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关键词： osteosarcoma   KRAS   IL-17A   metastasis   MMPs  

摘要： Dysregulation of Kirsten rat sarcoma virus (KRAS) plays crucial roles in many tumors. It is reported that KRAS could promote proliferation of osteosarcoma (OS) cells. Nonetheless, the contribution of KRAS to the invasion and spread of OS is still not well understood. This study aimed to investigate KRAS-driven metastasis and the mechanisms behind it in human OS. Tissue microarrays were utilized to assess KRAS expression and its relationship with clinicopathological characteristics. The migratory and invasive abilities of OS cells were evaluated through wound-healing assays and transwell analysis. Furthermore, the regulatory mechanisms of KRAS in human OS were analyzed using RNA sequencing, tandem mass tags assays, multiple immunofluorescence assays, micro-CT, and bioluminescence imaging. In vivo experiments were conducted using established lung metastatic models. Our data showed that downregulation of KRAS in human OS cells could inhibit cell migration and invasion in vitro and in vivo (tumor metastasis model by tail vein injection in BALB/c nude mice). We identify IL-17A, a crucial marker of IL-17 signal pathway, as a downstream target of KRAS. The reduction of KRAS may suppress matrix metalloproteinase (MMP1), MMP3, and MMP9, which are recognized as proteins associated with tumor metastasis, through a mechanism dependent on IL-17 signaling. In summary, these findings indicate that KRAS could serve as a potential biomarker for therapeutic strategies in human OS. Mechanistically, our data revealed that KRAS knockdown affects tumor metastasis by inactivating IL-17 signal pathway via IL-17A-dependent manner. Kirsten rat sarcoma virus (KRAS) is a gene that plays important roles in many types of cancer. In this study, we investigated how KRAS affects the spread of osteosarcoma (OS), a type of bone cancer. We found that reducing the activity of KRAS in OS cells can slow down their ability to migrate and invade other parts of the body. We also identified a protein called

关键词： il17ra   il17rc   Evolution   m6A   Antiviral immunity   Miichthys miiuy  

摘要： Interleukin-17 receptor A (IL17RA) and IL17RC form a receptor complex critical for initiating IL-17A-mediated immune responses, a hallmark of T helper 17 (Th17) cells. In this study, il17ra and il17rc were identified in miiuy croaker (Miichthys miiuy) and bioinformatics analysis revealed their evolutionary and structural conservation, underscoring their roles in immunity. However, there has been little research on the IL-17 receptor family from the perspective of N6-methyladenosine (m6A) modifications. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we identified strong m6A modifications on the last exons of il17ra and il17rc, validated by MeRIP-PCR. Poly(I:C) stimulation significantly upregulated il17ra and il17rc expression, while reducing their m6A modification levels, implicating these changes in antiviral immunity. Interestingly, cycloleucine (CL), a well-known methylation inhibitor, did not alter the expression of il17ra and il17rc but promoted the nuclear-to-cytoplasmic transport of il17ra mRNA, potentially influencing its translation process. These findings provide valuable insights into the regulatory roles of m6A modifications in il17ra and il17rc function and highlight their importance in the antiviral immune response.

摘要： Profiling the HLA diversity at the population level benefits multiple clinical and anthropological applications, such as tracing population migration, identifying genetic relationships between different groups, quantifying the added diversity in a global donor pool and matching for solid organ and stem cell transplantation. We calculated nine-locus HLA-A similar to C similar to B similar to DRB1 similar to DRB3/4/5 similar to DQA1 similar to DQB1 similar to DPA1 similar to DPB1 allele and haplotype frequencies in about 170,000 volunteer donor genotypes from the NMDP Mexico (NMDP MX, previously Be The Match Mexico) donor center. These donors are predominantly of Mexican ancestry recruited from multiple regions in Mexico. The goal of the study was to describe the HLA genetic profiles of the Mexican population and investigate the contribution of these donors' HLA in serving Mexican, US and international patients in need of hematopoietic cell transplants. Additionally, we estimated that almost all Mexican patients will have an available 5 of 8 or better matched donor in the NMDP MX donor center with matches also available for some of the Latino patients in the U.S. We demonstrate that Mexican populations clustered genetically and shared multiple frequent alleles and haplotypes with populations from the US Mexican or Chicano, US South/Central American Hispanic, and some Latino populations. Operationally, 78 % of NMDP Mexico donors contributed genotypes that were observed a total of three times or less on the registry, increasing the diversity of the overall NMDP registry. More than 300 donor collections were facilitated through the NMDP MX donor center serving mostly Hispanic/Latino patients in the US and abroad. This study highlights the importance of adding the NMDP MX donors to the worldwide donor pool and paves the way for a data-driven strategy for future planning and donor recruitment.

