bluuebunny/crossref_metadata_2025_split huggingface dataset:
A numerical study of near-Earth asteroid family orbital dispersion
Authors: Humpage A , Christou A A 
Published: August 2024

ABSTRACT
We have studied the evolution of near-Earth asteroid (NEA) families and pairs to inform future searches. To do so, we integrated clusters of simulated NEAs with different initial conditions, namely the orbital inclination, ejection speed, and the effects of mean-motion resonances on the parent body prior to breakup while also varying the orbit, mass, and number of perturbing planetary bodies. We studied the orbital element dispersion rates of NEA family members and found a power-law increase in those families whose orbits brought them close to a planet. This allowed us to conclude that family dispersion is significantly affected by the Kozai–Lidov effect due to oscillations in the eccentricity, and that the rate of dispersion is slowest at high inclination relatively far from the nearest planet. In most cases, the ejection speed of the initial breakup does not affect the dispersion, except within weaker mean-motion resonances where more violent breakups will result in the ejection of a fraction of the asteroids, causing a large increase in dispersion. Within mean-motion resonances, where Kozai–Lidov oscillations are slowed, increases in the dispersion of a family are delayed, leading them to be identifiable for longer.
A comparative study of radio signatures from winds and jets: modelling synchrotron emission and polarization
Authors: Meenakshi Moun , Mukherjee Dipanjan , Bodo Gianluigi , Rossi Paola , Harrison Chris M 
Published: August 2024

ABSTRACT
Outflows driven by active galactic nuclei (AGNs) are seen in numerous compact sources; however, it has remained unclear how to distinguish between the driving mechanisms, such as winds and jets. Therefore, our study aims to offer observational insights from simulations to aid in this distinction. Specifically, in this paper, we investigate the evolution of wide-angled moderately relativistic magnetized winds and analyse their non-thermal radio emission and polarization properties. We find that the evolution of winds varies depending on factors such as power, density, and opening angle, which in turn influence their observable characteristics. Additionally, different viewing angles can lead to varying observations. Furthermore, we note distinctions in the evolution of winds compared to jets, resulting in disparities in their observable features. Jets typically exhibit a thin spine and hotspot(s). Winds manifest broader spines or an ‘hourglass-shaped’ bright emission in the cocoon, which are capped by bright arcs. Both display high polarization coinciding with the bright spine and hotspots/arcs, although these regions are relatively compact and localized in jets when compared to winds. We emphasize the importance of high resolution, as we demonstrate that emission features from both jets and winds can become indistinguishable at lower resolutions. The distribution of polarization is largely unaffected by resolution, though lower polarization becomes more noticeable when the resolution is decreased.
New onset of giant cell arteritis with ischaemic optic neuropathy following the seventh dose of COVID-19 mRNA vaccination: A case report and literature review
Authors: Ohmura Shin-ichiro , Yonezawa Haruka , Yukishima Toshitaka , Gohto Yuko , Obana Akira 
Published: August 2024

ABSTRACT
Coronavirus disease (COVID-19) vaccines have demonstrated excellent efficacy in reducing the morbidity and severity of the disease. However, some patients have been reported to develop systemic rheumatic diseases, such as rheumatoid arthritis, myocarditis, Guillain-Barre syndrome, and giant cell arteritis (GCA) following COVID-19 vaccination. We present a case of GCA with ischaemic optic neuropathy following COVID-19 mRNA vaccination. A 73-year-old woman developed headache, myalgia, scalp tenderness, and jaw claudication 4 days after her seventh dose of the vaccination; she also developed severe visual disturbances 1 month after the vaccination. The blood examination tests showed an increased serum C-reactive protein level and erythrocyte sedimentation rate. The echogram for the temporal artery showed a halo sign. Ophthalmic examination revealed ischaemic optic neuropathy in both eyes. The patient was treated with a high-dose glucocorticoid and tocilizumab under the diagnosis of GCA with ischaemic optic neuropathy, obtaining mild improvement of the symptoms. This report underscores the need for clinical vigilance and further data collection regarding GCA cases after COVID-19 vaccination.
BSBM-01 THE ROLE OF SEROTONERGIC RECEPTOR, HTR2B IN THE BRAIN METASTASIS FROM A CANCER NEUROSCIENCE PERSPECTIVE
Authors: Neman Josh , Iyer Mukund 
Published: August 2024

