Ontosight^® Newsletter Issue 11

Ontosight^® – Newsletter
October 7^th – October20^th, 2024 – Issue 11

Welcome to the 11^th edition of the Ontosight^® Newsletter! This issue features cutting-edge advancements in cancer treatment, neurobiology, and cardiovascular health, alongside innovative insights in proteomics and therapeutics. Additionally, we delve into the latest developments in immunology and infectious diseases. Join us as we explore the transformative research and regulatory updates that are shaping the future of healthcare!.

Featured Articles

1. Innovative Strategies in Cancer Treatment and Biomarkers

• Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy

This study introduces pH/cathepsin B-sensitive nanoparticles (PSRNs) to enhance the delivery of PROTACs, which target CDK4/6, for the treatment of colorectal cancer (CRC). The nanoparticles maintain stability in circulation, penetrate tumors, and release PROTACs inside cells, improving the degradation of target proteins. This approach also enhances the efficacy of immune checkpoint inhibitors by upregulating PD-L1 and suppressing regulatory T cells. In combination with α-PD-1 therapy, the strategy shows improved anti-tumor outcomes in a CRC model. [Article]

• USP7 depletion potentiates HIF2α degradation and inhibits clear cell renal cell carcinoma progression

This study identifies USP7 as a key factor in stabilizing HIF2α, an oncogenic driver in clear cell renal cell carcinoma (ccRCC). Inhibiting USP7 suppresses tumor growth, and combining USP7 inhibitors with afatinib enhances HIF2α degradation and tumor suppression. This reveals a novel therapeutic strategy for targeting ccRCC. [Article]

• Probiotic neoantigen delivery vectors for precision cancer immunotherapy

This study engineers probiotic E. coli Nissle 1917 as a cancer vaccine platform, enhancing neoepitope delivery for potent T cell-mediated immunity. The system boosts safety, immunogenicity, and effectively controls tumor growth in advanced cancer models. It activates dendritic cells, neoantigen-specific T cells, and natural killer cells, while reducing immunosuppressive cells in tumors, offering a promising approach for durable antitumor immunity. [Article]

• Bioinformatics data combined with single-cell analysis reveals patterns of immunoinflammatory infiltration and cell death in melanoma

This study used single-cell analytics and bioinformatics to investigate the molecular mechanisms and immune cell infiltration in melanoma. It identified 20 key differentially expressed genes and found that immune and inflammatory responses, as well as pathways like PI3K-Akt and HIF-1, are strongly associated with melanoma. Immune cells, particularly macrophages, play a significant role in melanoma progression. The findings highlight ferroptosis as a key cell death mechanism and suggest that macrophages are crucial in melanoma development, providing a direction for future research. [Article]

• Spatial proteomics identifies JAKi as treatment for a lethal skin disease

This study identifies key molecular changes associated with toxic epidermal necrolysis (TEN) using deep visual proteomics, revealing enriched type I and II interferon signatures and activated STAT1 in keratinocytes and immune cells. Targeted JAK inhibitors, such as tofacitinib, significantly reduced keratinocyte cytotoxicity and improved clinical outcomes in mouse models and seven patients with TEN. The findings highlight the JAK/STAT and interferon signaling pathways as crucial drivers of TEN, suggesting JAK inhibitors as a promising therapeutic option. [Article]

• Oncofetal MCB1 Is a Functional Biomarker for HCC Personalized Therapy

This study identifies MCB1 as an oncofetal protein upregulated in early hepatocellular carcinoma (HCC), promoting T-IC generation and driving HCC initiation through p53 degradation. MCB1 levels influence responses to chemotherapy and predict TACE benefits, while mediating resistance to targeted therapies by downregulating FGFR1 and VEGFR3. These findings suggest MCB1’s potential as a biomarker for personalized HCC therapy and a target for combinational treatment strategies. [Article]

2. Neurobiology and Metabolism: Insights into Alzheimer’s and Mental Health

• Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis

This study links apolipoprotein E (APOE) aggregates to the initiation of amyloid-β (Aβ) amyloidosis in Alzheimer’s disease (AD). Using a transgenic mouse model, researchers found that fibrillary APOE aggregates trigger Aβ accumulation in microglia, influenced by lipid metabolism and JAK/STAT signaling. The findings suggest that microglial uptake and aggregation of APOE may initiate Aβ plaque formation, contributing to AD pathogenesis. [Article]

• Glutamine metabolism modulates microglial NLRP3 inflammasome activity through mitophagy in Alzheimer’s disease

This study links glutamine metabolism to the activation of the NLRP3 inflammasome in microglia during Alzheimer’s disease (AD). Suppressing glutaminase, a key enzyme in glutamine metabolism, reduces NLRP3 activation by promoting mitophagy and limiting reactive oxygen species. The findings suggest glutamine metabolism as a potential therapeutic target for AD. [Article]

