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PubMed2026

TCGA-based identification of prognostic biomarkers and candidate traditional Chinese medicine compounds in papillary thyroid carcinoma: An observational study.

This study aimed to identify prognostic genes associated with papillary thyroid carcinoma (PTC) and explore candidate traditional Chinese medicine (TCM) compounds using integrated bioinformatics and molecular docking. In this observational study, PTC gene expression profiles and clinical data were obtained from The Cancer Genome Atlas. Differentially expressed genes were screened using differential-expression sequencing (DESeq2), followed by protein-protein interaction network analysis to identify hub genes. Their expression, diagnostic value, immune relevance, prognostic significance, protein-level validation, and single-cell distribution were assessed using gene expression profiling interactive analysis, receiver operating characteristic analysis, immune infiltration analysis, Kaplan-Meier survival analysis, the human protein atlas, and single-cell RNA-sequencing data. Candidate TCM compounds were predicted using symptom mapping (SymMap) and the TCM Systems Pharmacology Database and Analysis Platform, and molecular docking was performed to evaluate potential ligand-target interactions. Five hub genes, colony-stimulating factor 2, apolipoprotein E, fibronectin 1 (FN1), collagen type I alpha 1 chain (COL1A1), and intercellular adhesion molecule 1, were identified and found to be significantly upregulated in PTC tissues, with diagnostic value in receiver operating characteristic analysis. Immune infiltration analysis showed associations with macrophages, dendritic cells, and T helper 1 cells, whereas single-cell analysis demonstrated heterogeneous expression across immune and stromal cell populations, including fibroblasts. Higher FN1 and COL1A1 expression was associated with poorer outcomes. Immunohistochemistry supported the expression patterns, while single-cell analysis provided exploratory cell-type-level context for the cellular distribution of selected genes. Ginseng and Smilax glabra were predicted as common candidate TCMs, and docking suggested favorable binding between their active compounds and selected hub targets. Colony-stimulating factor 2, apolipoprotein E, FN1, COL1A1, and intercellular adhesion molecule 1 may be biologically relevant hub genes in PTC, while FN1 and COL1A1 may have prognostic value. Predicted TCM compounds provide preliminary computational evidence for possible compound-target interactions, requiring experimental and clinical validation.

Female↗

PubMed2026

Integrative pooled transcriptomic analysis reveals shared and distinct molecular signatures in adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphomas (PTCLs) are aggressive neoplasms of mature T cells with poor prognosis and limited therapies. ATLL originates from HTLV-1 infection, while PTCL comprises heterogeneous subtypes without a defined etiologic factor. Comparative molecular profiling of these malignancies remains limited. We conducted an integrative pooled transcriptomic analysis of publicly available Gene Expression Omnibus (GEO) microarray datasets to compare ATLL, PTCL, and normal T-cell samples. Differential expression, functional enrichment, and protein-protein interaction (PPI) network analyses were performed using STRING, Cytoscape, and Gephi. Key hub genes and functional modules were further analyzed through KEGG and Enrichr databases. Comparative analyses revealed upregulation of extracellular matrix (ECM) components (COL1A1, COL3A1, FN1, SPARC, THBS1) and immune-regulatory molecules (CD163, CXCL12-CXCR4, complement subunits). Shared pathways included ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling. PTCL showed enrichment in coagulation and angiogenesis, while ATLL displayed distinct enrichment of cytoskeletal, chemokine, immune-regulatory, and signaling-associated pathways. PPI networks identified ECM and chemokine signaling as key hubs, with subtype-specific modules related to immune regulation, proliferation, and metabolism. This integrative approach uncovers common and distinct oncogenic programs in ATLL and PTCL, emphasizing ECM remodeling and immune modulation as shared hallmarks. Hub genes such as COL1A1, FN1, and CXCL12-CXCR4 may represent candidate molecular signatures that warrant validation in independent patient cohorts and functional studies before their clinical utility can be established.

Humans↗

PubMed2025

Identification of pathogenic variants in six Chinese families with keratoconus of autosomal dominant inheritance: pathogenicity analysis and variable phenotype.

