Efficacy of perioperative pain management in paediatric cardiac surgery: a protocol for a network meta-analysis.

INTRODUCTION: Congenital heart disease is a common birth defect, but advancements in diagnosis and treatment have improved survival rates. Enhanced recovery after surgery (ERAS) programmes have emerged in paediatric cardiac surgery. Multimodal pain management, as a vital part of ERAS programmes, has been found to be effective in reducing pain and improving outcomes in cardiac surgery patients. Traditional methods of pain control using high-dose opioids can lead to complications, so nonopioid analgesics and regional anaesthesia techniques are being used to reduce the consumption. However, there is a significant variability in pain management practices in paediatric cardiac surgery. A network meta-analysis (NMA) is needed to comprehensively compare the effects of different analgesic interventions in this population. METHODS AND ANALYSIS: A comprehensive electronic literature database search will be performed using electronic databases, mainly including PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. All randomised controlled trials associated with perioperative pain management for paediatric cardiac surgery will be included. The primary outcome will be visual analogue score or numeric rating scale of pain and total opioid consumption (or equivalent) 24 hours after postoperative tracheal extubation. The Revised Cochrane Risk of Bias Tool will be employed to assess the quality of included articles. A random-effects pairwise meta-analysis will be performed to report the head-to-head comparison. Following the assessment of individual articles, an NMA will be conducted using a Bayesian framework with random-effects' models. ETHICS AND DISSEMINATION: Ethics approval is not necessary because this study will be based on publications. The results of this study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023477520.

Structure and fragmentation chemistry of the peptide radical cations of glycylphenylalanylglycine (GFG).

Herein, we explore the generation and characterization of the radical cations of glycylphenylalanylglycine, or [GFG]•+, formed via dissociative electron-transfer reaction from the tripeptide to copper(II) within a ternary complex. A comprehensive investigation employing isotopic labeling, infrared multiple-photon dissociation (IRMPD) spectroscopy, and density functional theory (DFT) calculations elucidated the details and energetics in formation of the peptide radical cations as well as their dissociation products. Unlike conventional aromatic-containing peptide radical cations that primarily form canonical π-radicals, our findings reveal that 75% of the population of the experimentally produced [GFG]•+ precursors are [GFα•G]+, where the radical resides on the middle α-carbon of the phenylalanyl residue. This unexpected isomeric ion has an enthalpy of 6.8 kcal/mol above the global minimum, which has an N-terminal captodative structure, [Gα•FG]+, comprising 25% of the population. The [b2-H]•+ product ions are also present in a ratio of 75/25 from [GFα•G]+/ [Gα•FG]+, the results of which are obtained from matches between the IRMPD action spectrum and predicted IR absorption spectra of the [b2-H]•+ candidate structures, as well as from IRMPD isomer population analyses.

tRNA-m1A methylation controls the infection of Magnaporthe oryzae by supporting ergosterol biosynthesis.

Ergosterols are essential components of fungal plasma membranes. Inhibitors targeting ergosterol biosynthesis (ERG) genes are critical for controlling fungal pathogens, including Magnaporthe oryzae, the fungus that causes rice blast. However, the translational mechanisms governing ERG gene expression remain largely unexplored. Here, we show that the Trm6/Trm61 complex catalyzes dynamic N1-methyladenosine at position 58 (m1A58) in 51 transfer RNAs (tRNAs) of M. oryzae, significantly influencing translation at both the initiation and elongation stages. Notably, tRNA m1A58 promotes elongation speed at most cognate codons mainly by enhancing eEF1-tRNA binding rather than affecting tRNA abundance or charging. The absence of m1A58 leads to substantial decreases in the translation of ERG genes, ergosterol production, and, consequently, fungal virulence. Simultaneously targeting the Trm6/Trm61 complex and the ergosterol biosynthesis pathway markedly improves rice blast control. Our findings demonstrate an important role of m1A58-mediated translational regulation in ergosterol production and fungal infection, offering a potential strategy for fungicide development.

Combination Therapy Consisting of Transarterial Chemoembolization, Lenvatinib, and Programmed Cell Death Protein 1 Blockade for Hepatocellular Carcinoma with Inferior Vena Cava Tumor Thrombus: A Case Series Study and Literature Review.

