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PubMed2025

Notch pathway defines an aggressive and immune-suppressive phenotype associated with checkpoint inhibitor resistance in pan-gastrointestinal adenocarcinomas.

The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-β, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P < 0.001) and three validation sets (GSE19417, P = 0.025; GSE84437, P = 0.001, GSE40967, P = 0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P = 0.047; PRJEB25780, P = 0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.

Humans↗

PubMed2026

The DLX/Notch axis is necessary for spatiotemporal regulation of neural cell fate.

Neuronal-glial cell fate switch during forebrain development is highly regulated. DLX transcription factors are necessary for promoting GABAergic interneuron differentiation and migration but the mechanisms for concomitant repression of glial fate in neural progenitors remain elusive. Here, the DLX2 regulatory network dynamic in the developing ventral telencephalon is characterised using a multi-omic approach at single-cell resolution, including single-cell whole genome spatial transcriptomics. We identify a secondary proliferative zone in the ventral subventricular zone and spatiotemporal-context dependent Notch pathway repression by DLX2 in maintaining progenitor populations and facilitating neural differentiation. We find that DLX2 controls cell fate determination by directly repressing Notch signalling genes as well as glial fate-promoting transcription factors, thereby inhibiting early adoption of oligodendroglial differentiation during neurogenesis. Here, we show that temporal cell fate switch is mediated by DLX2 via a multilayer gene regulatory network, redefining current understanding of neuronal-glial cell specification mechanisms in the developing telencephalon.

Animals↗

PubMed2025

Genetic insight into lung neuroendocrine tumors: Notch and Wnt signaling pathways as potential targets.

BACKGROUND: The molecular landscape of lung neuroendocrine neoplasms is still poorly characterized, making it difficult to develop a molecular classification and personalized therapeutic approaches. Significant clinical heterogeneity of these malignancies has been highlighted among poorly differentiated histotypes and within the subgroup of well-differentiated neuroendocrine tumors (NET). Currently, the main prognostic factors of lung NET include stage, histotype, grade, peripheral location, and demographic parameters. To gain deeper insights into the genomic underpinnings of lung NETs, we conducted a pilot investigation to uncover potential genetic mutations and copy number variations (CNVs) implicated in their pathogenesis. METHODS: Formalin-fixed, paraffin-embedded intraoperative tumor biopsies and matched peripheral blood mononuclear cell samples were collected from six consecutive patients with lung NETs. The whole exome sequencing (WES) was performed to profile germline and somatic mutations, identify novel genetic alterations, and detect CNVs. Clinical and pathological data were systematically documented at diagnosis and during follow-up. RESULTS: The WES analysis identified a subset of mutations shared between germline and somatic; some were of particular clinical interest as they were associated with tumor proliferation and potential therapeutic targets such as the genes KDM5C, ATR, COL7A1, NOTCH4, PTPRS, SMO, SPEN, SPTA1, TAF1. These mutations were predominantly linked to chromatin remodeling and were involved in critical oncogenic pathways such as Notch and Wnt signaling. CONCLUSIONS: This pilot study highlights the potential role of NGS analysis on solid biopsy in the assessment of the mutational profile of lung NET. A comparison of germline and somatic mutations is critical to identifying putative tumor driver mutations. In perspective, the enrichment of a subpopulation of cancer cells in the blood, with one or more specific mutations, is information of enormous clinical relevance, either for prognosis or therapeutic decisions. Translational studies on large prospective series are required to establish the role of liquid biopsy in lung NET.

Humans↗

PubMed2021

RNA-seq Analysis of Peri-Implant Tissue Shows Differences in Immune, Notch, Wnt, and Angiogenesis Pathways in Aged Versus Young Mice.

