Efficacy and safety of a fixed-dose combination of dapagliflozin and linagliptin (AJU-A51) in patients with type 2 diabetes mellitus: A multicentre, randomized, double-blind, parallel-group, placebo-controlled phase III study.

AIMS: To evaluate the efficacy and safety of add-on dapagliflozin in patients with type 2 diabetes mellitus (T2D) who had inadequate glycaemic control with metformin and linagliptin. MATERIALS AND METHODS: A total of 235 patients with inadequate response to metformin (≥1000 mg/day) plus linagliptin (5 mg/day) were randomized to receive either dapagliflozin/linagliptin fixed-dose combination (FDC [AJU-A51]) 10/5 mg/day (n = 117) or linagliptin 5 mg plus placebo (n = 118) for 24 weeks. After the main treatment period, patients who received linagliptin plus placebo were treated with AJU-A51 for an additional 28 weeks. Change in glycated haemoglobin (HbA1c) from baseline to Week 24 was the primary endpoint. RESULTS: AJU-A51 significantly reduced HbA1c levels (from 7.93% ± 0.82% to 7.11% ± 0.61%) compared with linagliptin plus placebo (from 7.80% ± 0.71% to 7.87% ± 0.94%), with a least squares mean difference of -0.88% (95% confidence interval -1.07 to -0.68; p < 0.0001) at 24 weeks. The AJU-A51 group had a significantly higher proportion of patients who achieved HbA1c <7.0% at Week 24 than the control group (44.8% vs. 18.6%; p < 0.001). The AJU-A51 group maintained glycaemic efficacy up to 52 weeks, whereas the control group showed a substantial reduction in HbA1c after switching to AJU-A51 in the extension study period. Both groups had similar incidence of treatment-emergent and serious adverse events, and no cases of symptomatic hypoglycaemia were reported. CONCLUSIONS: Dapagliflozin and linagliptin FDC (AJU-A51) showed potent glucose-lowering effects, with good tolerability, in patients with T2D who had poor glycaemic control on metformin and linagliptin (ClinicalTrials.gov [NCT06329674]).

Clinical Feasibility of Vascular Navigation System During Laparoscopic Gastrectomy for Gastric Cancer: A Retrospective Comparison With Propensity-Score Matching.

PURPOSE: The usability of a new surgical navigation system that provides patient-specific vascular information for robotic gastrectomy in gastric cancer remains unexplored for laparoscopic gastrectomy owing to differences in surgical environments. This study aimed to evaluate the applicability and safety of this navigation system in laparoscopic gastrectomy and to compare the post-operative outcomes between procedures with and without its use. MATERIALS AND METHODS: Between June 2022 and July 2023, 38 patients across 2 institutions underwent laparoscopic gastrectomy using a navigation system (navigation group). The technical feasibility, safety, and accuracy of detecting variations in vascular anatomy were measured. The perioperative outcomes were compared with 114 patients who underwent laparoscopic gastrectomy without a navigation system (non-navigation group) using 1:3 propensity score matching during the same study period. RESULTS: In all patients in the navigation group, no adverse events associated with the navigation system occurred during surgery in any patient in the navigation group. No accidental vessel injuries necessitate auxiliary procedures. All vessels encountered during the gastrectomy were successfully reconstructed and visualized. Patient demographics and operative data were comparable between the 2 groups. The navigation group exhibited a significantly lower overall complication rate (10.5%) than the non-navigation group (26.3%, P=0.043). Notably, pancreas-related complications were absent in the navigation group but occurred in eight cases in the non-navigation group (7.0%, P=0.093), although the difference was not statistically significant. CONCLUSIONS: The patient-specific surgical navigation system demonstrated clinical feasibility and safety for laparoscopic gastrectomy for gastric cancer, potentially reducing complication rates compared with laparoscopic gastrectomy without its use.

Elevated origin recognition complex subunit 6 expression promotes non-small cell lung cancer cell growth.

