bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-time experiences of racism and stress in association with postpartum weight retention: A longitudinal ecological momentary assessment study
Authors: Méndez D D , Tapia A L , Sanders S A , Casas A D , Smalls M , Davis E M , Rathbun S L , Gary-Webb T L , Burke L E , Omowale S S , Adodoadji L , Gianakas J J , Lai Y , Feghali M N , Wallace M L
Published: November 2024

Racial inequities in postpartum weight have been documented with limited studies on the influences of racism and other forms of discrimination. In a prospective longitudinal study applying ecological momentary assessment (EMA) and ambulatory assessment of weight, we measured the association between discrimination, stress and postpartum weight change. The Postpartum Mothers Mobile Study (PMOMS) is a cohort of 313 pregnant and birthing individuals who were followed during their second and third trimester through 1 year postpartum. They were recruited in clinical settings between 2017-2020 in a major city center in Pennsylvania. Measures of racism and gender-based discrimination were collected via random EMA surveys throughout pregnancy and postpartum; and weight was collected via blue-tooth enabled scales at least weekly. Among Black participants, a 10% increase in the number of days a participant experienced racial discrimination in the past month was associated with retaining 0.3 more pounds; 10% increase in EMA gender discrimination was associated with retaining 0.4 more pounds; and EMA stress reported in the past month was associated with decreased weight retention. Chronic experiences of racial and gender discrimination may contribute to weight retention immediately after pregnancy and beyond.
Linguistic choices in mindfulness training: A corpus-cognitive stylistic analysis of guided meditation on the Headspace app
Authors: Nuttall Louise
Published: November 2024

The concept of ‘mindfulness’ is widely discussed in relation to wellbeing and mental health. While extensive research in psychology has explored the benefits of mindfulness in treating various psychological conditions, little research has examined the language used to teach it. This article analyses linguistic choices in an introductory course on mindfulness meditation on the Headspace app. Twenty recorded sessions of guided mindfulness meditation are analysed using corpus methods in Wmatrix5. Keyword analysis reveals distinctive features of the tutors’ language on this course, including lexical choices identified as ‘Mindfulness Language’ in previous studies. Applying Cognitive Grammar as a framework for qualitative analysis, I identify a distinctive ‘construal’ and ‘grounding’ of experience through recurrent grammatical choices, including profiling of mental and physical processes using the ‘ing’ verb form, modification of processes using the adverb ‘just’, reference to parts of the listener using ‘the’, and the instantiation of specific conceptual metaphors. I argue that principles of mindfulness are ‘embodied’ by tutors through these linguistic choices, which may cumulatively train listeners to attend to their experiences in similar ways.
Unlocking cross-modal interplay of single-cell joint profiling with CellMATE
Authors: Wang Qi , Zhang Bolei , Guo Yue , Gong Luyu , Li Erguang , Yang Jingping
Published: November 2024

A key advantage of single-cell multimodal joint profiling is the modality interplay, which is essential for deciphering the cell fate. However, while current analytical methods can leverage the additive benefits, they fall short to explore the synergistic insights of joint profiling, thereby diminishing the advantage of joint profiling. Here, we introduce CellMATE, a Multi-head Adversarial Training-based Early-integration approach specifically developed for multimodal joint profiling. CellMATE can capture both additive and synergistic benefits inherent in joint profiling through auto-learning of multimodal distributions and simultaneously represents all features into a unified latent space. Through extensive evaluation across diverse joint profiling scenarios, CellMATE demonstrated its superiority in ensuring utility of cross-modal properties, uncovering cellular heterogeneity and plasticity, and delineating differentiation trajectories. CellMATE uniquely unlocks the full potential of joint profiling to elucidate the dynamic nature of cells during critical processes as differentiation, development, and diseases.
Self-adaptive smoothing model for cardinality estimation
Authors: Lin Yuming , Zhang Yinghao , Yang Yan , Li You , Zhang Jingwei
Published: November 2024

Cardinality estimation is a crucial component in query optimizers. After decades of research, employing autoregressive models for cardinality estimation has demonstrated remarkable accuracy. However, when queries involve attributes with large domain sizes, autoregressive model-based estimators struggle to accurately capture the data distribution, leading to poor performance. Furthermore, these models often exhibit significant errors when handling queries with low-selectivity predicates. To address these challenges, we propose a self-adaptive cardinality estimator named AdaCard. Initially, we employ a self-adaptive smoothing factor selection strategy to variably adjust the original data, thereby mitigating the impact of large domain sizes. Secondly, to correct errors stemming from Monte Carlo sampling, we utilize resampling to refine the handling of low-selectivity predicates, thereby improving accuracy. Through evaluation using four real-world benchmarks, we compared AdaCard with mainstream baselines. The final results show that our estimator has the lowest tail estimation error and improves accuracy by nearly 10$\times $ over the second-best method, with similar latency and model size.
Fatigue in Patients with Inflammatory Bowel Disease in Remission One Year After Diagnosis (the IBSEN III Study)
Authors: Holten Kristina A , Bernklev Tomm , Opheim Randi , Olsen Bjørn C , Detlie Trond Espen , Strande Vibeke , Ricanek Petr , Boyar Raziye , Bengtson May-Bente , Aabrekk Tone B , Asak Øyvind , Frigstad Svein Oskar , Kristensen Vendel A , Hagen Milada , Henriksen Magne , Huppertz-Hauss Gert , Høivik Marte Lie , Jelsness-Jørgensen Lars-Petter
Published: November 2024

Background and Aims

Fatigue is commonly observed in Crohn’s disease (CD) and ulcerative colitis (UC) but its association to achieving remission is not clearly established. In this study, we describe the odds for fatigue in patients with CD/UC 1 year after diagnosis based on different definitions of remission and identified factors associated with chronic fatigue (CF) among patients in endoscopic/radiological remission.