INTRODUCTION: Patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT) have poor prognosis. Combination therapy involving the blockade of programmed cell death protein 1 (PD-1) and tyrosine kinase inhibitors is an efficient treatment strategy for advanced HCC. However, surgical treatment after a combination of systemic therapy and transarterial chemoembolization (TACE) for HCC with IVCTT has not been widely reported, and the efficacy and safety of this treatment have not been studied. METHODS: In the 21 cases reported herein, the patients were treated with TACE, lenvatinib, and PD-1 blockade. The treatment responses, progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities were evaluated, and the related literature was reviewed. RESULTS: The overall response and disease control rates were 66.7% and 85.7%, respectively. The median PFS time was 16.0 months, with a 1-year PFS rate of 55.60%. The median OS was not reached, with a 1-year OS rate of 66.70%. Four patients underwent hepatectomy without serious complications and survived for 29.1, 24.7, 14.2, and 13.8 months. Three patients survived tumor-free, and 1 patient experienced intrahepatic recurrence. Pathological complete response and major pathological responses were observed in 1 and 3 patients, respectively. Treatment-related adverse events of any grade occurred in 8/9 patients (88.9%), and grade 3 treatment-related adverse events occurred in 1 patient. CONCLUSION: The combination of TACE, lenvatinib, and PD-1 is effective for HCC with IVCTT and has acceptable adverse effects.

The role of selenium intervention in gut microbiota homeostasis and gene function in mice with breast cancer on a high-fat diet.

Objective: This study aimed to investigate the effect of selenium on gut microbiota in mice with breast cancer under a high-fat diet. Methods: A total of 12 female BALB/c mice were randomly divided into two groups: 4 T1 + selenium+ high-fat diet group and 4 T1 + high-fat diet group. Mice were injected with 4 T1 cells on the right 4th mammary fat pad and kept on a high-fat diet. Fecal samples were collected, and DNA was extracted for metagenomic sequencing and bioinformatics analysis. Relevant target genes and pathways were annotated and metabolically analyzed to explore the intervention effect of selenium on breast cancer in the high-fat diet state. Results: Selenium supplementation in the high-fat diet altered the composition and diversity of gut microbiota in mice with breast cancer. The gut microbial composition was significantly different in the selenium intervention group, with an increased abundance of Proteobacteria, Actinobacteria, and Verrucomicrobia phyla and species such as Helicobacter ganmani, Helicobacter japonicus, and Akkermansia muciniphila, while phyla, such as Bacteroidetes, Firmicutes, Deferribacteres, and Spirochaetes, and species, such as Prevotella sp. MGM2, Muribaculum intestinale, Lactobacillus murinus, and Prevotella sp. MGM1, were decreased. Functional analysis revealed differential expression of genes related to carbohydrate-active enzymes, pathogen-host interactions, cell communication, cell auto-induction, membrane transporters, and virulence factors. Furthermore, 37 COGs and 48 metabolites with rising metabolic potential in the selenium intervention group were predicted. Conclusion: Selenium alters the homeostasis of gut microbiota in mice with breast cancer on a high-fat diet, affecting their composition, abundance, and associated metabolism. These findings suggest that the mechanism involves interfering with gut microbiota homeostasis, leading to altered synthesis of tumor-associated proteins and fatty acids and inducing tumor cell apoptosis and pyroptosis.

LKB1 suppresses KSHV reactivation and promotes primary effusion lymphoma progression.

Viruses normally reprogram the host cell metabolic pathways as well as metabolic sensors to facilitate their persistence. The serine-threonine liver kinase B1 (LKB1) is a master upstream kinase of 5'-AMP-activated protein kinase (AMPK) that senses the energy status and therefore regulates the intracellular metabolic homeostasis. Previous studies showed that AMPK restricts Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in endothelial cells during primary infection and promotes primary effusion lymphoma (PEL) cell survival. However, the role of LKB1 in KSHV lytic reactivation and KSHV-associated malignancies is unclear. In this study, we found that LKB1 is phosphorylated or activated in KSHV-positive PEL cells. Mechanistically, KSHV-encoded vCyclin mediated LKB1 activation in PEL cells, as vCyclin knockout ablated, while vCyclin overexpression enhanced LKB1 activation. Furthermore, knockdown of LKB1 inactivated AMPK and induced KSHV reactivation, as indicated by the increased expression of viral lytic genes and the increased virions in supernatants. Accordingly, AMPK inhibition by functional knockdown or a pharmacologic inhibitor, Compound C, promoted KSHV reactivation in PEL cells. Furthermore, inhibition of either LKB1 or AMPKα1 efficiently induced cell death by apoptosis of PEL cells both in vitro and in vivo. Together, these results identify LKB1 as a vulnerable target for PEL, which could be potentially exploited for treating other virus-associated diseases.IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with several human cancers, such as primary effusion lymphoma (PEL). Here, we showed that serine-threonine liver kinase B1 (LKB1), upstream of 5' AMP-activated protein kinase (AMPK), is activated by KSHV-encoded vCyclin and maintains KSHV latency in PEL cells. Inhibition of either LKB1 or AMPK enhances KSHV lytic replication from latency, which at least partially accounts for PEL cell death by apoptosis. Compound C, a potent AMPK inhibitor, induced KSHV reactivation and efficiently inhibited PEL progression in vivo. Thus, our work revealed that LKB1 is a potential therapeutic target for KSHV-associated cancers.