Exploring novel targets for non-small cell lung cancer (NSCLC) remains of utmost importance. This study focused on ORC6 (origin recognition complex subunit 6), investigating its expression and functional significance within NSCLC. Analysis of the TCGA-lung adenocarcinoma database revealed a notable increase in ORC6 expression in lung adenocarcinoma tissues, correlating with reduced overall survival, advanced disease stages, and other key clinical parameters. Additionally, in patients undergoing surgical resection of NSCLC at a local hospital, ORC6 mRNA and protein levels were elevated in NSCLC tissues while remaining low in adjacent normal tissues. Comprehensive bioinformatics analyses across various cancers suggested that ORC6 might play a significant role in crucial cellular processes, such as mitosis, DNA synthesis and repair, and cell cycle progression. Knocking down ORC6 using virus-delivered shRNA in different NSCLC cells, both primary and immortalized, resulted in a significant hindrance to cell proliferation, cell cycle progression, migration and invasion, accompanied by caspase-apoptosis activation. Similarly, employing CRISPR-sgRNA for ORC6 knockout (KO) exhibited significant anti-NSCLC cell activity. Conversely, increasing ORC6 levels using a viral construct augmented cell proliferation and migration. Silencing or knockout of ORC6 in primary NSCLC cells led to reduced expression of several key cyclins, including Cyclin A2, Cyclin B1, and Cyclin D1, whereas their levels increased in NSCLC cells overexpressing ORC6. In vivo experiments demonstrated that intratumoral injection of ORC6 shRNA adeno-associated virus markedly suppressed the growth of primary NSCLC cell xenografts. Reduced ORC6 levels, downregulated cyclins, and increased apoptosis were evident in ORC6-silenced NSCLC xenograft tissues. In summary, elevated ORC6 expression promotes NSCLC cell growth.

Non-fused Star-shape Giant Trimer Electron Acceptors for Organic Solar Cells with Efficiency over 19.

Organic solar cells (OSCs) based on giant molecular acceptors (GMAs) have attracted extensive attention due to their excellent power conversion efficiency (PCE) and operation stability. However, the large conjugated plane of GMAs poses great challenges in regulating the solubility, over-size aggregation and yield, which in turn further constrains their development in commercial products. Herein, we employ a non-fused skeleton strategy to develop novel non-fused star-shape trimers (3BTT6F and 3BTT6Cl) for improving device performance. Single-bond linkage can break the rigid planarity to form a 3D architecture, generating multidimensional charge transfer pathways. Importantly, the non-fused skeleton strategy can not only significantly improve solubility and synthesis yield, but also effectively suppress molecular excessive aggregation. Consequently, due to the optimized film-forming process and charge dynamics, 3BTT6F-based binary device obtains a high PCE of 17.52%, which is significantly higher than the reported fully fused trimers. Excitingly, 3BTT6F-based ternary device even obtains a top-level PCE of 19.26%. Furthermore, the non-fused star-shape configuration also endows these acceptors with enhanced intermolecular interaction in the active layer, demonstrating excellent operational stability. Our work emphasizes the potential of non-fused star-shape trimers, providing a new pathway for achieving highly efficient and stable OSCs.

The Effect of Periodontitis on Body Size Phenotypes in Adults without Diagnosed Chronic Diseases: The Korean National Health and Nutrition Examination Survey 2013-2015.

We aimed to examine the correlation between periodontitis and body size phenotypes in 7301 participants without diagnosed chronic diseases in the Korean National Health and Nutrition Examination Survey 2013-2015. The participants were categorized into the following body size phenotype groups based on body mass index and the presence of metabolic syndrome: metabolically healthy normal weight (MHNW), metabolically abnormal normal weight (MANW), metabolically healthy obese (MHO), and metabolically abnormal obese (MAO). The prevalence rates of mild and severe periodontitis were 18.1% and 7.5%, respectively. Patients with periodontitis were older, current smokers, had a lower family income, were less likely to engage in regular tooth brushing or exercise, and had a higher body mass index and glucose levels. Periodontitis was more prevalent in the MANW and MAO groups than in the MHNW and MHO groups. Compared with the MHNW phenotype, the MAO and MANW phenotypes were significantly associated with mild and severe periodontitis, and the MHO phenotype was significantly associated with mild periodontitis. The MANW and MAO phenotypes are independent risk factors for periodontitis in adults without diagnosed chronic diseases. To enhance public health, a greater focus and effective approaches for identifying metabolic disease phenotypes among individuals with periodontal disease may be clinically relevant.

Evaluation of soybean oil-wax oleogel as a healthy ingredient for aerogel whipped cream rich in unsaturated fatty acids.

