Ontosight^® Newsletter Issue 13

Ontosight^® – Newsletter
Special Edition: Powered by AI Innovation
November 4^th – November 17^th, 2024 – Issue 13

Welcome to a Special Edition of Ontosight^® Newsletter! This issue celebrates our thriving partnership with NVIDIA, which is accelerating advancements in healthcare and life sciences. With NVIDIA’s cutting-edge AI capabilities, we are transforming drug discovery, reducing research timelines, and bringing innovative therapies to patients faster.

Announcement: Why This Edition is Special

We are proud to share highlights from our collaboration with NVIDIA, including insights from the NVIDIA AI Summit 2024, where our groundbreaking contributions to AI-driven healthcare were recognized. From reducing drug discovery timelines to pioneering AI innovations, this partnership is shaping the future of life sciences.

Our Partnership with NVIDIA

• Revolutionizing Drug Discovery: By integrating NVIDIA’s GPU technology, we’ve screened 5.8 million molecules in under 8 hours, a tenfold improvement over traditional methods.
• Protein Interaction Analysis: With NVIDIA’s support, we process 200 million protein interactions in seconds, achieving up to 500x faster performance.
• Generative AI Models: Using NVIDIA’s platforms, our tools achieve 90% accuracy in predicting drug efficacy and safety, transforming early-stage drug development.

These advancements are not only accelerating research but also enabling more precise and impactful therapies.

Spotlight: NVIDIA AI Summit 2024

At the NVIDIA AI Summit, our contributions to AI-driven healthcare were prominently featured:

• Recognition by Jensen Huang
  Innoplexus was highlighted for its AI-driven solutions in drug discovery, affirming our position as a leader in innovation.
• Panel Discussion: “Leveraging AI to Accelerate India’s Digital Biology and Health Ecosystem”
  Our Co-founder and Group CTO, Gaurav Tripathi, joined esteemed leaders from NVIDIA, TCS, and AstraZeneca in an engaging panel discussion. Key takeaways included:
  • AI’s transformative role in expediting drug discovery.
  • Bridging critical healthcare gaps using digital biology.
  • Future possibilities at the intersection of AI and healthcare.
• Inception Pitch by Nitish Jain, CFA
  Perpetual Block, a Partex company, showcased its Generative AI solutions built on NVIDIA’s tech stack, demonstrating their revolutionary impact across industries.

Impact of NVIDIA in Life Sciences AI

NVIDIA’s advanced GPU frameworks and AI platforms, including NeMo and NIM microservices, empower us to:

• Drastically reduce research timelines with ultra-fast computations.
• Enhance the accuracy of predictive models, advancing personalized medicine.
• Seamlessly integrate AI tools into our pipeline for scalable and secure deployments.

These innovations enable us to tackle complex challenges in drug discovery, clinical trials, and patient outcomes.

Showcasing AI Innovations at Our Booth

At Inception Booth GI 16, we showcased our pioneering AI-driven solutions for drug discovery, drawing a wide range of visitors from various industries eager to explore our innovations.

Our team highlighted these groundbreaking AI products:

• Meta D3: An advanced AI-powered platform for drug discovery and development
• Asset 42: A state-of-the-art asset exchange platform

Ontosight Terminal & Knowledge Graph: A robust data layer and user interface platform

Featured Articles

1. Next-Gen Cancer Therapies and AI Innovations

• DLL4-targeted CAR-T therapy sensitizes neoadjuvant chemotherapy via eliminating cancer stem cells and reshaping immune microenvironment in HER2(+) breast cancer

This study identifies delta-like 4 (DLL4) as a key driver of resistance to trastuzumab, pertuzumab, and paclitaxel (THP) in HER2+ breast cancer. DLL4+ tumor cells show stemness and therapy resistance, while soluble DLL4 triggers neutrophil extracellular traps (NETs), blocking lymphocyte infiltration. DLL4-targeted CAR-T cells effectively eliminate DLL4+ cells and reverse resistance. This offers a strategy to sensitize HER2+ BC to THP therapy. [Article]

• GPRC5A promotes lung colonization of esophageal squamous cell carcinoma

This study explores early metastasis mechanisms in esophageal squamous cell carcinoma (ESCC). Single-cell RNA sequencing shows early lung-disseminated cancer cells adopt a trophoblast-like phenotype, driven by GPRC5A overexpression, which enhances implantation and metastasis. GPRC5A interacts with WWP1, degrading LATS1 and activating YAP1 signaling, crucial for lung metastases. Targeting YAP1 with CA3 or TED-347 reduces metastasis, highlighting the GPRC5A/WWP1/LATS1/YAP1 axis as a therapeutic target. [Article]