PURPOSE: Keratoconus (KC) is a bilateral, asymmetric disease causing corneal thinning, irregular astigmatism, and vision decline, with unclear etiology. This study aims to investigate pathogenic variants of candidate genes in Chinese KC families via whole exome sequencing (WES). METHODS: The Pentacam 3D anterior segment analysis system was applied for keratectasia detection, and the Corvis ST was used for corneal biomechanics measurement. Probands from KC families were screened via WES and further verified in other family members through Sanger sequencing. Additionally, qPCR was used to validate copy number variants and identify pathogenic gene loci. The identified variants were then classified according to the Standards and Guidelines for the Interpretation of Sequence Variants published by the American College of Medical Genetics and Genomics (ACMG). Finally, STRING protein-protein interaction (PPI) networks analysis was performed to investigate interactions among candidate gene-related proteins. RESULTS: Using WES, four heterozygous missense variants were detected in the ZNF469, KRT12, COL8A2, and COL18A1 genes: c.4384G > A: p.Asp1462Asn, c.1229T > G:p.Val410Gly, c.505A > G:p.Ile169Val, and c.1159G > A:p.Gly387Arg. Additionally, a heterozygous frameshift variant was detected in the PMS2 gene: c.1551_1572del:p.Ser517Argfs*71. The affected parents carried the same variants as the probands verified by Sanger sequencing. A copy number variant was detected in the DPP6 gene: seq[GRCh38] dup(7)(q36.2q36.2) chr7:g.153782360_ 153982491dup. According to ACMG guidelines, ZNF469, KRT12, COL8A2, and COL18A1 gene variants are Likely Pathogenic; PMS2 and DPP6 gene variants are Pathogenic. STRING analysis highlights a tightly interconnected network centered on COL8A2, involving COL18A1, FN1, ZNF469, and KRT12. DPP6 was involved in KC via affecting FN1. In four of six autosomal dominant KC (adKC) families, affected parents had the same variants as probands but milder phenotypes. CONCLUSION: In this study, six novel variants in ZNF469, KRT12, COL8A2, COL18A1, PMS2, and DPP6 were linked to adKC. Family phenotypes showed variable expressivity with irregular dominance inheritance. Abnormal KC-related gene protein expression may contribute to corneal structural instability. This study broadened KC genetic screening candidates and suggested genetic testing could aid early KC diagnosis and intervention.

Adult↗

PubMed2026

Biogenic Silver Nanoparticles from the Cell-Free Supernatant of Mychonastes sp. B1: Antibacterial and Antibiofilm Effects, and Wound Healing Activity Supported by Gene and Protein Expression Analysis.

The biogenic synthesis of silver nanoparticles (AgNPs) using microalgae provides a sustainable alternative to conventional physicochemical methods. In this study, AgNPs were synthesized from the cell-free supernatant of the freshwater microalga Mychonastes sp. B1 and characterized by ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), and field-emission scanning electron microscopy with energy-dispersive X-ray spectroscopy (FE-SEM/EDS). The nanoparticles were predominantly spherical (15-55 nm), highly stable (ζ =  - 42.8 mV), and appeared to be capped by extracellular polymeric substances. The biogenic AgNPs (GS-AgNPs) exhibited potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 2.0 µg/mL against Staphylococcus aureus and 2.5 µg/mL against Pseudomonas aeruginosa, and significantly (p < 0.05) inhibited biofilm formation. Fibroblast viability remained at or above 80% at AgNP concentrations up to 1.5 µg/mL, which promoted cell migration and increased wound closure by 8.1% at 24 h (p < 0.05). Exposure to 1.5 µg/mL AgNPs significantly upregulated extracellular matrix markers (Col1a1 2.3-fold, Fn1 3.3-fold at mRNA level; COL1A1 2.1-fold, FN1 2.7-fold at the protein level). These findings indicate that GS-AgNPs possess antimicrobial and wound healing properties, highlighting their potential as biocompatible nanomaterials for biomedical applications.

Silver↗

PubMed2026

A Molecularly Anchored Spatial Transcriptomic Framework for Precise CA1-Subiculum Parcellation and Region-Resolved Analysis in Alzheimer's Disease.

