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This study aims to investigate the effect of different levels of zinc oxide quantum dots (ZnO-QDs) on the growth performance and gut health in broilers. A total of 1125 1-day-old Ross 308 broilers were randomly divided into five groups with 15 replicates of 15 chicks each. The broilers were fed basal diets supplemented with 0, 40, 80, 120, or 160 mg Zn/kg as ZnO-QDs for 6 weeks. The results showed that dietary 80 and 120 mg Zn/kg ZnO-QD supplementation increased (P < 0.05) average daily gain (1.4-1.7%) and reduced feed conversion ratio (1.3%) compared to the basal diet group during various experimental periods. Meanwhile, 80 mg Zn/kg ZnO-QD supplementation increased (P < 0.05) trypsin activity (25.4%), villus height, and the ratio of villus height to crypt depth in the jejunum. Moreover, 80 mg Zn/kg ZnO-QD supplementation increased (P < 0.05) the activities of glutathione reductase (47.7%) and superoxide dismutase (30.9%), while 120 mg Zn/kg ZnO-QD supplementation decreased (P < 0.05) glutathione peroxidase activity (27.1%) in the jejunum. Furthermore, 40 mg Zn/kg ZnO-QD supplementation down-regulated (P < 0.05) the expression of genes; interleukin-2, transforming growth factor ß (TGF-ß), Cathelicidin-1, Cathelicidin-2, Cathelicidin-3, and Occludin, while 80-160 mg Zn/kg ZnO-QD supplementation up-regulated (P < 0.05) Claudin-2 expression in the jejunum. In conclusion, dietary ZnO-QD supplementation improved growth performance of broilers potentially by enhancing their intestinal health status. Based on nonlinear regression analysis, the appropriate level of ZnO-QD supplementation would be from 98.2 to 102.5 mg Zn/kg.

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Hyperuricemia, characterized by elevated uric acid levels and subsequent crystal deposition, contributing to conditions such as gout, cardiovascular events, and kidney injury, poses a significant health threat, particularly in developed countries. Current drug options for treatment are limited, with safety concerns, leading to suboptimal therapeutic outcomes in symptomatic hyperuricemia patients and a lack of pharmaceutical interventions for asymptomatic cases. Distinguishing from the previous drug design strategies, we directly target uric acid, the pathological molecule of hyperuricemia, resulting in a pyrimidine derivative capable of increasing the solubility and excretion of uric acid by forming a complex with it. Its prodrug showed an anti-hyperuricemia activity comparable to benzbromarone and a favorable safety profile in vivo. Our finding provides a strategy purely based on organic chemistry to address the largely unmet therapeutic needs on novel anti-hyperuricemia drugs.

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Spinal cord injury (SCI) compromises the blood-spinal cord barrier (BSCB) and induces neuroinflammation, potentially exacerbating neuronal damage. This underscores the importance of maintaining BSCB integrity and mitigating neuroinflammation in SCI treatment. Our study explores an innovative approach to treating SCI by utilizing platelet-rich plasma-derived exosomes (PRP-Exos) to stabilize BSCB function and alleviate neuroinflammation. We successfully isolated exosomes from platelet-rich plasma and conducted both in vivo and in vitro experiments to assess the therapeutic effects of PRP-Exos and explore their potential mechanisms in stabilizing the BSCB, reducing neuroinflammation, and promoting neural functional recovery.In vitro results demonstrate that PRP-Exos significantly reduce the permeability of bEnd.3 cells under hypoxic-hypoglycemic conditions, thereby restoring the integrity of tight junctions. Additionally, our study elucidates the critical role of the NF-κB signaling pathway in the amelioration of neuroinflammation by PRP-Exos. In the SCI model, local injection of hydrogel-encapsulated PRP-Exos reduced Evans blue dye leakage, enhanced the expression of tight junction proteins, alleviated the inflammatory environment in the damaged area, and improved neural functional recovery. In conclusion, PRP-Exos presents a promising and effective treatment option for SCI.

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[This corrects the article DOI: 10.1016/j.mtbio.2023.100928.].

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Metabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redoxhigh LUAD and redoxlow LUAD. Genetically, redoxhigh LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redoxhigh LUAD (72.5%) compared to redoxlow LUAD (17.4%), whereas EGFR mutations are more common in redoxlow LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redoxhigh LUAD. The redoxhigh phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redoxhigh phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.

