Ontosight® - Newsletter Issue - 8
Innoplexus - a Partex Company
The expert in AI technology for drug discovery and development.
Welcome to the 8th edition of Ontosight® Newsletter! This issue features groundbreaking research in oncology, cardiovascular medicine, metabolic diseases, neurodegenerative research, and tissue engineering. We also cover key regulatory updates in the pharmaceutical industry. Get ready for an exciting dive into the latest innovations shaping modern medicine!
Featured Articles
1. Cancer Research and Oncology
This study examines tertiary lymphoid structures (TLS) and their interactions with tumor cell aggregates in nasopharyngeal carcinoma. Through single-cell and spatially-resolved transcriptome analysis, it identifies key cell populations such as CXCL13+ fibroblasts and CD8+ T cells. The research highlights how these cells promote apoptosis of EBV-related malignant cells and enhance immunotherapy response. TLS-related cell signatures are linked to prognosis and response to PD-1 blockade, providing potential therapeutic insights for cancer treatment. [Article]
This study explores the cellular and molecular factors influencing response to CD19-targeting CAR-T therapy in relapsed/refractory Large B-Cell Lymphoma (LBCL). By analyzing blood samples from 50 patients treated with axicabtagene ciloleucel (axi-cel), the researchers identified baseline features such as elevated B cells and a high lymphocyte-to-monocyte ratio (ALC/AMC) associated with better outcomes. A predictive model incorporating these factors was validated in a larger cohort, showing a significant difference in progression-free survival. The findings suggest that baseline immune characteristics can predict CAR-T therapy response, aiding in patient selection. [Article]
This study investigates PANoptosis-related genes (PRGs) in colorectal cancer (CRC) and their clinical significance. Five key PRGs (BCL10, CDKN2A, DAPK1, PYGM, and TIMP1) were identified and validated in CRC cells and tissues. These genes were linked to immune microenvironment, immune cell infiltration, chemotherapy sensitivity, and tumor progression pathways. A novel prognostic model combining clinical indicators and key PRGs was developed to predict CRC outcomes. The findings provide new insights into CRC pathogenesis, prognosis, and potential therapeutic targets. [Article]
This study introduces a method to quantify the spatial proximity of immune cells in the tumor microenvironment using single-cell spatial data. Applied to lung adenocarcinoma patients, the proximity between cell types was found to be more predictive of prognosis than immune cell density. Proximity of T helper and B cells to cancer cells correlated with survival benefits, while M2 macrophage proximity to various immune cells indicated poor prognosis. The method provides a novel way to assess immune cell interactions and their impact on patient outcomes. [Article]
This retrospective study evaluates systemic treatments for brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients with non-sensitive mutations. Among 209 patients, three treatment regimens were compared: chemotherapy alone, chemotherapy plus immune checkpoint inhibitors (ICIs), and chemotherapy with ICIs and antiangiogenic therapy. The combination of all three therapies (C + I + A) significantly improved overall survival to 23.6 months, compared to 11.4 months with chemotherapy alone. The study highlights the effectiveness of tailored combination therapies in improving survival and reducing mortality risk in NSCLC patients with BMs. [Article]
This study explores the role of TBC1 domain-containing proteins (TBC1Ds) in cancer metabolism, particularly in triple-negative breast cancer (TNBC). Elevated expression of certain TBC1Ds (TBC1D31, TBC1D22B, and TBC1D7) was found to drive a glycolytic metabolic phenotype in TNBC, correlating with poor prognosis. TBC1D7's impact on glycolysis was shown to be independent of its known role in mTORC1 regulation. As a potential biomarker, TBC1D7 could help identify TNBC patients with poor prognosis who may benefit from anti-glycolytic therapies, offering a personalized approach to treatment. [Article]
This study presents a cross-modal multi-pathway automated prediction model to predict pathological complete response (pCR) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). By integrating temporal and spatial information from biopsy digital pathology images and multi-temporal ultrasound images, the model effectively predicts pCR status early in treatment. The findings highlight its potential as a valuable tool for personalizing treatment strategies based on individual responses, improving early NAC outcome predictions. [Article]
