Towards an actionable One Health approach.

BACKGROUND: Despite the increasing focus on strengthening One Health capacity building on global level, challenges remain in devising and implementing real-world interventions particularly in the Asia-Pacific region. Recognizing these gaps, the One Health Action Commission (OHAC) was established as an academic community for One Health action with an emphasis on research agenda setting to identify actions for highest impact. MAIN TEXT: This viewpoint describes the agenda of, and motivation for, the recently formed OHAC. Recognizing the urgent need for evidence to support the formulation of necessary action plans, OHAC advocates the adoption of both bottom-up and top-down approaches to identify the current gaps in combating zoonoses, antimicrobial resistance, addressing food safety, and to enhance capacity building for context-sensitive One Health implementation. CONCLUSIONS: By promoting broader engagement and connection of multidisciplinary stakeholders, OHAC envisions a collaborative global platform for the generation of innovative One Health knowledge, distilled practical experience and actionable policy advice, guided by strong ethical principles of One Health.

Effects of Cannabidiol and Δ9-Tetrahydrocannabinol on Cytochrome P450 Enzymes: A Systematic Review.

Due to legal, political, and cultural changes, the use of cannabis has rapidly increased in recent years. Research has demonstrated that the cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) inhibit and induce cytochrome P450 (CYP450) enzymes. The objective of this review is to evaluate the effect of CBD and THC on the activity of CYP450 enzymes and the implications for drug-drug interactions (DDIs) with psychotropic agents that are CYP substrates. A systematic search was conducted using PubMed, Scopus, Scientific Electronic Library Online (SciELO) and PsychINFO. Search terms included 'cannabidiol', 'tetrahydrocannabinol and 'cytochrome P450'. A total of seven studies evaluating the interaction of THC and CBD with CYP450 enzymes and psychotropic drugs were included. Both preclinical and clinical studies were included.Results from the included studies indicate that both CBD and THC inhibit several CYP450 enzymes including, but not limited to, CYP1A2, CYP3C19, and CYP2B6. While there are a few known CYP450 enzymes that are induced by THC and CBD, the induction of CYP450 enzymes is an understudied area of research and lacks clinical data. The inhibitory effects observed by CBD and THC on CYP450 enzymes vary in magnitude and may decrease the metabolism of psychotropic agents, changes in plasma levels of psychotropic medications, and increase adverse effects. Our findings clearly present interactions between THC and CBD and several CYP450 enzymes, providing clinicians evidence of a high risk of DDIs for patients who consume both cannabis and psychotropic medication. However, more clinical research is necessary before results are applied to clinical settings.

Large viewing angle integral imaging 3D display system based on a symmetrical compound lens array.

We propose a large viewing angle integral imaging 3D display system based on a symmetrical compound lens array (SCLA). The display system comprises a high-resolution 2D display panel, an SCLA, and a light shaping diffuser. The high-resolution 2D display panel presents an elemental image array, the SCLA modulates the light rays emitted from the 2D display panel to form 3D images in space, and the light shaping diffuser eliminates the gaps between 3D pixels of the 3D images. We find that the lateral aberration is a crucial factor that affects the resolution of the reconstructed 3D image. The symmetrical structure of the SCLA enables a reduced focal length and the elimination of lateral aberration, improving the viewing angle and the 3D image resolution simultaneously. The experimental results confirm that the proposed display system increases the viewing angle to 68.6°, achieving a comparable resolution of the full field of view while maintaining a simple structure.

The efficacy-associated biomarkers for immune checkpoint inhibitors in gastrointestinal cancer: a literature review.

Background and Objective: Immune checkpoint inhibitors (ICIs) have been widely applied and studied in the treatment of gastrointestinal (GI) cancers, and have achieved good results. However, in clinical practice, it has been observed that only some patients respond well to ICIs, and some patients may experience various degrees of adverse reactions during the treatment. Timely evaluation of the potential therapeutic effects and adverse reactions of ICIs for patients has important clinical significance. This review aimed to summarize recent progress regarding efficacy-associated biomarkers for ICIs in GI cancer. Methods: The literature on ICI treatment in GI cancers was searched in the PubMed, Embase, and Cochrane Library databases for publications up to April 2023. Key Content and Findings: Clinical practice and research has gradually revealed some biomarkers related to the treatment of GI cancers with ICIs, which can be roughly divided into three types: biomarkers that predict the effectiveness of ICIs treatment, biomarkers associated with resistance to ICIs, and biomarkers associated with immune related adverse events (irAEs). This review article provides a literature review on biomarkers related to the efficacy of ICIs in the treatment of GI cancers. Conclusions: According to existing clinical research results, there are multiple biomarkers that can be used for predicting and monitoring the efficacy and risk of adverse events of ICIs in the treatment of digestive system malignant tumors.