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HLA-DPB1*1500:01N differs from HLA-DPB1*05:01:01:01 by one nucleotide in exon 3.

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Background: Breast cancer (BC) is increasingly becoming the primary reason for death in women, which sounded the alarm. Thus, finding a novel management target for BC is imminent. Materials and Methods: The data on gene expression and clinicopathological characteristics were downloaded from The Cancer Genome Atlas (TCGA). The expression of GNPNAT1 in 40 paired breast cancer and adjacent tissues was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Univariate and Multivariate logistic regression methodology was applied to analyze the prognostic factors for lymph node metastasis (LNM). Based on the status of breast cancer-relative receptors, patients were distributed into six groups, and then the Kaplan-Meier survival analysis with a Log rank test was applied to investigate the involvement among the expression of GNPNAT1 and overall survival (OS). Results: We found higher expression of GNPNAT1 was connected with poor survival in breast cancer by COX regulation analysis. GO, KEGG, and GSEA analysis prompted that GNPNAT1 was connected with the defense mechanism of cells, cell proliferation, and division. Immunization infiltration analysis showed that high GNPNAT1 was negatively connected with 16 immunization infiltration cell types and positively connected with four immunization infiltration cell types. Conclusion: As a whole, our results indicated that GNPNAT1 might be a probable biomarker for diagnosis and prognosis in breast cancer.

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Many human tissues exhibit a highly oriented architecture that confers them with distinct mechanical properties, enabling adaptation to diverse and challenging environments. Hydrogels, with their water-rich "soft and wet" structure, have emerged as promising biomimetic materials in tissue engineering for repairing and replacing damaged tissues and organs. Highly oriented hydrogels can especially emulate the structural orientation found in human tissue, exhibiting unique physiological functions and properties absent in traditional homogeneous isotropic hydrogels. The design and preparation of highly oriented hydrogels involve strategies like including hydrogels with highly oriented nanofillers, polymer-chain networks, void channels, and microfabricated structures. Understanding the specific mechanism of action of how these highly oriented hydrogels affect cell behavior and their biological applications for repairing highly oriented tissues such as the cornea, skin, skeletal muscle, tendon, ligament, cartilage, bone, blood vessels, heart, etc., requires further exploration and generalization. Therefore, this review aims to fill that gap by focusing on the design strategy of highly oriented hydrogels and their application in the field of tissue engineering. Furthermore, we provide a detailed discussion on the application of highly oriented hydrogels in various tissues and organs and the mechanisms through which highly oriented structures influence cell behavior.

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In recent years, owing to the ongoing advancements in polymer materials, hydrogels have found increasing applications in the biomedical domain, notably in the realm of stimuli-responsive "smart" hydrogels. Nonetheless, conventional single-network stimuli-responsive "smart" hydrogels frequently exhibit deficiencies, including low mechanical strength, limited biocompatibility, and extended response times. In response, researchers have addressed these challenges by introducing a second network to create stimuli-responsive "smart" Interpenetrating Polymer Network (IPN) hydrogels. The mechanical strength of the material can be significantly improved due to the topological entanglement and physical interactions within the interpenetrating structure. Simultaneously, combining different network structures enhances the biocompatibility and stimulus responsiveness of the gel, endowing it with unique properties such as cell adhesion, conductivity, hemostasis/antioxidation, and color-changing capabilities. This article primarily aims to elucidate the stimulus-inducing factors in stimuli-responsive "smart" IPN hydrogels, the impact of the gels on cell behaviors and their biomedical application range. Additionally, we also offer an in-depth exposition of their categorization, mechanisms, performance characteristics, and related aspects. This review furnishes a comprehensive assessment and outlook for the advancement of stimuli-responsive "smart" IPN hydrogels within the biomedical arena. We believe that, as the biomedical field increasingly demands novel materials featuring improved mechanical properties, robust biocompatibility, and heightened stimulus responsiveness, stimuli-responsive "smart" IPN hydrogels will hold substantial promise for wide-ranging applications in this domain.

