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Jin-Wei Lin,1– 3 Pei-Ying Lin,1,2 Tse-Yao Wang,1,2 Ying-Ju Chen,1,2 David Hung-Tsang Yen,1– 5 Hsien-Hao Huang1– 3 1Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 2Emergency Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 3Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 4Department of Nursing, Yuanpei University of Medical Technology, Hsinchu, Taiwan; 5Chang Bing Show-Chwan Memorial Hospital, Changhua City, TaiwanCorrespondence: Hsien-Hao Huang, Department of Emergency Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112201, Taiwan, Email hhhuang@vghtpe.gov.twBackground: Frailty epitomizes the most complex consequence of an aging population. This study aimed to evaluate the impact of frailty, measured using the Clinical Frailty Scale (CFS), on outcomes of older people in an emergency department (ED).Methods: We conducted a prospective observational study enrolling patients aged 65 years and older in a medical center of Taiwan between March 8, 2021, and November 30, 2021. The primary outcome was 90-day mortality rate. Individuals were categorized into three groups based on the CFS scores. Logistic regression was employed to examine the influence of frailty on clinical outcomes following covariate adjustment. Survival analysis was conducted using Kaplan–Meier curves and Log rank tests.Results: A total of 473 individuals were included in the study, with a mean age of 82.1 years, and 60.5% of them were males. The 90-day mortality rate was 10.6%. Among these groups, the CFS score 7– 9 group had the highest 90-day mortality rate (15.9%), followed by the CFS score 4– 6 group (8.0%) and the CFS score 1– 3 group (7.1%). The multiple logistic regression analyses demonstrated a significant impact of CFS score on prognosis, with adjusted odd ratios of 1.24 (95% CI 1.06– 1.47) for 90-day mortality, 1.18 (95% CI 1.06– 1.31) for hospitalization, and 1.30 (95% CI 1.12– 1.52) for 180-day mortality. The Kaplan–Meier curves revealed a significantly higher 90-day mortality rate for patients with high CFS scores (Log rank tests, p = 0.019).Conclusion: In the older ED population, the severity of frailty assessed by the CFS emerged as a significant and important prognostic factor for hospitalization, 90-day mortality, and 180-day mortality.Keywords: frailty, emergency service, hospital, triage, mortality

AIM: To assess the clinical efficacy of visual therapy in children with abnormal visual functions and asthenopia.METHODS: Retrospective case study. The data of 57 patients(114 eyes), aged 8.25±1.94 years, who underwent visual training at the optometry center of Xi'an Children's Hospital between January 2022 and April 2023, were collected. Patient assessments before and after training included refractive errors, a visual fatigue scale questionnaire, and visual function tests. These tests included the Worth 4 Dot for binocular vision, the Von Graefe method for measuring latent strabismus at distance and near, the gradient method for assessing the accommodative convergence/accommodation(AC/A)ratio, the push-up test for convergence near point, the negative lens method for amplitude of accommodation, the cross-cylinder test for accommodative response, and the flipper test for accommodative flexibility. Training programs were tailored based on the initial assessments of visual function and asthenopia. Comparisons were made between pre-training, 1 and 3 mo post-training evaluations.RESULTS: At baseline and 1 mo post-training, the visual fatigue scores were 26.00±6.77 and 19.57±8.90, respectively(P0.05). Furthermore, no significant differences were noted in the binocular amplitude of accommodation, NRA, PRA, and near phoria between 1 and 3 mo after training(all P>0.05). The visual function parameters of 30 patients with low myopia(SE: -1.99±1.22 D), 3 patients with low hyperopia(SE: +1.01±0.13 D)and 24 patients with emmetropia(SE: +0.25±0.11 D)were not statistically significant before training and at 1 mo after training(all P>0.05). Certain visual functions significantly improved at 1 mo after training, and most had returned normal by 3 mo.CONCLUSION: Vision therapy significantly enhances binocular visual function and alleviates symptoms of asthenopia in children with visual dysfunction. It is an effective, straightforward, and easily applicable method for relieving children's visual fatigue.

Abstract This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8–not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4–15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7–63.5) and 69.7% (95% CI: 55.7–87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.

Abstract Background Many patients undergo dose reduction or early termination of chemotherapy to reduce chemoradiotherapy-related toxicity, which may increase their risk of survival. However, this strategy may result in underdosing patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This study aimed to analyze the relationship between the relative dose intensity (RDI) and survival outcomes in patients with LA-ESCC. Methods This retrospective study assessed patients with LA-ESCC (cT2N + M0, cT3-4NanyM0) receiving neoadjuvant chemoradiotherapy (NCRT) with curative-intent esophagectomy. The patients received 2 courses of paclitaxel plus carboplatin (TC) combination radiotherapy prior to undergoing surgery. During NCRT, RDI was computed, defined as the received dose as a percentage of the standard dose, and the incidence of dose delays was estimated (≥ 7 days in any course cycle). The best RDI cutoff value (0.7) was obtained using ROC curve. The Kaplan–Meier survival curves were compared using the log-rank test, the treatment effect was measured using hazard ratios (HR) and 95% confidence intervals (CI). Results We included 132 patients in this study, divided into RDI

In plasma transferred arc welding (PTAW), the weld pool temperature often fluctuates. The spray weld layer is prone to overheating, leading to adverse effect on its performance. This study investigated the influence of spray welding current on the weld pool temperature and in turn on the microstructure, microhardness and corrosion resistance of the PTAW-Ni layer on a steel substrate. Weld pool temperature increased with increasing spray welding current and varied along the welding gun path before reaching the steady state. With increasing pool temperature, more Fe diffused from the substrate into the spray weld layer, leading to a widened fusion zone, an increased dilution rate and a decreased microhardness. The spray weld layer has a dendritic microstructure. The dendrites have a higher Cr content, while the interdendritic regions have a higher Ni content. Increasing weld pool temperature increased diffusion, resulting in reduced enrichment of the Cr and Ni elements. The increase of Fe and decrease of Cr in the spray weld layer caused the decreasing corrosion resistance.

Abstract Prolyl 4-hydroxylases (P4Hs) are a family of key modifying enzymes in collagen synthesis. P4Hs have been confirmed to be closely associated with tumor occurrence and development. However, the expression of P4Hs in head and neck cancer (HNSC) as well as its relationship with prognosis and tumor immunity infiltration has not yet been analyzed. We investigated the transcriptional expression, survival data, and immune infiltration of P4Hs in patients with HNSC from multiple databases. P4H1-3 expression was significantly higher in HNSC tumor tissues than in normal tissues. Moreover, P4HA1 and P4HA2 were associated with tumor stage, patient prognosis, and immune cell infiltration. P4HA3 was related to patient prognosis and immune cell infiltration. Correlation experiments confirmed that P4HA1 may serve as a prognosis biomarker and plays a role in the progression of nasopharyngeal carcinoma. These findings suggest that P4HA1-3 may be a novel biomarker for the prognosis and treatment of HNSC, which is expected to support the development of new therapies for patients with head and neck tumors and improve patient outcomes.

