bluuebunny/crossref_metadata_2025 huggingface dataset:
Peekaboo! The Effect of Different Visible Cash Display and Amount Options During Mail Contact When Recruiting to a Probability-Based Panel
Authors: Bilgen Ipek , Dutwin David , Singh Roopam , Hendarwan Erlina
Published: November 2023

Recent studies consistently showed that making cash visible with a windowed envelope during mail contact increases response rates in surveys. The visible cash aims to pique interest and encourage sampled households to open the envelope. This article extends prior research by examining the effect of additional interventions implemented during mail recruitment to a survey panel on recruitment rates and costs. Specifically, we implemented randomized experiments to examine size (small, large) and location (none, front, back) of the window displaying cash, combined with what part of the cash is shown through the window envelope (numeric amount, face/image), and various prepaid incentive amounts (two $1, one $2, one $5). We used the recruitment effort for NORC’s AmeriSpeak Panel as the data source for this study. The probability-based AmeriSpeak Panel uses an address-based sample and multiple modes of respondent contact, including mail, phone, and in-person outreach during recruitment. Our results were consistent with prior research and showed significant improvement in recruitment rates when cash was displayed through a window during mail contact. We also found that placing the window on the front of the envelope, showing $5 through the envelope compared to $2 and $1, and showing the tender amount compared to the image on the cash through the window were more likely to improve the recruitment rates. Our cost analyses illustrated that the cost difference in printing window versus no window envelope is small. There is no difference in printing cost between front window and back window as they both require custom manufacturing. There is also no cost difference in printing envelopes with small windows versus large windows. Lastly, we found no evidence of mail theft based on our review of the United States Postal Service’s “track and trace” reports, seed mailings sent to staff, and undeliverable mailing rates.
Evaluation of Electron Tomography Capabilities for Shale Imaging
Authors: Frouté Laura , Boigné Emeric , Jolivet Isabelle C , Chaput Eric , Creux Patrice , Ihme Matthias , Kovscek Anthony R
Published: November 2023

Despite the advantageous resolution of electron tomography (ET), reconstruction of three-dimensional (3D) images from multiple two-dimensional (2D) projections presents several challenges, including small signal-to-noise ratios, and a limited projection range. This study evaluates the capabilities of ET for thin sections of shale, a complex nanoporous medium. A numerical phantom with 1.24 nm pixel size is constructed based on the tomographic reconstruction of a Barnett shale. A dataset of 2D projection images is numerically generated from the 3D phantom and studied over a range of conditions. First, common reconstruction techniques are used to reconstruct the shale structure. The reconstruction uncertainty is quantified by comparing overall values of storage and transport metrics, as well as the misclassification of pore voxels compared to the phantom. We then select the most robust reconstruction technique and we vary the acquisition conditions to quantify the effect of artifacts. We find a strong agreement for large pores over the different acquisition workflows, while a wider variability exists for nanometer-scale features. The limited projection range and reconstruction are identified as the main experimental bottlenecks, thereby suggesting that sample thinning, advanced holders, and advanced reconstruction algorithms offer opportunities for improvement.
Infelicitous Conditionals and KK
Authors: Hawthorne John , Isaacs Yoaav
Published: November 2023

Kevin Dorst (2019) uses the ‘manifest unassertability’ of conditionals of the form ‘If I don’t know p, then p’ as a new motivation for the KK thesis. In this paper we show that his argumentation is misguided. Plausible heuristics offer a compelling and nuanced explanation of the relevant infelicity data. Meanwhile, Dorst relies on tools that, quite independently of KK, turn out to be rather poor predictors of the infelicity of indicative conditionals.
Photodissociation cross sections and rates of NaO
Authors: Bai Tianrui , Yang Xinglin , Qin Zhi , Liu Linhua
Published: November 2023

