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PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗

PubMed2026

Stage-specific ROMO1 in rheumatoid arthritis: predictive immune insights into the MIF pathway and HLA-DR/IL2RA axis via integrated GWAS, transcriptomic, single-cell, and spatial profiling.

Emerging evidence links reactive oxygen species modulator 1 (ROMO1), a key mitochondrial ROS regulator, to rheumatoid arthritis (RA) pathogenesis. However, its exact mechanism remains elusive given the conflicting evidence about its specific function. We used a four-level integrative framework combining multi-omics data and literature‑supported mechanistic inference. At the genetic level, Mendelian randomization (MR) was performed to explore potential causal relationships between ROMO1, IL2RA, HLA-DR, MIF, and RA risk, followed by differential expression analysis and machine learning-based feature selection to identify key mROS genes. The temporal expression dynamics of ROMO1 were assessed in RA progression. At the cellular and tissue levels, we integrated single-cell RNA sequencing and spatial transcriptomics to map cell-type-specific expression and synovial localization of ROMO1-related immune cells and pathways. Finally, our multi-omics findings were contextualized with literature-supported mechanistic inference. (1) MR results were consistent with a potential protective effect of ROMO1 on RA (OR = 0.52) and its potential regulation of risk factors IL2RA (OR = 0.46) and HLA-DR (OR = 0.40). Conversely, IL2RA (OR = 1.42), HLA-DR (OR = 1.88), and MIF (OR = 1.17) were positively associated with RA risk. Additionally, ROMO1 was identified as a top candidate diagnostic predictor with stage-specific dynamics: downregulated in the early but upregulated in the late/remission stages. (2) Single-cell RNA sequencing showed ROMO1's cell-specific expression in CD14+ HLA-DR+ CD74+ monocytes and CD4+ IL2RA+ T cells. Cell communication analysis further suggested that these cells may participate in MIF pathway regulation. Spatial transcriptomics subsequently identified that ROMO1-related cells localized to synovial pathological regions, with MIF pathway changes correlated with RA progression. (3) Finally, literature-supported mechanistic inference suggests that ROMO1 may modulate mROS levels to promote anti-inflammatory M2 macrophage polarization, which could theoretically contribute to reduced systemic inflammation and the alleviation of multi-organ decline in RA. This integrated multi-omics investigation, supported by literature-based mechanistic inference, suggests ROMO1 as a stage-dependent biomarker candidate and potential immune regulator in RA.

Humans↗

PubMed2026

Effects of Acute Low- and Moderate-Dose Alcohol on Chronic Disease-Related Biomarkers in Healthy Light and Heavy Drinkers.

BACKGROUND: Alcohol consumption is a major contributor to global chronic disease, with growing evidence indicating health risks even at low levels of intake. However, mechanistic understanding of these risks relies heavily on preclinical models and observational data, leaving a critical gap in controlled experimental evidence regarding how alcohol perturbs human biological systems in vivo. METHODS: The present study utilized plasma samples from a randomized, placebo-controlled trial to evaluate the effects of low-dose (0.35 g/kg) and moderate-dose (0.60 g/kg) alcohol on disease-relevant biomarkers in 32 healthy adults (mean age = 25.0 ± 3.8 years; 21 female/11 male), characterized by light (n = 15) or heavy (n = 17) drinking. This design enabled evaluation of effects across dose, timescale, and drinking history, as well as assessment of their interactions. Plasma was collected at prebeverage baseline and hourly for 4 h afterward. Immunoassays quantified 10 disease-related biomarkers: adiponectin, angiogenin, D-dimer, high-sensitivity C-reactive protein (hsCRP), Intercellular Adhesion Molecule-1 (ICAM-1), Lipocalin-2 (LCN2), Matrix Metalloproteinase-7 (MMP-7), Matrix Metalloproteinase-9 (MMP-9), soluble Receptor for Advanced Glycation End-products (sRAGE), and Triggering Receptor Expressed on Myeloid cells 2 (TREM2). RESULTS: Main effects of group indicated that even in this young healthy sample, heavy drinking status was associated with higher levels of adiponectin, angiogenin, ICAM-1, LCN2, and sRAGE, a profile suggesting altered vascular and metabolic activity. Acute alcohol administration induced changes in sRAGE and hsCRP. Specifically, moderate-dose alcohol triggered an increase in the immunoglobulin sRAGE, which may reflect an acute compensatory response to inflammation and/or oxidative stress. Compared to placebo, hsCRP was lower in the low-dose alcohol condition; however, this finding should be interpreted in light of CRP biology. MMP-7, MMP-9, and LCN2 showed time-dependent fluctuations that were independent of experimental condition, highlighting the critical importance of placebo-controlled designs to account for diurnal/postprandial variation in immune biomarkers. CONCLUSION: Findings provide translational evidence that alcohol is associated with multisystem biomarker changes relevant to chronic disease and that alcohol-related biomarker perturbations vary by dose and chronicity.