Guangtian Wang,1,2,* Zhihui Li,3,* Gongchen Wang,4,* Qixu Sun,5 Peng Lin,1 Qian Wang,2 Huishu Zhang,6 Yanyan Wang,7 Tongshuai Zhang,8 Feiyun Cui,9 Zhaohua Zhong1,2 1Teaching Center of Pathogenic Biology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 2Department of Microbiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 3Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, People’s Republic of China; 4Department of Vascular Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, People’s Republic of China; 5Department of Gastroenterology, Penglai People’s Hospital, Yantai, Shandong, 265600, People’s Republic of China; 6Teaching Center of Biotechnology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 7Teaching Center of Morphology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 8Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China; 9Department of Physiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, 150081, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhaohua Zhong; Feiyun Cui, Email zhongzh@hrbmu.edu.cn; feiyun@hrbmu.edu.cnAbstract: Angiogenesis, or the formation of new blood vessels, is a natural defensive mechanism that aids in the restoration of oxygen and nutrition delivery to injured brain tissue after an ischemic stroke. Angiogenesis, by increasing vessel development, may maintain brain perfusion, enabling neuronal survival, brain plasticity, and neurologic recovery. Induction of angiogenesis and the formation of new vessels aid in neurorepair processes such as neurogenesis and synaptogenesis. Advanced nano drug delivery systems hold promise for treatment stroke by facilitating efficient transportation across the the blood-brain barrier and maintaining optimal drug concentrations. Nanoparticle has recently been shown to greatly boost angiogenesis and decrease vascular permeability, as well as improve neuroplasticity and neurological recovery after ischemic stroke. We describe current breakthroughs in the development of nanoparticle-based treatments for better angiogenesis therapy for ischemic stroke employing polymeric nanoparticles, liposomes, inorganic nanoparticles, and biomimetic nanoparticles in this study. We outline new nanoparticles in detail, review the hurdles and strategies for conveying nanoparticle to lesions, and demonstrate the most recent advances in nanoparticle in angiogenesis for stroke treatment. Keywords: angiogenesis, ischemic stroke, nanoparticles, blood brain barrier, neurogenesis, neuroprotection therapy

Chinese plum (Prunus salicina Lindl.) originates from China and makes a large contribution to the global production of plums. The P. salicina ‘Wushancuili’ has a green coloration and high fruit quality and is economically important in eliminating poverty and protecting ecology in the Yangtze River Three Gorges Reservoir. However, rain-induced cracking (rain-cracking, literally skin cracking caused by rain) is a limitation to ‘Wushancuili’ fruit production and causes severe losses. This study reported a high-quality ‘Wushancuili’ genome assembly consisting of a 302.17-Mb sequence with eight pseudo-chromosomes and a contig N50 of 23.59 Mb through the combination of Illumina sequencing, Pacific Biosciences HiFi Ⅲ sequencing, and high-throughput chromosome conformation capture technology. A total of 25 109 protein-coding genes are predicted and 54.17% of the genome is composed of repetitive sequences. ‘Wushancuili’ underwent a remarkable orthoselection during evolution. Gene identification revealed that loss-of-function in four core MYB10 genes results in the anthocyanin deficiency and absence of red color, revealing the green coloration due to the residual high chlorophyll in fruit skin. Besides, the occurrence of cracking is assumed to be closely associated with cell wall modification and frequently rain-induced pathogen enrichment through transcriptomic analysis. The loss of MYB10 genes might render fruit more susceptible to pathogen-mediated cracking by weakening the epidermal strength and reactive oxygen species (ROS) scavenging. Our findings provided fundamental knowledge regarding fruit coloration and rain-cracking and will facilitate genetic improvement and cultivation management in Chinese plums.

Abstract Introduction Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). Methods This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. Results The study enrolled 49 HVs, with a median age of 39 (range 18–73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (C max) and area under the concentration–time curve from time 0 to infinity (AUC0–inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition. Conclusion RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. Trial Registration ISRCTN13175485.

Cardiovascular disease (CVD) is one of the leading causes of mortality in humans, and oxidative stress plays a pivotal role in disease progression. This phenomenon typically arises from weakening of the cellular antioxidant system or excessive accumulation of peroxides. This review focuses on a specialized form of oxidative stress—disulfide stress—which is triggered by an imbalance in the glutaredoxin and thioredoxin antioxidant systems within the cell, leading to the accumulation of disulfide bonds. The genesis of disulfide stress is usually induced by extrinsic pathological factors that disrupt the thiol-dependent antioxidant system, manifesting as sustained glutathionylation of proteins, formation of abnormal intermolecular disulfide bonds between cysteine-rich proteins, or irreversible oxidation of thiol groups to sulfenic and sulfonic acids. Disulfide stress not only precipitates the collapse of the antioxidant system and the accumulation of reactive oxygen species, exacerbating oxidative stress, but may also initiate cellular inflammation, autophagy, and apoptosis through a cascade of signaling pathways. Furthermore, this review explores the detrimental effects of disulfide stress on the progression of various CVDs including atherosclerosis, hypertension, myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, cardiac hypertrophy, and heart failure. This review also proposes several potential therapeutic avenues to improve the future treatment of CVDs.

Background Oesophageal squamous cell carcinoma (OSCC) poses a considerable health burden, particularly in regions such as East Asia. This study aims to investigate the long-term outcomes of OSCC patients who are smokers and drinkers.Materials and methods In this retrospective analysis, data from Sichuan Cancer Hospital and Institute Esophageal Cancer Case Management Database between January 2010 and December 2017 were examined. Patients were categorised into different groups based on their smoking and alcohol consumption history: None, Smoker, Non-Smoker, Smoke-Only, Drinker, Non-Drinker, Drinker-Only, and Both. Survival outcomes were compared between the groups using Kaplan-Meier analysis and propensity score matching (PSM). The primary outcome was overall survival (OS), measured from surgery to death or last follow-up in April 2022.Results The OS median was 45.4 months for all patients after oesophagectomy. Smokers had a significantly lower median OS of 36.6 months compared with Non-Smokers with 66.2 months (p

Yunling cattle is a new breed of beef cattle bred in Yunnan Province, China, which has the advantages of fast growth, excellent meat quality, improved tolerance ability, and important landscape value. Copy number variation (CNV) is a significant source of gene structural variation and plays a crucial role in evolution and phenotypic diversity. Based on the latest reference genome ARS-UCD2.0, this study analyzed the genome-wide distribution of CNVs in Yunling cattle using short-read whole-genome sequencing data (n = 129) and single-molecule long-read sequencing data (n = 1), and a total of 16,507 CNVs were detected. After merging CNVs with overlapping genomic positions, 3,728 CNV regions (CNVRs) were obtained, accounting for 0.61% of the reference genome. The functional analysis indicated significant enrichment of CNVRs in 96 GO terms and 57 KEGG pathways, primarily related to cell adhesion, signal transduction, neuromodulation, and nutritional metabolism. Additionally, 111 CNVRs overlapped with 76 quantitative trait loci (QTLs), including Subcutaneous fat thickness QTL, Longissimus muscle area QTL, and Marbling score QTL. Several CNVR-overlapping genes, including BZW1, AOX1, and LOC100138449, overlap with regions associated with meat color and quality QTLs. Furthermore, Vst analysis showed that PSMB4, ERICH1, SMC2, and PPP4R3A were highly divergent between Yunling and Brahman cattle. In summary, we have constructed the genomic CNV map of Yunling cattle for the first time using whole-genome resequencing. This provides valuable genetic variation resources for the study of the Yunling cattle genome and contributes to the study of economic traits in Yunling cattle.

Craniospinal irradiation (CSI) poses a challenge to treatment planning due to the large target, field junction, and multiple organs at risk (OARs) involved. The aim of this study was to evaluate the performance of knowledge-based planning (KBP) in CSI by comparing original manual plans (MP), KBP RapidPlan initial plans (RPI), and KBP RapidPlan final plans (RPF), which received further re-optimization to meet the dose constraints.

