Aberrant Function Research Articles

Altered local spontaneous activity and functional connectivity density in major depressive disorder patients with anhedonia.

The purpose of this study was to investigate the alterations of intrinsic brain function in major depressive disorder (MDD) patients with and without anhedonia based on whole-brain level by using two novel measures, four-dimensional spatial-temporal consistency of local neural activity (FOCA) and local functional connectivity density (lFCD). A total of 26 MDD patients with anhedonia (MDD-WA), 29 MDD patients without anhedonia (MDD-WoA), and 30 healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning and intrinsic brain function was explored by FOCA and lFCD. A two-sample t-test was conducted to explore FOCA and lFCD differences between MDD patients and HCs, then analysis of covariance (ANCOVA) and post hoc tests were performed to obtain brain regions with significant differences among three groups. Finally, the diagnostic performance of FOCA and lFCD values with significant inter-group difference was evaluated using receiver operating characteristic (ROC) curves. Compared to HCs, MDD patients showed decreased FOCA in the right cuneus (CUN) and left postcentral gyrus (PoCG), as well as diminished lFCD in the right CUN and left calcarine fissure and surrounding cortex (CAL). Interestingly, the MDD-WA group was more likely to exhibit decreased FOCA in the left PoCG and reduced lFCD in the left CAL after consideration for the effect of anhedonia in MDD patients. The MDD-WA group further showed increased FOCA in the bilateral caudate (CAU) and right ventral anterior nucleus (VA) when comparing to HCs. Additionally, as compared with MDD-WoA group, the MDD-WA group presented decreased FOCA in the right middle occipital gyrus (MOG), which was also negatively associated with the severity of anhedonia in MDD patients. Finally, FOCA values of the right MOG exhibited excellent discriminant validity in differentiating MDD-WA from MDD-WoA, and the other individual or combined indices of FOCA or lFCD values in the aforementioned distinct brain regions presented significant utility in distinguishing between MDD or MDD-WA and HCs. The present findings suggest that aberrant intrinsic brain function in the left CAL, left PoCG, bilateral CAU, right VA, and, especially the right MOG may be associated with anhedonia in patients with MDD. Altered FOCA in the right MOG may have the potential to be a diagnostic neuroimaging biomarker for MDD patients with anhedonia.

Molecular landscape of CD8+ T cells in pure red cell aplasia.

The aberrant function of lymphocytes is considered a significant contributing factor to pure red cell aplasia (PRCA), but the precise mechanism by which T lymphocytes induce erythroid development stagnation remains unclear. In our study, the CD8+ T lymphocytes were isolated from bone marrow aspirates of acquired PRCA patients and healthy controls. RNA sequencing (RNA-Seq) was performed to analyze gene expression profiles. Additionally, the expression levels of key molecules and transcription factors were assessed at the transcription and protein levels. The RNA-Seq analysis revealed a significant upregulation of genes associated with the PI3K/AKT/mTOR pathway in CD8+ T lymphocytes from patients with PRCA, compared to healthy controls. The mRNA expression of AKT, mTOR and key transcription factors T-bet were significantly upregulated in CD8+ T cells from patients with PRCA. Treatment with rapamycin, an mTOR inhibitor, attenuated the activation of CD8+ T lymphocytes in PRCA patients. Our findings demonstrate the activation of the PI3K/AKT/mTOR signaling pathway in CD8+ T lymphocytes of PRCA patients, suggesting its involvement in PRCA pathogenesis. Targeting this pathway may offer a potential therapeutic strategy for PRCA characterized by CD8+ T cell dysregulation.

