0.833) and the model of the conventional risk factors (Harrell's C-index: 0.841, 95% CI, 0.817-0.865) and exhibited an excellent goodness of fit between the predicted and observed probabilities of CV death. CONCLUSIONS: The ECG score could be useful to predict CV death independently and may add value to the conventional CV risk estimators regarding the risk stratification of CV death in asymptomatic low-risk general populations.

The ECG score based on the Minnesota code classification can independently predict CV death and significantly improve the predictive power of the conventional CV risk estimators in asymptomatic low-risk general population.The combined ECG score comprised the ECG score, age and the presence of diabetes and current smoking predicted CV mortality more accurately than the conventional SV risk estimators.ECG may still be a viable CV risk stratification tool for population-based health screening projects.

Multiple Hepatic Lipoma: A Case Report of Captive Hill Mynah with Iron Storage Disease.

The present case describes multiple hepatic lipomas in a common hill mynah (Gracula religiosa). A 21-year-old female captive common hill mynah died without any notable clinical symptoms. An autopsy and histopathological examinations were conducted to determine the exact cause of death. On gross observation, the liver demonstrated a yellowish white surface color and multiple nodules indicating neoplastic lesions. Histopathological assessment found that the nodules purely comprised mature adipocytes. Furthermore, the liver exhibited an excessive accumulation of iron in hepatocytes and Kupffer cells and the infiltration of chronic inflammatory cells, suggesting iron storage disease (ISD). Based on the results, the present case was diagnosed as multiple hepatic lipomas with ISD. To the authors' best knowledge, multiple hepatic lipomas accompanying ISD lesions have not been reported previously. Hence, the present case is the first case report of hepatic multiple lipomas with ISD in veterinary medicine.

Case report: Fatal neonatal sepsis associated with Escherichia fergusonii infection in a common bottlenose dolphin (Tursiops truncatus).

A 25-day-old male common bottlenose dolphin (Tursiops truncatus) died suddenly while swimming at a dolphinarium. The gross examination revealed ulceration on the dorsal and pectoral fins and rostrum. Severe congestion, hemorrhage, and edema were observed in the gastrointestinal tract, liver, mesenteric lymph nodes, lungs, and kidneys. Fibrinosuppurative arthritis of the atlantooccipital joint and extension of fibrin into the spinal canal caused compression of the spinal cord. Histopathological examination revealed tracheitis, fibrinosuppurative bronchopneumonia and enteritis. In the central nervous system, meningeal vessel congestion in the brain, and intraparenchymal hemorrhages with neurodegeneration were observed in the spinal cord. Based on the histopathological findings, representative samples, including lung, liver, mesenteric lymph node, blood obtained from the jugular vein, and fluid sample of the ascites, were inoculated on tryptic soy agar and blood agar for routine bacterial isolation. Each isolated bacterial colony was streaked aseptically onto tryptic soy agar and blood agar for pure culture. After then, polymerase chain reaction (PCR) was performed for further identification of pathogenic microorganisms. PCR identified Escherichia fergusonii, Shewanella haliotis, Enterococcus faecalis, and Staphylococcus schleiferi. E. fergusonii was considered the primary etiologic agent in this case since it was the only species identified in all representative samples. The cause of death in this animal was E. fergusonii sepsis. To the best of our knowledge, this is the first case of neonatal sepsis associated with E. fergusonii infection in a dolphin, and suggests E. fergusonii as an opportunistic pathogen associated with sepsis in dolphins.

Comparative Bleeding Risk in Patients with Atrial Fibrillation with Cancer versus Without Cancer from Nationwide Prospective Cohort.