BACKGROUND: The precise molecular delineation of the interface between the Subiculum (Sub) and cornu ammonis 1 (CA1) is a challenge in hippocampal research, as conventional cytoarchitectural boundaries are often ambiguous and limit reproducible regional annotation. Here, we developed a molecularly anchored spatial transcriptomic framework to define CA1-Sub regional identities using high-definition spatial transcriptomics (Stereo-seq) and single-nucleus RNA sequencing (snRNA-seq) references. FINDINGS: Using a human hippocampal Stereo-seq dataset from 12 donors, we established a data-driven parcellation framework that defines reproducible molecular features distinguishing CA1 and Sub while capturing the transition between these regions. FN1 was identified as a Sub-enriched marker in a subset of EX_Sub and, together with ETV1 and additional regional markers, enabled molecular assignment of CA1 and Sub identities across datasets. The Sub association of FN1 and ETV1 was further supported by human 10X Genomics spatial transcriptomics, mouse in situ hybridization data, and a mouse spatial transcriptomic dataset. Applying this framework to Alzheimer's disease (AD) tissues revealed region-specific transcriptional alterations across CA1 and Sub, including enrichment of mitochondrial energy metabolism-related transcripts in the Sub, suggesting exploratory transcriptional associations of altered metabolic function. CONCLUSIONS: This study provides a molecularly anchored framework for human CA1-Sub parcellation that complements conventional annotation. By defining regional molecular states while preserving the biological continuum across CA1-Sub interface, this approach enables more consistent regional analysis of human hippocampus tissue across donors, datasets, and disease conditions.

Journal Article↗

PubMed2026

Coordinated inflammatory macrophage and vascular smooth muscle cell remodeling signatures in human atherosclerosis: An integrative single-cell and bulk transcriptomic analysis.

Atherosclerotic plaque progression is shaped by coordinated inflammatory and remodeling programs involving immune cells and vascular wall cells. Inflammatory macrophage activation and vascular smooth muscle cell (VSMC) phenotypic remodeling are central features of human atherosclerosis, but their transcriptomic relationships during plaque progression remain incompletely characterized. This study integrated single-cell and bulk transcriptomic datasets to examine highly inflammatory macrophage states, VSMC remodeling-related transcriptional programs, and candidate ligand-receptor expression patterns in human atherosclerotic plaques. Human atherosclerotic plaque single-cell RNA sequencing data from GSE260657 and bulk transcriptomic data from GSE28829 were analyzed. After quality control, 7628 cells were retained for single-cell analysis. Major cell types were annotated using canonical markers, followed by reclustering of macrophages and VSMC-related cells. Functional module scoring, differential expression analysis, Gene Ontology biological process enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to characterize macrophage transcriptional states. Slingshot was applied to infer VSMC pseudotime ordering. CellChat and NicheNet were used to prioritize candidate ligand-receptor expression patterns and ligand-associated VSMC target gene programs. External bulk transcriptomic analysis was performed to examine whether single-cell-derived inflammatory and remodeling signatures were represented at the tissue-transcriptome level during plaque progression. Macrophage reclustering identified a highly inflammatory macrophage state characterized by prominent inflammatory activation, cytokine-response, and stress-response features. Genes upregulated in this population were enriched in pathways related to tumor necrosis factor (TNF) response, nuclear factor kappa B signaling, leukocyte activation, cytokine signaling, lipid and atherosclerosis, toll-like receptor signaling, and inflammasome-associated inflammation. VSMC reclustering revealed contractile VSMCs, PTHLH+ synthetic VSMCs, KRT7+ VSMC-like cells, interferon-responsive VSMCs, pericyte-like mural cells, and osteogenic/modulated VSMCs. Pseudotime analysis showed a broad contractile-to-osteogenic/modulated transcriptional continuum accompanied by increased expression of remodeling-associated genes and selected inflammatory or remodeling-associated receptor genes. CellChat and NicheNet analyses prioritized candidate ligand-receptor and ligand-associated target gene expression patterns involving SPP1-CD44, TNF-TNFRSF1A, IL1B-IL1R1/IL1RAP, MIF-ACKR3, PDGFB-PDGFRB, and FN1-SDC1/ITGB1. In GSE28829, inflammatory macrophage-, osteogenic/modulated VSMC-, candidate ligand-receptor expression-, SPP1-CD44 candidate axis-, and NicheNet-prioritized target program-related signatures were more prominent in advanced plaques and were positively correlated with each other. This integrative transcriptomic analysis identified a highly inflammatory macrophage state and a VSMC remodeling continuum in human atherosclerotic plaques. Candidate ligand-receptor and ligand-associated target gene expression patterns linked inflammatory macrophage activation with osteogenic/modulated VSMC remodeling at the computational level. External bulk data further showed coordinated enrichment of inflammatory and remodeling signatures in advanced plaques. These findings provide a descriptive and hypothesis-generating transcriptomic framework for understanding inflammatory macrophage activation and VSMC remodeling in human atherosclerosis.

atherosclerosis↗

PubMed2026

Unravelling the biological nexus of smoking and postpartum depression: a meta-analysis and functional genomics approach.