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OBJECTIVE: To evaluate the therapeutic efficacy and safety of agomelatine for treating the sleep and mood disorders in epilepsy patients. METHODS: Retrospective data were derived from 113 epilepsy patients for at least 8 weeks. All the subjects were divided into two groups, one was treated with agomelatine, the other was treated with escitalopram. Their depression and anxiety states were assessed by Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Scales. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The HAMA, HAMD and PSQI scores in both groups significantly declined after the treatments with agomelatine and escitalopram. However, the agomelatine group exhibited greater improvement in terms of HAMA and PSQI scores compared to the escitalopram group. No severe adverse events were observed in agomelatine group. SIGNIFICANCE: Agomelatine performed better in HAMA and PSQI scores compared to escitalopram, where no significant increase in seizure frequency or side effects were observed. Possibly, agomelatine presents a promising therapeutic option for treating the sleep or mood disorders in epilepsy patients.

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Polyetheretherketone (PEEK) material has become a potential bone replacement material due to its elastic modulus, which is close to that of human bone, and stable chemical properties. However, its biological inertness has hindered its clinical application. To improve the biological inertia of PEEK material, a hyaluronic acid (HA) hydrogel coating loaded with platelet-rich plasma (PRP) and nerve growth factor (NGF) was constructed on the surface of PEEK material in this study. After the hybrid hydrogel coating was constructed, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), Fourier transform infrared spectroscopy (FT-IR), degradation tests, and enzyme-linked immunosorbent assays (ELISAs) were used to evaluate its characteristics and biological properties. The osteogenic and angiogenic potentials were also investigated in vitro and in vivo. Our results showed that the HA hydrogel loaded with RPP and NGF on the PEEK surface degraded slowly and could sustainably release various growth factors, including NGF. The results of in vitro tests showed that the hybrid hydrogel on the surface of PEEK effectively promoted osteogenesis and angiogenesis. The in vivo experiment also confirmed that the PEEK surface hydrogel could promote osseointegration of the implant and the integration of new bone and neovascularization. Our results suggest that the cross-linked hyaluronic acid hydrogel loaded with PRP and NGF can significantly improve the biological inertia of PEEK material, endowing PEEK material with good osteogenic and angiogenic ability.

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The microbiome in a specific human organ has been well-studied, but few reports have investigated the multi-organ microbiome as a whole. Here, we aim to analyse the intra-individual inter-organ and intra-organ microbiome in deceased humans. We collected 1608 samples from 53 sites of 7 surface organs (oral cavity, esophagus, stomach, small intestine, appendix, large intestine and skin; n = 33 subjects) and performed microbiome profiling, including 16S full-length sequencing. Microbial diversity varied dramatically among organs, and core microbial species co-existed in different intra-individual organs. We deciphered microbial changes across distinct intra-organ sites, and identified signature microbes, their functional traits, and interactions specific to each site. We revealed significant microbial heterogeneity between paired mucosa-lumen samples of stomach, small intestine, and large intestine. Finally, we established the landscape of inter-organ relationships of microbes along the digestive tract. Therefore, we generate a catalogue of bacterial composition, diversity, interaction, functional traits, and bacterial translocation in human at inter-organ and intra-organ levels.

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Rationale: Vitamin D (VD) has been suggested to have antitumor effects, however, research on the role of its transporter vitamin D-binding protein (VDBP, gene name as GC) in tumors is limited. In this study, we demonstrated the mechanism underlying the inhibition of vasculogenic mimicry (VM) by VDBP in hepatocellular carcinoma (HCC) and proposed an anti-tumor strategy of combining anti-PD-1 therapy with VD. Methods: Three-dimensional cell culture models and mice with hepatocyte-specific GC deletion were utilized to study the correlation between VDBP expression and VM. A patient-derived tumor xenograft (PDX) model was further applied to validate the therapeutic efficacy of VD in combination with an anti-PD-1 drug. Results: The study revealed that VDBP expression is negatively correlated with VM in HCC patients and elevated VDBP expression is associated with a favorable prognosis. The mechanism studies suggested VDBP hindered the binding of Twist1 on the promoter of VE-cadherin by interacting with its helix-loop-helix DNA binding domain, ultimately leading to the inhibition of VM. Furthermore, VD facilitated the translocation of the vitamin D receptor (VDR) into the nucleus where VDR interacts with Yin Yang 1 (YY1), leading to the transcriptional activation of VDBP. We further demonstrated that the combination of VD and anti-PD-1 led to an improvement in the anti-tumor efficacy of an anti-PD-1 drug. Conclusion: Collectively, we identified VDBP as an important prognostic biomarker in HCC patients and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.