Aerosol whipped cream, widely used in various foods, relies on solid fats rich in saturated fatty acids (SFAs) for stable gas entrapment. In this study, the potential of oleogels as a healthy fat substitute for formulating aerosol whipped cream was studied. The analysis focused on the effects of different types (beeswax [BW], rice bran wax [RW], and carnauba wax) and the quantities of wax on the properties of the aerosol whipped creams. The BW-oleogel-based aerosol whipped cream exhibited the highest foam ability and foam stability. The superior physical properties of the bees wax-oleogel were attributed to the higher overrun and height stability of its whipped cream compared to RW and carnauba oleogels. The 6% BW-whipped cream showed significantly higher overrun and cream stability. The 6% BW oleogel whipped cream contained 4.4 times lower SFAs than the dairy milk fat whipped cream. This study represents the first exploration into the feasibility of formulating oleogel-based aerosol whipped cream using liquid vegetable oil.

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

Background: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. Conclusion: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Discovery of novel arylpyridine derivatives for motile ciliogenesis.

Motile cilia are crucial for maintaining healthy bodily functions by facilitating fluid transport and removing foreign substances or debris from the body. The dysfunction of motile cilia leads to ciliopathy. In particular, damage to the motile cilia of the airways can cause or worsen respiratory disease, making it an attractive target for therapeutic interventions. However, there are no treatments to induce motile ciliogenesis. Forkhead box transcription factor J1 (FOXJ1), the master regulator, has been implicated in motile cilia formation. Mice lacking the Foxj1 gene show loss of axoneme, a key component of cilia, that further highlights the importance of FOXJ1 in motile cilia formation. This prompted us to identify new small molecules that could induce motile ciliogenesis. A phenotype-based high-throughput screening (HTS) in a Tg(foxj1a:eGFP) zebrafish model was performed and a novel hit compound was identified. Among the synthesized compounds, compound 16c effectively enhanced motile ciliogenesis in a transgenic zebrafish model. To further test the efficacy of compound 16c on a mammalian airway system consisting of multiciliated cells (MCCs), ex vivo mice tracheal epithelial cell culture was adopted under an air-liquid interface system (ALI). Compound 16c significantly increased the number of MCCs by enhancing motile ciliogenesis. In addition, compound 16c exhibited good liver microsomal stability, in vivo PK profiles with AUC, and oral bioavailability. There was no significant inhibition of CYP and hERG, and no cell cytotoxicity was shown. In an elastase-induced COPD (chronic obstructive pulmonary disease) mouse model, compound 16c effectively prevented the development and onset of COPD. Taken together, compound 16c has great promise as a therapeutic agent for treating and alleviating motile ciliopathies.

Clinical application of whole-genome sequencing of solid tumors for precision oncology.

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.

Real-Time Observation for MoS2 Growth Kinetics and Mechanism Promoted by the Na Droplet.

While the molten salt-catalyzed chemical vapor deposition (CVD) technique is recognized for its effectiveness in producing large-area transition metal chalcogenides, understanding their growth mechanisms involving alkali metals remains a challenge. Here, we investigate the kinetics and mechanism of sodium-catalyzed molybdenum disulfide (MoS2) growth and etching through image analysis conducted using an integrated CVD microscope. Sodium droplets, agglomerated via the thermal decomposition of the sodium cholate dispersant, catalyze the precipitation of supersaturated MoS2 laminates and induce growth despite fragmentation during this process. Triangular MoS2 crystals display a distinct self-exhausting exponential behavior and slow growth of thermodynamically favorable crystallographic faces, exhibiting a sulfur-dominant pressure. The growth and etching processes are facilitated by the scooting of sodium droplets along grain edges, displaying comparable rates. Leveraging these kinetics makes it possible to engineer atypical MoS2 shapes. This combined microscope not only enhances the understanding of growth mechanisms but also contributes to the facile development of next-generation nanomaterials.

Evaluating the Impact of Airborne Fine Particulate Matter and Heavy Metals on Oxidative Stress via Vitamin Supplementation.