PURPOSE: Postpartum depression (PPD) is a prevalent psychological condition among birthing women. While several psycho-socio-economic and neurobiological factors influence its development, its relationship with smoking behavior and nicotine addiction remains largely inconclusive. METHODS: In this combinatorial study, we first evaluate the relationship between smoking and depressive behaviors in postpartum women using data extracted from pertinent primary epidemiological studies. Additionally, to discern the molecular and cellular mechanisms underlying this association, we identified common genetic elements and evaluated their functional attributes using in silico analyses. RESULTS: Meta-analytical assessment of systematically collected data from 38 studies indicated that smoking women are twice as likely to develop PPD, compared to their non-smoking counterparts. While geocultural attributes did not affect this relationship, timing of smoking was a significant moderator, with current and gestational smoking statuses being more strongly linked with PPD outcome, compared to the past smoking habit. Further, depression scores in smoking postpartum women were higher than those in non-smoking controls. Analysis of the common protein-encoding genes underlying the pathophysiology of nicotine addiction and PPD revealed several critical hub proteins (viz., AKT1, JUN, CTNNB1, PTEN, EGFR, ESR1, SRC, STAT3, FN1, IL1B, IL6, TNF, TP53, GAPDH, INS, MYC, and ALB) which were predicted to alter multiple pathophysiological pathways associated with transcriptional expression, intra- and intercellular signaling transduction, metabolism, and immune functions. CONCLUSION: Our results indicate that smoking is strongly associated with depressive behavior in postpartum women, although this association involve mediation of additional environmental and psychosocial elements. Moreover, network analysis of common genetic elements identified several potentially disrupted neurophysiological pathways in postpartum women with smoking and depressive behaviors which may aid in characterizing the underlying relationship between the two conditions.

Humans↗

PubMed2024

High yield of monogenic short stature in children from Kurdistan, Iraq: A genetic testing algorithm for consanguineous families.

PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.

Humans↗

PubMed2026

Mapping articular cartilage maturation across postnatal development by proteomics.

OBJECTIVE: Articular cartilage has a specialised extracellular matrix that provides tensile strength and resistance to compression, but repair capacity is limited. Matrix remodelling during growth is essential for long-term tissue function, yet the underlying protein-level adaptations remain poorly characterised in large-animal models relevant to human joint biology. DESIGN: Using non-targeted, label-free mass spectrometry-based proteomics, we profiled full-thickness articular cartilage from goats across seven postnatal ages from neonatal to adult (n = 3 per age). Cartilage proteins were extracted using guanidine-based solubilisation and analysed by mass spectrometry. Selected proteins were further examined by immunohistochemistry. RESULTS: We identified 799 proteins across the seven ages, of which 157 matrisome components grouped into six categories. Development was associated with increased abundance of proteins involved in matrix organisation and stabilisation, including COL6A1, LOX, TIMP3 and CILP. Enrichment analysis revealed a shift from collagen biosynthesis and fibrillogenesis in early postnatal cartilage to elastic fibre organisation, integrin-matrix interactions and glycosaminoglycan metabolism in mature tissue, consistent with transition from matrix assembly to maintenance. Lysozyme increased with age, suggesting a structural role that warrants further study. Several proteins enriched in mature cartilage, including CILP, HTRA1, FN1 and SPP1, have also been implicated in osteoarthritis, suggesting that some molecular features of mature ECM maintenance are shared with diseased tissue. Immunohistochemistry confirmed stable COL2 localisation, loss of deep-zone COL10 staining with maturation and emergence of superficial PRG4 expression in adult cartilage. CONCLUSIONS: Our findings define the proteomic trajectory of cartilage maturation and provide a molecular reference for joint development and matrix ageing.

Animals↗

PubMed2025

Polygenic enrichment analysis in multi-omics levels identifies cell/tissue specific associations with schizophrenia based on single-cell RNA sequencing data.

