Childhood obesity has become a global public health issue. Current research indicates that early life obesogen exposure has emerged as a significant risk factor for childhood obesity. While obesogens have been confirmed to influence the development and progression of childhood obesity through mechanisms such as endocrine disruption and epigenetic programming, controversies remain regarding the establishment of causal relationships, assessment of combined exposures, and validation of transgenerational effects in humans. In recent years, novel approaches including multi-omics technologies, exposome-based analysis, and multigenerational cohort studies have integrated dynamic biomarker monitoring with analyses of social-environmental interactions, offering new perspectives and methodologies for constructing a systematic "exposure-mechanism-outcome" research framework. This article reviews literature from PubMed and Web of Science up to August 2025 on the association between early life obesogen exposure and childhood obesity, summarizing evidence on the health effects of early life obesogen exposure, major exposure pathways and internal exposure assessment, interactions and amplifying effects of social and environmental factors, as well as the biological mechanisms underlying obesogen action. It further examines current research frontiers and challenges, aiming to provide a theoretical foundation for early prevention and precision intervention of childhood obesity.

Psoriasis, a chronic, immune-mediated inflammatory disease characterized by hyperproliferation of keratinocytes, is difficult to cure and prone to relapse, often leading to systemic damage. Triptolide (TPL) can modulate cutaneous immune responses and inflammation, yet its therapeutic window is narrow with significant toxicity. To enhance skin targeting and retention of TPL while reducing systemic absorption and toxicity, a TPL/hyaluronic acid/phospholipid polymeric micelle (TPL/HA-DOPE) was constructed via HA's targeting of the CD44 receptor on skin cells. The prepared TPL/HA-DOPE exhibited a uniform spherical morphology with particle size of (130.4±1.23) nm, drug loading capacity of (19.74±0.084) %, and encapsulation efficiency of (85.53±1.34) %. Transdermal permeation studies in vitro and in vivo demonstrated that TPL/HA-DOPE not only enhanced uptake in HaCaT cells but also exhibited excellent skin retention. In a murine model of psoriasis, the TPL/HA-DOPE gel at the dose of 50 μg/(kg•d) showed the most significant improvement in erythema, scaling, and epidermal thickening. Histological analysis confirmed that TPL/HA-DOPE markedly reduced stratum corneum thickness, epidermal hyperplasia, and inflammatory cell infiltration. Ki67 immunostaining proved that its anti-inflammatory mechanism might be achieved by reducing the number of Ki67-positive cells and lowering the levels of inflammatory factors IL-6 and TNF-α. The above results demonstrate that HA-DOPE as a drug delivery carrier for the treatment of psoriasis-like skin diseases has high value of scientific research and good prospects for clinical application.

Objective:To explore the safety and reliability of retrosigmoid approach BONEBRIDGE implantation in patients with auricle reconstruction using skin expansion flap.Methods:A retrospective analysis was conducted on 43 congenital aural atresia cases (43 ears) who underwent BONEBRIDGE implantation from September 2019 to January 2023 in Beijing Tongren Hospital. 30 males and 13 females were included in this work. The implantation age was 9-36 years old (median age=10 y/o). All cases underwent auricle reconstruction surgery using the posterior ear flap expansion method, with 36 cases using the single expanded postauricular flap method and 7 cases using two-flap method. BONEBRIDGE implant surgery was performed during the third stage of auricle reconstruction or after all stages. The hearing improvements were evaluated by comparing the changes in pure tone hearing threshold and speech recognition rate of patients before and after BONEBRIDGE implantation. Routine follow-up was conducted to observe the hearing results and complications. SPSS 14.0 software was applied for data statistical analysis.Results:All 43 patients healed well and had no surgical complications when discharge. The average bone conduction hearing threshold after surgery was (8.2±6.6) dBHL, and there was no statistically significant difference compared to the preoperative [(8.1±5.7) dBHL] ( P=0.95). After surgery, the threshold of hearing assistance with power on was significantly lower than that without hearing assistance [(32.8±4.6) dBHL vs (60.5±5.5) dBHL], and the difference was statistically significant ( P<0.001). The speech recognition rate of monosyllable words, disyllabic words and short sentences in quiet environment increased to 72%, 84%, and 98% respectively. The differences were statistically significant ( P<0.001). The speech recognition rate of monosyllabic words, disyllabic words, and short sentences in noise environment was significantly increased by 70%, 80%, and 92% respectively ( P<0.001). After a follow-up of 4 to 47 months (median=24 months), the hearing results were stable and the aesthetic outcomes were satisfying. One patient had delayed hematoma around coil of the implant. After aspiration and compressed dressing for one week, hematoma was not recurrent. Conclusion:For patients after auricle reconstruction using expanded postauricular flap, the preference of retrosigmoid approach is a good choice in terms of safety and reliability of operation, as well as aesthetic appearance.