Abstract High heterogeneity and complex interactions of malignant cells in breast cancer has been recognized as a driver of cancer progression and therapeutic failure. However, complete understanding of common cancer cell states and their underlying driver factors remain scarce and challenging. Here, we revealed seven consensus cancer cell states recurring cross patients by integrative analysis of single-cell RNA sequencing data of breast cancer. The distinct biological functions, the subtype-specific distribution, the potential cells of origin and the interrelation of consensus cancer cell states were systematically elucidated and validated in multiple independent datasets. We further uncovered the internal regulons and external cell components in tumor microenvironments, which contribute to the consensus cancer cell states. Using the state-specific signature, we also inferred the abundance of cells with each consensus cancer cell state by deconvolution of large breast cancer RNA-seq cohorts, revealing the association of immune-related state with better survival. Our study provides new insights for the cancer cell state composition and potential therapeutic strategies of breast cancer.

Abstract The disruption of circadian rhythms caused by long-term shift work can cause metabolic diseases such as obesity. Early growth response 3 (EGR3) is a member of early growth response (EGR) family, which is involved in several cellular responses, had been reported as a circadian rhythm gene in suprachiasmatic nucleus. In this research, EGR3 was found to be widely expressed in the different tissue of human and mice, and downregulated in adipose tissue of obese subjects and high-fat diet mice. Moreover, EGR3 was found negatively regulated by cortisol. In addition, EGR3 is a key negative modulator of hADSCs and 3T3-L1 adipogenesis via regulating HDAC6, which is a downstream target gene of EGR3 and a negative regulator of adipogenesis and lipogenesis. These findings may explain how circadian rhythm disorder induced by shift works can cause obesity. Our study revealed a potential therapeutic target to alleviate metabolic disorders in shift workers and may provide better health guidance to shift workers.

To investigate the hot deformation characteristics, workability, and interfacial microstructure of the titanium/steel bimetallic composite, hot compression simulations were carried out on the TA1/SUS430 composite within the temperatures of 750 °C–1050 °C, accompanied by strain rates spanning from 0.01 s⁻1–10 s⁻1. The hyperbolic sine Arrhenius constitutive equation and back-propagation artificial neural network (BP-ANN) model for flow stresses of this bimetallic composite were developed. 2D and 3D hot processing maps were established to study processability. The results revealed the calculated average activation energy (Q) was 277.9671 kJ/mol. The BP-ANN model demonstrated higher prediction accuracy than the Arrhenius model, with a correlation coefficient (R2) of 0.99947. As the strain increases, the area of the unstable region in the processing map expands, and the failure mode is characterized by the formation of microcracks at the bonded interface. Interfacial exfoliation manifested under elevated temperature and high strain rate deformation conditions. High power dissipation (η) values were observed within the processing parameters of 875°C–950 °C/0.01 s−1-0.03 s−1. The bimetal exhibited superior deformation coordination at low strain rates. TiC predominantly constituted the interface products at lower temperatures, while at higher temperatures, phases containing both Fe and Ti dominated. Furthermore, the deformed steel stratum manifested a pronounced cubic orientation //CD and a less dominant recrystallized γ orientation. This γ texture attenuated progressively with increased deformation temperatures, while the strain rate has less impact.

Abstract Yunling cattle is a new breed of beef cattle bred in Yunnan Province, China. It is bred by crossing the Brahman, the Murray Grey and the Yunnan Yellow cattle. Yunling cattle can adapt to the tropical and subtropical climate environment, and has good reproductive ability and growth speed under high temperature and high humidity conditions, it also has strong resistance to internal and external parasites and with good beef performance. In this study, we generated a high-quality chromosome-level genome assembly of a male Yunling cattle using a combination of short reads sequencing, PacBio HiFi sequencing and Hi-C scaffolding technologies. The genome assembly(3.09 Gb) is anchored to 31 chromosomes(29 autosomes plus one X and Y), with a contig N50 of 35.97 Mb and a scaffold N50 of 112.01 Mb. It contains 1.62 Gb of repetitive sequences and 20,660 protein-coding genes. This first construction of the Yunling cattle genome provides a valuable genetic resource that will facilitate further study of the genetic diversity of bovine species and accelerate Yunling cattle breeding efforts.

Chenyu Tang,1 Ping Lin,2 Yige Zhao,1 Panpan Wang,1 Ping Wang3 1Department of Dermatology, Hangzhou Third People’s Hospital, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Gerontology, Hangzhou Third People’s Hospital, Hangzhou, People’s Republic of China; 3Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou, People’s Republic of ChinaCorrespondence: Ping Wang, Department of Dermatology, Hangzhou Third People’s Hospital, Xihu Avenue No. 38, Hangzhou, Zhejiang, 310009, People’s Republic of China, Tel +86-13588812862, Email dermwang@aliyun.comPurpose: To summarize the clinical, histopathological and therapeutic features of senile gluteal dermatosis.Patients and Methods: Retrospective analysis of 230 cases who visited the outpatient clinic of Hangzhou No. 3 People’s Hospital for skin lesions on the buttocks and hips from 2018.8– 2023.8 were included in the study, basic clinical information was collected, and they were subjected to physical examination of the buttocks and hips, and 36 cases were senile gluteal dermatosis, of which 7 underwent histopathological biopsy.Results: A total of 230 patients were included, of which 36 were diagnosed with geriatric buttock dermatosis, with a mean age of (84.2± 12.6) years, mean body mass index of (21.7± 3.8) kg/m2, and a male to female ratio of 2:1. There was a significant correlation between the occurrence of the disease and age, gender, body mass index, sedentary time, type of chair used, and hypertension (P< 0.05). The severity of the lesions may be associated with longer sitting time and prolonged use of bamboo chairs (P< 0.05). Histopathologic changes were not specific. The skin lesions could subside after general treatment such as improvement of lifestyle, use of pressure-reducing air mattresses, salicylic acid cream, and moisturizing creams.Conclusion: Senile gluteal dermatosis is a common senile physical dermatosis, mainly manifested as brownish scaly plaques, erythema and crusted ulcers, which can often be cured under reasonable treatment.Keywords: skin diseases, physical, gluteal dermatosis, pressure injury, friction

Abstract Background Cyclin-dependent kinase-2 (CDK-2) is an important regulatory factor in the G1/S phase transition. CDK-2 targeting has been shown to suppress the viability of multiple cancers. However, the exploration and application of a CDK-2 inhibitor in the treatment of glioblastoma are sparse. Methods We synthesized P129 based on isolongifolanone, a natural product with anti-tumor activity. Network pharmacology analysis was conducted to predict the structural stability, affinity, and pharmacological and toxicological properties of P129. Binding analysis and CETSA verified the ability of P129 to target CDK-2. The effect of P129 on the biological behavior of glioma cells was analyzed by the cell counting kit-8, colony formation, flow cytometry, and other experiments. Western blotting was used to detect the expression changes of proteins involved in the cell cycle, cell apoptosis, and epithelial–mesenchymal transition. Results Bioinformatics analysis and CETSA showed that P129 exhibited good intestinal absorption and blood–brain barrier penetrability together with high stability and affinity with CDK-2, with no developmental toxicity. The viability, proliferation, and migration of human glioma cells were significantly inhibited by P129 in a dose- and time-dependent manner. Flow cytometry and western blotting analyses showed G0/G1 arrest and lower CDK-2 expression in cells treated with P129 than in the controls. The apoptotic ratio of glioma cells increased significantly with increasing concentrations of P129 combined with karyopyknosis and karyorrhexis. Apoptosis occurred via the mitochondrial pathway. Conclusion The pyrazole ring-containing isolongifolanone derivate P129 exhibited promising anti-glioma activity by targeting CDK-2 and promoting apoptosis, indicating its potential importance as a new chemotherapeutic option for glioma.