Humans↗

PubMed2026

Generation of spCAS9 expressing human mesenchymal stem cell line to study gene function during osteoblast differentiation.

Human bone marrow-derived stromal cells (hMSCs) are a great resource for studying how genes influence cell fate and differentiation into various cell types like osteoblasts, adipocytes, and chondrocytes, among other cell types. However, genetic manipulation of primary hMSCs has been challenging due to their short lifespan and cellular senescence after limited passaging. Their low and unstable transfection efficiency also complicates gene delivery or inactivation, hindering long-term functional studies. The limited lifespan has been effectively solved by immortalizing hMSCs with telomerase reverse transcriptase (hMSCs-TERT). The use of these cells is ideal for functional studies of osteoblast and adipocyte differentiation through genetic manipulation, providing a stable and reliable model. Here, we have engineered a stable CAS9 expressing hMSC-TERT cell line (hMSC-TERTCAS9) via lentiviral transduction. The constitutive expression of spCas9 enables efficient and reproducible gene editing. We demonstrate the potential of these hMSC-TERTCAS9 cells for generating gene disruptions using plasmid delivery of guide RNAs as a fast and efficient strategy for targeted genome editing. The edited cells can be sorted and expanded as single cells to obtain homogenous clonal cell lines with mono- as well as bi-allelic gene deletions, a crucial step for producing reliable experimental results. We further validate this cell line as a powerful tool for studying gene function during hMSC proliferation and differentiation, providing 3 distinct examples of its utility. Through the generation of indels, single-cell sorting, and clonal selection, we have efficiently inactivated the vitamin D receptor and created both larger (256 nucleotides) gene disruptions in Forkhead box protein O1 and precise removals of a small genomic sequence (73 nucleotides) coding for microRNA MIR675. This novel hMSC-TERTCAS9 cell line represents a significant advancement, offering a stable, efficient, and versatile platform for advanced genetic studies, high-throughput screening, and the creation of reliable cellular disease models.

CRISPR-Cas9↗

PubMed2026

Effects of semaglutide and empagliflozin on markers of endothelial function in persons with type 2 diabetes: A post hoc analysis of a randomized clinical trial.