Methods

Patients ≥ 18 years old with CD/UC were recruited from the IBSEN III cohort. Using the Fatigue Questionnaire, and dichotomizing the score, CF was defined as the presence of substantial fatigue (SF) for ≥6 months. Remission was divided into symptomatic (CD: Harvey–Bradshaw Index score < 5/UC: SCCAI score < 3), biochemical (fecal calprotectin ≤ 250 µg/g), endoscopic/radiological (CD: normal intestinal MRI/CT combined with normal endoscopy/UC: Mayo endoscopic score 0), and histological (normal mucosal biopsies). Both the likelihood of SF/CF, depending on the definition of remission, and associations between CF and selected factors for CD/UC in endoscopic/radiological remission were evaluated using binary logistic regression analysis.

Results

In total, 711/1416 patients were included. For both CD and UC, symptomatic remission significantly reduced the odds for SF and CF. In addition, the odds for SF were significantly reduced for UC in biochemical remission. Among those in endoscopic/radiological remission (n = 181), CF was independently associated with sleep disturbances (OR = 10.40, 95%CI [3.28;32.99], p < 0.001) and current treatment with infliximab (OR = 4.31, 95%CI [1.15;16.17], p = 0.03).

Conclusions

Stricter definitions of disease remission were not associated with a decreased likelihood of fatigue. For patients in endoscopic/radiological remission, CF was independently associated with sleep disturbances and current treatment with infliximab.
Amyloid-beta metabolism in age-related neurocardiovascular diseases
Authors: Aivalioti Evmorfia , Georgiopoulos Georgios , Tual-Chalot Simon , Bampatsias Dimitrios , Delialis Dimitrios , Sopova Kateryna , Drakos Stavros G , Stellos Konstantinos , Stamatelopoulos Kimon
Published: November 2024

Epidemiological evidence suggests the presence of common risk factors for the development and prognosis of both cardio- and cerebrovascular diseases, including stroke, Alzheimer's disease, vascular dementia, heart, and peripheral vascular diseases. Accumulation of harmful blood signals may induce organotypic endothelial dysfunction affecting blood–brain barrier function and vascular health in age-related diseases. Genetic-, age-, lifestyle- or cardiovascular therapy–associated imbalance of amyloid-beta (Aβ) peptide metabolism in the brain and periphery may be the missing link between age-related neurocardiovascular diseases. Genetic polymorphisms of genes related to Aβ metabolism, lifestyle modifications, drugs used in clinical practice, and Aβ-specific treatments may modulate Aβ levels, affecting brain, vascular, and cardiac diseases. This narrative review elaborates on the effects of interventions on Aβ metabolism in the brain, cerebrospinal fluid, blood, and peripheral heart or vascular tissues. Implications for clinical applicability, gaps in knowledge, and future perspectives of Aβ as the link among age-related neurocardiovascular diseases are also discussed.
Inference with Extremes: Accounting for Extreme Values in Count Regression Models
Authors: Randahl David , Vegelius Johan
Published: November 2024

Processes that occasionally, but not always, produce extreme values are notoriously difficult to model, as a small number of extreme observations may have a large impact on the results. Existing methods for handling extreme values are often arbitrary and leave researchers without guidance regarding this problem. In this paper, we propose an extreme value and zero-inflated negative binomial (EVZINB) regression model, which allows for separate modeling of extreme and nonextreme observations to solve this problem. The EVZINB model offers an elegant solution to modeling data with extreme values and allows researchers to draw additional inferences about both extreme and nonextreme observations. We illustrate the usefulness of the EVZINB model by replicating a study on the effects of the deployment of UN peacekeepers on one-sided violence against civilians.
Universal Jurisdiction as International Solidarity with Survivors of Atrocity Crimes
Authors: Frodé Karin M
Published: November 2024

The primary justification for universal jurisdiction (UJ) is its use as a tool to end impunity for certain international crimes. It is also linked to deterrence, as perpetrators of such crimes can face, and have indeed faced, legal action when they travel or reside overseas. Yet, UJ is also the subject of concerns, including the risk of politically motivated prosecutions and the undermining of fair trial rights and legal process. This article contends that the case for UJ can be strengthened, taking as its starting point scholarship that foregrounds the experiences of diaspora communities, rather than the traditional grounding of UJ in abstract appeals to shared humanity. Building on the insights that this earlier work enables us to uncover, this article seeks to reinforce the normative case for UJ by reframing it as international solidarity with survivors of atrocity crimes. First, international solidarity, as a unity of interests in accountability and effective remedies among survivors, other members of the diaspora, states, civil society and international organizations, underlines the connectedness among different actors that play a role in UJ. Secondly, uncovering such connectedness adds to the justifications for UJ the need to rebuild the trust of survivors in the (inter)national criminal justice system by underlining shared interests in access to justice. This is particularly timely in the context of Afghanistan, where survivors are often left without recourse to effective remedies for past and ongoing atrocities. In building the case for UJ from a solidarity perspective, the article incorporates lessons from a project the author is involved in concerning the potential of UJ for holding members of the Taliban accountable for atrocity crimes; a collective effort commissioned by diaspora from Afghanistan. It contributes to this project by strengthening the call for survivors to form a central part of accountability efforts across the world.
Conformal prediction with local weights: randomization enables robust guarantees
Authors: Hore Rohan , Barber Rina Foygel
Published: November 2024