• Vagal sensory neuron-derived FGF3 controls insulin secretion

This study reveals that fibroblast growth factor 3 (Fgf3) is upregulated in vagal ganglia during acute metabolic stress, enhancing glucose-stimulated insulin secretion (GSIS) and improving glucose metabolism. Overexpression of Fgf3 in pancreatic vagal neurons boosts insulin secretion and glucose clearance, while its ablation worsens glucose intolerance. The findings highlight Fgf3 as a key regulator of pancreatic β-cell activity via vagal afferent signaling. [Article]

• Substantia nigra hyperechogenicity and brain ventricular size as biomarkers of early dementia with Lewy bodies

This study identifies transcranial sonography (TCS) parameters, such as substantia nigra (SN) hyperechogenicity and widened frontal horns of lateral ventricles, as predictors of early dementia with Lewy bodies (DLB). DLB and Parkinson’s disease patients showed higher SN hyperechogenicity compared to Alzheimer’s patients and controls. The findings suggest that TCS could be a useful non-invasive tool for diagnosing early-stage DLB. [Article]

• Major depressive disorder, neuroticism, suicidal behaviors, and depression severity are associated with cytokine networks and their intricate interactions with metabolic syndrome

This study examines immune profile alterations in outpatients with major depressive disorder (MDD) and their associations with symptoms such as suicidal ideation and neuroticism. Outpatient MDD is characterized by upregulated immune-related proteins, indicating a neurotoxic cytokine profile, while metabolic syndrome (MetS) further enhances immune activation. These immune changes are linked to the severity of MDD symptoms, neuroticism, and suicidal behaviors. [Article]

3. Cardiovascular Health Insights: Metabolic Links and Risk Factors

• Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction

This study explores how SGLT2 inhibitors (dapagliflozin) impact metabolism in heart failure (HF) across a range of left ventricular ejection fractions (LVEF). Dapagliflozin increased ketone and fatty acid metabolism, with a stronger ketogenic effect in lower LVEF. Changes in fatty acid and amino acid metabolism were linked to worse HF outcomes, suggesting potential therapeutic targets across HF subtypes. [Article]

• Risk factors and clinical significance of post-stroke incident ischemic lesions

Incident ischemic lesions (IILs) were found in 15.5% of stroke patients 6 months after the initial event, mainly clinically silent but linked to worse cognitive and functional outcomes and higher stroke recurrence risk. Small vessel disease was the primary risk factor for IILs. Assessing IILs through follow-up MRI could improve long-term prognostication for stroke patients. [Article]

• Shear-Sensing by C-Reactive Protein: Linking Aortic Stenosis and Inflammation

Shear stress in aortic valve stenosis (AS) induces the dissociation of pentameric C-reactive protein (pCRP) into proinflammatory monomeric CRP (mCRP), which contributes to endothelial activation and platelet activation. Studies demonstrated that mCRP levels were significantly higher in patients before transcatheter aortic valve implantation compared to after, with mCRP also observed on excised stenotic aortic valves. This shear-induced mechanism of pCRP dissociation may be relevant to other conditions with increased shear rates, such as atherosclerosis. [Article]

• Multiple triglyceride-derived metabolic indices and incident cardiovascular outcomes in patients with type 2 diabetes and coronary heart disease

This study investigates the relationship between triglyceride-derived metabolic indices—specifically the atherogenic index of plasma (AIP), triglyceride-glucose (TyG) index, and triglyceride glucose-body mass index (TyG-BMI)—and cardiovascular outcomes in patients with type 2 diabetes (T2DM) and coronary heart disease (CHD). The results indicate that higher levels of AIP, TyG index, and TyG-BMI are associated with an increased risk of major adverse cardiac and cerebrovascular events (MACCEs), with AIP showing the strongest predictive ability. The findings suggest that monitoring AIP may be crucial for lipid management in patients with T2DM and CHD. [Article]

4. Innovations in Proteomics and Therapeutics

• Thermal proteome profiling reveals fructose-1,6-bisphosphate as a phosphate donor to activate phosphoglycerate mutase 1

This study identifies fructose-1,6-bisphosphate (FBP) as a phosphate donor that activates phosphoglycerate mutase 1 (PGAM1), enhancing glycolysis and cell proliferation. FBP modifies PGAM1 through histidine phosphorylation, linking sugar metabolism to cancer growth. The findings also highlight potential inhibitors of PGAM1, offering new avenues for cancer treatment targeting metabolic pathways. [Article]

• Quantum Dots-caused Retinal Degeneration in Zebrafish Regulated by Ferroptosis and Mitophagy

This study investigates the effects of InP/ZnS quantum dots (QDs) on zebrafish retinas, revealing that they induce retinal degeneration. The mechanism involves endocytosis by retinal pigment epithelial cells, leading to impaired splicing of the prpf8 gene, reduced glutathione levels, and subsequent ferroptosis and mitophagy. The findings highlight potential health risks associated with InP/ZnS QDs and their impact on eye development. [Article]