Metabolic reprogramming and immunological changes in the microenvironment of esophageal cancer: future directions and prospects

BackgroundEsophageal cancer (EC) is the seventh-most prevalent cancer worldwide and is a significant contributor to cancer-related mortality. Metabolic reprogramming in tumors frequently coincides with aberrant immune function alterations, and extensive research has demonstrated that perturbations in energy metabolism within the tumor microenvironment influence the occurrence and progression of esophageal cancer. Current treatment modalities for esophageal cancer primarily include encompass chemotherapy and a limited array of targeted therapies, which are hampered by toxicity and drug resistance issues. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, has exhibited promising results; however, a substantial proportion of patients remain unresponsive. The optimization of these immunotherapies requires further investigation. Mounting evidence underscores the importance of modulating metabolic traits within the tumor microenvironment (TME) to augment anti-tumor immunotherapy.MethodsWe selected relevant studies on the metabolism of the esophageal cancer tumor microenvironment and immune cells based on our searches of MEDLINE and PubMed, focusing on screening experimental articles and reviews related to glucose metabolism, amino acid metabolism, and lipid metabolism, as well their interactions with tumor cells and immune cells, published within the last five years. We analyzed and discussed these studies, while also expressing our own insights and opinions.ResultsA total of 137 articles were included in the review: 21 articles focused on the tumor microenvironment of esophageal cancer, 33 delved into research related to glucose metabolism and tumor immunology, 30 introduced amino acid metabolism and immune responses, and 17 focused on the relationship between lipid metabolism in the tumor microenvironment and both tumor cells and immune cells.ConclusionThis article delves into metabolic reprogramming and immune alterations within the TME of EC, systematically synthesizes the metabolic characteristics of the TME, dissects the interactions between tumor and immune cells, and consolidates and harnesses pertinent immunotherapy targets, with the goal of enhancing anti-tumor immunotherapy for esophageal cancer and thereby offering insights into the development of novel therapeutic strategies.

Resilience to Global Health Challenges Through Nutritional Gut Microbiome Modulation

As the world faces an escalating challenge of non-communicable diseases (NCDs), with phenotypes ranging from allergic chronic immuno-inflammatory diseases to neuropsychiatric disorders, it becomes evident that their seeds are sown during the early stages of life. Furthermore, within only a few decades, human obesity has reached epidemic proportions and now represents the most serious public health challenge of our time. Recent demonstrations that a growing number of these conditions are linked to aberrant gut microbiota composition and function have evoked active scientific interest in host-microbe crosstalk, characterizing and modulating the gut microbiota in at-risk circumstances. These efforts appear particularly justified during the most critical period of developmental plasticity when the child’s immune, metabolic, and microbiological constitutions lend themselves to long-term adjustment. Pregnancy and early infancy epitomize an ideal developmental juncture for preventive measures aiming to reduce the risk of NCDs; by promoting the health of pregnant and lactating women today, the health of the next generation(s) may be successfully improved. The perfect tools for this initiative derive from the earliest and most massive source of environmental exposures, namely the microbiome and nutrition, due to their fundamental interactions in the function of the host immune and metabolic maturation.

Depth of focus as a function of spherical aberration using adaptive optics in pseudophakic subjects.

To measure visual acuity at three different defocus planes in pseudophakic subjects with varying levels of spherical aberration induced by an adaptive optics visual simulator. The study aimed to simulate Extended Depth of Focus (EDOF) intraocular lenses (IOLs). Private hospital (IMO, Barcelona, Spain). Observational case series; modelling theory. Through-focus visual acuity was measured in 26 pseudophakic subjects (age 63 ± 10 years old) with an adaptive optics visual simulator optimized for clinical use (VAO, Voptica SL, Murcia, Spain). Measurements were made under five different conditions of induced negative spherical aberration: 0, -0.07, -0.15, -0.23 and -0.30 μm (pupil diameter: 4.5 mm). Results were also modelled using ray tracing simulations. On average, depth of focus was extended when spherical aberration increased from -0.07 to -0.15 μm (4.5 mm pupil diameter). Some indivisuals (27%) experienced improved depth of focus with higher magnitudes of spherical aberration, while others (23%) exhibited no benefit from increased (negative) SA, as visual acuity dropped below acceptable levels. Depth of focus calculations based on ray tracing showed general agreement with the measurements. The visual conditions of EDOF IOLs were artificially recreated in a population of pseudophakic patients implanted with a monofocal IOL. The variability seen across subjects in visual acuity at different defocus planes suggests that visual simulators might be capable of screening subjects for suitability and tolerability of these advanced technology lenses.

A promising future for breast cancer therapy with hydroxamic acid-based histone deacetylase inhibitors.

