Ontosight Newsletter Issue 9

Ontosight – Newsletter

September 9th - September 22nd, 2024 - Issue 9

Welcome to the 9th edition of the Ontosight Newsletter! This issue features groundbreaking research in cancer research and therapeutics, metabolism and aging, neuroscience and mental health, genomics and molecular biology, immunology, and innovative technologies and drug discovery. We also highlight key regulatory updates in the biomedical field. Get ready to explore the latest advancements shaping the future of healthcare!

Featured Articles

1. Cancer Research and Therapeutics

• A cuproptosis nanocapsule for cancer radiotherapy

Residual tumors after radiotherapy often develop radiation resistance, leading to recurrence and metastasis. Researchers found that up-regulating FDX1 and LIAS, key regulators of cuproptosis, enhances sensitivity to this cell death mechanism. Using a copper-containing nanocapsule, they demonstrated that radiation-triggered cuproptosis overcomes resistance, showing a 40% cure rate and activating systemic antitumor immunity Read More.

• The deubiquitinating enzyme USP11 regulates breast cancer progression by stabilizing PGAM5

PGAM5 plays a crucial role in breast cancer, promoting cell proliferation, invasion, and ferroptosis regulation. USP11 stabilizes PGAM5 by de-ubiquitination, enhancing breast cancer growth and metastasis. Targeting the USP11/PGAM5 complex may serve as a potential strategy for breast cancer treatment Read More.

• Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy

Lin28 inhibits the maturation of tumor-suppressor miRNA let-7, promoting cancer progression. Researchers developed Lin28A-miRNA-PROTACs to degrade Lin28A, restoring let-7 levels and reducing cancer cell proliferation and migration. In mouse models, this approach effectively inhibited tumor growth, and when combined with tamoxifen, led to tumor regression, offering a promising cancer treatment strategy Read More.

• Mechanistic study of quercetin in the treatment of hepatocellular carcinoma with diabetes via MEK/ERK pathway

Hepatocellular carcinoma (HCC) with diabetes is increasingly common, and quercetin, a flavonoid with antitumor and antidiabetic effects, shows promise as a treatment. This study identified IL6 and MMP9 as potential quercetin targets, with quercetin promoting apoptosis and inhibiting proliferation and EMT in HepG2 cells under high glucose by reducing IL6 and inhibiting the MEK/ERK pathway. Quercetin may delay HCC-diabetes progression by modulating these pathways Read More.

2. Metabolism and Aging

• Metformin decelerates aging clock in male monkeys

In a 40-month study on male cynomolgus monkeys, metformin was shown to delay aging, particularly reversing brain aging by about 6 years. Using advanced biological markers like transcriptomics and proteomics, researchers found metformin had neuroprotective effects, enhancing cognitive function and activating the anti-oxidative Nrf2 pathway. This study demonstrates metformin's potential as a geroprotective agent in primates, with implications for human aging treatments Read More.

• Iron chelation as a new therapeutic approach to prevent senescence and liver fibrosis progression

Iron overload and cellular senescence contribute to liver fibrosis. In a mouse model of chronic liver injury, iron accumulation coincided with fibrosis and senescence in hepatocytes. Treatment with the iron chelator deferiprone reduced iron levels, fibrosis, and senescence, shifting the senescence-associated secretome (SASP) towards an anti-inflammatory profile. These findings suggest iron accumulation as a targetable driver for reducing pathological senescence in liver fibrosis Read More.

3. Neuroscience and Mental Health

• Manganese exposure leads to depressive-like behavior through disruption of the Gln-Glu-GABA metabolic cycle

Long-term manganese (Mn) exposure is linked to Parkinson's-like disease and depression. In mice, Mn accumulation in the hippocampus led to depressive-like behavior and cognitive impairment, damaging neuronal dendritic spines and astrocytes. Mn disrupted the GlnGluGABA metabolic cycle by downregulating GAD1 in astrocytes. Overexpressing Gad1 in astrocytes reversed synaptic damage and improved behavior, revealing GAD1's crucial role in Mn-induced depression and neurotoxicity Read More.

