Ontosight^® Newsletter Issue 20

Ontosight^® – Newsletter
February 10^th – February 23^th, 2025 – Issue 20

Welcome to the 20^th edition of Ontosight^® Newsletter! This issue highlights groundbreaking research in neurodegenerative diseases, cardiovascular health, and metabolic disorders, alongside AI-driven innovations in diagnostics and digital health. Explore advances in cancer treatment, including immunotherapy and precision medicine, as well as emerging insights into infectious diseases. Plus, stay updated on key regulatory approvals shaping the future of healthcare.

Featured Articles

1. Neurodegenerative Diseases & Neuroscience

• Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease

This study identifies FAM171A2 as a Parkinson’s disease (PD) risk gene that promotes the uptake and spread of pathological α-synuclein (α-syn) fibrils in neurons, exacerbating neurotoxicity. The extracellular domain of FAM171A2 interacts selectively with α-syn fibrils through electrostatic forces. Knocking down FAM171A2 reduces α-syn spread, offering neuroprotection. Bemcentinib is identified as a potential drug that blocks this interaction, making FAM171A2 a promising therapeutic target for PD. [Article]

• Large-scale proteomic analyses of incident Parkinson's disease reveal new pathophysiological insights and potential biomarkers

This study analyzed 2,920 plasma proteins in 51,804 UK Biobank participants, identifying 38 proteins linked to Parkinson’s disease (PD), with ITGAV, HNMT, and ITGAM showing strong associations. Lipid metabolism dysfunction was detected 15 years before PD onset, with certain protein levels declining progressively. Machine learning models using the top 16 proteins achieved high accuracy in predicting PD risk, offering potential for early biomarkers and precision therapies. [Article]

• Drug repurposing for Alzheimer's disease and other neurodegenerative disorders

This review explores drug repurposing as a strategy for developing therapies for Alzheimer’s disease (AD) and other neurodegenerative disorders (NDD). It highlights the advantages of repurposed drugs, such as existing safety data, but also challenges like lack of intellectual property protection. The study discusses computational and data-driven approaches for identifying candidates and proposes strategies to overcome barriers, emphasizing repurposing’s crucial role in drug development. [Article]

• The impact of kidney function on Alzheimer's disease blood biomarkers: implications for predicting amyloid-β positivity

This study examines the impact of kidney function on Alzheimer’s disease (AD) blood biomarkers using data from 242 participants. While impaired kidney function (lower eGFR) was associated with higher biomarker levels, these associations lost significance after adjusting for age and sex, except for Aβ40, Aβ42, NfL, and GFAP. Including kidney function in predictive models did not improve Aβ-positivity detection, suggesting that mild renal impairment does not significantly affect the diagnostic accuracy of key AD biomarkers like p-tau217. [Article]

• A primary cilia-autophagy axis in hippocampal neurons is essential to maintain cognitive resilience

This study explores how osteocalcin (OCN), a blood-borne hormone, supports neuronal plasticity and cognitive resilience by regulating autophagy through the primary cilium (PC) protein–autophagy axis. The GPR158 receptor at the PC of hippocampal neurons mediates OCN's effects via a cAMP signaling pathway. Aging reduces autophagy and PC proteins, but restoring them improves cognition in aged mice, highlighting a potential target for combating age-related cognitive decline. [Article]

2. Cardiovascular & Metabolic Health

• Sex-Specific Association of Myocardial Fibrosis With Mortality in Patients With Aortic Stenosis

This study investigated sex differences in myocardial fibrosis and its prognostic significance in aortic stenosis (AS) patients undergoing aortic valve replacement (AVR). While women had lower late gadolinium enhancement (LGE) than men, extracellular volume fraction (ECV%) was similar. Both higher ECV% and LGE were associated with increased mortality in both sexes, indicating that myocardial fibrosis is a key prognostic factor for AS patients, regardless of sex. [Article]

• Association between internal exposure to acrylamide and sleep health: evidence from NHANES 2013-2016

This study examined the link between acrylamide (AA) exposure and sleep health in 2,753 U.S. adults using biomarkers from blood and urine. Higher AA biomarker levels were significantly associated with an increased risk of short sleep duration (SSD) and elevated systemic inflammation, with stronger effects observed in smokers. These findings highlight AA’s potential health risks, emphasizing the need for further research and intervention strategies. [Article]

• Aspirin and clinical outcomes in individuals with incidentally diagnosed coronary artery stenosis

