Potential Signatures Research Articles

Identification of ROS and KEAP1-related genes and verified targets of α-hederin induce cell death for CRC.

In this study, we analyzed and verified differentially expressed genes (DEGs) in ROS and KEAP1 crosstalk in oncogenic signatures using GEO data sets (GSE4107andGSE41328). Multiple pathway enrichment analyses were finished based on DEGs. The genetic signature for colorectal adenocarcinoma (COAD) was identified by using the Cox regression analysis. Kaplan-Meiersurvival and receiver operating characteristiccurve analysis were used to explore the prognosis value of specific genes in COAD. The potential immune signatures and drug sensitivity prediction were also analyzed. Promising small-molecule agents were identified and predicted targets of α-hederin in SuperPred were validated by molecular docking. Also, expression levels of genes and Western blot analysis were conducted. In total, 48 genes were identified as DEGs, and the hub genes such as COL1A1, CXCL12, COL1A2, FN1, CAV1, TIMP3, andIGFBP7 were identified. The ROS and KEAP1-associated gene signatures comprised of hub key genes were developed for predicting the prognosis and evaluating the immune cell responses and immune infiltration in COAD. α-hederin, a potential anti-colorectal cancer(CRC) agent, was found to enhance the sensitivity of HCT116 cells, regulate CAV1 and COL1A1, and decrease KEAP1, Nrf2, and HO-1 expression significantly. KEAP1-related genes could be an essential mediator of ROS in CRC, and KEAP1-associated genes were effective in predicting prognosis and evaluating individualized CRC treatment. Therefore, α-hederin may be an effective chemosensitizer for CRC treatments in clinical settings.

Exploring the detection of AQNs in large liquid detectors

Recent work from the last years has raised the possibility that a portion of Dark Matter could consist of exotic particles, such as axion (anti)quark nuggets (AQN, AQ̅N). After a brief review outlining the main features of axion antiquark nuggets, we explore potential experimental signatures that can be leveraged to search for these stable supermassive particles in future surface and underground experiments using large liquid detectors. These expected signals are discussed in relation with the specific characteristics of each detection system.

JADES: The incidence rate and properties of galactic outflows in low-mass galaxies across 3 < z < 9

We investigate the incidence and properties of ionised gas outflows in a sample of 52 galaxies with stellar masses between 107 M⊙ and 109 M⊙ observed with ultra-deep JWST/NIRSpec MSA spectroscopy as part of the JWST Advanced Deep Extragalactic Survey (JADES). The high-spectral resolution (R2700) NIRSpec observations allowed us to identify for the first time the potential signature of outflows in the rest-frame optical nebular lines in low-mass galaxies at z > 4. The incidence fraction of ionised outflows, traced by broad components, is about 25–40%, depending on the intensity of the emission lines. The low incidence fraction might be due to both the sensitivity limit and the fact that outflows are not isotropic, but have a limited opening angle, which only results in detection when this is directed toward our line of sight. Evidence for outflows increases slightly with stellar mass and star formation rate. The median velocity and mass-loading factor (i.e. the ratio of the mass outflow rate and star formation rate) of the outflowing ionised gas are 350 km s−1 and η = 2.0−1.5+1.6, respectively. These are 1.5 and 100 times higher than the typical values observed in local dwarf galaxies. Some of these high-redshift outflows can escape the gravitational potential of the galaxy and dark matter halo and enrich the circumgalactic medium and possibly even the intergalactic medium. Our results indicate that outflows can significantly impact the star formation activity in low-mass galaxies within the first 2 Gyr of the Universe.

Comparative extracellular vesicles proteomics unravels host-pathogen interactions: New insights in bacterial and fungal endophthalmitis in murine models