This cross-sectional study aimed to assess the interrelationships between PM2.5 exposure, heavy metal concentrations, and oxidative stress indicators, while evaluating the impact of antioxidant intake, such as vitamins, on these associations. PM2.5 exposure assessments were conducted using portable sensor-based monitors; biomarker analyses for heavy metals and oxidative stress were performed in 114 non-smoking adults. We observed that personal or ambient PM2.5 exposure levels were not associated with increased levels of heavy metals in blood and urine, nor with oxidative stress levels in urine. However, the concentrations of cadmium and lead in blood, and those of chromium and nickel in urine, were significantly associated with the urinary malondialdehyde (MDA) concentration. Additionally, increases in blood cadmium, urinary chromium, and nickel levels were significantly associated with higher urinary MDA concentrations in the non-vitamin-supplement group, but this trend was not observed in the regular vitamin supplement group. Our findings suggest that a regular intake of vitamin supplements might modulate the relationship between heavy metal exposure and oxidative stress, indicating potential protective effects against oxidative damage induced by PM2.5 and heavy metals. This study highlights the complexity of environmental pollutant exposure and its impact on human health, emphasizing the need for further research to elucidate the underlying mechanisms and explore potential protective strategies.

Topological Fermi-arc surface state covered by floating electrons on a two-dimensional electride.

Two-dimensional electrides can acquire topologically non-trivial phases due to intriguing interplay between the cationic atomic layers and anionic electron layers. However, experimental evidence of topological surface states has yet to be verified. Here, via angle-resolved photoemission spectroscopy (ARPES) and scanning tunnelling microscopy (STM), we probe the magnetic Weyl states of the ferromagnetic electride [Gd2C]2+·2e-. In particular, the presence of Weyl cones and Fermi-arc states is demonstrated through photon energy-dependent ARPES measurements, agreeing with theoretical band structure calculations. Notably, the STM measurements reveal that the Fermi-arc states exist underneath a floating quantum electron liquid on the top Gd layer, forming double-stacked surface states in a heterostructure. Our work thus not only unveils the non-trivial topology of the [Gd2C]2+·2e- electride but also realizes a surface heterostructure that can host phenomena distinct from the bulk.

Introduction to the forensic research via omics markers in environmental health vulnerable areas (FROM) study.

This research group (forensic research via omics markers in environmental health vulnerable areas: FROM) aimed to develop biomarkers for exposure to environmental hazards and diseases, assess environmental diseases, and apply and verify these biomarkers in environmentally vulnerable areas. Environmentally vulnerable areas-including refineries, abandoned metal mines, coal-fired power plants, waste incinerators, cement factories, and areas with high exposure to particulate matter-along with control areas, were selected for epidemiological investigations. A total of 1,157 adults, who had resided in these areas for over 10 years, were recruited between June 2021 and September 2023. Personal characteristics of the study participants were gathered through a survey. Biological samples, specifically blood and urine, were collected during the field investigations, separated under refrigerated conditions, and then transported to the laboratory for biomarker analysis. Analyses of heavy metals, environmental hazards, and adducts were conducted on these blood and urine samples. Additionally, omics analyses of epigenomes, proteomes, and metabolomes were performed using the blood samples. The biomarkers identified in this study will be utilized to assess the risk of environmental disease occurrence and to evaluate the impact on the health of residents in environmentally vulnerable areas, following the validation of diagnostic accuracy for these diseases.

Multilevel Conductance States of Vapor-Transport-Deposited Sb2S3 Memristors Achieved via Electrical and Optical Modulation.

The pursuit of advanced brain-inspired electronic devices and memory technologies has led to explore novel materials by processing multimodal and multilevel tailored conductive properties as the next generation of semiconductor platforms, due to von Neumann architecture limits. Among such materials, antimony sulfide (Sb2S3) thin films exhibit outstanding optical and electronic properties, and therefore, they are ideal for applications such as thin-film solar cells and nonvolatile memory systems. This study investigates the conduction modulation and memory functionalities of Sb2S3 thin films deposited via the vapor transport deposition technique. Experimental results indicate that the Ag/Sb2S3/Pt device possesses properties suitable for memory applications, including low operational voltages, robust endurance, and reliable switching behavior. Further, the reproducibility and stability of these properties across different device batches validate the reliability of these devices for practical implementation. Moreover, Sb2S3-based memristors exhibit artificial neuroplasticity with prolonged stability, promising considerable advancements in neuromorphic computing. Leveraging the photosensitivity of Sb2S3 enables the Ag/Sb2S3/Pt device to exhibit significant low operating potential and conductivity modulation under optical stimulation for memory applications. This research highlights the potential applications of Sb2S3 in future memory devices and optoelectronics and in shaping electronics with versatility.

Corrigendum: Trickle infection with Heligmosomoides polygyrus results in decreased worm burdens but increased intestinal inflammation and scarring.

[This corrects the article DOI: 10.3389/fimmu.2022.1020056.].