Photodissociation of NaO may be important for the sodium chemistry in various astrophysical regions. This work produces the photodissociation cross sections and rates of NaO over the temperature range from 0 to 15 000 K. First, the state-resolved cross sections for transitions from the ground and first excited states of NaO are investigated using ab initio potential energy curves and transition dipole moments. The temperature-dependent cross sections were then obtained by assuming a Boltzmann distribution to describe the population of the initial state. Detailed comparisons with experimental cross sections at 200 and 300 K reveal that the X 2Π → 1 2∆ and X 2Π → 2 2Σ− transitions may be the main photodissociation pathways for NaO in the wavelengths of about 2400–2580 Å, while the X 2Π → B 2Σ− transition may play a dominant role in the wavelengths of about 3534–4230 Å. Finally, photodissociation rates in the interstellar, solar, and blackbody radiation fields were determined. In the interstellar and solar radiation fields, the X 2Π → B 2Σ− transition dominates at low temperatures and the A 2Σ+ → 2 2Σ+ transition dominates at high temperatures. The total photodissociation rates in ultraviolet-rich and visible-rich radiation fields are almost insensitive to the temperature. The photodissociation cross sections and rates of NaO should be useful for investigating the chemical evolution of the sodium element in planetary exospheres, atmospheres of cool stars, and envelopes of evolved stars.
B/PS bulges and barlenses from a kinematic viewpoint – II
Authors: Zakharova Daria , Tikhonenko Iliya S , Sotnikova Natalia Ya , Smirnov Anton A
Published: November 2023

Internal dynamics and kinematics of galaxies have imprints on the line-of-sight velocity distribution (LOSVD). Gauss–Hermite parametrization allows one to identify the kinematics features of the system in terms of skewness (h3) and broadness (h4) deviations of an LOSVD. Such a method provides information about the type of orbits since a $h_3\!-\!\overline{V}$ correlation is a sign of elongated orbits, and the anticorrelation is a sign of circular or near-circular orbits. In previous works, analysis of the $h_3\!-\!\overline{V}$ relation provided a tool to identify a hidden bar or B/PS bulge (edge-on, PA = 90°) and to probe their strength. We prepared two N-body galaxy models with clear B/PS bulges: one has an ordinary bar (the X model), and the second one has a barlens embedded into a bar (the BL model) to investigate the mechanism of formation of h3 features at any position of an observer. We show that the $h_3\!-\!\overline{V}$ correlation appears in the regions where bar and disc particles are mixing. We also reveal that the model with a barlens has an $h_3\!-\!\overline{V}$ anticorrelation in the centre, and we show that barlens-specific orbits are responsible for this signal. Moreover, this feature can be observed only for galaxies with compact bulges and barlenses. The results of this work are applicable for the interpretation of future integral-field unit (IFU) data for real galaxies with B/PS bulges, especially for objects with barlenses.
Redefining the Evolutionary History of the Rock Dove, Columba livia, Using Whole Genome Sequences
Authors: Hernández-Alonso Germán , Ramos-Madrigal Jazmín , van Grouw Hein , Ciucani Marta Maria , Cavill Emily Louisa , Sinding Mikkel-Holger S , Gopalakrishnan Shyam , Pacheco George , Gilbert M Thomas P
Published: November 2023

The domestic pigeon's exceptional phenotypic diversity was key in developing Darwin's Theory of Evolution and establishing the concept of artificial selection. However, unlike its domestic counterpart, its wild progenitor, the rock dove Columba livia has received considerably less attention. Therefore, questions regarding its domestication, evolution, taxonomy, and conservation status remain unresolved. We generated whole-genome sequencing data from 65 historical rock doves that represent all currently recognized subspecies and span the species’ original geographic distribution. Our dataset includes 3 specimens from Darwin's collection, and the type specimens of 5 different taxa. We characterized their population structure, genomic diversity, and gene-flow patterns. Our results show the West African subspecies C. l. gymnocyclus is basal to rock doves and domestic pigeons, and suggests gene-flow between the rock dove's sister species C. rupestris, and the ancestor of rock doves after its split from West African populations. These genomes allowed us to propose a model for the evolution of the rock dove in light of the refugia theory. We propose that rock dove genetic diversity and introgression patterns derive from a history of allopatric cycles and dispersion waves during the Quaternary glacial and interglacial periods. To explore the rock dove domestication history, we combined our new dataset with available genomes from domestic pigeons. Our results point to at least 1 domestication event in the Levant that gave rise to all domestic breeds analysed in this study. Finally, we propose a species-level taxonomic arrangement to reflect the evolutionary history of the West African rock dove populations.
Human follicular fluid elicits select dose- and age-dependent effects on mouse oocytes and cumulus–oocyte complexes in a heterologous in vitro maturation assay
Authors: Dipali Shweta S , Suebthawinkul Chanakarn , Burdette Joanna E , Pavone Mary Ellen , Duncan Francesca E
Published: November 2023