AIMS: The endothelium maintains vascular health by regulating blood flow and protecting against inflammatory damage. In type 2 diabetes (T2DM), however, hyperglycemia, hypertension, and hyperlipidemia place a significant burden on the endothelium, potentially leading to atherosclerosis and cardiovascular disease (CVD). While semaglutide and empagliflozin have been shown to reduce CVD risk in T2DM, it remains unclear whether these benefits are mediated by improved endothelial function. This post-hoc analysis explores the effects of these agents on markers of endothelial function, i.e. the reactive hyperaemic index (RHI) and the endothelial-derived cell adhesion molecules (CAMs) E-Selectin, ICAM-1, P-Selectin, and VCAM-1. METHODS: This was a post-hoc analysis of a 32-week randomized trial evaluating the separate and combined effects of semaglutide and empagliflozin on cardio-renal organ damage. One hundred and twenty participants with type 2 diabetes, age ≥ 50 were randomized to four groups (semaglutide, empagliflozin, the combination or placebo). An increase in RHI and/or a decrease in CAMs were considered beneficial. RESULTS: RHI increased compared to baseline (0.11, 95%CI [0.008;0.21], p = 0.03) but not compared to placebo in the semaglutide group (0.11, 95%CI [-0.04;0.24], p = 0.16). There was no effect on RHI in the empagliflozin group. Compared to placebo, E-Selectin decreased significantly in the semaglutide and combination groups (-9, 95%CI [-14.1;-5.1] p < 0.01 and - 9, 95%CI [-14.3; -5.2] p < 0.01, respectively). VCAM-1 increased in the same groups, compared to placebo (12.3, 95%CI[2.8;20.8] p = 0.01 and 16.2, 95%CI [7.2;24.3], p < 0.01, respectively).P-Selectin and ICAM-1 was not significantly affected in any of the groups, compared to placebo (p ≥ 0.11 and p ≥ 0.09, respectively). CONCLUSION: Semaglutide improved endothelial function compared to baseline, but not significantly versus placebo, which likely is due to limited power. CAM responses were heterogeneous, suggesting distinct roles in endothelial dysfunction and atherosclerosis. ClinicalTrialsRegister.eu: EudraCT 2019-000781-38.

Aged↗

PubMed2026

Phase 3 Trial of Oral Infigratinib in Children with Achondroplasia.

BACKGROUND: Achondroplasia is a genetic skeletal condition caused by FGFR3 pathogenic variants. Infigratinib, an oral FGFR1-3 tyrosine kinase inhibitor, down-regulates key pathways in the pathogenesis of achondroplasia. METHODS: In this phase 3, multicenter, double-blind, placebo-controlled trial, we randomly assigned children with achondroplasia (3 to 17 years of age) in a 2:1 ratio to receive infigratinib (at a dose of 0.25 mg per kilogram of body weight) or placebo once daily for 52 weeks. The primary end point was the change from baseline in the annualized height velocity in the infigratinib group as compared with the placebo group at week 52. Key secondary end points were the change from baseline in the height z score and in the upper-to-lower body segment ratio at week 52. The primary analysis evaluated the treatment effect at week 52 in the full analysis population, with missing data handled with a prespecified imputation approach. RESULTS: In all, 114 patients underwent randomization: 75 patients to receive infigratinib (with 1 withdrawal before treatment) and 39 patients to receive placebo. The difference between infigratinib and placebo in the least-squares mean change from baseline to week 52 was 1.74 cm per year (95% confidence interval [CI], 1.31 to 2.17; P<0.001) for the annualized height velocity, 0.32 (96% CI, 0.23 to 0.41; P<0.001) for the height z score, and -0.02 (96% CI, -0.06 to 0.01) for the upper-to-lower body segment ratio. Adverse events occurred in 71 of 74 patients (96%) in the infigratinib group and in 37 of 39 patients (95%) in the placebo group; serious adverse events occurred in 4 of 74 patients (5%) and 1 of 39 patients (3%), respectively. No serious adverse events or adverse events leading to treatment discontinuation were considered by the investigator to be related to infigratinib or placebo. CONCLUSIONS: In children with achondroplasia, treatment with once-daily oral infigratinib for 52 weeks resulted in a significantly greater increase from baseline in the annualized height velocity than placebo. (Funded by BridgeBio Pharma; PROPEL 3 ClinicalTrials.gov number, NCT06164951; EudraCT number, 2023-506130-67.).

Adolescent↗

PubMed2026

Liver transcriptome analysis revealed multiple immune processes and lipid metabolism pathways involved in the defense response of the turbot (Scophthalmus maximus) against Aeromonas salmonicida.