Comparison of the bleeding risk for long-term oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (AF) with and without cancers has been inconsistent. This study aimed to clarify the differences in the bleeding risk in patients with AF with cancers and those without cancers during the long-term OAC.The CODE-AF prospective registry enrolled 5,902 consecutive patients treated for AF at 10 tertiary referral centers in Korea. Of the enrolled patients, 464 (7.8%) were diagnosed with cancers and were followed for all stroke and bleeding events (net composite events).The age, CHA2DS2-VASC, and HAS-BLED scores were similar between AF patients with and without cancers. Male population greatly comprised patients with AF with cancers. They were equally prescribed with direct OAC compared to those without cancers. The incidence rate for clinically relevant nonmajor (CRNM) bleeding events was higher in the patients with AF with cancers than in those without cancers (4.4 per 100 person-years versus 2.8 per 100 person-years, P = 0.023), and net composite events were also more frequent in patients with AF with cancers than in those without cancers (6.4 per 100 person-years versus 4.0 per 100 person-years, P = 0.004). Patients with AF with cancers showed a significantly higher rate of CRNM bleeding (hazard ratio [HR] 1.54, confidence interval [CI] 1.05-2.25, P = 0.002) than those without cancers.Based on the AF cohort, AF with cancers could face a significantly higher risk for CRNM bleeding events in the long-term OAC than those without cancers.

The anti-platelet activity of panaxadiol fraction and panaxatriol fraction of Korean Red Ginseng in vitro and ex vivo.

Background: The anti-platelet activity of the saponin fraction of Korean Red Ginseng has been widely studied. The saponin fraction consists of the panaxadiol fraction (PDF) and panaxatriol fraction (PTF); however, their anti-platelet activity is yet to be compared. Our study aimed to investigate the potency of anti-platelet activity of PDF and PTF and to elucidate how well they retain their anti-platelet activity via different administration routes. Methods: For ex vivo studies, Sprague-Dawley rats were orally administered 250 mg/kg PDF and PTF for 7 consecutive days before blood collection via cardiac puncture. Platelet aggregation was conducted after isolation of the washed platelets. For in vitro studies, washed platelets were obtained from Sprague-Dawley rats. Collagen and adenosine diphosphate (ADP) were used to induce platelet aggregation. Collagen was used as an agonist for assaying adenosine triphosphate release, thromboxane B2, serotonin, cyclic adenosine monophosphate, and cyclic guanosine monophosphate (cGMP) release. Results: When treated ex vivo, PDF not only inhibited ADP and collagen-induced platelet aggregation, but also upregulated cGMP levels and reduced platelet adhesion to fibronectin. Furthermore, it also inhibited Akt phosphorylation induced by collagen treatment. Panaxadiol fraction did not exert any anti-platelet activity in vitro, whereas PTF exhibited potent anti-platelet activity, inhibiting ADP, collagen, and thrombin-induced platelet aggregation, but significantly elevated levels of cGMP. Conclusion: Our study showed that in vitro and ex vivo PDF and PTF treatments exhibited different potency levels, indicating possible metabolic conversions of ginsenosides, which altered the content of ginsenosides capable of preventing platelet aggregation.

Insight into Defect Engineering of Atomically Dispersed Iron Electrocatalysts for High-Performance Proton Exchange Membrane Fuel Cell.

Atomically dispersed and nitrogen coordinated iron catalysts (Fe-NCs) demonstrate potential as alternatives to platinum-group metal (PGM) catalysts in oxygen reduction reaction (ORR). However, in the context of practical proton exchange membrane fuel cell (PEMFC) applications, the membrane electrode assembly (MEA) performances of Fe-NCs remain unsatisfactory. Herein, improved MEA performance is achieved by tuning the local environment of the Fe-NC catalysts through defect engineering. Zeolitic imidazolate framework (ZIF)-derived nitrogen-doped carbon with additional CO2 activation is employed to construct atomically dispersed iron sites with a controlled defect number. The Fe-NC species with the optimal number of defect sites exhibit excellent ORR performance with a high half-wave potential of 0.83 V in 0.5 M H2 SO4 . Variation in the number of defects allows for fine-tuning of the reaction intermediate binding energies by changing the contribution of the Fe d-orbitals, thereby optimizing the ORR activity. The MEA based on a defect-engineered Fe-NC catalyst is found to exhibit a remarkable peak power density of 1.1 W cm-2 in an H2 /O2 fuel cell, and 0.67 W cm-2  in an H2 /air fuel cell, rendering it one of the most active atomically dispersed catalyst materials at the MEA level.