Histone deacetylases (HDACs) play a critical role in chromatin remodelling and modulating the activity of various histone proteins. Aberrant HDAC functions has been related to the progression of breast cancer (BC), making HDAC inhibitors (HDACi) promising small-molecule therapeutics for its treatment. Hydroxamic acid (HA) is a significant pharmacophore due to its strong metal-chelating ability, HDAC inhibition properties, MMP inhibition abilities, and more. They were found to increase the efficacy of the approved drugs when used in combination. In this review we presented bioinformatic analysis using available data from the Cancer Genome Atlas and Genotype-Tissue Expression databases, outlined the recent advancements in the application of HA-based HDACi for BC during preclinical investigation and clinical trials, tried to offer the rationale for targeting HDAC in BC with HA-based HDACi, summarised the challenges faced in the successful clinical application of HDACi, and proposed potential strategies to address these challenges, aiming to enhance treatment outcomes in BC. Abbreviations: ABCG2, ATP-binding cassette super-family G member 2; ABC, ATP-binding cassette; ADP, Adenosine diphosphate; APC, Antigen presenting cell; AML, Acute myeloid leukemia; ARH1, Aplysia ras homolog 1; BCRP, Breast cancer resistance protein; BRCA, Breast invasive carcinoma; Bax, B-cell lymphoma associated X; CK5, Cytokeratin 5; CK14, Cytokeratin 14; CK17, Cytokeratin 17; CoRESTMiDAC, Co-repressor for element-1-silencing transcription factor; CRM1, Chromosomal maintenance 1; CTCL, Cutaneous T-cell lymphoma; DNMT, DNA methyltransferase; DFS, Disease-free survival; ER, Oestrogen receptor; EMT, Epithelial-mesenchymal transition; FGFR1, Fibroblast growth factor receptor 1; GEPIA, Gene Expression Profiling Interactive Analysis; GTEx, Genotype tissue expression; HAT, Histone acetylase; HDAC, Histone deacetylase; HDF, Human dermal fibroblast; HER2, Human epidermal growth factor receptor 2; HDLP, Histone deacetylase-like protein; Hsp90, Heat shock protein 90; HSF1, Heat shock factor 1; HeLa, Henrietta Lacks; HER1, Human epidermal growth factor receptor 1; IARC, International Agency for Research on Cancer; IL-10, Interleukin-10; KAP1, KRAB associated protein 1; MDM2, Mouse double minute 2 homolog; MDR, Multidrug resistance; MCF-7, Michigan cancer foundation-7; MEF-2, Myocyte enhancer factor-2MMP- Matrix metalloproteinase; NAD, Nicotinamide adenine dinucleotide; NuRD, Nucleosome remodelling and deacetylation; NF- κ B, Nuclear factor kappa light chain enhancer of activated B cell; NES, Nuclear export signal; NLS, Nuclear localization signal; NCoR, Nuclear receptor corepressor; NCT, National clinical trial; OS, Overall survival; PR, Progesterone receptor; PI3K, Phosphoinositide 3-kinase; PAX3, Paired box gene 3; P-gp, P-glycoprotein; ROS, Reactive oxygen species; SIRT, Sirtuin; SMRT, Silencing mediator for retinoid and thyroid receptor; STAT3, Signal transducer and activator of transcription-3; SAR, Structure-activity relationship; SHP1, Src homology region 2 domain-containing phosphatase 1; SAHA, Suberoylanilide hydroxamic acid; SMEDDS, Self micro emulsifying drug delivery system; TNBC, Triple-negative breast cancer; TSA, Trichostatin A; ZBG, Zinc binding group.

Effects of aged garlic extract on macrophage functions: a short review of experimental evidence (Review).