Aeromonas salmonicida is a significant pathogen causing notable economic losses in Scophthalmus maximus aquaculture. This study utilized Illumina sequencing technology to examine the transcriptional response characteristics of S. maximus liver at 24 h following A. salmonicida infection. A total of 2363 differentially expressed genes (DEGs) were identified when compared to the negative control group. The immunity-related Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, as well as metabolism-related PPAR signaling pathway and insulin signaling pathway, were notably enriched. Significant differences exist in the expression of key genes within the PPAR pathway, particularly cd36, acsl4a, pparαa, and plin2, all of which mediate the interaction between lipid metabolism and the immune response. These results offer valuable insights into the immunometabolic regulatory mechanism of S. maximus response to A. salmonicida infection.

Animals↗

PubMed2026

Aflibercept With Versus Without Reduced-Fluence Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: Optical Coherence Tomography Angiographic Changes From a Randomized Clinical Trial.

OBJECTIVES: To report the longitudinal optical coherence tomography angiography (OCTA) changes in polypoidal choroidal vasculopathy (PCV) treated with intravitreal aflibercept monotherapy or in combination with reduced-fluence PDT. DESIGN: Image analysis of a double-masked, sham-controlled, randomized clinical trial. SUBJECTS: 55 eyes of 55 treatment-naïve participants with symptomatic macular PCV completing 52 weeks of follow-up. METHODS: Participants underwent protocolized, multimodal imaging, including OCT, OCTA, fluorescein angiography, and indocyanine green angiography at baseline, week 12, and week 52. Quantitative OCTA parameters included total lesion area, branching neovascular network (BNN) area, and BNN vessel density (VD). Qualitative features included trunk vessel presence and OCTA signal within the polypoidal lesion (PL). Eyes were categorized by treatment arm and PL closure at week 52. MAIN OUTCOME MEASURES: Longitudinal OCTA changes and predictors of PL closure at week 52. RESULTS: We included 55 eyes (28 combination therapy and 27 monotherapy). Total lesion area decreased at week 12 but returned toward baseline at week 52 (combination: 3.72 ± 3.01mm2 at baseline, 2.86 ± 2.50mm2 at week 12, 3.59 ± 3.26mm2 at week 52; monotherapy: 3.77 ± 2.23mm2 at baseline, 3.27 ± 2.36mm2 at week 12, and 3.47 ± 2.58mm2 at week 52). BNN area decreased at week 12 and remained reduced at week 52 in both treatment arms (combination: 2.29 ± 2.08 mm2 at baseline, 1.46 ± 1.36mm2 at week 12, and 1.53 ± 1.32mm2 at week 52; monotherapy: 2.39 ± 1.85mm2 at baseline, 1.87 ± 1.68mm2 at week 12, and 1.82 ± 1.38mm2 at week 52). BNN VD reduction was greater in the combination arm at week 12 (-10 ± 15% vs - 3 ± 12%, P = .02). The proportion of eyes with trunk vessels increased over time in both arms (combination: 35.7% at baseline, 59.3% at week 12, and 67.8% at week 52; monotherapy: 25.9% at baseline, 44.4% at week 12, and 71.4% at week 52). In multivariable analysis, baseline BCVA predicted BCVA change at week 52 (β=-0.96 [-1.21 to -0.72], P < .01), and baseline CST predicted CST change (β=0.93 [0.75 to 1.10], P < .01). Greater reduction in BNN VD at week 12 was independently associated with PL closure at week 52 (OR 0.62 [0.39 to 0.97], P = .03). CONCLUSIONS: Early reduction in BNN vessel density, rather than reduction in lesion size, was associated with subsequent PL closure. OCTA-derived vascular changes may serve as noninvasive biomarkers for predicting treatment response in PCV.

Humans↗

PubMed2026

Effect of semaglutide on kidney outcomes in the SELECT, FLOW, and SOUL trials: a prespecified pooled analysis.