Predictors of length of hospital stay after pediatric Ebstein anomaly corrective surgery: a retrospective cohort study.

BACKGROUND: The remarkable advancements in surgical techniques over recent years have shifted the clinical focus from merely reducing mortality to enhancing the quality of postoperative recovery. The duration of a patient's hospital stay serves as a crucial indicator in evaluating postoperative recovery and surgical outcomes. This study aims to identify predictors of the length of hospital stay for children who have undergone corrective surgery for Ebstein Anomaly (EA). METHODS: We conducted a retrospective cohort study on children (under 18 years of age) diagnosed with EA who were admitted for corrective surgery between January 2009 and November 2021 at Fuwai Hospital. The primary outcome was the Time to Hospital Discharge (THD). Cox proportional hazard models were utilized to identify predictors of THD. In the context of time-to-event analysis, discharge was considered an event. In cases where death occurred before discharge, it was defined as an extended THD, input as 100 days (exceeding the longest observed THD), and considered as a non-event. RESULTS: A total of 270 children were included in this study, out of which three died in the hospital. Following the Cox proportional hazard analysis, six predictors of THD were identified. The hazard ratios and corresponding 95% confidence intervals were as follows: age, 1.030(1.005,1.055); C/R > 0.65, 0.507(0.364,0.707); Carpentier type C or D, 0.578(0.429,0.779); CPB time, 0.995(0.991,0.998); dexamethasone, 1.373(1.051,1.795); and transfusion, 0.680(0.529,0.875). The children were categorized into three groups based on the quartile of THD. Compared to children in the ≤ 6 days group, those in the ≥ 11 days group were associated with a higher incidence of adverse outcomes. Additionally, the duration of mechanical ventilation and ICU stay, as well as hospital costs, were significantly higher in this group. CONCLUSION: We identified six predictors of THD for children undergoing corrective surgery for EA. Clinicians can utilize these variables to optimize perioperative management strategies, reduce adverse complications, improve postoperative recovery, and reduce unnecessary medical expenses.

Alterations in the Intestinal Microbiome and Metabolic Profile of British Shorthair Kittens Fed with Milk Replacer.

With the rising popularity of pet cats as companion animals, the survival of newborn kittens is often threatened by factors such as inadequate nursing, maternal behavior and blood incompatibility. These challenges require the use of milk replacers for nurturing. To investigate the effects that feeding kittens with an experimental milk replacer (EMR) have on growth and development, intestinal microbiota, immune response and nutrient metabolism, 12 British shorthair kittens were randomly divided into two groups after nursing for the first week of life. Kittens were fed queen's milk or EMR, whereby kittens fed queen's milk served as the control (CON) group. The findings revealed that the CON group exhibited superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC) (p < 0.01) on day 7. However, the EMR group had better growth performance during the later stage of the experiment (p < 0.05); the immunocompetence and antioxidant capacity of the EMR group were not significantly different from those of the CON group in the middle and late stages of the experiment, and the mean values of all the indexes were slightly better than those of the control group. Sequencing of the 16S rRNA gene in microbiota demonstrated that EMR increased the colonization of bacterial genera, including Lachnospiraceae, Enterococcus, Rothia and Ligilactobacillus. Compared to the CON group, acetate acid (p < 0.05), propionate acid (p < 0.01) and total SCFAs (p < 0.01) in the EMR group were significantly increased. Moreover, the intake of the EMR resulted in the production of distinct metabolites implicated in the metabolism of lipids and amino acids, among other nutrients, thus invigorating the associated metabolic pathways. These results elucidate the impact of administering a milk replacer on gastrointestinal health and nutrient assimilation in kittens. The study provides insights into the use of milk powder alternatives and sets the stage for future research on the formulation and effectiveness of kitten milk replacers.