PurposeEndophthalmitis, an intraocular infection, often results in devastating outcomes due to frequent misdiagnosis and delayed treatment initiation. Extracellular Vesicles (EVs) have long been lauded for its potential as a biomarker in several infections. Previously, we have profiled EVs in bacterial and fungal infected murine model of endophthalmitis. In this study, we reported a comparative analysis of bacterial and fungal endophthalmitis to understand the disease pathobiology and identify a potential signature molecule for diagnosis of infectious endophthalmitis. MethodsEndophthalmitis was induced by intravitreal injection of bacteria (S. aureus and P. aeruginosa) and fungus (A. flavus and C. albicans) in C57BL/6 mice followed by enucleation at 24 h. EVs were isolated by ultracentrifugation and total proteins were subjected to LC-MS/MS. A comparative analysis of the EV protein cargo during bacterial and fungal endophthalmitis was performed in this study along with the pathway assessment by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology. ResultsProteome analysis of EVs revealed the presence of over 1500 proteins in each of the infected and control groups. Comparative (bacteria versus fungal) study revealed that the protein cargo of the EVs was very distinct among the infected sets with a very few common proteins. Crucial differentially expressed proteins (DEPs) common to both infections were Complement Cascade 8-alpha (C8α), chymase, sorting nexin-29 and glutathione-S-transferase and common pathways were metabolic pathways, Staphylococcus aureus infection, PPAR signalling pathway, cAMP signalling pathway, TGFβ signalling pathway and HIF-1 signalling pathway. ConclusionThis study comprehensively investigates the global proteome of EVs derived from mice model of bacterial and fungal endophthalmitis. Proteomic analysis reveals the disparate EV protein cargo underlining the differences in the pathogenesis of bacterial and fungal endophthalmitis with C8α, chymase, sorting nexin 29 and glutathione-S-transferase common to both infections.

Exploring Pyroptosis-related Signature Genes and Potential Drugs in Ulcerative Colitis by Transcriptome Data and Animal ExperimentalValidation.

Ulcerative colitis (UC) is an idiopathic, relapsing inflammatory disorder of the colonic mucosa. Pyroptosis contributes significantly to UC. However, the molecular mechanisms of UC remain unexplained. Herein, using transcriptome data and animal experimentalvalidation, we sought to explore pyroptosis-related molecular mechanisms, signature genes, and potential drugs in UC.Gene profiles (GSE48959, GSE59071, GSE53306, and GSE94648) were selected from the Gene Expression Omnibus (GEO) database, which contained samples derived from patients with active and inactive UC, as well as health controls. Gene Set Enrichment Analysis (GSEA), Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on microarrays to unravel the association between UC and pyroptosis. Then, differential expressed genes (DEGs) and pyroptosis-related DEGs were obtained by differential expression analyses and the public database. Subsequently, pyroptosis-related DEGs and their association with the immune infiltration landscape were analyzed using the CIBERSORT method. Besides, potential signature genes were selected by machine learning (ML) algorithms, and then validated by testing datasets which included samples of colonic mucosal tissue and peripheral blood. More importantly, the potential drug was screened based on this. And these signature genes and the drug effect were finally observed in the animal experiment.GSEA and KEGG enrichment analyses on key module genes derived from WGCNA revealed a close association between UC and pyroptosis. Then, a total of 20 pyroptosis-related DEGs of UC and 27 pyroptosis-related DEGs of active UC were screened. Next, 6 candidate genes (ZBP1, AIM2, IL1β, CASP1, TLR4, CASP11) in UC and 2 candidate genes (TLR4, CASP11) in active UC were respectively identified using the binary logistic regression(BLR), least absolute shrinkage and selection operator (LASSO), random forest (RF) analysis and artificial neural network (ANN), and these genes also showed high diagnostic specificity for UC in testing sets. Specially, TLR4 was elevated in UC and further elevated in active UC. The results of the drug screen revealed that six compounds (quercetin, cyclosporine, resveratrol, cisplatin, paclitaxel, rosiglitazone) could target TLR4, among which the effect of quercetin on intestinal pathology, pyroptosis and the expression of TLR4 in UC and active UC was further determined by the murine model.These findings demonstrated that pyroptosis may promote UC, and especially contributes to the activation of UC. Pyroptosis-related DEGs offer new ideas for the diagnosis of UC. Besides, quercetin was verified as an effective treatment for pyroptosis and intestinal inflammation. This study might enhance our comprehension on the pathogenic mechanism and diagnosis of UC and offer a treatment option for UC.

Identification and validation of potential diagnostic signature and immune cell infiltration for HIRI based on cuproptosis-related genes through bioinformatics analysis and machine learning.