In this work, we consider the problem of building distribution-free prediction intervals with finite-sample conditional coverage guarantees. Conformal prediction (CP) is an increasingly popular framework for building such intervals with distribution-free guarantees, but these guarantees only ensure marginal coverage: the probability of coverage is averaged over both the training and test data, meaning that there might be substantial undercoverage within certain subpopulations. Instead, ideally we would want to have local coverage guarantees that hold for each possible value of the test point’s features. While the impossibility of achieving pointwise local coverage is well established in the literature, many variants of conformal prediction algorithm show favourable local coverage properties empirically. Relaxing the definition of local coverage can allow for a theoretical understanding of this empirical phenomenon. We propose randomly localized conformal prediction (RLCP), a method that builds on localized CP and weighted CP techniques to return prediction intervals that are not only marginally valid but also offer relaxed local coverage guarantees and validity under covariate shift. Through a series of simulations and real data experiments, we validate these coverage guarantees of RLCP while comparing it with the other local conformal prediction methods.
Cut-free labelled calculi and decidability for intuitionistic sentential logic with identity
Authors: Galmiche Didier , Hornbeck Brandon , Méry Daniel
Published: November 2024

In this paper we consider the intuitionistic non-Fregean sentential calculus with Suszko’s identity ($\mathsf{ISCI}$). After recalling the basic concepts of the logic and its associated Hilbert proof system, we introduce a new sound and complete class of models for $\mathsf{ISCI}$, called Topological Beth (${\mathsf{TB}}$) models, that can be viewed as algebraic counterparts (and extensions) of sheaf-theoretic topological models of intuitionistic logic. From this semantical study we define a family of sound and cut-free complete labelled calculi that capture both the Kripke and the ${\mathsf{TB}}$ semantics. Using a key property of the forcing relation in ${\mathsf{TB}}$ models, called regularity, we show termination and decidability results. Finally we discuss the automation of the proof search in one of the labelled calculi and its implementation.
GutMetaNet: an integrated database for exploring horizontal gene transfer and functional redundancy in the human gut microbiome
Authors: Jiang Yiqi , Wang Yanfei , Che Lijia , Yang Shuo , Zhang Xianglilan , Lin Yu , Shi Yucheng , Zou Nanhe , Wang Shuai , Zhang Yuanzheng , Zhao Zicheng , Li Shuai Cheng
Published: November 2024

Metagenomic studies have revealed the critical roles of complex microbial interactions, including horizontal gene transfer (HGT) and functional redundancy (FR), in shaping the gut microbiome’s functional capacity and resilience. However, the lack of comprehensive data integration and systematic analysis approaches has limited the in-depth exploration of HGT and FR dynamics across large-scale gut microbiome datasets. To address this gap, we present GutMetaNet (https://gutmetanet.deepomics.org/), a first-of-its-kind database integrating extensive human gut microbiome data with comprehensive HGT and FR analyses. GutMetaNet contains 21 567 human gut metagenome samples with whole-genome shotgun sequencing data related to various health conditions. Through systematic analysis, we have characterized the taxonomic profiles and FR profiles, and identified 14 636 HGT events using a shared reference genome database across the collected samples. These HGT events have been curated into 8049 clusters, which are annotated with categorized mobile genetic elements, including transposons, prophages, integrative mobilizable elements, genomic islands, integrative conjugative elements and group II introns. Additionally, GutMetaNet incorporates automated analyses and visualizations for the HGT events and FR, serving as an efficient platform for in-depth exploration of the interactions among gut microbiome taxa and their implications for human health.
ScDrugAct: a comprehensive database to dissect tumor microenvironment cell heterogeneity contributing to drug action and resistance across human cancers
Authors: Xu Yanjun , Zhang Yifang , Song Kaiyue , Liu Jiaqi , Zhao Rui , Zhang Xiaomeng , Pei Liying , Li Mengyue , Chen Zhe , Zhang Chunlong , Wang Peng , Li Feng
Published: November 2024

The transcriptional heterogeneity of tumor microenvironment (TME) cells is a crucial factor driving the diversity of cellular response to drug treatment and resistance. Therefore, characterizing the cells associated with drug treatment and resistance will help us understand therapeutic mechanisms, discover new therapeutic targets and facilitate precision medicine. Here, we describe a database, scDrugAct (http://bio-bigdata.hrbmu.edu.cn/scDrugAct/), which aims to establish connections among drugs, genes and cells and dissect the impact of TME cellular heterogeneity on drug action and resistance at single-cell resolution. ScDrugAct is curated with drug–cell connections between 3838 223 cells across 34 cancer types and 13 857 drugs and identifies 17 274 drug perturbation/resistance-related genes and 276 559 associations between >10 000 drugs and 53 cell types. ScDrugAct also provides multiple flexible tools to retrieve and analyze connections among drugs, genes and cells; the distribution and developmental trajectories of drug-associated cells within the TME; functional features affecting the heterogeneity of cellular responses to drug perturbation and drug resistance; the cell-specific drug-related gene network; and drug–drug similarities. ScDrugAct serves as an important resource for investigating the impact of the cellular heterogeneity of the TME on drug therapies and can help researchers understand the mechanisms of action and resistance of drugs, as well as discover therapeutic targets.
EPCO-07. INTEGRATING SPATIALLY RESOLVED MULTI-OMICS DATA TO UNCOVER DYSFUNCTIONAL METABOLISM DRIVEN NETWORKS THAT ENHANCE INFILTRATION OF DIFFUSE GLIOMAS
Authors: Ma Yanxia , Nguyen Nhat , Singh Sanjay , Basi Akshay , Mak Duncan , Gomez Javier , Burks Jared , Seely Erin , Lang Frederick , Ene Chibawanye
Published: November 2024

