Ontosight^® Newsletter Issue 3

Ontosight^® – Newsletter
June 17^th – June 30^th, 2024 – Issue 3

Welcome to the 3^rd edition of Ontosight^® – Newsletter! This issue highlights significant advancements in genetic editing, offering new insights into gene regulation and precision techniques. We also explore breakthroughs in nutritional science, cancer therapies, and neuroscience, alongside the latest findings in infectious disease research, focusing on microbial signatures and viral mechanisms.

Featured Articles

1. Revolutionary Genetic Editing and Cellular Reprogramming

• Cell cycle length governs heterochromatin reprogramming during early development in non-mammalian vertebrates

H3K9me3, a heterochromatin mark, undergoes global erasure and re-establishment after fertilization, crucial for early development. In medaka (Japanese killifish), rapid cell cycles during cleavage stages lead to passive erasure of H3K9me3, while slower cycles at mid-blastula transition enable H3K9me3 re-accumulation via Setdb1. This mechanism is also observed in zebrafish and Xenopus laevis, suggesting a conserved cell cycle-dependent process for H3K9me3 reprogramming across various non-mammalian vertebrates and invertebrates. [Article]

• Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

Aging is a major risk factor for Alzheimer’s disease (AD), and a whole-genome CRISPR screen identified the neddylation pathway as a regulator of neuronal age and AD neurodegeneration. Inhibition of neddylation increased aging markers and Tau aggregation in neurons with the APPswe/swe mutation, reducing cell viability. This effect was also seen in AD and Parkinson’s disease models. The study highlights that cellular aging can uncover late-onset disease traits, suggesting new targets to influence AD progression and strategies to model age-related phenotypes in stem cell models. [Article]

• An aptamer-mediated base editing platform for simultaneous knock-in and multiple gene knockout for allogeneic CAR-T cells generation

Gene editing technologies are advancing adoptive cellular therapies, but conventional methods like CRISPR-Cas9 can cause unwanted genomic alterations due to DNA double-strand breaks. The novel Pin-point™ base editing platform, which uses RNA aptamers, offers high efficiency and precision for simultaneous gene knockouts and site-specific transgene integration in human T cells. It achieves reduced chromosomal translocations and avoids the need for extra sequence-targeting components. This platform’s ability to perform complex and accurate genome editing underscores its potential for advanced cell therapies. [Article]

2. Nutritional Science and Metabolic Health

• Ketogenic diet-induced bile acids protect against obesity through reduced calorie absorption

The ketogenic diet (KD) lowers body weight and fasting glucose, with gut microbiota and metabolites playing a role. KD increases serum levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA) in mice, which reduce weight and glucose by decreasing the gut bacterium Lactobacillus murinus ASF361 and inhibiting bile salt hydrolase (BSH) activity. TDCA and TUDCA protect against obesity, and similar associations are seen in human studies. This highlights a novel host-gut microbiota interaction mechanism and suggests TDCA and TUDCA as potential obesity treatments alongside KD. [Article]

• Dual-trajectory of TyG levels and lifestyle scores and their associations with ischemic stroke in a non-diabetic population: a cohort study

This study examined how the Triglyceride-glucose (TyG) index and lifestyle factors affect ischemic stroke risk in non-diabetics. Analyzing data from 44,403 participants, it found that high TyG levels, even with a good lifestyle, were linked to increased stroke risk. The highest risk was associated with the highest TyG levels and moderate lifestyle scores. The study highlights the need for further research on the impact of lifestyle changes for those with elevated TyG levels. [Article]

3. Groundbreaking Cancer Therapies and Mechanisms

• Pan-cancer proteogenomics expands the landscape of therapeutic targets

This study uses proteogenomics data from 1,043 cancer patients to identify drug targets across 10 cancer types. It finds variations in protein abundance, identifies key druggable dependencies, and prioritizes mutant KRAS peptides as potential immunotherapy targets. The results, available at targets.linkedomics.org, offer a comprehensive view of protein and peptide targets for drug development. [Article]

• Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer

This study presents HRS-4642, a highly selective and long-acting non-covalent inhibitor for KRAS G12D, a common mutation in solid tumors. With a strong affinity of 0.083 nM, HRS-4642 showed effective results in preclinical models and early-phase clinical trials. CRISPR-Cas9 screening revealed that proteasome inhibition enhances HRS-4642’s efficacy, and combining it with the proteasome inhibitor carfilzomib improved anti-tumor effects and created a more immune-friendly tumor environment. This offers a promising new therapy for KRAS G12D-mutant cancers. [Article]