Cuproptosis has emerged as a significant contributor in the progression of various diseases. This study aimed to assess the potential impact of cuproptosis-related genes (CRGs) on the development of hepatic ischemia and reperfusion injury (HIRI). The datasets related to HIRI were sourced from the Gene Expression Omnibus database. The comparative analysis of differential gene expression involving CRGs was performed between HIRI and normal liver samples. Correlation analysis, function enrichment analyses, and protein-protein interactions were employed to understand the interactions and roles of these genes. Machine learning techniques were used to identify hub genes. Additionally, differences in immune cell infiltration between HIRI patients and controls were analyzed. Quantitative real-time PCR and western blotting were used to verify the expression of the hub genes. Seventy-five HIRI and 80 control samples from three databases were included in the bioinformatics analysis. Three hub CRGs (NLRP3, ATP7B and NFE2L2) were identified using three machine learning models. Diagnostic accuracy was assessed using a receiver operating characteristic (ROC) curve for the hub genes, which yielded an area under the ROC curve (AUC) of 0.832. Remarkably, in the validation datasets GSE15480 and GSE228782, the three hub genes had AUC reached 0.904. Additional analyses, including nomograms, decision curves, and calibration curves, supported their predictive power for diagnosis. Enrichment analyses indicated the involvement of these genes in multiple pathways associated with HIRI progression. Comparative assessments using CIBERSORT and gene set enrichment analysis suggested elevated expression of these hub genes in activated dendritic cells, neutrophils, activated CD4 memory T cells, and activated mast cells in HIRI samples versus controls. A ceRNA network underscored a complex regulatory interplay among genes. The genes mRNA and protein levels were also verified in HIRI-affected mouse liver tissues. Our findings have provided a comprehensive understanding of the association between cuproptosis and HIRI, establishing a promising diagnostic pattern and identifying latent therapeutic targets for HIRI treatment. Additionally, our study offers novel insights to delve deeper into the underlying mechanisms of HIRI.

Comprehensive DNA methylation profiling by MeDIP-NGS identifies potential genes and pathways for epithelial ovarian cancer.

Ovarian cancer, among all gynecologic malignancies, exhibits the highest incidence and mortality rate, primarily because it is often presents with non-specific or no symptoms during its early stages. For the advancement of Ovarian Cancer Diagnosis, it is crucial to identify the potential molecular signatures that could significantly differentiate between healthy and ovarian cancerous tissues and can be used further as a diagnostic biomarker for detecting ovarian cancer. In this study, we investigated the genome-wide methylation patterns in ovarian cancer patients using Methylated DNA Immunoprecipitation (MeDIP-Seq) followed by NGS. Identified differentially methylated regions (DMRs) were further validated by targeted bisulfite sequencing for CpG site-specific methylation profiles. Furthermore, expression validation of six genes by Quantitative Reverse Transcriptase-PCR was also performed. Out of total 120 differentially methylated genes (DMGs), 68 genes were hypermethylated, and 52 were hypomethylated in their promoter region. After analysis, we identified the top 6 hub genes, namely POLR3B, PLXND1, GIGYF2, STK4, BMP2 and CRKL. Interestingly we observed Non-CpG site methylation in the case of POLR3B and CRKL which was statistically significant in discriminating ovarian cancer samples from normal controls. The most significant pathways identified were focal adhesion, the MAPK signaling pathway, and the Ras signaling pathway. Expression analysis of hypermethylated genes was correlated with the downregulation of the genes. POLR3B and GIGYF2 turned out to be the novel genes associated with the carcinogenesis of EOC. Our study demonstrated that methylation profiling through MeDIP-sequencing has effectively identified six potential hub genes and pathways that might exacerbate our understanding of underlying molecular mechanisms of ovarian carcinogenesis.

Dysregulations of amino acid metabolism and lipid metabolism in urine of children and adolescents with major depressive disorder: a case-control study.