Macrophages play crucial roles in both the innate and adaptive immune systems, contributing to the removal of pathogens and subsequent immune responses. Conversely, aberrant macrophage functions are associated with the onset and progression of various diseases, highlighting macrophages as potential therapeutic targets. Aged garlic extract (AGE) is derived from garlic that has undergone a maturation process of over 10 months in an ethanol solution and contains a variety of bioactive components which are produced in the aging process. Previous animal studies and clinical trials have demonstrated that AGE and its constituents exert a range of health benefits, including immune modulation and amelioration of disease conditions. Experimental studies indicate that AGE modulates macrophage functions associated with pathological conditions. To facilitate understanding of AGE's potential as a functional alleviation for macrophage-associated diseases, the present short review summarizes experimental evidence supporting the notion that AGE and its components modify macrophage functions, including phagocytosis, production of reactive oxygen species and polarization.

Autophagy intersection: Unraveling the role of the SNARE complex in lysosomal fusion in Alzheimer's disease.

Autophagy is a fundamental cellular process critical for maintaining neuronal health, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD). This review explores the intricate role of the SNARE complex in the fusion of autophagosomes with lysosomes, a crucial step in autophagic flux. Disruptions in this fusion process, often resulting from aberrant SNARE complex function or impaired lysosomal acidification, contribute to the pathological accumulation of autophagosomes and lysosomes observed in AD. We examine the composition, regulation, and interacting molecules of the SNARE complex, emphasizing its central role in autophagosome-lysosome fusion. Furthermore, we discuss the potential impact of specific SNARE protein mutations and the broader implications for neuronal health and disease progression. By elucidating the molecular mechanisms underlying SNARE-mediated autophagic fusion, we aim to highlight therapeutic targets that could restore autophagic function and mitigate the neurodegenerative processes characteristic of AD.

CTGCT, Centre of Excellence for the Technologies of Gene and Cell Therapy: Collaborative Translation of Scientific Discoveries into Advanced Treatments for Neurological Rare Genetic Diseases and Cancer

The emerging field of precision medicine relies on scientific breakthroughs to understand disease mechanisms and develop cutting-edge technologies to overcome underlying genetic and functional aberrations. The establishment of the Centre of Excellence for the Technologies of Gene and Cell Therapy (CTGCT) at the National Institute of Chemistry (NIC) in Ljubljana represents a significant step forward, as it is the first centre of its kind in Slovenia. The CTGCT is poised to spearhead advances in cancer immunotherapy and personalised therapies for neurological and other rare genetic diseases. The centre’s overarching mission is to extend beyond the NIC’s scientific excellence in basic research and bring new therapeutic solutions toward clinical application. The CTGCT aims to develop a broad pipeline of biomedical tools, including innovative synthetic biology tools, gene editing and splicing technologies, RNA-based technologies, immune regulation engineering and novel viral and non-viral delivery systems. The CTGCT is supported by partner institutions from the UK, the Netherlands and Germany, which already have academic good manufacturing practice (GMP) facilities for the manufacture of advanced therapy medicinal products (ATMPs) and is committed to active collaboration with clinicians and patient organizations at all stages of development to improve access to gene and cell therapies (GCTs) for patients. The Centre also seeks to collaborate with national and international academic and industrial partners, and the newly established GMP facilities will address a critical bottleneck in the translation of GCTs from research to practice. Finally, CTGCT's translational research and technology transfer units will ensure the impactful dissemination of research and innovation activities in Slovenia, throughout the Western Balkans and Eastern Europe region, and beyond. With its comprehensive approach and forward-looking vision, the CTGCT will drive transformative advances in gene and cell therapies for the benefit of patients on a global scale.