BACKGROUND

Diffuse infiltration is an aggressive feature of high-grade gliomas with survival implications. The contribution of crosstalk between non-neoplastic and neoplastic cells to tumor infiltration remains largely understudied due to the lack of profiling techniques that retain spatial information. Spatial multi-omic profiling is a promising approach to comprehensively analyze transcript-omics, prote-omics and metabol-omics on the same tissue section while preserving information about the spatial organization of cells. Integration of these spatial studies allows for inferring the consequences of complex cell-cell communication underlying tumor infiltration. We hypothesize that the glioma edge is enriched with pro-infiltration ligands-receptors driving tumor infiltration. Strategies that disrupt these ligand-receptor networks may suppress glioma infiltration and improve clinical outcomes.

METHODS

We utilized a glioma tissue micro-array (TMA) to establish the neoplastic and non-neoplastic heterogeneity in the GBM infiltration edge. Each TMA slide consists of pathologist annotated tumor core and edge samples of Glioblastoma (IDH Wildtype, WHO Grade 4; n=10), Diffuse Astrocytoma (IDH Mutant, WHO Grade 3; n=3), Oligodendroglioma (IDH mutant, WHO Grade 2; n=5) and 2 non-brain control samples. We performed spatial multi-omics profiling on adjacent sections of the TMA using 10x Xenium spatial transcriptomics, imaging mass cytometry (IMC) and mass spectrometry imaging (MSI). Integration, visualization, and quantification of the spatial data was done on VisioPharm.

RESULTS

In GBM, we identified candidate mRNA transcripts and proteins for ligands enriched at the infiltrating edge (compared to tumor core; p<0.0001) that correlated with a poor progression free survival (PFS; r2=0.22). These candidate ligands were also significantly enriched at the edge of oligodendroglioma WHO Grade 2 and astrocytoma WHO Grade 3.

CONCLUSIONS

Spatial multi-omics profiling on a TMA consisting of Glioma WHO grades 2-4 identified differentially expressed and targetable pro-tumor infiltration ligands associated with lower PFS in GBM. Functional studies to uncover the role of metabolites enriched at the glioma edge for the expression of the identified pro-infiltration ligands are ongoing.
EPCO-10. PROTEIN GENERATOR ENABLES PROTEOMICS-BASED SUBTYPING OF IDH MUTANT ASTROCYTOMA
Authors: Wang Hui , Tang Jihong , Liu Xing , Fan Wenhua , Jiang Tao , Wang Jiguang
Published: November 2024

The understanding of the proteomic landscape of IDH mutant astrocytoma has been limited in previous studies. To address this knowledge gap, we developed an innovative approach using artificial intelligence (AI) to generate proteomic profiles of tumors based on their transcriptome data. Particularly, we employed a combination of Variational Auto-Encoder and Contrastive Language Image Pretraining techniques to develop an AI model. The model was trained on publicly available databases containing matched RNA and protein data. Leveraging this extensive dataset, we applied the trained model to infer proteomic profiles for over one thousand adult IDH mutant astrocytoma specimens using their transcriptome sequencing data. This novel approach allowed us to explore and identify previously undiscovered subtypes based on the predicted proteomic profiles. As a result, we identified seven distinct clusters: IDHmut-noncodel-Proliferative, IDHmut-noncodel-Mesenchymal, IDHmut-noncodel-Mitochondrial, IDHmut-NFkB-signal, IDHmut-codel-Proliferative, IDHmut-Metabolism, and IDHmut-Neuronal. Of particular clinical significance, the IDHmut-noncodel-Proliferative and IDHmut-noncodel-Immune-Mesenchymal subtypes displayed the worst prognoses, while the IDHmut-Neuronal, IDHmut-NFkB-signal, and IDHmut-Metabolism subtypes exhibited relatively better survival outcomes. Remarkably, within the IDHmut-noncodel-Proliferative cluster, we observed a high prevalence of CDKN2A homozygous deletion, providing a potential explanation for its poor survival prognosis. Conversely, the IDHmut-noncodel-Mesenchymal cluster did not demonstrate any significant genetic events but exhibited elevated expression of mesenchymal marker genes. Furthermore, this cluster displayed notable characteristics, including the presence of gemistocytic differentiated tumor cells and infiltration of activated CD8 T lymphocytes. Moreover, we encompassed an evolutionary analysis of 189 initial-recurrent IDH mutant astrocytoma pairs, and discovered that gemistocytic differentiation represents an early event in tumor progression. In summary, we introduced a novel method utilizing an AI model to generate proteomic profiles, thus enabling the discovery of previously unknown subtypes of IDH mutant glioma with clinical relevance. These findings contribute to a deeper understanding of the molecular landscape of IDH mutant astrocytoma, potentially leading to improved prognostication and personalized treatment strategies.
EPCO-13. HUMAN ENDOGENOUS RETROVIRUS (HERV) PLAYS A CRITICAL ROLE IN ONCOGENIC MECHANISM INIDH1-WILD TYPE GLIOBLASTOMAS
Authors: Johnson William E , Malgulwar Prit Benny , Huse Jason T
Published: November 2024