Disrupted intestinal mucosal barrier mediated by alcohol consumption aggravates systemic microplastic accumulation.

Waste plastics are degraded into microplastics (MPs), which are easily accumulated in the human body through digestive tracts, via the food chain. Alcohol is a widely consumed chemical throughout the world with the ability to alter the intestinal barrier. For this reason, this study was aimed to investigate exact relevance between alcohol consumption and organ distributions of MPs in an ethanol feeding animal model characterized by disrupted intestinal mucosal barriers. In this study, C57BL/6 mice were separated into control, control + MP, ethanol (EtOH), and EtOH + MP groups. Mice in the EtOH group ingested a Lieber-DeCarli diet containing EtOH. Mice in the MP groups ingested 0.1 mg/kg fluorophore polymerized polystyrene microplastics via oral gavage polystyrene MPs via oral gavage. The EtOH + MP group showed higher MP accumulation in the liver than the control + MP group. The same pattern was observed in the intestines, spleen, and brain. This pattern was more prominent in the intestines, with the EtOH + MP group showing the most severe damage due to EtOH ingestion. This result suggests that the intestinal mucosa disruption caused by EtOH ingestion exacerbates MP accumulation in the organs. Moreover, hepatic steatosis was more severe in the EtOH + MP group than in the EtOH group, suggesting the secondary manifestation mediated by MP accumulation. This study reports a novel MP accumulation pattern in the body by providing novel insights into alcohol-induced gut permeability and microplastics toxicity from the perspective of gut-liver axis.

Considerations on the methane correction factor and fraction of methane parameters in the IPCC first-order decay model for active aeration landfills.

Understanding the behavior of organic carbon in municipal solid waste landfills is a major challenge for estimating methane (CH4) emissions using the Intergovernmental Panel on Climate Change (IPCC) first-order decay (FOD) model. According to the IPCC guidelines, the default values of CH4 correction factor (MCF) and fraction of CH4 (F) for active aeration landfills are set as 0.4 and 0.5, respectively. However, whether it is reasonable to apply the default values of MCF and F to active aeration landfills is questionable. This study aims to estimate the MCF and develop a method to determine the F value for active aeration landfills. In this investigation, three landfill sites were operated as active aeration landfills to estimate the MCF and the F. The study results indicate that MCF values were lower than the default value of 0.4 provided in the IPCC guidelines under aerobic conditions with a CH4 concentration of less than 5%. According to the carbon balance analyses, there was a mismatch between the theoretical CH4/CO2 ratio based on the F default value of 0.5 and the measured CH4/CO2 ratio. Using the F calculation method proposed in this study, the theoretical CH4/CO2 ratio and the measured CH4/CO2 ratio was calculated equally. The F values during air injection ranged from 0.25 to 0.93 at three landfill sites, suggesting that adapting the F default value of 0.5 for active aeration landfills may lead to significant errors in the estimation of CH4 emissions using the IPCC FOD model.

Rhythm Control and Cardiovascular or Cerebrovascular Outcomes in Patients with Atrial Fibrillation: A Study of the CODE-AF Registry.

BACKGROUND: It is not clear whether the data regarding rhythm control during atrial fibrillation (AF) contained in AF registries is prognostically significant. Thus, this study investigated the relationship between rhythm control and cardiovascular outcomes in patients in contemporary AF registries. METHODS: This study was conducted using data from 6670 patients with AF receiving oral anticoagulation in the CODE-AF registry. We used propensity overlap weighting to account for differences in baseline characteristics between the rhythm control and rate control groups. The primary outcome was a composite of the rate of death due to cardiovascular causes, stroke, acute coronary syndrome, and heart failure. The secondary outcomes were individual components of the primary outcome. RESULTS: In the CODE-AF registry, 5407 (81.1%) patients were enrolled three months after AF diagnosis. During a median follow-up period of 973 days (interquartile range: 755-1089 days), a primary outcome event occurred in 72 patients in the rhythm control group (1.4 events per 100 person-years) and in 211 patients in the rate control group (1.8 events per 100 person-years). However, after overlap weighting, the incidence rates were 1.4 and 1.5 events per 100 person-years, respectively. No significant difference was found in either the primary outcome (weighted HR: 0.87; 95% CI: 0.66-1.17; p = 0.363) or secondary outcomes between the rhythm control and rate control groups. CONCLUSION: In a prospective AF registry in which most of the population was enrolled at least three months after AF diagnosis, no difference in the risk of cardiovascular or cerebrovascular outcomes was found between the rhythm control and rate control groups, suggesting the early rhythm control should be considered to improve the outcome of patients.