BACKGROUND: The GLP-1 receptor agonist semaglutide reduces clinically important kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD). We aimed to assess the pooled effects of semaglutide on kidney outcomes in prespecified analyses of participant-level data from the diverse populations of the SELECT, FLOW, and SOUL randomised placebo-controlled trials. METHODS: Participants with CKD (FLOW) or atherosclerotic cardiovascular disease (SELECT and SOUL) were randomly assigned semaglutide (once-weekly subcutaneous 1·0 mg [FLOW], once-weekly subcutaneous 2·4 mg [SELECT], or once-daily oral 14 mg [SOUL]) or matching placebo, added to standard of care. The primary outcome in this pooled analysis was time to first occurrence of a kidney composite, defined as onset of persistent 50% or greater reduction in estimated glomerular filtration rate (eGFR), kidney failure (persistent eGFR <15 mL/min per 1·73 m2, or initiation of kidney replacement therapy), kidney-related death, or cardiovascular-related death. Safety was also assessed. FINDINGS: The pooled participants from the trials (N=30 787) had a mean follow-up of 39·5-47·5 months. Among participants assigned to semaglutide, 973 first events of the primary kidney composite occurred compared with 1134 first events for placebo (hazard ratio [HR] 0·84 [95% CI 0·77-0·91]). First events of a narrower secondary kidney composite (excluding cardiovascular-related death from the primary outcome) were also reduced with semaglutide versus placebo (347 and 416, respectively; 0·80 [0·69-0·92]). Safety outcomes were overall similar between groups, and in line with other GLP-1 receptor agonist trials. Serious adverse events were numberically lower with semaglutide than with placebo. INTERPRETATION: Data pooled from three large phase 3 trials suggest that semaglutide reduces the risk of major kidney outcomes in a broad population with cardio-kidney-metabolic disease while having a favourable risk-benefit profile. In people with cardio-kidney-metabolic disease, with and without diabetes, semaglutide (oral or injected) prevents kidney-related and cardiovascular complications and induces adverse events in line with GLP-1 receptor agonist studies, regardless of baseline characteristics within the cardio-kidney-metabolic spectrum. This was a participant-level analysis conducted in a large database of three randomised controlled trials of similar design and examining the same treatment, but there were some differences in participants' baseline characteristics, and in the dose and route of administration of treatment. This pooled analysis adds evidence for the benefit of GLP-1 receptor agonists in general, and semaglutide in particular, in a broad population of people with cardio-kidney-metabolic disease, suggesting that the benefit of semaglutide might not be explained only by its glycaemic effects, weight-management effects, or both. FUNDING: Novo Nordisk.

Humans↗

PubMed2026

Signal recognition particle 14 binds to importin α in Plasmodium falciparum.

BACKGROUND: The eukaryotic signal recognition particle (SRP) consists of six proteins and one SRP RNA. This ribonucleoprotein complex assembles inside the nucleus. Nucleocytoplasmic transport is an essential process for the biogenesis of signal recognition particles (SRPs) as well as for the survival of a cell. There are studies on cells that indicate the import receptor is responsible for import of SRP proteins into nucleus, but there is a lack of evidence that SRP proteins directly bind with import receptors. METHODS AND RESULTS: Coding sequences of SRP 14 and importin α were amplified from synthesized cDNA and genomic DNA, respectively, of Plasmodium falciparum cultivated in vitro culture. The amplified products were cloned and expressed in E. coli, followed by purification. A binding study was conducted on glutathione-agarose as well as in a 96-well plate format at different concentrations of SRP 14 with immobilized importin α. CONCLUSION: This is the first report of direct binding between importin α and a eukaryotic signal recognition particle 14 (SRP 14). A cost-effective 96-well plate-based assay has also been developed to study the binding of cargoes of importin α.

Plasmodium falciparum↗

PubMed2026

Integrative machine learning and transcriptomic analysis reveals molecular mechanisms underlying low survival rate in larval Chinese Bahaba (Bahaba taipingensis).