Abstract
Greater than 12% of cancer patients develop brain metastases and median survival remains an abysmal 4-6 months. Throughout the metastatic cascade, tumor cells attract and reprogram stromal cells, such as myeloid derived suppressor cells (MDSCs), which support cancer growth by promoting tissue remodeling, EMT, invasion, immunosuppression, angiogenesis. Once tumor cells have breached the brain’s CNS defenses, infiltrating immune cells can penetrate the glia limitans and enter the CNS parenchyma to help establish the brain metastatic niche. However, there is scant understanding of MDSC’s contribution to the brain metastatic microenvironment. The brain metastatic environment is particularly unique because CNS-resident cells such as microglia, astrocytes, choroid plexus, and neurons function as local mediators to alter invading immune cell plasticity and differentiation. We now demonstrate that MDSCs in the brain environment upregulate the serotonergic receptor, HTR2B, to increase levels of pNF-κB and its associated signaling genes (IL-6, IL-1B, COX2, CXCL2, NOS2). HTR2B modulation in MDSCs alters their pNF-κB activation and downregulates expression of pNF-κB signaling genes. Additionally, MDSCs in this environment support tumor cell proliferation while hindering their acquisition of neuronal traits. A better understanding of the role of HTR2B in brain metastasis may allow us to develop new treatment strategies for patients of this devastating disease.
BSBM-03 TARGETABLE GENE EXPRESSION CHANGES MEDIATE EXTRAVASATION OF BREAST CANCER CELLS FROM THE CIRCULATION AND LOCAL PROLIFERATION IN THE BRAIN
Authors: Kalistratova Venina , Morshed Ramin , Chalif Eric , Gill Sabraj , Khela Harmon , Lad Meeki , Sati Ankita , Mathur Aakriti , Aghi Manish 
Published: August 2024

Abstract
As breast cancer migrates into the brain, it acquires distinct genomic, immunologic and phenotypic changes through interactions with the local microenvironment. We sought to determine how targetable gene expression changes mediate breast cancer extravasation into and proliferation within the brain. We created a brain metastatic cell line (“brain-seeking”) via serial intracardiac injection of mCherry+ 4T1 breast cancer cells in Balb/c mice and flow cytometry isolation of micrometastases. We conducted in vitro and in-vivo studies to uncover immunological and genetic differences between primary breast cancer and brain metastases. In culture, we observed significant upregulation in adhesion (p=0.01) and invasion (p=0.0004) along with upregulation of adhesion-promoting genes such as Sdc3, Serpine2 or ECM1 in the brain-seeking cells. We observed significant differences in survival of Balb/c mice injected intracranially with brain-seeking cells compared to the 4T1 breast cancer cells (p=0.04). In the mammary fat pad (MFP), parental 4T1 cells caused increased mortality compared to brain-seeking cells (p=0.003). This rejection of brain-seeking 4T1 cells in the MFP could be due to their prior adaptation to the brain microenvironment, while rejection of parental 4T1 cells in the brain microenvironment could be due to them lacking those adaptations. Consistent with this finding, of 20,382 analyzed genes in both cell lines, 108 related to immune regulation were significantly upregulated in brain-seeking cells including Cxcl1, Dusp1, C3. Flow cytometry showed increased cytotoxic and helper T cells in intracranially injected parental 4T1 cells vs. brain-seeking cells (p &lt;0.001). In the MFP, however, 4T1 parental cells displayed CD3+ T cell depletion and an increased number of neutrophils (p &lt;0.05) while the “brain-seeking cells” showed increased numbers of CD3+ and CD4+ cells (p &lt;0.01) and macrophages (p&lt;0.05). These findings suggest that brain metastases evolve from their primary tumor through adhesive and invasive adaptations promoting extravasation, along with unique immunological adaptations that allow them to proliferate free of immune surveillance in the brain microenvironment.
BSBM-06 SINGLE-CELL SPATIAL ANALYSIS OF METASTATIC BRAIN TUMORS REVEALS INTRACELLULAR BACTERIAL SIGNAL AND THEIR CORRELATION WITH THE TUMOR MICROENVIRONMENT
Authors: Morad Golnaz , Damani Ashish , Melendez Brenda , Singh Bharat , Wong Matthew , Sahasrabhojane Pranoti , Hoballah Yasmine , Veguilla Fabiana , Losh Jillian , Ajami Nadim , Ferguson Sherise , Wargo Jennifer 
Published: August 2024

