Acetaminophen (APAP) is the primary cause of drug-induced acute liver failure. Ovarian tumor deubiquitinase 6A (OTUD6A), a recently discovered deubiquitinase of the OTU family, has been primarily studied in tumor contexts. However, its role in APAP-induced liver injury (AILI) remains unclear. Therefore, this study aimed to investigate the involvement of OTUD6A in the pathogenesis of AILI. Our findings demonstrated a substantial upregulation of OTUD6A in both the liver tissue and isolated hepatocytes of mice following APAP stimulation. OTUD6A knockout exacerbated APAP-induced inflammation, hepatocyte necrosis, and liver injury, whereas OTUD6A overexpression alleviated these pathologies. Mechanistically, OTUD6A directly interacted with the enhancer of zeste homolog 2 (EZH2) and selectively removed K48-linked polyubiquitin chains from EZH2, enhancing its stability. This resulted in increased protein levels of EZH2 and H3K27me3, as well as reduced endoplasmic reticulum (ER) stress and cell death in hepatocytes. Collectively, our research uncovers a novel role for OTUD6A in mitigating APAP-induced liver injury by promoting EZH2 stabilization.

Pregnancy ; Female ; Humans ; Diabetes, Gestational/diagnosis* ; Retrospective Studies ; Prognosis ; Pregnancy Outcome ; Maternal Age

Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD). It is a disease with highly heterogeneous clinical manifestations, severity and outcomes, which are associated with individual sensitivity, as well as property, dosage, duration and frequency of exposure to the antigens.The 2020 adult HP guideline reclassifies it and describes its radiographic features in detail.HP often occurs in adults, also affects the pediatric population and is one of the most common ILDs in children.The most common factors causing HP in children are avian and fungal antigens in the home environment.The diagnosis of HP is based on clear antigens, typical symptoms and characteristic radiological manifestations.The serum-specific IgG antibody, bronchoalveolar lavage fluid, and pulmonary function tests can help diagnose HP clearly, and lung histopathology is required for children whose diagnosis cannot be confirmed.Early diagnosis and adequate avoidance of antigen exposure are the keys to its treatment and prognosis.

To evaluate the effect of bronchoalveolar lavage (BAL) on the clinical prognosis of children with macrolide drug-resistant Mycoplasma pneumoniae pneumonia (MRMPP) in a retrospective cohort study based on propensity score matching (PSM).A retrospective cohort study based on propensity score matching retrospectively collected the clinical data of hospitalized patients diagnosed with mycoplasma macrolide drug-resistant pneumonia (MRMPP) in Respiratory Department of Hunan Children′s Hospital from January 2020 to August 2023. According to whether bronchoalveolar lavage (BAL) was performed during hospitalization, the children were divided into BAL group and non-BAL group, and the baseline information of the two groups was matched by propensity scores, and the clinical prognosis was compared. A total of 302 children were screened, and 150 cases were successfully matched, including 59 cases in the BAL group and 91 cases in the non-BAL group. The results showed that the differences between the non-BAL group and the BAL group before PSM( P<0.05) were significantly different in age [(4.60±2.97)years vs (5.41±3.02) years, t=-2.273, P=0.024], shortness of breath (9.4% vs 22.5%, χ 2=9.864, P=0.002), and radiographic manifestations [lung interstitial changes (29.8% vs 15.3%, χ 2=8.009, P=0.005), lung consolidation (17.3% vs 55.9%, χ 2=48.457, P<0.001), spotted flaky infiltrates (52.4% vs 27.9%, χ 2=17.056, P<0.001)], bacterial infection (3.2% vs 9.2%, χ 2=4.845, P=0.028), duration of azithromycin or doxycycline use [4(2, 5) days vs 5(3, 6) days, Z=-2.374, P=0.018], White Blood Cell Count at admission [7.94 (6.25, 10.34)×10 9/L vs 7.21 (5.65, 9.01)×10 9/L, Z=-2.445, P=0.014], D Dimer [0.58 (0.44, 0.83) μg/ml vs 0.80 (0.52, 1.12) μg/ml, Z=-3.154, P=0.002], but there was no significant difference between the two groups in the above indexes after PSM ( P>0.05). The duration of hospitalization, cough relief, disappearance of rales and fever in the BAL group was shortened in the BAL group compared with that in the non-BAL group [5 (4, 7) days vs 7 (5, 8) days, Z=-2.373, P=0.018], and the difference was statistically significant ( P<0.05). Linear regression analysis of PSM cohort study showed that BAL was negatively correlated with fever time (β=-4.369, 95% CI:-8.600--0.138, P<0.05). In conclusion, BAL can shorten the fever time of MRMPP, and early BAL in addition to conventional treatment has a positive effect on the prognosis of children.

