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OBJECTIVE: The objective of the study was to systematically evaluate and perform a meta-analysis on the adherence to high-flow nasal cannula (HFNC) humidified oxygen therapy and its influencing factors in elderly patients with stable chronic obstructive pulmonary disease (COPD). METHODS: Relevant literature on HFNC and COPD was retrieved from PubMed, EMbase, Web of Science, and Cochrane Library databases. Cross-sectional studies, case–control studies, and cohort studies were included. Screening and quality assessment were conducted using Endnote X9 software. Quality scores were assigned using the Newcastle–Ottawa Scale and the AHRQ assessment tool. Basic information, sample size, and adherence-related factors were extracted, and heterogeneity and publication bias were assessed. RESULTS: A total of 321 articles were initially identified, with 8 English articles involving 325 patients included after screening. Quality assessment yielded five high-quality articles (score > 8), two medium-quality articles (score = 7), and one low-quality article (score = 6). Meta-analysis results showed a COPD patient HFNC adherence rate of 32.7%. Negative factors included the number of acute exacerbations (odds ratio [OR] =2.17), adverse reactions (OR = 4.13), regular follow-up (OR = 9.45), educational level (OR = 5.38), and concurrent medications (OR = 4.71). Positive factors included age < 70 years (OR = 0.45), duration of use (OR = 0.30), inhalation technique (OR = 0.31), treatment satisfaction (OR = 0.35), and adverse reactions (OR = 0.15). Funnel plot and Egger’s test results indicated minimal publication bias. CONCLUSION: Adherence to HFNC in elderly COPD patients is relatively low, influenced by negative factors such as the number of acute exacerbations, adverse reactions, regular follow-up, educational level, and concurrent medications. Positive factors include age < 70 years, duration of use, inhalation technique, treatment satisfaction, and adverse reactions.

Abstract Objective To examine the effects of Jintiange on enhancing the healing of osteoporotic fractures in aged rats. Methods An osteoporotic fracture model of femur was established using 70 SD rats (aged > 12 months), which were randomly numbered and divided into an experimental group and a control group, each with an equal sample size (n = 35). The experimental group received Jintiange capsule ingredients via intragastric administration, while the control group received an equal volume of saline via the same method. X-ray examinations were conducted at the 4th and 12th weeks to evaluate fracture healing in the rats. After 12 weeks, micro-CT scanning was employed to assess the microstructure of the healthy femurs, and the parameters of the experimental and control groups were compared. Results After 4 weeks, the mean fracture healing scores were 0.78 ± 0.43 in the experimental group and 0.56 ± 0.51 in the control group. After 12 weeks, the mean scores were 1.50 ± 0.71 in the experimental group and 0.96 ± 0.68 in the control group. The scores in the experimental group were higher than those in the control group (P

The preclinical evaluation of drug-induced cardiotoxicity is critical for developing novel drug, helping to avoid drug wastage and post-marketing withdrawal. Although human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and the engineered heart organoid have been used for drug screening and mimicking disease models, they are always limited by the immaturity and lack of functionality of the cardiomyocytes. In this study, we constructed a Cardiomyocytes-on-a-Chip (CoC) that combines micro-grooves (MGs) and circulating mechanical stimulation to recapitulate the well-organized structure and stable beating of myocardial tissue. The phenotypic changes and maturation of CMs cultured on the CoC have been verified and can be used for the evaluation of cardiotoxicity and cardioprotective drug responses. Taken together, these results highlight the ability of our myocardial microarray platform to accurately reflect clinical behaviour, underscoring its potential as a powerful pre-clinical tool for assessing drug response and toxicity.

Highlights An alternative electromagnetic attenuation pathway is proposed in the MXene-polymer hybrid structure, distinct from conduction loss, for generalizing the results to a wider range of electromagnetic-thermal driven soft materials and devices. By efficiently harvesting and converting electromagnetic energy, the response time of the hybrid polymer to microwave exhibits 87% reduction with merely 0.15 wt% MXene. A new mode of self-powered motion sensing based on deformation-driven piezoelectric effect is developed, enhancing the material’s intelligence.

Abstract Background To develop an artificial intelligence (AI)-based model using Radiomics, deep learning (DL) features extracted from 18F-fluorodeoxyglucose (18F-FDG) Positron emission tomography/Computed Tomography (PET/CT) images of tumor and cervical lymph node with clinical feature for predicting cervical lymph node metastasis (CLNM) in patients with esophageal squamous cell carcinoma (ESCC). Methods The study included 300 ESCC patients from the First Affiliated Hospital of Zhengzhou University who were divided into a training cohort and an internal testing cohort with an 8:2 ratio. Another 111 patients from Shanghai Chest Hospital were included as the external cohort. For each sample, we extracted 428 PET/CT-based Radiomics features from the gross tumor volume (GTV) and cervical lymph node (CLN) delineated layer by layer and 256 PET/CT-based DL features from the maximum cross-section of GTV and CLN images We input these features into seven different machine learning algorithms and ultimately selected logistic regression (LR) as the model classifier. Subsequently, we evaluated seven models (Clinical, Radiomics, Radiomics-Clinical, DL-Clinical, DL-Radiomics, DL-Radiomics-Clinical) using Radiomics features, DL features and clinical feature. Results The DL-Radiomics-Clinical (DRC) model demonstrated higher AUC of 0.955 and 0.916 compared to the other six models in both internal and external testing cohorts respectively. The DRC model achieved the highest accuracy among the seven models in both the internal and external test sets, with scores of 0.951 and 0.892, respectively. Conclusions Through the combination of Radiomics features and DL features from PET/CT imaging and clinical feature, we developed a predictive model exhibiting exceptional classification capabilities. This model can be considered as a non-invasive method for predication of CLNM in patients with ESCC. It might facilitate decision-making regarding to the extend of lymph node dissection, and to select candidates for postoperative adjuvant therapy.

Abstract Background Radiation-induced lung injury (RILI) is associated with alveolar epithelial cell death and secondary fibrosis in injured lung. Mesenchymal stem cell (MSC)-derived exosomes have regenerative effect against lung injury and the potential to intervene of RILI. However, their intervention efficacy is limited because they lack lung targeting characters and do not carry sufficient specific effectors. SARS-CoV-2 spike glycoprotein (SARS-CoV-2-S-RBD) binds angiotensin-converting enzyme 2 (ACE2) receptor and mediates interaction with host cells. MiR-486-5p is a multifunctional miRNA with angiogenic and antifibrotic potential and acts as an effector in MSC-derived exosomes. Ferroptosis is a form of cell death associated with radiation injury, its roles and mechanisms in RILI remain unclear. In this study, we developed an engineered MSC-derived exosomes with SARS-CoV-2-S-RBD- and miR-486-5p- modification and investigated their intervention effects on RIPF and action mechanisms via suppression of epithelial cell ferroptosis. Results Adenovirus-mediated gene modification led to miR-486-5p overexpression in human umbilical cord MSC exosomes (p

Abstract Background The aim of this study is to investigate the real-world efficacy and safety of nivolumab in combination with chemotherapy for patients with advanced human epidermal growth factor receptor 2 (HER2)-negative gastric cancer (GC). Methods We enrolled patients diagnosed with unresectable advanced or metastatic GC who received nivolumab plus chemotherapy as first-line systemic treatment. The combined positive score (CPS), indicating the number of programmed cell death-ligand 1 (PD-L1)-stained cells, was utilized. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method. Adverse events (AEs) were graded, and treatment was ceased upon disease progression or intolerance. Results A total of 27 patients were included in the study, comprising 15 patients with CPS ≥ 5 and 12 patients with CPS

This study was designed to evaluate the diagnostic efficacy of relevant parameters of 18F-prostate-specific membrane antigen (PSMA)-1007 PET/CT in predicting the pathological grade of primary prostate cancer. Briefly, a prospective analysis was performed on 53 patients diagnosed with prostate cancer by systematic puncture biopsy, followed by 18F-PSMA-1007 PET/CT examination prior to treatment within 10 d. The patients were grouped in accordance with the Gleason grading system revised by the International Association of Urology Pathology (ISUP). They were divided into high-grade group (ISUP 4–5 group) and low-grade group (ISUP 1–3 group). The differences in maximum standardized uptake value (SUVmax), tumor-to-background ratio (TBR), intraprostatic PSMA-derived tumor volume (iPSMA-TV), and intraprostatic total lesion PSMA (iTL-PSMA) between the high- and low-grade group were statistically significant (p