Zhengyu Fang,1,&ast; Peihong Lin,1,&ast; Rui Gao,1,&ast; Wenjing Yang,1 Aizhen Zhou,2 Wenying Yu1,3 1School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China; 2Department of Traditional Chinese Medicine, Zhejiang Pharmaceutical University, Ningbo, 315500, People’s Republic of China; 3Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aizhen Zhou; Wenying Yu, Tel +86 571 88215623, Email zhouaz@zjpc.net.cn; zjyuwenying@163.comBackground: Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, is a potential candidate for cancer chemotherapy. However, Tet has poor aqueous solubility and a short half-life, which limits its bioavailability and efficacy. Liposomes have been widely utilized to enhance the bioavailability and efficacy of drugs.Methods: In this study, Tet-loaded stealth liposomes (S-LPs@Tet) were prepared by ethanol injection method. Furthermore, physicochemical characterisation, biopharmaceutical behaviour, therapeutic efficacy, and biocompatibility of S-LPs@Tet were assessed.Results: The prepared S-LPs@Tet had an average particle size of 65.57 ± 1.60 nm, a surface charge of − 0.61 ± 0.10 mV, and an encapsulation efficiency of 87.20% ± 1.30%. The S-LPs@Tet released Tet in a sustained manner, and the results demonstrated that the formulation remained stable for one month. More importantly, S-LPs significantly enhanced the inhibitory ability of Tet on the proliferation and migration of lung cancer cells, and enabled Tet to escape phagocytosis by immune cells. Furthermore, in vivo studies confirmed the potential for long-circulation and potent tumor-suppressive effects of S-LPs@Tet. Moreover, ex vivo and in vivo safety experiments demonstrated that the carrier material S-LPs exhibited superior biocompatibility.Conclusion: Our research suggested that S-LPs@Tet has potential applications in lung cancer treatment.Keywords: tetrandrine, S-LPs, lung cancer, immune escape, in vivo imaging

Abstract Background To investigate the impact of radiotherapy (RT) on recurrence and survival in patients with locally advanced upper rectal cancer underwent curative resection. Methods 363 locally advanced upper rectal cancer cases were identified from the database of our hospital from 2010 to 2018. All patients underwent curative resection and had the lower margin of the tumor located 10–15 cm from the anal verge, among them, 69 patients received pre- or post-operative radiotherapy and 294 patients without. Local control and survivals were compared, and stratification grouping based on European Society for Medical Oncology risk factors were further compared. 1:2 propensity score matching analysis was used to reduce the impact of confounding factors. Results There were 207 patients after 1:2 matching (RT group:non-RT group = 69:138). The 5-year overall survival (OS) of the RT group and non-RT group after matching was 84.1% and 80.9%, respectively(P = 0.440); the 5-year local recurrence-free survival (LRFS) was 96.5% and 94.7%, respectively(P = 0.364); the 5-year distant metastasis-free survival (DMFS) was 76.8% and 76.9%, respectively(P = 0.531). Subgroup analysis showed that radiotherapy could not significantly improve the overall survival, local recurrence, and distant metastasis with or without poor prognostic features. In the high-risk subgroup, the 5-year OS was 76.9% and 79.6% for patients treated with radiotherapy and without (P = 0.798), LRFS was 94.8% and 94.2%, respectively (P = 0.605), DMFS 68.7% and 74.7%, respectively (P = 0.233). Conclusions Our results suggest that radiotherapy could not improve local control and survival for locally advanced upper rectal cancer patients underwent curative resection, even in the cases with poor prognostic features.

In traditional Chinese medicine (TCM), artificial intelligence (AI)-assisted syndrome differentiation and disease diagnoses primarily confront the challenges of accurate symptom identification and classification. This study introduces a multi-label entity extraction model grounded in TCM symptom ontology, specifically designed to address the limitations of existing entity recognition models characterized by limited label spaces and an insufficient integration of domain knowledge. This model synergizes a knowledge graph with the TCM symptom ontology framework to facilitate a standardized symptom classification system and enrich it with domain-specific knowledge. It innovatively merges the conventional bidirectional encoder representations from transformers (BERT) + bidirectional long short-term memory (Bi-LSTM) + conditional random fields (CRF) entity recognition methodology with a multi-label classification strategy, thereby adeptly navigating the intricate label interdependencies in the textual data. Introducing a multi-associative feature fusion module is a significant advancement, thereby enabling the extraction of pivotal entity features while discerning the interrelations among diverse categorical labels. The experimental outcomes affirm the model's superior performance in multi-label symptom extraction and substantially elevates the efficiency and accuracy. This advancement robustly underpins research in TCM syndrome differentiation and disease diagnoses.

Objectives: The present study was conducted to explore the performance of micronutrients in the prediction and prevention of coronavirus disease 2019 (COVID-19). Methods: This is an observational case-control study. 149 normal controls (NCs) and 214 COVID-19 patients were included in this study. Fat-soluble and water-soluble vitamins were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, and inorganic elements were detected by inductively coupled plasma-mass spectrometry (ICP-MS) analysis. A logistic regression model based on six micronutrients were constructed using DxAI platform. Results: Many micronutrients were dysregulated in COVID-19 compared to normal control (NC). 25-Hydroxyvitamin D3 [25(OH)D3], magnesium (Mg), copper (Cu), calcium (Ca) and vitamin B6 (pyridoxic acid, PA) were significantly independent risk factors for COVID-19. The logistic regression model consisted of 25(OH)D3, Mg, Cu, Ca, vitamin B5 (VB5) and PA was developed, and displayed a strong discriminative capability to differentiate COVID-19 patients from NC individuals [area under the receiver operating characteristic curve (AUROC) = 0.901]. In addition, the model had great predictive ability in discriminating mild/normal COVID-19 patients from NC individuals (AUROC = 0.883). Conclusions: Our study showed that micronutrients were associated with COVID-19, and our logistic regression model based on six micronutrients has potential in clinical management of COVID-19, and will be useful for prediction of COVID-19 and screening of high-risk population.

Abstract Patients with chronic obstructive pulmonary disease (COPD) who exhibit elevated blood eosinophil levels often experience worsened lung function and more severe emphysema. This implies the potential involvement of eosinophils in the development of emphysema. However, the precise mechanisms underlying the development of eosinophil-mediated emphysema remain unclear. In this study, we employed single-cell RNA sequencing to identify eosinophil subgroups in mouse models of asthma and emphysema, followed by functional analyses of these subgroups. Assessment of accumulated eosinophils unveiled distinct transcriptomes in the lungs of mice with elastase-induced emphysema and ovalbumin-induced asthma. Depletion of eosinophils through the use of anti-interleukin-5 antibodies ameliorated elastase-induced emphysema. A particularly noteworthy discovery is that eosinophil-derived cathepsin L contributed to the degradation of the extracellular matrix, thereby leading to emphysema in pulmonary tissue. Inhibition of cathepsin L resulted in a reduction of elastase-induced emphysema in a mouse model. Importantly, eosinophil levels correlated positively with serum cathepsin L levels, which were higher in emphysema patients than those without emphysema. Expression of cathepsin L in eosinophils demonstrated a direct association with lung emphysema in COPD patients. Collectively, these findings underscore the significant role of eosinophil-derived cathepsin L in extracellular matrix degradation and remodeling, and its relevance to emphysema in COPD patients. Consequently, targeting eosinophil-derived cathepsin L could potentially offer a therapeutic avenue for emphysema patients. Further investigations are warranted to explore therapeutic strategies targeting cathepsin L in emphysema patients.