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95％ confidence interval (CI), 1.01?1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95％ CI, 1.49?2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95％ CI, 0.48?1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95％ CI, 0.39?1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A (USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95％ CI, 0.32?0.82; P=0.0077), PFS (adjusted HR, 0.51; 95％ CI, 0.38?0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95％ CI, 2.75?8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95％ CI, 1.88?6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12C mutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

Per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants (POPs). They are widely used in food packaging, tableware coating, stain resistant furniture, and other industrial production. Humans are exposed to PFASs on a daily basis through drinking water and intaking food, use of consumer products containing PFASs, and occupational exposure during the production of PFASs or related products. A growing body of toxicological studies has shown that PFASs exposure disrupts the thyroid hormone (TH) system and causes hypothyroidism, which is further supported by population epidemiological studies. PFASs can damage thyroid follicular cells and sodium/iodine transporters to impair iodine uptake by thyroid cells. They interfere with the synthesis of thyroglobulin, reduce the activity of thyroid peroxidase, and affect the synthesis and secretion of TH. They interfere with TH transportation and biological effects via TH competitive binding thyroid transporter or thyroid hormone receptor. They suppress TH signaling pathway and deiodinase activity, interfere negative feedback mechanism, and accelerate TH metabolism and excretion. The processes of TH synthesis, transport, degradation, and biological effects may all be affected by PFASs exposure. This paper described possible toxic mechanisms of PFASs on the thyroid from four aspects: TH biosynthesis, transport, action on target cells, and metabolic excretion stage, and summarized the thyroid toxicity associated with PFASs exposure.

Objective To explore the effect of peripheral blood markers on the efficacy and prognosis of patients with advanced esophageal cancer treated with immune checkpoint inhibitors (ICIs). Methods The case data of 61 patients with advanced esophageal cancer who met the inclusion criteria were collected. Data on clinical indicators and peripheral blood markers as well as objective response rate (ORR) and progression-free-survival (PFS) were obtained. Results The median PFS of the included patients was 7.10 months (95%CI: 5.12-9.07). The ORR of patients with baseline lactate dehydrogenase (LDH) < 201 was better than that of patients with LDH≥201 (P < 0.05). Univariate analysis showed that baseline LDH0 < 201, neutrophil to lymphocyte ratio (NLR) < 3.9, platelet-to-lymphocyte ratio (PLR) < 240.3, and LDH1 < 249.0 two weeks after ICI treatment were significantly associated with significant improvement in PFS (P < 0.05). In multivariate analysis, patients with NLR0 < 3.9 had longer PFS (P < 0.05). Conclusion LDH0 < 201, NLR0 < 3.9, PLR0 < 240.3, and LDH1 < 249.0 are positively correlated with the prognosis of patients with advanced esophageal cancer treated with ICIs.