• Distinct ventral hippocampal inhibitory microcircuits regulating anxiety and fear behaviors

Anxiety and fear share overlapping brain structures, but recent research reveals distinct long-range projection pathways from the ventral hippocampus for each emotion. This study shows that local GABAergic inhibitory microcircuits in the ventral hippocampus regulate specific pyramidal neurons to control anxiety and fear behaviors in mice, providing new insights into how different emotional states are encoded Read More.

• Inhibiting Ca(2+) channels in Alzheimer's disease model mice relaxes pericytes, improves cerebral blood flow, and reduces immune cell stalling and hypoxia

In early Alzheimer's disease (AD), pericytes constrict capillaries, reducing cerebral blood flow (CBF) and trapping immune cells. This study shows that Ca2+ entry via L-type voltage-gated calcium channels (CaVs) controls pericyte contraction. Blocking CaVs with nimodipine improved CBF, reduced immune cell stalling, and alleviated brain hypoxia in AD model mice. These findings suggest that reducing pericyte calcium levels may offer a therapeutic strategy to improve brain energy supply and potentially cognitive function in AD Read More.

• Gut Microbiota-Metabolite-Brain Axis Reconstitution Reverses Sevoflurane-Induced Social and Synaptic Deficits in Neonatal Mice

Early-life exposure to sevoflurane causes social dysfunction and synaptic development issues in mice, with altered gut microbiota and bile acid metabolism playing a key role. Sevoflurane-exposed mice showed reduced social interaction and decreased spine density. Fecal microbiota transplantation (FMT) and bile acid regulation restored social behaviors and synaptic development, highlighting the gut microbiota-metabolite-brain axis as a potential target for intervention against sevoflurane-induced neurotoxicity Read More.

4. Genomics and Molecular Biology

• In vivo DNA replication dynamics unveil aging-dependent replication stress

Aging affects DNA replication dynamics in regenerating livers, with old mice showing inefficient origin firing and a replication stress response compared to young mice. While inhibitors of ATR checkpoint kinase restored origin firing in old mice, they triggered inflammation without significantly increasing cell cycle entry. These results highlight aging-related replication stress and the key role of ATR in managing stress-induced inflammation during aging Read More.

• Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance

In a study of 59 NICU patients with developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME), exome sequencing identified 40 genetic abnormalities, including key duplications in SCN1A and SCN2A. Over one-third of DEE patients were resistant to anti-seizure medications, but 80% responded positively to a ketogenic diet. The study highlights the potential of genetic categorization and ketogenic diet efficacy in managing drug-resistant epilepsy Read More.

• Gene-level alignment of single-cell trajectories

Genes2Genes is a Bayesian dynamic programming framework that aligns single-cell trajectories by identifying gene matches and mismatches between reference and query data. It improves upon current methods by highlighting distinct alignment patterns. In real and simulated datasets, Genes2Genes accurately inferred alignments and demonstrated its utility in disease cell-state analysis. A proof-of-concept revealed differences between in vitro and in vivo T cell differentiation, offering insights to optimize in vitro culture conditions Read More.

• All-Atom Protein Sequence Design Based on Geometric Deep Learning

GeoSeqBuilder is a deep learning framework that generates protein sequences and predicts side chain conformations to create complete all-atom structures. It achieves a native residue recovery rate of 51.6% and has successfully designed sequences for thioredoxin and a three-helical bundle, resulting in soluble, thermally stable proteins. The tool also improved enzyme activity in redesigned hydrophobic cores, demonstrating its potential for novel protein design Read More.

5. Immunology and Inflammation

• Harnessing ZIKV NS2A RNA for alleviating acute hepatitis and cytokine release storm by targeting translation machinery

Zika virus protein NS2A acts as an RNA molecule to suppress proinflammatory cytokine translation, reducing inflammation in acute hepatitis and graft-versus-host disease (GVHD). By disrupting the eIF2/eIF2B complex, NS2A RNA lowers cytokine levels and tissue damage, indicating potential as a therapy for acute inflammatory diseases linked to cytokine release syndrome (CRS) Read More.

• Chicoric acid acts as an ALOX15 inhibitor to prevent ferroptosis in asthma

Chicoric acid (CA) is identified as a promising treatment for asthma by inhibiting ALOX15, a key target in ferroptosis. Through bioinformatics, in vitro, and in vivo studies, CA reduces ALOX15 expression and ferroptosis, improving asthma symptoms. This research highlights CA's potential and introduces new therapeutic strategies using natural compounds for diseases linked to ferroptosis Read More.