Background::The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking.Methods::We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases.Results::We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control.Conclusions::REDH is accessible at http://www.redhdatabase.com/. This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

To evaluate the effect of bronchoalveolar lavage (BAL) on the clinical prognosis of children with macrolide drug-resistant Mycoplasma pneumoniae pneumonia (MRMPP) in a retrospective cohort study based on propensity score matching (PSM).A retrospective cohort study based on propensity score matching retrospectively collected the clinical data of hospitalized patients diagnosed with mycoplasma macrolide drug-resistant pneumonia (MRMPP) in Respiratory Department of Hunan Children′s Hospital from January 2020 to August 2023. According to whether bronchoalveolar lavage (BAL) was performed during hospitalization, the children were divided into BAL group and non-BAL group, and the baseline information of the two groups was matched by propensity scores, and the clinical prognosis was compared. A total of 302 children were screened, and 150 cases were successfully matched, including 59 cases in the BAL group and 91 cases in the non-BAL group. The results showed that the differences between the non-BAL group and the BAL group before PSM( P<0.05) were significantly different in age [(4.60±2.97)years vs (5.41±3.02) years, t=-2.273, P=0.024], shortness of breath (9.4% vs 22.5%, χ 2=9.864, P=0.002), and radiographic manifestations [lung interstitial changes (29.8% vs 15.3%, χ 2=8.009, P=0.005), lung consolidation (17.3% vs 55.9%, χ 2=48.457, P<0.001), spotted flaky infiltrates (52.4% vs 27.9%, χ 2=17.056, P<0.001)], bacterial infection (3.2% vs 9.2%, χ 2=4.845, P=0.028), duration of azithromycin or doxycycline use [4(2, 5) days vs 5(3, 6) days, Z=-2.374, P=0.018], White Blood Cell Count at admission [7.94 (6.25, 10.34)×10 9/L vs 7.21 (5.65, 9.01)×10 9/L, Z=-2.445, P=0.014], D Dimer [0.58 (0.44, 0.83) μg/ml vs 0.80 (0.52, 1.12) μg/ml, Z=-3.154, P=0.002], but there was no significant difference between the two groups in the above indexes after PSM ( P>0.05). The duration of hospitalization, cough relief, disappearance of rales and fever in the BAL group was shortened in the BAL group compared with that in the non-BAL group [5 (4, 7) days vs 7 (5, 8) days, Z=-2.373, P=0.018], and the difference was statistically significant ( P<0.05). Linear regression analysis of PSM cohort study showed that BAL was negatively correlated with fever time (β=-4.369, 95% CI:-8.600--0.138, P<0.05). In conclusion, BAL can shorten the fever time of MRMPP, and early BAL in addition to conventional treatment has a positive effect on the prognosis of children.

Cervical cancer is the fourth most common cancer among women worldwide,and several screen-ing methods are currently available,with DNA testing for human papillomavirus(HPV)considered to be the most effective technique compared to other screening methods.However,due to the lack of organized screen-ing programs and facilities in developing countries,effective screening of cervical cancer is difficult to imple-ment,thereby delaying disease prediction and contributing to the high incidence of cervical cancer.In order to improve cervical cancer screening coverage in women,a simple,time-saving and non-invasive screening method is needed.At present,more and more evidence supports the validity and practicability of self-sampling as an al-ternative method for primary HPV screening.In this paper,we reviewed the application progress of HPV self-sampling in cervical cancer screening from three aspects:vaginal self-collection,initial urine sample self-collec-tion and menstrual blood sample self-collection.