Acellular embryoid body and hydroxybutyl chitosan composite hydrogels promote M2 macrophage polarization and accelerate diabetic cutaneous wound healing.

Diabetic wound healing is delayed due to persistent inflammation, and macrophage-immunomodulating biomaterials can control the inflammatory phase and shorten the healing time. In this study, acellular embryoid bodies (aEBs) were prepared and mixed with thermosensitive hydroxybutyl chitosan (HBC) hydrogels to produce aEB/HBC composite hydrogels. The aEB/HBC composite hydrogels exhibited reversible temperature-sensitive phase transition behavior and a hybrid porous network. In vitro analysis showed that the aEB/HBC composite hydrogels exhibited better antimicrobial activity than the PBS control, aEBs or HBC hydrogels and promoted M0 to M2 polarization but not M1 to M2 macrophage repolarization in culture. The in vivo results showed that the aEB/HBC composite hydrogels accelerated cutaneous wound closure, re-epithelialization, ingrowth of new blood vessels, and collagen deposition and reduced the scar width during wound healing in diabetic mice over time. Macrophage phenotype analysis showed that the aEB/HBC composite hydrogels induce M2 macrophage reactions continually, upregulate M2-related mRNA and protein expression and downregulate M1-related mRNA and protein expression. Therefore, the aEB/HBC composite hydrogels have excellent antimicrobial activity, promote M2 macrophage polarization and accelerate the functional and structural healing of diabetic cutaneous wounds.

Role of inositol polyphosphate-4-phosphatase type II in oncogenesis of digestive system tumors.

Inositol polyphosphate-4-phosphatase type II (INPP4B) is a newly discovered PI(3,4,5)P3 phosphatase. Many studies have revealed that INPP4B is upregulated or downregulated in tumors of the digestive system, and the abnormal expression of INPP4B may be attributed to the occurrence, development, and prognosis of tumors of the digestive system. This paper reviews studies on the correlations between INPP4B and digestive system tumors and the roles of INPP4B in the development of different tumors to provide a theoretical basis for further research on its molecular mechanism and clinical application. "INPP4B" and "tumor" were searched as key words in PubMed and in the CNKI series full text database retrieval system from January 2000 to August 2023. A total of 153 English-language studies and 30 Chinese-language studies were retrieved. The following enrollment criteria were applied: (1) Studies contained information on the biological structure and functions of INPP4B; (2) studies covered the influence of abnormal expression of INPP4B in digestive system tumors; and (3) studies covered the role of INPP4B in the diagnosis, treatment, and prognosis of digestive system tumors. After excluding the literature irrelevant to this study, 61 papers were finally included in the analysis. INPP4B expression is low in gastric cancer, colon cancer, pancreatic cancer, and liver cancer but it has high expression in esophageal cancer, colon cancer, pancreatic cancer, and gallbladder cancer. INPP4B is involved in the occurrence and development of digestive system tumors through the regulation of gene expression and signal transduction. The abnormal expression of INPP4B plays an important role in the development of digestive system tumors. Studies on INPP4B provide new molecular insights for the diagnosis, treatment, and prognosis evaluation of digestive system tumors.

Adipose-Derived Stem Cell Exosomes Antagonize the Inhibitory Effect of Dihydrotestosterone on Hair Follicle Growth by Activating Wnt/ß-Catenin Pathway.