关键词： IL-17 inhibitors   inflammatory bowel disease   Secukinumab  

摘要： IL-17 inhibitors effectively treat psoriasis and psoriatic arthritis but may increase the risk of inflammatory bowel disease (IBD). We assessed their association with IBD compared to apremilast. Utilising the TriNetX database, we analysed patients with psoriasis or ankylosing spondylitis initiating IL-17 inhibitors or apremilast. We used propensity score matching and Cox models to estimate IBD risk. Among 13,216 matched patients per group, 142 developed IBD with IL-17 inhibitors versus 60 with apremilast (aHR = 2.50, 95% CI: 1.85-3.39). IL-17 inhibitors increase IBD risk, necessitating careful patient selection and monitoring.

关键词： Pharmacokinetics   Population pharmacokinetic model   Safety   TQH2722   IL-4Ra monoclonal antibody   Phase I  

摘要： The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of TQH2722, an Interleukin-4 receptor alpha (IL-4Ra) monoclonal antibody, in healthy subjects. In this randomized, doubleblind and placebo-controlled trial, TQH2722 was subcutaneously injected as single-ascending dose (n = 46;50, 150, 300, 600 and 1200 mg) or multiple-ascending dose (n = 20;150 and 600 mg;four doses every 2 weeks). Subjects were monitored for adverse events and blood samples were collected for pharmacokinetics. A population pharmacokinetic model was developed and validated. TQH2722 was well tolerated with no serious or severe adverse events observed. After a single dose, the maximum concentration occurred at 3-7 days, with t1/2 ranged from 2.65 to 17.43 days. Four repeated dosing caused about 3-fold degree of accumulation for Cmax and AUC. Regardless of single or multiple doses, the exposure showed a nonlinear and greater than dose proportional increase. A two-compartment model taking into account the mechanistic target-mediated drug disposition process with parallel linear and nonlinear Michaelis-Menten (MM) elimination and first-order absorption well described the pharmacokinetics of TQH2722. In conclusion, TQH2722 was safe and well tolerated, and its PK profiles were well characterized, supporting its further clinical development in patients. (c) 2025 Published by Elsevier Inc. on behalf of American Pharmacists Association.

关键词： chicken   YF1∗7.1   immunity   MHC-Y   MHC   MDV   N-myristoylation   lipopeptides  

摘要： Major histocompatibility complex I (MHC-I) and MHC-Ilike molecules play a central role in mediating immunity. Through their conservation across all taxa of jawed vertebrates, the MHC-I-like proteins have adapted to present non-peptidic antigens to distinct T cell populations. While our understanding of the structure-function relationship of MHC-I and MHC-I-like molecules in humans and mice is well established, the nature of the antigens presented by MHC-I- like molecules in "non-model" species remains unclear. Here, using a mammalian recombinant expression system combined with mass spectrometry approaches, we identified N-myristoylated peptides as endogenous ligands for the chicken MHC-I-like protein YF1*7.1. Given the importance of N-myristoylation in viral pathogenesis, we determined the crystal structure of YF1*7.1 in complex with two N-myristoylated peptides derived from Marek's disease virus (MDV), demonstrating the molecular basis that underpins the presentation of N-myristoylated peptides from MDV, a highly contagious and fatal viral neoplastic disease in chickens. Thus, the identified ligands are distinct from unmodified peptides found in classical MHC-I and -II as well as diverse amphipathic lipids captured by CD1 proteins. Collectively, our study lays the foundation for further molecular and functional characterization of YF1*7.1 and more broadly of the role of the MHC-I encoded by the MHC-Y gene cluster in protection against highly contagious viral neoplastic diseases in chickens.