LncRNA MIAT binding to GATA3 activates MAPK signaling pathway and influences bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) manifests in premature neonates with aberrant pulmonary function. Numerous long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of BPD. This study aims to elucidate the impact of the lncRNA myocardial infarction-associated transcript (MIAT) on the initiation and progression of BPD. Initially, BPD murine models were established through hyperoxia induction in newborn mice. Subsequently, MIAT and GATA binding protein 3 (GATA3) expression levels were assessed, and intravenous administration of short hairpin RNAs (shRNAs) targeting MIAT and GATA3 was performed. Pulmonary histological alterations were examined through histological staining. Levels of inflammatory mediators were quantified using enzyme-linked immunosorbent assay (ELISA) kits. The interaction between MIAT and GATA3 was scrutinized through RNA immunoprecipitation, RNA pull-down, and fluorescence in situ hybridization. The downstream mechanisms of GATA3 were explored using bioinformatics analysis. In summary, lncRNA MIAT exhibited elevated expression in the lung tissues of BPD-afflicted mice. MIAT localized to the nucleus and interacted with GATA3, thereby activating the mitogen-activated protein kinase (MAPK) pathway. Knockdown of MIAT or silencing of GATA3 attenuated the inflammatory response, deactivated the MAPK pathway, and ameliorated BPD symptoms in mice, on the other hand, p-Cresyl sulfate potassium can activate the MAPK signaling pathway and attenuates the effects of si-MIAT or si-GAT3. These improvements were characterized by enhanced alveolar differentiation and reduced glycogen and collagen deposition. In conclusion, lncRNA MIAT plays a pivotal role in activating the MAPK pathway and exacerbating hyperoxia-induced BPD in mice through the binding to GATA3. It's an important discovery for the pathogenesis of BPD and may provide some new treatment for infants diagnosed with BPD.

In vitro examination of Piezo1-TRPV4 dynamics: implications for placental endothelial function in normal and preeclamptic pregnancies.

Mechanosensation is essential for endothelial cell (EC) function, which is compromised in early-onset preeclampsia (EPE), impacting offspring health. The ion channels Piezo-type mechanosensitive ion channel component 1 (Piezo1) and transient receptor potential cation channel subfamily V member 4 (TRPV4) are coregulated mechanosensors in ECs. Current evidence suggests that both channels could mediate aberrant placental endothelial function in EPE. Using isolated fetoplacental ECs (fpECs) from early control (EC) and EPE pregnancies, we show functional coexpression of both channels and that Ca2+ influx and membrane depolarization in response to chemical channel activation is reduced in EPE fpECs. Downstream of channel activation, Piezo1 alone can induce phosphorylation of endothelial nitric oxide synthase (eNOS) in fpECs, while combined activation of Piezo1 and TRPV4 only affects eNOS phosphorylation in EPE fpECs. Additionally, combined activation reduces the barrier integrity of fpECs and has a stronger effect on EPE fpECs. This implies altered Piezo1-TRPV4 coregulation in EPE. Mechanistically, we suggest this to be driven by changes in the arachidonic acid metabolism in EPE fpECs as identified by RNA sequencing. Targeting of Piezo1 and TRPV4 might hold potential for EPE treatment options in the future.NEW & NOTEWORTHY This study shows Piezo-type mechanosensitive ion channel component 1 (Piezo1) and transient receptor potential cation channel subfamily V member 4 (TRPV4) coexpression and functionality within primary human fetoplacental endothelial cells (fpECs), mediating nitric oxide (NO) production and barrier integrity. In early-onset preeclampsia (EPE), fpEC channel functionality and coregulation are impaired, affecting Ca2+ signaling and endothelial barrier function. Combined channel activation significantly reduces endothelial barrier integrity and increases NO production in EPE. Changes in arachidonic acid metabolism are suggested as a key underlying factor mediating impaired channel functionality in EPE fpECs.

A multidomain PARP14 construct suitable for bacterial expression.

Poly-ADP-ribose polymerase-14 (PARP14) can modify proteins and nucleic acids by the reversible addition of a single ADP-ribose molecule. Aberrant PARP14 functions have been related to cancer and inflammation, and its domains are involved in processes related to viral infection. Previous research indicates that PARP14 functions might be mediated via a multitude of target proteins. In vitro studies of this large multidomain enzyme have been complicated by difficulties to obtain biochemical quantities of pure protein. Here we present a strategy that allows bacterial expression and purification of a functional multidomain construct of PARP14. We substituted an internal KH domain and its neighboring unstructured region with a SUMO domain to obtain a protein construct that encompasses three macrodomains, a WWE domain, and a PARP catalytic domain. We show that the resulting construct retains both ADP-ribosyltransferase and de-MARylase activities. This construct will be useful in structural and functional studies of PARP14.

Aberrant promoter methylation, expression and function of RASSF1A gene in a series of Italian parathyroid tumors.