• A PROTAC degrader suppresses oncogenic functions of PTK6 inducing apoptosis of breast cancer cells

This study examines PTK6, a tyrosine kinase driving breast cancer progression. While kinase inhibitors have failed clinically, the researchers developed MS105, a PTK6 PROTAC degrader that overcomes these limitations. MS105 degrades PTK6, inducing apoptosis and inhibiting cell growth, unlike kinase inhibitors. It offers a promising therapeutic approach by mimicking PTK6 downregulation more effectively. [Article]

• An AI-driven preoperative radiomic subtype for predicting the prognosis and treatment response of patients with papillary thyroid carcinoma

This study develops a Deep Learning Radiomics Signature of Inflammation (DLRI) to predict prognosis and treatment response in Papillary Thyroid Carcinoma (PTC). DLRI, derived from preoperative ultrasound images, accurately identifies the inflammatory subtype and correlates with poor disease-free survival. High-risk DLRI patients benefit significantly from anti-inflammatory traditional Chinese medicine (TCM). DLRI offers a noninvasive tool for prognosis and treatment guidance, warranting further studies. [Article]

• Meta-Analysis of Exposure-Adverse Event Relationships for Antibody-Drug Conjugates

This study examines the relationship between adverse events (AEs) and exposure parameters of antibody–drug conjugates (ADCs). Analysis of clinical data from six ADCs across three payloads revealed that deruxtecan and MMAE ADC toxicities correlate with free payload exposure, while pyrrolobenzodiazepine ADC toxicities depend on the dose. These findings highlight shared AE profiles for ADCs with the same payload, providing insights to enhance safety and guide development. [Article]

2. Neuroscience Insights: Sleep, Alzheimer’s, and Memory Mechanisms

• Sleep deprivation leads to non-adaptive alterations in sleep microarchitecture and amyloid-β accumulation in a murine Alzheimer model

This study explores sleep deprivation in wild-type and APP/PS1 mice, an Alzheimer’s disease model. Wild-type mice show increased norepinephrine oscillations, absent in APP/PS1 mice, which coincide with amyloid-β accumulation. Proteome analysis reveals impaired protein clearance in APP/PS1 mice. Disrupted norepinephrine oscillations may drive early amyloid pathology and heighten sleep-loss vulnerability in Alzheimer’s. [Article]

• Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

This study analyzed 628,943 astrocytes across five brain regions and Alzheimer’s disease (AD) stages using single-nucleus RNA sequencing. It identified astrocyte subclusters with region- and stage-specific responses to AD. A trophic factor-rich subcluster declined with disease progression, while another showed a late-stage increase followed by exhaustion. These findings highlight the dynamic and complex astrocyte responses in AD. [Article]

• Oxidative Stress-mediated Loss of Hippocampal Parvalbumin Interneurons Contributes to Memory Precision Decline After Acute Sleep Deprivation

This study examines how acute sleep deprivation (ASD) affects memory and brain function. Mice deprived of sleep showed memory decline, increased oxidative stress in PV interneurons, and disrupted brain oscillations in the CA1 region. Chemogenetic activation of PV interneurons improved memory and oscillations, while inhibition mimicked the deficits. Antioxidant treatment reversed these effects. The results suggest that ASD-induced oxidative stress in PV interneurons disrupts neural activity and impairs memory. [Article]

3. Frontiers in Genomics and Molecular Biology

• Regulated N-glycosylation controls chaperone function and receptor trafficking

This study reveals a novel pathway in the endoplasmic reticulum (ER) that regulates N-glycosylation, involving the oligosaccharyltransferase OST-A. OST-A activity is modulated by interactions with the ER chaperone HSP90B1 and the protein CCDC134. This pathway protects HSP90B1 during folding, preventing its hyperglycosylation and degradation. Disrupting this process impairs WNT and IGF1R signaling, leading to osteogenesis imperfecta, a bone development disorder. The findings highlight the regulatory role of ER-specific factors in N-glycosylation. [Article]

• Charting and probing the activity of ADARs in human development and cell-fate specification