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INTRODUCTION: EGFR C797X (C797S or C797G) mutation is the most frequent on-target mechanism of resistance to osimertinib. The hypothesis that the allelic context of C797X/T790M has implications for treatment is on the basis of sporadic reports and needs validation with larger cohorts. METHODS: We identified patients with EGFR C797X-mutant NSCLC from nine centers who progressed on osimertinib, all analyzed in a single laboratory through next-generation sequencing. We analyzed genomic profiles and assessed associations between clinical outcomes and C797X status. RESULTS: A total of 365 EGFR C797X-mutant cases were categorized into four subtypes on the basis of allelic context: in cis (75.3%), in trans (6.4%), cis&trans (10.4%), and C797X-only (7.9%). Genomically, the cis&trans subtype displayed the highest frequency of concurrent alterations at osimertinib resistance sites (21.1%), while the in cis subtype had the lowest (8.4%). Clinically, cis&trans patients exhibited the worst progression-free survival (PFS) on both previous (median 7.7 mo) and subsequent treatment (median 1.0 mo) and overall survival (median 3.9 mo). In subsequent treatments, in cis patients exhibited superior PFS with combined brigatinib and cetuximab (median 11.0 mo) compared with other regimens (p = 0.005), while in trans patients exhibited variable outcomes with combined first or second- and third-generation EGFR inhibitor (PFS range: 0.7-8.1 mo, median 2.6 mo). Notably, subtype switching was observed after subsequent treatments, predominantly toward the in cis subtype. CONCLUSIONS: Allelic context could define four EGFR C797X-mutant NSCLC subtypes with heterogeneous genetic landscapes and distinct clinical outcomes. Subsequent treatments further complicate the scenario through subtype switching.

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Survival causal effect estimation based on right-censored data is of key interest in both survival analysis and causal inference. Propensity score weighting is one of the most popular methods in the literature. However, since it involves the inverse of propensity score estimates, its practical performance may be very unstable, especially when the covariate overlap is limited between treatment and control groups. To address this problem, a covariate balancing method is developed in this paper to estimate the counterfactual survival function. The proposed method is nonparametric and balances covariates in a reproducing kernel Hilbert space (RKHS) via weights that are counterparts of inverse propensity scores. The uniform rate of convergence for the proposed estimator is shown to be the same as that for the classical Kaplan-Meier estimator. The appealing practical performance of the proposed method is demonstrated by a simulation study as well as two real data applications to study the causal effect of smoking on survival time of stroke patients and that of endotoxin on survival time for female patients with lung cancer respectively.

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ObjectiveTo establish the clinical comprehensive evaluation index system for Chinese patent medicine（CPM） based on Evidence and Value：Impact on DEcisionMaking（EVIDEM） framework， so as to promote the scientific， systematic and standardized implementation of clinical comprehensive evaluation of CPM. MethodThe clinical comprehensive evaluation index system was determined through literature review， semi-structured interview and Delphi method， and the weights of each index were clarified by analytic hierarchy process（AHP）. ResultThe recovery rates of both rounds of expert consultation were 100%， and the authority coefficient of experts was 0.90 and 0.905， respectively. Kendall's coordination coefficients（W） of the second- and third-level indicators in the first-round consultation were 0.320 and 0.283（P<0.001）， and in the second round were 0.411 and 0.351， respectively（P<0.001）. The finally constructed clinical comprehensive evaluation index system for CPM included 6 first-level indicators， 13 second-level indicators and 28 third-level indicators. Among the first-level indicators， the weights of effectiveness， safety， economy， innovation， suitability and accessibility were 37.34%， 32.68%， 11.85%， 5.87%， 5.79% and 6.47%， respectively. ConclusionThis study has constructed a universal clinical comprehensive evaluation index system for CPM， and the domain and criteria are introduced and interpreted in detail， which can provide reference and information for carrying out the clinical comprehensive evaluation of CPM， but it needs to be refined and improved in combination with the clinical practice of CPM for specialized diseases.