A Beam Angle Selection Method to Improve Plan Robustness Against Position Error in Intensity-Modulated Radiotherapy for Left-Sided Breast Cancer.

PURPOSE: We report a dosimetric study in whole breast irradiation (WBI) of plan robustness evaluation against position error with two radiation techniques: tangential intensity-modulated radiotherapy (T-IMRT) and multi-angle IMRT (M-IMRT). METHODS: Ten left-sided patients underwent WBI were selected. The dosimetric characteristics, biological evaluation and plan robustness were evaluated. The plan robustness quantification was performed by calculating the dose differences (Δ) of the original plan and perturbed plans, which were recalculated by introducing a 3-, 5-, and 10-mm shift in 18 directions. RESULTS: M-IMRT showed better sparing of high-dose volume of organs at risk (OARs), but performed a larger low-dose irradiation volume of normal tissue. The greater shift worsened plan robustness. For a 10-mm perturbation, greater dose differences were observed in T-IMRT plans in nearly all directions, with higher ΔD98%, ΔD95%, and ΔDmean of CTV Boost and CTV. A 10-mm shift in inferior (I) direction induced CTV Boost in T-IMRT plans a 1.1 (ΔD98%), 1.1 (ΔD95%), and 1.7 (ΔDmean) times dose differences greater than dose differences in M-IMRT plans. For CTV Boost, shifts in the right (R) and I directions generated greater dose differences in T-IMRT plans, while shifts in left (L) and superior (S) directions generated larger dose differences in M-IMRT plans. For CTV, T-IMRT plans showed higher sensitivity to a shift in the R direction. M-IMRT plans showed higher sensitivity to shifts in L, S, and I directions. For OARs, negligible dose differences were found in V20 of the lungs and heart. Greater ΔDmax of the left anterior descending artery (LAD) was seen in M-IMRT plans. CONCLUSION: We proposed a plan robustness evaluation method to determine the beam angle against position uncertainty accompanied by optimal dose distribution and OAR sparing.

Research on the Multiple Small Target Detection Methodology in Remote Sensing.

This study focuses on advancing the field of remote sensing image target detection, addressing challenges such as small target detection, complex background handling, and dense target distribution. We propose solutions based on enhancing the YOLOv7 algorithm. Firstly, we improve the multi-scale feature enhancement (MFE) method of YOLOv7, enhancing its adaptability and precision in detecting small targets and complex backgrounds. Secondly, we design a modified YOLOv7 global information DP-MLP module to effectively capture and integrate global information, thereby improving target detection accuracy and robustness, especially in handling large-scale variations and complex scenes. Lastly, we explore a semi-supervised learning model (SSLM) target detection algorithm incorporating unlabeled data, leveraging information from unlabeled data to enhance the model's generalization ability and performance. Experimental results demonstrate that despite the outstanding performance of YOLOv7, the mean average precision (MAP) can still be improved by 1.9%. Specifically, under testing on the TGRS-HRRSD-Dataset, the MFE and DP-MLP models achieve MAP values of 93.4% and 93.1%, respectively. Across the NWPU VHR-10 dataset, the three models achieve MAP values of 93.1%, 92.1%, and 92.2%, respectively. Significant improvements are observed across various metrics compared to the original model. This study enhances the adaptability, accuracy, and generalization of remote sensing image object detection.

Meiotic transcriptional reprogramming mediated by cell-cell communications in humans and mice revealed by scATAC-seq and scRNA-seq.

Meiosis is a highly complex process significantly influenced by transcriptional regulation. However, studies on the mechanisms that govern transcriptomic changes during meiosis, especially in prophase I, are limited. Here, we performed single-cell ATAC-seq of human testis tissues and observed reprogramming during the transition from zygotene to pachytene spermatocytes. This event, conserved in mice, involved the deactivation of genes associated with meiosis after reprogramming and the activation of those related to spermatogenesis before their functional onset. Furthermore, we identified 282 transcriptional regulators (TRs) that underwent activation or deactivation subsequent to this process. Evidence suggested that physical contact signals from Sertoli cells may regulate these TRs in spermatocytes, while secreted ENHO signals may alter metabolic patterns in these cells. Our results further indicated that defective transcriptional reprogramming may be associated with non-obstructive azoospermia (NOA). This study revealed the importance of both physical contact and secreted signals between Sertoli cells and germ cells in meiotic progression.