Ontosight Newsletter Issue 26

Ontosight® - Biweekly Newsletter

May 05th, 2025 - June 01st, 2025 - Issue 26

Welcome to the 26th edition of Ontosight® Newsletter! This issue features innovations in cancer biology, neurodegeneration, precision medicine, and molecular genetics. Discover novel targets in immunotherapy resistance, new biomarkers for Alzheimer’s, and AI-powered diagnostic tools. Plus, explore recent global regulatory approvals spanning oncology, rare diseases, and advanced therapeutics.

Featured Articles

1. Cancer Biology & Therapeutics

• Integrative Single-Cell and Spatial Transcriptomics Analysis Reveals ECM-remodeling Cancer-associated Fibroblast-Derived POSTN as a Key Mediator in Pancreatic Ductal Adenocarcinoma Progression

This study used integrated single-cell and spatial transcriptomics to identify eight fibroblast subtypes in pancreatic ductal adenocarcinoma (PDAC), highlighting ECM-remodeling fibroblasts as key drivers of tumor progression. These fibroblasts, enriched in tumors and linked to poor prognosis, promote cancer via the POSTN-ITGAV/ITGB5 axis and activation of the PI3K/AKT/β-catenin pathway. Targeting this axis may offer a promising therapeutic strategy. Read More

• Immunological biomarkers and gene signatures predictive of radiotherapy resistance in non-small cell lung cancer

This study used bioinformatics and machine learning to identify four key genes—TGFBI, FAS, PTK6, and FA2H—linked to radiotherapy resistance in non-small cell lung cancer (NSCLC). TGFBI emerged as most strongly associated with poor prognosis. Immune profiling revealed differences in naive B cells and M0 macrophages between risk groups, suggesting potential therapeutic strategies to overcome resistance. Read More

• Drug repurposing of fostamatinib against cancer via potential cytotoxicity and immune checkpoint regulation

This study identifies fostamatinib, a SYK inhibitor approved for ITP, as a potential repurposed therapy for FLT3-ITD+ acute myeloid leukemia (AML). It suppressed AML cell proliferation, induced apoptosis, and acted via the PI3K-AKT pathway. Fostamatinib also downregulated immune checkpoints like PD-L1 and CD47, supporting its therapeutic promise in resistant AML cases. Read More

• Boosting mRNA cancer vaccine efficacy via targeting Irg1 on macrophages in lymph nodes

This study identifies macrophage-derived itaconate, produced via Irg1, as a key metabolite limiting mRNA cancer vaccine efficacy. Knocking down Irg1 enhances dendritic cell function and T cell responses. Combining Irg1-targeting siRNA with mRNA vaccines significantly boosts anti-tumor effects, especially alongside anti-PD-1 therapy, offering a promising strategy to improve vaccine outcomes. Read More

• Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma

This study uses single-cell profiling to reveal that EZH2 mutations in lymphomas have widespread effects on the epigenome and override KMT2D mutations. Mutant-EZH2 notably increases epigenetic heterogeneity, suggesting a new oncogenic mechanism. The work also introduces tools to map epigenetic networks and uncover novel histone modification interactions. Read More

2. Neurodegeneration, Alzheimer's & Brain Health

• Development and validation of a novel Simoa assay for NPTX2 in Alzheimer's disease and Down syndrome

This study introduces a novel Simoa-based assay for measuring NPTX2 in cerebrospinal fluid, showing reduced levels in Alzheimer's and Down syndrome patients. NPTX2 levels correlated strongly with cognitive performance, tau pathology, and cortical thickness. Notably, its association with cognition was stronger than traditional AD biomarkers, highlighting its diagnostic potential. Read More

• Unique lipid cargoes in APOE4 human brain-derived extracellular vesicles recruit cell adhesion molecules and promote tauopathy in Alzheimer’s disease

This study reveals that brain-derived extracellular vesicles (BDEVs) from APOE ε4/4 Alzheimer's patients enhance tau propagation and neuronal excitability compared to ε3/3 BDEVs. Multi-omics analysis links this effect to enriched FFA 18:2 and NCAM1, which together promote tau seeding. Blocking NCAM1 reduces tau pathology and inflammation, highlighting a potential therapeutic target in AD. Read More