Follicular fluid (FF) is a primary microenvironment of the oocyte within an antral follicle. Although several studies have defined the composition of human FF in normal physiology and determined how it is altered in disease states, the direct impacts of human FF on the oocyte are not well understood. The difficulty of obtaining suitable numbers of human oocytes for research makes addressing such a question challenging. Therefore, we used a heterologous model in which we cultured mouse oocytes in human FF. To determine whether FF has dose-dependent effects on gamete quality, we performed in vitro maturation of denuded oocytes from reproductively young mice (6–12 weeks) in 10%, 50%, or 100% FF from participants of mid-reproductive age (32–36 years). FF impacted meiotic competence in a dose-dependent manner, with concentrations >10% inhibiting meiotic progression and resulting in spindle and chromosome alignment defects. We previously demonstrated that human FF acquires a fibro-inflammatory cytokine signature with age. Thus, to determine whether exposure to an aging FF microenvironment contributes to the age-dependent decrease in gamete quality, we matured denuded oocytes and cumulus–oocyte complexes (COCs) in FF from reproductively young (28–30 years) and old (40–42 years) participants. FF decreased meiotic progression of COCs, but not oocytes, from reproductively young and old (9–12 months) mice in an age-dependent manner. Moreover, FF had modest age-dependent impacts on mitochondrial aggregation in denuded oocytes and cumulus layer expansion dynamics in COCs, which may influence fertilization or early embryo development. Overall, these findings demonstrate that acute human FF exposure can impact select markers of mouse oocyte quality in both dose- and age-dependent manners.
Diagnostic standard: assessing glomerular filtration rate
Authors: Delanaye Pierre , Pottel Hans , Cavalier Etienne , Flamant Martin , Stehlé Thomas , Mariat Christophe
Published: November 2023

Creatinine-based estimated glomerular filtration rate (eGFR) is imprecise at individual level, due to non-GFR-related serum creatinine determinants, including atypical muscle mass. Cystatin C has the advantage of being independent of muscle mass, a feature that led to the development of race- and sex-free equations. Yet, cystatin C–based equations do not perform better than creatinine-based equations for estimating GFR unless both variables are included together. The new race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation had slight opposite biases between Black and non-Black subjects in the USA, but has poorer performance than that the previous version in European populations. The European Kidney Function Consortium (EKFC) equation developed in 2021 can be used in both children and adults, is more accurate in young and old adults, and is applicable to non-white European populations, by rescaling the Q factor, i.e. population median creatinine, in a potentially universal way. A sex- and race-free cystatin C–based EKFC, with the same mathematical design, has also be defined. New developments in the field of GFR estimation would be standardization of cystatin C assays, development of creatinine-based eGFR equations that incorporate muscle mass data, implementation of new endogenous biomarkers and the use of artificial intelligence. Standardization of different GFR measurement methods would also be a future challenge, as well as new technologies for measuring GFR. Future research is also needed into discrepancies between cystatin C and creatinine, which is associated with high risk of adverse events: we need to standardize the definition of discrepancy and understand its determinants.
ANGI-02. CELL MIGRATION SIMULATOR-BASED BIOMARKERS FOR GLIOBLASTOMA
Authors: Hou Jay , McMahon Mariah , Jubenville Tyler , Chen Clark , Sarkaria Jann , Odde David
Published: November 2023