Abstract Insulin has been shown to modulate neuronal processes through insulin receptors. The ion channels located on neurons may be important targets for insulin/insulin receptor signaling. Both insulin receptors and acid-sensing ion channels (ASICs) are expressed in dorsal root ganglia (DRG) neurons. However, it is still unclear whether there is an interaction between them. Therefore, the purpose of this investigation was to determine the effects of insulin on the functional activity of ASICs. A 5 min application of insulin rapidly enhanced acid-evoked ASIC currents in rat DRG neurons in a concentration-dependent manner. Insulin shifted the concentration–response plot for ASIC currents upward, with an increase of 46.2 ± 7.6% in the maximal current response. The insulin-induced increase in ASIC currents was eliminated by the insulin receptor antagonist GSK1838705, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol-3 kinase antagonist wortmannin. Moreover, insulin increased the number of acid-triggered action potentials by activating insulin receptors. Finally, local administration of insulin exacerbated the spontaneous nociceptive behaviors induced by intraplantar acid injection and the mechanical hyperalgesia induced by intramuscular acid injections through peripheral insulin receptors. These results suggested that insulin/insulin receptor signaling enhanced the functional activity of ASICs via tyrosine kinase and phosphatidylinositol-3 kinase pathways. Our findings revealed that ASICs were targets in primary sensory neurons for insulin receptor signaling, which may underlie insulin modulation of pain.

Abstract Background The modified pancreatitis activity scoring system (mPASS) was proposed to assess the activity of acute pancreatitis (AP) while it doesn’t include indicators that directly reflect pathophysiology processes and imaging characteristics. Objectives To determine the threshold of admission mPASS and investigate radiomics and laboratory parameters to construct a model to predict the activity of AP. Methods AP inpatients at institution 1 were randomly divided into training and validation groups based on a 5:5 ratio. AP inpatients at Institution 2 were served as test group. The cutoff value of admission mPASS scores in predicting severe AP was selected to divide patients into high and low level of disease activity group. LASSO was used in screening features. Multivariable logistic regression was used to develop radiomics model. Meaningful laboratory parameters were used to construct combined model. Results There were 234 (48 years ± 10, 155 men) and 101 (48 years ± 11, 69 men) patients in two institutions. The threshold of admission mPASS score was 112.5 in severe AP prediction. The AUC of the radiomics model was 0.79, 0.72, and 0.76 and that of the combined model incorporating rad-score and white blood cell were 0.84, 0.77, and 0.80 in three groups for activity prediction. The AUC of the combined model in predicting disease without remission was 0.74. Conclusions The threshold of admission mPASS was 112.5 in predicting severe AP. The model based on CECT radiomics has the ability to predict AP activity. Its ability to predict disease without remission is comparable to mPASS. Critical relevance statement This work is the first attempt to assess the activity of acute pancreatitis using contrast-enhanced CT radiomics and laboratory parameters. The model provides a new method to predict the activity and prognosis of AP, which could contribute to further management. Key Points Radiomics features and laboratory parameters are associated with the activity of acute pancreatitis. The combined model provides a new method to predict the activity and prognosis of AP. The ability of the combined model is comparable to the modified Pancreatitis Activity Scoring System. Graphical Abstract

Highlights MXene/TiO2 hybrids are prepared by a simple calcination treatment, and their electromagnetic response is customized by in situ atomic reconstruction engineering. Based on the excellent electromagnetic response of MXene/TiO2 hybrids, a series of electromagnetic devices are constructed. Multi-spectrum stealth is realized covering visible-light, infrared radiation and GHz.

IntroductionAllogeneic hematopoietic cell transplantation (alloHCT) possessed direct cytotoxicity and graft-versus-multiple myeloma effect (GvMM). Growing trials have shown survival benefits of performing alloHCT in both newly diagnosed and relapsed MM.MethodsWe aimed to provide a comprehensive analysis in the recent 10 years to verify the efficacy and survival outcome of alloHCT in MM patients. A total of 61 studies which provide data between 14/04/2013 and 14/04/2023 and a total of 15,294 data from MM patients who had undergone alloSCT were included in our study. The best response rates (CR, VGPR, PR) and survival outcomes (1-, 2-, 3-,5-, and 10-year OS, PFS, NRM) were assessed. We further conducted meta-analysis in the NDMM/frontline setting and RRMM/salvage setting independently.ResultsThe pooled estimate CR, VGPR, and PR rates were 0.45, 0.21, and 0.24, respectively. The pooled estimates of 1-, 2-, 3-, 5-, and 10-year OS were 0.69, 0.57, 0.45, 0.45, and 0.36, respectively; the pooled estimates of 1-, 2-, 3-, 5-, and 10-year PFS were 0.47, 0.35, 0.24, 0.25, and 0.28, respectively; and the pooled estimates of 1-, 2-, 3-, 5-, and 10-year NRM were 0.16, 0.21, 0.16, 0.20, and 0.15, respectively. In the NDMM/upfront setting, the pooled estimate CR rate was 0.54, and those for 5-year OS, PFS, and NRM were 0.69, 0.40, and 0.11, respectively. In a relapsed setting, the pooled estimate CR rate was 0.31, and those for 5-year OS, PFS, and NRM were 0.24, 0.10, and 0.15, respectively.DiscussionOur results showed constant OS, PFS, and NRM from the third year onwards till the 10th year, suggesting that alloSCT has sustained survival benefits. Good response rate and promising survival outcome were observed in the NDMM/ frontline setting.ConclusionAlthough comparing with other treatments, alloSCT had a lower response rate and poorer short-term survival outcome, long-term follow-up could reveal survival benefits of alloSCT in MM patients.

Background Statins are widely used for treating patients with ischemic stroke at risk of secondary cerebrovascular events. It is unknown whether Asian populations benefit from more intensive statin‐based therapy for stroke recurrence. Therefore, in the present study we evaluated the effectiveness and safety of high‐dose and moderate‐dose statins for patients who had experienced mild ischemic stroke during the acute period. Methods and Results This multicenter prospective study included patients with mild ischemic stroke who presented within 72 hours of symptom onset. The outcomes of patients in the high‐intensity and moderate‐intensity statin treatment groups were compared, with the main efficacy outcome being stroke recurrence and the primary safety end point being intracranial hemorrhage. The propensity score matching method was employed to control for imbalances in baseline variables. Subgroup analyses were conducted to evaluate group differences. In total, the data of 2950 patients were analyzed at 3 months, and the data of 2764 patients were analyzed at 12 months due to loss to follow‐up. According to the multivariable Cox analyses adjusted for potential confounders, stroke recurrence occurred similarly in the high‐intensity statin and moderate‐intensity statin groups (3 months: adjusted hazard ratio [HR], 1.12 [95% CI, 0.85–1.49]; P=0.424; 12 months: adjusted HR, 1.08 [95% CI, 0.86–1.34]; P=0.519). High‐intensity statin therapy was associated with an increased risk of intracranial hemorrhage (3 months: adjusted HR, 1.81 [95% CI, 1.00–3.25]; P=0.048; 12 months: adjusted HR, 1.86 [95% CI, 1.10–3.16]; P=0.021). The results from the propensity score‐matched analyses were consistent with those from the Cox proportional hazards analysis. Conclusions Compared with moderate‐intensity statin therapy, high‐dose statin therapy may not decrease the risk of mild, noncardiogenic ischemic stroke recurrence but may increase the risk of intracranial hemorrhage. Registration URL: www.chictr.org.cn/. Unique Identifier: ChiCTR1900025214.

