Search Results (198)

Background and Objectives: The role of biventricular pacing (BVP) is less well-established in patients with heart failure with reduced ejection fraction (HFrEF) without left bundle branch block (LBBB). Conduction system pacing (CSP) has gained significant traction and may provide a safe and more physiological alternative to BVP in these patients. A few small studies studying this question have reported conflicting results. This meta-analysis aims to compare procedural and clinical outcomes between CSP and BVP in this group. Materials and Methods: An online literature search was systematically conducted to retrieve studies comparing CSP and BVP in HFrEF patients with non-LBBB. Four studies with 461 patients were included. Results: Implant-derived paced QRS duration was significantly shorter (mean difference [MD] −19.7 ms, 95% confidence interval [CI] −36.2 to −3.3, p = 0.0355) with CSP. Echocardiographic response with significantly greater improvement in left ventricular ejection fraction (MD 5.6%, 95% CI 3.1 to 8.0, p = 0.0106) was also observed with CSP. There were no statistically significant differences in clinical outcomes such as all-cause mortality (relative risk [RR] 0.53, 95% CI 0.18 to 1.60, p = 0.133) and heart failure hospitalization (RR 0.54, 95% CI 0.19 to 1.56, p = 0.129). Conclusions: This meta-analysis suggests that CSP may have better electrical synchrony and echocardiographic response compared to BVP in HFrEF patients with non-LBBB. Further randomized studies with longer follow-up may be required to elucidate potential benefits in clinical outcomes. Full article

Background/Objectives: Left atrial function can be a tool for risk stratification for hypertrophic cardiomyopathy (HCM). Over the past decade, there has been growing interest in the application of strain analysis for earlier and more accurate prediction of cardiovascular disease prognosis. This study aimed to investigate the performance of left atrial strain analysis compared to conventional left atrial measures in predicting clinical outcomes in Asian patients with HCM. Methods and Results: This was a retrospective study involving 291 patients diagnosed with HCM between 2010 and 2017. Left atrial volumes were assessed using the method of discs in orthogonal plans at both end diastole and end systole. Left atrial (LA) strain was obtained using a post-hoc analysis with TOMTEC software. We tested the various left atrial parameters against outcomes of (1) heart failure hospitalization and (2) event-free survival from a composite of adverse events, including all-cause mortality, ventricular tachycardia (VT)/ventricular fibrillation (VF) events, appropriate device therapy if an implantable cardioverter defibrillator (ICD) was implanted, stroke, and heart failure hospitalization. The patients had a mean age of 59.0 ± 16.7 years with a male preponderance (71.2%). The cumulative event-free survival over a follow-up of 3.9 ± 2.7 years was 55.2% for patients with an abnormal LA strain versus 82.4% for patients without one (p < 0.001). Multivariable Cox regression analyses were performed separately for each LA parameter, adjusting for age, sex, LV mass index, LV ejection fraction (EF), E/e’, the presence of LV outflow tract (LVOT) obstruction at rest, and atrial fibrillation. An analysis showed that all parameters except for LAEF demonstrated an independent association with heart failure hospitalization. Left atrial strain outperformed the rest of the parameters by demonstrating an association with a composite of adverse events. Conclusions: In Asian patients with HCM, measures of left atrial strain were independently associated with heart failure hospitalization and a composite of adverse outcomes. Left atrial strain may be used as a tool to predict adverse outcomes in patients with HCM. Full article

Background/Objectives: RAF pathway aberrations are one of the hallmarks of lung cancer. Sorafenib is a multi-kinase inhibitor targeting the RAF pathway and is FDA-approved for several cancers, yet its efficacy in lung cancer is controversial. Previous clinical research showed that a ARAF p.S214C mutation exhibited exceptional responsiveness to sorafenib in lung adenocarcinoma. Methods: Considering this promising clinical potential, the oncogenic potential and sorafenib response of the ARAF p.S214C mutation were investigated using lung cancer models. ARAF p.S214C mutant, ARAF wild-type (WT), and EGFP control genes were ectopically expressed in lung adenocarcinoma cell lines retroviral transduction. In vitro and in vivo sorafenib sensitivity studies were performed, followed by transcriptomics and proteomics analyses. Results: Compared to the ARAF-WT and EGFP-engineered cells, the ARAF p.S214C-engineered cells activated Raf-MEK-ERK signaling and exhibited enhanced oncogenic potential in terms of in vitro cell proliferation, colony and spheroid formation, migration, and invasion abilities, as well as in vivo tumorigenicity. The ARAF p.S214C-engineered cells also displayed heightened sensitivity to sorafenib in vitro and in vivo. RNA sequencing and reverse-phase protein array analyses demonstrated elevated expression of genes and proteins associated with tumor aggressiveness in the ARAF p.S214C mutants, and its sorafenib sensitivity was likely moderated through inhibition of the cell cycle and DNA replication. The ERK and PI3K signaling pathways were also significantly deregulated in the ARAF p.S214C mutants regardless of sorafenib treatment. Conclusions: This study demonstrates the oncogenicity and sorafenib sensitivity of the ARAF p.S214C mutation in lung cancer cells, which may serve as a biomarker for predicting the sorafenib response in lung cancer patients. Importantly, investigating the gene–drug sensitivity pairs in clinically exceptional responders may guide and accelerate personalized cancer therapies based on specific tumor mutations. Full article

