Ontosight^® Newsletter Issue 18

Ontosight^® – Newsletter
January 13^th – January 26^th, 2025 – Issue 18

Welcome to the 18^th edition of Ontosight^® Newsletter! This issue highlights breakthroughs in cancer research, neuroscience, infectious diseases, metabolic disorders, and emerging therapies. Discover novel immune evasion mechanisms, AI-driven drug discovery, biomarker-based dementia classification, advances in diabetes care, and cutting-edge regenerative medicine. Stay updated on the latest in healthcare innovation!

Featured Articles

1. Cancer Research and Treatments

• Immune evasion through mitochondrial transfer in the tumour microenvironment

This study uncovers a novel immune evasion mechanism in which cancer cells transfer mutated mitochondria to tumor-infiltrating lymphocytes (TILs), impairing their antitumor function. These transferred mitochondria inhibit mitophagy in TILs, leading to metabolic dysfunction and immune suppression. The findings suggest that mitochondrial DNA mutations in tumors are linked to poorer outcomes for immune checkpoint inhibitors, highlighting a potential target for improving cancer immunotherapy. [Article]

• Adjuvant Chemotherapy After Resection of Localized Pancreatic Adenocarcinoma Following Preoperative FOLFIRINOX

This study found that adjuvant chemotherapy, particularly (m)FOLFIRINOX or other multiagent regimens, significantly improved overall survival (OS) after resection of pancreatic adenocarcinoma following preoperative (m)FOLFIRINOX. However, the benefit was lower in patients who received 8 or more preoperative cycles, had a radiological response, or had ypN0 disease. Single-agent adjuvant chemotherapy did not show a significant OS benefit, highlighting the importance of multiagent regimens. [Article]

• Improved Efficacy of Triple-Negative Breast Cancer Immunotherapy via Hydrogel-Based Co-Delivery of CAR-T Cells and Mitophagy Agonist

This study highlights that poor CAR-T cell infiltration and functional exhaustion limit their efficacy in solid tumors like TNBC. AI-screened mitophagy agonist BC1618 enhances CAR-T function by improving mitochondrial health. Injectable hydrogels for co-delivery of CAR-T cells and BC1618 create a favorable tumor microenvironment, boosting antitumor response and treatment effectiveness. [Article]

• Quantum-Computing-Enhanced Algorithm Unveils Potential KRAS Inhibitors

This study presents a quantum–classical generative model for designing KRAS inhibitors for cancer therapy. The approach led to the synthesis of 15 molecules, with two showing promise as potential inhibitors. The findings highlight quantum computing’s potential in drug discovery, outperforming classical models in generating validated hits. [Article]

2. Neuroscience and Brain Health

• Identification of the subventricular tegmental nucleus as brainstem reward center

This study identifies the subventricular tegmental nucleus (SVTg) as a brainstem reward center involved in motivation and emotional regulation. In mice, SVTg activation induces reward behaviors, reduces anxiety, and promotes dopamine release while inhibiting the depression-linked lateral habenula. Findings in rats, monkeys, and humans suggest SVTg as a key hub for reward processing and mental health. [Article]

• Depressive Symptoms and Amyloid Pathology

This large-scale study examined the link between depressive symptoms and amyloid pathology in older adults without dementia. Depressive symptoms were not associated with increased amyloid pathology in cognitively normal individuals and were linked to a lower likelihood of amyloid pathology in those with mild cognitive impairment. Findings suggest that mechanisms other than amyloid accumulation may underlie late-life depression. [Article]

• Polygenic Risk Discriminates Lewy Body Dementia From Alzheimer's Disease

This study explored genetic and biomarker-based classification of Alzheimer's disease (AD) and Lewy body dementia (LBD). AD polygenic risk scores (PRS) without APOE performed similarly to plasma p-tau181 in distinguishing AD from LBD and controls. Amyloid beta positivity in LBD was linked to APOE but not AD-PRS or p-tau181. Combining AD-PRS, APOE, and p-tau181 improved diagnostic accuracy, highlighting their complementary roles in disease classification. [Article]

• Predicting survival in brain metastases using radiomic tumor heterogeneity signatures

This study developed an interpretable model integrating radiomic features and RNA sequencing data to predict survival in NSCLC patients with brain metastases. The model demonstrated strong predictive performance, achieving high AUC and C-index values. RNA sequencing revealed immune-related pathway enrichment in low-risk patients, with increased CD8+ T-cell infiltration, suggesting a favorable tumor microenvironment. These findings support personalized treatment strategies based on radiomics and transcriptomics. [Article]

3. Infectious Diseases and Immunology

• Structure-guided discovery of viral proteins that inhibit host immunity

This study develops a systematic approach to identify viral proteins that inhibit host immune defenses. By screening phage-encoded inhibitors of bacterial Thoeris and CBASS immune systems, researchers uncover seven inhibitor families that block immune protein active sites. Notably, some phage inhibitors can also suppress human and plant immune pathways, highlighting phages as a reservoir of immune-modulatory proteins with broad cross-species effects. [Article]

• Mitochondrial respiratory complex III sustains IL-10 production and promotes tumor immune evasion

This study identifies a link between mitochondrial complex III-dependent ROS production and IL-10 regulation in macrophages. Inhibiting ROS production with S3QEL 1.2 suppresses IL-10 by downregulating c-Fos, reducing tumor-supportive immunosuppression. In vivo, this approach lowers tumor growth and improves survival in melanoma-bearing mice, suggesting a potential strategy to enhance antitumor immunity. [Article]

• Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease

This study explores the role of neutrophil extracellular traps (NETs) in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). It finds that NET formation, influenced by NR4A3, drives myofibroblast differentiation, contributing to lung fibrosis. Elevated plasma NET markers correlate with RA-ILD subtypes, highlighting NETs as potential therapeutic targets. [Article]