The number of total joint replacements (TJRs) in the United States is increasing annually. Cementless implants are intended to improve upon traditional cemented implants by allowing bone growth directly on the surface to improve implant longevity. One major complication of TJR is implant loosening, which is related to deficient osseointegration in cementless TJRs. Although poor osseointegration in aged patients is typically attributed to decreased basal bone mass, little is known about the molecular pathways that compromise the growth of bone onto porous titanium implants. To identify the pathways important for osseointegration that are compromised by aging, we developed an approach for transcriptomic profiling of peri-implant tissue in young and aged mice using our murine model of osseointegration. Based on previous findings of changes of bone quality associated with aging, we hypothesized that aged mice have impaired activation of bone anabolic pathways at the bone-implant interface. We found that pathways most significantly downregulated in aged mice relative to young mice are related to angiogenic, Notch, and Wnt signaling. Downregulation of these pathways is associated with markedly increased expression of inflammatory and immune genes at the bone-implant interface in aged mice. These results identify osseointegration pathways affected by aging and suggest that an increased inflammatory response in aged mice may compromise peri-implant bone healing. Targeting the Notch and Wnt pathways, promoting angiogenesis, or modulating the immune response at the peri-implant site may enhance osseointegration and improve the outcome of joint replacement in older patients. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

AGING↗

PubMed2025

Cetobacterium somerae ZNN-1 promotes goblet cell differentiation through glutamine-mediated Notch signaling suppression.

INTRODUCTION: The gut microbiota acts as a crucial mediator in the interaction between the diet components and the host metabolism. However, the molecular mechanism by which the gut microbiota adapts to dietary components and subsequently regulates host physiological responses remains unclear. OBJECTIVES: This study aimed to investigate the response of gut microbiota to a plant-based protein diet (soybean meal, SM) and the effects of gut microbiota on host intestinal barrier function, along with the underlying mechanisms in a fish model. METHODS: Histopathological examination, and transepithelial electrical resistance test were used to evaluate the effects of Cetobacterium somerae on intestinal barrier function. Potential molecular mechanisms were validated by integrating whole-genome sequencing, microbiota composition sequencing, transcriptomics, and metabolomics, and utilizing in vitro cell models and mouse-derived organoid models. RESULTS: The results revealed that the SM diet significantly increased the abundance of Cetobacterium somerae in fish. Administration of C.somerae ZNN-1, a dominant strain isolated from the intestine of fish fed with the SM diet, enhanced the intestinal barrier function, particularly increasing the number of goblet cells in the intestine. Whole genome analysis of C. somerae ZNN-1 showed carbohydrate metabolism-associated genes were the most abundant in its metabolic modules. C.somerae ZNN-1 supplementation significantly inhibited the Notch signaling pathway in fish intestine. Metabolomics analysis revealed that administration of C.somerae ZNN-1 increased the glutamine level in fish gut. In vitro experiments demonstrated that glutamine regulated the differentiation of goblet cell by inhibiting the Notch signaling pathway in both human intestinal epithelial cell model and mouse intestinal organoid model. CONCLUSION: C. somerae served as a key bacterium adapted to soybean meal-derived carbohydrates, and it promoted goblet cell differentiation by inhibiting the Notch pathway. This study provides a new perspective for unraveling the interaction mechanisms among diet components, intestinal microbiota and host health.

Animals↗

PubMed2026

Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by pruritic skin nodules of unknown etiology. Little is known about genetic changes in PN pathogenesis, particularly somatic events, which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 patients with PN and 10 patients with atopic dermatitis (AD) for comparison. Somatic mutational analysis revealed that PN lesional skin harbors recurrent somatic mutations in fibrotic, neurotropic, and cancer-associated genes that are absent in adjacent PN nonlesional skin. Nonsynonymous mutations were most frequently present in NOTCH1 and the Notch signaling pathway, a key regulator of cellular proliferation and tissue fibrosis. In contrast, NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, identified recurrently deleted and downregulated genes in PN lesional skin, which are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, a multicenter analysis revealed increased risk of NOTCH1-associated diseases in patients with PN. In characterizing the somatic landscape of PN, this study highlights the potential role of Notch pathway dysregulation in PN pathogenesis and fibrosis.

Humans↗

PubMed1986

Local function of the Notch gene for embryonic ectodermal pathway choice in Drosophila.

Mutations at the Notch locus affect the fate of cells in the neurogenic region of the Drosophila embryo so that epidermal precursors become neuroblasts. We have analyzed the cellular requirements for wild-type Notch gene function by means of genetic mosaics, using a cuticle marker to distinguish hypodermal cell genotype. Cells that were genotypically Notch never gave rise to hypoderm within the neurogenic region of mosaic embryos. Mosaic dividing lines within the neurogenic region juxtapose N+ hypoderm with regions of neural hypertrophy. This autonomous action of Notch in hypodermal cells is consistent with a local function of the protein during neurogenesis. Comparison of clone distribution in Notch mosaics and controls suggests that islands of wild-type hypodermal cells fail to differentiate cuticle.