Glioblastoma is the most aggressive malignant brain tumor with the poor survival due to its invasive nature driven by cell migration. There is still no effective treatment targeting glioma cell migration based on their transcriptomic information, due to the lack of understanding in the links to the fundamental mechanics of cell migration. In the previous studies, we developed a physics-based motor-clutch model, the cell migration simulator (CMS), to identify the basic mechanisms of cell migration in various cell types. In this study, we found that glioblastoma patient-derived (xenograft) (PD(X)) cell lines across mesenchymal (MES), proneural (PN), classical (CL) subtypes and two institutions (N = 13 patients) had optimal motility and traction force on stiffnesses around 9.3kPa, with otherwise heterogeneous and uncorrelated motility, traction, and F-actin flow. We applied the CMS as a consistent framework to describe the physical parameters of glioblastoma patient cell migration. Using single cell migration and force generation data on compliant 2D surfaces, we found all glioma PD(X) lines (11 patients) had balanced myosin/adhesion ratios resulting in effective migration. Mesenchymal (MES) lines had enhanced F-actin polymerization resulting in higher motility. Adherent PDX lines had increased myosin-adhesion amount resulting in higher traction force. The CMS also predicted the differential cell migration under cytoskeletal drugs between glioma subtypes. Finally, we found 18 genes in actin cytoskeleton and focal adhesion pathways significantly correlated with the glioma physical parameters, which were being used to estimate the physical parameters of a larger cohort (66 patients) and to strategize targeting their cell migration. Overall, we described a consistent physics-based framework for parameterizing individual glioblastoma patients, connecting to clinical transcriptomic data, and predicting drug effects, that can potentially be used to develop subtype and patient-specific anti-migratory therapeutic strategies.
ANGI-03. NOVEL ROLE OF ENDOTHELIAL CELL AQUAPORIN-1 IN GLIOBLASTOMA VASCULAR PERMEABILITY AND TUMOR-ASSOCIATED EDEMA
Authors: Cleveland Abigail , Huang Menggui , Fan Yi
Published: November 2023

Glioblastomas are the most common malignant brain tumors in adults, with a median survival of only 12-15 months. Glioblastomas are marked by an aberrant, leaky vasculature that promotes a hypoxic, immunosuppressive microenvironment. This aberrant vascularity not only affects treatment sensitivity but the integrity of the blood brain barrier (BBB). Disruption of the BBB can lead to increased flow of water into intercellular spaces, causing vasogenic edema. Increased intracranial pressure due to vasogenic edema in glioblastoma patients is a significant cause of morbidity and mortality. Severity of edema not only correlates with patient survival, but causes numerous harmful side effects, such as aphasia, cognitive decline, and acute herniation syndrome. Currently, the mainstay of treatment for brain tumor edema is glucocorticosteroids, such as dexamethasone. However, this treatment causes immune suppression and severe long-term adverse effects. To determine the potential role of vascular endothelial cells (ECs) in edema formation, we performed single cell RNAseq on a genetically engineered glioblastoma mouse model, which recapitulates the edema seen in human patients. We found that ECs from glioblastomas and normal brain tissue had distinct expression patterns, with selective expression of a water channel protein called Aquaporin-1 (AQP1) in glioblastoma ECs. In addition, siRNA-mediated AQP1 knockdown decreased GBM EC monolayer permeability. Inhibiting the water channel function of AQP1 alone through Bacopaside II treatment, however, did not alter EC monolayer permeability. Several tight junctions are downregulated in GBM ECs compared to normal brain ECs, and knocking down AQP1 via siRNA restored expression of the tight junction protein Claudin-5. These data suggest that AQP1 induces brain tumor edema by inhibiting tight junction protein expression via its non-water-channel function and that targeting AQP1 in glioblastoma ECs would be a novel therapeutic strategy to improve the BBB and decrease edema levels in vivo.
ANGI-08. COMPREHENSIVE ANALYSIS OF MECHANISM OF GLIOBLASTOMA INVASION USING PATIENT DERIVED XENOGRAFT MODELS
Authors: Kijima Noriyuki , Tachi Tetsuro , Kuroda Hideki , Murakami Koki , Hirayama Ryuichi , Okita Yoshiko , Kagawa Naoki , Kishima Haruhiko
Published: November 2023

