Ontosight Newsletter Issue 22

Ontosight – Newsletter

March 10th – March 23rd, 2025 – Issue 22

Welcome to the 22nd edition of Ontosight Newsletter! This issue features cutting-edge research across multiple domains, including immunotherapy breakthroughs in cancer treatment, insights into neuroinflammation in ALS and Alzheimer’s disease, the role of gut microbiota in inflammatory disorders, and new perspectives on cardiovascular and metabolic diseases. Additionally, we explore advancements in precision medicine, bioinformatics, and regulatory updates shaping the healthcare landscape. Stay informed with the latest scientific discoveries and innovations in life sciences!

Featured Articles

1. Immunotherapy & Cancer Research

• A single-cell atlas reveals immune heterogeneity in anti-PD-1-treated non-small cell lung cancer

Anti-PD-(L)1 therapy is standard for NSCLC, but patient responses vary. Using single-cell RNA and TCR sequencing on 234 post-chemoimmunotherapy tumor samples, researchers identified five distinct tumor immune microenvironment (TIME) subtypes. Major pathological response (MPR) correlated with FGFBP2+ NK-like T cells, memory B cells, and effector T cells, while non-MPR patients had more CCR8+ Tregs. Precursor exhausted T cells were linked to better recurrence-free survival, offering insights into treatment response heterogeneity. [Article]

• DNMT1 inhibition reprograms T cells to NK-like cells with potent antitumor activity

BCL11B suppresses NK cell transcriptional programs by interacting with DNMT1, which stabilizes BCL11B and maintains DNA methylation to repress NK-related genes. DNMT1 also independently silences a subset of NK genes. Inhibiting DNMT1 or EZH2 enhances T-to-NK reprogramming, generating NK-like cells with stronger antitumor activity than BCL11B-deficient ITNKs or CAR-T cells. These findings highlight epigenetic strategies for developing potent NK-like cells for cancer immunotherapy. [Article]

• Machine Learning and Mendelian Randomization Reveal a Tumor Immune Cell Profile for Predicting Bladder Cancer Risk and Immunotherapy Outcomes

This study developed a tumor-infiltrated immune cell (TIIC) signature score to predict bladder cancer (BLCA) prognosis using RNA expression and scRNA-seq data. A machine-learning-based TIIC model showed strong correlations with survival, tumor stage, and immunotherapy response. Patients with high TIIC scores had better survival and enhanced PD-L1 therapy response. Additionally, SNP rs3763840 was significantly associated with BLCA, providing insights for prognosis and treatment strategies. [Article]

• Single-cell and transcriptome analyses revealed CTHRC1 as a potential therapeutic target mediating invasion and tumor microenvironment in TNBC

This study explores the role of CTHRC1 in the tumor microenvironment of triple-negative breast cancer (TNBC). Higher CTHRC1 expression correlates with tumor progression, increased invasive gene expression, and M2 macrophage infiltration. CTHRC1-positive CAFs regulate immune suppression and tumor invasion, highlighting their potential role in TNBC progression. [Article]

• AMPK-dependent Parkin activation suppresses macrophage antigen presentation to promote tumor progression

This study reveals that Parkin, an E3 ubiquitin ligase, regulates immune responses in the tumor microenvironment (TIME). Parkin deficiency in mice enhances innate and adaptive immunity, slowing tumor progression and improving survival. Mechanistically, Parkin suppresses macrophage antigen presentation via autophagy, and its deletion enhances immune checkpoint blockade therapy. These findings highlight Parkin as a potential target for improving cancer immunotherapy. [Article]

2. Neuroscience & Neurodegenerative Diseases

• Single-cell transcriptomic and functional studies identify glial state changes and a role for inflammatory RIPK1 signaling in ALS pathogenesis

This study explores neuroinflammation in ALS using single-nucleus RNA sequencing, identifying altered glial states linked to inflammation and necroptotic signaling via RIPK1. Inhibiting RIPK1 in SOD1G93A mice delayed disease progression and modulated glial responses. iPSC-derived tri-cultures revealed potential CSF biomarkers influenced by RIPK1 activity, highlighting its role in ALS pathogenesis. [Article]

• ATP11B Modulates Microglial Lipid Metabolism and Alleviates Alzheimer's Disease Pathology

This study explores the role of ATP11B in microglial lipid metabolism and its impact on Alzheimer's disease (AD). ATP11B deficiency disrupts lipid processing, leading to pathological lipid droplet accumulation, impaired mitochondrial metabolism, and worsened AD pathology. Overexpression of ATP11B alleviates cognitive impairments, Aβ deposition, and inflammation in AD mice, highlighting its potential as a therapeutic target. [Article]

• APOE genotype determines cell-type-specific pathological landscape of Alzheimer's disease

This study examines APOE genotype-specific effects on Alzheimer's disease (AD) using single-nucleus RNA sequencing. APOE2 carriers showed enhanced synaptic and myelination pathways, preserving related proteins, while APOE3 homozygotes exhibited downregulation and reduced protein levels. APOE4 carriers had mixed effects, with increased pro-inflammatory microglial signatures but weaker responses to amyloid-β pathology. These findings highlight distinct molecular alterations in AD based on APOE genotype. [Article]

• Enhancing TREM2 expression activates microglia and modestly mitigates tau pathology and neurodegeneration

This study investigates TREM2's role in tau pathology and neurodegeneration using a tauopathy mouse model. Overexpression of wild-type TREM2 reduces phosphorylated tau and enhances microglial activation, while the R47H variant shows a loss-of-function effect. These findings highlight TREM2’s impact on microglial responses and tau pathology, offering insights for potential AD therapies. [Article]

