Ontosight^® Newsletter Issue 17

Ontosight^® – Newsletter
December 30^th – January 12^th, 2025 – Issue 17

Welcome to the 17^th edition of Ontosight^® Newsletter! This issue features groundbreaking advancements across oncology, neuroscience, gut microbiota, cardiovascular innovations, and drug development. Explore cutting-edge research on immune therapies, neurodegenerative disorders, gut microbiome's role in health, novel cardiac treatments, and personalized medicine breakthroughs, alongside key regulatory updates shaping the healthcare landscape.

Featured Articles

1. Advances in Cancer Research and Therapeutics

• CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells

The study presents CD70-targeted, multi-gene-edited CAR-natural killer (70CAR-iNK) cells derived from induced pluripotent stem cells as a universal immune therapy. These cells show robust cytotoxicity against diverse tumors, eliminate alloreactive T cells, and improve survival in xenograft models. 70CAR-iNK cells offer promising potential for next-generation cancer immunotherapy. [Article]

• Cancer-associated fibroblasts induce almonertinib resistance in non-small cell lung cancer

This study explores almonertinib resistance in NSCLC, showing that cancer-associated fibroblasts (CAFs), induced by almonertinib-stimulated TGF-β1 secretion, enhance tumor cell survival and drug resistance. Resistance is linked to reduced YAP/TAZ signaling, as demonstrated through phenotypic and molecular analyses. Targeting CAFs and the YAP/TAZ pathway may improve therapeutic outcomes. [Article]

• SMAC-armed oncolytic virotherapy enhances the anticancer activity of PD1 blockade by modulating PANoptosis

This study introduces VSV-S, a vesicular stomatitis virus engineered with the SMAC/DIABLO gene, which enhances PANoptosis and CD8+ T cell-mediated antitumor immunity in HNSCC. VSV-S also reduces PDL1 levels, and when combined with PD1 blockade, demonstrates synergistic therapeutic efficacy. This approach highlights VSV-S as a promising strategy to advance virotherapy for HNSCC. [Article]

• Promotion of Triple Negative Breast Cancer Immunotherapy by Combining Bioactive Radicals with Immune Checkpoint Blockade

This study presents O3-001@lipo, a nano-system combining ozone and the CD47 inhibitor RRx-001, activated by irradiation to produce reactive nitrogen species (RNS) with potent cytotoxic effects. The system induces immunogenic cell death, promotes T-lymphocyte infiltration, and reprograms the tumor microenvironment to an anti-tumor state. This approach significantly enhances immunotherapy efficacy, offering a novel strategy for treating immune-deficient tumors like triple-negative breast cancer. [Article]

2. Neurodegenerative Diseases and Brain Health

• Exploring the triglyceride-glucose index's role in depression and cognitive dysfunction: Evidence from NHANES with machine learning support

This study examines the relationships between the triglyceride-glucose (TyG) index, BMI, depression, and cognitive dysfunction in older adults using NHANES data and machine learning. Findings show the TyG index is linked to lower cognitive function and higher depression scores, with BMI and lipid metabolism playing significant roles. Further research is needed to confirm these associations and explore mechanisms. [Article]

• Sexually dimorphic dopaminergic circuits determine sex preference

This study identifies the ventral tegmental area dopaminergic (VTADA) neurons as key regulators of sociosexual preferences in mice. Both male and female mice show a shift from female to male preference under survival threats, mediated by dimorphic changes in VTADA neuron excitability. The findings highlight distinct neural circuits for male and female preferences, revealing the VTADA-NAc and VTADA-medial preoptic area pathways as critical to these social decisions. [Article]

• Locus coeruleus signal intensity and emotion regulation in agitation in Alzheimer's disease

This study explores the relationship between locus coeruleus integrity, emotion regulation, and agitation in Alzheimer's disease. Findings suggest that compromised locus coeruleus structure and dysfunction in the affect-related executive regulation network are linked to increased agitation severity. The results support the hypothesis that locus coeruleus overactivity and emotion dysregulation contribute to agitation in Alzheimer's, highlighting the need for further research into causal mechanisms across disease stages. [Article]

• Neurological post-COVID syndrome is associated with substantial impairment of verbal short-term and working memory

This study assesses cognitive deficits in Post-COVID Syndrome (PCS) patients, revealing higher fatigue, depression, and anxiety levels compared to non-PCS patients and healthy controls. Neuropsychological testing shows PCS patients have impaired mental flexibility, working memory, and reaction times. These findings underscore the need to optimize treatment and rehabilitation for PCS patients with neurologic symptoms. [Article]

3. Gut Microbiota and Metabolic Disorders

• Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics

This study investigates tirzepatide's hepatoprotective effects in MAFLD mice, showing it reduces liver enzymes, triglycerides, and cholesterol. Mechanistically, tirzepatide lowers fatty acid uptake, enhances mitochondrial-lysosomal function, and promotes cholesterol efflux. These findings provide insights into tirzepatide's potential therapeutic action in MAFLD. [Article]

• Meat intake in relation to composition and function of gut microbiota

This large population-based study explores the impact of meat intake on gut microbiota composition, showing that processed red meat reduces microbial diversity and affects 322 species. It links processed red meat intake to microbial pathways related to amino acid degradation and several health biomarkers, such as increased fasting insulin and triglyceride levels. The findings suggest that meat, especially processed red meat, may influence gut microbiota and health-related biomarkers. [Article]

• Gut microbes modulate the effects of the flavonoid quercetin on atherosclerosis

This study shows that quercetin supplementation reduces atherosclerosis in ApoE knockout mice, but only in those with a conventional gut microbiome. Metabolomic analysis reveals that quercetin increases certain metabolites, such as 3,4-DHBA, which are associated with reduced atherosclerosis burden. The findings suggest that quercetin's effects on atherosclerosis are mediated by gut microbial metabolism. [Article]

