Background Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children and adolescents. Current research suggests that environmental factors, such as per- and polyfluoroalkyl substances (PFAS), may be associated with an increased risk of ADHD in offspring. However, most epidemiological evidence originates from non-Chinese populations, with limited research investigating the association between prenatal PFAS and ADHD-like symptoms in Chinese school-aged children. Objective To examine the association between prenatal PFAS exposure and ADHD-like symptoms in 7-year-old children. Methods Based on the Shanghai Birth Cohort, this study included 488 mother-child pairs. PFAS were measured in maternal serum during the second trimester using ultra-performance liquid chromatography-tandem mass spectrometry. The analysis focused on eight specific compounds from three PFAS categories [perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS)]. The hyperactivity subscale of the Strengths and Difficulties Questionnaire (SDQ) was used to assess ADHD-like symptoms in children at age 7. Basic demographic information was collected via questionnaires and medical records. Negative binomial regression models were used to evaluate the relationship between individual exposures to the three typical PFAS categories (PFOA, PFOS, and PFHxS) and children's ADHD-like symptoms, while the bayesian kernel machine regression (BKMR) mixture model was employed to assess the overall effect of PFAS mixture exposure on ADHD-like symptoms. Results The detection rates of the eight target PFAS in maternal second-trimester serum were all above 85%, with PFOA exhibiting the highest median concentration (10.21 ng·mL⁻¹). Overall, 14.75% of the children exhibited ADHD-like symptoms. Results from the negative binomial regression models showed that second-trimester exposures to PFOA (IRR=1.15, 95%CI: 1.05, 1.26), n-PFOS (IRR=1.08, 95%CI: 1.01, 1.15), 6m-PFOS (IRR=1.13, 95%CI: 1.05, 1.21), and 1m-PFOS (IRR=1.11, 95%CI: 1.03, 1.18) were associated with an increased risk of ADHD-like symptoms in 7-year-old children. Stratified analyses suggested potentially statistically significant associations in girls [e.g., for PFOA, boys vs. girls: 1.09 (0.96, 1.23) vs. 1.25 (1.09, 1.44), P-int=0.31]. The BKMR mixture model indicated that the risk of ADHD-like symptoms trended upward with increasing PFAS mixture concentrations, although this association was statistically significant only among girls (P < 0.05). Conclusion Prenatal PFAS exposure may be associated with an increased risk of ADHD-like symptoms in 7-year-old children, and this adverse association appears to be more prominent in girls.

Objective To investigate the protective effect and underlying mechanisms of HydroMg, a novel sustained-release hydrogen donor, in a model of doxorubicin (DOX)-induced chronic cardiotoxicity. Methods H9C2 cells were treated with 1 μmol/L DOX and/or 1 μg/mL HydroMg, and mitochondrial membrane potential, reactive oxygen species (ROS) levels, and apoptosis were measured. In the animal experiment, mice were divided into control, HydroMg, DOX, and DOX＋HydroMg groups. The HydroMg group received intraperitoneal injection of HydroMg (100 mg/kg). Chronic cardiotoxicity was established by intraperitoneal injection of DOX (5 mg/kg every week) for four consecutive weeks; In the DOX＋HydroMg group, HydroMg (100 mg/kg) was administered intraperitoneally 4–5 h prior to each DOX injection. Cardiac function and remodeling were evaluated by echocardiography and heart weight index (HWI). The long-term survival of mice were analyzed. Subsequently, transcriptome sequencing was performed on myocardial tissues from the DOX group to identify key molecular alterations compared with controls. Results At the cellular level, HydroMg treatment effectively reversed DOX-induced mitochondrial dysfunction and oxidative stress, as evidenced by restored membrane potential, reductions in total ROS and mitochondrial superoxide levels by approximately 30% and 9%, respectively, and a decrease in the apoptosis rate from 34.13% to 18.27%. In the animal model, compared with the DOX group, HydroMg intervention increased left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) by 9.62% and 5.82%, respectively, attenuated the reduction in HWI (4.41 mg/mm vs 3.53 mg/mm), and improved the 4-week survival rate (80% vs 60%). Transcriptomic analysis revealed that the core molecular features of DOX-induced cardiotoxicity, including widespread suppression of oxidative phosphorylation and antioxidant pathways. Conclusions HydroMg protects against DOX-induced chronic cardiotoxicity by alleviating oxidative stress and improving mitochondrial function, and provides a potential therapeutic strategy against DOX-related cardiotoxicity.

