bluuebunny/crossref_metadata_2025_split huggingface dataset:
MYO5B and the Polygenic Landscape of Very Early-Onset Inflammatory Bowel Disease in an Ethnically Diverse Population
Authors: Watson Ashleigh , Harris R Alan , Engevik Amy C , Oezguen Numan , Nicholson Maribeth R , Dooley Sarah , Stubler Rachel , Satter Lisa Forbes , Karam Lina B , Kellermayer Richard 
Published: August 2024

Abstract

Background
Genetic discovery in very early-onset inflammatory bowel disease (VEO-IBD) can elucidate not only the origins of VEO-IBD, but also later-onset inflammatory bowel disease. We aimed to investigate the polygenic origins of VEO-IBD in a cohort with a high proportion of Hispanic patients.

Methods
Patients with VEO-IBD who underwent whole exome sequencing at our center were included. Genes were categorized as genes of interest (GOIs) (129 genes previously described to be associated with VEO-IBD) or non-GOIs. VEO-IBD “susceptibility” single nucleotide variants (SNVs) were identified through enrichment compared with gnomAD (Genome Aggregation Database) and ALFA (Allele Frequency Aggregator) and were scored by Combined Annotation Dependent Depletion for deleteriousness. Gene networks carrying susceptibility SNVs were created. Myosin 5b immunofluorescence was also studied.

Results
Fifty-six patients met inclusion criteria, and 32.1% identified as Hispanic. Monogenic disease was infrequent (8.9%). Significant enrichment of GOI susceptibility SNVs was observed, notably in MYO5B, especially in Hispanics. MEFV, TNFAIP3, SH3TC2, and NCF2 were also central participants in the GOI networks. Myosin 5b immunofluorescence in colonic mucosa was significantly reduced in those with MYO5B susceptibility SNVs compared with control subjects. Seven genes (ESRRA, HLA-DQ1, RETSAT, PABPC1, PARP4, CCDC102A, and SUSD2) were central participants in the non-GOI networks.

Conclusions
Our results support the polygenic nature of VEO-IBD, in which key participants, like MYO5B, were identified through network analytics. Rare variant load within susceptibility genes may be relevant not only for the genetic origins of inflammatory bowel disease, but also for the age of disease onset. Our findings could guide future work in precision medicine.
Evaluating the protective effect of dapsone on experimental osteoarthritis models induced by MIA in male rats
Authors: Nazari Kimia , Hosseindoost Saereh , Dehpour Ahmad Reza , Kheirandish Yasaman , Shafaroodi Hamed 
Published: August 2024

Abstract

Objectives
Osteoarthritis, a degenerative condition that results in significant morbidity, is typically managed with treatments aimed at symptom relief rather than addressing the underlying degeneration. Dapsone, recognized for its anti-inflammatory, antioxidant, antiexcitotoxic, and antiapoptotic properties, has demonstrated promising effects in various neurodegenerative diseases. This study explores the potential of dapsone to mitigate articular destruction, inflammation, and pain in rat models of osteoarthritis.

Methods
Osteoarthritis was induced in rats by injecting MIA into the right knee joint. Dapsone was then administered intraperitoneally at 5, 10, or 20 mg/kg every 2 days for 2 weeks. Behavioural tests were done on days 0, 7, and 14. On day 14, the articular cartilage was histologically analysed using H&E staining. Serum levels of NF-kB, IL-1β, and TNF-α were evaluated by ELISA.

Results
Dapsone effectively reduces pain, inflammation, and articular cartilage damage in osteoarthritis. Specifically, it improves mechanical allodynia and thermal hyperalgesia, reduces inflammatory markers (TNF-α, IL-1β, and NF-κB), and protects against cartilage destruction and chondrocyte loss, with the most significant effects at 20 mg/kg.