Abstract Objective In this study, we aimed to enhance the treatment protocols and help understand the harm caused by the accidental ingestion of magnetic beads by children. Methods Data were collected from 72 children with multiple gastrointestinal perforations or gastrointestinal obstructions. The 72 pediatric patients were divided into a perforation and a non-perforation group. The data collected for the analysis included the gender, age, medical history, place of residence (rural or urban), and symptoms along with the educational background of the caregiver, the location and quantity of any foreign bodies discovered during the procedure, whether perforation was confirmed during the procedure, and the number of times magnetic beads had been accidentally ingested. Results The accuracy rate of preoperative gastrointestinal perforation diagnosis via ultrasound was 71%, while that of the upright abdominal X-ray method was only 46%. In terms of symptoms, the risk of perforation was 13.844 and 12.703 times greater in pediatric patients who experienced vomiting and abdominal pain with vomiting and abdominal distension, respectively, compared to patients in an asymptomatic state. There were no statistical differences between the perforation and the non-perforation groups in terms of age, gender, medical history, and the number of magnetic beads ingested (P > 0.05); however, there were statistical differences in terms of white blood cell count (P = 0.048) and c-reactive protein levels (P = 0.033). A total of 56% of cases underwent a laparotomy along with perforation repair and 19% underwent gastroscopy along with laparotomy. All pediatric patients recovered without complications following surgery. Conclusion Abdominal ultrasonography and/or upright abdominal X-ray analyses should be carried out as soon as possible in case of suspicion of accidental ingestion of magnetic beads by children. In most cases, immediate surgical intervention is required. Given the serious consequences of ingesting this type of foreign body, it is essential to inform parents and/or caregivers about the importance of preventing young children from using such products.

Abstract Background Previous studies have demonstrated that natural killer (NK) cells migrated into the liver from peripheral organs and exerted cytotoxic effects on hepatocytes in virus-induced liver failure. Aim This study aimed to investigate the potential therapeutic role of chemokine receptors in the migration of NK cells in a murine hepatitis virus strain 3 (MHV-3)-induced fulminant hepatic failure (MHV-3-FHF) model and its mechanism. Results By gene array analysis, chemokine (C–C motif) receptor 5 (CCR5) was found to have remarkably elevated expression levels in hepatic NK cells after MHV-3 infection. The number of hepatic CCR5+ conventional NK (cNK) cells increased and peaked at 48 h after MHV-3 infection, while the number of hepatic resident NK (rNK) cells steadily declined. Moreover, the expression of CCR5-related chemokines, including macrophage inflammatory protein (MIP)-1α, MIP-1β and regulated on activation, normal T-cell expressed and secreted (RANTES) was significantly upregulated in MHV-3-infected hepatocytes. In an in vitro Transwell migration assay, CCR5-blocked splenic cNK cells showed decreased migration towards MHV-3-infected hepatocytes, and inhibition of MIP-1β or RANTES but not MIP-1α decreased cNK cell migration. Moreover, CCR5 knockout (KO) mice displayed reduced infiltration of hepatic cNK cells after MHV-3 infection, accompanied by attenuated liver injury and improved mouse survival time. Adoptive transfer of cNK cells from wild-type mice into CCR5 KO mice resulted in the abundant accumulation of hepatic cNK cells and aggravated liver injury. Moreover, pharmacological inhibition of CCR5 by maraviroc reduced cNK cell infiltration in the liver and liver injury in the MHV-3-FHF model. Conclusion The CCR5-MIP-1β/RANTES axis played a critical role in the recruitment of cNK cells to the liver during MHV-3-induced liver injury. Targeted inhibition of CCR5 provides a therapeutic approach to ameliorate liver damage during virus-induced acute liver injury.

Abstract Background While the treatment guidelines have been established for pure urothelial carcinoma (pUC), patients with variant type urothelial carcinoma (vUC) face limited effective treatment options. The effectiveness of immune checkpoint inhibitors (ICI) in patients with vUC remains uncertain and necessitates additional research. Method We conducted a retrospective, multicenter study to explore the effectiveness of ICI in patients with pUC or vUC in Taiwan. We evaluated the overall response rate (ORR) through univariate logistic regression analysis and examined the overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis. Additionally, we employed univariate and multivariate Cox proportional hazards models to analyze the data. Result A total of 142 patients (116 pUC, 26 vUC) were included in our final analysis. The ORR was marginally higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%, p = 0.26). Among all patients, 12.9% with pUC achieved a complete response (CR) after ICI treatment, while no vUC cases achieved CR (p = 0.05). There were no significant differences in PFS (median 3.6 months vs. 4.1 months, p = 0.34) or OS (median 16.3 months vs. 11.0 months, p = 0.24) when comparing patients with pUC or vUC. In the subgroup analysis, patients with pUC who underwent first-line ICI treatment exhibited significantly improved OS compared to those with vUC (24.6 months vs. 9.1 months, p = 0.004). Conclusion The use of ICI as monotherapy is a feasible and effective treatment approach for patients with metastatic vUC.

BackgroundTuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) and can be difficult to diagnose and treat. We aimed to describe the clinical presentation, diagnosis, disease spectrum, outcome, and prognostic factors of patients treated for TBM in China.MethodsA multicenter retrospective study was conducted from 2009 to 2019 enrolling all presumptive TBM patients referred to Xijing tertiary Hospital from 27 referral centers in and around Shaanxi province, China. Patients with clinical features suggestive of TBM (abnormal CSF parameters) were included in the study if they had adequate baseline information to be classified as “confirmed,” “probable,” or “possible” TBM according to international consensus TBM criteria and remained in follow-up. Patients with a confirmed alternative diagnosis or severe immune compromise were excluded. Clinical presentation, central nervous system imaging, cerebrospinal fluid (CSF) results, TBM score, and outcome—assessed using the modified Barthel disability index—were recorded and compared.FindingsA total of 341 presumptive TBM patients met selection criteria; 63 confirmed TBM (25 culture positive, 42 Xpert-MTB/RIF positive), 66 probable TBM, 163 possible TBM, and 49 “not TBM.” Death was associated with BMRC grade III (OR = 5.172; 95%CI: 2.298–11.641), TBM score ≥ 15 (OR = 3.843; 95%CI: 1.372–10.761), age > 60 years (OR = 3.566; 95%CI: 1.022–12.442), and CSF neutrophil ratio ≥ 25% (OR = 2.298; 95%CI: 1.027–5.139). Among those with confirmed TBM, nearly one-third (17/63, 27.0%) had a TBM score 60 years) have higher TBM scores or CSF neutrophil ratios, have signs of disseminated/miliary TB, and are at greatest risk of death. In general, more effort needs to be done to improve early diagnosis and treatment outcome in TBM patients.

IntroductionThis study assessed the relationship between the progression of Parkinson’s disease (PD) with cognitive impairment and changes in serum uric acid (UA) and homocysteine (Hcy) concentrations and explored the factors influencing PD with cognitive impairment.MethodsThe study randomly selected 74 patients with PD and evaluated their cognitive function using the Montreal Cognitive Assessment Scale (MoCA). Patients with PD were divided into two subgroups: those with and without cognitive impairment. PD severity was evaluated and graded using the Hoehn and Yahr (H–Y) scale. Another 60 middle-aged and older individuals without PD during the same period were selected as a control group. Blood UA and Hcy concentrations in each group were measured to assess the relationship between PD, cognitive impairment, and changes in UA and Hcy concentrations.ResultsThe PD group with cognitive impairment had a lower UA concentration and higher Hcy concentration. The UA concentration was significantly higher in the early PD stages than in the middle and late stages (P

Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's quality of life but also poses a constant threat to their life expectancy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, affects cell differentiation, tissue growth, and disease development. However, its role in airway mucus hypersecretion induced by COPD remains elusive. In this study, USP7 expression was significantly upregulated in airway epithelial samples from patients with COPD, and USP7 was also overexpressed in mouse lung and human airway epithelial cells in models of airway mucus hypersecretion. Inhibition of USP7 reduced the expression of nuclear factor kappa B (NF-κB), phosphorylated-NF-κB (p-NF-κB), and phosphonated inhibitor of nuclear factor kappa B (p-IκBα), and alleviated the airway mucus hypersecretion in vivo and in vitro. Further research revealed that USP7 stimulated airway mucus hypersecretion through the activation of NF-κB nuclear translocation. In addition, the expression of mucin 5AC (MUC5AC) was suppressed by the NF-κB inhibitor erdosteine. These findings suggest that USP7 stimulates the NF-κB signaling pathway, which promotes airway mucus hypersecretion. This study identifies one of the mechanisms regulating airway mucus secretion and provides a new potential target for its prevention and treatment.