The mechanisms underlying major depressive disorder (MDD) in children and adolescents are unclear. Metabolomics has been utilized to capture metabolic signatures of various psychiatric disorders; however, urinary metabolic profile of MDD in children and adolescents has not been studied. We analyzed urinary metabolites in children and adolescents with MDD to identify potential biomarkers and metabolic signatures. Here, liquid chromatography-mass spectrometry was used to profile metabolites in urine samples from 192 subjects, comprising 80 individuals with antidepressant-naïve MDD (AN-MDD), 37 with antidepressant-treated MDD (AT-MDD) and 75 healthy controls (HC). We performed orthogonal partial least squares discriminant analysis to identify differential metabolites and employed logistic regression and receiver operating characteristic analysis to establish a diagnostic panel. In total, 143 and 71 differential metabolites were identified in AN-MDD and AT-MDD, respectively. These were primarily linked to lipid metabolism, molecular transport, and small molecule biochemistry. AN-MDD additionally exhibited dysregulated amino acid metabolism. Compared to HC, a diagnostic panel of seven metabolites displayed area under the receiver operating characteristic curves of 0.792 for AN-MDD, 0.828 for AT-MDD, and 0.799 for all MDD. Furthermore, the urinary metabolic profiles of children and adolescents with MDD significantly differed from those of adult MDD. Our research suggests dysregulated amino acid metabolism and lipid metabolism in the urine of children and adolescents with MDD, similar to results in plasma metabolomics studies. This contributes to the comprehension of mechanisms underlying children and adolescents with MDD.

Commonality and heterogeneity of pacemaker mechanisms in the male reproductive organs.

During emission, the first phase of ejaculation, smooth muscle in organs of the male reproductive tract (MRT) vigorously contract upon sympathetic nerve excitation to expel semen consisting of sperm and seminal plasma. During inter-ejaculation phases, the epididymis, seminal vesicles and prostate undergo spontaneous phasic contractions (SPCs), this transporting and maintaining the quality of sperm and seminal plasma. Recent studies have revealed platelet-derived growth factor receptor α-expressing (PDGFRα+) subepithelial interstitial cells in seminal vesicles subserve the role of pacemaker cells that electrically drive SPCs in this organ. PDGFRα+ smooth muscle cells in the epididymis also appear to function as pacemaker cells implicating PDGFRα as a potential signature molecule in MRT pacemaking. The dominant mechanism driving pacemaking in these organs is the cytosolic Ca2+ oscillator. This operates through entrainment of the release-refill cycle of Ca2+ stores, the released Ca2+ ions opening Ca2+-activated chloride channels, including in some cases ANO1 (TMEM16A), with the resultant pacemaker potential activating L-type voltage-dependent Ca2+ channels in the smooth muscle causing contraction (viz. SPCs). A second pacemaker mechanism, namely the membrane oscillator also has a role in specific cases. Further investigations into the commonality and heterogeneity of MRT pacemakers will open an avenue for understanding the pathogenesis of male infertility associated with deterioration of seminal plasma.

Ancient mitogenomes from Pre-Pottery Neolithic Central Anatolia and the effects of a Late Neolithic bottleneck in sheep (Ovis aries).

Occupied between ~10,300 and 9300 years ago, the Pre-Pottery Neolithic site of Aşıklı Höyük in Central Anatolia went through early phases of sheep domestication. Analysis of 629 mitochondrial genomes from this and numerous sites in Anatolia, southwest Asia, Europe, and Africa produced a phylogenetic tree with excessive coalescences (nodes) around the Neolithic, a potential signature of a domestication bottleneck. This is consistent with archeological evidence of sheep management at Aşıklı Höyük which transitioned from residential stabling to open pasturing over a millennium of site occupation. However, unexpectedly, we detected high genetic diversity throughout Aşıklı Höyük's occupation rather than a bottleneck. Instead, we detected a tenfold demographic bottleneck later in the Neolithic, which caused the fixation of mitochondrial haplogroup B in southwestern Anatolia. The mitochondrial genetic makeup that emerged was carried from the core region of early Neolithic sheep management into Europe and dominates the matrilineal diversity of both its ancient and the billion-strong modern sheep populations.