Aberrant epigenetic features are key events involved in parathyroid tumorigenesis, including DNA methylation, histone methylation, and non-coding RNAs. Ras Association Domain Family Protein1 Isoform A (RASSF1A) and Adenomatous Polyposis of Colon (APC) are frequently downregulated in human cancers. Here, we investigated their deregulated expression and the potential role in parathyroid neoplasms. methylation of RASSF1A and APC promoters was analyzed in a series of parathyroid adenomas (PAds, n = 80) and parathyroid carcinomas (PCas, n = 9) from Italian patients with primary hyperparathyroidism, RESULTS: RASSF1A and APC promoter methylation occurred in about 90% of PAds samples. PCas displayed RASSF1A promoter methylation, while APC promoter was methylated only in 2 samples. Of note, RASSF1A promoter methylation negatively correlated with PAds tumor size. However, RASSF1A transcript and protein levels were reduced in PAds and PCas compared with parathyroid normal glands. Investigating the potential mechanism involved in RASSF1A promoter methylation, we found that DNA methyltransferases (DNMTs) activity was variable in PAds and inversely correlated with RASSF1A protein levels. In addition, the RASSF1A promoter methylation negatively correlated with long-non-coding Antisense Intronic Noncoding RASSF1A (ANRASSF1A) mRNA levels, excluding the involvement of ANRASSF1 in RASSF1A regulation. In HEK293A cells transfected with the calcium sensing receptor (CASR), loss of RASSF1A increased basal phosphorylated Extracellular signal-regulated kinase (pERK/ERK) levels blunting the CASR-induced increases. RASSF1A and APC promoter methylation is a hallmark of parathyroid tumors; deregulation of DNMTs activity contributes to modulation of RASSF1A expression. Loss of RASSF1A may be involved in the tuning of ERK pathway in parathyroid tumors.

Role of early growth response-1 as a tumor suppressor in oral squamous cell carcinoma

BackgroundOral squamous cell carcinoma (OSCC) exhibits pronounced local invasiveness and a propensity for lymph node metastasis. Given its frequent detection at advanced stages and the consequential postoperative functional impairments, the identification of effective molecular markers for early detection and treatment is imperative. Early growth response-1 (EGR-1) serves as a versatile transcription factor expressed across various cell types. Its role in cancer is contentious, acting as either an oncogene or a tumor suppressor gene.MethodsThis study undertook comprehensive analyses, including big data scrutiny, expression profiling using 50 OSCC samples, and in vitro functional assessments, to elucidate EGR-1’s involvement in OSCC.ResultsComparative analysis revealed significantly reduced EGR-1 expression in oral cancer tissues compared to healthy controls or normal oral mucosa. In vitro experimentation with multiple OSCC cell lines demonstrated that EGR-1 curbed cell proliferation, migration, and invasion capabilities. Additionally, it was observed that EGR-1 prompted G0/G1 arrest in OSCC cells by modulating the activity of cell cycle regulators.ConclusionsThese findings strongly support EGR-1’s tumor-suppressive role in OSCC and hint at the potential for novel OSCC therapies aimed at restoring aberrant EGR-1 function.

Astrocytes play critical roles in neuroinflammation and Parkinson’s disease

Parkinson’s disease (PD) is a multifactorial disorder characterized mainly by the loss of dopaminergic neurons in the substantia nigra of the brain. The pathogenesis of a spontaneous PD is suggested to be multifactorial, an aberrant immune function being one of the factors influencing PD-associated neurodegeneration. It was found that negrostriatal astrocytes get involved in this process. Astrocytes play vital roles in brain homeostasis as well as participate in the local innate immune response triggered by a variety of insults. Astrocytes are not immune cells, but when sensing injury-associated molecular patterns they transform through a process called “reactivity” and become important regulators of the immune response. However, the underlying molecular mechanisms of astrocytes’ contribution to the PD-associated neurodegeneration are not fully understood. A better understanding of astrocyte functions in PD may provide insights into PD pathogenesis and novel therapeutic approaches for the disease. This paper reviews the role of astrocytes in innate immunity and PD.