WRN Nuclease-Mediated EcDNA Clearance Enhances Antitumor Therapy in Conjunction with Trehalose Dimycolate/Mesoporous Silica Nanoparticles.

Current research on tumor fibrosis has focused on cancer-associated fibroblasts, which may exert dual functions of tumor promotion and inhibition. Little attention has been paid to whether tumor cells themselves can undergo fibrotic transformation and whether they can inhibit parenchymal cells similar to pulmonary fibrosis, thus achieving the goal of inhibiting the malignant progression of tumors. To explore the significance of inducing tumor fibrosis for cancer treatment. This study utilizes mesoporous silica nanoparticles (MSN) loaded with Trehalose dimycolate (TDM) to induce tumor cell fibrosis through the dual effects of TDM-induced inflammatory granuloma and MSN-induced foreign body granuloma. The results show that TDM/MSN (TM) can effectively induce tumor fibrosis, manifested specifically by collagen internalization, and suppression of proliferation and invasion capabilities, suggesting the potential role of tumor fibrosis therapy. However, further investigation reveals that extrachromosomal DNA (ecDNA) mediates resistance to fibrosis induction. To comprehensively enhance the efficacy, WRN exonuclease is conjugated to TM to form new nanoparticles (TMW) capable of effectively eliminating ecDNA, globally promoting tumor cell fibroblast-like transformation, and validated in a PDX model to inhibit cancer progression. Therefore, TMW, through inducing tumor cell fibrosis to inhibit its malignant progression, holds great potential as a clinical treatment strategy.

Relationship between intra-operative urine output and postoperative acute kidney injury in paediatric cardiac surgery: A retrospective cohort study.

BACKGROUND: Intra-operative urine output (UO) has been shown to predict postoperative acute kidney injury (AKI) in adults; however, its significance in children undergoing cardiac surgery remains unknown. OBJECTIVE: To explore the association between intra-operative UO and postoperative AKI in children with congenital heart disease. DESIGN: A retrospective observational study. SETTING: A tertiary hospital. PATIENTS: Children aged >28 days and <6 years who underwent cardiac surgery at Fuwai Hospital from 1 April 2022 to 30 August 2022. MAIN OUTCOME MEASURES: AKI was identified by the highest serum creatinine value within postoperative 7 days using Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: In total, 1184 children were included. The incidence of AKI was 23.1% (273/1184), of which 17.7% (209/1184) were stage 1, 4.2% (50/1184) were stage 2, and others were stage 3 (1.2%, 14/1184). Intra-operative UO was calculated by dividing the total intra-operative urine volume by the duration of surgery and the actual body weight measured before surgery. There was no significant difference in median [range] intra-operative UO between the AKI and non-AKI groups (2.6 [1.4 to 5.4] and 2.7 [1.4 to 4.9], respectively, P  = 0.791), and multivariate logistic regression analyses showed that intra-operative UO was not associated with postoperative AKI [adjusted odds ratio (OR) 0.971; 95% confidence interval (CI), 0.930 to 1.014; P  = 0.182]. Regarding the clinical importance of severe forms of AKI, we further explored the association between intra-operative UO and postoperative moderate-to-severe AKI (adjusted OR 0.914; 95% CI, 0.838 to 0.998; P  = 0.046). CONCLUSIONS: Intra-operative UO was not associated with postoperative AKI during paediatric cardiac surgery. However, we found a significant association between UO and postoperative moderate-to-severe AKI. This suggests that reductions in intra-operative urine output below a specific threshold may be associated with postoperative renal dysfunction. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05489263.

EGR3 Inhibits Tumor Progression by Inducing Schwann Cell-Like Differentiation.