This study explores the role of M2 macrophages in prostate cancer (PCa) progression and prognosis. Using single-cell RNA sequencing (scRNA-seq) and mRNA expression data, the researchers identified key M2 macrophage-related genes and constructed a risk score model based on nine prognostic gene signatures. M2 macrophages were found to promote PCa proliferation, invasion, and migration. The findings suggest that M2 macrophages and their associated genes are significant in PCa development and could serve as predictive biomarkers for prognosis and treatment response. [Article]
This study provides a comprehensive analysis of SEPT9, a cytoskeletal GTPase, across various cancers, revealing its role in tumorigenesis, prognosis, and treatment. SEPT9 is found to be highly expressed in many cancers, including lung squamous cell carcinoma (LUSC), where it is linked to poor clinical outcomes and affects drug sensitivity. Functional analyses indicate that SEPT9 influences tumor progression and immune microenvironments, enhancing immunotherapy effectiveness. A prognostic model incorporating SEPT9 and other mitotic spindle-related genes was developed, improving predictions and therapeutic strategies for LUSC patients. [Article]
2. Cardiovascular and Metabolic Diseases
In a trial of patients with heart failure and a left ventricular ejection fraction ≥40%, finerenone significantly reduced worsening heart failure events and cardiovascular deaths compared to placebo (rate ratio, 0.84). It also decreased heart failure events (rate ratio, 0.82) but had no significant effect on cardiovascular mortality. Finerenone increased hyperkalemia risk but reduced hypokalemia. [Article]
In a meta-analysis of four trials involving 13,846 patients with heart failure, mineralocorticoid receptor antagonists (MRAs) reduced cardiovascular death or heart failure hospitalizations by 23% overall. MRAs were more effective in patients with heart failure and reduced ejection fraction (HFrEF) compared to those with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). Specifically, MRAs reduced heart failure hospitalizations in both groups, but cardiovascular death and all-cause mortality were significantly decreased only in the HFrEF group. MRAs increased the risk of hyperkalemia but reduced hypokalemia. [Article]
In a phase 3 trial comparing asundexian (50 mg daily) to apixaban for stroke prevention in atrial fibrillation, asundexian was found to have a higher incidence of stroke or systemic embolism (1.3% vs. 0.4%) and fewer major bleeding events (0.2% vs. 0.7%). The trial was stopped early due to these results. Asundexian was less effective in preventing strokes but had a better safety profile concerning major bleeding compared to apixaban. [Article]
This study examines the impact of protein-disrupting variants in LDL metabolism genes (LDLR, APOB, PCSK9) on aortic stenosis (AS) and aortic valve peak velocity. It found that LDLR variants, which increase LDL-C levels, are linked to a higher risk of AS, while APOB and PCSK9 variants, which lower LDL-C levels, are associated with reduced AS risk. These findings suggest that lifelong LDL-C alterations due to genetic variants significantly influence AS risk, highlighting the potential benefit of early lipid-lowering therapy in preventing AS. [Article]
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This study reveals that neuropeptide Y (NPY) in sympathetic neurons helps protect against obesity by maintaining the proliferation of mural cells in adipose tissues, which are crucial for thermogenesis. NPY+ sympathetic axons are primarily associated with perivascular regions in brown and white adipose tissues. Loss of NPY from sympathetic neurons leads to reduced thermogenic capability, increased susceptibility to obesity, and impaired energy expenditure without affecting food intake. [Article]
This study reveals that sortilin, an endosomal trafficking component, regulates the localization and degradation of mitochondrial ACSL1, a key enzyme in fatty acid oxidation. During beige fat activation, sortilin facilitates the movement of ACSL1 from mitochondria to the endolysosomal pathway. Sortilin depletion leads to increased mitochondrial ACSL1, activation of AMPK/PGC1α signaling, and improved beige fat function. This process helps prevent obesity and insulin resistance induced by a high-fat diet. The findings suggest targeting sortilin could be a promising strategy for treating metabolic diseases. [Article]