Abstract
Metastatic brain tumors are associated with significant morbidity and mortality. Recent trials have demonstrated the potential efficacy of immunotherapy for the management of brain metastasis (BrM), albeit in only a subset of patients. Understanding the BrM microenvironment and identifying the factors that shape this complex milieu can facilitate optimizing treatment strategies for this disease. The microbiome has been recognized as a hallmark of cancer with a major role in shaping response to immunotherapy. However, the role of the microbiome in BrM is largely unknown. We have previously reported that bacterial signals can be detected in BrM tumors via metagenomic analyses and staining. Here we present the spatial correlation between the intra-tumoral bacterial signal and the transcriptional changes in the tumor microenvironment. Tissue digital spatial profiling (DSP) and single-cell DSP were conducted on BrM tissue microarrays using the NanoString GeoMx® and CosMx® platforms, respectively. These assays incorporated a custom panel of pan-bacterial 16S rRNA probes, enabling a comparison between tumor regions and cells that showed a positive signal for bacterial 16S rRNA versus those that did not. DSP of BrM tumors revealed anti-bacterial responses and enrichment of innate immune activity in areas with 16S signal, suggesting an active host response to intra-tumoral 16S signals. Furthermore, single-cell DSP demonstrated a heterogenous distribution of cell types harboring the 16S signal in the tumor microenvironment. In tumor cells, intracellular 16S signal was associated with an upregulation of transcripts related to neuroinflammation, chemokine, and interleukin signaling. Furthermore, immune transcriptional changes were identified in the immediate neighborhood of 16S-positive cells. Overall, this study introduces bacterial signals as a novel element within metastatic brain tumors and demonstrates their association with anti-bacterial responses and immune activity. These findings set the foundation for future mechanistic and translational studies to evaluate microbiome modulation strategies in enhancing care for brain metastasis.
BSBM-08 FGFR1 PROMOTES ER+ BREAST CANCER BRAIN METASTASIS AND MODULATES INTERACTIONS WITH NEURONS
Authors: Fox Morgan , Jaramillo-Gomez Jenny A , Alvarez-Eraso Karen L F , Contreras-Zarate Maria J , Koliavas Stella , Sartorius Carol , Kabos Peter , Wellberg Elizabeth , Cittelly Diana 
Published: August 2024

Abstract
While triple-negative and HER2+ breast cancer (BC) have higher rates of brain metastasis (BM), BM affect 16% of metastatic ER+ BC patients, and often occur in older or post-menopausal women. Preclinical models of ER+ BCBM require exogenous estrogen (E2) supplementation and are often performed in young mice. Hence, lack of clinically relevant models mimicking the progression of BM in the E2-deprived or aged microenvironment has hindered a better understanding of the mechanisms underlying ER+ BM. FGFR1-amplification is the only genomic alternation shown to predict increased risk of late metastatic recurrence in anti-estrogen-treated ER+ BC, paracrine activation of FGFR1 has been shown to promote tumor progression of ER+ BC in postmenopausal mouse models, and canonical FGF2/FGFR1 signaling decreases in the brain with aging. Thus, we hypothesize that FGFR1 plays non-canonical functions in the brain TME that support ER+ BCBM in the aged/E2-depleted brain TME. To define the dependency on E2 and aging, UCD65 (ER+ PDX, FGFR1-amp-14x) cells were intracardially injected into young-OVX mice (&lt;14weeks), young-OVX mice +E2, and aged-naïve mice (52+weeks), and metastases quantified via IVIS. In young mice, E2 promoted BM in 61% mice compared to 0% in OVX mice. By contrast, 38% of aged-naïve mice presented BM, suggesting increased promotion of BM in aged mice. BMs in aged-naïve mice did not result from low E2 levels, as independent studies showed similar incidence of BM in aged-naïve vs aged-OVX mice. FGFR1 knockdown in UCD12 (ER+ PDX, FGFR1-amp-12x) and UCD65 did not alter proliferation alone in vitro, but reduced growth in organotypic coculture and decreased BM colonization and outgrowth in vivo in aged mice. Mechanistically, FGFR1 KD decreased density of synapses (punctate colocalization PSD95 and Synapsin) in UCD65 spheres plated with organotypic brain slices. Ongoing studies are defining the role of neuronal activity to promote FGFR1-dependent colonization of ER+ BCBM.
BSLM-04 INTRATHECAL DELIVERY OF PEPTIDE-PULSED TYPE 1 CONVENTIONAL DENDRITIC CELL VACCINE IS HIGHLY EFFICACIOUS FOR THE TREATMENT OF BREAST CANCER-ASSOCIATED LEPTOMENINGEAL DISEASE IN PRECLINICAL MODELS
Authors: Law Vincent , Snyder Colin , Chen Zhihua , Kalinski Pawel , Czerniecki Brian , Forsyth Peter 
Published: August 2024