Waterborne exposure to the antineoplastic 5-fluorouracil alters lipid composition in larval zebrafish (Danio rerio)

Antineoplastic medications are present in aquatic environments and are measured at relatively high concentrations in hospital sewage effluent. Thus, it is important to characterize risk associated with waterborne exposures to anticancer drugs. The drug 5-fluorouracil (5-FU) is used to treat several types of cancers, acting to inhibit cell division and cellular metabolism. The objectives of this study were to determine the effects of 5-FU on developmental endpoints and lipid composition in zebrafish. 5-FU did not negatively affect development nor survival in developing zebrafish at concentrations up to 1000 μg/L. However, 5-FU increased neutral lipid content in zebrafish larvae, indicating potential for lipid dysregulation. To further discern effects on lipids, lipidomics was conducted and a total of 164 lipids belonging to 14 lipid classes were identified. Significant changes (false discovery rate < 0.05) in abundance were detected for 19 lipids including some ceramides, ether-linked phosphatidylethanolamines, and sphingomyelins among others. We also measured the expression levels of 14 lipid-related enzymes and transporters (e.g., acox3, dgat1, fads2, fasn, elovl2) using real-time PCR; however, mRNA abundance levels were not affected, suggesting transcriptional changes may not be a primary mechanism underlying lipid dysregulation. Locomotor activity was measured in zebrafish as lipids are needed for swimming activity in larvae. Exposure to 5-FU did not affect locomotor activity up to 1000 μg/L. We conclude that lipids accumulate in larval zebrafish with exposure to 5-FU, which can subsequently affect lipid composition. These data reveal potential lipid signatures of 5-FU exposure and contribute to risk assessments for antineoplastic exposure in aquatic environments.

Multicausal disruption of complement system activity in schizophrenia: abnormal transcription of C4, complement control proteins and microglia specific genes in brain and blood

IntroductionThe synaptic pruning process is based on the joint action of the complement system and microglia. In schizophrenia, accumulating evidence support that abnormal synaptic pruning during adolescence may be due to an altered Complement system activity. While this hypothesis is supported by C4 overexpression in various brain regions of individuals with schizophrenia, such alterations should be replicated and extended to other brain regions. Moreover, transcriptional studies of genes encoding regulators of the complement system activity (complement control proteins, CCP) and microglia-specific genes are lacking. Furthermore, it remains unknown whether brain and peripheral expression of such genes are related.ObjectivesTo explore expression of C4 as well as 4 CCP encoding genes and 10 microglia-specific genes at the brain and peripheral levels in individuals with schizophrenia as compared to healthy controls.MethodsWe analyzed candidate gene expression from 9 Gene Expression Omnibus datasets obtained from 333 individuals with schizophrenia and 306 healthy controls (HC). We first compared expression of the candidate genes between individuals with schizophrenia and HC in postmortem brain samples from 7 different brain regions. Then, the same comparison was made in 4 different peripheral tissues.ResultsRegarding the complement system, we observed C4 overexpression in the DLPFC, parietal, temporal cortex and associative striatum of individuals with schizophrenia. We report distinct altered expression patterns of CCP genes in the DLPFC, hippocampus and cerebellum of individuals with schizophrenia. Only CD46 expression was altered in the blood of individuals with schizophrenia. Regarding microglia, we report an underexpression of several microglia-specific genes in the cerebellum, associative striatum, hippocampus and parietal cortex of individuals with schizophrenia vs. HC. At the peripheral level, we observed a mixed altered expression pattern in the whole blood of individuals with schizophrenia.ConclusionsFirstly, our results suggest that the CCP-mediated regulatory mechanisms of the Complement system are impaired in the brain of individuals with schizophrenia, potentially contributing to an excessive Complement system activity (CSA). Secondly, our results support the hypothesis of a widespread underexpression of microglia-specific genes in brain tissues of individuals with schizophrenia. Functionally, the observed transcriptional alterations may be related to the synaptic pruning impairment. Alternatively, they may translate a compensatory mechanism for neuroinflammation. In the whole blood, the altered transcriptional pattern may represent a potential peripheral signature of SZ.Disclosure of InterestNone Declared