This study investigates the role of adenosine deaminases acting on RNA (ADARs) in early cell-fate specification. By analyzing time-course RNA editing profiles in human organs from fetal to adult stages, and utilizing human pluripotent stem cell (hPSC) differentiation models, the researchers observed that knocking out ADARs leads to a global decrease in RNA editing. Interestingly, ADAR knockout also results in an enrichment of adipogenic cells, suggesting a critical role for ADARs in human adipogenesis. This work provides new insights into how ADARs influence cell-fate decisions during development. [Article]

• A comprehensive human embryo reference tool using single-cell RNA-sequencing data

This study develops a comprehensive single-cell RNA sequencing reference for human embryo development, integrating six published datasets covering stages from zygote to gastrula. This reference enables accurate lineage annotations and serves as a universal tool for benchmarking and authenticating human embryo models. The researchers also created a prediction tool that allows query datasets to be compared to the reference, providing predicted cell identities. Using this tool, they identified potential misannotations in published human embryo models, emphasizing the importance of using relevant references for accurate model validation. [Article]

4. Global Health Insights and Infectious Disease Breakthroughs

• COVID-19 pandemic interventions reshaped the global dispersal of seasonal influenza viruses

This study analyzes the impact of COVID-19 restrictions on global influenza circulation. During the pandemic’s peak (April 2020 – March 2021), influenza prevalence dropped over 95%, with circulation continuing in Asia and Africa. As restrictions eased, influenza returned to pre-pandemic circulation patterns, influenced by international travel. By May 2023, seasonal influenza resumed normal movements, though at a smaller scale. The study highlights the need for ongoing surveillance as regions like Africa become more suitable for year-round influenza circulation. [Article]

• Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia

This study develops a lentiviral gene therapy for Diamond-Blackfan anemia (DBA) that targets erythroid-specific expression of the GATA1 gene. In preclinical models and patient samples, the therapy boosted red blood cell production without affecting stem cell function or causing premalignant changes. These results support a first-in-human trial for DBA gene therapy. [Article]

• Whole-blood model reveals granulocytes as key sites of dengue virus propagation, expanding understanding of disease pathogenesis

This study develops an in vitro whole-blood model using hirudin to study Dengue virus (DENV) infection. The model shows that monocytes and granulocytes are highly susceptible to DENV, with granulocytes identified as new targets. B cells bind the virus but produce minimal infectious progeny. NK and T cells are also infected, though less permissively. Ex vivo analysis of patient blood confirms these findings. This model offers insights into DENV immunopathogenesis and can help in developing new therapeutic strategies. [Article]

• Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1

This study examines the humoral immune response to SARS-CoV-2 lineages XBB and JN.1, finding that JN.1 induces stronger plasma neutralization and superior memory B cells producing neutralizing antibodies from IGHV3-53/3-66. However, KP.2 and KP.3 subvariants show significant immune evasion, highlighting the need for updated boosters targeting these variants. The findings stress the importance of adapting vaccine formulations to address evolving strains, particularly JN.1 and its subvariants. [Article]

5. Bioinnovation, Medical Advances and Treatments

• Reconstructing the regulatory programs underlying the phenotypic plasticity of neural cancers

This study developed a machine-learning model to predict fecal microbial loads from relative abundance data. Applying it to a large metagenomic dataset, they found microbial load is the primary determinant of gut microbiome variation, influenced by factors like age, diet, and medication. The analysis shows that changes in microbial load, rather than disease conditions, often explain gut microbiome alterations, emphasizing its importance in microbiome research. [Article]

• Tirzepatide for Obesity Treatment and Diabetes Prevention

This phase 3 trial evaluated the 3-year safety and efficacy of tirzepatide in individuals with obesity and prediabetes. Participants (n=2539) were randomized to receive tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 176 weeks, followed by a 17-week off-treatment period. Results showed significant weight loss with tirzepatide (up to -19.7%) compared to placebo (-1.3%), and fewer participants developed type 2 diabetes in the tirzepatide groups (1.3% vs. 13.3%). Gastrointestinal side effects were common but mild to moderate, mostly during dose escalation. Tirzepatide significantly reduced both weight and the risk of developing type 2 diabetes over 3 years. [Article]

• Clinical functional proteomics of intercellular signaling in pancreatic cancer

This study developed TMEPro, a proteomic strategy to profile the glycosylated secreted and membrane proteome of PDAC tumors. The analysis revealed reciprocal signaling between stromal and cancer cells through the PDGFR-PTPN11-FOS axis and the shedding of the AXL receptor, which correlates with lymph node metastasis. Inhibition of AXL shedding and its kinase activity showed a synergistic effect in inhibiting cancer growth, offering new insights for PDAC diagnostics and therapeutics. [Article]