Conclusions
Dapsone effectively prevents pain, inflammation, and cartilage damage in osteoarthritis rats, suggesting its potential as a therapeutic option for managing osteoarthritis.
Extrarenal manifestations in inherited kidney diseases
Authors: Hoefele Julia , Eble Julian , Hermle Tobias , Wuttke Matthias , Schultheiss Ulla T 
Published: August 2024

ABSTRACT
Monogenic kidney diseases result from an abundance of potential genes carrying pathogenic variants. These conditions are primarily recognized for manifesting as kidney disorders, defined as an impairment of the structure and/or function of the kidneys. However, the impact of these genetic disorders extends far beyond the kidneys, giving rise to a diverse spectrum of extrarenal manifestations. These manifestations can affect any organ system throughout the body, leading to a complex clinical presentation that demands a comprehensive understanding and interdisciplinary management of affected persons. The intricate interplay between genetic variants, molecular pathways, and systemic interactions underscores the importance of exploring the extrarenal aspects of inherited kidney diseases. This exploration not only deepens our comprehension of the diseases themselves but also opens avenues for more holistic diagnostics, treatment strategies, and improved interdisciplinary patient care. This article delves into the intricate realm of extrarenal manifestations in inherited kidney diseases, shedding light on the far-reaching effects that these genetic conditions can exert beyond the confines of the kidney system.
BSBM-02 SIRPΑ INTRACELLULAR SIGNALING MEDIATED MITOCHONDRIAL FISSION IN TRIPLE-NEGATIVE BREAST CANCER CELLS IS ASSOCIATED WITH BREAST-TO-BRAIN METASTASIS
Authors: Tsai Yu-Ting , Wilson Adam , Miller Lance , Cook Katherine , Zhao Dawen , Lesser Glenn , Soto-Pantoja David 
Published: August 2024

Abstract
Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, often leads to brain metastasis (35%). Current need for standard treatment requires the development of new therapies. The CD47/SIRPα interaction drives immune escape. However, SIRPα’s expression and role in cancer cells remain poorly understood. Single-cell RNA-Seq data reveals SIRPα upregulation in TNBC, supported by strong immunoreactivity in patient biopsies and a 3.5-fold increase in breast-to-brain metastatic lesions. (n=9-19; p&lt;0.01). Consistently, the protein expression of SIRPα TNBC 4T1 and EO771 brain-tropic cells (4T1Br3/EO771Br4) is significantly higher than the parental cells (n=3; p&lt;0.05). Stably overexpressed SIRPα and knockout TNBC cell lines show that SIRPα regulates SHP2 phosphorylation in cancer cells, and SIRPα/SHP2 axis regulates TNBC cell migration. According to the gene ontology from Bulk RNA-Seq data on orthotopic tumors, anti-SIRPα treatment affects the genes related to mitochondria and organelle membrane clusters, correlating to mitochondrial fission and fusion dynamics. Our data shows a doubling in Drp1 (mitochondria fission) protein expression in TNBC brain-tropic cells compared to parental, whereas MFN2 (mitochondria fusion) has a 50% decrease in expression. Moreover, SIRPα knockout cell line also downregulates mitochondria fission with decreased Drp1 and increased MFN2 expression. Allosteric SHP2 inhibitor treatment on TNBC brain-tropic cells also shows a dose-dependent inhibition of Drp1 (n=3, p&lt;0.001) and MFN2 enhancement (n=3, p=0.0184) with Erk signaling inhibition. SIRPα/SHP2/Erk axis shifts mitochondria fusion to fission, leading to cancer metastasis. SIRPα blockade by antibody reduced metastatic brain lesion formation in two in vivo models by approximately 90% (n=4-7; p &lt;0.05). Spatial proteomics revealed changes in adaptive and innate suppressive and inflammatory signaling that may be associated with the observed changes in SIRPα intracellular signaling. This was associated with shift in ECM proteins that may influence mitochondrial function to influence metastasis., thus providing a potential mechanism for how SIRPα promotes TNBC brain metastasis.
BSBM-10 GENETIC DELETION OF ERΑ OR ERΒ IN REACTIVE ASTROCYTES DECREASES REACTIVE GLIOSIS AND PROMOTES BRAIN METASTASIS
Authors: Koliavas Stella , Contreras-Zárate Maria J , Jaramillo-Gomez Jenny A , Fox Morgan , Nguyen Alicia , Cittelly Diana M 
Published: August 2024