3. Gut Microbiome & Inflammatory Diseases

• Dietary whey protein protects against Crohn's disease by orchestrating cross-kingdom interaction between the gut phageome and bacteriome

This study investigates how diet influences gut phageome-bacteriome interactions in Crohn’s disease (CD). Whey protein consumption reshapes the gut phageome, reducing CD risk by promoting Akkermansia muciniphila lysis and enhancing Streptococcus thermophilus, which counteracts intestinal inflammation. These findings highlight potential dietary and microbial strategies for CD management. [Article]

• Caffeic Acid Protects Against Ulcerative Colitis via Inhibiting Mitochondrial Apoptosis and Immune Overactivation in Drosophila

This study explores the protective effects of caffeic acid (CA) against ulcerative colitis (UC) using a Drosophila model. CA supplementation alleviates intestinal damage by restoring gut balance, reducing harmful bacteria, and inhibiting inflammatory and apoptotic pathways. These findings highlight CA's potential as a therapeutic option for UC. [Article]

• Gut Microbiota Serves as a Crucial Independent Biomarker in Inflammatory Bowel Disease (IBD)

This review highlights the critical role of gut microbiota in inflammatory bowel disease (IBD) pathogenesis, emphasizing dysbiosis, microbial metabolites, and immune interactions. It discusses potential microbiome-targeted therapies, such as probiotics and dietary interventions, while advocating for further research to refine clinical applications. [Article]

4. Cardiovascular & Inflammatory Disorders

• Exploring the impact of metabolic comorbidities on epicardial adipose tissue in heart failure with preserved ejection fraction

This study underscores the role of epicardial adipose tissue (EAT) in heart failure with preserved ejection fraction (HFpEF), showing that EAT is significantly elevated in HFpEF patients regardless of diabetes or BMI. It highlights correlations between EAT and key biomarkers, suggesting that therapies targeting EAT may be a promising avenue for HFpEF management. [Article]

• Association between triglyceride-glucose index and its combination with obesity indicators and depression

This study establishes a significant association between the triglyceride-glucose (TyG) index and depression, with stronger correlations observed when combined with obesity indicators (waist circumference, waist-to-height ratio, and BMI). The findings suggest that metabolic dysregulation plays a key role in depression risk, highlighting the potential for metabolic markers in depression screening and prevention strategies. [Article]

• Nonlinear Relation Between Cardiac Mortality and Excess Temperature in Heatwaves: Exposure Response in 2.39 Million Patients

This study analyzed 2.39 million heart disease deaths in China (2013–2019) to assess the impact of different heatwave types using an excess cumulative temperature metric (ECT-HW). Compound heatwaves posed the highest mortality risk (OR: 1.86), exceeding nighttime-only (OR: 1.16) and daytime-only (OR: 1.19) heatwaves. Mortality risks followed nonlinear patterns for single-phase heatwaves but increased steadily for compound heatwaves. Findings suggest that traditional binary heatwave definitions underestimate heart disease mortality risks, emphasizing the need for tailored healthcare strategies in a warming climate. [Article]

5. Precision Medicine & Bioinformatics

• Identification and validation of key biomarkers associated with immune and oxidative stress for preeclampsia by WGCNA and machine learning

This study identified leptin (LEP) as a key gene in preeclampsia (PE) through bioinformatics and experimental validation. LEP was upregulated and linked to immune dysregulation and oxidative stress, influencing T follicular helper cells, dendritic cells, and neutrophils. Additionally, 28 miRNAs and 15 drugs were predicted to target LEP, highlighting its potential as a diagnostic biomarker and therapeutic target for PE. [Article]

• Spatially resolved mapping of cells associated with human complex traits

This study introduces gsMap, a method integrating spatial transcriptomics with genome-wide association studies to map trait-associated cells spatially. Applied to brain data, gsMap reveals that schizophrenia-linked glutamatergic neurons align more with cognitive traits than mood disorders, clustering near the dorsal hippocampus with calcium signaling gene upregulation. In contrast, depression-associated neurons localize near the deep medial prefrontal cortex, with neuroplasticity-related gene upregulation, offering deeper insights into disease pathology. [Article]

• Highly efficient in vivo hematopoietic stem cell transduction using an optimized self-complementary adeno-associated virus

This study optimizes in vivo gene therapy for hematopoietic stem cells (HSCs) using AAV6 vectors and Cre recombination, achieving functional recombination in over two-thirds of HSCs. It identifies second-strand synthesis as a key bottleneck for transgene expression and confirms that bone marrow HSCs are highly accessible to transduction. The findings highlight AAV6’s preferential targeting of HSCs, providing insights for advancing in vivo HSC gene therapies. [Article]

• Prediction model of axillary lymph node status using an automated breast volume ultrasound radiomics nomogram in early breast cancer with negative axillary ultrasound

This study develops and validates an automated breast volume ultrasound (ABVS)-based nomogram for assessing axillary lymph node (ALN) metastasis in AUS-negative early breast cancer. Using radiomics features and machine learning, the best-performing model (Model 3) achieved high accuracy (AUC: 0.827 training, 0.768 validation). The nomogram effectively predicts ALN burden, aiding in personalized preoperative treatment planning. [Article]

Additional Highlights

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

Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice [Article]

Cryo-trojan mesenchymal stem cells as non-living tumor-homing supercarriers for enhanced drug delivery and immune activation in prostate cancer[Article]

Ginkgo biloba Extract GBE50 ameliorates cerebrovascular dysfunction and cognitive impairment in a mouse model of Alzheimer's disease[Article]

European agencies catch up with speedier regulatory pathways for CGTs in the US[News]