Systemic drug repurposing for pancreatic cancer based on genetic and epigenetic network analysis using a systems biology approach and deep neural learning of drug-target interactions

Pancreatic cancer is a malignant tumor associated with a high mortality rate. This research presents a systems biology approach to explore the mechanisms of pancreatic ductal adenocarcinoma (PDAC), aiming to identify significant biomarkers that can serve as drug targets. We propose a systematic drug repurposing strategy that incorporates a deep neural network (DNN)-based drug-target interaction (DTI) model along with drug design specifications to develop a potential multi-molecule drug for PDAC treatment. We first established candidate protein-protein interaction networks and gene regulatory networks using big data mining techniques. Real PDAC and non-PDAC genome-wide genetic and epigenetic networks (GWGENs) were systematically identified using their corresponding microarray data through system identification and system order detection methods. The top 6,000 core GWGENs of PDAC and non-PDAC were extracted using the Principal Network Projection method. Subsequently, we annotated the core GWGENs using the Kyoto Encyclopedia of Genes and Genomes pathways to construct their respective core signaling pathways. By comparing upstream microenvironmental factors, core signaling pathways, and downstream aberrant cellular functions between PDAC and non-PDAC, we investigated the carcinogenic mechanisms of PDAC. Notably, c-MYC, forkhead box O3, and tumor suppressor p53 were identified as significant biomarkers for potential drug targets. Furthermore, the DNN-based DTI model predicted the interaction probabilities between candidate molecular drugs and these biomarkers. Based on drug design specifications such as regulatory ability, sensitivity, and toxicity, suitable multi-molecular potential drugs were selected. Ultimately, gemcitabine and MK-2206 were identified as a promising multi-molecular drug combination for PDAC treatment.

DeepRSMA: a cross-fusion-based deep learning method for RNA-small molecule binding affinity prediction.

RNA is implicated in numerous aberrant cellular functions and disease progressions, highlighting the crucial importance of RNA-targeted drugs. To accelerate the discovery of such drugs, it is essential to develop an effective computational method for predicting RNA-small molecule affinity (RSMA). Recently, deep learning-based computational methods have been promising due to their powerful nonlinear modeling ability. However, the leveraging of advanced deep learning methods to mine the diverse information of RNAs, small molecules, and their interaction still remains a great challenge. In this study, we present DeepRSMA, an innovative cross-attention-based deep learning method for RSMA prediction. To effectively capture fine-grained features from RNA and small molecules, we developed nucleotide-level and atomic-level feature extraction modules for RNA and small molecules, respectively. Additionally, we incorporated both sequence and graph views into these modules to capture features from multiple perspectives. Moreover, a transformer-based cross-fusion module is introduced to learn the general patterns of interactions between RNAs and small molecules. To achieve effective RSMA prediction, we integrated the RNA and small molecule representations from the feature extraction and cross-fusion modules. Our results show that DeepRSMA outperforms baseline methods in multiple test settings. The interpretability analysis and the case study on spinal muscular atrophy demonstrate that DeepRSMA has the potential to guide RNA-targeted drug design. The codes and data are publicly available at https://github.com/Hhhzj-7/DeepRSMA.

Abstract A011: Binding of the exon junction complex shapes the landscape of m6A in RNA - a possible source of m6A dysregulation in cancer

Abstract N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic mRNA. Increasing evidence shows that m6A is involved in the biological functions of cancer cells, including proliferation, invasion, metastasis, and drug resistance. Dysregulation of m6A deposition and its associated machinery, including writers, erasers and readers, is observed in multiple cancer types, and the dysregulation profiles have potential as diagnostic, prognostic and/or predictive biomarkers. In healthy cells, m6A modifications are installed co-transcriptionally by the writer enzyme METTL3, resulting in an enrichment of m6A in the 3’UTR of genes. For many years, the mechanistic origin for the m6A enrichment in the 3’UTR was unclear. Recently, the Gregory lab and others have developed a model where the exon junction complex (EJC) plays a key role in directing m6A deposition by hindering access of METTL3 to short exons and exon/intron junctions. In this study, we build on this model using a novel, proximity-barcoding based assay (EpiPlex™) for the simultaneous detection of m6A and inosine. Working with HEK293T cells, we modulated the activity of a central component of the EJC, the RNA helicase EIF4A3. Both genetic knockdown and chemical inhibition of EIF4A3 resulted in increased m6A levels and more diffuse localization at the 3’UTR. New m6A sites appear on short exons and near exon/intron junctions. These data corroborate the necessity of EIF4A3 for EJC assembly and confirm the model that the EJC prevents METTL3 from accessing and methylating exon junctions. Additionally, we find that blocking of the exon junction is reliant on EIF4A3’s helicase activity. Although the role of EJC in the cell cycle and cancer are still investigational, it is likely that m6A dysregulation is induced by aberrant EJC function, which presents a potential molecular mechanism for the dysregulation of multiple genetic pathways in cancer progression. Citation Format: Andrew Price, Erdem Sendinc, Byron Purse, Richard I Gregory, Gudrun Stengel. Binding of the exon junction complex shapes the landscape of m6A in RNA - a possible source of m6A dysregulation in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A011.