Chinese Bahaba (Bahaba taipingensis) is a Class I protected marine fish endemic to China. Low larvae survival during artificial breeding severely hinder population recovery. To investigate the molecular mechanism of high mortality in larval fish, this study performed RNA-seq on liver from naturally deceased (ND) and mass-dead (MD) individuals, combined with least absolute shrinkage and selection operator (LASSO) regression and random forest (RF) algorithms to screen for core signature genes. A total of 873 differentially expressed genes (DEGs) were identified, including 112 upregulated and 761 downregulated genes. GO and KEGG enrichment analyses revealed significant enrichment in amino acid metabolism disorders, one‑carbon folate pool impairment, PPAR signaling abnormalities, ECM-receptor interaction, focal adhesion pathway, indicating widespread metabolic suppression accompanied by extracellular matrix remodeling and signaling disturbances in the livers of MD fish. MAD pre-filtering combined with dual machine learning algorithms yielded 18 robust core signature genes, among which SLC38A4, MMP1, FADD, FKBP5, and APOB were consistently identified as high-frequency core genes by both algorithms. SLC38A4 exhibited the highest importance score in the RF model and was significantly downregulated, making it the primary molecule distinguishing ND from MD phenotypes. ROC curve analysis showed that both models achieved an AUC of 1.000 (95% CI lower bound: 0.610), confirming the precise discriminatory ability of the core genes. GSEA further demonstrated significant enrichment of this core gene set in ND samples. This study provides the first systematic elucidation of the molecular mechanisms underlying liver dysfunction in low survival rate B. taipingensis, characterized by amino acid transport impairment, metabolic reprogramming, and structural remodeling, offering theoretical foundations for health assessment, early mortality risk warning, and artificial breeding conservation of this species.

Animals↗

PubMed2026

Does high fructose consumption trigger microglia activation and neuroinflammation? A systematic review.

This systematic review evaluated the effects of fructose intake on neuroinflammatory markers in rodent models. The search terms Fructose AND neuroinflammation OR Neurodegeneration OR chemokines OR interleukins OR microglia OR behaviour OR memory OR cognition were used in Google Scholar, Scopus and Web of Science. Thirteen animal studies investigating fructose-induced neuroinflammation that matched the eligibility criteria were included in the study. Across the studies, 16 inflammatory markers were identified and significantly altered following exposure to fructose. The findings consistently demonstrated elevated expression of pro-inflammatory cytokines, TNF-α, IL-6, and IL-1β, following fructose administration. Fructose consumption also dysregulated MCP-1, fractalkine, and CX3CR1 levels, thereby promoting inflammatory signalling and microglial activation. Furthermore, fructose exposure significantly increased IBA-1 and CD11b, indicating sustained neuroimmune activation. Alterations in important inflammatory pathways involving TLR4, NLRP3, NF-κB, MyD88, iNOS, and cyclooxygenases (COX-1 and COX-2) were also observed. In contrast, expression of the anti-inflammatory regulator peroxisome proliferator-activated receptor gamma (PPARγ) was reduced after fructose treatment. Overall, the findings suggest that chronic fructose consumption induces neuroinflammation through multiple inflammatory and immune-related mechanisms in the brain. These effects appear to be dose- and duration-dependent and may contribute significantly to neurodegeneration and cognitive impairment.

Microglia↗

PubMed2026

Comparative Transcriptomics Reveals Shared Downstream Pathways in Craniofacial Pathology.

Treacher Collins syndrome and Nager syndrome are craniofacial developmental disorders caused by defects in ribosome biogenesis and RNA splicing, respectively, yet they exhibit overlapping abnormalities affecting neural crest cell-derived craniofacial structures. To investigate shared downstream pathogenic mechanisms, we performed a comparative transcriptomic analysis of zebrafish polr1c and sf3b4 mutant models from our previous studies. Comparative analysis identified 17 shared differentially expressed genes (DEGs) between polr1c and sf3b4 mutants, with the majority of shared genes dysregulated in the same direction, indicating a coordinated rather than random transcriptional response. Gene ontology analysis identified ATP-dependent protein folding chaperone activity as the only shared molecular function, driven in part by upregulation of hsp90aa1.2, indicating a common proteostasis response. Because chaperone activity is linked to extracellular matrix (ECM) protein processing, we cross-referenced DEGs from both mutants against the curated zebrafish matrisome. Three of the 17 shared DEGs (serpinh1b, il11a, and lepa) were matrisome-associated and upregulated in both mutants. Serpinh1b, a collagen-specific chaperone, was strongly expressed in craniofacial cartilage and mesenchymal populations during pharyngeal arch development and exhibited nearly identical fold changes in both mutants. Il11a is of particular interest because its receptor, IL11RA, is known to be associated with human craniosynostosis, suggesting potential relevance to craniofacial development. Together, it is possible to hypothesize that shared chaperone-associated transcriptional changes, together with altered ECM-related gene expression, may contribute to polr1c- and sf3b4-associated craniofacial disorders, warranting further functional validation.