The most prevalent type of alopecia is androgenetic alopecia (AGA), which has a high prevalence but no effective treatment. Elevated dihydrotestosterone (DHT) level in the balding area was usually thought to be critical in the pathophysiology of AGA. The canonical Wnt/ß-catenin signaling pathway plays a key role in promoting hair follicle development and sustaining the hair follicle cycle. Adipose-derived stem cell exosomes (ADSC-Exos) are widely used in the field of regenerative medicine due to the advantages of being cell free and immune privileged. Still, few studies have reported the therapeutic effect on hair disorders. As a result, we sought to understand how ADSC-Exos affected hair growth and explore the possibility that ADSC-Exos could counteract the hair-growth-inhibiting effects of DHT. This research using human hair follicle organs, in vitro dermal papilla cells, and in vivo animal models showed that ADSC-Exos not only encouraged healthy hair growth but also counteracted the inhibitory effects of DHT on hair growth. Additionally, we discovered that ADSC-Exos increased Ser9 phosphorylated glycogen synthase kinase-3ß levels and facilitated nuclear translocation of ß-catenin, which may have been blocked by the specific Wnt/ß-catenin signaling pathway inhibitor dickkopf-related protein 1. Our findings suggested that ADSC-Exos are essential for hair regeneration, which is anticipated to open up new therapeutic possibilities for clinical alopecia, particularly for the treatment of AGA.

Assessing food security performance from the One Health concept: an evaluation tool based on the Global One Health Index.

BACKGROUND: Food systems instantiate the complex interdependencies across humans, physical environments, and other organisms. Applying One Health approaches for agri-food system transformation, which adopts integrated and unifying approaches to optimize the overall health of humans, animals, plants, and environments, is crucial to enhance the sustainability of food systems. This study develops a potential assessment tool, named the global One Health index-Food Security (GOHI-FS), aiming to evaluate food security performance across countries/territories from One Health perspective and identify relevant gaps that need to be improved for sustainable food systems. METHODS: We comprehensively reviewed existing frameworks and elements of food security. The indicator framework of GOHI-FS was conceptualized following the structure-process-outcome model and confirmed by expert advisory. Publicly available data in 2020 was collected for each indicator. The weighting strategy was determined by the Fuzzy Analytical Hierarchy Process. The data for each indicator was normalized and aggregated by weighted arithmetic mean. Linear regressions were performed to evaluate the associations of GOHI-FS with health and social-economic indicators. RESULTS: The GOHI-FS includes 5 first-level indicators, 19 second-level indicators and 45 third-level indicators. There were 146 countries/territories enrolled for evaluation. The highest average score of first-level indicators was Nutrition (69.8) and the lowest was Government Support and Response (31.3). There was regional heterogeneity of GOHI-FS scores. Higher median scores with interquartile range (IQR) were shown in North America (median: 76.1, IQR: 75.5-76.7), followed by Europe and Central Asia (median: 66.9, IQR: 60.1-74.3), East Asia and the Pacific (median: 60.6, IQR: 55.5-68.7), Latin America and the Caribbean (median: 60.2, IQR: 57.8-65.0), Middle East and North Africa (median: 56.6, IQR: 52.0-62.8), South Asia (median: 51.1, IQR: 46.7-53.8), and sub-Saharan Africa (median: 41.4, IQR: 37.2-46.5). We also found significant associations between GOHI-FS and GDP per capita, socio-demographic index, health expenditure and life expectancy. CONCLUSIONS: GOHI-FS is a potential assessment tool to understand the gaps in food security across countries/territories under the One Health concept. The pilot findings suggest notable gaps for sub-Saharan Africa in numerous aspects. Broad actions are needed globally to promote government support and response for food security.

China's application of the One Health approach in addressing public health threats at the human-animal-environment interface: Advances and challenges.

Background: Due to emerging issues such as global climate change and zoonotic disease pandemics, the One Health approach has gained more attention since the turn of the 21st century. Although One Health thinking has deep roots and early applications in Chinese history, significant gaps exist in China's real-world implementation at the complex interface of the human-animal-environment. Methods: We abstracted the data from the global One Health index study and analysed China's performance in selected fields based on Structure-Process-Outcome model. By comparing China to the Belt & Road and G20 countries, the advances and gaps in China's One Health performance were determined and analysed. Findings: For the selected scientific fields, China generally performs better in ensuring food security and controlling antimicrobial resistance and worse in addressing climate change. Based on the SPO model, the "structure" indicators have the highest proportion (80.00%) of high ranking and the "outcome" indicators have the highest proportion (20.00%) of low ranking. When compared with Belt and Road countries, China scores above the median in almost all indicators (16 out of 18) under the selected scientific fields. When compared with G20 countries, China ranks highest in food security (scores 72.56 and ranks 6th), and lowest in climate change (48.74, 11th). Conclusion: Our results indicate that while China has made significant efforts to enhance the application of the One Health approach in national policies, it still faces challenges in translating policies into practical measures. It is recommended that a holistic One Health action framework be established for China in accordance with diverse social and cultural contexts, with a particular emphasis on overcoming data barriers and mobilizing stakeholders both domestically and globally. Implementation mechanisms, with clarified stakeholder responsibilities and incentives, should be improved along with top-level design.