IDH1-wildtype (WT) GBMs are the most common and aggressive tumors of the central nervous system (CNS), with a median survival rate of 12-15 months, and are resistant to clinical therapies due to their heterogenous molecular phenotype. In this study, we developed a pipeline to dissect the potential role of human endogenous retroviruses (HERVs) in patient derived glioma stem cells (GSCs) and integrated our findings with published epigenomic datasets for enhancers (H3K27ac), CTCF, and chromatin toplogy (Hi-C). We found high expression of several HERV transcripts in IDH1-WT GBMs as compared to IDH1-mutant variants. Epigenomic analysis of these upregulated HERVs showed association with both enhancer marks and CTCF deposition. Annotation of HERVs to their nearest genes, followed by Gene Set Enrichment Analysis (GSEA), identified involvement of actin-filament based mechanisms and regulation of immune phenotype. Integration of these findings identified MER61 (ERVMER61-1), a potential regulator of Interleukin-6 and showed alteration in chromatin looping and enhancer occupancy. To summarize, our work points to novel mechanisms of GBM pathogenesis, through involvement of HERVs in cell migratory and immune dysfunction, warranting further investigations into these oncogenic mechanism to identify and develop novel therapeutic options for GBM.
EPCO-16. METHOD TO MODEL AND CORRECT NOISE IN SINGLE-NUCLEI RNA-SEQUENCING DATA FROM POST-MORTEM BRAIN
Authors: Peng Jacqueline J , O’Rourke Donald M , Nasrallah MacLean P , Binder Zev A , Silverbush Dana
Published: November 2024

Post-mortem brain samples are crucial for neuropathological research. For brain cancers, they provide insights about disease progression, microenvironmental factors, and treatment resistance. In some brain diseases, brain tissue may only be available post-mortem. Establishing a reference atlas of healthy brain also requires post-mortem donations. Beyond logistical and ethical challenges of post-mortem samples, there are also post-mortem factors that mask biological signal. In this study, we specifically aim to model post-mortem gene expression changes in single-nuclei RNA-sequencing (snRNA-seq) data. We analyze a public snRNA-seq dataset of pediatric high-grade glioma (pHGG) that has matched samples at initial resection and autopsy. We find a clear gene signature, composed of mitochondrial genes, stress-related genes, and metabolism-related genes, that is upregulated post-mortem. This signature also appears in post-mortem snRNA-seq data from other brain diseases and healthy donors. We classify it as “post-mortem noise”. We model the post-mortem noise as a combination of technical and biological artifact. The technical artifact is correlated with the percentage of mitochondrial reads and is a general measure of sample quality. The biological artifact is correlated with post-mortem interval and represents gene expression changes due to post-mortem stress. We apply our model to the pHGG data by regressing out the technical and biological artifact. Removing the post-mortem noise results in an improvement in malignant versus normal cell prediction, cell type classification, and the uncovering of pathways related to glioma progression. We confidently identify several normal cell types and predict their interactions with cancer cells, highlighting the utility of wider possible margins post-mortem. Therefore, after removing post-mortem noise, we analyze glioma progression at an unparalleled timepoint and characterize late-stage changes in the tumor microenvironment. In conclusion, we develop a method that models post-mortem noise in snRNA-seq brain data. Our method can be broadly applied to future brain cancer studies using post-mortem tissue.
EPCO-33. OMICON: A CLOUD PLATFORM FOR FAIR RESEARCH ON GENE COEXPRESSION NETWORKS IN NORMAL HUMAN BRAIN AND BRAIN TUMORS
Authors: Eliscu Rebecca , Padmanabhan Divya , Sudhakaran Sanoj , Nair Sharat , Suresh Shravan , Joseph Pratheeksh , Jacob Alex , Ravindran Vineet , Feroz Mizba , Ajayakumar Akshay , Reghuvaran Renjith , Raj Shiny , Vijay Aswathy , Lakshmi Gouri , Vava Remya , Escobar Carolina , Thormann Martin , Shamsian Shawn , Oldham Michael
Published: November 2024