Extracellular Matrix↗

PubMed2026

Decoding tumor immune microenvironment heterogeneity by single-cell and spatial multi-omics: From immunotherapy resistance to translational biomarkers.

Immune checkpoint blockade has transformed cancer therapy, yet primary and acquired resistance remain major clinical challenges. Increasing evidence indicates that immunotherapy resistance cannot be fully explained by tumor-intrinsic alterations or conventional biomarkers such as PD-L1 expression, tumor mutational burden, or microsatellite instability. Instead, therapeutic response is shaped by the tumor immune microenvironment (TIME) as a heterogeneous, spatially organized, and dynamically evolving ecosystem. Single-cell omics has revealed diverse immune and stromal cell states, including progenitor and terminally exhausted T cells, suppressive myeloid programs, B-cell/TLS-associated immune-reactive states, and CAF-mediated exclusion phenotypes. Spatial transcriptomics, spatial proteomics, and imaging-based approaches further demonstrate that these cell states assemble into distinct immune niches, including immune-inflamed, T-cell-excluded, myeloid-suppressive, metabolic/hypoxic, and TLS-associated niches. These spatial ecosystems determine whether antitumor immune cells can access malignant cells, receive antigen-presenting support, or become restrained by stromal, vascular, metabolic, and myeloid barriers. In this review, we summarize how single-cell and spatial multi-omics redefine TIME heterogeneity in immunotherapy resistance, highlight ligand-receptor communication networks linking cell states to spatial immune dysfunction, and discuss emerging translational biomarkers for patient stratification. We further propose that future immunotherapy biomarkers should evolve from static single-marker assays toward longitudinal, spatially resolved, and interpretable multi-omics models that guide precision combination immunotherapy.

Humans↗

PubMed2026

Adjuvant CDK4/6 inhibitors in early-stage breast cancer: Clinical evidence and considerations for risk stratification and treatment selection.

Hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer is the most common biologic subtype and carries a persistent risk of recurrence, particularly in patients with high-risk, early-stage disease. Cyclin-dependent kinase 4 and 6 inhibitors, initially established as a standard component of first-line therapy in the metastatic setting based on improvements in progression-free and overall survival, have since been evaluated in the adjuvant setting. While adjuvant palbociclib did not improve invasive disease-free survival, the monarchE and NATALEE trials demonstrated that abemaciclib and ribociclib, respectively, reduce recurrence risk in patients with high-risk, early-stage disease, with emerging overall survival data further supporting their use. However, the absolute magnitude of benefit varies substantially with baseline risk, and treatment-related toxicity and adherence challenges must be considered, as approximately 20% to 25% of patients discontinue therapy before completion. The integration of these agents into clinical practice also intersects with ongoing efforts to deescalate axillary surgery, as treatment eligibility has been largely defined by anatomic staging, particularly nodal status. Available data suggest that the incremental impact of axillary surgery on identifying candidates for cyclin-dependent kinase 4 and 6 inhibition is modest, especially among the favorable-risk populations now eligible for surgical deescalation. As the field evolves, advances in molecular risk stratification, genomic profiling, and dynamic biomarkers are poised to shift treatment selection from anatomic staging toward biologically driven approaches. Multidisciplinary decision-making that integrates tumor biology, anticipated absolute benefit, toxicity, patient preferences, and surgical considerations will be essential to ensure individualized care.

