Ontosight^® Newsletter Issue 5

Ontosight^® – Newsletter
July 15^th – July 28^th, 2024 – Issue 5

Welcome to the 5th edition of Ontosight^® Newsletter! This issue, we spotlight major advancements in cancer research, groundbreaking neurological discoveries, and new frontiers in immunotherapy. We also feature innovative approaches in drug delivery systems and critical updates in metabolic health treatments. Explore our curated articles and stay updated with the latest news driving progress in the medical and scientific communities.

Featured Articles

1. Cutting-Edge Cancer Research

• Longitudinal on-treatment circulating tumor DNA as a biomarker for real-time dynamic risk monitoring in cancer patients: The EP-SEASON study

The study explored the use of circulating tumor DNA (ctDNA) dynamics, particularly cell-free Epstein-Barr virus DNA (cfEBV DNA), to monitor real-time recurrence risks in nasopharyngeal carcinoma (NPC) patients. In the EP-SEASON study involving 1,000 NPC patients, cfEBV DNA levels were assessed at 11 time points during treatment. The study found that ctDNA dynamics correlated with changes in recurrence risk and identified ctDNA patterns linked to different survival outcomes, highlighting the potential for individualized patient management. [Article]

• PARP10 promotes the repair of nascent strand DNA gaps through RAD18 mediated translesion synthesis

Replication stress from chemotherapeutic agents like cisplatin can arrest replication forks, leaving single-stranded DNA (ssDNA) gaps. This study identifies PARP10 as key in repairing these gaps by recruiting RAD18, which ubiquitinates PCNA, thereby attracting the TLS polymerase REV1 for gap filling. PARP10’s role is critical, especially in BRCA-deficient cells, where its inactivation leads to increased gap accumulation and cytotoxicity, highlighting its importance in genomic stability. [Article]

• Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis

Scribble (SCRIB), a cell polarity regulator, plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression. In mouse models, SCRIB deficiency combined with KrasG12D and Trp53 heterozygous deletion promotes invasive PDAC, metastasis, and reduced survival. SCRIB-null tumors show reduced collagen and cancer-associated fibroblasts due to lowered interleukin 1α (IL1α) levels, leading to impaired CAF activation and increased YAP activation, enhancing cell survival. Clinically, decreased SCRIB expression correlates with poor outcomes in human PDAC, highlighting SCRIB’s tumor suppressor role. [Article]

2. Neurological Insights and Innovations

• Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes

Microglia use tunneling nanotubes (TNTs) to connect with neurons and facilitate the exchange of organelles and proteins. In neurodegenerative diseases like Parkinson’s and Alzheimer’s, microglia utilize TNTs to remove toxic aggregates and share healthy mitochondria with affected neurons, reducing oxidative stress and restoring neuronal function. Disruption of mitochondrial function impairs this protective mechanism, and mutations in genes such as Lrrk2 and Trem2 affect TNT-mediated neuroprotection, linking these variants to neurodegenerative disease pathology. [Article]

• Ultrasensitive detection of aggregated α-synuclein using quiescent seed amplification assay for the diagnosis of Parkinson’s disease

The study introduces Quiescent Seed Amplification Assay (QSAA), a modified technique for amplifying α-synuclein (αSyn) aggregates in brain and skin samples from Parkinson’s disease (PD) patients. QSAA demonstrates high sensitivity (90.2%) and specificity (91.4%) for distinguishing PD from non-PD cases, outperforming traditional immunofluorescence methods. This approach improves the detection of αSyn aggregates while preserving tissue integrity, advancing our understanding of αSyn misfolding in PD. [Article]

• Beta2 adrenergic receptor-mediated abnormal myelopoiesis drives neuroinflammation in aged patients with traumatic brain injury

Aged patients experience worse neurological recovery after traumatic brain injury (TBI) due to abnormal myelopoiesis, characterized by increased neutrophil and classical monocyte levels and reduced nonclassical monocytes. This dysfunction is driven by heightened β2-adrenergic receptor activity via the central amygdaloid nucleus-bone marrow axis, which is more pronounced in older individuals. Blocking β2-adrenergic receptors can correct this myelopoiesis imbalance and improve recovery outcomes, suggesting a new potential therapeutic strategy for enhancing recovery in the elderly after TBI. [Article]

3. Breakthroughs in Immunotherapy and Infectious Diseases

• The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD

In dry age-related macular degeneration (AMD), increased AKT2 inhibits PGC-1α, downregulating SIRT5 and disrupting TFEB-dependent lysosomal function in retinal-pigmented epithelium (RPE) cells. This disruption leads to lysosome and autophagy signaling abnormalities, mitochondrial dysfunction, and drusen formation. Overexpression of AKT2 in mice mimics a dry AMD-like phenotype, and RPE cells with the AMD risk variant CFH Y402H show impaired TFEB/TFE3 function. Targeting the AKT2/SIRT5/TFEB pathway may help delay dry AMD progression. [Article]

• CD5 deletion enhances the antitumor activity of adoptive T cell therapies

CD5 inhibits CAR T cell activation and function, contributing to limited effectiveness in treating cancers. This study demonstrates that CRISPR-Cas9-mediated knockout of CD5 enhances CAR T cell antitumor activity, improving cytotoxicity, expansion, and persistence in various cancer models without added toxicity. CD5 is identified as a key inhibitor of T cell function, suggesting it as a potential target to improve T cell therapies. [Article]

• Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux

RSV infection disrupts cholesterol transport from lysosomes to the endoplasmic reticulum by inhibiting lysosomal acid lipase, activating the SREBP2-LDLR axis, and increasing cholesterol accumulation in lysosomes. This high cholesterol impairs autophagy by affecting autolysosome formation and promotes RSV fusion protein accumulation. Cholesterol depletion or LDLR knockdown reduces RSV-F storage and effectively inhibits RSV infection in vivo, highlighting LDLR as a potential target for anti-RSV therapies. [Article]

4. Breakthroughs in Metabolic Health

• Obesity increases genomic instability at DNA repeat-mediated endogenous mutation hotspots

Obesity is linked to increased cancer risk, potentially due to disruptions in metabolic and cellular pathways that lead to genomic instability. This study reveals that obesity enhances H-DNA-induced DNA damage and mutations in a tissue-specific manner, while reducing DNA repair efficiency. The findings suggest that obesity affects endogenous mutation hotspots, offering insights into the mechanisms connecting obesity with cancer development. [Article]

• Circulating Liquid Biopsy Biomarkers in Glioblastoma: Advances and Challenges

Gliomas, especially glioblastoma (GBM), are aggressive CNS tumors with low survival rates despite treatment advancements. Traditional diagnostic methods like MRI, CT scans, and tissue biopsies face limitations in distinguishing tumor progression from treatment effects and are invasive. Liquid biopsies, using blood or cerebrospinal fluid (CSF) samples, offer a minimally invasive alternative for GBM diagnosis and monitoring by detecting tumor-related components such as cell-free nucleic acids, proteins, and extracellular vesicles. While promising, liquid biopsies face challenges like lack of standardized procedures and limited clinical utility. Combining these biomarkers with traditional tissue biopsies may enhance diagnostic accuracy and monitoring of GBM. [Article]

• Efficacy of Semaglutide in Reactive Hypoglycemia Related to Dumping Syndrome after Bariatric Surgery

This clinical case highlights the effectiveness of semaglutide, a GLP-1 receptor agonist, in treating postprandial hypoglycemia caused by Dumping Syndrome (DS) following gastric bypass surgery. A 31-year-old female patient with persistent hypoglycemia, poorly managed by other medications, experienced significant reduction in symptoms and improved glycemic control with semaglutide. The treatment reduced the time spent with blood glucose <70 mg/dl from 12% to 1% and maintained these improvements for up to 8 months. Semaglutide thus offers a promising option for managing reactive hypoglycemia post-bariatric surgery, enhancing patient quality of life. [Article]

5. Innovations in Drug Delivery Systems

• Artificial Mucus Layer Formed in Response to ROS for the Oral Treatment of Inflammatory Bowel Disease

This study introduces an oral hydrogel precursor solution made from thiol-modified hyaluronic acid (HASH) for treating inflammatory bowel disease (IBD). HASH forms an artificial mucus layer that coats inflamed intestinal regions, blocking microbial invasion and reducing immune response. Additionally, it positively modulates gut microbiota by increasing diversity and the abundance of beneficial bacteria. The ROS-responsive nature of HASH makes it a promising alternative to rectal hydrogel treatments for IBD. [Article]

• Magnetic Polysaccharide Mesenchymal Stem Cells Exosomes Delivery Microcarriers for Synergistic Therapy of Osteoarthritis

This study presents magnetic polysaccharide hydrogel particles as innovative microcarriers for osteoarthritis (OA) therapy. Composed of hyaluronic acid and chondroitin sulfate, these microcarriers encapsulate magnetic nanoparticles, stem cell exosomes, and the anti-inflammatory drug diclofenac sodium. The combined release of exosomes and diclofenac from the microcarriers showed enhanced efficacy in alleviating OA symptoms and promoting cartilage repair in both in vitro and in vivo models. This approach offers a promising strategy for exosome-based OA therapy and similar conditions. [Article]

• Hydrogels: A Promising Therapeutic Platform for Inflammatory Skin Diseases Treatment

This review highlights the use of hydrogels as advanced treatments for inflammatory skin diseases like psoriasis and atopic dermatitis. Hydrogels offer benefits such as biocompatibility, controlled drug delivery, and reduced side effects. The review discusses hydrogel design, including their components and properties, and explores various therapeutic agents that can be incorporated, such as traditional drugs, novel compounds, and biologics. It also evaluates clinical trial data on the effectiveness and safety of hydrogel-based treatments and addresses current challenges and future opportunities, including improving skin barrier penetration and developing multifunctional hydrogels. [Article]

Additional Highlights

Explore more groundbreaking research and guidelines in our newsletter:

• IArtificial intelligence in chronic kidney diseases: methodology and potential applications [Article]
• Pretreatment CT-based machine learning radiomics model predicts response in unresectable hepatocellular carcinoma treated with lenvatinib plus PD-1 inhibitors and interventional therapy [Article]
• Trackins (Trk-Targeting Drugs): A Novel Therapy for Different Diseases [Article]
• Sumitomo Pharma’s DSP-5336 Receives FDA Fast Track Designation for Relapsed/Refractory AML [News]
• FDA Approves Samsung Bioepis’ EPYSQLI® as Biosimilar to Soliris [News]
• MHRA approves Pfizer-BioNTech’s Comirnaty JN.1 vaccine [News]
• AC Immune’s ACI-35.030 (now “JNJ-2056”) Granted FDA Fast Track Designation for Alzheimer’s Disease [News]
• European Commission Approves Pfizer’s DURVEQTIX® for Hemophilia B [News]
• FDA Approves LEQSELVI™ (deuruxolitinib) for Severe Alopecia Areata [News]
• New clot-busting drug recommended by NICE set to save NHS £millions [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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