• Multiscale drug screening for cardiac fibrosis identifies MD2 as a therapeutic target

The study identifies artesunate as a promising treatment for cardiac fibrosis, inhibiting fibroblast activity and collagen deposition while improving heart function in engineered tissues and mouse models. It works by targeting the MD2/TLR4 signaling pathway to reduce fibrotic gene expression. This research highlights a new therapeutic approach for cardiac fibrosis using a comprehensive drug screening strategy. [Article]

• Deep learning model with pathological knowledge for detection of colorectal neuroendocrine tumor

This study introduces an efficient method for differentiating colorectal neuroendocrine tumors (NETs) from colorectal carcinoma (CRC) using only 2% of relevant pathological image patches. The model achieved high accuracy with AUROCs of 0.9974, 0.9724, and 0.9513 across different datasets. By reducing unnecessary immunohistochemical tests, this approach enhances treatment precision for colorectal tumors and promotes the use of artificial intelligence in clinical applications. [Article]

5. Immunology and Infectious Diseases

• Single-cell spatiotemporal analysis of the lungs reveals Slamf9+ macrophages involved in viral clearance and inflammation resolution

This study explores how the lungs recover from severe pneumonia caused by SARS-CoV-2 in a Syrian hamster model. It identifies a population of resilient Slamf9+ macrophages that help clear the virus and subsequently differentiate to aid in inflammation resolution and restore alveolar macrophages. These findings are supported by similar results in a mouse model and human autopsy data. [Article]

• Lactylation of RNA m(6)A demethylase ALKBH5 promotes innate immune response to DNA herpesviruses and mpox virus

This study reveals that the RNA demethylase ALKBH5 undergoes lactylation, which is essential for an effective antiviral immune response against DNA herpesviruses like HSV-1. Lactylated ALKBH5 enhances interferon-beta mRNA production by promoting its demethylation. These findings suggest a new regulatory mechanism in innate immunity and potential therapeutic targets for herpesvirus infections. [Article]

• Machine learning-based model for CD4(+) conventional T cell genes to predict survival and immune responses in colorectal cancer

This study identifies eight CD4 T cell genes (CD4TGs) linked to colorectal cancer (CRC) outcomes and develops a prognostic model based on these genes. The model reliably predicts patient survival and correlates with tumor malignancy. It introduces new biomarkers for evaluating CRC risks, potentially improving treatment strategies and clinical outcomes. [Article]

• The IL-4-IL-4Rα axis modulates olfactory neuroimmune signaling to induce loss of smell

IL-4 and IL-13 have distinct effects on olfaction, with loss of smell in mice triggered solely by IL-4, independent of structural damage to the olfactory neuroepithelium. IL-4 signaling influences neuronal interactions with immune cells, linking olfactory impairment to neuroinflammation. [Article]

Additional Highlights

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

• Waste clearance shapes aging brain health [Review]
• AlphaFold reveals how sperm and egg hook up in intimate detail [News]
• Missing immune cells may explain why COVID-19 vaccine protection quickly wanes [News]
• Zealand Pharma provides U.S. regulatory update on dasiglucagon in congenital hyperinsulinism [News]
• Zealand Pharma announces that Boehringer receives U.S. FDA Breakthrough Therapy designation and initiates two Phase III trials in MASH for survodutide [News]
• Estigene Bio, Songdo Bio Plant Obtains US FDA cGMP Approval [News]
• Update on Novavax’s COVID-19-Influenza Combination and Stand-alone Influenza Phase 3 Trial [News]

Company Name	Drug Name	Regulatory Body	Approval/Type	Disease	Link
Roche	Itovebi	FDA	Marketing Approval	Advanced hormone receptor-positive, HER2-negative breast cancer with PIK3CA mutation	Link
AstraZeneca	Enhertu	China’s NMPA	Marketing Approval	HER2-mutant metastatic non-small cell lung cancer	Link
Pfizer	HYMPAVZI™ (marstacimab-hncq)	FDA	Marketing Approval	Hemophilia A or B without inhibitors	Link
Dong-A ST	Imuldossa	FDA	Marketing Approval	Inflammatory diseases such as plaque psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis	Link
UroGen	UGN-102	FDA	NDA Acceptance	Bladder cancer	Link
Novocure	Optune Lua®	FDA	Marketing Approval	Metastatic non-small cell lung cancer	Link
Novavax	Nuvaxovid™	European Commission	Marketing Authorization	COVID-19	Link
Acadia Pharmaceuticals	DAYBUE™ (trofinetide)	Health Canada	Marketing Approval	Rett Syndrome	Link
Allergan Aesthetics	BOTOX® Cosmetic	FDA	Marketing Approval	Moderate to Severe Forehead Lines, Frown Lines, Crow’s Feet Lines, and Platysma Bands	Link
Abbvie	VYALEV™	FDA	Marketing Approval	Advanced Parkinson’s Disease	Link

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