Abstract

BACKGROUND
Approximately 5% of advanced stage breast cancer (BC) will develop leptomeningeal disease (LMD), a rare form of metastasis in the meninges. The prognosis for LMD is dismal and current treatments are ineffective. Here, we found intrathecal (IT) delivery of MHC class II peptide-pulsed conventional Type 1 dendritic cells (cDC1s) could cure mice harbouring either HER2+ or triple negative breast cancer (TBNC) LMD. The data from our preclinical studies led to a Phase 1 clinical trial of cDC1s in HER2+ and TNBC LMD (NCT05809752; in progress).

METHODS
We created a “murine Ommaya” that mimics the clinically used Ommaya reservoir and allows for repeated IT injections of novel drugs at 3 – 7ml volume directly into the cerebral spinal fluid (CSF). A pipeline was developed for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and using these targets we generated tumor-targeting cDC1 vaccine. We tested the efficacy of this therapy in murine BC-LMD by administering through the murine Ommaya.

RESULTS
We found cDC1 vaccine was highly effective against HER2+ LMD and TNBC-LMD; LMD mice that received IT cDC1s had reduced tumour burden and prolonged survival. Complete responses to treatment ranged between 30 - 70% in HER2+ LMD and TNBC-LMD and were CD4+ T cell and B cell dependent. Notably, some cured mice were protected against LMD reinoculation. Subsequent single cell RNA-sequencing analyses of pre- and post-treatment CSF revealed an adaptive change in the immune cellular landscape. We noted an elevation of Th1 proinflammatory cytokines such as IFN-g in the CSF. This was recapitulated in the CSF samples of patients enrolled in an on-going phase 1 trial, where early data showed IT cDC1 vaccine triggered a dramatic increase in the concentration of several proinflammatory Th1 cytokines.

CONCLUSIONS
IT cDC1 vaccine is effective against BC-LMD and prevents LMD recurrence. A future approach includes testing IT cDC1 platform in LMD from other cancers (e.g. melanoma etc.).
BSLM-10 MOLECULAR AND HISTOLOGICAL CHARACTERIZATION OF NSCLC PROGRESSION TO LEPTOMENINGEAL METASTASIS WITH COMORBID INTRAPARENCHYMAL DISEASE
Authors: Kandigian Savannah E , Chande Sampada , Dolezal Darin , Tang Tang , Wang Dejiang , Arnal-Estapé Anna , Cheok Stephanie K , McGuone Declan , Liu Yang , Goldberg Sarah B , Blondin Nicholas A , Chiang Veronica L , Nguyen Don X 
Published: August 2024

Abstract
Leptomeningeal disease (LMD) is a rare form of central nervous system (CNS) metastasis wherein tumor cells invade the cerebrospinal fluid (CSF) filled space that surrounds the brain and spinal cord. For patients with LMD, prognosis is extremely poor even with aggressive treatment. The mechanisms of progression to LMD and the adaptations tumor cells make to survive in this metabolically sparse microenvironment are poorly understood. As 60% of patients with LMD have concurrent or prior parenchymal metastases, our laboratory examined our established murine models of parenchymal metastases for signs of leptomeningeal infiltration. We identify two xenograft non-small cell lung cancer (NSCLC) models of intraparenchymal metastasis following intra-arterial injection that show progression to LMD in a subset of cases. In the H2030-BrM3 model, this occurs de novo, whereas the EGFR-mutant PC9-R2 model progresses to LMD only following onset of resistance to tyrosine kinase inhibitor treatment. Subsequent in vivo passaging of the H2030-BrM3 line through the cerebral lateral ventricles resulted in the H2030-LMD2 cell line, which has high affinity for leptomeningeal metastases and shows extensive perivascular invasion within the brain parenchyma. In vitro, the H2030-LMD2 line shows altered clustering behavior and increased survival when cultured in suspension. RNA-sequencing of this cell line across adherent and suspension culture conditions shows multiple biological processes upregulated in the LMD-tropic line, including chemotaxis, apical junction formation, and TGF-β signaling. Targetable pathways emerging from this analysis will be functionally investigated for their role in promoting progression to LMD, including through validation in the syngeneic KPN1-BrM line which has been selected for its CNS affinity and shows progression to LMD. Spatial sequencing and multiplexed immunofluorescence will furthermore investigate the tumor microenvironment in the perivascular niche and subarachnoid spaces. These findings will be clinically corroborated with molecular characterization of the CSF of patients with leptomeningeal metastases.
BSLM-11 ESTABLISHING AND VALIDATING IN VIVO MODELS FOR LEPTOMENINGEAL METASTASES IN BREAST CANCER: INSIGHTS AND THERAPEUTIC IMPLICATIONS
Authors: Kumar Dinesh , Silvestri Vanesa , Robinson Christina , Difilippantonio Simone , Steeg Patricia 
Published: August 2024