Animals↗

PubMed2025

Multi-context modeling of driver pathways reveals common and specific mechanisms across 23 cancer types.

Discovery of cancer driver pathways is essential for targeted therapies, since these pathways govern tumor progression and treatment resistance. However, their context-specific patterns across populations remain poorly understood. Leveraging pan-cancer genomic data, we apply our two models, EntCDP and ModSDP, to perform stratified analyses from four perspectives: region, tumor type, age group, and risk factors. Our results reveal the regional biases in perturbed pathways, such as PI3K-Akt in Chinese patients and GPCR in American patients with bladder cancer. Subtype comparisons highlight the mTOR signaling in lung adenocarcinoma and the FoxO signaling in lung squamous cell carcinoma. Pediatric-adult comparisons emphasize the enrichment of Ras signaling in pediatric acute myeloid leukemia and PAK signaling in pediatric glioblastoma, respectively. Risk factor associations further link Notch-mediated pathways to alcohol consumption and CDKN-regulated pathways to obesity-related cancers. Our findings demonstrate the utility of stratified driver pathway analysis in uncovering common and specific mechanisms, which can help prioritize context-aware therapeutic targets.

Humans↗

PubMed2025

A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1.

BACKGROUND: NOTCH1 is associated with two disorders of vascular development, Adams-Oliver Syndrome 5 (AOS5) and aortic valve disease 1 (AOVD1). Here we report a disease-causing variant in NOTCH1 that has a previously undemonstrated effect on splicing. Additionally, we found that the proband has the optic phenotype of familial exudative vitreoretinopathy (FEVR) which has been reported for probands with pathogenic variants in genes in the notch signaling pathway, but never for NOTCH1. CASE PRESENTATION: The proband presented with a ventricular septal defect, pulmonic stenosis, and ocular findings consistent with familial exudative vitreoretinopathy (FEVR), which NOTCH1 has not been associated with to date. Trio exome sequencing identified a paternally inherited variant of uncertain significance in NOTCH1:c.2153 A > G. We assessed the variant's effect using RT-PCR, finding an increased use of a cryptic donor compared to the control. On this basis, we were able to re-classify this variant as pathogenic. CONCLUSIONS: We expand the phenotypic spectrum of NOTCH1 and contribute to the building evidence that variants in NOTCH1 cause a spectrum of disorders of vascular development.

Humans↗

PubMed2026

Integrated Genome-Wide Association Studies and Selection Signature Analysis Reveal the Genetic Architecture of the Wattle Trait in Goats.

Wattles are finger-like appendages on the ventral neck of goats, serving as a distinctive morphological marker for breed identification that serves potential implications for production performance. However, their genetic basis remains incompletely characterized. Here, we integrated a genome-wide association study (GWAS) and selection signature analysis to identify candidate genes and genomic regions associated with the wattle trait in goats. Using a linear mixed model, GWAS on 463 goats (23 wattled and 440 non-wattled) identified 385 quantitative trait loci (QTLs) at a 5% false discovery rate, yielding 346 candidate genes. The most significant association signal was observed on chromosome 10 (72.61-73.48 Mb), where the lead SNP (rs636481767) is located within a region containing GJD2, GREM1, and FMN1, showing strong linkage disequilibrium (r2 > 0.6) with surrounding loci. Subsequent selection signature analysis (23 wattled and 23 non-wattled) identified 83 genomic regions harboring 119 candidate genes. The strongest signals were detected at MFSD14B on chromosome 8 (FST = 0.154, log2π-ratio = 2.611) and PDLIM7 on chromosome 7 (FST = 0.144, log2π-ratio = 0.806). KEGG pathway enrichment analysis revealed that GWAS-associated genes were involved in glycosylation and immune responses, whereas selection-signature genes were enriched in DNA repair and the Hippo, Notch, and Wnt pathways. Furthermore, cross-species PheWAS revealed that human FMN1 is associated with dermatological, skeletal, and metabolic phenotypes, while porcine FMN1 is associated with backfat thickness and loin muscle depth. Overall, this study provides molecular markers of potential value for goat breeding and pinpoints key candidate genes for future functional validation of wattle development.