Objective Systemic lupus erythematosus (SLE) is a type of autoimmune disease that involves multiple organs involved as well as cytokine dysregulation. The treatment of SLE is still challenging due to the side effects of the different drugs used. Receptor-interacting protein kinase 1 (RIPK1) is a kinase involved in T cell homeostasis and autoinflammation. Although clinical trials have shown that RIPK1 inhibition exhibits significant efficacy in different autoimmune diseases, its role in SLE remains unclear.Methods MRL/lpr lupus-prone mice received RIPK1 inhibitor ZJU37 or vehicle intraperitoneally for 10 weeks. A BM12-induced chronic graft-versus-host-disease (cGVHD) lupus-like model was introduced in RIPK1 D138N mice or C57BL/6 mice. Nephritis, serum autoantibody levels, dysregulation of adaptive immune response and cytokines were compared in treated and untreated mice.Results ZJU37 alleviated the clinical features of the MRL/lpr mice including nephritis and anti-dsDNA antibody production. In addition, ZJU37 treatment reduced the proportion of double-negative T cells in the spleen and the cytokines of TNFα, IFN-γ, IL-6, IL-17 and IL-1β in the serum. Moreover, RIPK1 D138N mice were able to prevent the cGVHD lupus-like model from SLE attack, manifesting as anti-dsDNA antibody production, the proliferation of germinal centre B cells, plasma cells, and T follicular helper cells as well as IgG and C3 deposits in kidneys.Conclusion RIPK1 inhibition has a protective effect in the mouse model of SLE and can potentially become a new therapeutic target for SLE in humans.

Flavonoids are found in the roots, stems, leaves, and fruits of many plant taxa. They are related to plant growth and development, pigment formation, and protection against environmental stress. Flavonoids function as antioxidants and exert anti-inflammatory effects in the cardiovascular system by modulating classical inflammatory response pathways, such as the TLR4-NF-ĸB, PI3K-AKT, and Nrf2/HO-1 signalling pathways. There is increasing evidence for the therapeutic effects of flavonoids on hypertension, atherosclerosis, and other diseases. The potential clinical value of flavonoids for diseases of the cardiovascular system has been widely explored. For example, studies have evaluated the roles of flavonoids in the regulation of blood pressure via endothelium-dependent and non-endothelium-dependent pathways and in the regulation of myocardial systolic and diastolic functions by influencing calcium homeostasis and smooth muscle-related protein expression. Flavonoids also have hypoglycaemic, hypolipidemic, anti-platelet, autophagy, and antibacterial effects. In this paper, the role and mechanism of flavonoids in cardiovascular diseases were reviewed in order to provide reference for the clinical application of flavonoids in the future.

ABSTRACT COVID-19 caused by Omicron BA.1 has resulted in a global humanitarian crisis. In this COVID-19 pandemic era, hypertension has been receiving increased attention. Omicron BA.1 infection combined with hypertension created a serious public health problem and complicated the treatment and prognosis of COVID-19. The aim of our study was to assess the implications of hypertension for the clinical manifestations of adult patients (APs) infected with Omicron BA.1. This single-center retrospective cohort study enrolled consecutive COVID-19 APs, who were admitted to Tianjin First Central Hospital from 01 August 2022 to 30 November 2022. All included APs were divided into two groups: hypertension and non-hypertension group. The APs’ baseline demographic, laboratory, clinical, and radiological characteristics were collected and analyzed. Of 512 APs admitted with PCR proven COVID-19, 161 (31.45%) APs had comorbid hypertension. Hypertension APs have older age, higher body mass index, lower Ct-values of the viral target genes at admission, and longer hospital stay than non-hypertension APs. Furthermore, hypertension aggravates the clinical classification, impairs liver, kidney, and myocardium function, and abnormalizes the coagulation system in Omicron BA.1- infected APs. Moreover, hypertension elevates inflammation levels and lung lesion involvement while weakened virus-specific IgM level in APs with Omicron BA.1 infection. Hypertension APs tend to have worse clinical conditions at baseline than those non-hypertension APs. This study indicates that hypertension is a contributor to the poor clinical manifestations of Omicron BA.1-infected APs and supports that steps to control blood pressure should be a vital consideration for reducing the burden of Omicron BA.1 infection in hypertension individuals.IMPORTANCEThis study provided inclusive insight regarding the relationship between hypertension and Omicron BA.1 infection and supported that hypertension was an adverse factor for COVID-19 APs. In conclusion, this study showed that hypertension was considered to be associated with severe conditions, and a contributor to poor clinical manifestations. Proper medical management of hypertension patients is an imperative step in mitigating the severity of Omicron BA.1 variant infection.

Abstract Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing “immune classes” among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune “risk factors.” By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

Background: Secondary failure of platelet recovery (SFPR) is a common complication that influences survival and quality of life of patients with β-thalassemia major (β-TM) after hematopoietic stem cell transplantation (HSCT). Objectives: A model to predict the risk of SFPR in β-TM patients after HSCT was developed. Design: A retrospective study was used to develop the prediction model. Methods: The clinical data for 218 β-TM patients who received HSCT comprised the training set, and those for another 89 patients represented the validation set. The least absolute shrinkage and selection operator regression algorithm was used to identify the critical clinical factors with nonzero coefficients for constructing the nomogram. Calibration curve, C-index, and receiver operating characteristic curve assessments and decision curve analysis (DCA) were used to evaluate the calibration, discrimination, accuracy, and clinical usefulness of the nomogram. Internal and external validation were used to test and verify the predictive model. Results: The nomogram based on pretransplant serum ferritin, hepatomegaly, mycophenolate mofetil use, and posttransplant serum albumin could be conveniently used to predict the SFPR risk of thalassemia patients after HSCT. The calibration curve of the nomogram revealed good concordance between the training and validation sets. The nomogram showed good discrimination with a C-index of 0.780 (95% CI: 70.3–85.7) and 0.868 (95% CI: 78.5–95.1) and AUCs of 0.780 and 0.868 in the training and validation sets, respectively. A high C-index value of 0.766 was reached in the interval validation assessment. DCA confirmed that the nomogram was clinically useful when intervention was decided at the possibility threshold ranging from 3% to 83%. Conclusion: We constructed a nomogram model to predict the risk of SFPR in patients with β-TM after HSCT. The nomogram has a good predictive ability and may be used by clinicians to identify SFPR patients early and recommend effective preventive measures.

Background: Neglected tropical diseases (NTDs) usually affect the population living in poverty, especially in low- and middle-income countries located in tropical and subtropical regions. This study aimed to assess the awareness of NTDs and willingness to participate in prevention and control measures and their associated factors among healthcare students in Asian countries. Methods: This cross-sectional study was conducted by recruiting healthcare students from Asia mainly Bangladesh, India, Indonesia, Malaysia, and Syria. Data was collected via online Google form and analyzed in both descriptive and general linear model by using Statistical Package for the Social Sciences (SPSS). Results: A total of 1115 respondents participated; among them, 66.1% were medical and the majority (>70%) of the respondents revealed their willingness to participate in the prevention and control programmes. Being a medical student (B = 2.00, P

In the conventional process of geological hazard assessment, issues such as subjectivity in selecting susceptibility factor weights, randomness, and fuzziness in factor grading are prevalent. The application of a single assessment model can only provide qualitative evaluation of geological hazard susceptibility, lacking quantitative analysis. To overcome these challenges, this study employs an enhanced integrated algorithm (XGBoost) and cloud model. Among 189 disaster potential points in Chaoyang City, twelve susceptibility factors including slope, meteorological conditions, vegetation coverage and elevation were selected. The XGBoost classification algorithm was used to determine susceptibility factor weights. The results showed that the algorithm classification achieved high performance with fitting accuracy of 96.5%. On this basis, the cloud model was employed to transform the fuzzy factor grading into a quantitative problem, establishing a susceptibility evaluation index system for geological hazards in Chaoyang City, thereby assessing their susceptibility. To validate the evaluation index system, the Dadongshan landslide in Chaoyang City was selected as the assessment unit. Results indicate a high susceptibility level for this evaluation unit, consistent with actual conditions. The methodology proposed in this study is promising and can offers reference for evaluating geological hazard susceptibility.