Glioblastoma (GBM) has a poor prognosis despite intensive treatments such as surgical resection, radiation, and chemotherapy, thus new therapeutic strategies are urgently needed to improve the outcome. In addition, invasive nature of glioblastoma is one of the reasons for treatment failure, thus regulating glioblastoma invasion is essential to improve the outcome of GBM patients. To develop new treatment strategies, patient derived xenografts (PDXs) are essential tools for preclinical and translational research for glioblastoma because PDXs recapitulated histological features of original patients’ tumors such as invasion. In this study, we aim to comprehensively analyze the mechanism of glioblastoma invasion using PDXs. We have injected GFP-tagged glioblastoma PDXs lines into the right cerebrum of immunodeficient mice and dissected the right and left cerebrum separately when the mice got tumors. We dissociated the brain, sorted tumor cells by flow cytometry, and extracted RNA from tumor cells in right and left cerebrum, respectively. We performed RNA sequencing and analyzed the transcriptome differences between tumor cells from right cerebrum and left cerebrum. We found significant differences in expression of extracellular matrix related proteins, cell motility related proteins, and cell adhesion related proteins between these two. These findings suggest that PDXs will be of use for comprehensively investigating the mechanism of glioblastoma invasion and extracellular matrix related proteins, cell motility related proteins, and cell adhesion related proteins have significant roles of glioblastoma invasion.
ANGI-10. METRONOMIC 5 DRUG ANTI-ANGIOGENESIS THERAPY FOR RECURRENT EPENDYMOMA
Authors: Olsen Braden , Maher Ossama , Niazi Toba , Ragheb John , Khatib Ziad
Published: November 2023

Low dose continuous (metronomic) anti-angiogenesis therapy is a treatment regimen currently under investigation for chemo-refractory tumors to target tumor vasculature. This effect has been shown to improve survival in primary brain tumors such as medulloblastoma. The Dana Farber Antiangiogenic Chemotherapy Phase II Trial and MEMMAT trial are investigations into outcomes of metronomic anti-angiogenesis therapy for children with recurrent ependymoma, among other primary brain tumors. We retrospectively report 9 pediatric patients diagnosed between the ages of 1 and 8 with surgery and radiation refractory posterior fossa ependymoma that were treated with 5 drug metronomic anti-angiogenesis therapy including celecoxib, thalidomide, fenofibrate, and alternating low dose etoposide and cyclophosphamide. For one patient, we added bevacizumab every other week. 7 patients had anaplastic presentation of ependymoma. All patients either had gross total resection or multiple subtotal resections. Tumor markers include GFAP, S100, EMA, OLIG 2, CD99, and Ki-67. Side effects were primarily hematologic but also included muscle pain, constipation, and dizziness, however treatment was tolerated well overall. The primary reason for stopping treatment early was progression of disease, no patients stopped therapy for side effects. There was no change in response to therapy based on tumor markers found. 2-year survival was 78% and 2-year progression free survival was 56%. 3/9 patients have no recurrent disease, two of these patients had anaplastic ependymoma and 1 presented with metastatic disease to the spine. We show improved outcomes with a minimal side effect profile for metronomic anti-angiogenesis therapy in pediatric patients with recurrent ependymoma refractory to surgical and radiation therapy.
BIOM-01. PROGNOSTIC IMPLICATIONS OF SMALL CELL LUNG CANCER (SCLC) TRANSCRIPTIONAL SUBTYPING FOR CENTRAL NERVOUS SYSTEM (CNS) METASTASES
Authors: Skakodub Anna , Tringale Kathryn , Egger Jacklynn , Eichholz Jordan , Yu Yao , Gomez Daniel , Rimner Andreas , Li Bob , Yamada Yoshiya , Wilcox Jessica , Moss Nelson , Imber Brandon , Rekhtman Natasha , Baine Marina , Rudin Charles , Pike Luke
Published: November 2023

BACKGROUND

Small cell lung cancer (SCLC) is characterized by a high propensity for brain metastases (BM) and is associated with a poor prognosis. Subtypes characterized by high versus low neuroendocrine states (expressing ASCL1 or NEUROD1) have been identified. This study aims to evaluate the influence of transcription factor-defined SCLC subtypes on the incidence and outcomes of BM.