Animals↗

PubMed1992

A genetic analysis of deltex and its interaction with the Notch locus in Drosophila melanogaster.

During Drosophila development networks of genes control the developmental pathways that specify cell fates. The Notch gene is a well characterized member of some cell fate pathways, and several other genes belonging to these same pathways have been identified because they share a neurogenic null phenotype with Notch. However, it is unlikely that the neurogenic genes represent all of the genes in these pathways. The goal of this research was to use a genetic approach to identify and characterize one of the other genes that acts with Notch to specify cell fate. Mutant alleles of genes in the same pathway should have phenotypes similar to Notch alleles and should show phenotypic interactions with Notch alleles. With this approach we identified the deltex gene as a potential cell fate gene. An extensive phenotypic characterization of loss-of-function deltex phenotypes showed abnormalities (such as thick wing veins, double bristles and extra cone cells) that suggest that deltex is involved in cell fate decision processes. Phenotypic interactions between deltex and Notch as seen in double mutants showed that Notch and deltex do not code for duplicate functions and that the two genes function together in many different developing tissues. The results of these investigations lead to the conclusion that the deltex gene functions with the Notch gene in one or more developmental pathways to specify cell fate.

Animals↗

PubMed2026

Multidimensional Proteomics Reveals the Pro-apoptotic Mechanism of Platycodin D: Targeting RFC4 to Regulate the Notch Signaling Axis in Non-Small Cell Lung Cancer.

Platycodin D (PD), a major bioactive saponin isolated from the traditional Chinese medicine Platycodon grandiflorus, has shown promising therapeutic potential against non-small cell lung cancer (NSCLC). However, the functional mechanisms of PD in NSCLC progression remains unclear. This study aimed to explore the pharmacological mechanism of PD against NSCLC. Thermal proteome profiling approach, molecular docking, cellular thermal shift assay and peptide-centric local stability assay were employed to identify the potential binding target of PD. Subsequent Western Blot and immunoprecipitation-Western Blot experiments were conducted to investigate the downstream signaling pathways of the target. Furthermore, proteomic and ubiquitinomic profiling of PD-treated cells were performed to investigate its functions on global. replication factor C subunit 4 (RFC4) was identified as a potential binding target of PD by thermal proteome profiling and their binding sites were further exposed by peptide-centric local stability assay. PD-RFC4 complex promotes the degradation of Notch1 and Notch3 by reducing nuclear entry of their domains. Compared with control treatment, the differentially expressed proteins induced by PD were found to be primarily involved in ferroptosis, ubiquitination, platinum drug resistance, and ribosome-related processes. The ubiquitin proteome analysis revealed that proteins associated with the Notch pathway underwent ubiquitin modifications. PD binds to RFC4 and inhibits its activity, leading to downregulation of the Notch signaling pathway, ultimately triggering cancer cell apoptosis. PD is a natural product with potential therapeutic value for NSCLC.

Saponins↗

PubMed2026

The genomic landscape of HER2 negative metastatic breast cancer with loss of estrogen and progesterone receptors.

INTRODUCTION: Loss of estrogen receptor (ER) and/or progesterone receptor (PR) might occur during the metastatic progression of ER positive and HER2 negative (ER+/HER2-) breast cancer (BC), but the underpinning molecular alterations remain elusive. We explored the genomic context of HER2- tumors with ER and/or PR loss to investigate potential drivers and actionable alterations that might help personalize treatment of ER+/HER2- BC. METHODS: We accessed data from metastatic HER2- BC included in the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/-, n = 66) to those maintaining ER positivity (ER+/+, n = 364) or ER negativity (ER-/-, n = 50). We also compared metastatic ER+/+ BC with loss of PR (PR+/-, n = 111) to those maintaining PR positivity (PR+/+, n = 192) or PR negativity (PR-/-, n = 41). RESULTS: In line with previous reports, ER+/- BC was associated with aggressive clinico-pathological characteristics and poor outcome. ER+/- BC showed significantly higher frequency of TP53 and RB1 mutations and lower frequency of PIK3CA and GATA3 mutations compared to ER+/+. ER+/- or PR+/- status was mutually exclusive with ESR1 mutations and was associated with a significantly higher tumor mutational burden. Moreover, ER+/- BC were enriched in driver alterations in the genes of the Notch and Retinoblastoma pathways and showed a significantly lower frequency of level 1 actionable alterations according to OncoKB. CONCLUSIONS: Loss of ER and/or PR may identify a distinct evolutionary trajectory of ER+/HER2- metastatic progression, largely non-overlapping with ESR1-mutant endocrine resistance. Further studies on matched primary and metastatic samples are warranted.