• Biomarker screen for efficacy of oncolytic virotherapy in patient-derived pancreatic cancer cultures

This study investigates the efficacy of five oncolytic viruses (OVs) against pancreatic ductal adenocarcinoma (PDAC) using fourteen patient-derived cultures. Results show varied responses to OVs, with no single OV universally superior. Sensitivity was linked to PDAC molecular subtypes and cellular pathways, such as the expression of Galectin-1 and cGAS. Combination therapies, such as MV-NIS with a cGAS inhibitor, improved tumor cell killing. The findings suggest a need for personalized treatment strategies in oncolytic virotherapy for PDAC. [Article]

4. Advanced Neuroscience and Cognitive Function

• The Efficacy of Combining Cognitive Training and Noninvasive Brain Stimulation: A Transdiagnostic Systematic Review and Meta-Analysis

This review evaluates the effectiveness of combining cognitive training (CT) with noninvasive brain stimulation (NIBS) compared to CT alone. Analyzing 72 studies with 2,518 participants, the meta-analysis found that while combining NIBS with CT led to a small but significant improvement in learning and memory (g = 0.18), it did not have a long-term impact or benefit other cognitive outcomes, symptoms, or daily functioning. The studies had varying methodological quality, highlighting the need for better-designed trials to assess the clinical relevance of this combined approach. [Article]

• Pathogenic tau induces an adaptive elevation in mRNA translation rate at early stages of disease

In a Drosophila tauopathy model, tau pathology leads to higher mRNA translation rates and accumulation of translation machinery in nuclear envelope invaginations. Increased NMD and rapamycin treatment further elevate translation, suggesting that enhanced mRNA translation is an adaptive mechanism to counteract neurodegeneration. [Article]

5. Cutting-Edge Infectious Disease Research and Immune Response

• Strain-specific gut microbial signatures in type 2 diabetes identified in a cross-cohort analysis of 8,117 metagenomes

This study of 8,117 metagenomes identifies 19 microbial species associated with type 2 diabetes (T2D), like Clostridium bolteae and Butyrivibrio crossotus. It reveals strain-specific diversity and functional changes, such as altered glucose metabolism, linked to T2D. The findings offer new insights into microbial mechanisms affecting T2D risk. [Article]

• The Function of the PRRSV–Host Interactions and Their Effects on Viral Replication and Propagation in Antiviral Strategies

Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses in the swine industry, affecting pig lungs and lymphatic organs. PRRSV is a single-stranded RNA virus with a complex replication cycle primarily in alveolar macrophages. Despite various vaccines being developed, including inactive, modified live, and DNA vaccines, challenges such as high variability and rapid evolution of the virus hinder vaccine effectiveness. This review focuses on the intricate PRRSV-host interactions and immune escape mechanisms, highlighting the need for novel antiviral strategies to better understand and combat PRRSV. [Article]

• A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses

The THX mouse model, created by grafting human cord blood cells into genetically modified, immunodeficient mice and using estrogen for immune cell differentiation, successfully mimics human immunity. These mice develop a comprehensive human immune system, including B cells, T cells, and lymphoid tissues. They exhibit diverse antigen receptor repertoires and can generate mature antibody responses, including to vaccines for Salmonella and SARS-CoV-2. THX mice also produce human cytokines and can develop lupus autoimmunity. This model offers a valuable platform for studying human immune responses and developing vaccines and therapies. [Article]

Additional Highlights

Explore more groundbreaking research and news in our newsletter:

• Integrated machine learning algorithms reveal a bone metastasis-related signature of circulating tumor cells in prostate cancer [Article]
• Neuronal senescence may drive brain aging [Article]
• 5 FDA Decisions to Watch in the Second Half of 2024 [Article]
• Merck’s ADC Pact With Daiichi Hits Regulatory Setback in FDA Rejection [News]
• U.S. Food and Drug Administration Grants Second Approval for EPKINLY® (epcoritamab-bysp) to Treat Patients with Relapsed or Refractory Follicular Lymphoma [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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