567 Multigenerational impacts on DNA methylation signatures in autism spectrum disorder

OBJECTIVES/GOALS: to investigate the potential impact of grandparental factors and multigenerational epigenetic inheritance on the development of ASD METHODS/STUDY POPULATION: Our study recruited participants from the CHARGE (Child Autism Risks from Genetics and the Environment) study, including grandparents, parents, and children. A questionnaire was used to gather information about the participants’ exposure to environmental factors. Saliva samples werecollected from 349 participants. Newborn dried blood spotsfrom probands and parents are still being collected from the California New born Registry. DNA was extracted from 349 saliva samples from 85 families and subjected to whole genome bisulfite sequencing (WGBS) to analyze DNA methylation. Sequence alignments and bioinformatic analyses will be performed using R packages called DMRichR and Comethyl. RESULTS/ANTICIPATED RESULTS: Sequence alignments and bioinformatic analyses are ongoing, utilizing DMRichR to identify individual genomic loci associated with ASD in each of the three generations and Comethyl to compare correlation patterns between methylation marks and selected variables, including grand parental exposures. New born blood spot collections of parents and probands are ongoing and will be used to identify potential ASD epigenomic signatures that are tissue and life-stage independent. DISCUSSION/SIGNIFICANCE: This research will provide new insights into the increased prevalence and underlying etiology of ASD that should pave the way for future research in the field. DNA Methylation signatures can help create molecular biomarkers which can be used together with behavioral clinical tests for diagnosis of ASD.

Convergent Mutations and Single Nucleotide Variants in Mitochondrial Genomes of Modern Humans and Neanderthals.

The genetic contributions of Neanderthals to the modern human genome have been evidenced by the comparison of present-day human genomes with paleogenomes. Neanderthal signatures in extant human genomes are attributed to intercrosses between Neanderthals and archaic anatomically modern humans (AMHs). Although Neanderthal signatures are well documented in the nuclear genome, it has been proposed that there is no contribution of Neanderthal mitochondrial DNA to contemporary human genomes. Here we show that modern human mitochondrial genomes contain 66 potential Neanderthal signatures, or Neanderthal single nucleotide variants (N-SNVs), of which 36 lie in coding regions and 7 result in nonsynonymous changes. Seven N-SNVs are associated with traits such as cycling vomiting syndrome, Alzheimer's disease and Parkinson's disease, and two N-SNVs are associated with intelligence quotient. Based on recombination tests, principal component analysis (PCA) and the complete absence of these N-SNVs in 41 archaic AMH mitogenomes, we conclude that convergent evolution, and not recombination, explains the presence of N-SNVs in present-day human mitogenomes.

Peripheral blood transcriptomic analysis identifies potential inflammation and immune signatures for central retinal artery occlusion

Central retinal artery occlusion (CRAO) is an acute retinal ischaemic disease, but early diagnosis is challenging due to a lack of biomarkers. Blood samples were collected from CRAO patients and cataract patients. Gene expression profiles were distinct between arterial/venous CRAO blood (A–V group) and venous CRAO/control blood (V–C group) samples. Differentially expressed genes (DEGs) were subjected to GO and KEGG enrichment analyses. Hub genes were identified by Cytoscape and used to predict gene interactions via GeneMANIA. Immune cell infiltration was analysed by CIBERSORT. More than 1400 DEGs were identified in the A–V group and 112 DEGs in the V–C group compared to controls. The DEGs in both groups were enriched in the ribosome pathway, and those in the V–C group were also enriched in antigen processing/MHC pathways. Network analysis identified ribosomal proteins (RPS2 and RPS5) as the core genes of the A–V group and MHC genes (HLA-F) as the core genes of the V–C group. Coexpression networks showed ribosomal involvement in both groups, with additional immune responses in the V–C group. Immune cell analysis indicated increased numbers of neutrophils and T cells. Ribosomal and MHC-related genes were identified as potential CRAO biomarkers, providing research directions for prevention, diagnosis, treatment and prognosis.

Potential biomarker signatures in male infertility: integrative genomic analysis

BackgroundStudies have attributed 50% of infertility cases to male infertility, 15% of which is caused by idiopathic genetic factors. Currently, no specific biomarkers have been revealed for male infertility. Furthermore, research on genetic factors causing male infertility is still limited. As with other multifactorial genetic disorders, numerous risk loci for male infertility have been identified by genome-wide association studies (GWAS), although their clinical significance remains uncertain. Therefore, we utilized an integrative bioinformatics-based approach to identify biomarkers for male infertility. Bioinformatics analysis was performed using Open Targets Platform, DisGeNet, and GWAS Catalog. After that, the STRING database and the Cytoscape program were used to analyze protein–protein interaction. CytoHubba was used to determine the most significant gene candidates. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to assess biological functions that correspond to the male infertility disease pathway.ResultsWe identified 305 genes associated with male infertility and highlighted 10 biological risk genes as potential biomarkers for male infertility such as TEX11, SPO11, SYCP3, HORMAD1, STAG3, MSH4, SYCP2, SYCE1, RAD21L1, and AMH. Of all the genes, we took the top three genes, namely, TEX11, SPO11, and SYCP3 as the genes that have the most potential as biomarkers.ConclusionsTEX11, SPO11, and SYCP3 are involved in meiosis and spermatogenesis. We propose that further research in regarding these genes in detecting male infertility.