Humans↗

PubMed1992

Delta, notch, and shaggy: elements of a lateral signaling pathway in Drosophila.

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Animals↗

PubMed2025

Clinicopathologic and Genomic Characterization of SMARCA4-Deficient Carcinoma of the Gallbladder.

As a key subunit of the SWItch/sucrose nonfermentable chromatin-remodeling complex, SMARCA4 plays a critical role as a tumor suppressor in various tumors. However, the clinicopathological and molecular features of SMARCA4-deficient carcinoma of the gallbladder (SMARCA4-dGBC) have not been well explored. In this study, a retrospective cohort of 926 nonsquamous cell gallbladder carcinomas (GBCs) was analyzed on tissue microarrays using immunohistochemistry for SMARCA4, comprising 813 adenocarcinomas, 53 adenosquamous carcinomas, 43 undifferentiated carcinomas, 7 sarcomatoid carcinomas, 6 small cell neuroendocrine carcinomas, and 4 large cell neuroendocrine carcinomas. Twenty-six (2.8%) SMARCA4-dGBCs were identified and further analyzed using immunohistochemistry, whole-exome sequencing, and clinicopathological data. SMARCA4-dGBCs are frequently identified in advanced stages and exhibit diverse patterns of differentiation. The majority were identified as monotonous diffuse sheets, nests, and cords, whereas a subset exhibited gland-forming and rhabdoid morphologies (11.5%). Tumors retained mismatch repair proficiency (100%) but showed variable HER2 expression (11.5% scored as 2+/3+) and limited PD-L1 positivity. Genomic profiling revealed SMARCA4 alterations in 88.5% (23/26) of patients, predominantly deletions (91.3%) and truncating mutations-p.K892∗ and p.R979∗-that disrupt the critical ATPase/helicase domains. Co-occurring TP53 mutations (56.5%) highlighted the presence of synergistic chromatin-remodeling defects. Enrichment of oncogenic signaling pathways, including the RTK-RAS (78.3%), TP53 (60.9%), NOTCH (47.8%), and HIPPO (39.1%) pathways, was observed. Patients with SMARCA4-dGBC exhibited significantly shorter progression-free survival (median, 6 vs 14 months) and overall survival (median, 11 vs 16 months) than those with SMARCA4-retained tumors. Overall, these findings revealed that SMARCA4-dGBC is a rare, distinct entity characterized by the destabilization of the SWItch/sucrose nonfermentable complex, genomic instability, and resistance to conventional therapies. The prevalence of targetable pathways, such as RTK-RAS and cell cycle dysregulation, highlights opportunities for precise therapeutic strategies involving EZH2, CDK4/6, or ATR inhibitors. SMARCA4 immunohistochemistry and molecular profiling are essential for accurate diagnosis, prognostic stratification, and therapeutic innovation of this GBC subtype.

Humans↗

PubMed1989

Notch is required for successive cell decisions in the developing Drosophila retina.

Mutations in the Notch locus affect a variety of developmental decisions in Drosophila. In this paper, we examine the role of Notch in the developing retina. We reduced Notch activity at successive intervals during development of the retina, and then examined the effect on individual cells. When Notch activity was reduced, cells responded by selecting inappropriate developmental pathways. We found that all cell types appear to require Notch when establishing their fate. To examine further Notch's role in eye development, we examined two alleles of Notch--split and facet-glossy. split flies show defects in the initial clustering of photoreceptors, whereas the defects in facet-glossy flies are due to the misrouting of presumptive primary pigment cells into the secondary pigment cell pathway. Our results suggest that Notch plays a permissive role in the cell-cell interactions used to assemble the eye.

Alleles↗

PubMed2026

Genome-wide cis-expression Quantitative Trait Loci (eQTL) and transcriptomic signals reveal distinct molecular regulation across correlated feed efficiency traits.