Objective To investigate the impact of PD1-TCF1+CD8+ stem-like memory T cells on immunotherapy prognosis and tertiary lymphoid structure in tumors. Methods Pathological tissue sections were collected from 33 patients treated with immunotherapy, 18 cases of NSCLC and 15 cases of ESCC. The expression of PD1-TCF1+CD8+T cells was detected through quantitative analysis by multiplex immunofluorescence. Survival curves were described by the Kaplan-Meier method. Pearson's correlation test was used for correlation analysis. Results The high levels of PD1-TCF1+CD8+T cells had a better PFS in NSCLC and ESCC cohorts. In the NSCLC cohort, high levels of PD1-TCF1+CD8+ T cells were significantly and positively correlated with the number (P=0.0151) and size (P=0.0007) of TLSs. Conclusion In patients with NSCLC and ESCCs, high PD1-TCF1+CD8+ stem-like memory T cell expression indicates improved prognosis and immune response and is associated with the formation of TLSs in the tumor microenvironment of NSCLC.

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRAS^G12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFR^L858R and EGFR^Δ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01‍‒‍1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49‍‒‍2.63; P<0.0001), while classical activating mutations with EGFR^T790M showed no difference compared to classical activating mutations without EGFR^T790M in OS (adjusted HR, 0.96; 95% CI, 0.48‍‒‍1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39‍‒‍1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A(USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32‍‒‍0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38‍‒‍0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75‍‒‍8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88‍‒‍6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRAS^G12Cmutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFR^T790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/genetics* ; Extracellular Matrix Proteins/genetics* ; Immune Checkpoint Inhibitors/therapeutic use* ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins p21(ras)/genetics* ; Treatment Outcome

AlM: The Chinese medicinal herb Hanfangji is dried roots of Stephania tetrandra S. Moore (Family, Menispermaceae). Tetrandrine and fangchinoline are two major constituents of Hanfangji and these bisbenzyltetrahydroisoquinoline alkaloids possess anti - cancer and other pharmacological activities. To facilitate further pharmacodynamic investigation of these compounds, a pharmacokinetic investigation was performed in rats and in vitro. METHODS: Pharmacokinetics of tetrandrine and fangchinoline were characterized in rats p.o. or i.v. dosing an aqueous extract of Hanfangji or the individual compound. Unbound levels of systemic exposure to these two alkaloids were assessed using in vitro studies of plasma protein binding, blood-plasma partition, and lysosomal trapping. All the study samples were analyzed by liquid chromatography/mass spectrometry.RESULTS: We found two pharmacokinetic features of tetrandrine and fangchinoline. First, the two compounds had blood levels of systemic exposure substantially higher than the respective plasma levels of systemic exposure. Second, the two compounds exhibited significantly higher systemic exposure levels after p.o. dosing an aqueous extract of Hanfangji than the respective exposure levels after p.o. dosing the individual compound, at the same compound dose levels and under the same conditions for analytical measurement and the same conditions for animal study. Unbound fractions of tetrandrine and fangchinoline in rat plasma were 2%-5% and the concentrations of the alkaloids in rat erythrocytes were 5-times higher than those in rat plasma. Lysosomal inhibitor could block their trapping in lysosomes and significantly reduce their concentrations in HEK-293 cells. CONCLUSlON: The following pharmacokinetic aspects should be noted in pharmacodynamic investigation of tetrandrine and fangchinoline: extensive binding with plasma proteins, extensive binding with erythrocytes, and trapping by lysosomes of tissue cells substantially reduce the levels of unbound tetrandrine and fangchinoline in the systemic circulation.

Abstract Bisphenols (BPs), which are mainly used in the production of polycarbonates and epoxy resins, are common endocrine disruptors (EDCs) in natural environments. Human mainly exposes to BPs via ingestion and skin. Previous studies have deteted BPs in human urine, serum, and milk samples, and children and pregnant women have a high level of exposure to to BPs. Based on international and national publications pertaining to BPs since 2009, this review describes the exposure to BPs in human urine, serum, and milk and summarizes neuroendocrine dysfunctions, oxidative stress injury and epigenetics changes caused by BPs, so as to provide insights into reducing the exposure to and health risk of BPs.