This study examined the net benefit of aspirin in 1,483 asymptomatic individuals with incidentally diagnosed coronary stenosis using propensity score matching. Over a 6.3-year follow-up, aspirin did not significantly reduce cardiovascular events but was linked to a higher bleeding risk. The findings suggest that aspirin use should be personalized rather than universally recommended for asymptomatic individuals with coronary stenosis. [Article]

• Association between air pollution and cardiovascular disease risk in middle-aged and elderly individuals with diabetes: inflammatory lipid ratio accelerates this progression

This study examined the link between air pollution and cardiovascular disease (CVD) risk in 5,430 middle-aged and older adults, particularly those with diabetes. Higher exposure to PM1, PM2.5, PM10, and O3 significantly increased CVD risk in diabetics, with inflammatory lipid ratio (ILR) further exacerbating this effect. These findings highlight the need for public health interventions to reduce air pollution exposure in diabetic populations. [Article]

3. AI, Machine Learning & Digital Health

• Disease diagnostics using machine learning of B cell and T cell receptor sequences

This study introduces Mal-ID, an AI-based method that analyzes B cell (BCR) and T cell (TCR) receptor sequences to diagnose infectious and immune-related diseases. Using data from 542 individuals across conditions like COVID-19, HIV, lupus, and type 1 diabetes, Mal-ID achieved high classification accuracy (AUROC 0.986). The model provides biological insights, distinguishing diseases without prior antigen-specific knowledge, highlighting its potential for clinical diagnostics. [Article]

• Integration of 101 machine learning algorithm combinations to unveil m6A/m1A/m5C/m7G-associated prognostic signature in colorectal cancer

This study develops an RNA methylation-related signature (RMS) to predict colorectal cancer (CRC) prognosis by analyzing m6A/m5C/m1A/m7G RNA modifications across five patient cohorts (989 samples). RMS accurately stratifies patients into high- and low-risk groups, with low-risk patients showing better immune response and treatment benefits. Additionally, potential drugs and the TERT gene were identified as targets for high-risk patients, offering insights for personalized CRC treatment and immunotherapy strategies. [Article]

• Systematic inference of super-resolution cell spatial profiles from histology images

This study presents HistoCell, a weakly-supervised deep-learning method that infers single-nucleus-level spatial cell profiles (cell types, states, and networks) directly from histology images. HistoCell achieves state-of-the-art performance in predicting cell characteristics across multiple cancer tissues and improves spatial transcriptomics deconvolution. It enables the discovery of clinically relevant spatial biomarkers for prognosis, drug response, and cancer progression, making it a powerful tool for histology-based cancer research and diagnostics. [Article]

• Dynamic Visualization of Computer-Aided Peptide Design for Cancer Therapeutics

This study explores trends in computer-aided peptide design for cancer therapy, highlighting growing research in cell-penetrating peptides, peptide vaccines, and computational methods like molecular docking and deep learning. The U.S. and China lead contributions, with deep learning emerging as a key future direction. [Article]

• IDO1 modulates pain sensitivity and comorbid anxiety in chronic migraine through microglial activation and synaptic pruning

This study identifies IDO1 in the anterior cingulate cortex (ACC) as a key driver of pain sensitization and anxiety in chronic migraine. Inhibiting or knocking down IDO1 reduced pain, restored neuronal balance, and alleviated anxiety in a mouse model, suggesting IDO1 as a potential therapeutic target for chronic migraine. [Article]

4. Cancer Research & Treatment

• Validation of a digital pathology-based multimodal artificial intelligence biomarker in a prospective, real-world prostate cancer cohort treated with prostatectomy

This study validates a multimodal AI (MMAI) biomarker for predicting prostate cancer outcomes in 143 Swedish patients who underwent radical prostatectomy. MMAI scores were strongly associated with biochemical recurrence (BCR) and adverse pathology (AP), reinforcing its prognostic value beyond North America and across different treatment approaches. [Article]

• Predicting hepatocellular carcinoma survival with artificial intelligence

This study demonstrates that machine learning can effectively predict survival probabilities in hepatocellular carcinoma (HCC) patients across all stages. Models achieved high accuracy, with up to 92% for advanced-stage survival prediction. AI-based approaches show promise for improving prognostic assessments in HCC. [Article]

• Integration of single-cell and bulk RNA-sequencing data reveals the prognostic potential of epithelial gene markers for prostate cancery

This study developed an 11-gene epithelial expression signature that improves biochemical recurrence-free survival (BCRFS) prediction and risk stratification in prostate cancer. The signature outperforms traditional clinical markers and shows potential for non-invasive prognostic use via peripheral blood biomarkers. [Article]

