anakinra (PerkinRA)

[Progress in the application of anakinra in pediatric autoinflammatory diseases].

Weng R H RH, Yang J J, He T Y TY

ASXL1- Mutant Clonal Hematopoiesis is Associated with Calcific Aortic Valve Disease and Promotes Valvular Calcification In Vitro.

Small Aeron M AM, Xue Liying L, Itoh Shinsuke S, De Jeronimo Diaz Cesar C et al.

Calcific aortic valve disease (CAVD) is a common valvular heart condition and has no effective medical therapy. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the acquisition of somatic mutations in hematopoietic stem cells which provides a selection advantage, has been associated with incident aortic stenosis (AS), particularly when driven by TET2 mutations. We evaluated the association of CHIP and gene-specific CHIP subtypes with AS in the UK Biobank (UKB) and with aortic valve hemodynamics in the Atherosclerosis Risk in Communities (ARIC) study to prioritize gene driver mutations for mechanistic study. We then generated human ASXL1 -mutant THP-1 derived macrophage like cells and evaluated the ability of THP-1 conditioned media to promote a calcific response in human valvular interstitial cells (VICs). We additionally performed mass spectrometry proteomics to characterize the ASXL1- mutant THP-1 macrophage secretome. Therapeutically relevant inflammatory pathways were inhibited with anakinra (interleukin [IL]-1) or tocilizumab (IL-6). Among 449,109 individuals in the UKB with whole exome sequencing, large CHIP clones and non- DNMT3A CHIP subtypes (e.g., TET2 , ASXL1 , and JAK2 CHIP) were independently associated with risk of incident AS. Among 1,963 individuals in ARIC with CHIP sequencing and echocardiographic data, only ASXL1 CHIP was associated with worse aortic valve hemodynamics. In vitro, ASXL1 -mutant human THP-1-derived macrophage-like cells had increased AIM2 inflammasome activation. THP-1 media promoted VIC calcification, which was accelerated in ASXL1 mutant macrophages. Proteomic profiling identified inflammatory proteins linked to valvular calcification. Accelerated VIC calcification was reduced by IL-1 inhibition by anakinra or IL-6 inhibition by tocilizumab. Integrating human cohort data with experimental evidence using ASXL1 -mutant human macrophage-like cells and human valve cells, these findings identify ASXL1 -mutant CHIP as a distinct inflammatory subtype associated with valvular calcification and support IL-1 and IL-6 signaling as candidate therapeutic pathways for future investigation in CAVD.

Exact Formula of the Total Quasi-Steady State Approximation in Competitive Target-Mediated Drug Disposition.

Kim Taehong T, Cha Jaeyun J, Jeon Hyeseon H, Yun Hwi-Yeol HY et al.

Competitive target-mediated drug disposition (competitive TMDD) arises when 2 drugs compete for the same target receptor. The full competitive TMDD model characterizes these dynamics; yet, its complexity motivated the use of a reduced model, which is invalid under high receptor concentrations. While this problem can be resolved by using the total quasi-steady state approximation, which remains valid for broad parameter regimes, the exact formula of the total quasi-steady state approximation-based reduced model-competitive qTMDD-remained unknown for 15 years, as it requires solving a cubic equation and identifying a biologically meaningful solution. Consequently, researchers have relied on computationally expensive numerical approximations, limiting practical applicability. Here, we derive-for the first time-a real-valued exact formula for competitive qTMDD by leveraging analytic properties of cubic equations and geometric characteristics of their roots in the complex plane. This formulation improved computational speed by approximately 18-fold compared to numerical approximation methods, enabling competitive qTMDD-based Bayesian inference that was previously impractical. Applied to clinical trial data for anakinra and rhIL-7-hyFc, competitive qTMDD estimated pharmacological parameters comparable to those from the full competitive TMDD model while requiring only approximately 28% of the computation time. Importantly, it maintains robust accuracy even at low sampling density, whereas previous reduced models exhibit bias. By ensuring precise biological interpretation of drug systems even in complex real-world scenarios, the exact formula of competitive qTMDD has the potential to streamline the drug development and clinical testing process. Our exact formula also consists entirely of real-valued terms, allowing seamless integration into existing pharmacometrics software.

Cardio-oncology-relevant programmes in the cervical cancer tumour microenvironment: an exploratory multi-omics and endothelial-cell study.

Cai Rongrong R, Shen Suqin S, Gu Chunyan C

Bevacizumab and immune-checkpoint inhibitors (ICIs) improve outcomes in advanced cervical cancer but may cause cardiovascular toxicity (CVT). Public cervical-cancer transcriptomic datasets do not contain cardiac tissue or adjudicated CVT outcomes; consequently, tumour-microenvironment (TME) expression cannot by itself establish a cardiac susceptibility mechanism. We reanalysed the available data to ask the narrower question of whether cervical tissues contain angiogenic, endothelial, inflammatory, T-cell-exhaustion, and TGF-β/fibrotic programmes that are biologically relevant to cardio-oncology. All nine single-cell RNA-sequencing specimens in GSE208653 were analysed: two HPV-negative healthy cervix, two HPV-positive histologically normal cervix, two high-grade squamous intraepithelial lesions, two squamous-cell carcinomas, and one adenocarcinoma. After prespecified quality control, 74,457 cells were integrated with Harmony and annotated into broad lineages. Prespecified module scores and four ligand-receptor expression-product scores were aggregated by biological specimen; malignant versus non-malignant differences were evaluated with exact specimen-label permutation tests and Benjamini-Hochberg correction. Four GSE208654 Visium count matrices were analysed descriptively at spot level. Coexpression among the five programmes was assessed in 304 TCGA-CESC primary tumours. qRT-PCR summary data from HUVEC (ATCC PCS-100-010) and primary human aortic endothelial cells (HAEC; ATCC PCS-100-011) were reinterpreted as endothelial pharmacology, not cardiac validation. The scRNA-seq atlas contained 32 clusters spanning epithelial, immune, endothelial, and stromal lineages. None of the five specimen-level programmes differed significantly between malignant and non-malignant specimens after multiple-testing correction (all q ≥ 0.119). Likewise, none of the VEGFA-KDR, IL1B-IL1R1, TGFB1-TGFBR2, or LGALS9-HAVCR2 expression-product scores was significant (all q ≥ 0.143). The four spatial specimens showed heterogeneous spot-level expression but, with one specimen per histology and no slide coordinates in the supplied matrices, did not support group-level spatial inference. TCGA tumours showed coordinated intratumoural expression, strongest between angiogenesis and TGF-β/fibrosis (Spearman ρ=0.707; q = 2.24 × 10⁻46), but TCGA-CESC contained no CVT endpoint. VEGFA increased KDR, ICAM1, VCAM1, and EDN1 mRNA in HUVEC, and bevacizumab attenuated these changes; IL-1β induced inflammatory transcripts in HAEC, and anakinra attenuated IL6, TNF, and CXCL8. Cervical tissues contain cardio-oncology-relevant transcriptional programmes, but the available data neither demonstrate cardiac expression nor identify bevacizumab- or ICI-induced CVT susceptibility. The endothelial experiments show expected pathway responsiveness and pharmacological blockade, not treatment-induced cardiotoxicity. Prospective analyses must compare CVT-positive and CVT-negative treated patients using matched clinical outcomes and, ideally, blood or cardiac-relevant biospecimens.