• Oral and Fecal Microbiota as Accurate Non-invasive Tools for Detection of Pancreatic Cancer in the Chinese Population

This study identifies oral and fecal microbiome biomarkers for pancreatic cancer (PCA) through 16S rRNA sequencing. Significant dysbiosis was found in PCA patients, with key taxa like Streptococcus in oral samples and Bifidobacterium, Klebsiella, and Akkermansia in fecal samples. Fecal microbiome classifiers showed high diagnostic accuracy (AUC 0.963), particularly in Chinese populations, and could predict PCA metastasis. [Article]

4. Cardiovascular Innovations and Studies

• Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors and the Prevention of Cirrhosis Among Patients With Type 2 Diabetes

This cohort study compared the effects of glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors on cirrhosis and liver outcomes in type 2 diabetes patients. GLP-1RAs showed no significant impact on cirrhosis risk, while SGLT-2 inhibitors were associated with a reduced incidence of cirrhosis and decompensated cirrhosis compared to dipeptidyl peptidase 4 (DPP-4) inhibitors. [Article]

• Cardiovascular health, genetic predisposition, and dementia risk among atherosclerotic cardiovascular disease patients

This study examined the interaction between cardiovascular health (CVH) and genetic predisposition on dementia risk in 30,818 ASCVD patients. Higher CVH levels were linked to a reduced risk of vascular dementia (VaD), with a stronger effect in those with lower genetic risk. However, CVH was not associated with Alzheimer's disease (AD) risk, though improvements in sleep and glucose control were related to lower VaD risk. [Article]

• Novel Therapies to Reduce Rehospitalization Risk in Worsening Heart Failure

This review assessed the impact of novel heart failure therapies on reducing rehospitalization risks in patients with worsening heart failure (WHF). The analysis of 9 clinical trials involving 18,540 patients found that early administration of sodium-glucose co-transporter 2 inhibitors, ARNI, and ferric carboxymaltose significantly reduced rehospitalization rates. These findings suggest that initiating these therapies during hospitalization could improve patient outcomes and reduce rehospitalization risks in WHF management. [Article]

5. Advanced Drug Development and Innovations in Personalized Medicine

• Sequential Targeting Chondroitin Sulfate-Bilirubin Nanomedicine Attenuates Osteoarthritis via Reprogramming Lipid Metabolism in M1 Macrophages

This study highlights a novel therapy targeting macrophage activity in osteoarthritis (OA) using licofelone-loaded nanoparticles (LCF-CSBN). These nanoparticles selectively reprogram lipid metabolism in M1 macrophages, facilitating their transition to anti-inflammatory M2 macrophages. In OA model rats, intra-articular LCF-CSBN reduced joint inflammation, oxidative stress, and cartilage degeneration, showcasing its potential as a targeted OA treatment. [Article]

• A reactive oxygen species-responsive hydrogel loaded with Apelin-13 promotes the repair of spinal cord injury by regulating macrophage M1/M2 polarization and neuroinflammation

This study introduces a ROS-responsive hydrogel loaded with Apelin-13 (Apelin-13@ROS-hydrogel) as a novel therapeutic strategy for spinal cord injury (SCI). The hydrogel regulates macrophage polarization, reduces neuroinflammation, and enhances ROS scavenging, promoting functional recovery and tissue repair in SCI models. These findings highlight the potential of combining Apelin-13 and ROS-responsive delivery systems for improved SCI treatment outcomes. [Article]

• Intranasal administration of stem cell-derived exosome alleviates cognitive impairment against subarachnoid hemorrhage

This study explores the therapeutic effects of intranasally delivered mesenchymal stem cell (MSC)-derived exosomes in a subarachnoid hemorrhage (SAH) rat model. Exosome treatment improved cognitive function, reduced apoptosis and inflammation, and preserved blood-brain barrier integrity. PET/CT imaging revealed targeted brain delivery, with exosomes localizing in the olfactory nerve, cerebrum, and brainstem. These findings highlight the potential of intranasal MSC-derived exosomes as a novel treatment for SAH. [Article]

• Computational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody-drug conjugates

Researchers developed a pertuzumab variant (Ptz-SA) to overcome resistance caused by the HER2 S310F mutation in cancer. Using computational design, two mutations (T30S/D31A) restored binding and enabled potent antitumor activity in vitro and in vivo, particularly as an antibody-drug conjugate. Structural analysis revealed how Ptz-SA circumvents mutation-induced steric hindrance. It also binds the HER2 S310Y mutation, offering a strategy against resistance in HER2-targeted therapies. [Article]

• NVP-2, in combination with Orlistat, represents a promising therapeutic strategy for acute myeloid leukemia

CDK9 regulates genes critical for proliferation and survival in AML cells, including mTOR, SREBF1, and Bcl-2. Knockdown studies revealed CDK9 and FASN as essential for AML cell growth, with pathways like MCL1, c-Myc, and Akt/mTOR/SREBF1 playing key roles. Combined treatment with NVP-2 and Orlistat shows potential as a clinical therapy for AML. [Article]

Additional Highlights

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

• MAF1 inhibits hepatocarcinogenesis by fostering an immunostimulatory tumor microenvironment [Article]
• Moderate-intensity interval exercise exacerbates cardiac lipotoxicity in high-fat, high-calorie diet-fed mice[Article]
• Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD[Article]
• Oxidative/Nitrosative Stress, Apoptosis, and Redox Signaling: Key Players in Neurodegenerative Diseases[Review]
• GSK’s Shingrix new prefilled syringe presentation accepted for review by US FDA[News]

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