• Disease-specific neuropathological alterations of the locus coeruleus in Alzheimer's disease, Down syndrome, and Parkinson's disease

This study compared locus coeruleus (LC) degeneration across AD, PD, and DS-AD brains, revealing the greatest noradrenergic neuron loss in AD and PD with dementia. Despite high amyloid and tau levels, DS-AD showed less LC loss but elevated DYRK1A, which correlated with reduced biogenic amines. Findings suggest LC degeneration may occur independently of amyloid and tau pathologies Read More

• Brain MRI signatures across sex and CSF Alzheimer's disease biomarkers

This study analyzed MRI and CSF biomarkers in Alzheimer's patients, revealing distinct brain atrophy and connectivity patterns across amyloid and tau biomarker groups. Amyloid was linked to subcortical and brainstem atrophy Read More

Comparison of safety of lecanemab and aducanumab: a real-world disproportionality analysis using the FDA adverse event reporting system

This study compared adverse drug events (ADEs) of lecanemab and aducanumab using FDA data, identifying nervous system disorders as a common signal for both. Lecanemab had more ADE signals and a shorter median time-to-onset (33 vs. 146 days). Notably, some ADEs showed gender differences and included previously unlisted events, highlighting the need for continued safety monitoring. Read More

3. Precision Medicine, Biomarkers & Omics

• Enhanced Early Detection of Colorectal Cancer via Blood Biomarker Combinations Identified Through Extracellular Vesicle Isolation and Artificial Intelligence Analysis

This study presents the ZAHV-AI system, which combines a novel EV isolation method (ZAHVIS) with AI to enable rapid, cost-effective colorectal cancer (CRC) diagnosis. Using EV-derived miRNAs and CEA levels, the system achieved outstanding diagnostic accuracy (AUC up to 1.0 for early-stage CRC). This approach offers a powerful tool for early CRC detection and monitoring. Read More

• Single nuclear-spatial transcriptomic sequencing reveals distinct puncture-induced cell subpopulations in the intervertebral disc of a rat model

This study used spatial and single-nucleus RNA sequencing to map cell dynamics in intervertebral disc degeneration (IVDD). It identified key stress-induced cell types—Lcn2⁺ annulus fibrosus cells and Col3hi nucleus pulposus cells—linked to fibrosis and degeneration. Pdgfra⁺ AF cells were shown to migrate into the NP, contributing to fibrosis. The findings highlight oxidative stress as a key driver of IVDD and underscore the complex cellular origins of disc fibrosis. Read More

• Potential supplementary tumor markers for liquid biopsy in non-small cell lung cancer

This study evaluated a chip-based digital PCR (dPCR) platform for detecting key EGFR mutations (19del, T790M) in NSCLC serum samples, showing moderate predictive value. Certain serum tumor markers (CA199, ProGRP, CA125, CEA) correlated with mutation presence and variant rates. These findings support serum-based dPCR as a useful, non-invasive tool for EGFR genotyping and patient selection in NSCLC. Read More

4. Genetics & Molecular Mechanisms

• ZNF280A links DNA double-strand break repair to human 22q11.2 distal deletion syndrome

This study identifies ZNF280A as a crucial chromatin factor required for long-range DNA-end resection and homologous recombination repair of DNA double-strand breaks. Loss of ZNF280A impairs DNA repair, causes genomic instability, and increases sensitivity to DNA damage. ZNF280A deficiency is linked to 22q11.2 distal deletion syndrome, with its reintroduction rescuing DNA repair defects, highlighting a potential mechanism underlying the syndrome’s clinical features. Read More

• Optimized genomic editing of a common Duchenne muscular dystrophy mutation in patient-derived muscle cells and a new humanized mouse model

This study used single-cut CRISPR gene editing with AAV9 delivery to restore dystrophin expression in a humanized Duchenne muscular dystrophy (DMD) mouse model with exon 52 deletion. Both intraperitoneal and facial vein injections effectively restored dystrophin in skeletal muscles and heart, improving muscle function and reducing disease markers. These findings support CRISPR-based exon skipping as a promising DMD therapy. Read More

