Ontosight^® Newsletter Issue 12

Ontosight^® – Newsletter
October 21^st – November 3^rd, 2024 – Issue 12

Welcome to the 12^th edition of the Ontosight® Newsletter! This issue explores groundbreaking oncology treatments, neurological insights in Parkinson’s and Alzheimer’s, and immune innovations in cancer and infection management. You’ll also find highlights on machine learning applications in healthcare and recent regulatory approvals for new therapies. Dive in for the latest in scientific advancements!

Featured Articles

1. Oncology and Cancer Research

• Transarterial chemoembolization combined with molecular targeted agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma

In patients with unresectable hepatocellular carcinoma (uHCC) beyond the up-to-seven criteria, transarterial chemoembolization (TACE) combined with molecular-targeted agents and immune checkpoint inhibitors (TACE-MTAs-ICIs) improved survival outcomes over TACE alone. The TACE-MTAs-ICIs group had significantly longer overall survival (27.2 vs. 15.9 months) and progression-free survival (15.4 vs. 4.8 months) than the TACE group. The combination therapy showed a higher response rate but with more reversible severe adverse events. [Article]

• Inhibition of Notch enhances efficacy of immune checkpoint blockade in triple-negative breast cancer

In triple-negative breast cancer (TNBC), inhibiting Notch-driven cytokine programs reduces immunosuppressive tumor-associated macrophages (TAMs), enhancing responsiveness to immune checkpoint blockade (ICB). This approach activates cytotoxic T cells in primary tumors and significantly reduces lung metastases by lowering Notch-dependent circulating factors and increasing PD-L1 sensitivity to ICB. The findings suggest a promising combination strategy for TNBC treatment. [Article]

• VEGFB ameliorates insulin resistance in NAFLD via the PI3K/AKT signal pathway

Non-alcoholic fatty liver disease (NAFLD) is influenced by insulin resistance, and VEGFB plays a role in regulating lipid metabolism and glucose balance. This study shows that VEGFB activation enhances insulin sensitivity, reduces lipid accumulation, and supports glucose homeostasis through the PI3K/AKT pathway. VEGFB could be a potential therapeutic target for managing NAFLD and metabolic syndrome. [Article]

• RNA methylation patterns of tumor microenvironment cells regulate prognosis and immunotherapeutic responsiveness in patients with triple-negative breast cancer

This study examines RNA methylation’s role in shaping the tumor microenvironment (TME) to improve immunotherapy for triple-negative breast cancer (TNBC). Distinct TME cell clusters based on RNA methyltransferase expression were analyzed, revealing unique immune and metabolic profiles that correlate with prognosis and treatment response. Findings highlight specific TME cell subgroups that influence TNBC growth and immune modulation, offering insights for enhanced immunotherapy strategies. [Article]

2. Neurological and Cognitive Research

• Single-cell transcriptomic and proteomic analysis of Parkinson’s disease brains

This study on Parkinson’s disease (PD) reveals inflammatory processes and specific brain cell vulnerabilities, identified through single-nucleus transcriptomics and proteomics in postmortem prefrontal cortex samples. Key findings include elevated brain-resident T cells in PD, disrupted neuron-astrocyte interactions, and down-regulated synaptic proteins. Comparisons with Alzheimer’s disease suggest distinct neuronal vulnerability patterns between the two neurodegenerative diseases. [Article]

• Effects of brain microRNAs in cognitive trajectory and Alzheimer’s disease

This study examined 528 microRNAs (miRNAs) in relation to cognitive decline, Alzheimer’s disease (AD) pathology, and clinical diagnosis, analyzing data from the dorsolateral prefrontal cortex of 641 donors. Researchers identified 311 miRNAs differentially expressed in AD, with 137 linked to both AD-related and independent mechanisms. Pathway analysis highlighted roles in transcription, signaling, senescence, and lipoproteins, with some miRNAs showing sex-specific patterns and 15 potentially having a causal role in AD. [Article]

• Smartphone addiction, depression, distress, eustress, loneliness, and sleep deprivation in adolescents

This study identified three latent profiles of smartphone addiction among adolescents: non-addicted (20.87%), addicted (29.82%), and risky (49.31%). While addicted adolescents showed similar patterns of depression, stress, loneliness, and sleep deprivation, distinctions among risky and non-addicted groups offered new insights into these associations. These findings have implications for both researchers and practitioners working on adolescent smartphone addiction. [Article]

• TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer’s disease

This study investigates the role of the TRPV1 channel in mediating immune responses in Alzheimer’s disease (AD), particularly in the context of the APOE4 genetic risk factor. Results show that APOE4 microglia exhibit increased cholesterol biosynthesis, leading to persistent immune activation and T cell infiltration. TRPV1-mediated calcium influx reduces cholesterol accumulation and promotes autophagy in microglia, highlighting its potential as a neuroprotective target in AD by mitigating neuroinflammation and neurodegeneration associated with APOE4-related tauopathy. [Article]

3. Molecular and Cellular Research

• Caspase-2 kills cells with extra centrosomes

This study reveals that extra centrosomes trigger caspase-2-driven apoptosis in blood cells that fail to complete cytokinesis. Activation of caspase-2 requires the PIDDosome complex, with PIDD1 priming at extra centrosomes essential for this process. The mechanism involves caspase-2 processing of the BCL2 protein BID, leading to mitochondrial outer membrane permeabilization and apoptosis, while cells deficient in BID can still undergo cell death through p53-mediated pathways, highlighting the centrosome’s role in preventing polyploidization by inducing apoptosis. [Article]

• A natural killer cell mimic against intracellular pathogen infections

This study shows that intracellular Staphylococcus aureus can survive antibiotic treatment, leading to persistent infections. The authors propose a new therapeutic approach using natural killer cell-like mimics (NKMs) that effectively eliminate these bacteria, outperforming traditional antibiotics. This strategy highlights the potential of immune-based therapies for treating intracellular bacterial infections. [Article]

• High mitochondrial DNA levels accelerate lung adenocarcinoma progression

This study investigates the role of mitochondrial DNA (mtDNA) copy number in lung adenocarcinoma progression in mice. Increased mtDNA levels were linked to larger tumor burdens, while mtDNA depletion slowed tumor growth, suggesting a tumor-intrinsic role for mtDNA in cancer progression. The findings indicate that targeting mtDNA could offer new therapeutic strategies for lung cancer. [Article]

4. Immunology and Infectious Diseases

• Facilitating and restraining virus infection using cell-attachable soluble viral receptors

This study reveals that SARS-CoV-2 infects cells through the receptor binding domain (RBD) of its spike protein interacting with the ACE2 receptor. Only the peptidase domain (PD) of ACE2 is required for infection, provided it is near the cell membrane. Additionally, RBD-binding antibodies and miniproteins on cell surfaces can act as viral receptors, suggesting that engineered RBD-binders could modulate cellular susceptibility to infection, with potential therapeutic applications. [Article]

• Investigating the causal links between obstructive sleep apnea and gastrointestinal diseases mediated by metabolic syndrome through mendelian randomization

This study links obstructive sleep apnea (OSA) with a higher risk of certain gastrointestinal diseases, including chronic gastritis, inflammatory bowel disease, and nonalcoholic fatty liver disease. Key metabolic factors like BMI and hypertension were found to mediate these associations, highlighting the role of metabolic syndrome in potentially reducing OSA’s impact on gastrointestinal health. [Article]

• Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma

In hepatocellular carcinoma, high intratumoral tertiary lymphoid structures (TLS) correlate with a positive response to neoadjuvant immunotherapy, leading to better relapse-free survival. In regressed tumor areas, TLS show a unique morphology supporting T cell memory, suggesting TLS can serve as predictive and prognostic markers in immunotherapy and aid in long-term immune response maintenance. [Article]

• Network pharmacology to unveil the mechanism of Astragali Radix in the treatment of lupus nephritis via PI3K/AKT/mTOR pathway

Using network pharmacology, molecular docking, and in vitro studies, this research examined how Astragali Radix aids in treating lupus nephritis. Analysis identified 211 target genes linked to lupus nephritis and the PI3K/AKT/mTOR pathway as central to its therapeutic effect. In vitro experiments showed that Astragali powder inhibits this pathway in kidney cells, with compounds like (R)-isomucronulatol demonstrating strong binding to key proteins in this pathway, suggesting potential for treatment. [Article]

5. Machine Learning, Innovative Technologies and Bioinformatics Applications

• Integrative spatial and genomic analysis of tumor heterogeneity with Tumoroscope