Abstract Background Neutrophils consume a large amount of energy when performing their functions. Compared with other white blood cells, neutrophils contain few mitochondria and mainly rely on glycolysis and gluconeogenesis to produce ATP. The inflammatory site is hypoxic and nutrient poor. Our aim is to study the role of abnormal adenosine metabolism of neutrophils in the asthmatic airway inflammation microenvironment. Method In this study, an asthma model was established by intratracheal instillation of Aspergillus fumigatus extract in Ecto-5'-Nucleotidase (CD73) gene–knockout and wild-type mice. Multiple analyses from bronchoalveolar lavage fluid (BALF) were used to determine the levels of cytokines and chemokines. Immunohistochemistry was used to detect subcutaneous fibrosis and inflammatory cell infiltration. Finally, adenosine 5’-(α, β-methylene) diphosphate (APCP), a CD73 inhibitor, was pumped subcutaneously before Aspergillus attack to observe the infiltration of inflammatory cells and subcutaneous fibrosis to clarify its therapeutic effect. Result PAS staining showed that CD73 knockout inhibited pulmonary epithelial cell proliferation and bronchial fibrosis induced by Aspergillus extract. The genetic knockdownof CD73 significantly reduced the production of Th2 cytokines, interleukin (IL)-4, IL-6, IL-13, chemokine (C–C motif) ligand 5 (CCL5), eosinophil chemokine, neutrophil IL-17, and granulocyte colony-stimulating factor (G-CSF). In addition, exogenous adenosine supplementation increased airway inflammation. Finally, the CD73 inhibitor APCP was administered to reduce inflammation and subcutaneous fibrosis. Conclusion Elevated adenosine metabolism plays an inflammatory role in asthma, and CD73 could be a potential therapeutic target for asthma.

AbstractBackground Bile acids play crucial roles in various metabolisms, as well as Lactobacillus in the intestine. But studies on their roles in acute coronary syndrome (ACS) are still insufficient. The aim of this study was to investigate their role and potential association with the severity of coronary lesions and the prognosis of ACS.Methods Three hundred and sixty ACS patients were selected. Detection of gut Lactobacillus levels was done through 16S rDNA sequence analysis. Evaluation of the extent of lesions was done using the SYNTAX (SS) score. Mediation analysis was used to assess the relationship between serum total bile acid (TBA), Lactobacillus, atherosclerotic lesions and prognosis of ACS.Results Logistic regressive analysis disclosed that serum TBA and Lactobacillus were independent predictors of coronary lesions (high vs. low SS: serum TBA adjusted odds ratio (aOR) = 0.8, 95% confidence interval (CI): 0.6–0.9, p

Abstract Background Autophagy related protease 4B (ATG4B) is a protease required for autophagy processing, which is strongly implicated in cancer progression. Phosphorylation of ATG4B is crucial for activation of its protease activity. However, little is known about the relationship of ATG4B and its phosphorylated form at Ser 383 and 392 sites (pS383/392-ATG4B), with clinical outcomes, particularly in colorectal cancer (CRC). Methods The ATG4B gene expression in CRC patients was obtained from The Cancer Genome Atlas (TCGA) database to analyze its clinical relevance. Tissue microarrays composed of 118 CRC patient specimens were used to determine the associations of ATG4B and pS383/392-ATG4B protein levels with prognosis. The biological functions of ATG4B in CRC cells were inspected with cell proliferation, mobility and spheroid culture assays. Results ATG4B gene expression was elevated in tumor tissues of CRC patients compared to that in adjacent normal tissues and high level of ATG4B expression was associated with poor survival. Similarly, protein levels of ATG4B and pS383/392-ATG4B were highly correlated with worse overall survival and disease-free survival. Stratification analysis results showed that high level of ATG4B had significantly higher risk of mortality in males and elderly patients compared to those female patients and patients 60 years or younger. In contrast, multivariate Cox’s regression analysis indicated that high level of pS383/392-ATG4B was significantly linked to unfavorable overall survival and disease-free survival of males and elderly patients, whereas, it had no correlation with female patients and patients 60 years or younger. Moreover, high level of ATG4B was positively associated with increased mortality risk in patients with advanced AJCC stages (III and IV) and lymph node invasion (N1 and N2) for both overall survival and disease-free survival. Nevertheless, high level of pS383/392-ATG4B was positively correlated with increased mortality risk in patients with early AJCC stages (I and II) and without lymph node invasion (N0). In addition, silencing ATG4B attenuated migration, invasion, and further enhanced the cytotoxic effects of chemotherapeutic drugs in two and three-dimensional cultures of CRC cells. Conclusions Our results suggest that ATG4B and pS383/392-ATG4B might be suitable biomarkers and therapeutic targets for CRC.

Abstract Objective To investigate and analyze the etiology and prognosis of patients with new‐onset status epilepticus (NOSE). Methods We conducted a retrospective analysis of all adult patients (≧16 years old) who were admitted to Sichuan Provincial People's Hospital between January 2018 and December 2020 with status epilepticus (SE) and no prior epilepsy history. Results We collected data from 85 patients, aged from 16 to 90 years, of whom 49 were male and 36 were female. Fifty‐five of these cases (64.7%) were younger than 60 years of age. Acute symptomatic SE was mostly seen in the NOSE (53.9%), followed by unknown SE (25.9%), progressive SE (11.8%), and remote SE (9.4%). The differences in the etiology of NOSE between age groups were statistically significant (P

Obesity and diabetes are closely related metabolic disorders that have become major public health concerns worldwide. Over the past few decades, numerous studies have explored the underlying mechanisms of these disorders and identified various risk factors, including genetics, lifestyle, and dietary habits. Traditional Chinese Medicine (TCM) has been increasingly recognized for its potential to manage obesity and diabetes. Weight loss is difficult to sustain, and several diabetic therapies, such as sulfonylureas, thiazolidinediones, and insulin, might make it harder to lose weight. While lifestyle changes should be the primary approach for people interested in lowering weight, drugs are also worth investigating. Since some of the newer glucose-lowering medications that cause weight loss, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), are additionally utilized or are under consideration for use as anti-obesity drugs, the frontier between glucose-lowering medication and weight loss drugs appears to be shifting. This review provides an overview of the literature on the underlying mechanisms of obesity and diabetes and the prospect of TCM in their management. We discuss the various TCM interventions, including acupuncture, herbal medicine, and dietary therapy, and their effects on metabolic health. We also highlight the potential of TCM in regulating gut microbiota, reducing inflammation, and improving insulin sensitivity. The findings suggest that TCM may provide a promising approach to preventing and managing obesity and diabetes. However, further well-designed studies are needed to confirm the efficacy and safety of TCM interventions and to elucidate their underlying mechanisms of action.

ObjectiveTo investigate the mechanism of RNA-binding protein hnRNP A1 in mouse hippocampal neurons (HT22) on glycolysis.MethodsRIP and CLIP-qPCR were performed by HT22 in vitro to observe the mechanism of hnRNP A1 regulating the expression of key proteins in glycolysis. The RNA binding domain of hnRNP A1 protein in HT22 was inhibited by VPC-80051, and the effect of hnRNP A1 on glycolysis of HT22 was observed. Lentivirus overexpression of hnRNP A1 was used to observe the effect of overexpression of hnRNP A1 on glycolysis of Aβ25–35-injured HT22. The expression of hnRNP A1 in brain tissues of wild-type mice and triple-transgenic (APP/PS1/Tau) AD mice at different ages was studied by Western blot assay.ResultsThe results of RIP experiment showed that hnRNP A1 and HK1 mRNA were significantly bound. The results of CLIP-qPCR showed that hnRNP A1 directly bound to the 2605-2821 region of HK1 mRNA. hnRNP A1 inhibitor can down-regulate the expression of HK1 mRNA and HK1 protein in HT22 cells. Overexpression of hnRNP A1 can significantly reduce the toxic effect of Aβ25–35 on neurons via the hnRNP A1/HK1/ pyruvate pathway. In addition, inhibition of hnRNP A1 binding to amyloid precursor protein (APP) RNA was found to increase Aβ expression, while Aβ25–35 also down-regulated hnRNP A1 expression by enhancing phosphorylation of p38 MAPK in HT22. They interact to form bidirectional regulation, further down-regulating the expression of hnRNP A1, and ultimately aggravating glycolytic dysfunction. Protein immunoblotting showed that hnRNP A1 decreased with age in mouse brain tissue, and the decrease was greater in AD mice, suggesting that the decrease of hnRNP A1 may be a predisposed factor in the pathogenesis of AD.