• Molecular mechanisms of deer antler in promoting osteogenic differentiation of human mesenchymal stem cells via JUN modulation

This study reveals that deer antler promotes human mesenchymal stem cell (hMSC) osteogenic differentiation by downregulating the JUN gene and modulating the immune microenvironment. Bioinformatics and molecular docking identified Retinol and Progesterone as key bioactive compounds targeting JUN. JUN was strongly linked to osteogenesis and immune cell infiltration, offering insights into deer antler's bone regenerative mechanisms. Read More

• Cell state-specific cytoplasmic density controls spindle architecture and scaling

This study shows that during neural differentiation, mitotic spindles become smaller despite unchanged microtubule dynamics, due to a more dilute cytoplasm. Reduced free tubulin levels activate CPAP, shifting microtubule mass toward spindle poles. These findings reveal that cytoplasmic density plays a key role in regulating spindle architecture and organelle size. Read More

• Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis

This study reveals that lipid peroxidation during ferroptosis initiates at endoplasmic reticulum-mitochondria contact sites (EMCSs), which expand and promote mitochondrial damage. Modulating EMCSs influences ferroptosis sensitivity, with untethering protecting and stabilizing enhancing ferroptosis, particularly impacting triple-negative breast cancer subtypes. These findings identify EMCSs as critical hubs for ferroptosis regulation and potential therapeutic targets. Read More

5. Diagnostic & Prognostic Advancements

• AI in motion: the impact of data augmentation strategies on mitigating MRI motion artifacts

This study evaluated how data augmentation strategies affect AI model performance in MRI with motion artifacts. Models using general and MRI-specific augmentations showed improved segmentation and measurement accuracy under artifact conditions. MRI-specific augmentation slightly outperformed standard methods but with minimal additional benefit. Incorporating domain-specific knowledge enhances AI robustness for clinical MRI applications. Read More

• Development of Machine-Learning-Based Models for Detection of Cognitive Impairment in Patients Receiving Maintenance Hemodialysis

This study developed and validated machine learning models to quickly screen for cognitive impairment in dialysis patients using a few key questions from the MMSE and CASI. Among six models tested, the random forest model performed best, achieving 94% accuracy and 0.95 AUC. The tool enables accurate cognitive screening in under 5 minutes, aiding early detection in clinical settings. Read More

• Neutrophil Percentage-to-Albumin Ratio as a Prognostic Marker for Mortality in Ischemic Stroke Patients

This study found that a high neutrophil percentage-to-albumin ratio (NPAR) is independently associated with increased all-cause mortality in ischemic stroke (IS) patients at 30 days, 90 days, 1 year, and during hospitalization. Using data from the MIMIC-IV database, the analysis showed a nonlinear relationship between rising NPAR and mortality risk. NPAR outperformed individual markers in predicting outcomes, suggesting its potential as a prognostic biomarker in IS. Read More

• Potential supplementary tumor markers for liquid biopsy in non-small cell lung cancer

This study evaluated a chip-based digital PCR (dPCR) platform for detecting EGFR mutations (19del and T790M) in serum samples from NSCLC patients. The dPCR assay showed moderate predictive value and identified correlations between EGFR mutations and specific serum tumor markers. Elevated CA199 and ProGRP levels were linked to higher mutation detection rates, suggesting potential for non-invasive genotyping and patient stratification. Read More

Additional Highlights

Explore more groundbreaking research and regulatory updates in our biweekly newsletter:

• Micronutrient antioxidant supplementation alleviates valproic acid-induced oxidative stress and male infertility via the NRF2/HO-1 pathway

• Roche provides update on FDA Advisory Committee meeting on Columvi combination for people with relapsed or refractory diffuse large B-cell lymphoma

• England's NICE recommends FILSPARI® (sparsentan) as a treatment option for IgA nephropathy

• Patritumab Deruxtecan Biologics License Application for Patients with Previously Treated Locally Advanced or Metastatic EGFRMutated Non-Small Cell Lung Cancer Voluntarily Withdrawn

• Stealth BioTherapeutics Announces Delay in FDA Action Date for Barth Syndrome Application