Genome-wide coexpression analysis of bulk human brain samples is a powerful approach for identifying highly reproducible transcriptional signatures of cell types and cell states, since it can survey huge numbers of individuals, cells, and transcripts. However, it is difficult to optimize gene coexpression network construction, compare gene coexpression modules from independent datasets, or even locate gene expression datasets with similar attributes. To address these challenges, we have developed the OMICON platform (theomicon.ucsf.edu) to promote FAIR (Findable, Accessible, Interoperable, Reusable) research practices involving human brain gene coexpression networks. OMICON contains structured gene expression data for >17K bulk human brain samples (~10K normal and ~7K malignant glioma), which were collected from diverse public repositories and consortia (e.g., GEO, TCGA, CGGA, CPTAC, REMBRANDT, IvyGAP, GTEx, NABEC, the Allen Institute). To promote interoperability, we have standardized metadata for hundreds of dataset and sample attributes, including single-nucleotide and copy-number mutations. For each dataset, we have used the FindModules R function to construct dozens of gene coexpression networks by iterating over module detection parameters. These efforts have identified ~100K gene coexpression modules, which have been extensively characterized via enrichment analysis with thousands of curated gene sets. All datasets, metadata, gene coexpression networks, enrichment results, and analysis steps can be browsed with an interactive workflow visualization tool, which promotes accessibility, reusability, and reproducibility by maintaining complete data provenance with unique identifiers. To promote findability, we have built an advanced search engine to identify datasets, samples, modules, and more, by filtering standardized metadata (e.g., find gene coexpression modules in human glioblastoma datasets that are significantly enriched with markers of T-cells). A detailed description of OMICON’s functionality is described on our Help page: theomicon.ucsf.edu/home/help. Through this functionality, OMICON seeks to build community and focus therapeutic efforts around reproducible analyses of transcriptional variation in normal human brain and brain tumors.
EPCO-34. DECIPHERING THE LONGITUDINAL TRAJECTORIES OF GLIOBLASTOMA BY INTEGRATIVE SINGLE-CELL GENOMICS
Authors: Spitzer Avishay , Johnson Kevin C , Nomura Masashi , Garofano Luciano , Nehar-belaid Djamel , Darnell Noam Galili , Greenwald Alissa C , Bussema Lillian , Oh Young Taek , Varn Frederick S , D’Angelo Fulvio , Gritsch Simon , Anderson Kevin J , Migliozzi Simona , Castro L Nicolas Gonzalez , Chowdhury Tamrin , Robine Nicolas , Reeves Catherine , Park Jong Bae , Lipsa Anuja , Hertel Frank , Golebiewska Anna , Niclou Simone P , Nusrat Labeeba , Kellet Sorcha , Das Sunit , Moon Hyo-Eun , Paek Sun Ha , Bielle Franck , Laurenge Alice , Stefano Anna Luisa Di , Mathon Bertrand , Picca Alberto , Sanson Marc , Tanaka Shota , Saito Nobuhito , Ashley David M , Keir Stephen T , Huse Jason T , Yung W K Alfred , Lasorella Anna , Iavarone Antonio , Verhaak Roel G W , Tirosh Itay , Suvà Mario L
Published: November 2024

The evolution of cellular heterogeneity in IDH-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. To address it, we assembled a longitudinal cohort of 121 primary and recurrent GBM specimens from 59 patients, with extensive clinical annotations, and profiled it by single-nucleus RNA-sequencing and bulk tumor DNA sequencing. In most cases, longitudinal samples diverged in their composition of cell types and cell states. However, almost all theoretical trajectories were observed in our cohort such that the overall distribution of cell types and cell states was comparable between primary and recurrent samples. The most consistent longitudinal effect (66% of patients) was a lower malignant cell fraction at recurrence and a reciprocal increase in proportions of glio-neuronal TME cell types; in some cases, this was further accompanied by a coordinated shift of malignant cells towards neuronal-like states. MGMT methylation and radiation-related small deletion phenotypes were linked to particular trajectories, with depletion of mesenchymal-like cells and enrichment of hypoxia-related malignant cells, respectively. Importantly, changes in malignant states were also associated with specific changes in TME composition. In summary, our analysis highlights diverse longitudinal GBM trajectories that are shaped by treatment response and TME interactions.
EPCO-38. IDENTIFYING THE MOLECULAR SIGNATURE OF INFILTRATING EDGE IN GLIOBLASTOMA AS DRIVERS OF TUMOUR INVASION AND RECURRENCE
Authors: Ivanova Alyona , Ayyadhury Shamini , Wu Megan , Munoz David G , Pugh Trevor , Das Sunit
Published: November 2024

Complete tumour resection in glioblastoma patients is not possible. Residual therapy-resistant edge-derived cells drive tumour recurrence and infiltrative expansion in glioblastoma. Features that are specific to malignant edge-derived cells may serve as predictive biomarkers to allow individual tailoring of the treatment plan to slow down tumour invasion and prevent tumour recurrence in GBM patients following standard therapy. Intratumoural spatial heterogeneity facilitates therapeutic resistance and recurrence in glioblastoma. Our knowledge on glioblastoma heterogeneity is mostly restricted to the surgically resectable tumour core, while the functional characterization of tumour cells at the infiltrating edge remains largely elusive due to the presence of normal functional brain tissue in the peritumoural lesion. Edge-derived cells exhibit larger capacity for infiltrative expansion and are the main drivers of treatment failure and tumour recurrence, making them action targets for novel treatment approaches in glioblastoma. To resolve the transcriptional heterogeneity of GBM within the spatial context, we profiled gene expression of different tumour regions (“edge” and “core”) obtained at initial surgical resection from primary and recurrent IDH-WT GBM patients with Visium 10x and GeoMx. We show that infiltrative edge-derived cells are spatially segregated and are characterized by regionally shared distinct genomic and transcriptomic signatures that promote invasiveness and underly disease recurrence. Tumour edge is enriched for neuronal signatures, while tumour core displays larger transcriptional subpopulation diversity and abundance of proliferative cells with a high capacity for self-renewal, consistent with the proliferative and cancer stem cell-enriched phenotype in early GBM progressors. Upregulated DEGs of tumour edge cells are significantly associated with ion regulation of transport, chemical synaptic transmission, and nervous system development. These modules may represent tumour cell hijacking of neuronal programs specifically at the tumour periphery as described in the context of glioma-neuron synaptic communication and formation of neurite-like microtubes. Upregulation of ion regulation transport at the tumour periphery indicates enhanced neuronal activity and excitability driving infiltrating growth.
EPCO-40. TRANSCRIPTIONAL TRAJECTORY INFERENCE OF IMAGE-LOCALIZED, MULTI-REGIONAL HIGH-GRADE GLIOMA BIOPSIES REVEALS DISTINCT POPULATION ECOLOGIES AND SEX-ASSOCIATED ENRICHED PATHWAYS
Authors: Curtin Lee , Bond Kamila , Singleton Kyle , Jackson Pamela , Sereduk Christopher , Krishna Chandan , Zimmerman Richard , Patra Devi , Donev Kliment , Mrugala Maciej , Tran Nhan , Hu Leland , Bendok Bernard , Al-Dalahmah Osama , Canoll Peter , Swanson Kristin
Published: November 2024