OBJECTIVE: Understanding the specific cellular origin and tissue heterogeneity in schizophrenia is critically important for exploring the disease etiology. This study aims to investigate these aspects by performing multiple analyses based on omics data. METHOD: We performed single-cell disease relevance score (scDRS) algorithm to link brain single-cell RNA sequencing (scRNA-seq) with schizophrenia risk across multi-omics scales at single-cell resolution. This approach identified cell types with overexpression of schizophrenia-related genes implicated by multi-omics panels (ATAC-seq, RNA-seq, TWAS, and GWAS). Schizophrenia-related genes from these multi-omics panels were extracted and combined with scRNA-seq data to calculate scDRS. Subsequently, the cell-type vs. disease association and tissue heterogeneity were assessed using scDRS for each omics panel. RESULTS: We identified two novel cell subpopulations in the brain that differentially express SCUBE3 (59 cells, 7.0 %) and FN1 (21 cells, 2.5 %). At the individual cell level, schizophrenia-associated cell subpopulations included microglial cell associated with ATAC-seq panel (Passociation = 0.002, Pheterogeneity = 0.009) and deep layer neuron suggestively associated with GWAS panel (Passociation = 0.033, Pheterogeneity = 0.017). At the brain tissue level, microglial cell was significantly associated with cortical plate in ATAC-seq panel (Passociation = 0.002, Pheterogeneity = 0.011). Gene level analysis identified several genes associated with schizophrenia across multi-omics panels. CONCLUSIONS: Our study outlines the signature of cell subpopulations, brain regions, and disease risk genes in schizophrenia at single-cell resolution across multi-omics scales. These findings provide a reference for future precision medicine approaches targeting specific cell types and brain regions in schizophrenia.

Schizophrenia↗

PubMed2026

CRISPR activation reveals SOX5/6/9 as key transcriptional regulators directing iPSC-derived cells toward a notochordal lineage.

Intervertebral disc (IVD) degeneration, a leading cause of chronic lower back pain, is associated with loss of vacuolated notochordal cells (NCs) and fibrotic remodeling of the nucleus pulposus. Emerging therapies increasingly focus on NCs, which are rare but therapeutically relevant cells for regenerating degenerated IVDs. In this study, we used CRISPR-based transactivation (CRISPRa) to direct the differentiation of human induced pluripotent stem cells (iPSCs) into the NC lineage. We tested CRISPRa-mediated activation of NOTO, TBXT, FOXA2, SOX5, SOX6, and SOX9, coupled with single-cell sequencing of Aggrecan-2A-mScarlet reporter iPSCs. This approach identified the SOX5/6/9 combination (SOX-trio) as critical for promoting NC lineage commitment. The SOX-trio yielded the largest cell population expressing a range of genes previously associated with NC identity, including SHH, FOXA1, FOXA2, FOXJ1, FN1, ALCAM, KRT8, and KRT18. Our study demonstrates the integration of CRISPRa with single-cell technologies as a powerful platform for investigating and enriching iPSC-derived NCs, supporting future regenerative strategies across various fields.

Humans↗

PubMed2026

Thyroid-stimulating hormone receptor mediates peripheral-central neuroimmune crosstalk in autoimmune thyroid diseases.

BACKGROUND: Organ-specific autoimmune diseases, particularly Graves' disease (GD) and its extrathyroidal manifestation, Graves' orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum. METHODS: Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein-protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region. RESULTS: Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell-cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand-receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds - venetoclax, irinotecan, and dutasteride - with predicted favorable docking scores and stable binding poses in our simulations. CONCLUSIONS: These findings demonstrate that TSHR acts as a molecular hub mediating peripheral-central neuroimmune crosstalk in GD and GO. The results support a broader "disease-molecule axis" framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Receptors, Thyrotropin↗

PubMed2026

Single-cell profiling reveals a novel CAF subpopulation linking stromal heterogeneity to immune suppression in breast cancer subtypes.