关键词： tumor necrosis factor inhibitors   pharmacokinetics   decision support systems   immunogenicity   therapeutic drug monitoring  

摘要： Background Proactive therapeutic drug monitoring facilitates early dose optimization to prevent primary and secondary failure to antitumor necrosis factor (TNF). We aimed to investigate the impact of dashboard-guided induction dosing strategy on anti-TNF durability and *** We conducted a single-center cohort analysis of patients with Crohn's disease (CD) and Ulcerative colitis (UC) who initiated treatment with infliximab or adalimumab between January 2020 and March 2023. Induction was prospectively personalized using a pharmacokinetic model-guided dosing strategy, with drug measurements at week 2, 6, and 14, and the first dose adjustment occurred in week 4. Data were recorded retrospectively. We assessed treatment durability, pharmacokinetic outcomes, clinical remission (CR), and endoscopic remission (ER), at both weeks 24 and 56. Multivariate analysis and Kaplan-Meier curves were used to compare *** We enrolled 147 patients (92 CD /55 UC). Anti-TNF drug survival probability was 85.00% after a year. Seventy-seven percent of patients were prescribed an intensified dose in the first year, which was associated with improved drug durability. Only 1 patient out of 147 developed antibodies to adalimumab, none to infliximab. After 24 and 52 weeks of treatment 92.5% (136/147) and 72.78% (107/147) of patients achieved CR, respectively. ER was observed in 59.39% (79/133) of patients. The use of immunomodulators or carriage of HLA DQA1*05 variant was not associated with adverse treatment or pharmacokinetic *** Optimizing anti-TNF induction with a dashboard-guide dosing strategy proves to be a valuable approach to enhance treatment durability and clinical outcomes in inflammatory bowel disease patients. Immunogenicity appears to be mitigated by the model, which even mitigates the impact of immunomodulators and overcomes HLA DQA1*05 effect. Proactive therapeutic drug monitoring improves anti-TNF survival, enhances drug durability,

关键词： HLA-DRB4*01:193   HLA   novel allele   sequencing-based typing  

摘要： HLA-DRB4*01:193 differs from HLA-DRB4*01:03:01:01 by one nucleotide substitution in codon 166 in exon 3.

关键词： Sepsis   IL-33   Myocardial injury   Inflammation   Oxidative stress   Apoptosis  

摘要： Septic myocardial injury, a severe sepsis complication linked to high morbidity and mortality, remains a major global clinical challenge. Interleukin-33 (IL-33), a damage-associated pro-inflammatory factor, has been implicated in regulating immune responses and inflammation, but its specific role in septic myocardial injury has not been fully elucidated. This study examined IL-33's role in septic myocardial injury using Gene Expression Omnibus (GEO) database datasets, alongside in vitro and in vivo experiments. Our results indicated a significant upregulation of IL-33 in septic myocardial injury, as demonstrated in both clinical and experimental settings. Blocking IL-33 significantly enhanced cardiac function and alleviated cardiomyocyte damage. Mechanistic investigations revealed that neutralizing IL-33 mitigates inflammation, oxidative stress, and apoptosis in cardiomyocytes by regulating the nuclear factor kappa B (NF-kappa B)/signal transducer and activator of transcription 3 (STAT3)/suppressors of cytokine signaling 3 (SOCS3) signaling pathway. Peritoneal macrophages are recognized as a potential origin of IL-33, and targeting IL-33 derived from these cells further reduced cardiomyocyte injury. The study underscores IL-33's crucial involvement in septic myocardial injury pathogenesis, indicating that IL-33 may serve as a promising therapeutic target.