METHODS

We identified 164 patients with SCLC based on their ASCL1 and NEUROD1 expression status by immunohistochemistry. Four transcriptional subtypes were defined: ASCL1+/NEUROD1- (A+/N-), ASCL1+/NEUROD1+ (A+/N+), ASCL1-/NEUROD1+ (A-/N+), and ASCL1-/NEUROD1- (A-/N-). Cumulative incidence competing risk analyses examined the incidence of central nervous system (CNS) progression. Cox proportional hazards models were utilized to assess both overall survival (OS) and CNS progression-free survival (CNS-PFS).

RESULTS

Out of 164 patients, the majority fell into either A+/N- or A+/N+ subtypes (n = 62, n = 63, respectively). BM were detected at the time of diagnosis in 12% (20/164) of patients, while 18% (29/164) developed BM later. In two distinct cohorts of patients (initially free from BM and with de novo BM at diagnosis), the 12-month cumulative incidence of CNS progression was numerically highest for the A+/N- subtype (HR = 11.8, 95%CI: 4.7-22.4, and HR = 44, 95%CI: 10.5-74.7, respectively). OS in both A+/N- and A-/N+ subtypes was worse compared to the A+/N+ subtype (HR = 1.62, 95%CI: 1.03-2.56, and HR = 1.63, 95%CI: 1.06-2.60, respectively). Similarly, CNS-PFS was poorer in same A+/N- and A-/N+ subtypes (HR = 3.10, 95%CI: 1.39-6.93, and HR = 3.38. 95% CI: 1.49-7.67) when compared to A+/N+.

CONCLUSIONS

This study is the first to explore CNS-specific outcomes based on transcription factor SCLC subtypes. Among patients without BM at SCLC diagnosis, those exclusively expressing ASCL1 or NEUROD1 demonstrated poorer outcomes than those with co-expression. Further investigation is warranted to elucidate the implications of SCLC subtyping, ultimately facilitating tailored disease management.
BIOM-17. WHOLE GAIN OF CHROMOSOME 19, NOT CO-GAIN OF CHROMOSOMES 19 AND 20, IS A FAVORABLE PROGNOSTIC BIOMARKER IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Nuechterlein Nicholas , Cimino Patrick , Holland Eric
Published: November 2023

BACKGROUND

IDH-wildtype glioblastoma carries an abysmal prognosis, but long-term survivors exist. Previous studies have suggested that co-gain of chromosomes 19 and 20 (+19/+20) is a favorable prognostic marker. We sought to validate this claim and investigate whether gain of chromosome 19 (+19) is a superior prognostic indicator.

METHODS

We collected somatic copy number alteration data for primary glioblastoma tumors from TCGA (N = 356) and paired primary (N = 169) and recurrent (N = 167) glioblastoma tumors from GLASS. We assessed the frequency of these events and conducted survival analyses with univariate and multivariate Cox proportional hazard models to examine the association between +19/+20 and +19 and patient outcomes.

RESULTS

Among primary glioblastomas, the frequency of +19/+20 (20.8% vs. 23.7%) and +19 (34.6% vs. 36.7%) did not differ between TCGA and GLASS. However, the presence of +19/+20 was significantly reduced in GLASS recurrent tumors compared to primary tumors (14.3%, p = 0.04), while +19 without +19/+20 was unchanged (13.8%), indicating that +19/+20 is selected against in recurrent glioblastoma. Tumors harboring +19/+20 did not exhibit improved overall survival (OS) or progression-free survival (PFS) in TCGA (p = 0.21 and p = 0.14, respectively), nor did they demonstrate improved OS in GLASS (p = 0.32). Conversely, tumors with +19 showed significantly better OS and PFS in TCGA (HR = 1.4, p< 0.01; HR = 1.5, p< 0.01, respectively) and improved OS in GLASS (HR = 1.6, p< 0.01). In multivariate survival analyses, +19 remained a prognostic factor independent of +19/+20, patient sex, age, MGMT promoter methylation status, and KPS in TCGA (p< 0.05) and +19/+20 and age in GLASS (p = 0.01).

