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关键词： Glp-1 receptor agonists   Glucagon-like peptide-1   Pediatric obesity  

摘要： Purpose of Review: The aim of this review is to provide a comprehensive summary of current clinical evidence on the relationship between GLP-1 receptor agonists and pediatric obesity, to evaluate these findings from metabolic and therapeutic perspectives, and to offer potential directions for future research in the field. Recent Findings: Obesity is a chronic disease that threatens health across all age groups, particularly children and adolescents. Lifestyle modification and nutrition-based approaches are regarded as the cornerstone strategies for treating pediatric obesity;however, they have important limitations in achieving sustainable long-term weight loss. This has increased interest in pharmacological treatment options. GLP-1 receptor agonists were originally developed for the treatment of type 2 diabetes mellitus, and they are now among the pharmacological agents with therapeutic indications not only in adults but also in pediatric and adolescent populations. As clinical evidence of their effects on body weight has accumulated, these agents have been incorporated into obesity treatment indications. In current clinical practice, the GLP-1 receptor agonists with approved indications for the treatment of pediatric obesity are liraglutide and semaglutide. Summary: Available evidence indicates that GLP-1 receptor agonists represent a promising pharmacotherapeutic option for the treatment of obesity in children and adolescents. Nevertheless, more comprehensive studies are needed regarding the long-term efficacy, safety profiles, and clinical positioning of these agents. Future research is expected to clarify the role of GLP-1 receptor agonists in the management of pediatric obesity. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2026.

关键词： Obstructive sleep apnea   Chronic kidney disease   Kidney injury molecule-1   Glomerular filtration rate   Albumin   creatinine ratio  

摘要： Purpose Obstructive sleep apnea (OSA) increases the risk of chronic kidney disease (CKD) through exposure to nocturnal hypoxemia. Elevated urine Kidney Injury Molecule-1 (KIM-1) can reflect kidney injury before conventional measures of CKD [estimated glomerular filtration rate (eGFR) and urine albumin: creatinine ratio (ACR)] become abnormal. We investigated if urine KIM-1 is elevated in patients with OSA and if this is associated with an increased estimated risk of CKD progression. Methods Adults (n = 1271) completed diagnostic OSA testing and quantification of eGFR, ACR and KIM-1. OSA severity and nocturnal hypoxemia were quantified using the oxygen desaturation index (ODI, 4%), mean oxygen saturation (SpO(2)), and the duration of SpO(2) < 90% (T90). Mean KIM-1 concentrations were compared between patients with no/mild (ODI < 15), moderate (15 <= ODI <= 30) and severe OSA (ODI > 30) and the associations between urine KIM-1 and nocturnal hypoxemia with the estimated risk of CKD progression were assessed. Results In the entire cohort, participants with severe OSA (n = 411) had higher KIM-1 than the no/mild (n = 545) and moderate OSA (n = 315) groups (all comparisons, p <= 0.047). KIM-1 was positively associated (standardized beta;95% CI) with ODI (0.11;0.05-0.17) and T90 (0.12;0.06-0.18) and negatively associated with mean SpO(2) (-0.14;-0.21--0.08). Similar relationships were found in a sub-group of participants (n = 976) with normal eGFR and ACR. Higher KIM-1 was also associated with an increased estimated risk of CKD progression. Conclusion OSA-related hypoxemia is associated with increased urine KIM-1, reflecting kidney injury, both after and, more importantly, before eGFR and ACR become abnormal. Furthermore, elevated KIM-1 is associated with an increased estimated risk of CKD progression.