Background: The combination of aztreonam (ATM) and avibactam (AVI) presents an important therapeutic option for carbapenem-resistant Enterobacterales, particularly the NDM-producing Enterobacterales. In 2024, both the CLSI and EUCAST published their methods in antimicrobial susceptibility testing for this combination of agents. Materials and Methods: Forty carbapenem-resistant Enterobacterales isolates, including Escherichia coli (n = 35), Enterobacter cloacae complex (n = 2), Klebsiella pneumoniae complex (n = 2), and Citrobacter freundii complex (n = 1) were included in this study. All isolates harbored the NDM carbapenemase except one, which had no known detected carbapenemases. Four antimicrobial susceptibility testing methods of the combination of ATM and AVI were evaluated on these isolates, including the CLSI broth disk elution (BDE) method, the disk diffusion (DD) method of aztreonam–avibactam (AZA) following the EUCAST breakpoints, the MIC test strip (MTS) method of AZA following the EUCAST breakpoints, and the gradient strip stacking (SS) method. BDE was used as the standard of comparison. Results: Using BDE as the standard of comparison, the AZA DD, AZA MTS, and SS methods had 100% categorical agreement (CA), 0% very major error (VME), and 0% major error (ME). The essential agreement (EA) between the AZA MTS and SS method was 57.5%. Conclusions: The AZA DD, AZA MTS, and the SS methods showed complete concordance with the BDE method. However, the MICs obtained from the AZA MTS and SS were not comparable. Full article

Skin cancer, particularly melanoma, remains a major public health concern due to its high mortality rate. Current treatment options, including chemotherapy with dacarbazine and doxorubicin, have shown limited efficacy, achieving only a 20% objective response rate over six months, along with severe side effects such as cardiotoxicity. Given these limitations, there is a growing interest in herbal medicine as a source of novel anticancer compounds. Bambusa stenostachya, a bamboo species native to Taiwan, was investigated for its potential anti-melanoma properties using network pharmacology and molecular docking. LC-MS analysis identified seven bioactive compounds, including quinic acid and isovitexin, which satisfied Lipinski’s drug-likeness criteria. Among the seven bioactive compounds identified, five belong to the flavonoid family, while two are classified as phenolic compounds that modulate signaling pathways related to cancer and exhibit antioxidant activity, respectively. Through pathway enrichment analysis, four key melanoma-associated genes (PIM1, MEK1, CDK2, and PDK1) were identified as potential therapeutic targets. Ensemble docking results demonstrated that naringin-7-rhamnoglucoside exhibited the highest binding affinity (−6.30 kcal/mol) with phosphoinositide-dependent kinase-1, surpassing the affinities of standard chemotherapeutic agents. Additionally, the average docking scores for naringin-7-rhamnoglucoside and the remaining three proteins were as follows: PIM1 (−5.92), MEK1 (−6.07), and CDK2 (−5.26). These findings suggest that the bioactive compounds in B. stenostachya may play a crucial role in inhibiting melanoma progression by modulating metabolic and signaling pathways. Further in vitro and in vivo studies are necessary to validate these computational findings and explore the potential of B. stenostachya as a complementary therapeutic agent for melanoma. Full article