Abstract
Astrocytes surround brain metastasis (BM) and play both anti-metastatic and pro-metastatic roles throughout BM progression. We have shown that pre-menopausal levels of 17-β-Estradiol (E2) promotes BM of estrogen receptor (ER) negative breast cancer (BC), in part by stimulating ER+ astrocytes to secrete factors that promote proliferation, migration, and invasion of ER-BC cells. E2 exert its function through activation of ERα or ERb, and astrocytic ERα and ERβ play diverse and often interdependent roles modulating neuroinflammatory responses in the brain. Yet, how ERs impact astrocytic function in the context of BM remains unknown. We hypothesize that genetic deletion of astrocytic ERs modulates their function during BM progression and blocks E2-dependent BM. Using a Cre-loxP system, we selectively deleted ERα or ERβ in GFAP+ reactive astrocytes (GFAPCre/+), and measured BM progression after intracardiac injection of E0771 GFPLuc+ cells in ovariectomized (OVX) female mice treated or not with E2. While E2 increased BM in control GFAP+/+ERαfl/fl and GFAP+/+ERbfl/fl mice compared to OVX mice, OVX mice with ERα or ERβ deletion in reactive astrocytes (GFAPCre/+ERαfl/fl or GFAPCre/+ERbfl/fl) showed increased BM with levels comparable to those of E2-treated control mice. Thus, genetic deletion of ERs in GFAP+ reactive astrocytes promoted E2-independent growth of BM. Immunofluorescence staining showed that BM- associated stroma of mice with ERα and ERb deletion contained significantly less reactive astrocytes (GFAP+) than control mice, suggesting that loss of ERs decreases reactive gliosis. Brain immune profiling of BM- bearing mice showed loss of ERα or ERb had a significantly increased fraction of pro-inflammatory microglia compared to OVX-control mice, suggesting that loss of astrocytic ERα and ERb promotes a neuroinflammatory TME. Together, these data suggest that loss of astrocytic ERs promotes E2-independent BM by suppressing the ability of astrocytes to become reactive and exert their anti-metastatic role through BM progression.
BSBM-13 DISTINCT UPTAKE AND ELIMINATION PROFILES FOR TRASTUZUMAB, HUMAN IGG AND BIOCYTIN-TMR IN EXPERIMENTAL HER2+ BRAIN METASTASES OF BREAST CANCER
Authors: Silvestri Vanesa , Tran Andy , Chung Monika , Chung Natalie , Gril Brunilde , Robinson Christina , Difilippantonio Simone , Wei Debbie , Kruhlak Michael , Peer Cody , Figg W Douglas , Khan Imran , Steeg Patricia 
Published: August 2024

Abstract
The aim of this study is an improved understanding of drug distribution in brain metastases. Rather than single point snapshots, we analyzed the time course and route of drug/probe elimination (clearance), focusing on the intramural periarterial drainage (IPAD) pathway. Mice with JIMT1-BR HER2+ experimental brain metastases were injected with biocytin-TMR and either trastuzumab or human IgG. Drugs/probes circulated for 5 min to 48 h, followed by perfusion. Brain sections were stained for human IgG, vascular basement membrane proteins laminin or collagen IV, and periarterial α-SMA. A machine learning algorithm was developed to identify metastases, metastatic microenvironment, and uninvolved brain in confocally scanned brain sections. Drug/probe intensity over time and total imaged drug exposure (iAUC) were calculated for 27,249 lesions and co-immunofluorescence with IPAD-vascular matrix analyzed in 11,668 metastases. In metastases, peak trastuzumab levels were 5-fold higher than human IgG but 4-fold less than biocytin-TMR. The elimination phase constituted 85–93% of total iAUC for all drugs/probes tested. For trastuzumab, total iAUC during uptake was similar to the small molecule drug probe biocytin-TMR, but slower trastuzumab elimination resulted in a 1.7-fold higher total iAUC. During elimination trastuzumab and IgG were preferentially enriched in the α-SMA+ periarterial vascular matrix, consistent with the IPAD clearance route; biocytin-TMR showed heterogeneous elimination pathways. Drug/probe elimination is an important component of drug development for brain metastases. We identified a prolonged elimination pathway for systemically administered antibodies through the periarterial vascular matrix that may contribute to the sustained presence and efficacy of large antibody therapeutics.
BSLM-12 IDENTIFICATION OF THE GDNF: NCAM SIGNALING AXIS AS A NOVEL TARGET AGAINST BREAST CANCER LEPTOMENINGEAL METASTASIS
Authors: Ma Danhui , Wang Lihua , Yu Seok-Yeong , Cui Xiuyu , Fecci Peter , Jeck William , Neff Jadee , Sipkins Dorothy 
Published: August 2024