The mechanism and function of the expression of Schwann characteristics by nevus cells in the mature zone of the dermis are unknown. Early growth response 3 (EGR3) induces Schwann cell-like differentiation of melanoma cells by simulating the process of nevus maturation, which leads to a strong phenotypic transformation of the cells, including the formation of long protrusions and a decrease in cell motility, proliferation, and melanin production. Meanwhile, EGR3 regulates the levels of myelin protein zero (MPZ) and collagen type I alpha 1 chain (COL1A1) through SRY-box transcription factor 10 (SOX10)-dependent and independent mechanisms, by binding to non-strictly conserved motifs, respectively. Schwann cell-like differentiation demonstrates significant benefits in both in vivo and clinical studies. Finally, a CD86-P2A-EGR3 recombinant mRNA vaccine is developed which leads to tumor control through forced cell differentiation and enhanced immune infiltration. Together, these data support further development of the recombinant mRNA as a treatment for cancer.

A multi-source heterogeneous medical data enhancement framework based on lakehouse.

Obtaining high-quality data sets from raw data is a key step before data exploration and analysis. Nowadays, in the medical domain, a large amount of data is in need of quality improvement before being used to analyze the health condition of patients. There have been many researches in data extraction, data cleaning and data imputation, respectively. However, there are seldom frameworks integrating with these three techniques, making the dataset suffer in accuracy, consistency and integrity. In this paper, a multi-source heterogeneous data enhancement framework based on a lakehouse MHDP is proposed, which includes three steps of data extraction, data cleaning and data imputation. In the data extraction step, a data fusion technique is offered to handle multi-modal and multi-source heterogeneous data. In the data cleaning step, we propose HoloCleanX, which provides a convenient interactive procedure. In the data imputation step, multiple imputation (MI) and the SOTA algorithm SAITS, are applied for different situations. We evaluate our framework via three tasks: clustering, classification and strategy prediction. The experimental results prove the effectiveness of our data enhancement framework.

A novel lectin with a distinct Gal_Lectin and CUB domain mediates haemocyte phagocytosis in oyster Crassostrea gigas.

Invertebrate lectins exhibit structural diversity and play crucial roles in the innate immune responses by recognizing and eliminating pathogens. In the present study, a novel lectin containing a Gal_Lectin, a CUB and a transmembrane domain was identified from the Pacific oyster Crassostrea gigas (defined as CgGal-CUB). CgGal-CUB mRNA was detectable in all the examined tissues with the highest expression in adductor muscle (11.00-fold of that in haemocytes, p < 0.05). The expression level of CgGal-CUB mRNA in haemocytes was significantly up-regulated at 3, 24, 48 and 72 h (8.37-fold, 12.13-fold, 4.28-fold and 10.14-fold of that in the control group, respectively) after Vibrio splendidus stimulation. The recombinant CgGal-CUB (rCgGal-CUB) displayed binding capability to Mannan (MAN), peptidoglycan (PGN), D-(+)-Galactose and L-Rhamnose monohydrate, as well as Gram-negative bacteria (Escherichia coli, V. splendidus and Vibrio anguillarum), Gram-positive bacteria (Micrococcus luteus, Staphylococcus aureus, and Bacillus sybtilis) and fungus (Pichia pastoris). rCgGal-CUB was also able to agglutinate V. splendidus, and inhibit V. splendidus growth. Furthermore, rCgGal-CUB exhibited the activities of enhancing the haemocyte phagocytosis towards V. splendidus, and the phagocytosis rate of haemocytes was descended in blockage assay with CgGal-CUB antibody. These results suggested that CgGal-CUB served as a pattern recognition receptor to bind various PAMPs and bacteria, and enhanced the haemocyte phagocytosis towards V. splendidus.

The involvement of CaMKKI in activating AMPKα in yesso scallop Patinopecten yessoensis under high temperature stress.