This study investigates the role of lysine crotonylation of NEDD8-activating enzyme E1 regulatory subunit (NAE1) in cardiac hypertrophy. Elevated crotonylation of NAE1, particularly at lysine 238, was linked to exacerbated cardiac hypertrophy in mouse models and human patients. Using knock-in mice with crotonylation-defective (NAE1 K238R) and crotonylation-mimicking (NAE1 K238Q) mutations, the study found that crotonylation enhances pathological hypertrophy by promoting the neddylation and stability of gelsolin (GSN), leading to adverse cytoskeletal remodeling. These findings suggest that targeting NAE1 crotonylation could offer new therapeutic approaches for cardiac hypertrophy. [Article]
3. Neurodegenerative Diseases and Cognitive Disorders
This study investigates microglial activation in Alzheimer’s disease (AD) and its potential as a biomarker. Researchers found that microglial synchronicity is disrupted in AD, leading to regional desynchronization in the brain. Using TSPO-PET imaging and single-cell radiotracing in mice and human datasets, they demonstrated that microglial desynchronization correlates with cognitive decline. The findings suggest that microglia synchronicity could serve as a biomarker for AD progression. [Article]
This study reveals that pimozide, an antipsychotic drug, inhibits lysosome function to reduce fatty acid and cholesterol release in glioblastoma (GBM). However, GBM develops resistance by increasing glutamine consumption and lipogenesis via SREBP-1. This creates a feedforward loop that drives drug resistance. Combining pimozide with inhibitors targeting glutamine metabolism disrupts this loop, causing mitochondrial damage and oxidative stress, leading to GBM cell death. The findings suggest a promising therapeutic strategy by combining glutamine metabolism inhibition with lysosome suppression. [Article]
This study analyzed 1.65 million RNA-sequencing profiles from 437 older individuals to identify cellular changes linked to Alzheimer's disease (AD). Researchers found two key microglial subpopulations—one driving amyloid-β buildup and another mediating its effect on tau protein. An astrocyte subpopulation was also linked to tau-related cognitive decline. The findings reveal two brain aging pathways, one leading to AD and the other to healthy aging, offering new insights for personalized treatments. [Article]
This study reveals that cochlear outer hair cells (OHCs), responsible for hearing, are vulnerable to DNA damage from the drug cisplatin, leading to hearing loss in mice. It shows that BRCA1, a DNA repair factor, is activated in response to cisplatin-induced damage and helps protect OHCs. Loss of BRCA1 accelerates OHC damage and hearing loss. This is the first in vivo evidence that BRCA1 plays a key role in repairing DNA damage in OHCs, helping prevent sensorineural hearing loss caused by drug-induced or age-related damage. [Article]
4. Regenerative Medicine and Tissue Engineering
This study developed a hydrogel microneedle patch (MNP) that delivers mitochondria-rich extracellular vesicles (EVs) to treat radiation-induced chronic wounds. By using metformin to enhance mitochondrial biogenesis in stem cells, they increased EV secretion (Met-EVs), which improved mitochondrial function and reduced oxidative stress in damaged tissues. The patch gradually releases these Met-EVs, promoting anti-inflammatory responses and accelerating wound healing in mice. This approach shows promise for treating chronic wounds. [Article]
This study identifies p63-expressing progenitor cells as key players in lung repair following injury. After bleomycin-induced lung damage, p63+ progenitors rapidly proliferate and differentiate into alveolar type 1 and 2 cells. Using genetic tracing, the researchers show that these progenitors originate from airway secretory cells and are essential for efficient alveolar regeneration. The findings suggest secretory-cell-derived p63+ progenitors as a potential therapeutic target for lung regeneration. [Article]
Additional Highlights
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Experimental Medicine , Faculty of Medicine, UBC, Vancouver | Medical Content Writing
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