Abstract 2445: Peripheral blood immune phenotypes in pancreatic ductal adenocarcinoma

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a major cancer killer with a low 5-year survival rate of 12%. Diagnosing PDAC at an early stage is one of the strongest predictors of long-term survival. Therefore, novel methods for early detection of PDAC must be explored. In this pilot study we aimed to compare the peripheral blood immune cell phenotypes in PDAC cases and cancer-free controls. Method: CyTOF (cytometry by time-of-flight) was used to evaluate peripheral blood mononuclear cells (PBMC) from newly diagnosed treatment naïve patients with PDAC and sex and age matched cancer-free controls using a 29-marker immune phenotyping panel. Multiple analysis approaches including dimensionality reduction using tSNE and clustering using Phenograph were used to evaluate the results. Immune subsets having differential abundance differences were verified by manual gating. Results: Twenty patients were included in this pilot study (15 PDAC cases; 5 Cancer-free controls). Among the 15 PDAC cases, 5 were early stage (Stage 1-2). Thirty-two unique immune cell clusters were identified using the Phenograph algorithm: 10 unique clusters with properties consistent with monocytes/macrophages, 9 CD4 T cell clusters, 6 CD8 T cell clusters and 4 NK cells clusters. When comparing the case and control groups we noted lower percentages of CD8+CD27+ T-cells in cases. This was further verified by manual gating that confirmed the distribution of CD8+CD27+ T-cells relative to all T-cells were decreased in PDAC patients. In addition, a 57% increase in naïve CD4 T cells was found in case samples compared to controls. A principal component analysis of the clustering results identified two unique clusters of immune profiles that emerged providing a potential peripheral blood immune cell signature that could stratify and differentiate PDAC cases from controls. A CD14+CD16+CD4LoCD38+CD45RO+ population of monocytes was the primary cell population driving this difference. Conclusion: This study provides early evidence to indicate that a distinct PBMC immune phenotype may differentiate PDAC patients from control subjects. Further analysis in larger sample sets is warranted for in-depth characterization and identification of unique immune based biomarkers for PDAC detection. Citation Format: Kevin D. Pavelko, Jose C. Villasboas, William R. Taylor, Karen A. Doering, John B. Kisiel, Shounak Majumder. Peripheral blood immune phenotypes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2445.

Kerr-scalaron Metric and Astronomical Consequences near the Galactic Center Black Hole

Astronomical tests of spacetime metric and gravitation theory near the Galactic center (GC) black hole, Sgr A*, have gained momentum with the observations of compact stellar orbits near the black hole and measurement of the black hole shadow. Deviation from the Kerr metric is a potential signature of modified gravity theory. In this work, we use the Newman–Janis algorithm to construct an axially symmetric and asymptotically flat metric in f(R) scalaron gravity theory. We call it the Kerr-scalaron metric. To study the astronomical consequences of the new metric, we use the compact stellar orbits and the black hole shadow. We use the observed size of the emission ring of the GC black hole shadow for estimating the deviation of the new metric from general relativity. It has been found that scalarons with masses within 10−17–10−16 eV are compatible with the observed emission ring size for a black hole spin of χ = 0.9. The Schwarzschild limit of the pericenter shift is estimated for compact stellar orbits near the black hole. General relativistic pericenter shift in wider orbits, including S stars such as S4716 and S2, has been reproduced with these scalarons. The parameter f SP measuring the deviation from Schwarzschild pericenter shift has been found to be f SP = 1.00–1.04 within stellar orbits with semimajor axes of 45–100 au. Scalarons have the capability to dominate Schwarzschild precession for orbits with semimajor axes much smaller than 45 au. Lense–Thirring (LT) precession with the new metric is estimated for the compact orbits. The massive scalarons produce LT precession with magnitude (12.25–24.5) μas yr−1 in the orbit of S2. The LT precession timescale is within 0.1% of the age of the S stars.