Calcium/calmodulin dependent protein kinase kinase (CaMKK), a highly conserved protein kinase, is involved in the downstream processes of various biological activities by phosphorylating and activating 5'-AMP-activated protein kinase (AMPK) in response to the increase of cytosolic-free calcium (Ca2+). In the present study, a CaMKKI was identified from Yesso scallop Patinopecten yessoensis. Its mRNA was ubiquitously expressed in haemocytes and all tested tissues with the highest expression level in mantle. The expression level of PyCaMKKI mRNA in adductor muscle was significantly upregulated at 1, 3 and 6 h after high temperature treatment (25 °C), which was 3.43-fold (p < 0.05), 5.25-fold (p < 0.05), and 5.70-fold (p < 0.05) of that in blank group, respectively. At 3 h after high temperature treatment (25 °C), the protein level of PyAMPKα, as well as the phosphorylation level of PyAMPKα at Thr170 in adductor muscle, and the positive co-localized fluorescence signals of PyCaMKKI and PyAMPKα in haemocyte all increased significantly (p < 0.05) compared to blank group (18 °C). The pull-down assay showed that rPyCaMKKI and rPyAMPKα could bind each other in vitro. After PyCaMKKI was silenced by siRNA, the mRNA and protein levels of PyCaMKKI and PyAMPKα, and the phosphorylation level of PyAMPKα at Thr170 in adductor muscle were significantly down-regulated (p < 0.05) compared with the negative control group receiving an injection of siRNA-NC. These results collectively suggested that PyCaMKKI was involved in the activation of PyAMPKα in response to high temperature stress and would be helpful for understanding the function of PyCaMKKI-PyAMPKα pathway in maintaining energy homeostasis under high temperature stress in scallops.

Perceived Overload on Short Video Platforms and Its Influence on Mental Health Among the Elderly: A Moderated Mediation Model.

Background: In the post-epidemic era, the problem of short-video app addiction among older adults has become increasingly prominent, and people have begun to pay attention to the negative emotional and psychological consequences of Perceived Overload of short-video apps. Given the growing mental health concerns of older adults, it is critical to understand the potential relationship between the Perceived Overload of short video apps for older adults and older adults' mental health. Methods: This study applied the stress-strain-outcome (SSO) framework to explore the relationship between perceived overload of a short-video application and loneliness, mental health, and Confucianism tenets in 1300 Chinese older adults. The relationship between perceived overload and loneliness, mental health, and Confucianism tenet moderated mediation models of perceived overload and mental health were created using SPSS 26.0 and PROCESS 4.1 for SPSS. Results: The perceived overload of a short video application for older adults directly predicted loneliness and mental health in older adults, and the Confucianism tenet moderated the mediation process between perceived overload and mental health. Perceived overload affects mental health through loneliness in older adults. Discussion: The results of this study are of practical significance for understanding the current problem of short-video addiction among older adults. Understanding the effects of perceived overload on older adults' loneliness and mental health can help prevent loneliness and mental health problems caused by short-video addiction among older adults on the one hand, and on the other hand, it can also help to develop targeted coping strategies and create psychological intervention programs based on the Confucianism tenet of intervention ethics to improve mental health in a changing technological stress environment.

Topical JAK inhibition ameliorates EGFR inhibitor-induced rash in rodents and humans.

Epidermal growth factor receptor inhibitors (EGFRis) are used to treat many cancers, but their use is complicated by the development of a skin rash that may be severe, limiting their use and adversely affecting patient quality of life. Most studies of EGFRi-induced rash have focused on the fully developed stage of this skin disorder, and early pathological changes remain unclear. We analyzed high-throughput transcriptome sequencing of skin samples from rats exposed to the EGFRi afatinib and identified that keratinocyte activation is an early pathological alteration in EGFRi-induced rash. Mechanistically, the induction of S100 calcium-binding protein A9 (S100A9) occurred before skin barrier disruption and led to keratinocyte activation, resulting in expression of specific cytokines, chemokines, and surface molecules such as interleukin 6 (Il6) and C-C motif chemokine ligand 2 (CCL2) to recruit and activate monocytes through activation of the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, further recruiting more immune cells. Topical JAK inhibition suppressed the recruitment of immune cells and ameliorated the severity of skin rash in afatinib-treated rats and mice with epidermal deletion of EGFR, while having no effect on EGFRi efficacy in tumor-bearing mice. In a pilot clinical trial (NCT05120362), 11 patients with EGFRi-induced rash were treated with delgocitinib ointment, resulting in improvement in rash severity by at least one grade in 10 of them according to the MASCC EGFR inhibitor skin toxicity tool (MESTT) criteria. These findings provide a better understanding of the early pathophysiology of EGFRi-induced rash and suggest a strategy to manage this condition.

Noncanonical WNT5A controls the activation of latent TGF-ß to drive fibroblast activation and tissue fibrosis.

Transforming growth factor ß (TGF-ß) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-ß remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-ß in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-ß. The activation of latent TGF-ß requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-ß, rebalanced TGF-ß signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-ß in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.

The relationship of peripheral blood lncRNA-PVT1 and miR-146a levels with Th17/Treg cytokines in patients with Hashimoto's thyroiditis and their clinical significance.