Abstract Trait matching between mutualistic species is usually expected to maintain mutualism, but empirical studies of trait complementarity and coadaptation in multi‐species assemblages—which represent the reality of most interactions in nature—are few. Here, we studied trait matching between the leafflower shrub Kirganelia microcarpa and three associated seed‐predatory leafflower moths (Epicephala spp.) across 16 populations. Behavioral and morphological observations suggested that two moths (E. microcarpa and E. tertiaria) acted as pollinators while a third (E. laeviclada) acted as a cheater. These species differed in ovipositor morphology but showed trait complementarity between ovipositor length and floral traits at both species level and population level, presumably as adaptations to divergent oviposition behaviors. However, this trait matching varied among populations. Comparisons of ovipositor length and floral traits among populations with different moth assemblages suggested an increase of ovary wall thickness where the locular‐ovipositing pollinator E. microcarpa and cheater E. laeviclada were present, while stylar pit depth was less in populations with the stylar pit‐ovipositing pollinator E. tertiaria. Our study indicates that trait matching between interacting partners occurs even in extremely specialized multi‐species mutualisms, and that although these responses vary, sometimes non‐intuitively, in response to different partner species. It seems that the moths can track changes in host plant tissue depth for oviposition.

Abstract Osteoblasts play an important role in the regulation of bone homeostasis throughout life. Thus, the damage of osteoblasts can lead to serious skeletal diseases, highlighting the urgent need for novel pharmacological targets. This study introduces chemical genetics strategy by using small molecule forskolin (FSK) as a probe to explore the druggable targets for osteoporosis. Here, this work reveals that transglutaminase 2 (TGM2) served as a major cellular target of FSK to obviously induce osteoblast differentiation. Then, this work identifies a previously undisclosed allosteric site in the catalytic core of TGM2. In particular, FSK formed multiple hydrogen bonds in a saddle‐like domain to induce an “open” conformation of the β‐sandwich domain in TGM2, thereby promoting the substrate protein crosslinks by incorporating polyamine. Furthermore, this work finds that TGM2 interacted with several mitochondrial homeostasis‐associated proteins to improve mitochondrial dynamics and ATP production for osteoblast differentiation. Finally, this work observes that FSK effectively ameliorated osteoporosis in the ovariectomy mice model. Taken together, these findings show a previously undescribed pharmacological allosteric site on TGM2 for osteoporosis treatment, and also provide an available chemical tool for interrogating TGM2 biology and developing bone anabolic agent.

Abstract The relativistic Bethe–Salpeter method is adopted to study the OZI-allowed strong decays of the $$2^+$$ 2 + state $$B^{*}_{2}(5747)^{0}$$ B 2 ∗ ( 5747 ) 0 , with emphasis on the relativistic corrections. We first study the partial waves in the wave functions used and find that there are P, D, and F partial waves in the $$B^{*}_{2}(5747)^{0}$$ B 2 ∗ ( 5747 ) 0 meson, with ratios of $$P/D/F=1:0.421:0.051$$ P / D / F = 1 : 0.421 : 0.051 . We also find that $$S/P/D=1:0.354:0.046$$ S / P / D = 1 : 0.354 : 0.046 for $$B^*$$ B ∗ , and $$S/P=1:0.343$$ S / P = 1 : 0.343 for the B meson. The large components of the D wave in $$B^{*}_{2}(5747)^{0}$$ B 2 ∗ ( 5747 ) 0 and the P wave in $$B^{(*)}$$ B ( ∗ ) mean that large relativistic effects exist in these states. Second, we calculate the strong decays, and the total decay width $$\Gamma (B^{*}_{2}(5747)^{0})=25.9$$ Γ ( B 2 ∗ ( 5747 ) 0 ) = 25.9 MeV and the branching fraction $$\Gamma (B^{*}_{2}(5747)^{0} \rightarrow B^{*}\pi )$$ Γ ( B 2 ∗ ( 5747 ) 0 → B ∗ π ) / $$\Gamma (B^{*}_{2}(5747)^{0} \rightarrow B\pi )=0.96$$ Γ ( B 2 ∗ ( 5747 ) 0 → B π ) = 0.96 obtained are consistent with experimental data. Third, we study the contributions of different partial waves in the initial and final wave functions, and find that the relativistic effects are about $$15\%$$ 15 % and $$11\%$$ 11 % for $$B^{*}_{2}(5747)^{0} \rightarrow B\pi $$ B 2 ∗ ( 5747 ) 0 → B π and $$B^{*}_{2}(5747)^{0} \rightarrow B^{*}\pi $$ B 2 ∗ ( 5747 ) 0 → B ∗ π , respectively, which are much smaller than our expected effects, showing that the relativistic corrections cancel each other in these decays.

Abstract Background Lung adenocarcinoma (LUAD) is a heavy social burden worldwide. Because the mechanisms involved in LUAD remain unclear, the prognosis of LUAD remains poor. Consequently, it is urgent to investigate the potential mechanisms of LUAD. Junctional adhesion molecule-like protein (JAML), is recognized as a tumorigenesis molecule in gastric cancer. However, the role of JAML in LUAD is still unclear. Here we aimed to evaluate the role of JAML in LUAD. Methods qRT-PCR, Western blotting and immunohistochemistry were conducted to investigate the expression of JAML in LUAD tissues. JAML was knocked down and overexpressed in LUAD cells using transient transfection by siRNA and plasmids or stable transfection by lentivirus. Proliferation potential of LUAD cells were detected by Cell Counting Kit-8, EdU incorporation and Colony formation assay. Migration and invasion abilities of LUAD cells were determined by wound healing, transwell migration and invasion assays. Cell cycle and cell apoptosis were detected by flow cytometry. The effects of JAML in vivo were studied in xenograft tumor models. Western blotting was used to explore the molecular mechanisms of JAML function. In addition, rescue experiments were performed to verify the possible mechanisms. Results JAML expression was elevated in LUAD tissues compared with peritumor tissues, and this upregulation was positively related to pT and pTNM. Furthermore, both in vitro and in vivo, JAML silencing markedly repressed malignant behaviors of LUAD cells and vice versa. Knockdown of JAML also mediated cell cycle arrest at G0/G1 phase and promoted apoptosis in LUAD cells. Mechanistically, silencing JAML repressed the process of epithelial-mesenchymal transition by inactivating the Wnt/β-catenin pathway in LUAD cells. Effects of JAML can be rescued by Wnt/β-catenin pathway activator in A549 cells. Conclusions Our data reveal the oncogenic role of JAML in LUAD, indicating that JAML may be a predictive biomarker and novel therapeutic target for LUAD.

IntroductionCancer patients treated with paclitaxel often develop chemotherapy-induced peripheral neuropathy, which has not been effectively treated with drugs. The anti-diabetic drug metformin is effective in the treatment of neuropathic pain. The aim of this study was to elucidate effect of metformin on paclitaxel-induced neuropathic pain and spinal synaptic transmission.MethodsElectrophysiological experiments on rat spinal slices were performed in vitro and mechanical allodynia quantified in vitro.ResultsThe present data demonstrated that intraperitoneal injection of paclitaxel produced mechanical allodynia and potentiated spinal synaptic transmission. Intrathecal injection of metformin significantly reversed the established mechanical allodynia induced by paclitaxel in rats. Either spinal or systemic administration of metformin significantly inhibited the increased frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in spinal dorsal horn neurons from paclitaxel-treated rats. We found that 1 h incubation of metformin also reduced the frequency rather than the amplitude of sEPSCs in the spinal slices from paclitaxel-treated rats.DiscussionThese results suggested that metformin was able to depress the potentiated spinal synaptic transmission, which may contribute to alleviating the paclitaxel-induced neuropathic pain.

There lacks biomarkers in current epilepsy diagnosis, and epilepsy is thus exposed to inadequate treatment, making it necessarily important to conduct search on new biomarkers and drug targets. The P2Y12 receptor is primarily expressed on microglia in the central nervous system, and acts as intrinsic immune cells in the central nervous system mediating neuroinflammation. In previous studies, P2Y12R in epilepsy has been found capable of controlling neuroinflammation and regulating neurogenesis as well as immature neuronal projections, and its expression is altered. P2Y12R is involved in microglia inhibition of neuronal activity and timely termination of seizures in acute seizures. In status epilepticus, the failure of P2Y12R in the process of “brake buffering” may not terminate the neuronal hyperexcitability timely. In chronic epilepsy, neuroinflammation causes seizures, which can in turn induce neuroinflammation, while on the other hand, neuroinflammation leads to neurogenesis, thereby causing abnormal neuronal discharges that give rise to seizures. In this case, targeting P2Y12R may be a novel strategy for the treatment of epilepsy. The detection of P2Y12R and its expression changes can contribute to the diagnosis of epilepsy. Meanwhile, the P2Y12R single-nucleotide polymorphism is associated with epilepsy susceptibility and endowed with the potential to individualize epilepsy diagnosis. To this end, functions of P2Y12R in the central nervous system were hereby reviewed, the effects of P2Y12R in epilepsy were explored, and the potential of P2Y12R in the diagnosis and treatment of epilepsy was further demonstrated.