Humans↗

PubMed2026

Molecular characterization and biological characteristics of a highly pathogenic recombinant ALV-J strain (HUE2023) with cross-clade gp85 recombination.

Avian leukosis virus subgroup J (ALV-J) has undergone extensive diversification into phylogenetically distinct clades, yet whether recombination between these clades within the gp85 envelope glycoprotein generates variants with altered pathogenicity has received little direct investigation. A field strain (HUE2023) was recovered from breeding roosters displaying vascular tumors. The viral genome was sequenced and subjected to phylogenetic and recombination analyses. The three-dimensional structure of gp85 was predicted with AlphaFold3; electrostatic surface potentials and surface hydrophobicity were computed using the Adaptive Poisson-Boltzmann Solver and the Eisenberg hydrophobicity scale, respectively. Pathogenicity and immunosuppressive effects were assessed in Hy-Line Brown chickens. Recombination analysis revealed that HUE2023 is an inter-clade recombinant derived from Clade 1.1 (major parent: JS14NT01) and Clade 1.2 (minor parent: JS09GY3). A single-residue deletion at position 61 within receptor-binding domain 1 (RBD-1), unique to the recombinant, induced a localized conformational rearrangement that generated a concentrated electronegative surface patch and a contiguous hydrophobic pocket not observed in either parental gp85. Animal challenge showed that HUE2023 is highly pathogenic: female chickens in the high-dose group reached only 61% survival and displayed significant growth retardation (P < 0.05) together with marked immunosuppression. The recombination in the RBD-1 led to local conformational rearrangement, resulting in a concentrated and negatively charged surface area as well as a continuous hydrophobic pocket, which were never present in any of the parental gp85 sequences. These results indicate that gp85 recombination across clades can yield variants with fundamentally altered receptor-binding surfaces and argue for integrating structural surveillance into ALV-J monitoring programmes.

Animals↗

PubMed2026

Role of omentin-1 in the global proteome of porcine pituitary cells: insights into proliferation- and apoptosis-related processes.

The anterior pituitary integrates endocrine regulation, cellular growth, and adaptive responses. Adipokines, secreted mainly by adipose tissue, act as hormonal signals linking metabolism, inflammation, appetite, and reproduction. They regulate hypothalamic-pituitary-ovarian axis by modulating hormone secretion and intracellular signaling. The presence of adipokine receptors in anterior pituitary suggests local metabolic-endocrine interactions. Omentin-1, predominantly expressed in visceral adipose tissue, participates in glucose metabolism and ovarian steroid regulation. Recent findings indicate that omentin-1 modulates tropic hormones, their receptors, and adipokine balance in anterior pituitary cells. We hypothesized that omentin-1 affects protein expression and signaling pathways involved in pituitary cell proliferation and apoptosis. This study examined its effects in anterior pituitary cells from Large White and Meishan pigs. Proteomic analysis identified 230 candidate differentially abundant proteins after omentin-1 treatment: 30 downregulated and 3 upregulated in Large White pigs, and 107 downregulated and 90 upregulated in Meishan pigs, associated with enriched 116 Gene Ontology terms. Key proteins were associated with cell cycle, DNA replication, gene expression, and posttranscriptional/posttranslational regulation. Responses differed between breeds. CDK5RAP2 and SIX1 were linked to proliferative control in Large White pigs, whereas AKT1S1 and RHOA were among the proteins associated with the broader proteomic response observed in Meishan pigs. Meishan pigs showed dynamic apoptotic protein regulation, including HTRA2, PARP2, and DFFA. Complementary in vitro experiments demonstrated that omentin-1 downregulated cyclins and caspase-3, upregulated BCL2, increased BCL2/BAX ratio, and modulated ERK1/2, AKT, AMPKα, and STAT3 phosphorylation. Together, these findings suggest that omentin-1 modulates proteomic networks and intracellular signaling associated with anterior pituitary cell function during the mid-luteal phase of the estrous cycle.

Animals↗

PubMed2026

Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS: From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION: Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING: Summit Therapeutics.

Humans↗