Abstract
The molecular mechanisms that regulate breast cancer cell (BCC) metastasis within the leptomeninges (LM), and the adaptive mechanisms that allow tumors to thrive under cellular stressors within the nutrient-poor LM niche are poorly understood, limiting the development of effective therapies. Macrophages are well-described to play pro-tumoral roles in many tissues, yet how BCCs might subvert meningeal macrophages to enhance their survival in this unique microenvironment are only beginning to be investigated. Utilizing mouse models of BCC LM metastasis, we find that BCC cross-talk with meningeal macrophages provides significant pro-survival signaling through the hijacking of macrophage glial-derived neurotrophic factor (GDNF) signaling. GDNF is minimally expressed in the healthy adult brain and LM but is secreted by reactive CNS microglia and macrophages in response to stroke and other brain injury, where it serves to block apoptotic neuronal stress responses. We found that GDNF could protect BCCs expressing the GDNF receptor, neural cell adhesion molecule (NCAM), from cell death induced by nutrient deprivation in vitro, upregulating numerous genes involved in cell survival and proliferation. Flow cytometry of meningeal cell isolates from tumored mice revealed that border-associated macrophages (BAMs) and monocyte-derived macrophages (MDMs) were the predominant sources of GDNF in the meningeal microenvironment. In vivo studies in mice demonstrated that intrathecal anti-GDNF antibody blockade, macrophage-specific GDNF ablation, or deletion of NCAM from BCCs inhibited their growth within LM. Lastly, immunohistochemical analysis of meningeal-based tumor patient samples showed that these metastases were highly enriched for BCC-NCAM and stromal-GDNF expression. These findings highlight novel roles for macrophages and the GDNF: NCAM signaling axis in BCC LM disease development.
BSLM-13 EXTRACTION AND WHOLE TRANSCRIPTOME SEQUENCING OF CELL FREE RNA FROM HUMAN CEREBROSPINAL FLUID: A METHOD TO IDENTIFY BIOMARKERS OF BRAIN HEALTH AND DISEASE
Authors: Garcia Maxine Umeh , Taiwo Rukayat , Barisano Giuseppe , Spiliotopoulos Elias , Herrick Daniel , Godfrey Bryanna , Trinh Thy , Lee Seunghyun , Perez Pablo Nunez , Ngo Thuy , Gephart Melanie Hayden 
Published: August 2024

Abstract

BACKGROUND
Brain biopsy carries a morbidity risk of ~5%, which has significantly limited samples available for research, hindering our understanding and treatment of brain metastases (BrM) and Leptomeningeal Disease (LMD). However, cerebrospinal fluid (CSF) – which circulates the CNS, significantly interfacing with brain tumor tissues and carries tumor cell-free nucleic acids and LMD cells – provides a critically understudied biospecimen to understand BrM/LMD biology. We previously found brain tumor-specific cell-free DNA (cfDNA) in CSF, even when not detectable in blood; and showed that the mutant fraction of cfDNA mirrored treatment response and disease progression. Expanding to study CSF cell-free mRNA (cfRNA) allowed us to extend from mutation-driven cancers (e.g., BRAF/melanoma, EGFR/lung cancer) to investigate the transcriptional profiles of not only cancer, but also brain-resident cells.

METHODS
We have banked, and have ready-access to, 300+ CSF samples from patients with brain tumors and LMD, many of whom were treated at Stanford Hospital (2012 – 2023). We then leveraged a combination of total RNA extraction and whole transcriptome RNA sequencing to interrogate gene expression patterns present in CSF cfRNA. A method we term CSF-Seq.

RESULTS
CSF-Seq has revealed expression profiles in LMD CSF not found in CSF of non-LMD cancers, like gliomas, and non-cancer controls, like hydrocephalous. Importantly, CSF-Seq accurately recapitulates our previous panel-based qPCR method, demonstrating upregulated cancer-associated genes like CEACAM6 and MUC1 in breast and lung LMD, and ubiquitous expression of brain-associated genes, like MBP, across all CSF samples. This demonstrates our ability to retrieve well-established, validated target genes, while positioning us to discover novel gene signatures in LMD.