INTRODUCTION: Feed efficiency (FE) is a complex trait which determines livestock production profitability, yet the molecular mechanisms behind it remain unclear. This study investigated the blood transcriptomic profile of lambs, alongside genotype data with the aim to uncover the genetic basis of FE traits such as absolute dry matter intake (DMIabsolute), DMI adjusted for body size (DMIadjusted), average daily live weight gain (ADG), and residual feed intake (RFI). MATERIALS AND METHODS: Bulk RNA-Seq and genotype data were analysed using three complementary approaches: differential gene expression (DGE) analysis, weighted gene co-expression network analysis (WGCNA), and cis-expression Quantitative Trait Loci (cis-eQTL) mapping. These methods were used independently to identify genes and regulatory networks associated with FE traits and to investigate evidence supporting multi-trait candidate gene selection. RESULTS: DGE analysis revealed 2, 24, 85 and 4 differentially expressed genes for DMIabsolute, DMIadjusted, ADG, and RFI (Padjusted < 0.05), functionally enriched in sensory perception, ATP-dependent chromatin remodeling, Notch signaling and immune response pathways. 9 gene modules significantly associated with the FE traits (P ≤ 0.05) with correlations ranging from r = -0.56 to 0.49, were identified using WGCNA. Single nucleotide polymorphism (SNP)-level cis-eQTL analysis identified 93 eSNPs associated with 74 genes (false discovery rate (FDR) < 0.05), while permutation-derived gene level analysis identified 280 eGenes (FDR < 0.2, empirical P < 0.03). Across the three analyses, applying thresholds of DGE (Padjusted < 0.05), WGCNA (correlation, P ≤ 0.05), and cis-eQTL gene-level significance (empirical P < 0.05), multiple overlapping genes were identified including DNMT3A, KANSL1, NCOR1 for DMIadjusted, ACOX2, FANCF, CIMIP2B, LOC101115106, ARMH2, LOC132657496 for ADG, and LOC114114576 for RFI representing regulators of variations in FE. DISCUSSION: The integration of DGE, WGCNA, and cis-eQTL analyses identified key genes and regulatory mechanisms associated with variation in FE traits. These results highlight that integrated multi-trait candidate gene identification approaches can reveal key genes that lower feed intake while maintaining animal growth, supporting breeding strategies aimed at improving efficiency and long-term economic sustainability in sheep.

average daily gain (ADG)↗

PubMed2026

Development and preclinical evaluation of a decoy DLL4-encoding oncolytic HSV-1 for high-grade glioma.

Preclinical and clinical investigation of oncolytic HSV-1 (oHSV) treatment for cancer has indicated increased Notch signaling in tumors after treatment. Since Notch activation often heralds cancer cell stemness, angiogenesis, and invasion, the induction of this pathway after oHSV virotherapy can support tumor growth and limit response to virotherapy. Here, we evaluated the impact of blocking DLL4, a Notch ligand, on virotherapy. Matched tumor biopsies pre- and post-oHSV (CAN-3110, NCT03152318) treatment revealed an induction of DLL4 post-therapy. We observed that expression of a recombinant soluble decoy DLL4 (sDLL4) could block Notch activation in tumor cells. Thus, we engineered an oHSV vector designed to encode soluble DLL4 (OVsDLL4) to block ligand-mediated Notch signaling. RNA sequencing and gene set enrichment analysis revealed that, relative to control oHSV, OVsDLL4 blocked Notch and sprouting angiogenesis pathways after treatment. Despite slower virus replication in vitro, OVsDLL4 cytotoxicity remained effective against tumor cells. Transcriptome profiling also indicated a significant dysregulation of metabolic pathways related to oxidative phosphorylation and glutathione metabolism, in accordance with increased oxygen consumption observed by Seahorse analysis in cells expressing sDLL4. OVsDLL4-treated cells further showed increased reactive oxygen species relative to control oHSV-treated cells. Co-culture of infected tumor cells with immune cells revealed that OVsDLL4 treatment polarized them toward an inflammatory phenotype. In vivo, the therapeutic efficacy of OVsDLL4 was underscored, as treatment of glioma-bearing mice resulted in reduced tumor burden and prolonged survival.

Journal Article↗