• Human Metapneumovirus: an emerging respiratory pathogen and the urgent need for improved diagnostics, surveillance, and vaccine development

Human Metapneumovirus (HMPV) is a major cause of respiratory infections, particularly affecting vulnerable populations. Its symptoms overlap with RSV and COVID-19, complicating diagnosis, especially in low-resource settings. With no approved vaccines or antivirals, improved surveillance, scalable diagnostics, and AI-driven research are crucial for future outbreak preparedness. [Article]

4. Metabolic Disorders and Endocrinology

• How Health Systems Worldwide Fail Type 2 Diabetics

Health systems have failed to curb the rise of type 2 diabetes (T2DM), with cases quadrupling to 422 million by 2014 despite known causes and treatments. Key shortcomings include delayed detection, poor understanding of lifestyle factors, and policies that subsidize unhealthy behaviors. Addressing these systemic failures requires urgent national and global action to overcome political and economic barriers. [Article]

• Extracellular vesicle-mediated VEGF-A mRNA delivery rescues ischemic injury with low immunogenicity

VEGF-A gene therapy using extracellular vesicles (EVs) shows promise for treating ischemic vascular disease, offering efficient delivery with minimal immune response. Unlike viral vector approaches, EV-based therapy enhances neovascularization, improves arterial perfusion, and accelerates wound healing, making it a viable alternative for future clinical applications. [Article]

• Supplementation with essential amino acids improves body cell mass and reduces inflammation after ketogenic therapy

Supplementing with essential amino acids (EAAs) during the post-ketogenic transition phase of very low-energy ketogenic therapy (VLEKT) enhances fat loss, muscle strength, and reduces inflammation. These findings suggest EAAs help counteract potential drawbacks of carbohydrate reintroduction, improving long-term metabolic and body composition outcomes. [Article]

• Effects of the Mediterranean Diet on Metabolic Syndrome Components and Cardiometabolic Risk

The Mediterranean diet effectively mitigates metabolic syndrome by reducing central obesity, improving lipid profiles, enhancing insulin sensitivity, and lowering blood pressure. Its anti-inflammatory and antioxidant properties, derived from unsaturated fats, polyphenols, and fiber, contribute to better metabolic health. Combined with lifestyle changes like increased physical activity, this dietary approach offers a sustainable strategy for reducing cardiometabolic risk and preventing chronic diseases. [Article]

5. Emerging Therapies, Regenerative Medicine, and Precision Diagnostics

• Nanodrugs targeting ferroptosis regulation for osteoarthritis treatment

Osteoarthritis (OA) progression is linked to ferroptosis, making its regulation a promising therapeutic target. This study develops ROS-responsive Ce@D&P nanoparticles (NPs) that reduce ROS, mitigate inflammation, and inhibit ferroptosis in chondrocytes. Mechanistically, Ce@D&P NPs regulate oxidative stress and lipid metabolism, improving extracellular matrix balance. In a mouse OA model, intra-articular injection of Ce@D&P NPs alleviates cartilage damage and slows disease progression. [Article]

• Machine Learning to Predict Mortality in Older Cancer Patients

The Geriatric Cancer Scoring System (GCSS) was developed and externally validated to improve 12-month mortality prediction in older cancer patients using machine learning. Based on data from two French cohorts, key predictors included oncologic, geriatric, and biomarker factors, with the Random Survival Forest (RSF) model achieving the highest predictive accuracy (tAUC: 0.87). GCSS outperformed traditional models and may enhance personalized prognosis and treatment decisions. Further validation in international settings is needed to confirm its generalizability. [Article]

• Biomolecular Microneedle Initiates Fe(3)O(4)/MXene Heterojunction-Mediated Nanozyme-Like Reactions and Bacterial Ferroptosis to Repair Diabetic Wounds

This study develops a Fe₃O₄/MXene (FM) heterojunction that modulates ROS levels to enhance wound healing in diabetes. The FM heterojunction scavenges extracellular ROS while inducing bacterial ferroptosis by releasing iron ions. Incorporated into a GelMA-based microneedle (GFM), it promotes skin regeneration in infected diabetic wounds. The GFM microneedle, combined with photothermal therapy, demonstrates efficacy comparable to commercial wound dressings. [Article]

• N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes

This study identifies N-Cadherin as a key regulator of cardiomyocyte (CM) proliferation and heart regeneration. Its expression decreases with age but is upregulated in neonatal hearts post-injury, enhancing CM mitotic activity. N-Cadherin stabilizes β-Catenin to promote CM renewal, and its overexpression improves cardiac regeneration in adult mice. Targeting N-Cadherin may offer a promising strategy for heart repair after injury. [Article]

• Stratification System With Dual Human Endogenous Retroviruses for Predicting Immunotherapy Efficacy in Metastatic Clear-Cell Renal Cell Carcinoma

This study identifies two endogenous retrovirus (ERV) elements as key predictors of immune checkpoint inhibitor (ICI) response in metastatic clear-cell renal cell carcinoma (ccRCC). A dual ERV-based stratification system effectively categorizes patient risk and correlates with treatment outcomes. High-response ERV profiles show endothelial infiltration, while resistance is linked to immune suppressive cells and T-cell exhaustion. This ERV model outperforms traditional transcriptomic markers and may enhance precision oncology strategies. [Article]

Additional Highlights

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

• α-Synuclein Deposition in the Kidney May Contribute to Parkinson's Disease [Article]
• Roche receives FDA clearance with CLIA waiver for cobas® liat molecular tests to diagnose sexually transmitted infections at the point of care[News]
• Stealth BioTherapeutics Announces PDUFA Action Date Extension for Elamipretide to Treat Patients with Barth Syndrome[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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