Graphene Oxide/Polyethyleneimine-Modified Cation Exchange Membrane for Efficient Selective Recovery of Ammonia Nitrogen from Wastewater.

Competition for the migration of interfering cations limits the scale-up and implementation of the Donnan dialysis process for the recovery of ammonia nitrogen (NH4+-N) from wastewater in practice. Highly efficient selective permeation of NH4+ through a cation exchange membrane (CEM) is expected to be modulated via tuning the surface charge and structure of CEM. In this work, a novel CEM was designed to form a graphene oxide (GO)-polyethyleneimine (PEI) cross-linked layer by introducing self-assembling layers of GO and PEI on the surface of a commercial CEM, which rationally regulates the surface charge and structure of the membrane. The resulting positively charged membrane surface exhibits stronger repulsion for divalent cations compared to monovalent cations according to Coulomb's law, while, simultaneously, GO forms π-metal cation conjugates between metal cations (e.g., Mg2+ and Ca2+), thus limiting metal cation transport across the membrane. During the DD process, higher NH4+ concentrations resulted in a longer time to reach Donnan equilibrium and higher NH4+ flux, while increased Mg2+ concentrations resulted in lower NH4+ flux (from 0.414 to 0.213 mol·m-2·h-1). Using the synergistic effect of electrostatic interaction and non-covalent cross-linking, the designed membrane, referred to as GO-PEI (20) and prepared by a 20 min impregnation in the GO-PEI mixture, exhibited an NH4+ transport rate of 0.429 mol·m-2·h-1 and a Mg2+ transport rate of 0.003 mol·m-2·h-1 in single-salt solution tests and an NH4+/Mg2+ selectivity of 15.46, outperforming those of the unmodified and PEI membranes (1.30 and 5.74, respectively). In mixed salt solution tests, the GO-PEI (20) membrane showed a selectivity of 15.46 (~1.36, the unmodified membrane) for NH4+/Mg2+ and a good structural stability after 72 h of continuous operation. Therefore, this facile surface charge modulation approach provides a promising avenue for achieving efficient NH4+-selective separation by modified CEMs.

Tackling global health security by building an academic community for One Health action.

BACKGROUND: One Health approach is crucial to tackling complex global public health threats at the interface of humans, animals, and the environment. As outlined in the One Health Joint Plan of Action, the international One Health community includes stakeholders from different sectors. Supported by the Bill & Melinda Gates Foundation, an academic community for One Health action has been proposed with the aim of promoting the understanding and real-world implementation of One Health approach and contribution towards the Sustainable Development Goals for a healthy planet. MAIN TEXT: The proposed academic community would contribute to generating high-quality scientific evidence, distilling local experiences as well as fostering an interconnected One Health culture and mindset, among various stakeholders on different levels and in all sectors. The major scope of the community covers One Health governance, zoonotic diseases, food security, antimicrobial resistance, and climate change along with the research agenda to be developed. The academic community will be supported by two committees, including a strategic consultancy committee and a scientific steering committee, composed of influential scientists selected from the One Health information database. A workplan containing activities under six objectives is proposed to provide research support, strengthen local capacity, and enhance global participation. CONCLUSIONS: The proposed academic community for One Health action is a crucial step towards enhancing communication, coordination, collaboration, and capacity building for the implementation of One Health. By bringing eminent global experts together, the academic community possesses the potential to generate scientific evidence and provide advice to local governments and international organizations, enabling the pursuit of common goals, collaborative policies, and solutions to misaligned interests.

Effects of benthic bioturbation on anammox in nitrogen removal at the sediment-water interface in eutrophic surface waters.

