Ontosight® - Newsletter Issue - 15

Welcome to the 15th edition of Ontosight® Newsletter! This issue features groundbreaking research on cancer immunotherapy, neurological diseases, AI in biomedicine, cardiovascular health, and immune response targeting, along with key regulatory updates. Stay informed on the latest scientific advancements and regulatory developments in healthcare.

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Featured Articles

1. Tumor Microenvironment and Immunotherapy

• Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer

Anti-tumor immunity is critical for high-grade serous ovarian cancer (HGSC) prognosis but is poorly understood post-chemotherapy. Spatial and single-cell analyses of 117 HGSC samples reveal dynamic immune microcommunities, with Myelonets and myeloid-T cell interactions driving CD8+ T cell exhaustion and poor chemoresponse via NECTIN2-TIGIT signaling. Targeting these interactions shows promise for enhancing immune checkpoint blockade efficacy, offering new immunotherapeutic strategies for HGSC. [Article]

• Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity

Mannose metabolism regulates T cell differentiation and anti-tumor efficacy by promoting stem-like programs and restricting exhaustion. D-mannose supplementation enhances metabolic programming, O-GlcNAcylation of β-catenin, and Tcf7 expression, preserving epigenetic stemness. This approach improves adoptive T cell therapy by yielding long-term expanded T cells with enhanced anti-tumor activity, highlighting the therapeutic potential of mannose modulation in cancer immunotherapy. [Article]

• Genomic landscape of circulating tumor DNA in HER2-low metastatic breast cancer

This study analyzes 1071 metastatic breast cancer (MBC) patients to explore genetic and clinicopathological characteristics of HER2-low MBC. TP53, PIK3CA, and ESR1 mutations were frequent, with metabolic pathway alterations more prevalent in HER2-low compared to HER2-0 patients. HER2-low patients with ERBB2 mutations showed better outcomes with pyrotinib but no significant differences in chemotherapy or endocrine therapy responses. Dynamic ctDNA analysis and classification into three clusters provide insights for personalized treatment strategies. [Article]

• SPTLC2 drives an EGFR-FAK-HBEGF signaling axis to promote ovarian cancer progression

SPTLC2 enhances EGFR signaling in ovarian cancer (OC), promoting tumor growth, migration, and metastasis through the EGFR-FAK-HBEGF axis. Depletion of SPTLC2 suppresses OC progression, while overexpression has the opposite effect. High SPTLC2 expression correlates with aggressive OC phenotypes, highlighting its oncogenic role and potential as a therapeutic target in EGFR-driven OC. [Article]

• Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells

Fusobacterium nucleatum (F. nucleatum) promotes colorectal cancer (CRC) by colonizing gut crypts and reprogramming crypt cells into LY6A+ revival stem cells (RSCs), driving their hyperproliferation and transformation into tumor stem cells. Mechanistically, LY6A serves as a receptor for F. nucleatum, inducing RPS14 upregulation and tumorigenesis. Ablation of Ly6a or Rps14 reduces colonization and tumor progression, highlighting the F. nucleatum-LY6A-RPS14 axis as a key driver of CRC and a potential therapeutic target. [Article]

2. Neurological Diseases and Neuroinflammation

• Plasma proteomics identify biomarkers and undulating changes of brain aging

This study used multimodal brain imaging and proteomics to investigate brain aging in 10,949 adults, identifying 13 proteins associated with the brain age gap (BAG). Key biomarkers, BCAN and GDF15, showed significant links to dementia, stroke, and movement functions, with BCAN dysregulation impacting brain structures. Proteomic changes peaked at ages 57, 70, and 78, highlighting distinct biological pathways. These findings provide insights into the plasma proteomic landscape and biomarkers for brain aging and related disorders. [Article]

• Artificial intelligence-based rapid brain volumetry substantially improves differential diagnosis in dementia

This study demonstrates that AI-based rapid brain volumetry significantly improves diagnostic accuracy for Alzheimer's disease (AD) and frontotemporal dementia (FTD) across radiologists of all experience levels. AI assistance enhanced correct diagnoses, reduced errors, and cut processing time from 12–24 hours to under 5 minutes, integrating seamlessly into clinical workflows. This tool holds promise for early diagnosis and improved patient management in dementia. [Article]

• Telomere length, in vivo Alzheimer's disease pathologies and cognitive decline in older adults

This study found that longer telomere length (TL) in older adults, particularly those with cognitive impairment, is linked to greater tau deposition and faster cognitive decline. Mediation analysis suggests that increased tau deposition may mediate the relationship between longer TL and cognitive decline. These findings highlight a potential connection between TL and Alzheimer's disease pathologies, requiring further investigation. [Article]