关键词： Downward propagation   Planetary wave   Sudden stratospheric warming   Zonal wavenumber 1  

摘要： To elucidate dynamics of significant downward propagation (SDP) events of zonal wavenumber 1 (WN1) planetary waves from the stratosphere after sudden stratospheric warming (SSW) events and their influence on the extratropical troposphere, a case study of an SDP event in March 2023 and composite analyses for SDP events with and without SSW using JRA-3Q reanalysis are conducted. The March 2023 event is characterized by the equatorward propagation of enhanced WN1 components in the troposphere, which follows the WN1 downward propagation after the SSW. Exceptionally warm anomalies in East Asia including Japan in early March are associated with the equatorward propagation. A statistical investigation on the timing of all SDP and SSW events reveals that an SDP event is significantly more likely to occur after an SSW. The composite of the SDP event with SSW is characterized by stratospheric easterlies, in contrast to that without SSW, in which westerlies prevail in the stratosphere. Downward propagated WN1 components in the troposphere propagate equatorward and produce temperature anomalies in the extratropics, depending on the WN1 phase at high latitudes for both SDP events. When the WN1 ridge is positioned around the date line in SDP events with SSW, cold anomalies tend to cover East Asia including Japan. The WN1 component during the March 2023 event has the largest amplitude among SDP events with SSW and a ridge location around 90°W, which is far apart from the rest. These peculiar characteristics of the WN1 component would contribute to the extraordinary warm anomalies near Japan. © The Author(s) 2026.

关键词： Biomarkers   Hepatocellular carcinoma   Immune checkpoint inhibitors   Neutrophil-to-Lymphocyte Ratio  

摘要： Purpose: Immune checkpoint inhibitors (ICIs) are the preferred treatment for advanced hepatocellular carcinoma (HCC). However, most patients do not respond to initial immunotherapy alone, even when combined with other therapies. Our study aimed to profile ICI-based therapies for HCC patients in real-world clinical practice and to identify factors associated with survival and treatment efficacy. Methods: A retrospective cohort study was conducted to describe ICI-based therapies for HCC patients at our center, including combination modalities, effectiveness, and safety. Pre- and post-treatment indicators were collected to explore factors related to progression-free survival (PFS) and treatment efficacy in these patients. Results: All 110 patients received therapy based on immune checkpoint inhibitors (ICIs) using three strategies, with the majority (60.9%) undergoing triple combination therapy. The overall progression-free survival (PFS) was 7.0 months, and the objective response rate (ORR) was 26.4%. Analysis of PFS identified several independent risk factors: a history of hepatitis B virus (HBV) infection (hazard ratio [HR] = 1.78), a platelet-to-lymphocyte ratio (PLR) greater than 276.9 (HR = 2.19), and an international normalized ratio (INR) greater than 1.2 (HR = 3.49). Conversely, the use of PD-1 inhibitors was associated with a favorable outcome (HR = 0.44). The combination of a history of HBV infection with HBeAg positivity and TNM stage (III + IV) effectively distinguished responders from non-responders. Additionally, neutrophil count and the neutrophil-to-lymphocyte ratio (NLR) were significantly elevated in non-responders and exhibited dynamic changes during treatment. Conclusion: In HCC clinical practice, ICI-based systemic therapies are both effective and safe. Patient characteristics can serve as reliable predictors of progression-free survival (PFS) and treatment efficacy. Importantly, neutrophil count and the neutrophil-to-lymphocyte ratio (NLR) may al

关键词： Glucagon   Pancreatic alpha-cell   Sodium-glucose cotransporter 1   Type 2 diabetes  