Soluble epoxide hydrolase deletion rescues behavioral and synaptic deficits by AMPK-mTOR pathway in autism animals

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social defects often accompanied with emotional comorbidities. Aberrations in synaptic function and plasticity are the core feature in the pathophysiology of ASD. Targeting soluble epoxide hydrolase (sEH) has been found to exert protection in a wide-range of pathological conditions. However, the regulation of sEH deficiency on the synaptic deficits of ASD and the underlying mechanisms remain unclear. The valproate (VPA)-treated ASD animal model with genetic sEH knockout was applied in the present study. The results showed that the sEH expression was significantly increased in the prefrontal cortex of VPA-treated animals. Although no effect was found on tail malformation and body weight loss, genetic sEH deletion alleviated social deficits, and fear learning and memory extinction in the VPA-treated mice. After a series of electrophysiological assessments, we found that the beneficial effects of sEH deletion focused on the long-term synaptic plasticity, rather than presynaptic efficiency, in the VPA-treated mice. Furthermore, we observed that the dysregulated AMPK-mTOR pathway was restored under genetic sEH deletion in VPA-treated mice. Taken together, these findings uncovered an important role of sEH deficiency in the synaptic dysfunctions of ASD mediated by AMPK-mTOR pathway, providing a novel therapeutic target for ASD.

The role of genetic and epigenetic modifications as potential biomarkers in the diagnosis and prognosis of thyroid cancer.

Thyroid cancer (TC) is the most common endocrine cancer, which contributes to more than 43,600 deaths and 586,000 cases worldwide every year. Among the TC types, PTC and FTC comprise 90% of all TCs. Genetic modifications in genes are responsible for encoding proteins of mitogen-associated protein kinase cascade, which is closely related with numerous cellular mechanisms, including controlling programmed cell death, differentiation, proliferation, gene expression, as well as in genes encoding the PI3K (phosphatidylinositol 3-kinase)/protein kinase B (AKT) cascade, which has contribution in controlling cell motility, adhesion, survival, and glucose metabolism, have been associated with the TC pathogenesis. Various genetic modifications including BRAF mutations, RAS mutations, RET mutations, paired-box gene 8/peroxisome proliferator-activated receptor-gamma fusion oncogene, RET/PTC rearrangements, telomerase reverse transcriptase mutations, neurotrophic tyrosine receptor kinase fusion genes, TP53 mutations, and eukaryotic translation initiation factor 1A X-linked mutations can effectively serve as potential biomarkers in both diagnosis and prognosis of TC. On the other hand, epigenetic modifications can lead to aberrant functions or suppression of a range of signalling cascades, which can ultimately result in cancer. Various studies have observed the link between epigenetic modification and multiple cancers including TC. It has been reported that several epigenetic alterations including histone modifications, aberrant DNA methylation, and epigenetic modulations of non-coding RNAs can play significant roles as potential biomarkers in the diagnosis and prognosis of TC. Therefore, a good understanding regarding the genetic and epigenetic modifications is not only essential for the diagnosis and prognosis of TC, but also for the development of novel therapeutics. In this review, most of the major TC-related genetic and epigenetic modifications and their potential as biomarkers for TC diagnosis and prognosis have been extensively discussed.