BackgroundHashimoto’s thyroiditis (HT) is a chronic autoimmune disease that poses a risk factor for papillary thyroid carcinoma (PTC). The present study aimed to identify the key genes shared by HT and PTC for advancing the current understanding of their shared pathogenesis and molecular mechanisms.MethodsHT- and PTC-related datasets (GSE138198 and GSE33630, respectively) were retrieved from the Gene Expression Omnibus (GEO) database. Genes significantly related to the PTC phenotype were identified using weighted gene co-expression network analysis (WGCNA). Differentially expressed genes (DEGs) were identified between PTC and healthy samples from GSE33630, and between HT and normal samples from GSE138198. Subsequently, functional enrichment analysis was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Transcription factors and miRNAs regulating the common genes in PTC and HT were forecasted using the Harmonizome and miRWalk databases, respectively, and drugs targeting these genes were investigated using the Drug-Gene Interaction Database (DGIdb). The key genes in both GSE138198 and GSE33630 were further identified via Receiver Operating Characteristic (ROC) analysis. The expression of key genes was verified in external validation set and clinical samples using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC).ResultsIn total, 690 and 1945 DEGs were associated with PTC and HT, respectively; of these, 56 were shared and exhibited excellent predictive accuracy in the GSE138198 and GSE33630 cohorts. Notably, four genes, Alcohol Dehydrogenase 1B (ADH1B), Active BCR-related (ABR), alpha-1 antitrypsin (SERPINA1), and lysophosphatidic acid receptor 5 (LPAR5) were recognized as key genes shared by HT and PTC. Subsequently, EGR1 was identified as a common transcription factor regulating ABR, SERPINA1, and LPAR5 expression. These findings were confirmed using qRT-PCR and immunohistochemical analysis.ConclusionFour (ADH1B, ABR, SERPINA1, and LPAR5) out of 56 common genes exhibited diagnostic potential in HT and PTC. Notably, this study, for the first time, defined the close relationship between ABR and HT/PTC progression. Overall, this study provides a basis for understanding the shared pathogenesis and underlying molecular mechanisms of HT and PTC, which might help improve patient diagnosis and prognosis.

Single-nucleotide polymorphisms are connected with the risk of epilepsy on occurrence, progress, and the individual response to drugs. Progress in genomic technology is exposing the complex genetic architecture of epilepsy. Compelling evidence has demonstrated that purines and adenosine are key mediators in the epileptic process. Our previous study found the interconnection of P2Y12 receptor single-nucleotide polymorphisms and epilepsy. However, little is known about the interaction between the purine nucleoside A2A receptor and rate-limiting enzyme ecto-5′-nucleotidase/CD73 and epilepsy from the genetic polymorphism aspect. The aim of the study is to evaluate the impact of A2AR and CD73 polymorphisms on epilepsy cases. The study group encompassed 181 patients with epilepsy and 55 healthy volunteers. A significant correlation was confirmed between CD73 rs4431401 and epilepsy (p < 0.001), with TT genotype frequency being higher and C allele being lower among epilepsy patients in comparison with healthy individuals, indicating that the presence of the TT genotype is related to an increased risk of epilepsy (OR = 2.742, p = 0.006) while carriers of the C allele demonstrated a decreased risk of epilepsy (OR = 0.304, p < 0.001). According to analysis based on gender, the allele and genotype of rs4431401 in CD73 were associated with both male and female cases (p < 0.0001, p = 0.026, respectively). Of note, we found that A2AR genetic variants rs2267076 T>C (p = 0.031), rs2298383 C>T (p = 0.045), rs4822492 T>G (p = 0.034), and rs4822489 T>G (p = 0.029) were only associated with epilepsy in female subjects instead of male. It is evident that the TT genotype and T allele of rs4431401 in CD73 were genetic risk factors for epilepsy, whereas rs2267076, rs2298383, rs4822492, and rs4822489 polymorphisms of the A2AR were mainly associated with female subjects.

The co-chaperone DnaJ plays an important role in protein folding and regulation of various physiological activities, and participates in several pathological processes. DnaJ has been extensively studied in many species including humans, drosophila, mushrooms, tomatoes, and Arabidopsis. However, few studies have examined the role of DnaJ in wheat (Triticum aestivum), and the interaction mechanism between TaDnaJs and plant viruses. Here, we identified 236 TaDnaJs and performed a comprehensive genome-wide analysis of conserved domains, gene structure and protein motifs, chromosomal positions and duplication relationships, and cis-acting elements. We grouped these TaDnaJs according to their domains, and randomly selected six genes from the groups for tissue-specific analysis, and expression profiles analysis under hormone stress, and 17 genes for plant virus infection stress. In qRT-PCR, we found that among the 17 TaDnaJ genes tested, 16 genes were up-regulated after wheat yellow mosaic virus (WYMV) infection, indicating that the TaDnaJ family is involved in plant defense response. Subsequent yeast two-hybrid assays verified the WYMV NIa, NIb and 7KD proteins interacted with TaDJC (TraesCS7A02G506000), which had the most significant changes in gene expression levels after WYMV infection. Insights into the molecular mechanisms of TaDnaJ-mediated stress tolerance and sensitivity could inform different strategies designed to improve crop resistance to abiotic and biotic stress. This study provides a basis for future investigation of the TaDnaJ family and plant defense mechanisms.

Abstract Background The aim of the study was to assess programmed death‐ligand‐1 (PD‐L1) expression in different histological types and gene mutation status of patients with non‐small cell lung cancer (NSCLC). Methods A total of 4062 pathology‐confirmed lung cancer patients were retrospectively screened at Kaohsiung Chang Gung Memorial Hospital from November 2010 to June 2017. There were 699 NSCLC patients with confirmed PD‐L1 expression level retrospectively enrolled for analysis. Results There was a trend of higher PD‐L1 expression in squamous cell carcinoma and adenosquamous cell carcinoma than in adenocarcinoma (p = 063). Significant higher PD‐L1 expression in EGFR wild‐type was noted (p

In the era of precision medicine, with the deepening of the research on malignant tumor driving genes, clinical oncology has fully entered the era of targeted therapy. For non-small-cell lung cancer (NSCLC), the development of targeted drugs targeting driver genes, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has successfully opened up a new model of targeted therapy. At present, proto-oncogene rearranged during transfection (RET) fusion gene is an important novel oncogenic driving target, and specific receptor tyrosine kinase inhibitors (TKIs) targeting RET fusion have been approved. This article will review the latest research about the molecular characteristics, pathogenesis, detection, and clinical treatment strategies of RET rearrangements especially in China.

Summary: Background: The E2F family of transcription factors play a crucial role in the development of various cancers. However, E2F members lack targetable binding pockets and are typically considered “undruggable”. Unlike canonical small-molecule therapeutics, molecular glues mediate new E3 ligase–protein interactions to induce selective proteasomal degradation, which represents an attractive option to overcome these limitations. Methods: Human proteome microarray was utilized to identify a natural product-derived molecular glue for targeting E2F2 degradation. Co-IP analysis with stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics was carried out to further explore the E3 ligase for E2F2 degradation. Findings: In this study, we identified a molecular glue bufalin, which significantly promoted E2F2 degradation. Unexpectedly, E2F2 underwent ubiquitination and proteasomal degradation via a previously undisclosed atypical E3 ligase, zinc finger protein 91 (ZFP91). In particular, we observed that bufalin markedly promoted E2F2-ZFP91 complex formation, thereby leading to E2F2 polyubiquitination via K48-linked ubiquitin chains for degradation. E2F2 degradation subsequently caused transcriptional suppression of multiple oncogenes including c-Myc, CCNE1, CCNE2, MCM5 and CDK1, and inhibited hepatocellular carcinoma growth in vitro and in vivo. Interpretation: Collectively, our findings open up a new direction for transcription factors degradation by targeting atypical E3 ligase ZFP91. Meanwhile, the chemical knockdown strategy with molecular glue may promote innovative transcription factor degrader development in cancer therapy. Funding: This work was financially supported by the National Key Research and Development Project of China (2022YFC3501601), National Natural Sciences Foundation of China (81973505, 82174008, 82030114), and China Postdoctoral Science Foundation (2019M650396), the Fundamental Research Funds for the Central Universities.