Feifei Sun,1,&ast; Chenjing Wang,1,&ast; Yi Xu,1 Pingping Lin,1 Yaozhong Cao,2 Jiahui Zhang,3 Xin Li,1 Xin Jiang,1 Yao Fu,1 Yu Cao1 1Clinical Trials Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Clinical Medical Center, Xiuzheng Pharmaceutical Group, Hangzhou, Zhejiang, People’s Republic of China; 3Xiuzheng Bio-Medicine Research Institute, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Cao, Clinical Trials Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China, Tel +86 532 82911767, Email caoyu@qdu.edu.cnIntroduction: Hyperuricemia is a disease with abnormal purine metabolism, which leads to the increase of urate concentration. It is an independent risk factor for the occurrence and development of metabolic syndrome, type 2 diabetes, hypertension, cardiovascular disease, chronic kidney disease, and gout. The enzyme urate oxidase can metabolize urate to allantoin, resulting in decreased urate concentrations. Pegylated the urate oxidase can extend half-life and decrease immunogenicity of the protein. This trial aims to evaluate the safety, tolerability, pharmacokinetics(PK), pharmacodynamics(PD) and immunogenicity of a new intravenous PEGylated urate oxidase produced by Xiuzheng Bio-Medicine Research Institute Co., Ltd.Methods and Analysis: A randomized, double-blind, placebo-controlled, phase I, dose escalation study will be conducted in China. In total, 56 subjects will be enrolled in the study, with 24 healthy subjects in the low dose-escalation stage and 32 patients with hyperuricemia in the high dose-escalation stage. There is a bridging between the two stages. Subjects are randomized to PEGylated urate oxidase or the placebo in a 3:1 ratio in each group and followed up for 71 days observation. The primary outcomes include PK, PD, tolerability; the secondary outcomes include safety and immunogenicity.Ethics and Dissemination: The trial is performed abiding by the Declaration of Helsinki, Good clinical practice (GCP) and the guidelines of China National Medical Products Administration (NMPA). Relevant documents, including protocol, informed consent and drug inspection report, are all approved independently by the Medical Ethics Committee of the Affiliated Hospital of Qingdao University. The first subject was enrolled on January 17, 2022.Trial Registration: Clinicaltrials, NCT05226013 (Registered April 2, 2022, Retrospectively registered). ChinaDrugTrials, CTR20211801(Registered July 27, 2021).Keywords: PEGylated urate oxidase, healthy volunteers, patients with hyperuricemia, study protocol

Abstract Background Cellular states of different immune cells can affect the activity of the whole immune microenvironment. Methods Here, leveraging reference profiles of microenvironment cell states that were constructed based on single-cell RNA-seq data of melanoma, we dissected the composition of microenvironment cell states across 463 skin cutaneous melanoma (SKCM) bulk samples through CIBERSORT-based deconvolution of gene expression profiles and revealed high heterogeneity of their distribution. Correspondence analysis on the estimated cellular fractions of melanoma bulk samples was performed to identify immune phenotypes. Based on the publicly available clinical survival and therapy data, we analyzed the relationship between immune phenotypes and clinical outcomes of melanoma. Results By analysis of the relationships among those cell states, we further identified three distinct tumor microenvironment immune phenotypes: “immune hot/active”, “immune cold-suppressive” and “immune cold-exhausted”. They were characterized by markedly different patterns of cell states: most notably the CD8 T Cytotoxic state, CD8 T Mixed state, B non-regulatory state and cancer-associated fibroblasts (CAFs), depicting distinct types of antitumor immune response (or immune activity). These phenotypes had prognostic significance for progression-free survival and implications in response to immune therapy in an independent cohort of anti-PD1 treated melanoma patients. Conclusions The proposed strategy of leveraging single-cell data to dissect the composition of microenvironment cell states in individual bulk tumors can also extend to other cancer types, and our results highlight the importance of microenvironment cell states for the understanding of tumor immunity.

Abstract In multicellular organisms, regulatory cell death is a crucial aspect of growth and development. Ferroptosis, which was postulated roughly ten years ago, is a mode of cell death that differs from apoptosis, autophagy, and pyrodeath. This distinct pattern of cell death is triggered by an imbalance between oxidants and antioxidants and strongly associated with the metabolism of iron, lipids, amino acids, and glutathione. A growing body of research has implicated ferroptosis in the incidence and progression of many organ traumas and degenerative diseases. Recently, ferroptosis has gained attention as a crucial regulatory mechanism underlying the initiation and development of a variety of cardiovascular diseases, including myocardial ischemia/reperfusion injury, cardiomyopathy, arrhythmia, chemotherapy, and Corona Virus-2-induced cardiac injury. Pharmacological therapies that inhibit ferroptosis have great potential for the management of cardiovascular disorders. This review discusses the prevalence and regulatory mechanisms of ferroptosis, effect of ferroptosis on the immune system, significance of ferroptosis in cardiovascular diseases, and potential therapeutic value of regulating ferroptosis in a variety of heart diseases.

Abstract Background Glioma is one of the leading types of brain tumor, but few etiologic factors of primary glioma have been identified. Previous observational research has shown an association between viral infection and glioma risk. In this study, we used Mendelian randomization (MR) analysis to explore the direction and magnitude of the causal relationship between viral infection and glioma. Methods We conducted a two-sample bidirectional MR analysis using genome-wide association study (GWAS) data. Summary statistics data of glioma were collected from the largest meta-analysis GWAS, involving 12,488 cases and 18,169 controls. Single-nucleotide polymorphisms (SNPs) associated with exposures were used as instrumental variables to estimate the causal relationship between glioma and twelve types of viral infections from corresponding GWAS data. In addition, sensitivity analyses were performed. Results After correcting for multiple tests and sensitivity analysis, we detected that genetically predicted herpes zoster (caused by Varicella zoster virus (VZV) infection) significantly decreased risk of low-grade glioma (LGG) development (OR = 0.85, 95% CI: 0.76–0.96, P = 0.01, FDR = 0.04). No causal effects of the other eleven viral infections on glioma and reverse causality were detected. Conclusions This is one of the first and largest studies in this field. We show robust evidence supporting that genetically predicted herpes zoster caused by VZV infection reduces risk of LGG. The findings of our research advance understanding of the etiology of glioma.

Abstract Background The aim of the study is to explore the role of preoperative folate receptor-positive circulating tumor cell (FR+CTC) levels in predicting disease-free survival (DFS) and overall survival (OS) in patients with esophageal squamous cell carcinomas (ESCC). Methods Three ml blood samples were prospectively drawn from ESCC patients, and ligand-targeted polymerase chain reaction (LT-PCR) was used for the quantification of FR+CTCs. Other serum indicators were measured by traditional methods. Clinicopathological characteristics were obtained from the hospital medical record system, DFS and OS data were obtained by follow-up. The correlation between clinico-pathological characteristics, DFS, and OS and FR+CTCs were analyzed, respectively. Risk factors potentially affecting DFS and OS were explored by Cox regression analysis. Results there were no significant correlations between FR+CTCs and patient age, sex, albumin, pre-albumin, C-reactive protein (CRP), ferritin and CRP/Albumin ratio, tumor size, grade of differentiation, lymph node metastasis, TNM stage, perineural invasion/vessel invasion (all P > 0.05). Nevertheless, preoperative FR+CTCs were an independent prognostic factor for DFS (HR 2.7; 95% CI 1.31-, P = 0.007) and OS (HR 3.37; 95% CI 1.06-, P = 0.04). DFS was significantly shorter for patients with post-operative FR+CTCs ≥ 17.42 FU/3ml compared with patients

Radiation-induced brain injury (RBI) is a common long-term complication of radiotherapy for nasopharyngeal carcinoma (NPC) and seriously affects the quality of life and overall survival of patients. In the era of intensity-modulated radiation therapy (IMRT), the long-term complications after radiotherapy, especially RBI, are becoming increasingly concerning because a number of treated patients with NPC obtain long-term survival. At present, the understanding of RBI is still being explored, and its pathogenesis and treatment methods are continuously updated. This article reviews the research progress of RBI in patients with NPC.