Background/Objective: Platelet concentrates (PCs) are used in transfusion medicine to treat bleeding disorders. Staphylococcus aureus, a predominant PC contaminant, has been implicated in several adverse transfusion reactions. The aim of this study was to investigate the impact of PC storage on S. aureus resistance to quinolones, which are commonly used to treat S. aureus infections. Methods/Results: Four transfusion-relevant S. aureus strains (TRSs) were subjected to comparative transcriptome analyses when grown in PCs vs. trypticase soy broth (TSB). Results of these analyses revealed differentially expressed genes involved in antibiotic resistance. Of interest, the norB gene (encodes for the NorB efflux pump, which is implicated in quinolone resistance and is negatively regulated by MgrA) was upregulated (1.2–4.7-fold increase) in all PC-grown TRS compared to TSB cultures. Minimal Bactericidal Concentration (MBC) of ciprofloxacin and norfloxacin in PC-grown TRS compared to TSB showed increased resistance to both quinolones in PC cultures. Complementary studies with non-transfusion-relevant strains S. aureus RN6390 and its norB and mgrA deletion mutants were conducted. MBC of ciprofloxacin and norfloxacin and RT-qPCR assays of these strains showed that not only norB, but also norA and norC may be involved in enhanced quinolone resistance in PC-grown S. aureus. The role of norB in S. aureus virulence was also tested using the silkworm Bombyx mori animal model; lethal dose 50 (LD₅₀) assays revealed slightly higher virulence in larvae infected with the wild-type strain compared to the norB mutant. Conclusions: The PC storage environment enhances quinolone resistance in S. aureus and induces differential expression of efflux pump nor genes. Furthermore, our preliminary data of the involvement of NorB in virulence of S. aureus using a silkworm model merit further investigation with other systems such as a mammal animal model. Our results provide mechanistic insights to aid clinicians in the selection of antimicrobial treatment of patients receiving transfusions of S. aureus-contaminated PCs. Full article

Modular green wall, or living wall (LW) system, has evolved worldwide over the past decades as a popular green building feature and a nature-based solution. Differential climatic conditions across the globe make the standardisation of practices inapplicable to local scenarios. LW projects with differing goals and preferences like aesthetic (such as plant healthiness), water-saving, and minimal plant growth require optimal combinations of plant species to achieve single or multiple goals. This exploratory study aimed to deploy empirical field LW data to optimise analytical models to support plant species selection and LW design. Plant growth performance and water demand data of 29 commonly used plant species in outdoor modular LW systems without irrigation were collected in subtropical Hong Kong for 3 weeks. The 29 species tested were grouped into five plant forms: herbaceous perennials (16 spp), succulents (2 spp), ferns (2 spp), shrubs (7 spp), and trees (2 spp). Plant species-specific plant height, LAI, plant health rating, and water absorption amount were recorded every 6 days, together with photo records. Total water demand varied widely among plant species, ranging from 52.5 to 342.5 mL in 3 weeks (equivalent to 2.5 to 16.3 mL per day). The random forest algorithm proved that the water demand of the species was a dominant predictor of plant health tendency, among other parameters. Hierarchical clustering grouped plant species with similar water demand and health rating tendencies into four groups. The health rating threshold approach identified the top-performing species that displayed a healthy appearance as a basic prerequisite, coupled with one or two optional objectives: (1) water-saving and (2) slow-growing. The comparison among the plant selection scenarios based on projected LW performance (water demand, plant health, and growth) provided sound evidence for the optimisation of LW design for sustainability. LW projects with multiple objectives inherited a multitude of multi-scalar properties; thus, the simulation of LW performance in this study demonstrated a novel data-driven approach to optimise plant species selection and planting design with minimal resource input. Full article

Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy in solid tumors. Optimizing biodistribution is key to overcoming these challenges. Methods: A physiologically based pharmacokinetic (PBPK) model was developed that incorporates T-cell transmigration, retention, receptor binding, receptor turnover, and cellular engagement. Preclinical biodistribution data were modeled using two TCB formats: one lacking tumor target binding and another with target arm binding, each with varying CD3 affinities in a transgenic tumor-bearing mouse model. Results: The PBPK model successfully described the distribution of activated T-cells and various TCB formats. It accurately predicted preclinical biodistribution patterns, demonstrating that higher CD3 affinity leads to faster clearance from the blood and increased accumulation in T-cell-rich organs, often reducing tumor exposure. Simulations of HER2-CD3 TCB doses (0.1 µg to 100 mg) revealed monotonic increases in synapse AUC within the tumor. A bell-shaped dose-Cmax relationship for synapse formation was observed, and Tmax was delayed at higher doses. Blood PK was a reasonable surrogate for tumor synapse at low doses but less predictive at higher doses. Conclusions: We developed a whole-body PBPK model to simulate the biodistribution of T-cells and TCB molecules. The insights from this model provide a comprehensive understanding of the factors affecting PK, synapse formation, and TCB activity, aiding in dose optimization and the design of effective therapeutic strategies. Full article