BackgroundPsychological problems may promote peptic ulcers. Ulcer-like wounds can be formed after gastric endoscopic submucosal dissection (ESD). The influence of family support on the healing of gastric ESD-induced ulcers remains largely undetermined.ObjectiveIn the present study, we aimed to assess the Hospital Anxiety and Depression Scale (HADS) scores and the incidence of post-ESD complications in patients with family support in the care process and those in the non-relative group.Materials and methodsA total of 191 patients aged between 30 and 70 years who received gastric ESD were evaluated with the Chinese version of HADS. Differences in depression and anxiety between the two groups were compared using the chi-square test and t-test. Multivariable logistic regression models were used to examine whether anxiety and depression were the risk factors for post-ESD complications.ResultsThe mean values of HADS-A (4.61 ± 2.89 vs. 5.56 ± 3.07, p = 0.042) and HADS-D (4.14 ± 3.03 vs. 4.97 ± 2.61, p = 0.048) scores were significantly lower in patients with accompanying relatives compared with those in the non-relative group. Besides, through the pre-ESD and post-ESD self-contrast, the scores of anxiety and depression in the relative-group were 0.57 and 0.56, respectively (p < 0.001), while those in the non-relative group were increased by 1.43 and 1.49, respectively (p < 0.001). Multivariable logistic regression analysis revealed that HADS-A, HADS-D scores, and age were significantly correlated with post-ESD abdominal pain (P < 0.05).ConclusionsThe occurrence and degree of adverse emotions such as psychological anxiety and depression in patients who received gastric ESD with accompanying relatives during hospitalization may were reduced, and the incidence of gastric post-ESD abdominal pain may was also decreased.

Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (Treg) and down-regulated CD8+T cell differentiation in AIH mice induced by S-100 antigen. In vitro, HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-β1) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote Treg differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate Treg differentiation and function.

Abstract Background Ovarian cancer (OC) is the most lethal gynaecological tumor. Changes in glycolysis have been proven to play an important role in OC progression. We aimed to identify a novel glycolysis-related gene signature to better predict the prognosis of patients with OC. Methods mRNA and clinical data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Genotype Tissue Expression (GTEx) database. The “limma” R package was used to identify glycolysis-related differentially expressed genes (DEGs). Then, a multivariate Cox proportional regression model and survival analysis were used to develop a glycolysis-related gene signature. Furthermore, the TCGA training set was divided into two internal test sets for validation, while the ICGC dataset was used as an external test set. A nomogram was constructed in the training set, and the relative proportions of 22 types of tumor-infiltrating immune cells were evaluated using the “CIBERSORT” R package. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were determined by single-sample gene set enrichment analysis (ssGSEA) with the “GSVA” R package. Finally, the expression and function of the unreported signature genes ISG20 and SEH1L were explored using immunohistochemistry, western blotting, qRT-PCR, proliferation, migration, invasion and xenograft tumor assays. Results A five-gene signature comprising ANGPTL4, PYGB, ISG20, SEH1L and IRS2 was constructed. This signature could predict prognosis independent of clinical factors. A nomogram incorporating the signature and three clinical features was constructed, and the calibration plot suggested that the nomogram could accurately predict the survival rate. According to ssGSEA, the signature was associated with KEGG pathways related to axon guidance, mTOR signalling, tight junctions, etc. The proportions of tumor-infiltrating immune cells differed significantly between the high-risk group and the low-risk group. The expression levels of ISG20 and SEH1L were lower in tumor tissues than in normal tissues. Overexpression of ISG20 or SEH1L suppressed the proliferation, migration and invasion of Caov3 cells in vitro and the growth of xenograft tumors in vivo. Conclusion Five glycolysis-related genes were identified and incorporated into a novel risk signature that can effectively assess the prognosis and guide the treatment of OC patients.

IL-1β mediates inflammation and regulates immune responses, cell proliferation, and differentiation. Dysregulation of IL-1β is linked to inflammatory and autoimmune diseases. Elevated IL-1β levels are found in patients with severe COVID-19, indicating its excessive production may worsen the disease. Also, dry eye disease patients show high IL-1β levels in tears and conjunctival epithelium. Therefore, IL-1β signaling is a potential therapeutic targeting for COVID-19 and aforementioned diseases. No small-molecule IL-1β inhibitor is clinically approved despite efforts. Developing such inhibitors is highly desirable. Herein, a docking-based strategy was used to screen the TCM (Traditional Chinese Medicine) database to identify possible IL-1β inhibitors with desirable pharmacological characteristics by targeting the IL-1β/IL-1R interface. Primarily, the docking-based screening was performed by selecting the crucial residues of IL-1β interface to retrieve the potential compounds. Afterwards, the compounds were shortlisted on the basis of binding scores and significant interactions with the crucial residues of IL-1β. Further, to gain insights into the dynamic behavior of the protein–ligand interactions, MD simulations were performed. The analysis suggests that four selected compounds were stabilized in an IL-1β pocket, possibly blocking the formation of an IL-1β/IL-1R complex. This indicates their potential to interfere with the immune response, making them potential therapeutic agents to investigate further.

Abstract Background Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine involved in pain processing and hypersensitivity. It regulates not only the expression of a variety of inflammatory mediators but also the functional activity of some ion channels. Acid-sensing ion channels (ASICs), as key sensors for extracellular protons, are expressed in nociceptive sensory neurons and contribute to pain signaling caused by tissue acidosis. It is still unclear whether TNF-α has an effect on functional activity of ASICs. Herein, we reported that a brief exposure of TNF-α acutely sensitized ASICs in rat dorsal root ganglion (DRG) neurons. Methods Electrophysiological experiments on rat DRG neurons were performed in vitro and acetic acid induced nociceptive behavior quantified in vitro. Results A brief (5min) application of TNF-α rapidly enhanced ASIC-mediated currents in rat DRG neurons. TNF-α (0.1-10 ng/ml) dose-dependently increased the proton-evoked ASIC currents with an EC50 value of 0.12 ± 0.01 nM. TNF-α shifted the concentration-response curve of proton upwards with a maximal current response increase of 42.34 ± 7.89%. In current-clamp recording, an acute application of TNF-α also significantly increased acid-evoked firing in rat DRG neurons. The rapid enhancement of ASIC-mediated electrophysiological activity by TNF-α was prevented by p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190, but not by non-selective cyclooxygenase inhibitor indomethacin, suggesting that p38 MAPK is necessary for this enhancement. Behaviorally, TNF-α exacerbated acid-induced nociceptive behaviors in rats via activation of local p38 MAPK pathway. Conclusions These results suggest that TNF-α rapidly enhanced ASIC-mediated functional activity via a p38 MAPK pathway, which revealed a novel peripheral mechanism underlying TNF-α involvement in rapid hyperalgesia by sensitizing ASICs in primary sensory neurons.

Lysophosphatidic acid (LPA), a lipid metabolite, plays a role in both neuropathic and inflammatory pain through LPA1 receptors. P2X3 receptor has also been shown to participate in these pathological processes. However, it is still unclear whether there is a link between LPA signaling and P2X3 receptors in pain. Herein, we show that a functional interaction between them in rat dorsal root ganglia (DRG) neurons. Pretreatment of LPA concentration-dependently enhanced α,β-methylene-ATP (α,β-meATP)-induced inward currents mediated by P2X3 receptors. LPA significantly increased the maximal current response of α,β-meATP, showing an upward shift of the concentration-response curve for α,β-meATP. The LPA enhancement was independent on the clamping-voltage. Enhancement of P2X3 receptor-mediated currents by LPA was prevented by the LPA1 receptor antagonist Ki16198, but not by the LPA2 receptor antagonist H2L5185303. The LPA-induced potentiation was also attenuated by intracellular dialysis of either G-protein inhibitor or protein kinase C (PKC) inhibitor, but not by Rho inhibitor. Moreover, LPA significantly changed the membrane potential depolarization and action potential burst induced by α,β-meATP in DRG neurons. Finally, LPA exacerbated α,β-meATP- induced nociceptive behaviors in rats. These results suggested that LPA potentiated the functional activity of P2X3 receptors in rat primary sensory neurons through activation of the LPA1 receptor and its downstream PKC rather than Rho signaling pathway, indicating a novel peripheral mechanism underlying the sensitization of pain.