The intra- and inter-patient heterogeneity in high-grade glioma (HGG) continues to contribute to its poor prognosis. Clinical biopsies are often harvested from limited regions and typically are not image localized. Thus, they fail to capture the diversity within tumor regions, immune expression or normal cell abundances that play key roles in tumor development. It is important to gain an understanding of these subpopulation ecologies, their spatial resolution, and interactions between them that may then be exploited for future therapeutic benefit. Further, these may differ by patient characteristics such as sex, age at diagnosis and treatment status. Using an ongoing image-localized biopsy collection protocol, we have so far evaluated the bulk transcriptomics of 202 multi-regional biopsies from 58 patients to characterize HGG heterogeneity. These samples were processed through Monocle, a reverse graph embedding algorithm that groups samples into states and orders them along developmental trajectories. Deconvolution methods were previously used to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell subpopulations for each sample, which we have now overlaid on the Monocle graph. Monocle classified HGG into 4 main states along a three-pronged trajectory. These states reveal distinct population ecologies with associated enriched gene pathways. We also note significant immune pathway enrichments that differ between state and patient-reported sex. Together, these algorithms reveal a simple transcriptomic trajectory that helps us understand the development and evolution of HGG. Characterizing the in vivo diversity within and between high grade gliomas is important for understanding prognosis, stratifying future treatments and ultimately improving patient outcome.
EPCO-41. THE NUCLEOSOME REMODELING AND DEACETYLASE COMPLEX UNDERLIES SELECTIVE DEPENDENCY IN H3 G34-MUTANT DIFFUSE HEMISPHERIC GLIOMA
Authors: Roach Jordan , Kasper Lawryn , Andrews Jared , He Chen , Hover Laura , Adorno Jennifer Ocasio , Teis Robert , Laffy Julie , Nomura Masashi , Boop Frederick , Klimo Paul , Chiang Jason , Abraham Brian , Tirosh Itay , Suvà Mario , Baker Suzanne
Published: November 2024

Pediatric-type diffuse high-grade gliomas are fatal central nervous system malignancies of childhood. Recurrent mutations in histone H3.3 at amino acid 34 (glycine to arginine/valine) are a defining molecular feature of diffuse hemispheric glioma, H3 G34-mutant (H3 G34-mutant DHG), which arises preferentially in adolescents and young adults. Single-nuclei sequencing of age and anatomically matched H3 wild-type and H3 G34-mutant primary patient tumors identified aberrant neuronal-like transcriptional programs enriched for signatures of cortical interneurons derived from the medial ganglionic eminence. The extent to which these molecular signatures reflect cancer dependencies in H3 G34-mutant DHG is poorly understood. To identify transcriptional vulnerabilities governing cellular state and underlying developmental lineage, we performed CRISPR screening targeting the DNA-binding domains of 1,427 proteins in H3 G34-mutant DHG (n=6) and H3 K27-altered diffuse midline glioma (DMG) (n=3). Through these efforts, we identified developmentally relevant transcription factor vulnerabilities corresponding to neuronal and oligodendrocyte precursor cell-like hierarchies comprising H3 G34-mutant DHG and H3 K27-altered DMG cellular states, respectively. Intriguingly, we also identified multiple members of the nucleosome remodeling and deacetylase (NuRD) complex as selective dependencies in H3 G34-DHG compared to H3 K27-altered DMG and 32 other cancer cell line models screened using the same DNA-binding domain library. Genetic perturbation of the holo-NuRD structural subunit MBD3 conferred an upregulation of genes involved in neuronal differentiation and synapse formation consistent with NuRD-mediated modulation of the aberrant neuronal-like cell hierarchy observed in H3 G34-mutant DHG. To therapeutically target NuRD-associated class I HDAC activity, patient-derived H3 G34-mutant DHG cell lines were treated with quisinostat, a highly potent class I and II HDAC inhibitor. Pharmacologic inhibition of HDAC activity was sufficient to impair cell growth in vitro. Ongoing experiments are evaluating dependencies in vivo. Our results may suggest a differential requirement for chromatin repressive complex dysregulation in the pathogenesis of oncohistone-mutant pediatric-type diffuse high-grade gliomas.
EPCO-50. MOLECULAR DETERMINANTS OF CENTRAL NERVOUS SYSTEM TROPISM AND PROGRESSION IN COLORECTAL CANCER
Authors: Gui Chengcheng , Walch Henry , Mueller Kirin , Skakodub Anna , Miao Emily , Khatri Ishaani , Kumar Rahul , Mazzeo Michel Padilla , Shen Junchao , Cooper Claire , Hsu Audree , Patel Roshal , Ilica A Turan , Eichholz Jordan , Yu Kenny , Wilcox Jessica , Manca Paolo , Yu Yao , Yamada Yoshiya , Imber Brandon , Maron Steven , Foote Michael , Chatila Walid , Yaeger Rona , Schultz Nikolaus , Pike Luke
Published: November 2024

BACKGROUND

Brain metastases (BM) from colorectal cancer (CRC) are associated with dismal prognosis, but little is understood regarding their molecular characteristics. We identified genomic features that predispose to brain tropism, differentiate BM from extracranial disease, and predict early intracranial progression (IP) after BM-directed therapy.