Anaerobic ammonium oxidation (anammox) significantly contributes to nitrogen loss in freshwater ecosystems. The sediment-water interface (SWI), known as a "hot spot" for anammox, also harbors numerous macroinvertebrates. However, the impact of their bioturbation on anammox has generally been overlooked. This study compared the effects of three representative macroinvertebrates (i.e., Propsilocerus akamusi, Branchiura sowerbyi and Radix swinhoei) with different bioturbation modes on anammox and the N-removal processes at the SWI by using a microcosmic system. The results demonstrated that all three benthic macroinvertebrates promoted anammox in addition to denitrification processes. The highest N-removal was achieved in the presence of P. akamusi considered as a gallery-diffuser, where the relative abundance of Planctomycetes (to which the anammox bacteria belong) increased by 70%. P. akamusi increased the abundance of anammox hzsB gene by 2.58-fold and promoted potential anammox rate by 12.79 nmol N g-1 h-1, which in turn facilitated total N-removal mass increased by 2.42-fold. In the presence of B. sowerbyi and R. swinhoei, the potential anammox rates increased by 4.81 and 5.57 nmol N g-1 h-1, respectively. These results underscore the substantial impact of macroinvertebrates on anammox and N-removal processes, highlighting their crucial role in N pollution control, and sustaining the overall health and stability of eutrophic water bodies.

The relationship between typical dreams and mental health of residents in village-in-city.

Aim: This study aimed to explore the relationship between typical dreams and the mental health of residents in village-in-city. Methods: This study used the Chinese version of the Typical Dreams Questionnaire and Symptom Checklist 90 (SCL-90) to investigate the mental health status and typical dream themes of 1,190 residents recruited through random sampling from a village-in-city in Xi'an. Correlation analysis, t-test, and binary regression analysis were performed on the data using SPSS 24.0. Results: The five most frequent dream themes among residents in the village-in-city were "falling"; "school, teacher, study"; "being chased but not physically injured"; "enjoying delicious food"; and "repeatedly trying to do something," in the given order. The most frequent dream theme with negative SCL-90 factors was "falling" and with positive SCL-90 factors was "school, teacher, study." Typical dreams on different themes were significantly correlated with SCL-90 factors. The theme of "enjoying delicious food" was not significantly associated with most factors in SCL-90.

Correcting spatial-spectral crosstalk and chromatic aberrations in broadband line-scan spectral-domain OCT images.

Digital correction of optical aberrations allows for high-resolution imaging across the full depth range in optical coherence tomography (OCT). Many digital aberration correction (DAC) methods have been proposed in the past to evaluate and correct monochromatic error in OCT images. However, other factors that deteriorate the image quality have not been fully investigated. Specifically, in a broadband line-scan spectral-domain OCT system (LS-SD-OCT), photons with different wavelengths scattered from the same transverse location and in the imaged object will be projected onto different spatial coordinates onto the 2D camera sensor, which in this work is defined as spatial-spectral crosstalk. In addition, chromatic aberrations in both axial and lateral directions are not negligible for broad spectral bandwidths. Here we present a novel approach to digital recovery of the spatial resolution in images acquired with a broadband LS-SD-OCT, which addresses these two main factors that limit the effectiveness of DAC for restoring diffraction-limited resolution in LS-SD-OCT images. In the proposed approach, spatial-spectral crosstalk and chromatic aberrations are suppressed by the registration of monochromatic sub-band tomograms that are digitally corrected for aberrations. The new method was validated by imaging a standard resolution target, a microspheres phantom, and different biological tissues. LS-SD-OCT technology combined with the proposed novel image reconstruction method could be a valuable research tool for various biomedical and clinical applications.

Susceptibility Analysis of Glacier Debris Flow Based on Remote Sensing Imagery and Deep Learning: A Case Study along the G318 Linzhi Section.

