Ontosight^® Newsletter Issue 8

Ontosight^® – Newsletter
August 26^th – September 8^th, 2024 – Issue 8

Welcome to the 8^th edition of Ontosight^® Newsletter! This issue features groundbreaking research in oncology, cardiovascular medicine, metabolic diseases, neurodegenerative research, and tissue engineering. We also cover key regulatory updates in the pharmaceutical industry. Get ready for an exciting dive into the latest innovations shaping modern medicine!

Featured Articles

1. Cancer Research and Oncology

• Single-cell and spatial transcriptome analyses reveal tertiary lymphoid structures linked to tumor progression

This study examines tertiary lymphoid structures (TLS) and their interactions with tumor cell aggregates in nasopharyngeal carcinoma. Through single-cell and spatially-resolved transcriptome analysis, it identifies key cell populations such as CXCL13+ fibroblasts and CD8+ T cells. The research highlights how these cells promote apoptosis of EBV-related malignant cells and enhance immunotherapy response. TLS-related cell signatures are linked to prognosis and response to PD-1 blockade, providing potential therapeutic insights for cancer treatment. [Article]

• Baseline Immune State and T-cell Clonal Kinetics are Associated with Durable Response to CAR-T Therapy

This study explores the cellular and molecular factors influencing response to CD19-targeting CAR-T therapy in relapsed/refractory Large B-Cell Lymphoma (LBCL). By analyzing blood samples from 50 patients treated with axicabtagene ciloleucel (axi-cel), the researchers identified baseline features such as elevated B cells and a high lymphocyte-to-monocyte ratio (ALC/AMC) associated with better outcomes. A predictive model incorporating these factors was validated in a larger cohort, showing a significant difference in progression-free survival. The findings suggest that baseline immune characteristics can predict CAR-T therapy response, aiding in patient selection. [Article]

• Biological function and potential application of PANoptosis-related genes in colorectal carcinogenesis

This study investigates PANoptosis-related genes (PRGs) in colorectal cancer (CRC) and their clinical significance. Five key PRGs (BCL10, CDKN2A, DAPK1, PYGM, and TIMP1) were identified and validated in CRC cells and tissues. These genes were linked to immune microenvironment, immune cell infiltration, chemotherapy sensitivity, and tumor progression pathways. A novel prognostic model combining clinical indicators and key PRGs was developed to predict CRC outcomes. The findings provide new insights into CRC pathogenesis, prognosis, and potential therapeutic targets. [Article]

• The prognostic effect of infiltrating immune cells is shaped by proximal M2 macrophages in lung adenocarcinoma

This study introduces a method to quantify the spatial proximity of immune cells in the tumor microenvironment using single-cell spatial data. Applied to lung adenocarcinoma patients, the proximity between cell types was found to be more predictive of prognosis than immune cell density. Proximity of T helper and B cells to cancer cells correlated with survival benefits, while M2 macrophage proximity to various immune cells indicated poor prognosis. The method provides a novel way to assess immune cell interactions and their impact on patient outcomes. [Article]

• Triple therapy boosts survival in NSCLC patients with brain metastases: a retrospective cohort study of chemotherapy, ICIs, and antiangiogenic agents

This retrospective study evaluates systemic treatments for brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients with non-sensitive mutations. Among 209 patients, three treatment regimens were compared: chemotherapy alone, chemotherapy plus immune checkpoint inhibitors (ICIs), and chemotherapy with ICIs and antiangiogenic therapy. The combination of all three therapies (C + I + A) significantly improved overall survival to 23.6 months, compared to 11.4 months with chemotherapy alone. The study highlights the effectiveness of tailored combination therapies in improving survival and reducing mortality risk in NSCLC patients with BMs. [Article]

• TBC1 domain-containing proteins are frequently involved in triple-negative breast cancers in connection with the induction of a glycolytic phenotype

This study explores the role of TBC1 domain-containing proteins (TBC1Ds) in cancer metabolism, particularly in triple-negative breast cancer (TNBC). Elevated expression of certain TBC1Ds (TBC1D31, TBC1D22B, and TBC1D7) was found to drive a glycolytic metabolic phenotype in TNBC, correlating with poor prognosis. TBC1D7’s impact on glycolysis was shown to be independent of its known role in mTORC1 regulation. As a potential biomarker, TBC1D7 could help identify TNBC patients with poor prognosis who may benefit from anti-glycolytic therapies, offering a personalized approach to treatment. [Article]

• Cross-modal deep learning model for predicting pathologic complete response to neoadjuvant chemotherapy in breast cancer