• Deep learning reveals pathology-confirmed neuroimaging signatures in Alzheimer’s, vascular and Lewy body dementias

This study presents a deep learning framework, DeepSPARE, for identifying biomarkers of Alzheimer's disease (AD), vascular dementia (VD), and Lewy body dementia (LBD) using T1-weighted MRI scans. The model achieved high diagnostic accuracy and generated explainable heatmaps showing distinct brain alterations for each pathology. DeepSPARE indices correlated with cognitive tests, brain volume, and biomarkers, offering a noninvasive, precise tool for detecting neurodegenerative diseases and complementing histopathological diagnoses. [Article]

• Neuroprotective Effects of Dexamethasone in a Neuromelanin-Driven Parkinson's Disease Model

This study explored dexamethasone's effects on a neuromelanin-driven Parkinson’s disease (PD) model. Dexamethasone improved motor function, preserved dopaminergic neurons, suppressed reactive microglia, and reduced peripheral immune cell infiltration into the brain. These findings highlight its potential as a neuroprotective therapy targeting neuroinflammation in PD, warranting further research into glucocorticoid-based treatments.[Article]

3. Artificial Intelligence & Biomedical Applications

• Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy

This study used a deep-learning approach to optimize ionizable lipids for RNA delivery in lipid nanoparticles. A neural network trained on over 9,000 activity measurements accurately predicted RNA delivery in vitro and in vivo, identifying lipids FO-32 and FO-35 for efficient mRNA delivery to mouse muscle, nasal mucosa, and ferret lungs. This highlights deep learning's potential to enhance nanoparticle delivery efficiency.[Article]

• Prediction of gene expression-based breast cancer proliferation scores from histopathology whole slide images using deep learning

This study used deep learning to predict molecular proliferation signatures—an 11-gene score and the MKI67 marker—from digital whole slide images (WSIs) of invasive breast cancer. CNN models effectively predicted these signatures, showing strong correlation and accuracy. Prognostic analysis linked higher proliferation levels to increased risk of recurrence or death. This approach demonstrates the potential of CNNs to extract clinically relevant prognostic information from WSIs, aiding breast cancer research and treatment decisions.[Article]

• Systematic evaluation of machine learning models for postoperative surgical site infection prediction

This review evaluated 24 studies with 85 machine learning (ML) models for predicting surgical site infections (SSIs). Most models were internally validated, with performance commonly assessed using the C-statistic, though calibration metrics were rarely reported. ML models showed similar performance to regression methods but often lacked external validation and had high or unclear risk of bias. The review emphasizes the need for improved methodological quality, external validation, and comprehensive performance reporting in ML models for SSIs. [Article]

4. Cardiovascular Risk Factors and Disease Mechanisms

• Optimizing treatment of cardiovascular risk factors in cerebral small vessel disease using genetics

This study used Mendelian randomization to identify risk factors and drug targets for cerebral small vessel disease (cSVD) and lacunar stroke (LS). It found that high blood pressure, diabetes, obesity, smoking, and certain lipid levels increase LS risk, while HDL and physical activity offer protection. Drugs targeting blood pressure, HDL, triglycerides, and weight reduction may reduce LS risk, highlighting potential strategies for cSVD prevention. [Article]

• Insulin resistance, vulnerable plaque and stroke risk in patients with carotid artery stenosis

This study explored the relationship between insulin resistance (IR), vulnerable plaque, and stroke risk in patients with carotid artery stenosis. It found a positive association between the triglyceride-glucose (TyG) index (a marker for IR) and stroke risk. Vulnerable plaques were significant predictors of stroke and partially mediated the relationship between the TyG index and stroke risk, accounting for up to 18.3% of the association. [Article]

• Associations between subclinical thyroid dysfunction and cardiovascular risk factors according to age and sex

This study examined the link between subclinical thyroid dysfunction (ScTD) and cardiovascular risk factors (cvRFs) across age and sex groups using pooled data from large cohort studies. Blood pressure, lipid levels, and hs-CRP were generally similar across thyroid statuses, with exceptions like lower diastolic BP and LDL cholesterol in women with subclinical hyperthyroidism. These findings suggest that the increased cardiovascular risk in ScTD may involve mechanisms beyond traditional cvRFs. [Article]

• Phillygenin improves diabetic nephropathy by inhibiting inflammation and apoptosis via regulating TLR4/MyD88/NF-κB and PI3K/AKT/GSK3β signaling pathways