Hashimoto's thyroiditis (HT) is a prevalent autoimmune disease. We investigated the relationship of peripheral blood long noncoding RNA-plasmacytoma variant translocation 1 (lncRNA-PVT1) and microRNA (miR)-146a levels with Th17/Treg-related cytokines in HT patients and their clinical significance. Correlations of PVT1 and miR-146a with Th17/Treg-related cytokines were analyzed, and its clinical value in diagnosing HT was assessed. Results showed reduced lncRNA-PVT1 and interleukin (IL)-10 levels and increased miR-146a and IL-17 levels in HT patients. lncRNA-PVT1 negatively interrelated with miR-146a, IL-17, IL-23 and IL-6, and positively interrelated with IL-10; miR-146a positively correlated with IL-17, IL-23 and IL-6, but negatively correlated with IL-10 in HT patients. The area under the curve (AUC) of lncRNA-PVT1 and miR-146a levels for diagnosing HT were 0.822 and 0.844, respectively (sensitivity 88.73% and 86.62%, specificity 67.02% and 69.15%, cut-off values 0.76 and 2.73), with their combined detections yielding a higher AUC. Patients with poorly expressed lncRNA-PVT1 and highly expressed miR-146a had elevated HT incidence. lncRNA-PVT1 and miR-146a levels were also found to be an independent influencing factor for HT occurrence. Our findings suggest that HT patients have low peripheral blood lncRNA-PVT1 expression and high miR-146a expression. lncRNA-PVT1 and miR-146a level changes were correlated with Th17/Treg cytokine imbalance and could be a potential diagnostic tool and independent influencing factor for HT.

The possibly role of GnIH in stress and gut dysfunction in chicken.

Stress is known to disrupt the intestinal barrier and induce intestinal dysfunction. A critical role for gonadotropin inhibitory hormone (GnIH) in stress has emerged. However, whether GnIH mediates stress-induced intestinal dysfunction remains unknown. The present study explored this question through in vivo and in vitro experiments in hens. Our in vivo experiments showed that continuous intraperitoneal injection of GnIH not only significantly increased the concentration of stress hormones in serum, but also significantly elevated the mRNA expression of glucocorticoid receptor (GR) in the duodenum and jejunum. Moreover, morphological and molecular analyses revealed that GnIH disrupted the physical and chemical barriers of the intestine and dramatically increased inflammatory factor levels in the intestine and serum of hens. Interestingly, the microbiomics results showed that GnIH altered the structure and composition of the gut flora in the cecum, revealing an increased abundance of harmful intestinal bacteria such as Desulfovibrionaceae. Similar results were found in in vitro studies in which the GnIH-induced intestinal mucosal barrier was disrupted, and inflammation increased in jejunal explants, although no significant difference was found in the expression of GR between the control and GnIH groups. Our results demonstrated that GnIH not only directly damaged intestinal barriers and elevated intestinal inflammation but also mediated stress and microflora imbalance-induced intestinal function disorder, suggesting that GnIH is a potential therapeutic target for gut dysfunction, stress-induced intestinal function disorder, and inflammatory bowel disease in animals and humans.

MSC microvesicles loaded G-quadruplex-enhanced circular single-stranded DNA-9 inhibits tumor growth by targeting MDSCs.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) promote tumor growth, metastasis, and lead to immunotherapy resistance. Studies revealed that miRNAs are also expressed in MDSCs and promote the immunosuppressive function of MDSCs. Currently, few studies have been reported on inducible cellular microvesicle delivery of nucleic acid drugs targeting miRNA in MDSCs for the treatment of malignant tumors. RESULTS AND CONCLUSION: In this study, we designed an artificial DNA named G-quadruplex-enhanced circular single-stranded DNA-9 (G4-CSSD9), that specifically adsorbs the miR-9 sequence. Its advanced DNA folding structure, rich in tandem repeat guanine (G-quadruplex), also provides good stability. Mesenchymal stem cells (MSCs) were prepared into nanostructured vesicles by membrane extrusion. The MSC microvesicles-encapsulated G4-CSSD9 (MVs@G4-CSSD9) was delivered into MDSCs, which affected the downstream transcription and translation process, and reduced the immunosuppressive function of MDSCs, so as to achieve the purpose of treating melanoma. In particular, it provides an idea for the malignant tumor treatment.