AIM To investigate the clinical effects of Cinobufosin Injection combined with RALOX-HAIC regimen on patients with hepatocellular carcinoma.METHODS Ninety-two patients were randomly assigned into control group(46 cases)for intervention of RALOX-HAIC regimen,and observation group(46 cases)for intervention of both Cinobufosin Injection and RALOX-HAIC regimen.The changes in short-term effects,survival situation,inflammatory indices(LCN2,NLRP3 inflammasome,NLR,PLR),immune indices(NK cells,CD8+T cells,IL-17,Th17/Treg)and incidence of toxic and side effects were detected.RESULTS Based on mRECIST,the observation group demonstrated higher disease control rate and objective remission rate than the control group(P＜0.05),along with lower disease progression(P＜0.05).After the treatment,the two groups displayed decreased inflammatory indices,IL-17,Th17/Treg(P＜0.05),and increased NK cells,CD8+T cells(P＜0.05),especially for the observation group(P＜0.05).The observation group exhibited lower incidence of abdominal pain,nausea,vomiting,diarrhea,leukopenia and thrombocytopenia than the control group(P＜0.05),and no significant differences in overall survival and incidence of other toxic and side effects were found between the two groups(P＞0.05).CONCLUSION For the patients with hepatocellular carcinoma,Cinobufosin Injection combined with RALOX-HAIC regimen can safely and effectively enhance body immune functions,and reduce in vivo immune indices.

INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD. METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). The study was conducted at Hainan Branch, Ruijin Hospital Shanghai Jiao Tong University School of Medicine. Patient enrollment and baseline assessments commenced in November 2023. Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging. RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs . 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs . 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs . 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline. CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies. REGISTRATION ClinicalTrials.gov , NCT07034222.
Humans ; Alzheimer Disease/drug therapy* ; Male ; Female ; Aged ; Middle Aged ; Cognitive Dysfunction/drug therapy* ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism* ; Biomarkers ; East Asian People

OBJECTIVES: To assess the preliminary efficacy and safety of a dose-intensified C5VD regimen (cisplatin, 5-fluorouracil, vincristine, and doxorubicin) in children with locally advanced hepatoblastoma. METHODS: This prospective study enrolled 24 children with newly diagnosed, locally advanced hepatoblastoma who received the dose-intensified C5VD regimen at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children's Hospital between January 2020 and December 2023. Clinical characteristics, treatment outcomes, and chemotherapy-related toxicities were analyzed. RESULTS: Of the 24 patients, 13 were male and 11 were female, with a median age at diagnosis of 18.7 months (range: 3.5-79.4 months). All patients achieved complete macroscopic resection of hepatic lesions without liver transplantation. Serum alpha-fetoprotein levels decreased significantly after two chemotherapy cycles. During a median follow-up of 38.4 months (range: 15.8-50.7 months), all patients maintained continuous complete remission, with 3-year event-free survival and overall survival rates of 100%. Across 144 chemotherapy cycles, the incidence rates of grade 3-4 neutropenia, thrombocytopenia, and infections were 97%, 77%, and 71%, respectively; no treatment-related deaths occurred. Notably, 5 patients (21%) developed Brock grade ≥3 hearing loss, of whom 1 required a hearing aid. CONCLUSIONS The dose-intensified C5VD regimen demonstrates significant efficacy with an overall favorable safety profile in the treatment of newly diagnosed, locally advanced pediatric hepatoblastoma. Grade 3-4 myelosuppression and infection are the predominant toxicities. However, high‑dose cisplatin-induced ototoxicity remains a concern, highlighting the need for improved otoprotective strategies.
Humans ; Hepatoblastoma/pathology* ; Male ; Female ; Infant ; Liver Neoplasms/pathology* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child, Preschool ; Prospective Studies ; Doxorubicin/adverse effects* ; Child ; Cisplatin/adverse effects* ; Vincristine/adverse effects* ; Fluorouracil/adverse effects*

BACKGROUND: The clinical impact of post-percutaneous coronary intervention (PCI) quantitative flow ratio (QFR) in patients treated with PCI for chronic total occlusion (CTO) was still undetermined. METHODS: All CTO vessels treated with successful anatomical PCI in patients from PANDA III trial were retrospectively measured for post-PCI QFR. The primary outcome was 2-year vessel-oriented composite endpoints (VOCEs, composite of target vessel-related cardiac death, target vessel-related myocardial infarction, and ischemia-driven target vessel revascularization). Receiver operator characteristic curve analysis was conducted to identify optimal cutoff value of post-PCI QFR for predicting the 2-year VOCEs, and all vessels were stratified by this optimal cutoff value. Cox proportional hazards models were employed to calculate the hazard ratio (HR) with 95% CI. RESULTS: Among 428 CTO vessels treated with PCI, 353 vessels (82.5%) were analyzable for post-PCI QFR. 31 VOCEs (8.7%) occurred at 2 years. Mean value of post-PCI QFR was 0.92 ± 0.13. Receiver operator characteristic curve analysis shown the optimal cutoff value of post-PCI QFR for predicting 2-year VOCEs was 0.91. The incidence of 2-year VOCEs in the vessel with post-PCI QFR < 0.91 (n = 91) was significantly higher compared with the vessels with post-PCI QFR ≥ 0.91 (n = 262) (22.0% vs. 4.2%, HR = 4.98, 95% CI: 2.32-10.70). CONCLUSIONS Higher post-PCI QFR values were associated with improved prognosis in the PCI practice for coronary CTO. Achieving functionally optimal PCI results (post-PCI QFR value ≥ 0.91) tends to get better prognosis for patients with CTO lesions.