Objective:To assess the clinical effectiveness and safety of Omalizumab for treating pediatric allergic asthma in real world in China.Methods:The clinical data of children aged 6 to 11 years with allergic asthma who received Omalizumab treatment in 17 hospitals in China between July 6, 2018 and September 30, 2020 were retrospectively analyzed.Such information as the demographic characteristics, allergic history, family history, total immunoglobulin E (IgE) levels, specific IgE levels, skin prick test, exhaled nitric oxide (FeNO) levels, eosinophil (EOS) counts, and comorbidities at baseline were collected.Descriptive analysis of the Omalizumab treatment mode was made, and the difference in the first dose, injection frequency and course of treatment between the Omalizumab treatment mode and the mode recommended in the instruction was investigated.Global Evaluation of Treatment Effectiveness (GETE) analysis was made after Omalizumab treatment.The moderate-to-severe asthma exacerbation rate, inhaled corticosteroid (ICS) dose, lung functions were compared before and after Omalizumab treatment.Changes in the Childhood Asthma Control Test (C-ACT) and Pediatric Asthma Quality of Life Questionnaire (PAQLQ) results from baseline to 4, 8, 12, 16, 24, and 52 weeks after Omalizumab treatment were studied.The commodity improvement was assessed.The adverse event (AE) and serious adverse event (SAE) were analyzed for the evaluation of Omalizumab treatment safety.The difference in the annual rate of moderate-to-severe asthma exacerbation and ICS reduction was investigated by using t test.The significance level was set to 0.05.Other parameters were all subject to descriptive analysis.A total of 200 allergic asthma patients were enrolled, including 75.5% ( n=151) males and 24.5% ( n=49) females.The patients aged (8.20±1.81) years. Results:The median total IgE level of the 200 patients was 513.5 (24.4-11 600.0) IU/mL.Their median treatment time with Omalizumab was 112 (1-666) days.Their first dose of Omalizumab was 300 (150-600) mg.Of the 200 cases, 114 cases (57.0%) followed the first Omalizumab dosage recommended in the instruction.After 4-6 months of Omalizumab treatment, 88.5% of the patients enrolled ( n=117) responded to Omalizumab.After 4 weeks of treatment with Omalizumab, asthma was well-controlled, with an increased C-ACT score [from (22.70±3.70) points to (18.90±3.74) points at baseline]. Four-six months after Omalizumab administration, the annual rate of moderate-to-severe asthma exacerbation had a reduction of (2.00±5.68) per patient year( t=4.702 5, P<0.001), the median ICS daily dose was lowered [0 (0-240) μg vs. 160 (50-4 000) μg at baseline] ( P<0.001), the PAQLQ score was improved [(154.90±8.57) points vs. (122.80±27.15) points at baseline], and the forced expiratory volume in one second % predicted (FEV 1%pred) was increased [(92.80±10.50)% vs. (89.70±18.17)% at baseline]. In patients with available evaluations for comorbidities, including allergic rhinitis, atopic dermatitis or eczema, urticaria, allergic conjunctivitis and sinusitis, 92.8%-100.0% showed improved symptoms.A total of 124 AE were reported in 58 (29.0%) of the 200 patients, and the annual incidence was 0(0-15.1) per patient year.In 53 patients who suffered AE, 44 patients (83.0%) and 9 patients (17.0%) reported mild and moderate AE, respectively.No severe AE were observed in patients.The annual incidence of SAE was 0(0-1.9) per patient year.Most common drug-related AE were abdominal pain (2 patients, 1.0%) and fever (2 patients, 1.0%). No patient withdrew Omalizumab due to AE. Conclusions:Omalizumab shows good effectiveness and safety for the treatment of asthma in children.It can reduce the moderate-to-severe asthma exacerbation rate, reduce the ICS dose, improve asthma control levels, and improve lung functions and quality of life of patients.

T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFNγ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFNγ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

Objective:To investigate the clinical characteristics of patients with malignant tumors and immune checkpoint inhibitors (ICI) related multisystem adverse events as well as therapeutic efficacy of ICI.Methods:The general data, immune-related adverse events (irAE) type, onset time, severity and ICI efficacy of patients with malignant tumors who developed irAE after receiving ICI in China-Japan Friendship Hospital between January 2019 and November 2021 were retrospectively analyzed. All patients were divided into multisystem irAE group and single system irAE group according to whether patients with more than 1 organ or system developed irAE for once. The occurrence of irAE was summarized, and the clinical characteristics of patients were compared. Progression-free survival analysis was not performed owing to the pause of immunotherapy caused by some irAE, so the efficacy of ICI was evaluated by using ICI treatment duration (TD).Results:A total of 47 patients with malignant tumors and irAE were included in this study, with 70 times of irAE in total. The median onset time was 90 d (35 d, 196 d). Among them, 12 patients (25.53%) developed multisystem irAE (32 times of irAE in total); the other 35 patients (74.47%) developed single system irAE (38 times of irAE in total). Cutaneous toxicity for 7 times, thyroid toxicity for 7 times and pulmonary toxicity for 5 times were the most frequent among multisystem irAE group; pulmonary toxicity for 13 times, thyroid toxicity for 12 times and cutaneous toxicity for 5 times were the most frequent among single system irAE group. There were no statistically significant differences in the proportion of patients stratified by age, gender, the combination of other treatments and different body mass between the two groups (all P > 0.05). The median follow-up time was 20 months (9-40 months). The median TD of ICI was 16.00 months (95% CI 3.62-31.22 months) in multisystem irAE group and 4.60 months (95% CI 4.12-11.30 months) in single system irAE group; TD in multisystem irAE group was longer than that in single system irAE group, and the difference was statistically significant ( HR = 0.413, 95% CI 0.202-0.844, P = 0.038). Conclusions:The efficacy of ICI in patients with malignant tumors and multisystem irAE is better than that in those with single system irAE. It suggests that the better efficacy of ICI may be associated with greater risk of irAE. There is no significant difference in the clinical features between multisystem irAE and single system irAE.