METHODS

We analyzed next-generation sequencing (NGS) of tumor biopsies from three subgroups of CRC patients: patients with BM (BM+, n=379), patients with extracranial metastases (EM) but without BM (BM-/EM+, n=3968), and patients without metastatic disease (BM-/EM-, n=1061). NGS was performed with MSK-IMPACT, a targeted panel of >300 genes. First, we compared genomic alterations in primary tumors (PT) among the BM+, BM-/EM+, and BM-/EM- subgroups. Second, we focused on patients in the BM+ subgroup who received stereotactic radiosurgery (SRS) for limited BM, comparing tumor genomic alterations from different anatomic sites: BM (n=32), EM (n=62), and PT (n=68). Third, we focused on the 32 resected BM, identifying genomic alterations that predicted early IP, defined as new BM, leptomeningeal disease, or enlargement of existing BM, within 6 months of postoperative SRS.

RESULTS

PT of BM+ patients demonstrated lower rates of microsatellite instability, increased frequency of BRAF alterations, and fewer APC alterations compared with PT of BM-/EM+ and BM-/EM- patients. Among BM+ patients, SMAD4, MYC, and CDK8 alterations were enriched among resected BM specimens, compared with EM and PT specimens. Resected BM of patients with early IP demonstrated increased frequency of SMAD4 alterations, particularly biallelic SMAD4 loss, and decreased frequency of MYC alterations, compared with resected BM of patients without early IP.

CONCLUSION

Alterations in key driver genes are associated with initial development and progression of CRC BM. BRAF alterations are enriched in PT of patients who develop BM. SMAD4 alterations are enriched in BM compared to extracranial disease and furthermore predict early IP after BM-targeted therapy.
ANGI-01. EXTRANEURAL METASTATIC EPENDYMOMA: DISTANT METASTASIS TO THE PLEURA, LUNGS, LYMPH NODES, AND BONE
Authors: Guirguis Mina , Jiang Zhixin , Cai Chunyu , Youssef Michael
Published: November 2024

Ependymomas are neuroepithelial tumors arising from ependymal cells surrounding the cerebral ventricles that account for 1.6-1.8% of primary CNS tumors. They rarely metastasize to extraneural structures, with one study reporting an incidence of 6.2% with a mean time from diagnosis to extraneural metastasis of 75.6 months. This spread, when it does occur, has been reported to occur to the lungs, lymph nodes, liver, and bone. We describe the case of a patient with recurrent WHO Grade III ependymoma, ZFTA::RELA fusion positive, with extraneural metastatic disease to the thoracic spine, lungs, and pelvic bones. He was treated with multiple surgical resections, radiation therapy, and salvage chemotherapy for his extraneural metastasis to the lungs, bone, pleural space, and lymph nodes. His functional and respiratory statuses declined until he ultimately developed pneumonia, status epilepticus, then spontaneous respiratory arrest, which resulted in his passing away. Salvage chemotherapy for ependymoma has unclear mortality benefit and more research must be done to determine how best to treat patients with extraneural metastases, particularly those who fail traditional treatment with resection and radiation therapy.
ANGI-03. GLIOMA STEM CELLS INDUCE VASECTASIA – A NON-ANGIOGENIC BRAIN TUMOUR NEOVASCULARIZATION PROCESS DRIVEN BY INTERCELLULAR EGFR TRANSFER THROUGH EXTRACELLULAR VESICLES
Authors: Rak Janusz , Spinelli Cristiana , Adnani Lata , Wong Fang Cheng , Meehan Brian , Montermini Laura , Huang Sidong , Kim Minjun , Nishimura Tamiko , Croul Sidney , Nakano Ichiro , Riazalhosseini Yasser
Published: November 2024

Tumour neovascularization in glioblastoma (GBM) is abundant, abnormal and poorly understood, and it likely involves multiple co-existing mechnanisms with distinct modes of regulation. Since glioma stem cells (GSCs) engage in bidirectional interactions with the vasculature we dissected the resulting vascular responses elicited by either proneural (PN), or mesenchymal (MES) GSC subtypes established from patients isolates and able to drive progression of orthotopic intracranial xenografts in mice. We report here that while PN-GSCs elicited mostly angiogenesis-type vascular capillary growth processes, their MES-GSC counterparts elicited non-angiogenic growth of enlarged vessels (vasectesia), paradoxically associated with reduced blood vessel density. Vasectasia was dependent on the expression of oncogenic EGFR/EGFRvIII by MES-GSCs, and on the related kinase/signalling activity, as EGFR/EGFRvIII gene disruption and Dacomitinib treatment suppressed formation of large blood vessels in vivo and resulted in a preponderance of a small calliber (angiogenic) vasculature throughout xenografts. Notably, the analysis of spatial transcriptomes and single cell RNA sequencing revealed distinct molecular traits of endothelial cells asociated with vasectasia and angiogesis, the former enriched in Birc5, but depleted for angiogenic tip cell markers (Vegfr2, Apln). Mechnaistically, vasectasia was linked to the intercellular transfer of EGFR from MES-GSCs to endothelial cells resulting in ectopic activation of EGFR signalling in the endothelial cell bacground, both in vitro and in a model of in vivo blood vessel recruitment into implanted matrigel pellets. Simultaneous pharmacological blockade of both, angiogenesis (anti-VEGR2) and vasectasia (Dacomitinib) lead to a marked increase in survival of mice with aggressive GBM lesions initiated by MES-GSCs. We suggest that, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new, subtype-specific mechanism of GBM neovascularization, and a plausible target for agents aiming to modify vascular tumour microenvironment.