• Exploring cuproptosis-related molecular clusters and immunological characterization in ischemic stroke through machine learning

This study investigates the role of cuproptosis-related genes (CURGs) in ischemic stroke (IS) by analyzing immune cell interactions and developing a diagnostic model. Key pathways linked to IS, such as oxidative phosphorylation and NF-kappa B signaling, were identified, with CURGs primarily overexpressed in immune cells. The research established a risk prediction model and highlighted significant immune cell variations, enhancing understanding of IS mechanisms Read More.

6. Innovative Therapeutics, Technologies, and Drug Discovery

• Combining optical genome mapping and RNA-seq for structural variants detection and interpretation in unsolved neurodevelopmental disorders

This study combines optical genome mapping (OGM) and RNA-seq to detect and interpret structural variations (SVs) in exome sequencing-negative neurodevelopmental disorders (NDDs). OGM identified four SVs, and RNA-seq confirmed the pathogenicity of three cases involving key NDD-related genes. The approach highlights the value of integrating OGM and RNA-seq to uncover SVs, especially in non-coding regions, improving diagnostic accuracy for NDDs Read More.

• Artificial intelligence-assisted quantitative CT parameters in predicting the degree of risk of solitary pulmonary nodules

This study analyzed 355 solitary pulmonary nodules (SPNs) on CT to predict cancer invasiveness. CT value mean and nodule type were identified as independent predictors, with an AUC of 0.811 for high-risk nodules. Software-based CT assessment shows promise for guiding treatment decisions, though further validation is needed Read More.

• Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein

A DNMT1-targeted PROTAC degrader, KW0113, was developed to inhibit acute myelocytic leukemia (AML) cell growth by reversing DNA methylation abnormalities. KW0113 selectively degraded DNMT1 in a dose- and time-dependent manner, leading to tumor-suppressor gene reactivation. This study highlights the therapeutic potential of DNMT1-targeted PROTACs for AML treatment Read More.

• A Machine Learning Approach for Predicting Biochemical Outcome After PSMA-PET-Guided Salvage Radiotherapy in Recurrent Prostate Cancer

This study evaluated PSMA-PET-based salvage radiation therapy (sRT) for patients with post-prostatectomy PSA persistence or recurrence. Using data from 1029 patients across multiple countries, a random survival forest (RSF) model was developed to predict biochemical failure, showing improved accuracy over a Cox model. The RSF model demonstrated robust performance and offers enhanced predictive accuracy for guiding treatment decisions in recurrent prostate cancer Read More.

• Molecular glue-mediated targeted protein degradation: A novel strategy in small-molecule drug development

Molecular glues are a novel class of small molecules that induce protein-protein interactions, enabling the targeting of traditionally undruggable proteins. They play a key role in targeted protein degradation (TPD) techniques like PROTACs, molecular glue degraders, and lysosome-based approaches, offering new strategies for prolonged inhibition of disease-related proteins. This review highlights the clinical potential of molecular glues and their role in advancing TPD methods Read More.

Additional Highlights

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

• Transvascular transport of nanocarriers for tumor delivery

• GPCR Biosensors to Study Conformational Dynamics and Signaling in Drug Discovery

• Moderna’s Canadian Manufacturing Facility Receives Drug Establishment License From Health Canada

• 40 million deaths by 2050: toll of drug-resistant infections to rise by 70%

• Dupixent recommended for EU approval by the CHMP to treat eosinophilic esophagitis in children as young as 1 year old

• Wegovy® recommended by the European regulatory authorities for label update to reflect reduced heart failure symptoms and improved physical function

• Merck Receives Positive EU CHMP Opinions for KEYTRUDA® (pembrolizumab) Regimens as Treatment for Patients With Two Types of Gynecologic Cancers

• Zentalis Pharmaceuticals Announces FDA Has Lifted Partial Clinical Hold on Azenosertib Studies

• Astellas Announces FDA Listing of DIGITIVA™ for the Management of Heart Failure

• DARZALEX® (daratumumab)-based quadruplet regimen receives positive CHMP opinion for transplant-eligible patients with newly diagnosed multiple myeloma

• FDA Declines to Approve Vanda's Marketing Application for Tradipitant in Gastroparesis

• FluMist approved for self-administration in the US