Glacial debris flow is a common natural disaster, and its frequency has been increasing in recent years due to the continuous retreat of glaciers caused by global warming. To reduce the damage caused by glacial debris flows to human and physical properties, glacier susceptibility assessment analysis is needed. Most research efforts consider the effect of existing glacier area and ignore the effect of glacier ablation volume change. In this paper, we consider the impact of glacier ablation volume change to investigate the susceptibility of glacial debris flow. The susceptibility to mudslide was evaluated by taking the glacial mudslide-prone ditch of G318 Linzhi section of Sichuan-Tibet Highway as the research object. First, by using a simple band ratio method with manual correction, we produced a glacial mudslide remote sensing image dataset, and second, we proposed a deep-learning-based approach using a weight-optimized glacial mudslide semantic segmentation model for accurately and automatically mapping the boundaries of complex glacial mudslide-covered remote sensing images. Then, we calculated the ablation volume by the change in glacier elevation and ablation area from 2015 to 2020. Finally, glacial debris flow susceptibility was evaluated based on the entropy weight method and Topsis method with glacial melt volume in different watersheds as the main factor. The research results of this paper show that most of the evaluation indices of the model are above 90%, indicating that the model is reasonable for glacier boundary extraction, and remote sensing images and deep learning techniques can effectively assess the glacial debris flow susceptibility and provide support for future glacial debris flow disaster prevention.

Dehydroaromatization of Indolines and Cyclohexanones with Thiol Access to Aryl Sulfides under Basic Conditions.

Aryl sulfides are common and ubiquitous motifs in natural products and pharmaceuticals. Presented herein is the first example of the synthesis of diaryl sulfide derivatives via dehydroaromatization under simple basic conditions. Dehydroaromatization reactions between indolines or cyclohexanones with aryl thiols are performed in an environmentally benign manner by the use of air (molecular oxygen) as the oxidant, with producing water as the only byproduct. The methodology provides a simple and practical route to diaryl sulfides with wide functional groups in good to excellent yields. Preliminary mechanistic studies suggest that a radical process is involved in the transformation.

125I seed implantation enhances arsenic trioxide-induced apoptosis and anti-angiogenesis in lung cancer xenograft mice

Background and Purpose Arsenic trioxide (ATO) exerts anticancer effects on lung cancer. However, the clinical use of ATO is limited due to its systemic toxicity and resistance of lung cancer cells. The present study aimed to investigate the effects of ATO, alone and in combination with 125I seed implantation on tumor growth and proliferation in lung cancer xenograft mice, and investigate the possible molecular mechanisms. Methods The transmission electron microscope observed the tumor ultrastructure of lung cancer xenograft mice. The proliferation index of Ki-67 and the number and morphology of tumor microvessels were detected with immunohistochemical staining. The protein and mRNA expression were examined by western blot and real-time PCR assay. Results The in vivo results demonstrated that ATO combined with 125I seed significantly inhibited tumor growth and proliferation, as well as promoted apoptosis, and decreased the Ki-67 index and microvessel density in lung cancer xenograft mice. Moreover, ATO combined with 125I seed decreased the protein and mRNA expression levels of HIF-1α, VEGF, and BCL-2, and increased those of BAX and P53. Conclusions ATO combined with 125I seed significantly inhibited tumor growth and proliferation in lung cancer, which may be accomplished by inhibiting tumor angiogenesis and inducing apoptosis (AU)

CCL21/CCR7 axis as a therapeutic target for autoimmune diseases.

Chemokine receptor 7 (CCR7) is a G protein-coupled receptor containing 7 transmembrane domains that is expressed on various cells, such as naive T/B cells, central memory T cells, regulatory T cells, immature/mature dendritic cells (DCs), natural killer cells, and a minority of tumor cells. Chemokine ligand 21 (CCL21) is the known high-affinity ligand that binds to CCR7 and drives cell migration in tissues. CCL21 is mainly produced by stromal cells and lymphatic endothelial cells, and its expression is significantly increased under inflammatory conditions. Genome-wide association studies (GWAS) have shown a strong association between CCL21/CCR7 axis and disease severity in patients with rheumatoid arthritis, sjogren's syndrome, systemic lupus erythematosus, polymyositis, ankylosing spondylitis, and asthma. Disrupting CCL21/CCR7 interaction with antibodies or inhibitors prevents the migration of CCR7-expressing immune and non-immune cells at the site of inflammation and reduces disease severity. This review emphasizes the importance of the CCL21 /CCR7 axis in autoimmune diseases and evaluates its potential as a novel therapeutic target for these conditions.

Comprehensive analysis and molecular map of Hippo signaling pathway in lower grade glioma: the perspective toward immune microenvironment and prognosis.