Abstract Background The combination of the endocannabinoid system (ECS) and the type 2 cannabinoid receptor (CB2R) can activate various signal pathways, leading to distinct pathophysiological roles. This interaction has gained significant attention in recent research on fibrosis diseases. Focal adhesion kinase (FAK) plays a crucial role in regulating signals from growth factor receptors and Integrins. It is also involved in the transformation of fibroblasts into myofibroblasts. This study aims to investigate the impact of the CB2R agonist JWH133 on lung fibrosis and its potential to alleviate pulmonary fibrosis in mice through the FAK pathway. Methods The C57 mice were categorized into five groups: control, BLM, BLM + JWH133, BLM + JWH133 + NC, and BLM + JWH133 + FAK groups.JWH133 was administered to mice individually or in conjunction with the FAK vector. After 21 days, pathological changes in mouse lung tissues, inflammatory factor levels, hydroxyproline levels, and collagen contents were evaluated. Moreover, the levels of the FAK/ERK/S100A4 pathway-related proteins were measured. Results JWH133 treatment decreased inflammatory factor levels, attenuated pathological changes, and reduced extracellular matrix accumulation in the mouse model of bleomycin-induced pulmonary fibrosis; however, these effects were reversed by FAK. JWH133 attenuated fibrosis by regulating the FAK/ERK/S100A4 pathway. Conclusions The results presented in this study show that JWH133 exerts a protective effect against pulmonary fibrosis by inhibiting the FAK/ERK/S100A4 pathway.Therefore, JWH133 holds promise as a potential therapeutic target for pulmonary fibrosis.

Abstract Receptor‐interacting protein 1 (RIP1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. RIP1 kinase activity mediates apoptosis and necroptosis induced by tumor necrosis factor (TNF)‐α, Toll‐like receptors, and ischemic tissue damage. RIP1 has been implicated in several human pathologies and consequently, RIP1 inhibition may represent a therapeutic approach for diseases dependent on RIP1‐mediated inflammation and cell death. GDC‐8264 is a potent, selective, and reversible small molecule inhibitor of RIP1 kinase activity. This phase I, randomized, placebo‐controlled, double‐blinded trial examined safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single‐ (5–225 mg) and multiple‐ (50 and 100 mg once daily, up to 14 days) ascending oral doses of GDC‐8264 in healthy volunteers, and also tested the effect of food on the PKs of GDC‐8264. All adverse events in GDC‐8264‐treated subjects in both stages were mild. GDC‐8264 exhibited dose‐proportional increases in systemic exposure; the mean terminal half‐life ranged from 10–13 h, with limited accumulation on multiple dosing (accumulation ratio [AR] ~ 1.4); GDC‐8264 had minimal renal excretion at all doses. A high‐fat meal had no significant effect on the PKs of GDC‐8264. In an ex vivo stimulation assay of whole blood, GDC‐8264 rapidly and completely inhibited release of CCL4, a downstream marker of RIP1 pathway activation, indicating a potent pharmacological effect. Based on PK‐PD modeling, the GDC‐8264 half‐maximal inhibitory concentration for the inhibition of CCL4 release was estimated to be 0.58 ng/mL. The favorable safety, PKs, and PDs of GDC‐8264 support its further development for treatment of RIP1‐driven diseases.

Background: /purpose: Bone ring technique (BRT) is an effective method to reconstruct alveolar bone defects with simultaneous implant placement. This study aimed to evaluate the efficacy of the BRT in single maxillary anterior tooth implantation and its esthetic outcomes over 2–3 years of follow-up. Materials and methods: Fifteen patients with single maxillary incisor loss received autogenous BRT with simultaneous implant placement. The vertical/horizontal bone gain, remaining vertical bone height (RVBH), remaining buccal bone width (RBBW), and vertical/horizontal bone resorption around implant over 2–3 years of follow-up were measured by using cone-beam computed tomography. Esthetic results including white esthetic score (WES), pink esthetic score (PES), and papilla index (PI) were evaluated by clinical recorded photographs. Results: All implants showed evidence of osseointegration, and the mean vertical and horizontal bone gain of 14 sites was 5.55 ± 0.87 mm and 4.73 ± 0.70 mm, respectively. During 2–3 years of follow-up, all mean values of RBBW were more than 2 mm. Main vertical bone loss appeared within 4 months after surgery and the RVBH value decreased as the follow-up duration continued. Maximum buccal bone thickness resorption mostly appeared in the middle level of the implant during the primary two follow-up periods (P

Given the diversity of medical images, traditional image segmentation models face the issue of domain shift. Unsupervised domain adaptation (UDA) methods have emerged as a pivotal strategy for cross modality analysis. These methods typically utilize generative adversarial networks (GANs) for both image-level and feature-level domain adaptation through the transformation and reconstruction of images, assuming the features between domains are well-aligned. However, this assumption falters with significant gaps between different medical image modalities, such as MRI and CT. These gaps hinder the effective training of segmentation networks with cross-modality images and can lead to misleading training guidance and instability. To address these challenges, this paper introduces a novel approach comprising a cross-modality feature alignment sub-network and a cross pseudo supervised dual-stream segmentation sub-network. These components work together to bridge domain discrepancies more effectively and ensure a stable training environment. The feature alignment sub-network is designed for the bidirectional alignment of features between the source and target domains, incorporating a self-attention module to aid in learning structurally consistent and relevant information. The segmentation sub-network leverages an enhanced cross-pseudo-supervised loss to harmonize the output of the two segmentation networks, assessing pseudo-distances between domains to improve the pseudo-label quality and thus enhancing the overall learning efficiency of the framework. This method’s success is demonstrated by notable advancements in segmentation precision across target domains for abdomen and brain tasks.

Bupleurum is a kind of medicinal plant that has made a great contribution to human health because of the presence of bioactive metabolites: Bupleurum saikosaponins and flavonoids. Despite their importance, it has been a challenge to visually characterize the spatial distribution of these metabolites in situ within the plant tissue, which is essential for assessing the quality of Bupleurum. The development of a new technology to identify and evaluate the quality of medicinal plants is therefore necessary. Here, the spatial distribution and quality characteristics of metabolites of three Bupleurum species: Bupleurum smithii (BS), Bupleurum marginatum var. stenophyllum (BM), and Bupleurum chinense (BC) were characterized by Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). Twenty-nine metabolites, including saikosaponins, non-saikosaponins, and compounds from the saikosaponin synthesis pathway, were characterized. Some of these were successfully localized and visualized in the transverse section of roots. In these Bupleurum species, twelve saikosaponins, five non-saikosaponins, and five saikosaponin synthesis pathway compounds were detected. Twenty-two major influencing components, which exhibit higher ion intensities in higher quality samples, were identified as potential quality markers of Bupleurum. The final outcome indicates that BC has superior quality compared to BS and BM. MALDI-MSI has effectively distinguished the quality of these Bupleurum species, providing an intuitive and effective marker for the quality control of medicinal plants.