摘要： Pancreatic alpha-cells secrete glucagon, a hormone that elevates blood glucose levels. In type 2 diabetes, high plasma glucagon levels are associated with hyperglycemia. However, the underlying mechanisms of increasing glucagon secretion remain unclear. We focused on the intrinsic regulatory mechanisms of glucagon secretion in alpha-cells, in particular sodium- glucose cotransporter 1 (SGLT1), which is involved in the early steps of glucose sensing. We previously demonstrated that SGLT1 is expressed in alpha-cells and is significantly upregulated in diabetic mice compared with non-diabetic mice. In isolated islets from diabetic mice, SGLT1 knockdown attenuated glucagon hypersecretion, and in alpha TC1 cells, SGLT-specific substrates promoted glucagon secretion by raising intracellular calcium. On the basis of these findings, we hypothesized that SGLT1 upregulation in alpha-cells under diabetic conditions impairs the suppression of glucagon secretion, thereby contributing to hyperglycemia. However, a previous study showed that systemic SGLT1 knockout (KO) mice exhibit a higher proportion of alpha-cells in the islets and atypically high plasma glucagon levels. To clarify the roles of SGLT1 specifically in alpha-cells, we generated alpha-cell-specific SGLT1 KO mice using a tamoxifen-inducible Cre-loxP system and analyzed these mice fed a highfat, high-sucrose diet. The results clearly showed that, inconsistent with the results from the systemic SGLT1 KO mice, SGLT1 deficiency specifically in alpha-cells did not affect glucagon secretion, glucose tolerance, or alpha-cell proportion in the islets under diabetic conditions. Thus, though SGLT1 is upregulated in diabetic alpha-cells, this does not appear to contribute to hyperglucagonemia and impaired glucose tolerance in diabetic mice.

关键词： Peritoneal dialysis   Children   Peritoneal function   Genetic polymorphism  

摘要： BackgroundAquaporins (AQPs) are a class of proteins that transport water molecules across membranes, which can promote water transport in cells. We aimed to explore the correlation between different polymorphisms of AQP1 and peritoneal function in children on peritoneal dialysis (PD).MethodsChildren who underwent PD at the Children's Hospital of Fudan University from January 1, 2014, to December 31, 2023, were included. The AQP1 genotypes of the four polymorphisms were rs2075574 (TT, CT, CC), rs1049305 (GG, CG, CC), rs10253374 (TT, CT, CC) and rs17159702 (TT, CT, CC).ResultsA total of 187 children on chronic PD were included in the study. We found that the TT group with rs2075574 exhibited a lower baseline peritoneal equilibration test (PET) ultrafiltration level than the CC group (302 +/- 129 vs. 408 +/- 168 ml/m2, P = 0.015). For rs1049305, the CC group had a higher pKT/V than both the GG (2.71 +/- 1.25 vs. 2.27 +/- 0.79, P = 0.04) and CG groups (2.71 +/- 1.25 vs. 2.24 +/- 0.88, P = 0.03). Additionally, at 12-month follow-up, the CC (410 +/- 160 ml/m2, P = 0.04) and CG (393 +/- 174 ml/m2, P = 0.04) groups of rs1049305 showed higher PET ultrafiltration than the GG group (239 +/- 288 ml/m2). No significant correlation was observed between the four genotypes and adverse ***1 rs2075574 and rs1049305 polymorphisms might be associated with ultrafiltration and urea transport in children with *** AbstractA higher resolution version of the Graphical abstract is available as Supplementary information

关键词： Toripalimab-tpzi   Head and neck cancer   Immunotherapy   PD-1 inhibitor   Precision medicine  

摘要： The recent humanized anti-programmed death-1 (PD-1) monoclonal antibody, toripalimab-tpzi, has now become a promising immunotherapeutic agent in the control of head and neck cancer (HNC), especially head and neck squamous cell carcinoma (HNSCC), the most common form of the disease, constituting approximately 90 % of all cases. In this conceptual review, the authors critically examine the molecular processes, clinical activity, safety, biomarker-guided precision of their approach, resistance biology, and combination regimens of toripalimab-tpzi in HNSCC. Toripalimab-tpzi offers antitumor effects due to selective inhibition restricting the PD-1/programmed death-ligand 1 (PD-L1) axis, which restores cytotoxic T-cell activity and intensifies the antitumor immune responses. In the Phase I-III clinical trials on recurrent or metastatic HNSCC, the objective response rates of toripalimab-tpzi were around 20-36, the median progression-free survival (PFS) was 2.8–4.5 months, and the median overall survival was 10–15 months, especially with PD-L1-enriched populations. The safety profile is comparable to the PD-1 class effects, and the majority of the immune-related adverse events (irAEs) were grade 1-2 and grade 3-4 toxicities that were rare in less than 20 percent of the patients. The new evidence is pointing to the significance of patient selection according to biomarker to maximize therapeutic response. The single predictive utility of such markers as PD-L1 expression, tumor mutational burden, microsatellite instability, tumor-infiltrating lymphocytes, or immune gene signatures is variable, with the deficiency of single-biomarker systems. Integration therapy involving toripalimab-tpzi and platinum-based chemotherapy, radiotherapy, targeted therapies, or other immunomodulators has been shown to result in better response rates (up to 4060 % in select studies) and may result in resistance being overcome by intrinsic or acquired immunomodulatory mechanisms. Unlike previous gene