Abstract 3454: Cell-free DNA methylation and fragmentomic signatures identify tissue damage and predict cancer risk

Abstract Cell-free DNA (cfDNA) epigenetic and fragmentomic profiling has emerged as prominent non-invasive approaches for early cancer detection and subtyping. However, owing to difficulties in observing the early development of human malignancies, most cancer biomarker and evolution studies to date have primarily examined biologics following a diagnosis. Utilizing cfDNA as a screening tool for early disease detection requires assessment of blood plasma samples collected from asymptomatic individuals prior to the diagnosis of cancers. Here, we leverage the Ontario Health Study (OHS), a prospective longitudinal population cohort, to assess cfDNA profiles in blood plasma collected from participants that developed breast (n=476), prostate (n=342) and pancreatic (n=32) cancers throughout the study follow up time between 2009 and 2019. We performed cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) on baseline plasma samples from incident cancer cases up to eight years prior to diagnosis, in addition to matched controls (n=404) with no history of cancer through follow-up. Genome-wide plasma cfDNA differential methylation analysis revealed significantly hypermethylated regions, particularly among CpG island and shore regions, were predictive of early breast cancers, and overlapped hypermethylated regions in solid cancer tissues relative to adjacent normal tissues and peripheral blood leukocytes. Using a repeated cross-validation strategy we found that as few as 200 hypermethylated regions can identify individuals with breast cancer in blood up to seven years prior to diagnosis among discovery set samples (AUC=0.725) and are highly generalizable to samples processed in separate batches (AUC = 0.650). Remarkably, integrating biomarker hypermethylated regions with fragmentomic features including fragment length and 5’ tetranucleotide motif proportions further increased accuracy for detecting individuals with early prostate cancers (AUC=0.804). In addition, we observed shared genome-wide cfDNA methylome changes associated with aging and heavy alcohol consumption in cfDNA. We identified increased shedding of tissue-specific methylation markers from liver and pancreatic tissue among individuals consuming more than three drinks a week relative to non-drinkers, reflective of potential signatures of tissue damage. Citation Format: Nicholas Cheng, Kimberly Skead, Tom Oullette, Scott Bratman, Daniel De Carvalho, David Soave, Philip Awadalla. Cell-free DNA methylation and fragmentomic signatures identify tissue damage and predict cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3454.

The carbon-rich type Ic supernova 2016adj in the iconic dust lane of Centaurus A: Potential signatures of an interaction with circumstellar hydrogen

We present a comprehensive data set of supernova (SN) 2016adj located within the central dust lane of Centaurus A. SN 2016adj is significantly reddened and after correcting the peak apparent $B$-band magnitude ($m_B = 17.48 for Milky Way reddening and our inferred host-galaxy reddening parameters (i.e. V host and V host we estimated it reached a peak absolute magnitude of $M_B -18$. A detailed inspection of the optical and near-infrared (NIR) spectroscopic time series reveals a carbon-rich SN Ic and not a SN Ib/IIb as previously suggested in the literature. The NIR spectra show prevalent carbon-monoxide formation occurring already by $+$41 days past $B$-band maximum, which is $ 11$ days earlier than previously reported in the literature for this object. Interestingly, around two months past maximum, the NIR spectrum of SN 2016adj begins to exhibit H features, with a $+$97 days medium resolution spectrum revealing both Paschen and Bracket lines with absorption minima of $ 2,000$ km $, full-width-half-maximum emission velocities of $ 1,000$ km $, and emission line ratios consistent with a dense emission region. We speculate that these attributes are due to a circumstellar interaction (CSI) between the rapidly expanding SN ejecta and a H-rich shell of material that formed during the pre-SN phase. A bolometric light curve was constructed and a semi-analytical model fit suggests the SN synthesized 0.5 $M_ sun $ of 56Ni and ejected 4.7 $M_ sun $ of material, though these values should be approached with caution given the large uncertainties associated with the adopted reddening parameters and known light echo emission. Finally, inspection of the Hubble Space Telescope archival data yielded no progenitor detection.