• RNA neoantigen vaccines prime long-lived CD8(+) T cells in pancreatic cancer

This study investigates an mRNA–lipoplex neoantigen vaccine (autogene cevumeran) for pancreatic ductal adenocarcinoma (PDAC) in a phase 1 trial. At a 3.2-year median follow-up, patients with vaccine-induced CD8+ T cell responses had significantly longer recurrence-free survival than non-responders. The vaccine generated long-lived, cytotoxic T cells with persistent anti-tumor activity, reducing PDAC recurrence. These findings suggest mRNA–lipoplex vaccines could overcome key challenges in cancer immunotherapy. [Article]

• Integrative spatial analysis reveals tumor heterogeneity and immune colony niche related to clinical outcomes in small cell lung cancer

This study uses CODEX and multi-omics profiling to map the spatial landscape of SCLC, identifying a high-risk ASCL1+ tumor subtype and an immune niche (MT2) linked to better survival and immunotherapy response. Findings provide insights for patient stratification and personalized treatment. [Article]

• Cooperative nutrient scavenging is an evolutionary advantage in cancer

This study explores cooperative interactions among tumor cells as a potential therapeutic target. Researchers identified a collective nutrient-scavenging mechanism, where tumor cells secrete aminopeptidases (notably CNDP2) to digest extracellular peptides, providing essential amino acids for survival in nutrient-poor environments. Disrupting this mechanism pushed tumor populations to extinction, significantly reducing tumor growth in vitro and in vivo. These findings reveal a targetable metabolic vulnerability in cancer treatment. [Article]

5. Metabolic Disorders & Endocrinology

• β cell dedifferentiation, the underlying mechanism of diabetes in Wolfram syndrome

This study reveals that β cell dedifferentiation and lineage loss drive diabetes in Wolfram syndrome (WS) due to ER stress from WFS1 gene mutations. Wfs1-deficient mice showed gradual β cell loss and metabolic dysfunction, but deleting Txnip restored β cell function and prevented diabetes, suggesting Txnip inhibition as a potential WS therapy. [Article]

• Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK

This study identifies a glutaminolysis-AMPK-SUCLA2-IL-1β axis in adipose tissue macrophages (ATM) that regulates inflammation and obesity. Loss of AMPKα in myeloid cells promotes inflammation, impairs energy expenditure, and worsens obesity, while IL-1β neutralization or SUCLA2 knockdown reduces obesity in mice. These findings highlight metabolic reprogramming in ATM as a potential obesity treatment target. [Article]

• Liver-specific inactivation of Cideb improves metabolic profiles and ameliorates steatohepatitis and fibrosis in animal models for MASH

This study explores CIDEB inhibition as a potential therapeutic strategy for obesity and metabolic dysfunction-associated steatohepatitis (MASH). Using GalNAc-conjugated siRNAs, researchers demonstrated that Cideb knockdown in mice reduces cholesterol, triglycerides, hepatic steatosis, and fibrosis, while also promoting weight loss. The findings highlight CIDEB as a promising target for liver disease treatment, with siRNA candidates in development for human trials. [Article]

• NAFLD vs MASLD (metabolic dysfunction associated steatotic liver disease) - why the need for a change of nomenclature?

The nomenclature change from NAFLD to MASLD was driven by concerns over exclusionary confounders and stigmatizing language ("nonalcoholic" and "fatty"). Decided through a Delphi process, the new term highlights the metabolic origin of the disease (requiring at least one cardiometabolic risk factor). Additionally, the introduction of Met-ALD acknowledges cases with both metabolic and alcohol-related contributions, though further research is needed to clarify their individual patient-level impact. [Article]

Additional Highlights

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

• Altered immune landscape of cervical lymph nodes reveals Epstein-Barr virus signature in multiple sclerosis [Article]
• Lasers for treatment of androgenetic alopecia[Review]
• NIH research grants still frozen despite lawsuits challenging Trump order[News]
• Boehringer Ingelheim launches new trivalent poultry vaccine, includes protection against H5 avian influenza[News]
• Boehringer Ingelheim’s SEMINTRA® 4 mg/ml oral solution now launched for cats with chronic kidney disease and hypertension[News]
• Boehringer Ingelheim broadens oncology portfolio with license for Synaffix’s ADC technology[News]
• FDA Authorizes ImmunityBio to Provide Recombinant BCG (rBCG) to Urologists to Address TICE® BCG Shortage [News]
• ImmunityBio Announces UK Medicines and Healthcare Products Regulatory Agency Accepted Marketing Authorization Application for ANKTIVA® for the Treatment of Patients with BCG-unresponsive Non-Muscle Invasive Bladder Cancer Carcinoma In Situ [News]

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