Tumoroscope is a novel model designed to map cancer clones in tumor tissues with high precision by combining pathological images, whole exome sequencing, and spatial transcriptomics. Unlike prior methods, it deconvolves clonal proportions in spatial transcriptomics, providing insights into clone distribution patterns in tumors. Testing on prostate and breast cancer datasets, Tumoroscope identified spatial clonal interactions and clone-specific gene expressions, advancing the understanding of tumor heterogeneity. [Article]

• Interpretable machine learning model for new-onset atrial fibrillation prediction in critically ill patients: a multi-center study

This study developed a machine learning model using ICU data to predict new-onset atrial fibrillation (NOAF) in critically ill patients. Key predictors included age, ventilation status, and sepsis. The model, with high accuracy, helps identify high-risk patients early, potentially aiding in NOAF prevention and improving outcomes. [Article]

• An interpretable deep learning model for detecting BRCA pathogenic variants of breast cancer from hematoxylin and eosin-stained pathological images

This study developed a deep-learning model, Bi-directional Self-Attention Multiple Instance Learning (BiAMIL), to predict BRCA gene mutation status in breast cancer patients using H&E-stained pathology images. Trained on over 600,000 image tiles, BiAMIL achieved strong predictive accuracy in internal and external tests. The model also highlighted tumor-infiltrating lymphocytes and tumor cell morphology as features potentially linked to BRCA status, offering an interpretable, cost-effective alternative for assessing genetic susceptibility in breast cancer treatment. [Article]

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Additional Highlights

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

• Stem cell–homing biomimetic hydrogel promotes the repair of osteoporotic bone defects through osteogenic and angiogenic coupling [Article]
• A wearable and stretchable dual-wavelength LED device for home care of chronic infected wounds [Article]
• Maternal Cannabis Use During Pregnancy and Maternal and Neonatal Adverse Outcomes [Review]
• Wainzua (eplontersen) recommended for approval in the EU by CHMP for the treatment of adult patients with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis [News]
• Astellas Provides Update on Marketing Authorization Application for Avacincaptad Pegol (ACP) in the European Union [News]
• Camurus provides regulatory update on the US NDA for CAM2029 in acromegaly [News]
• Advisory Committee on Immunization Practices Recommends PREVNAR 20® (20-Valent Pneumococcal Conjugate Vaccine) for Adults Aged 50 and Older [News]
• Sangamo Therapeutics Announces Alignment With FDA on Accelerated Approval Pathway for ST-920 in Fabry Disease With BLA Submission Expected in 2025 [News]
• Novartis ribociclib (Kisqali®) recognized as Category 1 preferred breast cancer adjuvant treatment by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) [News]
• Lexicon Announces Outcome of FDA Advisory Committee for Zynquista™ (sotagliflozin) as an Adjunct to Insulin Therapy for Glycemic Control in Adults with Type 1 Diabetes and Chronic Kidney Disease [News]

Teva Statement on European Commission Decision; Company to Appeal [News]

Company Name	Drug Name	Regulatory Body	Approval/Type	Disease	Link
Astellas	VYLOYTM (zolbetuximab-clzb)	U.S. FDA	Marketing Approval	Advanced Gastric and Gastroesophageal junction (GEJ) Cancer	Link
Lilly	Kisunla™ (donanemab-azbt)	Japan’s MHRA	Marketing Authorization	Mild cognitive impairment and mild dementia due to Alzheimer’s disease in eligible adults	Link
Alvotech and Teva	SELARSDI™ (ustekinumab-aekn)	U.S. FDA	Marketing Approval	Adults with Crohn’s disease and ulcerative colitis	Link
Pfizer	ABRYSVO® (RSV Vaccine)	U.S. FDA	Marketing Approval	Respiratory Syncytial Virus Vaccine indicated for adults aged 18 to 59 at increased risk for disease	Link
Johnson & Johnson	EDURANT® (rilpivirine)	European Commission	Marketing Approval	HIV-1 infection in adults and children	Link
Johnson & Johnson	DARZALEX® (daratumumab)	European Commission	Marketing Approval	Newly diagnosed multiple myeloma (NDMM) who are transplant-eligible	Link
AstraZeneca	Fasenra (benralizumab)	European Commission	Marketing Approval	Relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA)	Link
Iterum Therapeutics	ORLYNVAH™ (sulopenem etzadroxil and probenecid)	U.S. FDA	Marketing Approval	Uncomplicated Urinary Tract Infections	Link
Novartis	Scemblix® (asciminib)	U.S. FDA	Marketing Approval	Adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP)	Link

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