CONCLUSION

Although previous studies have suggested that +19/+20 is a positive prognostic biomarker in glioblastoma, our findings indicate that this assertion should be reevaluated. Our results demonstrate that +19 is associated with favorable outcomes in the TCGA and GLASS datasets, whereas +19/+20, while possibly selected against in recurrent glioblastomas, is not.
BIOM-25. IDENTIFICATION OF PLASMA-DERIVED PREDICTIVE BIOMARKERS INCLUDING SERPINA3 FOR GLIOMA AND GLIOBLASTOMA
Authors: Etter Manina , Duchemin Wandrille , Shekarian Tala , Durano Célia , Vogel Julian , Ritz Marie-Françoise , Hutter Gregor
Published: November 2023

Advancement in the diagnosis and surveillance of gliomas has been limited posing both diagnostic and therapeutic challenges. Definitive diagnosis, distinction of progression versus pseudoprogression and prognosis assessment still depend on invasive neurosurgical biopsy procedure. Minimally-invasive plasma sampling could minimize the risks associated with invasive tissue sampling. Therefore, we aimed to identify specific plasma protein patterns of low- and high-grade glioma patients, compared to healthy individuals and investigated whether different plasma-derived protein signatures were associated with survival in glioma patients. Plasma samples were from patients with glioma grades I to IV collected during tumor removal and from healthy controls donating blood were processed for Liquid Chromatography Mass Spectrometry (LC/MS) proteomics after depletion of the 14 most abundant plasma proteins, in order to specifically detect low-abundant tumor-derived proteins. Overall, 646 proteins were measured across 104 plasma samples from glioma patients and 57 plasmas from the healthy cohort. PCA showed 2 clusters of samples, one containing low- and high-grade glioma samples and the other containing healthy and some grade IV (GBM) plasma samples. Interestingly, a spatial analysis of tumor location by MRI associated the GBM samples separated from healthy samples with subventricular vicinity. 26 differentially expressed proteins (DEPs) were identified discriminating between glioma and healthy samples and 30 DEPs discriminating GBM and healthy samples. The top most overexpressed proteins in gliomas vs controls were SERPINA3, F13A1, and TKT. Multivariate analysis identified SERPINA3, PPBP and MYH9 as strong discriminators of healthy vs GBM but also of low-grade vs GBM, indicating that these proteins may represent specific plasma biomarkers for GBM. SERPINA3, MYL1 and CLU were associated with poor survival in GBM. In conclusion, we describe sets of plasma derived proteins, in particular SERPINA3, as predictive biomarkers that could be used to assess tumor progression allowing patient-centered treatment options.
BIOM-29. FIBRONECTIN TYPE III DOMAIN CONTAINING 3B AS PROGNOSTIC BIOMARKER AND REGULATORY TARGET FOR MALIGNANT BRAIN TUMOR
Authors: Kwon Hyukjun , Yun Minji , Bang Minji , Lee Jungsul , Ko Hae Young , Chong Kyuha
Published: November 2023

Malignant brain tumor (MBT) is an aggressive tumor with high drug-resistance and recurrence rates. Using ‘Oncopression’ big data analysis, we found that a fibronectin-related protein, fibronectin type III domain containing 3B (FNDC3B), was specifically overexpressed in brain tumor patients and conducted a pilot and mechanism study on the role of FNDC3B in MBT. We evaluated the functional significance of FNDC3B in MBT using FNDC3B specific siRNA and performing cell viability assay, real-time qPCR, Western blot, 3D-invasion assay, and wound healing assay. Furthermore, using proteome profiler human phospho-kinase arrays, we investigated the correlated signaling which activated while FNDC3B-mediated MBT cell progression. We found that down-regulation of FNDC3B decreased tumor cell proliferation, migratory and invasiveness properties as well as stemness phenotype which are hallmarks of cancer progression. Furthermore, we demonstrate that PI3K/AKT signaling pathways were involved mainly in FNDC3B-related tumor growth and mesenchymal phenotypes. Although follow-up studies are necessary, the results of this study suggest that FNDC3B is worth investigating as a novel alternative diagnostic and therapeutic target candidate for MBT.
BIOM-36. PREOPERATIVE IMMUNE AND INFLAMMATORY FACTORS IN PERIPHERAL BLOOD PREDICT PROGNOSIS OF GLIOMA AND CORRELATE WITH GRADES AND SUBTYPES: A PROSPECTIVE MULTI-INSTITUTIONAL STUDY OF 1282 PATIENTS
Authors: Zhong Sheng , Yang Wenzhuo , Zhang Zhiyun , Xie Haoqun , Sai Ke , Mou Yonggao
Published: November 2023