Abstract
Leptomeningeal metastases (LM), characterized by cancer cell growth in the linings of the brain and spinal cord, and the cerebrospinal fluid (CSF) compartment, have a dire prognosis represent 5-15% of central nervous system metastases. LM occur in all subclasses of breast cancer and are currently treated with intrathecal methotrexate or liposomal cytarabine or radiation therapy. Despite initial response to current treatments, median survival remains poor. Relatively little is known on the development of LM, due to the lack of adequate mouse models. This study aimed to develop and validate in vivo models of LM and to use them to credential potential therapies. Three breast cancer models were established using intracisternal injections of tumor cells covering the HER2+, ER+ lobular and triple negative breast cancer subtypes. The HER2+ model was produced from the JIMT-1-BR cell line that previously was enriched for metastasis to the brain parenchyma, reflecting clinical observations of concurrent parenchymal and LM spread. Multiple endpoints were implemented to assess disease progression: bioluminescence imaging, histopathology, MRI, tumor cells in CSF. Bulk RNA sequencing on all LM-tropic cell lines revealed significant alterations in cytokine-cytokine receptor interactions, calcium signaling pathways, cell adhesion molecules, and TNF signaling pathways across all models. Notably, several genes including PORCN, PGBD5, FAM43A and FHOD3 were differentially expressed and consistently alter across all models. Validation of these key genes is underway. For the JIMT-1-BR HER2+ model, efficacy studies compared standard therapy (trastuzumab + paclitaxel) with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). T-DXd (10 mg/kg, iv q3w) demonstrated superior efficacy with extended survival and reduced extent of edema on MRI. This study established and validated three in vivo models of LM colonization. These models, incorporating diverse endpoints, and drug testing capabilities, offer a valuable platform for identifying novel therapeutic strategies to combat this aggressive form of breast cancer progression.
BMRK-04 EFFECT OF PRIMARY CANCER SITE AND EXTRACRANIAL PROGRESSION ON DEVELOPMENT OF BRAIN METASTASES IN PATIENTS TREATED WITH STEREOTACTIC BODY RADIOTHERAPY FOR OLIGOMETASTATIC SOLID TUMORS
Authors: Fan Kevin Yijun , Jerzak Katarzyna , Kumar Sudhir , Moravan Veronika , Said Badr Id , Das Sunit , Louie Alexander , Soliman Hany , Sahgal Arjun , Chen Hanbo 
Published: August 2024

Abstract

BACKGROUND
Patients with oligometastatic disease (OMD) may achieve long-term control with stereotactic body radiation therapy (SBRT). However, those who develop brain metastases (BrM) often have poor outcomes. We aimed to investigate variables associated with development of BrM in this population.

METHODS
Patients with ≤5 extracranial metastases from solid tumors treated with SBRT from 2008-2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis with death as a competing risk, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between widespread extracranial progression (≥5 sites) and CIBrM using a time-based conditional competing-risks analysis.

RESULTS
Among 404 patients, the most common primary sites were lung (32%), colorectal (26%), prostate (13%), breast (10%) and kidney (7%). Median follow-up was 49 months. Median PFS was 25 months and median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. The 5-year CIBrM was highest among patients with breast cancer (22%), lung cancer (15%) and kidney cancer (15%), and lowest among those with colorectal cancer (5%) and prostate cancer (0%). On multivariable analysis, primary site was associated with CIBrM (p&lt;0.001), with colorectal cancer (HR 0.34) and prostate cancer (HR 0.00) associated with lower CIBrM compared to lung cancer. Time from primary diagnosis to OMD, number of extracranial metastases, location of metastases, and total planning target volume (PTV) were not associated with CIBrM. Development of widespread extracranial progression within 24 (HR 4.1, p=0.004), 36 (HR 3.7, p=0.013), 48 (HR 5.9 p=0.009) and 60 (HR 23, p=0.017) months of OMD diagnosis was independently associated with higher CIBrM.

CONCLUSIONS
Primary site and extracranial progression, but not baseline measures of OMD volume and distribution, are associated with development of BrM in patients with OMD treated with SBRT.