This study presents a cross-modal multi-pathway automated prediction model to predict pathological complete response (pCR) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). By integrating temporal and spatial information from biopsy digital pathology images and multi-temporal ultrasound images, the model effectively predicts pCR status early in treatment. The findings highlight its potential as a valuable tool for personalizing treatment strategies based on individual responses, improving early NAC outcome predictions. [Article]

• Comprehensive scRNA-Seq Analysis to Identify New Markers of M2 Macrophages for Predicting the Prognosis of Prostate Cancer

This study explores the role of M2 macrophages in prostate cancer (PCa) progression and prognosis. Using single-cell RNA sequencing (scRNA-seq) and mRNA expression data, the researchers identified key M2 macrophage-related genes and constructed a risk score model based on nine prognostic gene signatures. M2 macrophages were found to promote PCa proliferation, invasion, and migration. The findings suggest that M2 macrophages and their associated genes are significant in PCa development and could serve as predictive biomarkers for prognosis and treatment response. [Article]

• SEPT9: From pan-cancer to lung squamous cell carcinoma

This study provides a comprehensive analysis of SEPT9, a cytoskeletal GTPase, across various cancers, revealing its role in tumorigenesis, prognosis, and treatment. SEPT9 is found to be highly expressed in many cancers, including lung squamous cell carcinoma (LUSC), where it is linked to poor clinical outcomes and affects drug sensitivity. Functional analyses indicate that SEPT9 influences tumor progression and immune microenvironments, enhancing immunotherapy effectiveness. A prognostic model incorporating SEPT9 and other mitotic spindle-related genes was developed, improving predictions and therapeutic strategies for LUSC patients. [Article]

2. Cardiovascular and Metabolic Diseases

• Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

In a trial of patients with heart failure and a left ventricular ejection fraction ≥40%, finerenone significantly reduced worsening heart failure events and cardiovascular deaths compared to placebo (rate ratio, 0.84). It also decreased heart failure events (rate ratio, 0.82) but had no significant effect on cardiovascular mortality. Finerenone increased hyperkalemia risk but reduced hypokalemia. [Article]

• Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis

In a meta-analysis of four trials involving 13,846 patients with heart failure, mineralocorticoid receptor antagonists (MRAs) reduced cardiovascular death or heart failure hospitalizations by 23% overall. MRAs were more effective in patients with heart failure and reduced ejection fraction (HFrEF) compared to those with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF). Specifically, MRAs reduced heart failure hospitalizations in both groups, but cardiovascular death and all-cause mortality were significantly decreased only in the HFrEF group. MRAs increased the risk of hyperkalemia but reduced hypokalemia. [Article]

• Asundexian versus Apixaban in Patients with Atrial Fibrillation

In a phase 3 trial comparing asundexian (50 mg daily) to apixaban for stroke prevention in atrial fibrillation, asundexian was found to have a higher incidence of stroke or systemic embolism (1.3% vs. 0.4%) and fewer major bleeding events (0.2% vs. 0.7%). The trial was stopped early due to these results. Asundexian was less effective in preventing strokes but had a better safety profile concerning major bleeding compared to apixaban. [Article]

• Rare Genetic Variants in LDLR, APOB, and PCSK9 Are Associated with Aortic Stenosis

This study examines the impact of protein-disrupting variants in LDL metabolism genes (LDLR, APOB, PCSK9) on aortic stenosis (AS) and aortic valve peak velocity. It found that LDLR variants, which increase LDL-C levels, are linked to a higher risk of AS, while APOB and PCSK9 variants, which lower LDL-C levels, are associated with reduced AS risk. These findings suggest that lifelong LDL-C alterations due to genetic variants significantly influence AS risk, highlighting the potential benefit of early lipid-lowering therapy in preventing AS. [Article]

• Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat

This study reveals that neuropeptide Y (NPY) in sympathetic neurons helps protect against obesity by maintaining the proliferation of mural cells in adipose tissues, which are crucial for thermogenesis. NPY+ sympathetic axons are primarily associated with perivascular regions in brown and white adipose tissues. Loss of NPY from sympathetic neurons leads to reduced thermogenic capability, increased susceptibility to obesity, and impaired energy expenditure without affecting food intake. [Article]

• Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis

This study reveals that sortilin, an endosomal trafficking component, regulates the localization and degradation of mitochondrial ACSL1, a key enzyme in fatty acid oxidation. During beige fat activation, sortilin facilitates the movement of ACSL1 from mitochondria to the endolysosomal pathway. Sortilin depletion leads to increased mitochondrial ACSL1, activation of AMPK/PGC1α signaling, and improved beige fat function. This process helps prevent obesity and insulin resistance induced by a high-fat diet. The findings suggest targeting sortilin could be a promising strategy for treating metabolic diseases. [Article]