HyperSCAN (Hyper Spectral Camera ANalyzer) is a hyperspectral imager which monitors the Earth’s environment and also an educational platform to integrate college students’ ideas and skills in optical design and data processing. The advantages of HyperSCAN are that it is designed for modular design, is compact and lightweight, and low-cost using commercial off-the-shelf (COTS) optical components. The modular design allows for flexible and rapid development, as well as validation within college lab environments. To optimize space utilization and reduce the optical path, HyperSCAN’s optical system incorporates a folding mirror, making it ideal for the constrained environment of a CubeSat. The use of COTS components significantly lowers pre-development costs and minimizes associated risks. The compact size and cost-effectiveness of CubeSats, combined with the advanced capabilities of hyperspectral imagers, make them a powerful tool for a broad range of applications, such as environmental monitoring of Earth, disaster management, mineral and resource exploration, atmospheric and climate studies, and coastal and marine research. We conducted a spatial-resolution-boost experiment using HyperSCAN data and various hyperspectral datasets including Urban, Pavia University, Pavia Centre, Botswana, and Indian Pines. After testing various data-fusion deep learning models, the best image quality of these methods is a two-branches convolutional neural network (TBCNN), where TBCNN retrieves spatial and spectral features in parallel and reconstructs the higher-spatial-resolution data. With the aid of higher-spatial-resolution multispectral data, we can boost the spatial resolution of HyperSCAN data. Full article

Background/Objective: Prostate cancer (PCa) remains a prevalent and deadly disease, particularly in its advanced stages. Despite various available treatments, resistance to drugs like enzalutamide continues to present significant challenges. This study aimed to investigate the role of Galectin-1 (Gal-1) in enzalutamide-resistant PCa and assess its potential as a therapeutic target to overcome resistance. Methods: The study utilized specific siRNA-mediated knockdown of Gal-1 in enzalutamide-resistant PCa cells to evaluate its effects on cell proliferation and response to enzalutamide treatment. An orthotopic mouse model was employed to examine the in vivo impact of Gal-1 knockdown. Pharmacological targeting of Gal-1 was conducted using LLS30, and its effects were assessed both in vitro and in vivo. RNA sequencing (RNA-seq) analysis was performed to explore the molecular mechanisms underlying the observed effects. Results: The findings demonstrated significant upregulation of Gal-1 in enzalutamide-resistant PCa cells. Gal-1 knockdown inhibited cell proliferation and resensitized resistant cells to enzalutamide treatment in the orthotopic mouse model. Elevated levels of androgen receptor full-length and AR-V7 are key mechanisms under-lying resistance to enzalutamide in PCa. Gal-1 knockdown suppressed AR and AR-V7 expression and their transcriptional activity. Treatment with LLS30 significantly suppressed the growth of enzalutamide-resistant PCa cells and exhibited synergistic effects when combined with enzalutamide. Notably, this combination therapy significantly inhibited the growth of enzalutamide-resistant xenografts in vivo. RNA-seq analysis revealed that LLS30 modulates AR and AR-V7 signaling through the inhibition of associated target genes. Conclusion: These findings highlight Gal-1 as a promising therapeutic target for overcoming enzalutamide resistance in PCa. Targeting the Gal-1/AR/AR-V7 axis with LLS30 presents a novel strategy to enhance enzalutamide efficacy and address drug resistance in advanced PCa. Full article

The purpose of this study was to assess the practical implications of supplementing soluble fiber in the diet of dogs. Dogs with a history of managed or active chronic enteropathy were randomized to receive either wheat dextrin (fiber group) or maltodextrin (placebo group) mixed with food once daily for 28 days. Owners recorded a daily fecal score one week prior to and during the supplementation period. Shallow shotgun sequencing, quantitative PCR abundances of core bacterial taxa, and short-chain fatty acid (SCFA) concentrations via gas chromatography/mass spectrometry were performed on fecal samples collected before and after supplementation. Seventeen dogs completed the study (fiber group: nine dogs; placebo group: eight dogs). The change in fecal score differed between groups, with the fiber group developing softer stools (p = 0.03). Alpha diversity, quantified PCR abundances of the SCFA-producing taxa, and fecal SCFA concentrations were not different after supplementation in either group. Fecal microbial communities differed between baseline and day 28 for fiber and placebo groups (p = 0.02, respectively); however, the size effect (ANOSIM R = 0.18 and R = 0.26, respectively) was minimal. In this small group of dogs fed variable commercial diets, the additional intake of wheat dextrin powder supplement was well accepted, but had minimal discernable clinical benefit, and could soften stools. Full article

