Biology subjects

Ogunbiyi, O.

Publications and source records attributed to Ogunbiyi, O..

3 recordsLinked to original sources

bioRxiv2025

Spatial transcriptomic analysis of muscle biopsy from treatment-naive juvenile dermatomyositis patients reveals mitochondrial abnormalities despite disease-related interferon driven signature

ObjectivesThis study aimed to investigate the spatial transcriptomic landscape of muscle tissue from treatment-naive juvenile dermatomyositis (JDM) patients in comparison to healthy paediatric muscle tissue. MethodsMuscle biopsies from three JDM patients and three age-matched controls were analysed using the Nanostring GeoMx(R) Digital Spatial Profiler. Regions of interest were selected based on muscle fibres without immune cells, immune cell infiltration and CD68+ macrophage enrichment. Differential gene expression, pathway analysis and pathways clustering analysis were conducted. Key findings were validated in 19 cases of JDM using immunohistochemistry and chemical stains, and a bulk RNAseq dataset of four cases of JDM. ResultsJDM muscle tissues exhibited significant interferon pathway activation and mitochondrial dysfunction compared to controls. A 15-gene interferon signature was significantly elevated in JDM muscle and macrophage-enriched regions, correlating with clinical weakness. In contrast, mitochondrial dysregulation, characterized by downregulated respiratory chain pathways, was present regardless of interferon activity or muscle strength. The interferon-driven and mitochondrial signatures were replicated in an independent RNAseq dataset from JDM muscle; lack of association between interferon signature and mitochondrial dysregulation was validated in 19 cases by conventional staining methods. Clustering analysis revealed distinct transcriptomic profiles between JDM and control tissues, as well as between JDM patients with varying clinical phenotypes. ConclusionsThis study highlights mitochondrial dysfunction as a consistent pathological feature in JDM muscle, which may be independent of interferon-driven inflammation. These findings highlight the potential for mitochondrial-targeted therapies in JDM management and emphasise the need for further studies to explore their therapeutic value. KEY MESSAGESWhat is already known on this topic O_LIJuvenile dermatomyositis (JDM) involves interferon-driven inflammation and immune-mediated muscle damage. C_LIO_LIMitochondrial abnormalities in blood immune cells persist despite treatment and contribute to disease pathology. C_LI What this study adds O_LIMitochondrial dysfunction is present in both muscle fibres and tissue-infiltrating immune cells within JDM muscle. C_LIO_LIThese abnormalities are detectable even in clinically less severe muscle weakness. C_LIO_LIDegree of mitochondrial abnormality at transcript and protein level may be independent of strength of IFN-driven signal. C_LIO_LIMitochondrial dysregulation detected at transcriptional level correlates with abnormal transcription of muscle (sarcomere) and the subcellular peroxisome organelle. C_LI How this study might affect research, practice, or policy O_LITargeting mitochondrial dysfunction could enhance treatment outcomes for JDM, especially in patients whose disease is refractory to current therapies. C_LIO_LIInsights from this study support the development of stratification tools to detect aspects of pathology which are not tightly correlated with IFN-driven pathology. C_LI

immunology↗

bioRxiv2024

Targeted inhibition of Bcl-xL following radiation reduces tumourigenesis in preclinical models of H3K27M-altered diffuse midline glioma

BackgroundDiffuse midline gliomas (DMGs) with histone H3K27M mutations represent a devastating paediatric brain cancer characterized by abysmal prognosis and limited treatment options. The only approved treatment is radiotherapy (RT), but most of the tumours relapse with fatal consequences. In this study, we sought to investigate whether irradiation leads to senescence induction and explore the efficacy of senolytics against DMG. MethodsWe have characterised the senescent phenotype of five genetically heterogeneous H3K27M-altered human DMG cell lines, combining cellular and/or molecular approaches. The sensitivity of senescent cells to Bcl-xL inhibition has been demonstrated in dose/response curves in vitro and in a PDX model of DMG. ResultsHere, we show that ionizing radiation induces senescence and SASP responses in both TP53 mutant and wild-type H3K27M-altered human DMG cell lines. We identify Navitoclax as a potent senolytic agent that selectively targets senescent DMG cells into apoptosis by inhibiting Bcl-xL. Related compounds, such as a proteolysis-targeting chimera (PROTAC)-mediated Bcl-xL degradation and a galacto-conjugated form of Navitoclax also show an effective senolytic activity in senescent cancer cells. Finally, we show that a combination therapy of irradiation and Navitoclax results in reduced tumor burden and increased mouse survival in an orthotopic xenograft DMG model. ConclusionThese results offer a rationale for further clinical development of senolytic therapies as part of multimodal treatment approaches for DMG patients/ Key PointsO_LIIonising irradiation induces senescence in human DMG cells independently of the p53 status. C_LIO_LIBcl-xL inhibition results in apoptosis of human DMG senescent cells in synergy with irradiation. C_LIO_LICombination of irradiation and BcL-xL inhibition reduces tumourigenesis in a PDX model of DMG. C_LI Importance of the StudyH3K27M-altered DMG are devastating paediatric tumours with an abysmal prognosis. The only approved treatment is radiotherapy but this is palliative and tumours almost always relapse with fatal consequences for the patients. In this study, we show that radiotherapy results in senescence induction in five genomically heterogeneous human DMG cell lines. We identify that drugs targeting the anti-apoptotic protein Bcl-xL show a strong senolytic activity in conjunction with radiotherapy both in vitro in DMG cells and in vivo in a PDX model of H3K27M-altered DMG. Treatment with Bcl-xL inhibitor Navitoclax, or related compounds targeting Bcl-xL protein degradation or containing a galactose conjugated form of Navitoclax results in DMG cancer cell apoptosis. As several of these inhibitors are currently being tested in ongoing clinical trials against other diseases, our data support the use of Bcl-xL inhibition mediated senolytics as an adjuvant therapy to radiotherapy to potentially improve outcomes in this challenging disease setting.

cancer biology↗

bioRxiv2024

Sex differences in early human fetal brain development

The influence of sex chromosomes and sex hormones on early human brain development is poorly understood. We therefore undertook transcriptomic analysis of 46,XY and 46,XX human brain cortex samples (n=64) at four different time points between 7.5 and 17 weeks post conception (wpc), in two independent studies. This developmental period encompasses the onset of testicular testosterone secretion in the 46,XY fetus (8wpc). Differences in sex chromosome gene expression included X-inactivation genes (XIST, TSIX) in 46,XX samples; core Y chromosome genes (n=18) in 46,XY samples; and two Y chromosome brain specific genes, PCDH11Y and RP11-424G14.1. PCDH11Y (protocadherin11 Y-linked) regulates excitatory neurons; this gene is unique to humans and is implicated in language development. RP11-424G14.1 is a novel long non-coding RNA. Fewer differences in sex hormone pathway-related genes were seen. The androgen receptor (AR, NR4A2) showed cortex expression in both sexes, which decreased with age. Global cortical sex hormone effects were not seen, but more localized AR mechanisms may be important with time (e.g., hypothalamus). Taken together, our data suggest that limited but potentially important sex differences occur during early human fetal brain development.

developmental biology↗