• Crotonylation of NAE1 Modulates Cardiac Hypertrophy via Gelsolin Neddylation

This study investigates the role of lysine crotonylation of NEDD8-activating enzyme E1 regulatory subunit (NAE1) in cardiac hypertrophy. Elevated crotonylation of NAE1, particularly at lysine 238, was linked to exacerbated cardiac hypertrophy in mouse models and human patients. Using knock-in mice with crotonylation-defective (NAE1 K238R) and crotonylation-mimicking (NAE1 K238Q) mutations, the study found that crotonylation enhances pathological hypertrophy by promoting the neddylation and stability of gelsolin (GSN), leading to adverse cytoskeletal remodeling. These findings suggest that targeting NAE1 crotonylation could offer new therapeutic approaches for cardiac hypertrophy. [Article]

3. Neurodegenerative Diseases and Cognitive Disorders

• Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease

This study investigates microglial activation in Alzheimer’s disease (AD) and its potential as a biomarker. Researchers found that microglial synchronicity is disrupted in AD, leading to regional desynchronization in the brain. Using TSPO-PET imaging and single-cell radiotracing in mice and human datasets, they demonstrated that microglial desynchronization correlates with cognitive decline. The findings suggest that microglia synchronicity could serve as a biomarker for AD progression. [Article]

• Combinatorial targeting of glutamine and lipid metabolism effectively suppresses glioblastoma

This study reveals that pimozide, an antipsychotic drug, inhibits lysosome function to reduce fatty acid and cholesterol release in glioblastoma (GBM). However, GBM develops resistance by increasing glutamine consumption and lipogenesis via SREBP-1. This creates a feedforward loop that drives drug resistance. Combining pimozide with inhibitors targeting glutamine metabolism disrupts this loop, causing mitochondrial damage and oxidative stress, leading to GBM cell death. The findings suggest a promising therapeutic strategy by combining glutamine metabolism inhibition with lysosome suppression. [Article]

• Cellular communities reveal trajectories of brain aging and Alzheimer’s disease

This study analyzed 1.65 million RNA-sequencing profiles from 437 older individuals to identify cellular changes linked to Alzheimer’s disease (AD). Researchers found two key microglial subpopulations—one driving amyloid-β buildup and another mediating its effect on tau protein. An astrocyte subpopulation was also linked to tau-related cognitive decline. The findings reveal two brain aging pathways, one leading to AD and the other to healthy aging, offering new insights for personalized treatments. [Article]

• BRCA1 Promotes Repair of DNA Damage in Cochlear Hair Cells and Prevents Hearing Loss

This study reveals that cochlear outer hair cells (OHCs), responsible for hearing, are vulnerable to DNA damage from the drug cisplatin, leading to hearing loss in mice. It shows that BRCA1, a DNA repair factor, is activated in response to cisplatin-induced damage and helps protect OHCs. Loss of BRCA1 accelerates OHC damage and hearing loss. This is the first in vivo evidence that BRCA1 plays a key role in repairing DNA damage in OHCs, helping prevent sensorineural hearing loss caused by drug-induced or age-related damage. [Article]

4. Regenerative Medicine and Tissue Engineering

• Hydrogel Microneedle Patches Loaded with Stem Cell Mitochondria-Enriched Microvesicles for Wound Healing

This study developed a hydrogel microneedle patch (MNP) that delivers mitochondria-rich extracellular vesicles (EVs) to treat radiation-induced chronic wounds. By using metformin to enhance mitochondrial biogenesis in stem cells, they increased EV secretion (Met-EVs), which improved mitochondrial function and reduced oxidative stress in damaged tissues. The patch gradually releases these Met-EVs, promoting anti-inflammatory responses and accelerating wound healing in mice. This approach shows promise for treating chronic wounds. [Article]

• Alveolar regeneration by airway secretory-cell-derived p63(+) progenitors

This study identifies p63-expressing progenitor cells as key players in lung repair following injury. After bleomycin-induced lung damage, p63+ progenitors rapidly proliferate and differentiate into alveolar type 1 and 2 cells. Using genetic tracing, the researchers show that these progenitors originate from airway secretory cells and are essential for efficient alveolar regeneration. The findings suggest secretory-cell-derived p63+ progenitors as a potential therapeutic target for lung regeneration. [Article]

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Additional Highlights

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

• Identification of mpox M1R and B6R monoclonal and bispecific antibodies that efficiently neutralize authentic mpox virus [Article]
• Causal Relationships Between Retinal Diseases and Psychiatric Disorders Have Implications for Precision Psychiatry [Article]
• Transparent mice made with light-absorbing dye reveal organs at work [Article]
• Cryotherapy for treating soft tissue injuries in sports medicine [Review]
• The gut microbiome modulate response to immunotherapy in cancer [Review]
• The Role of Obesity as a Cardiac Disease Risk Factor in Patients with Type 2 Diabetes [Review]
• Pfizer Launches PfizerForAll™, a Digital Platform that Helps Simplify Access to Healthcare [News]
• First Doses of Bavarian Nordic’s Mpox Vaccine Now Arriving in the Democratic Republic of Congo [News]
• As Mpox Cases Surge in Africa, WHO Declares a Global Emergency-Here’s What to Know [News]
• ADVANZ PHARMA secures temporary suspension of the European Commission decision on the OCALIVA® conditional marketing authorisation in Europe [News]

Company Name	Drug Name	Regulatory Body	Approval/Type	Disease	Link
Regeneron Pharmaceuticals	Ordspono™ (odronextamab)	European Union	Marketing Approval	Relapsed/Refractory Follicular Lymphoma, Diffuse Large B-cell Lymphoma	Link
Roche	PiaSky	European Union	Marketing Approval	Paroxysmal Nocturnal Hemoglobinuria	Link
SIFI	AKANTIOR®	European Commission	Marketing Approval	Acanthamoeba Keratitis	Link
BeiGene	BGB-16673	U.S. FDA	Fast Track Designation	Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma	Link
Celltrion	SteQeyma® (CT-P43)	European Commission	Marketing Approval	Chronic Inflammatory Diseases	Link
Astellas & Seagen	PADCEVTM (enfortumab vedotin) + KEYTRUDA® (pembrolizumab)	European Commission	Marketing Approval	Advanced Urothelial Cancer	Link
Bavarian Nordic	JYNNEOS® (MVA-BN) Vaccine	Health Sciences Authority (HSA)	Marketing Approval	Smallpox, Mpox	Link
Soleno Therapeutics	DCCR (Diazoxide Choline)	U.S. FDA	Priority Review for the NDA	Prader-Willi Syndrome	Link
GSK	Arexvy (RSV Vaccine)	European Commission	Marketing Approval	Lower RespiratoryTract Disease by RSV	Link
GSK	Nucala (mepolizumab)	MHLW	Marketing Approval	Chronic Rhinosinusitis with Nasal Polyps	Link
GSK	Bepirovirsen	MHLW	SENKU Designation	Chronic Hepatitis B	Link
Nuvectis Pharma	NXP800	U.S. FDA	Orphan Drug Designation	ARID1a-deficient Ovarian, Fallopian Tube, Primary Peritoneal Cancers	Link
Emergent BioSolutions	ACAM2000® Vaccine	U.S. FDA	Marketing Approval	Mpox	Link
Janssen (Johnson & Johnson)	RYBREVANT® (amivantamab) + Chemotherapy	European Commission	Marketing Approval in Combination	Advanced EGFR-mutated NSCLC	Link
Novavax	COVID-19 Vaccine (NVX-CoV2705)	U.S. FDA	Emergency Use Authorization	COVID-19	Link
Skyline Therapeutics	SKG1108	U.S. FDA	Orphan Drug Designation	Retinitis Pigmentosa	Link
Azurity Pharmaceuticals	NYMALIZE® (nimodipine)	U.S. FDA	Marketing Approval	Ischemic Deficits in Subarachnoid Hemorrhage	Link
Innovent Biologics	IBI363 (PD-1/IL-2α-bias Bispecific Antibody fusion protein)	U.S. FDA	Fast Track Designation	Advanced Melanoma	Link
Travere Therapeutics	FILSPARI® (sparsentan)	U.S. FDA	Full Approval	Kidney Function Decline in IgA Nephropathy	Link
Actimed Therapeutics	S-oxprenolol (ACM-002)	U.S. FDA	Orphan Drug Designation	Amyotrophic Lateral Sclerosis	Link
Moderna	COVID-19 Vaccine	MHRA	Authorization	SARS-COV-2 Variant JN.1	Link
Moderna	COVID-19 mRNA Vaccine	Taiwan Food & Drug Administration	Marketing Approval	SARS-COV-2 Variant JN.1	Link

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