Abstract Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) as a direct cellular target, and genetic knockdown of CK2α′ abolishes ECH-mediated mitochondrial fusion. Mechanistically, ECH allosterically regulates CK2α′ conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex. Then, the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α′+/− mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.

Abstract Objective This study compared the dose verification results between plans created based on computed tomography (CT) scan and digital virtual phantom. Methods We retrospectively analyzed the treatment plan of 10 patients with head and neck cancer. CT scanned phantom and digital virtual phantom measured using Delta4 3‐D matrix were used to generate verification plans for each patient. The doses based on the effective measurement volume of the two phantoms were compared, and the verification results were analyzed using gamma index analysis. Results For the body, the minimum dose, the maximum dose, the average dose, and the total dose were 0.72 ± 0.46 cGy, 251.86 ± 49.83 cGy, 58.10 ± 10.93 cGy, and 154.67 ± 20.28 cGy, respectively, in the CT‐scan group, and 0.62 ± 0.36 cGy, 248.34 ± 48.59 cGy, 57.20 ± 10.77 cGy, and 151.57 ± 19.73 cGy, respectively in the Uniform group. The difference between the groups was significant (P 95%, but the Uniform group had a higher passing rate than the CT‐scan group. Conclusions Because the passing rate was higher in the Uniform group than in the CT‐scan group, it is recommended to use digital virtual phantom modules to generate verification plans in clinical practice.

Abstract Background While the cities in China in which spinal cord injury (SCI) studies have been conducted previously are at the forefront of medical care, northwest China is relatively underdeveloped economically, and the epidemiological characteristics of SCI have rarely been reported in this region. Methods The SCI epidemiological survey software developed was used to analyze the data of patients treated with SCI from 2014 to 2018. The sociodemographic characteristics of patients, including name, age, sex, and occupation, were recorded. The following medical record data, obtained from physical and radiographic examinations, were included in the study: data on the cause of injury, fracture location, associated injuries, and level of injury. Neurological function was evaluated using the American Spinal Injury Association (ASIA) impairment scale. In addition, the treatment and complications during hospitalization were documented. Results A total of 3487 patients with SCI with a mean age of 39.5 ± 11.2 years were identified in this study, and the male to female ratio was 2.57:1. The primary cause of SCI was falls (low falls 47.75%, high falls 37.31%), followed by traffic accidents (8.98%), and impact with falling objects (4.39%). Of all patients, 1786 patients (51.22%) had complications and other injuries. According to the ASIA impairment scale, the numbers of grade A, B, C, and D injuries were 747 (21.42%), 688 (19.73%), 618 (17.72%), and 1434 (41.12%), respectively. During the hospitalization period, a total of 1341 patients experienced complications, with a percentage of 38.46%. Among all complications, pulmonary infection was the most common (437, 32.59%), followed by hyponatremia (326, 24.31%), bedsores (219, 16.33%), urinary tract infection (168, 12.53%), deep venous thrombosis (157, 11.71%), and others (34, 2.53%). Notably, among 3487 patients with SCI, only 528 patients (15.14%) received long-term rehabilitation treatment. Conclusion The incidence of SCI in northwest China was on the rise with higher proportion in males; fall and the MCVs were the primary causes of SCI. The occupations most threatened by SCI are farmers and workers. The investigation and analysis of the epidemiological characteristics of SCI in respiratory complications are important factors leading to death after SCI, especially when the SCI occurs in the cervical spinal cord. Finally, the significance of SCI rehabilitation should be addressed.

Abstract Background To investigate the ability of amide proton transfer (APT) weighted magnetic resonance imaging (MRI), arterial spin labeling (ASL), diffusion weighted imaging (DWI) and the combination for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). Methods Twenty-seven patients including nine LGGs and eighteen HGGs underwent conventional, APT, ASL and DWI MRI with a 3.0-T MR scanner. Histogram analyses was performed and quantitative parameters including mean apparent diffusion coefficient (ADC mean), 20th-percentile ADC (ADC 20th), mean APT (APT mean), 90th-percentile APT (APT 90th), relative mean cerebral blood flow (rCBF mean) and relative 90th-percentile CBF (rCBF 90th) were compared between HGGs and LGGs. The diagnostic performance was evaluated with receiver operating characteristic (ROC) analysis of each parameter and their combination. Correlations were analyzed among the MRI parameters and Ki-67. Results The APT values were significantly higher in the HGGs compared to the LGGs (p

PurposeTo develop and validate a machine learning-based CT radiomics method for preoperatively predicting the stages (stage I and non-stage I) of Wilms tumor (WT) in pediatric patients.MethodsA total of 118 patients with WT, who underwent contrast-enhanced computed tomography (CT) scans in our center between 2014 and 2021, were studied retrospectively and divided into two groups: stage I and non-stage I disease. Patients were randomly divided into training cohorts (n = 94) and test cohorts (n = 24). A total of 1,781 radiomic features from seven feature classes were extracted from preoperative portal venous–phase images of abdominal CT. Synthetic Minority Over-Sampling Technique (SMOTE) was used to handle imbalanced datasets, followed by a t-test and Least Absolute Shrinkage and Selection Operator (LASSO) regularization for feature selection. Support Vector Machine (SVM) was deployed using the selected informative features to develop the predicting model. The performance of the model was evaluated according to its accuracy, sensitivity, and specificity. The receiver operating characteristic curve (ROC) and the area under the ROC curve (AUC) was also arranged to assess the model performance.ResultsThe SVM model was fitted with 15 radiomic features obtained by t-test and LASSO concerning WT staging in the training dataset and demonstrated favorable performance in the testing dataset. Cross-validated AUC on the training dataset was 0.79 with a 95 percent confidence interval (CI) of 0.773–0.815 and a coefficient of variation of 3.76%, while AUC on the test dataset was 0.81, and accuracy, sensitivity, and specificity were 0.79, 0.87, and 0.69, respectively.ConclusionsThe machine learning model of SVM based on radiomic features extracted from CT images accurately predicted WT stage I and non-stage I disease in pediatric patients preoperatively, which provided a rapid and non-invasive way for investigation of WT stages.

ObjectiveWe aimed to evaluate the performance of nanopore amplicon sequencing detection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinical samples.MethodWe carried out a single-center, prospective cohort study in a Wuhan hospital and collected a total of 86 clinical samples, including 54 pharyngeal swabs, 31 sputum samples, and 1 fecal sample, from 86 patients with coronavirus disease 2019 (COVID-19) from Feb 20 to May 15, 2020. We performed parallel detection with nanopore-based genome amplification and sequencing (NAS) on the Oxford Nanopore Technologies (ONT) minION platform and routine reverse transcription quantitative polymerase chain reaction (RT-qPCR). In addition, 27 negative control samples were detected using the two methods. The sensitivity and specificity of NAS were evaluated and compared with those of RT-qPCR.ResultsThe viral read number and reference genome coverage were both significantly different between the two groups of samples, and the latter was a better indicator for SARS-CoV-2 detection. Based on the reference genome coverage, NAS revealed both high sensitivity (96.5%) and specificity (100%) compared with RT-qPCR (80.2 and 96.3%, respectively), although the samples had been stored for half a year before the detection. The total time cost was less than 15 h, which was acceptable compared with that of RT-qPCR (∼2.5 h). In addition, the reference genome coverage of the viral reads was in line with the cycle threshold value of RT-qPCR, indicating that this number could also be used as an indicator of the viral load in a sample. The viral load in sputum might be related to the severity of the infection, particularly in patients within 4 weeks after onset of clinical manifestations, which could be used to evaluate the infection.ConclusionOur results showed the high sensitivity and specificity of the NAS method for SARS-CoV-2 detection compared with RT-qPCR. The sequencing results were also used as an indicator of the viral load to display the viral dynamics during infection. This study proved the wide application prospect of nanopore sequencing detection for SARS-CoV-2 and may more knowledge about the clinical characteristics of COVID-19.