CONCLUSION
These results serve as a starting point for identifying key gene expression signatures associated with development of LMD and BrM progression. Further investigation focused on tumor-brain crosstalk, and gene signatures associated with response to treatment, will provide promising targets for therapeutic advancement.
BMRK-02 PROGNOSTIC VALUE OF CEREBROSPINAL FLUID TUMOR CELL COUNT IN LEPTOMENINGEAL DISEASE FROM SOLID TUMORS
Authors: Barbour Andrew , Blouw Barbara , Taylor Lynne , Graber Jerome , McGranahan Tresa , Blau Molly , Halasz Lia , Lo Simon , Tseng Yolanda , Venur Vyshak , Yang Jonathan 
Published: August 2024

Abstract
Leptomeningeal disease (LMD) affects 5-10% of patients with solid tumors. Treatment decisions for LMD rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs) improved the sensitivity of LMD diagnosis, but the prognostic value of CSF-TCs is unclear. This study assessed the prognostic value of CSF-TC density in patients with LMD from solid tumors, while determining an optimal CSF-TC density cutpoint for clinical-risk stratification. We conducted a single institution, retrospective cohort study of patients with newly diagnosed or previously treated LMD who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival. Of 31 patients, 29 had CSF-TCs detected on CNSide. Median CSF-TC density was 67.8 (interquartile range [IQR] = 4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide, and 0 of 2 patients with negative CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median survival from time of CSF-TC detection was 176 (IQR = 89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival (univariable hazard ratio [HR] = 1.39, 95% CI = 1.01-1.90, P =.04; multivariable HR = 1.50, 95% CI = 1.02-2.21, P =.04). An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively. CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.
BMRK-11 REAL-WORLD EXPERIENCE WITH CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID IN PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS
Authors: Hickman Richard , Miller Alexandra M , Holle Bridget M , Jee Justin , Liu Si-Yang , Ross Dara , Yu Helena , Riley Gregory J , Ombres Christina , Gewirtz Alexandra , Reiner Anne S , Nandakumar Subhiksha , Price Adam , Kaley Thomas J , Graham Maya S , Vanderbilt Chad , Rana Satshil , Hill Katherine , Chabot Kiana , Campos Carl , Nafa Khedoudja , Shukla Neerav , Karajannis Matthias , Li Bob , Berger Michael , Ladanyi Marc , Pentsova Elena , Boire Adrienne , Brannon A Rose , Bale Tejus , Mellinghoff Ingo K , Arcila Maria E 
Published: August 2024

Abstract
Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) offers a minimally invasive approach to identify somatic alterations for individuals with central nervous system (CNS) cancers. Here, we review our ‘real world’ experience using a clinically validated, FDA-authorized platform, MSK-IMPACTTM, to comprehensively profile ctDNA from CSF samples with and without clinically documented CNS involvement by cancer (1007 samples, 711 patients). The patient cohort included patients with over 90 distinct tumor types of primary CNS and metastatic origin, with lung cancer (n = 188), breast cancer (n = 150), and glioma (n = 148) representing the most common broad categories. We identified genetic alterations (ctDNA-positive) in 489/922 (53.0%) CSF samples from patients with clinically documented CNS cancer. Over half of these ctDNA-positive samples (248, 50.7%) possessed a biomarker that was predictive of response to an FDA-approved drug (OncoKB level 1). Furthermore, the distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Of patients without clinical documentation of CNS cancer, none of these 85 CSF samples were ctDNA-positive (specificity = 100%). Successive CSF sequencing over time identified clonal evolution and the emergence of resistance mechanisms to therapies. ctDNA positivity corresponded with shortened overall survival after CSF collection (HR: 3.23, 95% CI: 2.58-4.05, P &lt; 0.001). NGS of CSF cfDNA can detect clinically actionable somatic alterations in a large subset of CNS cancer patients and allows tracking of tumor evolution. Detection of somatic alterations in CSF may be a useful prognostic biomarker for survival in cancer patients.