关键词： Autism Spectrum Disorder   Latino Families   Community-Based Participatory Research   Phase 1 Clinical Trial   Intersectionality  

摘要： This study presents a qualitative examination of a Phase 1 clinical trial evaluating ¡Iniciando!, a culturally adapted intervention for Latino autistic young adults and their families. Employing a community-based participatory research (CBPR) approach, we gathered feedback from parents (n = 46) and young adults (n = 46; Mean Age = 20.53, SD = 2.15) through open-ended surveys and rankings of program modules and optional webinars. Inductive thematic analysis revealed significant perceived benefits, including enhanced social connections, practical life skills, and personal understanding. Parents and young adults provided valuable suggestions for program improvement, emphasizing the need for increased social interaction, personalized content, and flexible scheduling. The program's cultural fit was positively rated, with participants highlighting the importance of Spanish language use and incorporation of Latino cultural values. Findings provide preliminary support for integrating cultural responsiveness and neurodiversity-affirming practices in interventions for this underserved population, informing future program refinements and dissemination.

关键词： 2,3-dihydro-1,3,4-thiadiazole-benzenesulfonamide   triple inhibitors   EGFR   carbonic anhydrase   breast cancer  

摘要： A novel 2,3-dihydro-1,3,4-thiadiazole-benzenesulfonamide hybrid, N-(4-(( E )-1-((( Z )-5-acetyl-3-(4-sulfamoylphenyl)-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)ethyl)phenyl)-4-chloro benzamide (N-ASTPC), was rationally designed as a triple inhibitor targeting carbonic anhydrase IX (CAIX), carbonic anhydrase XII (CAXII), and the epidermal growth factor receptor (EGFR) - key targets overexpressed in cancer. Molecular docking and 200-ns molecular dynamics (MD) simulations confirmed stable and high-affinity interactions of N-ASTPC with the active sites of all three targets. MM-GBSA binding free energy calculations and ProLIF interaction profiling further supported these findings, while principal component analysis (PCA) revealed limited conformational drift, indicating robust complex formation. Additionally, density functional theory (DFT) assessments affirmed N-ASTPC's electronic stability and favorable reactivity. Biological assays demonstrated potent inhibitory activity with IC50 values of 0.039 mu M, 0.04 mu M, and 0.05 mu M for CAIX, CAXII, and EGFR, respectively, comparable or superior to standard inhibitors (acetazolamide and erlotinib). Regarding in vitro cytotoxicity, N-ASTPC displayed selective toxicity toward cancer cells over normal fibroblasts, with notable effects in MDA-MB-231 and MCF-7 breast cancer lines compared to doxorubicin. Flow cytometry showed that N-ASTPC induces significant S-phase arrest and robust early apoptosis, confirmed by a similar to 5.7-fold increase in Bax, similar to 4.5-fold increase in caspase-3, and similar to 2-fold decrease in Bcl-2 expression - consistent with mitochondrial apoptotic pathway activation. Collectively, these findings establish N-ASTPC as a promising multifunctional anti-cancer lead compound capable of simultaneously disrupting tumor cell metabolism and signaling via CAIX, CAXII, and EGFR inhibition. Its multi-modal mechanism and selective apoptotic induction underscore its potential for further preclinical develop