BACKGROUND: The tumor microenvironment critically influences breast cancer (BC) progression, immune surveillance, and therapeutic response. Cancer-associated fibroblasts (CAFs), a heterogeneous stromal population, are key regulators of these processes, yet their subtype-specific contributions in BC remain insufficiently defined. METHODS: We integrated three single-cell RNA sequencing datasets from 29 BC patients to characterize stromal populations. Bulk RNA-seq data from The Cancer Genome Atlas (TCGA) were analyzed to assess correlations between CAF subsets and immune infiltration. Gene signatures were derived to identify subtype-specific CAF-immune interactions, prognostic markers, and potential predictors of chemotherapy response. RESULTS: Three conserved stromal populations (iCAFs, myCAFs, and pericytes) were identified, along with a previously unrecognized subset, the cluster 3 (CL3) CAF-like cells, referred as metabolic stressed CAF (msCAF). msCAF cells displayed transcriptional programs associated with antigen presentation, stress response, glycolysis, and extracellular matrix remodeling. Their abundance was inversely correlated with T-cell infiltration and function, in a subtype-specific manner: triple negative breast cancer (TNBC) was enriched for msCAFs in immune-infiltrated but functionally constrained microenvironments, whereas Luminal A tumors exhibited weaker immune infiltration with heterogeneous CAF-immune associations. msCAFs were characterized by a conserved gene signature (HLA-A, HLA-C, IL32, EMP3) and subtype-specific genes related to T-cell exhaustion. Several genes demonstrated prognostic relevance with distinct patterns in Luminal A (IER3, TIMP1, TBX3, SEC61G) and TNBC (ADM, C4orf3, LDHA) tumors, as well as shared biomarkers (FN1, LOXL2, P4HA1). Multiple msCAF genes also predicted chemotherapy response, suggesting utility as treatment stratification biomarkers. CONCLUSION: msCAFs represent a clinically relevant CAF subset that drives immune suppression, impacts subtype-specific prognosis, and influences therapy response in BC. These findings highlight msCAFs as promising targets for enhancing immunotherapy and personalizing treatment strategies.

Humans↗

PubMed2026

An Update on Selected Giant Cell-Rich Tumors of Soft Tissue.

Giant cell-rich tumors of soft tissue present a significant diagnostic challenge due to pronounced morphological overlap, particularly in limited tissue samples. This review provides a streamlined update on the clinicopathological and molecular features of nine distinct entities: nodular fasciitis, juvenile xanthogranuloma, phosphaturic mesenchymal tumor, tenosynovial giant cell tumor, giant cell fibroblastoma, giant cell-rich solitary fibrous tumor, giant cell tumor of soft tissue, keratin-positive giant cell-rich tumor, and undifferentiated pleomorphic sarcoma. While these neoplasms are unified by a prominence of multinucleated giant cells, recent genomic insights have identified signature, diagnostically defining molecular drivers. We highlight characteristic gene fusions, including USP6, NTRK1, FN1, CSF1, COL1A1-PDGFB, NAB2-STAT6, and HMGA2-NCOR2, as well as entities characterized by non-recurrent or highly complex genomic alterations. Synthesizing these data, this review underscores the critical role of advanced molecular testing in resolving diagnostic ambiguities, refining tumor classification, and guiding targeted therapeutic strategies.

Humans↗

PubMed2026

A Functionally Constrained Immune Ecosystem in Microsatellite-stable Colorectal Cancer Resolved by Single-cell and Exome Profiling.

BACKGROUND/AIM: Microsatellite-stable (MSS) colorectal cancer (CRC) generally responds poorly to immune checkpoint blockade, but some MSS tumors are T-cell rich. We examined whether such infiltration reflected effective immunity or functional immune constraint. CASE REPORT: A 77-year-old woman underwent resection of a mismatch repair-proficient (pMMR), MSS, low-mutational-burden CRC with a synchronous adenoma. Whole-exome sequencing of tumor, adenoma and adjacent normal tissue detected no shared high-confidence somatic mutations between tumor and adenoma within the sensitivity of this WES analysis and identified tumor-specific APC, KRAS and TP53 alterations. Tumor single-cell RNA sequencing yielded 7,569 cells, with T-lineage populations comprising 83.5%. Cytotoxic T cells showed cytolytic and dysfunction-associated features, regulatory T cells (Tregs) showed suppressive remodeling, and Th17 cells showed inflammatory/profibrotic programs. CellChat nominated stromal MIF/FN1-CD74/CD44 and extracellular-matrix communication with T-cell compartments. CONCLUSION: This molecular case report shows that T-cell abundance and immune effectiveness can be uncoupled in MSS CRC.

Humans↗