This study investigates the therapeutic effects of Phillygenin (PHI), a bioactive compound from Forsythia suspensa, on diabetic nephropathy (DN). PHI was found to reduce inflammation and apoptosis in HG-induced MPCs and improve kidney function in diabetic mice. The mechanisms involved include modulation of the TLR4/MyD88/NF-κB and PI3K/AKT/GSK3β signaling pathways. PHI's ability to alleviate kidney injury and inflammation positions it as a potential therapeutic agent for DN. [Article]

• Metabonomic Biomarkers of Plaque Burden and Instability in Patients With Coronary Atherosclerotic Disease After Moderate Lipid‐Lowering Therapy

This study examines the use of metabolomic biomarkers to assess residual risk in coronary atherosclerotic disease (CAD) after lipid-lowering therapy. It identifies key metabolites, like triglycerides and apolipoprotein B, associated with CAD severity and plaque burden. These biomarkers were linked to a higher risk of major cardiac events, suggesting that metabolomics could provide a noninvasive tool for evaluating CAD prognosis..[Article]

5. Innovative Approaches to Targeting Immune Response

• Pentraxin-3 modulates hepatocyte ferroptosis and the innate immune response in LPS-induced liver injury

This study explores the role of pentraxin-3 (PTX3) in sepsis-induced liver injury. In Ptx3-deficient mice, endotoxemia-induced liver damage was alleviated, with improved survival and reduced liver enzyme levels. Mechanistically, PTX3 deficiency increased ferroptosis in hepatocytes and promoted macrophage recruitment via the CCL20/CCR6 axis, while enhancing M1 macrophage polarization through the NF-κB pathway. These findings suggest that PTX3 plays a critical role in sepsis-induced liver injury, offering potential therapeutic targets for acute infections. [Article]

• Efficient non-viral immune cell engineering using circular single-stranded DNA-mediated genomic integration

This study introduces the GATALYST system, a non-viral method for producing circular single-stranded DNAs (cssDNAs) up to 20 kb for efficient genome editing. The system enables high knock-in efficiency (up to 70%) in induced pluripotent stem cells and primary immune cells, with improved precision, safety, and scalability. The approach shows promise for clinical applications, including chimeric antigen receptor (CAR)-T and natural killer (NK) cell therapies. [Article]

• IL-23R is a senescence-linked circulating and tissue biomarker of aging

This study compares the efficacy of various senolytic drugs (venetoclax, navitoclax, fisetin, luteolin) in reversing aging and senescence biomarkers in mice. It identifies age-dependent changes in plasma proteins like IL-23R, CCL5, and CA13, which are reversed by senotherapeutics, particularly in kidney tissue. The findings suggest that circulating factors, such as IL-23R, could serve as biomarkers for systemic senescent cell burden and interorgan signaling related to aging. [Article]

• Epstein-Barr virus infection in patients with MOGAD

This study compares Epstein-Barr virus (EBV) serological status in multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). It found that while both conditions had high EBV antibody presence, MS patients had significantly higher levels of EBNA-1 and VCA antibodies compared to MOGAD patients. These findings suggest a potentially different role of EBV in the pathogenesis of MS and MOGAD. [Article]

Additional Highlights

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

• Omega-3 Fatty Acids as Protective Factors for Age-related Macular Degeneration [Article]
• Integration of lipidomics with targeted, single-cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer [Article]
• The skin’s ‘surprise’ power: it has its very own immune system [News]
• Fasting can reduce weight — but also hair growth [News]
• U.S. FDA Expands Indication for Impella Heart Pumps to Treat Pediatric Patients [News]
• Faron Announces Positive Update on Recent Interactions with UK Regulatory Authorities regarding bexmarilimab and expanding the BEXMAB Study to the UK [News]
• Positive CHMP opinion for the extension of indication of Palforzia® for the treatment of toddlers with confirmed peanut allergy [News]
• US FDA accepts GSK’s submission for the use of Nucala (mepolizumab) in COPD [News]
• Blenrep (belantamab mafodotin) combination accepted for priority review in China in relapsed/refractory multiple myeloma [News]
• Santhera Receives Positive Recommendation from NICE for AGAMREE® (Vamorolone) as a Treatment for Duchenne Muscular Dystrophy [News]
• European regulatory authority adopts positive opinion for an update of the Ozempic® label to reflect risk reduction of kidney disease-related events [News]

Stay informed about the latest in medical research and innovation. Join us in two weeks for more insights into the dynamic world of healthcare and life sciences advancements.

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