Background: Prostate cancer is a major global health burden, with biochemical recurrence (BCR) following radical prostatectomy affecting 20–40% of patients and posing significant challenges to prognosis and treatment. Emerging evidence suggests a critical role for differentially expressed in normal and neoplastic cell (DENN) domain-containing genes in oncogenesis; however, their implications in prostate cancer and BCR risk remain underexplored. Methods: This study systematically evaluated 151 single-nucleotide polymorphisms in DENN domain-containing genes in 458 patients with prostate cancer and BCR, followed by validation in an independent cohort of 185 patients. Results: Multivariate Cox regression analyses identified DENND2D rs610261 G>A as significantly associated with improved BCR-free survival in both cohorts (adjusted hazard ratio = 0.39, 95% confidence interval = 0.23–0.66, p = 0.001). Functional analysis revealed rs610261’s regulatory potential, with the protective A allele correlating with increased DENND2D expression in various human tissues. Compared to normal prostate tissues, DENND2D expression was reduced in prostate cancer, with higher expression being linked to favorable patient prognosis (p = 0.03). Gene set enrichment analysis revealed an association between DENND2D expression and the negative regulation of MYC target genes, including MAD2L1, ERH, and CLNS1A, which are overexpressed in prostate cancer and associated with poor survival. Furthermore, the elevated DENND2D expression promotes immune infiltration in prostate cancer, supporting its role in immune modulation. Conclusions: DENND2D is a prognostic biomarker for BCR in prostate cancer and offers new avenues for personalized treatment strategies. Full article

Both the prevalence and mortality of liver cancers continue to rise. Early surgical interventions, including liver transplantation or resection, remain the only curative treatment. Nerves in the periphery influence tumor growth within visceral organs. Emerging cancer neuroscience efforts linked parasympathetic vagus nerves with tumor pathology, underscoring the value of vagal nerve denervation methods within cancer mouse models. Here, we describe a selective hepatic vagotomy that largely maintains non-liver parasympathetic innervation in mice. To address vagal interactions in hepatic tumor pathology, we provide an adapted methodology utilizing an established liver metastatic model. We anticipate that this methodology will expand the burgeoning field of cancer neuroscience, enabling the study of the neuroimmune, neurometabolic, and/or nerve–microbiota interactions shaping liver cancer progression and treatment. Full article

Background: The biologics derived from human amniotic membranes (AMs) demonstrate potential pain-inhibitory effects in clinical settings. However, the molecular basis underlying this therapeutic effect remains elusive. HC-HA/PTX3 is a unique water-soluble regenerative matrix that is purified from human AMs. We examined whether HC-HA/PTX3 can modulate the gene networks and transcriptional signatures in the dorsal root ganglia (DRG) neurons transmitting peripheral sensory inputs to the spinal cord. Methods: We conducted bulk RNA-sequencing (RNA-seq) of mouse DRG neurons after treating them with HC-HA/PTX3 (15 µg/mL) for 10 min and 24 h in culture. Differential gene expression analysis was performed using the limma package, and Gene Ontology (GO) and protein–protein interaction (PPI) analyses were conducted to identify the networks of pain-related genes. Western blotting and in vitro calcium imaging were used to examine the protein levels and signaling of pro-opiomelanocortin (POMC) in DRG neurons. Results: Compared to the vehicle-treated group, 24 h treatment with HC-HA/PTX3 induced 2047 differentially expressed genes (DEGs), which were centered on the ATPase activity, receptor–ligand activity, and extracellular matrix pathways. Importantly, PPI analysis revealed that over 50 of these DEGs are closely related to pain and analgesia. Notably, HC-HA/PTX3 increased the expression and signaling pathway of POMC, which may affect opioid analgesia. Conclusions: HC-HA/PTX3 induced profound changes in the gene expression in DRG neurons, centered around various neurochemical mechanisms associated with pain modulation. Our findings suggest that HC-HA/PTX3 may be an important biological active component in human AMs that partly underlies its pain inhibitory effect, presenting a new strategy for pain treatment. Full article

This research aims to verify the relationships between destination ij3dentity, environmental concern, and environmentally responsible behavior (ERB), based on the Cognition–Affect–Behavior (C–A–B) model, in the Sun-Link-Sea Forest Recreation Area (SLSFRA) in Taiwan. This study also aims to address the gap in understanding whether tourists’ family structure, with or without children, influences the impact of destination identity on their environmental concerns and ERB. A total of 431 samples were collected through convenience sampling and analyzed using structural equation modeling. The findings indicated that destination identity significantly influenced environmental concern, which in turn affected the general and specific ERB. Environmental concern acted as a mediator between destination identity and ERB. Specifically, tourists who strongly identified with the destination were more inclined to be concerned that its environmental condition influenced their travel experience, encouraging them to take action to protect the environment. Families with children who had greater environmental concern exhibited stronger general and specific environmentally responsible behavior (ERB) compared to families without children, who were more influenced by the impact of forest destination identity on their ERB. Practical implications for management and future research suggestions are proposed for relevant organizations and researchers. Full article