Applying chemical enhanced oil recovery (EOR) to shale and tight formations is expected to accelerate China’s Shale Revolution as it did in conventional reservoirs. However, its screening and modeling are more complex. EOR operations are faced with choices of chemicals including traditional surfactant solutions, surfactant solutions in the form of micro-emulsions (nano-emulsions), and nano-fluids, which have similar effects to surfactant solutions. This study presents a systematic comparative analysis composed of laboratory screening and numerical modeling. It was conducted on three scales: tests of chemical morphology and properties, analysis of micro-oil-displacing performance, and simulation of macro-oil-increasing effect. The results showed that although all surfactant solutions had the effects of reducing interfacial tension, altering wettability, and enhancing imbibition, the nano-emulsion with the lowest hydrodynamic radius is the optimal selection. This is attributed to the fact that the properties of the nano-emulsion match well with the characteristics of these shale and tight reservoirs. The nano-emulsion is capable of integrating into the tight matrix, interacting with the oil and rock, and supplying the energy for oil to flow out. This study provides a comprehensive understanding of the role that surfactant solutions could play in the EOR of unconventional reservoirs.

ObjectiveTo analyze the clinical epidemiological characteristics including clinical features, disease prognosis of pneumococcal meningitis (PM), and drug sensitivity of S. pneumoniae isolates in Chinese children.MethodsA retrospective analysis was performed on the clinical, laboratory microbiological data of 160 hospitalized children less than 15 years of age with PM from January 2019 to December 2020 in 33 tertiary hospitals in China.ResultsA total of 160 PM patients were diagnosed, including 103 males and 57 females The onset age was 15 days to 15 years old, and the median age was 1 year and 3 months. There were 137 cases (85.6%) in the 3 months to

Introduction: Acori Tatarinowii Rhizoma (ATR) is a well-known traditional Chinese medicine that is used for treating neuropathic diseases. However, there is little information about the safety of ATR.Methods: The present study evaluated the acute and subacute oral toxicity of a water extract of ATR in Institute of Cancer Research (ICR) mice. In acute trials, a single administration of extract at a dose 5,000 mg/kg body weight led to no clinical signs of toxicity or mortality, indicating that the lethal dose (LD50) exceeded 5,000 mg/kg. A subacute toxicity test was done using daily doses of 1,250, 2,500, and 5,000 mg/kg of the ATR extract for 28 days, which did not show any adverse clinical symptoms or mortality. However, the male renal organ index and urea level in mice given 5,000 mg/kg was obviously abnormal, which was consistent with pathological results and suggested that this dose might cause kidney injury.Results: Doses of ATR lower than 2,500 mg/kg could be regarded as safe, although the potential cumulative effects of long-term use of high doses of ATR need to be considered.Discussion: The study highlights the function of ATR in reducing blood lipids and provides a new idea for its widespread clinical use in the future.

IntroductionThe severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike (S) protein is essential in mediating membrane fusion of the virus with the target cells. Several reports demonstrated that SARS-CoV-2 S protein fusogenicity is reportedly closely associated with the intrinsic pathogenicity of the virus determined using hamster models. However, the association between S protein fusogenicity and other virological parameters remains elusive.MethodsIn this study, we investigated the virological parameters (e.g., S1/S2 cleavage efficiency, plaque size, pseudoviral infectivity, pseudovirus entry efficiency, and viral replication kinetics) of eleven previous variants of concern (VOCs) and variants of interest (VOIs) correlating with S protein fusogenicity.Results and discussionS protein fusogenicity was found to be strongly correlated with S1/S2 cleavage efficiency and plaque size formed by clinical isolates. However, S protein fusogenicity was less associated with pseudoviral infectivity, pseudovirus entry efficiency, and viral replication kinetics. Taken together, our results suggest that S1/S2 cleavage efficiency and plaque size could be potential indicators to predict the intrinsic pathogenicity and S protein fusogenicity of newly emerged SARS-CoV-2 variants.

Background: SARS-CoV-2 Omicron lineage contains variants with multiple sequence mutations relative to the ancestral strain particularly in the viral spike gene. These mutations are associated inter alia with loss of neutralization sensitivity to sera generated by immunization with vaccines targeting ancestral strains or prior infection with circulating (non-Omicron) variants. Here we present a comparison of vaccine formulation elicited cross neutralization responses using two different assay readouts from a subpopulation of a Phase II/III clinical trial. Methods: Human sera from a Phase II/III trial (NCT04762680) was collected and evaluated for neutralizing responses to SARS-CoV-2 spike antigen protein vaccines formulated with AS03 adjuvant, following a primary series of two-doses of ancestral strain vaccine in individuals who were previously unvaccinated or as an ancestral or variant strain booster vaccine among individuals previously vaccinated with the mRNA BNT162b2 vaccine. Results: We report that a neutralizing response to Omicron BA.1 is induced by the two-dose primary series in 89% of SARS-CoV-2-seronegative individuals. A booster dose of each vaccine formulation raises neutralizing antibody titers that effectively neutralizes Omicron BA.1 and BA.4/5 variants. Responses are highest after the monovalent Beta variant booster and similar in magnitude to human convalescent plasma titers. Conclusion: The findings of this study suggest the possibility to generate greater breadth of cross-neutralization to more recently emerging viral variants through use of a diverged spike vaccine in the form of a Beta variant booster vaccine.

In the present paper, the La0.8Ba0.1Bi0.1FeO3 powders were synthesized via the auto-combustion method. The optical, the positron annihilation spectroscopy and the gas sensing properties of our sample were investigated simultaneously. FTIR spectrum revealed the antisymmetric deformation vibrations of the Fe–O and Fe–O–Fe bonds inside the octahedron FeO6. The optical bandgap (Egap) of the La0.8Ba0.1Bi0.1FeO3 compound was found to be equal to 2.23 eV. We confirmed by the positron annihilation studies, the existence of open volume defects and vacancy sized defects, at the grain/interfaces between vacancy clusters and grains at the interfaces intersection (triple-lines). Notably, the La0.8Ba0.1Bi0.1FeO3 perovskite exhibits an excellent response toward acetone gas, with ultra-fast response and recovery times to some parts-per-billion (ppb) of this tested gas.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease. This study aimed to investigate the involvement of endoplasmic reticulum stress (ERS) in IPF and explore its correlation with immune infiltration.MethodsERS-related differentially expressed genes (ERSRDEGs) were identified by intersecting differentially expressed genes (DEGs) from three Gene Expression Omnibus datasets with ERS-related gene sets. Gene Set Variation Analysis and Gene Ontology were used to explore the potential biological mechanisms underlying ERS. A nomogram was developed using the risk signature derived from the ERSRDEGs to perform risk assessment. The diagnostic value of the risk signature was evaluated using receiver operating characteristics, calibration, and decision curve analyses. The ERS score of patients with IPF was measured using a single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm. Subsequently, a prognostic model based on the ERS scores was established. The proportion of immune cell infiltration was assessed using the ssGSEA and CIBERSORT algorithms. Finally, the expression of ERSRDEGs was validated in vivo and in vitro via RT-qPCR.ResultsThis study developed an 8-ERSRDEGs signature. Based on the expression of these genes, we constructed a diagnostic nomogram model in which agouti-related neuropeptide had a significantly greater impact on the model. The area under the curve values for the predictive value of the ERSRDEGs signature were 0.975 and 1.000 for GSE70866 and GSE110147, respectively. We developed a prognostic model based on the ERS scores of patients with IPF. Furthermore, we classified patients with IPF into two subtypes based on their signatures. The RT-qPCR validation results supported the reliability of most of our conclusions.ConclusionWe developed and verified a risk model using eight ERSRDEGs. These eight genes can potentially affect the progression of IPF by regulating ERS and immune responses.