The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an in situ tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL⁺ B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual-conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL⁺ B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of αPD-1 and CAR-T therapies. The application of this in situ tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.

The prefrontal cortex (PFC) plays a pivotal role in orchestrating higher-order emotional and cognitive processes, a function that depends on the precise modulation of synaptic activity. Although pharmacological studies have demonstrated that dopamine signaling through dopamine D1 receptor (DRD1) in the PFC is essential for these functions, the cell-type-specific and molecular mechanisms underlying the neuromodulatory effects remain elusive. Using cell-type-specific knockout mice and patch-clamp recordings, we investigated the regulatory role of DRD1 on neurons and astrocytes in synaptic transmission and plasticity. Furthermore, we explored the mechanisms by which DRD1 on astrocytes regulate synaptic transmission and plasticity at the cellular level, as well as emotional and cognitive functions at the behavioral level, through two-photon imaging, microdialysis, high-performance liquid chromatography, transcriptome sequencing, and behavioral testing. We found that conditional knockout of the Drd1 in astrocytes (CKO^AST) increased glutamatergic synaptic transmission and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC), whereas Drd1 deletion in pyramidal neurons did not affect synaptic transmission. The elevated level of d-serine in the mPFC of CKO^AST mice increased glutamatergic transmission and LTP through NMDA receptors. In addition, CKO^AST mice exhibited abnormal emotional and cognitive function. Notably, these behavioral changes in CKO^AST mice could be reversed through the administration of d-serine degrease to the mPFC. These results highlight the critical role of the astrocytic DRD1 in modulating mPFC synaptic transmission and plasticity, as well as higher brain functions through d-serine, and may shed light on the treatment of mental disorders.

OBJECTIVES: To investigate the therapeutic mechanism of Sangma Zhike Formula (SMZKF) for relieving cough sensitivity and airway inflammation in rats with postinfectious cough (PIC). METHODS: Male SD rat models were established by cigarette smoke exposure with intranasal LPS instillation and capsaicin aerosol inhalation. From day 19 following the start of PIC modeling, the rats received daily treatment with saline (model group), low-, medium-, and high-dose SMZKF, and compound methoxyphenamine (ASM) via gavage for 10 consecutive days (n=8). The assessments included behavioral changes, cough sensitivity (latency and frequency), lung histopathology, inflammatory cell counts and cytokine/mediator levels in the bronchoalveolar lavage fluid (BALF), oxidative stress markers in the lung tissue, and expressions of proteins related with cough hypersensitivity and pyroptosis. RESULTS: The rat models of PIC exhibited reduced mental alertness, accelerated respiration, and pronounced symptoms such as coughing, sneezing, and facial scratching with significantly shortened cough latency and increased 5-min cough frequency. Histopathological analysis revealed collapsed alveolar structures, thickened alveolar septa, and extensive inflammatory cell infiltration in the bronchi and peribronchial regions, accompanied by elevated bronchial and alveolar inflammation scores of the rat models. In the BALF, inflammatory cell counts and the levels of IL-1β, TNF-α, IL-6, COX-2, PGE-2, and TXA-2 were all markedly elevated, and the pulmonary oxidative stress markers (ROS and MDA) and myeloperoxidase (MPO) activity were also significantly increased. The pulmonary expressions of cough hypersensitivity-related proteins (TRPV1, SP, CGRP, and NK1R) and pyroptosis-associated markers (P-NF-κB, NLRP3, ACS, cleaved caspase-1, cleaved IL-1β, and GSDMD-N) were significantly upregulated in the model group. SMZKF interventions significantly ameliorated these pathological changes in the rat models, and high-dose SMZKF produced a similar therapeutic efficacy to that of ASM. CONCLUSIONS SMZKF alleviates cough sensitivity and airway inflammation in PIC rats possibly by inhibiting TRPV1-mediated SP/NK1R signaling and the NLRP3/caspase-1/GSDMD pyroptosis pathway.
Animals ; Cough/metabolism* ; Rats, Sprague-Dawley ; Pyroptosis/drug effects* ; Male ; TRPV Cation Channels/metabolism* ; Rats ; Drugs, Chinese Herbal/pharmacology* ; Inflammation ; Signal Transduction