Veratramine Inhibits the Cell Cycle Progression, Migration, and Invasion via ATM/ATR Pathway in Androgen-Independent Prostate Cancer.

Prostate cancer (PC) is the second leading cause of cancer-related death among men. Treatment of PC becomes difficult after progression because PC that used to be androgen-dependent becomes androgen-independent prostate cancer (AIPC). Veratramine, an alkaloid extracted from the root of the Veratrum genus, has recently been reported to have anticancer effects that work against various cancers; however, its anticancer effects and the underlying mechanism of action in PC remain unknown. We investigated the anticancer effects of veratramine on AIPC using PC3 and DU145 cell lines, as well as a xenograft mouse model. The antitumor effects of veratramine were evaluated using the CCK-8, anchorage-independent colony formation, trans-well, wound healing assays, and flow cytometry in AIPC cell lines. Microarray and proteomics analyses were performed to investigate the differentially expressed genes and proteins induced by veratramine in AIPC cells. A xenograft mouse model was used to confirm the therapeutic response and in vivo efficacy of veratramine. Veratramine dose dependently reduced the proliferation of cancer cells both in vitro and in vivo. Moreover, veratramine treatment effectively suppressed the migration and invasion of PC cells. The immunoblot analysis revealed that veratramine significantly downregulated Cdk4/6 and cyclin D1 via the ATM/ATR and Akt pathways, both of which induce a DNA damage response that eventually leads to G1 phase arrest. In this study, we discovered that veratramine exerted antitumor effects on AIPC cells. We demonstrated that veratramine significantly inhibited the proliferation of cancer cells via G0/G1 phase arrest induced by the ATM/ATR and Akt pathways. These results suggest that veratramine is a promising natural therapeutic agent for AIPC.

A preliminary study about the potential risks of the UV-weathered microplastic: The proteome-level changes in the brain in response to polystyrene derived weathered microplastics.

The growing use of plastic materials has resulted in a constant increase in the risk associated with microplastics (MPs). Ultra-violet (UV) light and wind break down modify MPs in the environment into smaller particles known as weathered MPs (WMPs) and these processes increase the risk of MP toxicity. The neurotoxicity of weathered polystyrene-MPs remains unclear. Therefore, it is important to understand the risks posed by WMPs. We evaluated the chemical changes of WMPs generated under laboratory-synchronized environmentally mimetic conditions and compared them with virgin MPs (VMPs). We found that WMP had a rough surface, slight yellow color, reduced molecular weight, and structural alteration compared with those of VMP. Next, 2 µg of ∼100 µm in size of WMP and VMP were orally administered once a day for one week to C57BL/6 male mice. Proteomic analysis revealed that the WMP group had significantly increased activation of immune and neurodegeneration-related pathways compared with that of the VMP group. Consistently, in in vitro experiments, the human brain-derived microglial cell line (HMC-3) also exhibited a more severe inflammatory response to WMP than to VMP. These results show that WMP is a more profound inflammatory factor than VMP. In summary, our findings demonstrate the toxicity of WMPs and provide theoretical insights into their potential risks to biological systems and even humans in the ecosystem.

Corrigendum: Clinical implications of atrial fibrillatioN detection using wearabLE devices in patients with cryptogenic stroke (CANDLE-AF) trial: Design and rationale.

[This corrects the article DOI: 10.3389/fcvm.2022.837958.].