• Intravenous and intracranial GD2-CAR T cells for H3K27M(+) diffuse midline gliomas

This Phase I trial tested GD2-CART therapy in patients with H3K27M-mutant diffuse midline gliomas (DMGs), including DIPG and sDMG. The trial established the maximally tolerated intravenous (IV) dose (1 × 10⁶/kg) and demonstrated that sequential IV and intracerebroventricular (ICV) GD2-CART infusions induced tumor regressions and neurological improvements. Four patients showed significant tumor reductions (52-100%), with one achieving a complete response lasting over 30 months. The treatment was well-tolerated, with manageable side effects, including neurotoxicity and cytokine release syndrome. [Article]

Additional Highlights

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

• CRISPR builds a big tomato that’s actually sweet [Article]
• Bone marrow in the skull plays a surprisingly important role in ageing [Article]
• How human brains got so big: our cells learned to handle the stress that comes with size [News]
• Reducing pregnancy risk could be as easy as chewing gum [News]
• U.S. FDA Removes Clinical Hold on Novavax’s COVID-19-Influenza Combination and Stand-alone Influenza Phase 3 Trial [News]
• Dupixent sBLA accepted for FDA review for the treatment of chronic spontaneous urticaria [News]
• Merus Receives FDA extension of PDUFA for zenocutuzumab [News]
• Johnson & Johnson MedTech Receives IDE Approval for OTTAVA™ Robotic Surgical System [News]
• Neurotech Provides Update on BLA for NT-501 as a Treatment for Macular Telangiectasia Type 2 (MacTel) [News]
• Intercept Receives Complete Response Letter from FDA Addressing OCALIVA supplemental New Drug Application (sNDA) [News]
• Merck Receives Positive EU CHMP Opinion for KEYTRUDA® (pembrolizumab) Plus Chemotherapy as First-Line Treatment for Adult Patients With Unresectable Non-Epithelioid Malignant Pleural Mesothelioma (MPM) [News]
• Eisai Receives Positive Opinion from the CHMP in the European Union for Lecanemab in Early Alzheimer’s Disease [News]

Company Name	Drug Name	Regulatory Body	Approval/Type	Disease	Link
PTC Therapeutics	KEBILIDI™ (eladocagene exuparvovec-tneq)	U.S. FDA	Marketing Approval	AADC Deficiency	Link
Sanofi	Sarclisa (in combination with bortezomib, lenalidomide, and dexamethasone)	EMA-CHMP	Recommended for approval	Newly diagnosed multiple myeloma	Link
Sanofi	Dupixent (dupilumab)	EMA	Marketing Approval	Eosinophilic esophagitis	Link
Azurity Pharmaceuticals	DANZITEN (nilotinib)	U.S. FDA	Marketing Approval	Newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML)	Link
Mustang Bio	MB-108 (HSV-1 oncolytic virus)	U.S. FDA	Orphan Drug Designation	Malignant Glioma	Link
Moderna	mRESVIA™ (Respiratory Syncytial Virus mRNA vaccine)	Health Canada	Marketing Approval	Respiratory Syncytial Virus (RSV) in adults 60 years of age and older	Link
Autolus Therapeutics	AUCATZYL® (obecabtagene autoleucel – obe-cel)	U.S. FDA	Marketing Approval	Relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL)	Link
Johnson & Johnson	RYBREVANT®▼ (amivantamab) + LAZCLUZE®▼ (lazertinib)	EMA-CHMP	Recommended for approval	First-line treatment of patients with EGFR-mutated advanced non-small cell lung cancer	Link
Johnson & Johnson	Nipocalimab	U.S. FDA	Breakthrough Therapy Designation (BTD)	Moderate-to-severe Sjögren’s disease (SjD)	Link
Johnson & Johnson MedTech	VARIPULSE™ Platform	U.S. FDA	Marketing Approval	Treatment of drug refractory paroxysmal Atrial Fibrillation (AFib)	Link
Zai Lab and argenx	VYVGART Hytrulo (Efgartigimod Alfa Injection)	China’s NMPA	sBLA Approval	Chronic inflammatory demyelinating polyneuropathy (CIDP)	Link
Syndax	Revuforj® (revumenib)	U.S. FDA	Marketing Approval	Relapsed or Refractory Acute Leukemia with a KMT2A Translocation	Link

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