Background: The activation of YAP/TAZ transcriptional co-activators, downstream effectors of the Hippo/YAP pathway, is commonly observed in human cancers, promoting tumor growth and invasion. The aim of this study was to use machine learning models and molecular map based on the Hippo/YAP pathway to explore the prognosis, immune microenvironment and therapeutic regimen of patients with lower grade glioma (LGG). Methods: SW1783 and SW1088 cell lines were used as in vitro models for LGG, and the cell viability of the XMU-MP-1 (a small molecule inhibitor of the Hippo signaling pathway) treated group was evaluated using a Cell Counting Kit-8 (CCK-8). Univariate Cox analysis on 19 Hippo/YAP pathway related genes (HPRGs) was performed to identify 16 HPRGs that exhibited significant prognostic value in meta cohort. Consensus clustering algorithm was used to classify the meta cohort into three molecular subtypes associated with Hippo/YAP Pathway activation profiles. The Hippo/YAP pathway's potential for guiding therapeutic interventions was also investigated by evaluating the efficacy of small molecule inhibitors. Finally, a composite machine learning models was used to predict individual patients' survival risk profiles and the Hippo/YAP pathway status. Results: The findings showed that XMU-MP-1 significantly enhanced the proliferation of LGG cells. Different Hippo/YAP Pathway activation profiles were associated with different prognostic and clinical features. The immune scores of subtype B were dominated by MDSC and Treg cells, which are known to have immunosuppressive effects. Gene Set Variation Analysis (GSVA) indicated that subtypes B with a poor prognosis exhibited decreased propanoate metabolic activity and suppressed Hippo pathway signaling. Subtype B had the lowest IC50 value, indicating sensitivity to drugs that target the Hippo/YAP pathway. Finally, the random forest tree model predicted the Hippo/YAP pathway status in patients with different survival risk profiles. Conclusions: This study demonstrates the significance of the Hippo/YAP pathway in predicting the prognosis of patients with LGG. The different Hippo/YAP Pathway activation profiles associated with different prognostic and clinical features suggest the potential for personalized treatments.

Safety, tolerance, and pharmacokinetics of salvianolic acid B in healthy Chinese volunteers: A randomized, double-blind, placebo-controlled phase 1 clinical trial.

Background: Salvianolic acid B (Sal B) is one of the main active ingredients of Salvia miltiorrhiza Bunge. In China, many traditional Chinese medicines have been modified into injections for higher bioavailability and better efficacy. Salvianolic acid injection has been widely used in the clinic. Objective: This phase 1, randomized, double-blind, placebo-controlled, single-center study aimed to evaluate the safety, tolerance, and pharmacokinetics of Sal B injection in healthy Chinese volunteers. Methods: For the single-ascending-dose study, forty-seven healthy volunteers were randomly divided into 25, 75, 150, 200, 250, and 300 mg groups. For the multiple-ascending-dose study, sixteen healthy volunteers were randomly divided into 150 and 300 mg groups. In each group, volunteers were treated with Sal B or placebo randomly. Their safety was evaluated by a skin test, physical examination, vital sign, laboratory examination, 12-lead electrocardiogram, Holter, and clinical symptoms and signs. Blood samples were collected in 75, 150, and 300 mg single-ascending-dose study groups and 150 mg multiple-ascending-dose study groups to determine the concentration of salvianolic acid B. Results: In single-ascending-dose study groups, there were 41 adverse events in 24 cases (51.1%, 24/47). In multiple-ascending-dose study groups, there were 13 adverse events in eight cases (50.0%, 8/16). Sixty-six volunteers received the skin test, and three of them were excluded because of the positive result. Adverse events related to the treatment included increased alanine aminotransferase (4.0%), increased bilirubin (2.0%), increased creatinine kinase-MB (2.0%), increased brain natriuretic peptide (8.0%), increased urine N-acetyl-ß-D-glucosidase (4.0%), dizziness (2.0%), and chest discomfort (2.0%). No serious adverse events occurred. No volunteers withdrew from the trial. Peak plasma concentration and the area under the plasma concentration-time curve of salvianolic acid B progressively increased in a dose-dependent manner in 75, 150, and 300 mg single-ascending-dose study groups. There was no accumulation after 5 consecutive days of administration of 150 mg salvianolic acid B. Conclusion: Salvianolic acid B injections administered up to 300 mg in a single dose and 250 mg for 5 consecutive days showed excellent safety and tolerability in healthy Chinese volunteers. Clinical Trial Registration: www.chinadrugtrials.org.cn, identifier CTR20192236.