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Objective To evaluate the application value of hydrogel in image guided radiotherapy(IGRT)for prostate cancer(PCa).Methods Eighty PCa patients in the First Affiliated Hospital of Hebei North University from October 2022 to February 2023 were collected.The patients were divided into experiment group injected with hydrogel(n=33)and control group without hydrogel(n=47)by central random system allocation.The acute and advanced radiation proctitis(RP)incidence rate of the two groups were compared.Patients in experimental group were divided into RP group(n=5)and non-RP group(n=28).The independent risk factors leading to RP were analyzed by using logistic regression for PCa patients.Results In experiment group,12.1％(4/33)of the patients developed acute grade Ⅰ RP,and 3.0％(1/33)developed advanced grade Ⅰ RP.In control group,31.9％(15/47)of the patients developed acute grade Ⅰ RP,and 12.8％(6/47)developed acute grade Ⅱ RP;19.1％(9/47)of patients developed advanced grade Ⅰ RP,4.3％(2/47)developed advanced grade Ⅱ RP,and 2.1％(1/47)developed advanced grade Ⅲ RP.The incidence of acute and advanced RP in experiment group was lower than that in control group(P<0.05).The application of hydrogel effectively reduced rectal toxicity.Age,rectal volume,V70 and V78 were independent risk factors for the incidence of RP in Pca patients(P<0.05).The characteristics of hydrogel injection were not related to the incidence of RP for Pca patients.Conclusions Hydrogel can effectively reduce the rectal toxicity for Pca patients in IGRT and has little impact on the overall treatment.Hydrogel has certain clinical application and promotion value.

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The clinical data of a patient with Klinefelter syndrome (KS) complicated by partial androgen insensitivity syndrome (PAIS) was retrospectively analyzed.The patient, a 2-month-and-22-day-old baby, was admitted to Children′s Hospital Affiliated to Zhengzhou University due to abnormal external genitalia in October 2021.Upon birth, the patient exhibited abnormal external genitalia, manifested as clitoral hypertrophy.Hormonal examinations were consistent with those of peers, while chromosomal analysis revealed 47, XXY.Due to the severe undermasculinization, whole exome sequencing was conducted, indicating a heterozygous variant of the AR gene (c.1847G>A, p.Arg616His). The patient was diagnosed with PAIS, and her elder sister was diagnosed with complete androgen insensitivity syndrome.For further treatment, a multidisciplinary comprehensive evaluation is needed.This is a rare case of KS combined with PAIS, suggesting the possibility of AR gene mutations in KS children with severe undermasculinization.

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Objective:To investigate the clinical and pathological characteristics of chronic hepatitis B (CHB) with metabolic dysfunction-associated fatty liver disease (MAFLD), as well as associations with advanced fibrosis.Methods:CHB patients who underwent liver biopsy at Tianjin Second People′s Hospital from June 2016 to September 2019 were included in the study. The patients were divided into two groups based on whether they had concomitant MAFLD; a CHB group and a MAFLD-CHB group. t-tests and Chi-square tests were used to compare pathological characteristics and basic features in the two groups. Logistic regression analysis was used to analyze factors associated with advanced fibrosis. Results:The CHB group included 110 patients, and the MAFLD-CHB group included 272 patients. There were significant differences in smoking, alcohol consumption, hypertension incidence, body metabolic index, alanine aminotransferase, gamma-glutamyl transferase (GGT), high-density lipoprotein, low-density lipoprotein, fasting plasma glucose, and platelets (PLT) between the two groups (all P<0.05). The MAFLD-CHB group had a higher incidence of advanced fibrosis than the CHB group ( P<0.05). In logistic regression analysis MAFLD [odds ratio ( OR)=2.204, 95% confidence interval ( CI) 1.018-4.774, P=0.045], GGT ( OR=1.008, 95% CI 1.002-1.013, P=0.005), and PLT ( OR=0.995, 95% CI 0.991-0.999, P=0.019) were associated with advanced fibrosis (all P<0.05). In the MAFLD-CHB group type 2 diabetes ( OR=3.281, 95% CI 1.375-7.832, P=0.007), GGT ( OR=1.011, 95% CI 1.003-1.018, P=0.005), and PLT ( OR=0.993, 95% CI 0.988-0.998, P=0.004) were associated with advanced fibrosis ( P<0.05). Conclusion:Patients with MAFLD-CHB are more likely to develop advanced fibrosis than patients with CHB alone. In the MAFLD-CHB group type 2 diabetes mellitus was associated with advanced fibrosis. It is important to strictly control relevant risk factors in MAFLD-CHB patients, especially in patients with type 2 diabetes.