BACKGROUND

Peripheral blood immune and inflammatory factors can reflect glioma patients' immune status and inform anti-tumor immunotherapy, but research in this field is limited compared to tumor microenvironment studies. We aim to investigate the relationship between these circulating factors and glioma grades, subtypes, and prognosis.

METHODS

From October 2006 to April 2022, 1282 patients with primary gliomas were enrolled in this study, and their preoperative peripheral blood was collected. Correlations between immune and inflammatory factors and different glioma grades and subtypes were analyzed using ANOVA, t-test, and Ordinal Logistic Regression. ROC curve analysis was used to evaluate the diagnostic efficiency of these factors. In addition, the Cox regression model, K-M survival analysis, and other methods were used to study the relationship between these factors and the prognosis and survival of patients.

RESULTS

The results showed that with the higher clinical grade, the percentage of NK cells in peripheral blood increases while the percentage of Th and T lymphocytes decreases. C4 levels and percentage of B lymphocytes were higher in grade I gliomas than in other grades. The percentage of NK and Th cells also correlated with glioma subtypes. Immunoglobulin light chains were associated with a favorable prognosis, whereas a higher percentage of peripheral B lymphocytes in grade IV patients was associated with a poor prognosis.

CONCLUSIONS

The relationship between immune and inflammatory factors and the grades and subtypes of glioma can offer potential opportunities to intervene in these factors that could improve the prognosis of glioma patients. Additionally, it may be helpful to screen glioma and anti-tumor immunotherapy.
BIOM-50. EXOSOMAL MICRORNA EXPRESSION SIGNATURE IN BLOOD AND CEREBROSPINAL FLUID OF GLIOBLASTOMA PATIENTS
Authors: Yamashita Daisuke , Suehiro Satoshi , Nishikawa Masahiro , Inoue Akihiro , Kunieda Takeharu
Published: November 2023

Analysis of exosomes derived from plasma or cerebrospinal fluid (CSF) has emerged as a promising biomarker platform for therapeutic monitoring in glioblastoma patients. However, the contents of the various subpopulations of exosomes in these clinical specimens remain poorly defined. Here we characterize the relative abundance of miRNA species in exosomes derived from the plasma and CSF of glioblastoma patients. To this end, we first employed miRNA arrays to measure the expression of exosomal miRNAs in the plasma from glioblastoma patients (n = 24) and healthy volunteers (n = 7) as control. In addition, we performed global miRNA profiling of exosomal miRNAs in the CSF from glioblastoma patients (n = 5) and non-tumoral patients (n = 3; hydrocephalus patients) as control. In plasma derived exosomes, 80 miRNAs were altered by >2-fold in glioblastoma patients compared to controls. In CSF, 92 miRNAs were altered by >2-fold in glioblastoma patients compared to controls. Combined analysis of plasma and CSF revealed a similar fold difference in eight miRNAs. Next, we measured these eight miRNAs expression in in the plasma from pre- and post-operative glioblastoma patients (n = 9). Among these eight miRNAs, we identified only one miRNA (miR-34b-3p) that was upregulated in exosomes from pre-operative glioblastoma patients. Our results suggest that miR-34b-3p might have a potential as a novel diagnostic marker or a therapeutic tool for glioblastoma patients.
BIOM-54. VALIDATING MCM2 IMMUNOHISTOCHEMISTRY AS A SURROGATE MARKER FOR AGGRESSIVE MENINGIOMA
Authors: Shelbourn Allison , Nuechterlein Nicholas , Parada Carolina Da Silva , Eaton Jessica , