Ontosight^® Newsletter Issue 10

Ontosight^® – Newsletter
September 23^rd – October 6^th, 2024 – Issue 10

Welcome to the 10^th edition of the Ontosight^® Newsletter! This issue features groundbreaking research in oncology, including novel therapeutic targets for gastric and breast cancers, and insights into immune checkpoints. We also delve into neuroscience with studies on Alzheimer’s and cognitive health, alongside advances in immunology that enhance diagnosis and treatment strategies. Finally, stay updated with the latest regulatory news, including new approvals for innovative therapies across various diseases.

Featured Articles

1. Oncology Insights and Pioneering Cancer Research

• Phosphoproteomic subtyping of gastric cancer reveals dynamic transformation with chemotherapy and guides targeted cancer treatment

This study focuses on advanced gastric cancer (AGC), revealing three distinct subtypes based on phosphorylation signaling through deep phosphoproteomic analysis of biopsy samples. The research highlights dynamic mesenchymal transitions and kinome network rewiring during treatment, leading to an epithelial-mesenchymal transition (EMT) subtype. Targeting the AXL pathway is proposed as a potential therapeutic approach, with findings offering valuable resources for future AGC treatments and biomarkers. [Article]

• Deciphering the role of LGALS2: insights into tertiary lymphoid structure-associated dendritic cell activation and immunotherapeutic potential in breast cancer patients

This study identifies LGALS2 as a key marker in tertiary lymphoid structures (TLSs) within breast cancer, playing a crucial role in immune activation and tumor microenvironment modulation. Elevated LGALS2 expression correlates with prolonged survival and a robust immune response. The findings suggest its potential in TLS-directed immunotherapy and patient stratification for improved breast cancer treatment. [Article]

• GPR34 is a metabolic immune checkpoint for ILC1-mediated antitumor immunity

This study reveals that Type 1 innate lymphoid cells (ILC1s) exhibit antitumor activity, with GPR34 acting as a key receptor that inhibits their activation in the tumor microenvironment. Targeting GPR34 or its ligand, LysoPS, enhances ILC1 antitumor immunity. These findings suggest GPR34 as a metabolic immune checkpoint, offering potential for ILC1-based immunotherapy in cancer treatment. [Article]

• Novel bispecific antibody-drug conjugate targeting PD-L1 and B7-H3 enhances antitumor efficacy and promotes immune-mediated antitumor responses

This study evaluates a bispecific antibody-drug conjugate (BsADC) targeting PD-L1 and B7-H3 in laryngeal squamous cell carcinoma, showing superior tumor cytotoxicity compared to other ADCs. The BsADC enhances immune checkpoint inhibition, promotes immunogenic cell death (ICD), and activates tumor-specific immunity. These findings highlight its potential in advancing cancer treatment and overcoming resistance. [Article]

• Spatial single-cell protein landscape reveals vimentinhigh macrophages as immune-suppressive in the microenvironment of hepatocellular carcinoma

This study profiles the spatial heterogeneity of hepatocellular carcinoma (HCC) at a single-cell resolution, identifying distinct spatial patterns with prognostic and molecular features. It reveals that VIMhigh macrophages, co-occurring with regulatory T cells, promote tumor progression and enhance immune suppression via interleukin-1β secretion. These findings highlight the potential for personalized cancer treatments and the importance of spatial analysis in HCC. [Article]

• Comprehensive analysis reveals that P4HA3 is a prognostic and diagnostic gastric cancer biomarker that can predict immunotherapy efficacy

This study identifies Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) as a key factor associated with poor prognosis in gastric cancer (GC). Data analysis shows that elevated P4HA3 expression correlates with immune cell infiltration, tumor mutational burden, and immune checkpoint activity. P4HA3 is highlighted as a potential immune-related biomarker and therapeutic target for GC, offering promise for immunotherapy strategies. [Article]

2. Neuroscience and Insights into Cognitive Health

• Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer’s disease

This study highlights the role of mitochondrial dysfunction (MD) in Alzheimer’s disease (AD), identifying 825 differentially expressed MD-related genes through meta-analysis. It reveals that genes like CLU, MAPT, and NDUFS8 are influenced by epigenetic modifications and interact with inflammatory cytokines such as interleukin-17C. The findings suggest potential targets for AD prevention and intervention by addressing MD and inflammation. [Article]

• Neuronal wiring diagram of an adult brain

This study presents a neuronal wiring diagram of the entire brain of an adult female Drosophila melanogaster, mapping 139,255 neurons and 50 million chemical synapses. The resource includes annotations of cell types, nerves, neurotransmitters, and provides tools for data access and integration with other fly datasets. The analysis reveals information flow from sensory to motor pathways, offering insights into circuit mechanisms underlying sensorimotor behaviors and setting the stage for large-scale connectome projects in other species. [Article]

• Interactive effect of diabetes mellitus and subclinical MRI markers of cerebrovascular disease on cognitive decline and incident dementia: a memory-clinic study

This study explores the impact of diabetes and cerebrovascular disease (CeVD) on cognitive decline in older adults. It finds that diabetes, combined with high levels of white matter hyperintensities (WMHs), accelerates cognitive decline and increases dementia risk, independent of Alzheimer’s pathology. WMHs may serve as an imaging biomarker to identify diabetic individuals at higher risk, highlighting the potential for targeted interventions. [Article]

• The impact of depression and anxiety on mobile phone addiction and the mediating effect of self-esteem

This study examines the relationship between depression, anxiety, self-esteem, and mobile phone addiction (MPA) among Chinese college students. It finds that anxiety and self-esteem mediate the link between depression and MPA, with self-esteem also mediating the anxiety-MPA relationship. The findings offer insights for preventing and addressing mobile phone addiction in this population. [Article]

3. Immunology and Infectious Diseases

• Noninvasive, microbiome-based diagnosis of inflammatory bowel disease

This study developed a microbiome-based diagnostic test for inflammatory bowel disease (IBD) by analyzing metagenomic data from 5,979 fecal samples. Diagnostic models using selected bacterial species effectively distinguished ulcerative colitis and Crohn’s disease, achieving high accuracy across diverse populations. A new noninvasive test based on these bacterial biomarkers outperformed fecal calprotectin in diagnosing IBD. [Article]

• Exploring genetic and immune cell dynamics in systemic lupus erythematosus patients with Epstein-Barr virus infection via machine learning

This study identifies IFI27 as a key gene in Systemic Lupus Erythematosus (SLE) patients with Epstein-Barr Virus (EBV) infection, based on analysis of overlapping differentially expressed genes (DEGs). IFI27 was associated with CD4 cytotoxic T lymphocytes (CTLs) and B cell subtypes, showing high diagnostic performance. These findings offer insights into the molecular mechanisms linking SLE and EBV infection and suggest potential targets for diagnostics and therapy. [Article]

• Stress triggers irritable bowel syndrome through a spermidine-mediated decline in type I interferon

This study reveals that stress-induced overproduction of xanthine and changes in Lactobacillus murinus levels play a role in the pathogenesis of irritable bowel syndrome with diarrhea (IBS-D). Lactobacillus murinus-derived spermidine suppresses type I interferon (IFN)-α in plasmacytoid dendritic cells, leading to enhanced colonic muscle contractions and increased bowel movements. These findings offer insights into the stress-related mechanisms of IBS-D and potential drug targets for treatment. [Article]

• Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

In a study of 131 female patients with X-linked incontinentia pigmenti (IP), 36% were found to have autoantibodies neutralizing type I interferons (IFN-α and IFN-ω), a rate 23 times higher than in controls. These autoantibodies are linked to an increased risk of severe viral diseases, likely due to accelerated thymic involution. Patients without these autoantibodies showed no heightened viral disease risk, highlighting a specific vulnerability in those with autoantibodies. [Article]

4. Insights and Interventions in Metabolic Disorders and Diabetes

• Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy

Polycystic ovary syndrome (PCOS) is characterized by irregular ovulation, hyperandrogenism, and metabolic complications like obesity and insulin resistance. This study evaluates the effectiveness of glucagon-like peptide-1 (GLP1)-based multi-agonists, particularly GLP1/Estrogen (GLP1/E), compared to metformin in mouse models of PCOS. Results show that GLP1/E significantly improves metabolic issues and ovarian cyclicity without causing direct estrogenic effects, highlighting its potential for personalized treatment of PCOS. [Article]

• Multi Omics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism

This study explores the relationship between gut microbiota and insulin sensitivity across multiple tissues using a multiomics approach. Proteobacteria in the gut were consistently linked to reduced insulin sensitivity and higher HbA1c levels, while T cell-related signatures were positively associated with insulin sensitivity. Findings highlight the microbiome-gut-adipose-liver axis, offering potential therapeutic targets for improving systemic insulin action. [Article]

• Bioengineered Nanomedicines Targeting the Intestinal Fc Receptor Achieve the Improved Glucoregulatory Effect of Semaglutide in a Type 2 Diabetic Mice Model

This study develops FcRn-targeted nanoparticles (NPs) to enhance the oral delivery of semaglutide, a glucagon-like peptide-1 analogue, which suffers from low bioavailability. In transgenic mice with type 2 diabetes, the FcRn-targeted semaglutide-NPs showed improved glucose regulation compared to free semaglutide or nontargeted NPs, with effects similar to subcutaneous semaglutide. The NPs were retained longer in the ileum and colorectum, demonstrating their effectiveness in improving semaglutide’s pharmacological action in managing diabetes. [Article]

• The association between the amount and timing of coffee consumption with chronic kidney disease in diabetic patients

This study investigates the relationship between coffee consumption timing and the prevalence of chronic kidney disease (CKD) in diabetic patients, using data from 8,564 individuals from the NHANES survey. Results indicate that coffee consumption throughout the day is associated with a lower prevalence of CKD, particularly when consumed from dawn to forenoon, which correlates with a reduced risk (OR: 0.87). Conversely, higher coffee intake during noon-to-evening and evening-to-dawn periods is linked to an increased risk of CKD (OR: 1.35 and OR: 1.28, respectively). [Article]

5. Understanding Risks and Outcomes in Cardiovascular Health

• Multielectrode Catheter-Based Pulsed Field Ablation of Persistent and Long-Standing Persistent Atrial Fibrillation

This study evaluates a tailored ablation strategy using a pentaspline pulsed field ablation (PFA) catheter for persistent and long-standing persistent atrial fibrillation (AF). In 72 patients, the protocol achieved AF termination in 95.8% of cases, with 74.2% developing organized left-sided atrial flutter, which was successfully terminated using the PFA catheter. The single-procedure success rate was 74.6% after approximately 15 months, with an AF-free survival rate of 89.2%, indicating favorable clinical outcomes over a year of follow-up. [Article]

• Gallic Acid Alleviates Glucolipotoxicity-Induced Nephropathy by miR-709-NFE2L2 Pathway in db/db Mice on a High-Fat Diet

This study explores the therapeutic effects of gallic acid (GA) on diabetic nephropathy (DN) in a glucolipotoxicity-induced model using db/db mice. GA treatment reduced oxidative stress and kidney fibrosis by downregulating the miRNA miR-709a-5p, which is linked to DN pathology, and enhanced the activity of antioxidant enzymes. The findings suggest that GA could serve as a novel therapeutic approach for managing DN and related complications by mitigating oxidative stress and lipogenesis through NFE2L2 activation. [Article]

• SPA Promotes Atherosclerosis Through Mediating Macrophage Foam Cell Formation

This study investigates the role of surfactant protein A (SPA) in atherosclerosis, highlighting its increased expression in atherosclerotic lesions and its involvement in macrophage foam cell formation. SPA deficiency led to reduced lipid accumulation and atherosclerotic lesions in mice, as well as decreased expression of the scavenger receptor CD36, which is critical for cellular OxLDL influx. The findings suggest that SPA promotes atherosclerosis by enhancing macrophage foam cell formation through CD36 upregulation. [Article]

• Cellular communication network factor 2 regulates smooth muscle cell transdifferentiation and lipid accumulation in atherosclerosis

This study investigates the role of cellular communication network factor 2 (CCN2) in regulating vascular smooth muscle cell (SMC) plasticity during atherosclerosis. The findings show that CCN2 is upregulated in transdifferentiated SMCs, and its deficiency in SMCs leads to increased susceptibility to atherosclerosis and lipid-rich plaques. The research highlights CCN2’s protective role against atherosclerosis progression by maintaining vascular wall homeostasis. [Article]

Additional Highlights

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

• Non-Invasive Serum Markers of Non-Alcoholic Fatty Liver Disease Fibrosis: Potential Tools for Detecting Patients with Cardiovascular Disease [Review]
• Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with meta-regression of observational studies [Review]
• Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001) [Article]
• The huge toll of PhDs on mental health: data reveal stark effects [News]
• Fasenra recommended for approval in the EU by CHMP for the treatment of eosinophilic granulomatosis with polyangiitis [News]
• Pfizer Voluntarily Withdraws All Lots of Sickle Cell Disease Treatment OXBRYTA® (voxelotor) From Worldwide Markets [News]

Company Name	Drug Name	Regulatory Body	Approval/Type	Disease	Link
Takeda	FRUZAQLA (fruquintinib)	Japan’s MHLW	Marketing Approval	Unresectable advanced or recurrent colorectal cancer	Link
Ipsen	Kayfanda® (odevixibat)	European Commission	Marketing Approval	Cholestatic pruritus in Alagille Syndrome	Link
UCB	BIMZELX[®] (bimekizumab-bkzx)	FDA	Marketing Approval	Psoriatic arthritis, non-radiographic axial spondyloarthritis, ankylosing spondylitis	Link
Lilly	Kisunla™ (donanemab-azbt)	Japan’s MHLW	Marketing Approval	Early symptomatic Alzheimer’s disease	Link
IntraBio	AQNEURSA™ (levacetylleucine)	FDA	Marketing Approval	Niemann-Pick disease type C (NPC)	Link
AstraZeneca	Tagrisso (osimertinib)	FDA	Marketing Approval	Stage III EGFR-mutated non-small cell lung cancer (NSCLC)	Link
Bristol Myers Squibb	COBENFY™ (xanomeline and trospium chloride)	FDA	Marketing Approval	Schizophrenia in adults	Link
Sanofi	Dupixent (dupilumab)	FDA	Marketing Approval	Chronic obstructive pulmonary disease (COPD)	Link
Sanofi	Dupixent (dupilumab)	China’s NMPA	Marketing Approval	Chronic obstructive pulmonary disease (COPD)	Link
Fresenius	OtulfiTM (ustekinumab-aauz)	FDA	Marketing Approval	Crohn’s disease, ulcerative colitis, moderate to severe plaque psoriasis, active psoriatic arthritis	Link
Fresenius	FYB202 (ustekinumab biosimilar)	European Commission	Marketing Approval	Several serious inflammatory diseases	Link
AstraZeneca	Calquence (acalabrutinib)	FDA	Priority Review	Previously untreated mantle cell lymphoma (MCL)	Link
Novaliq & Théa	Vevizye (ciclosporin 0.1% eye drops)	European Commission	Marketing Approval	Severe dry eye disease (keratoconjunctivitis sicca)	Link

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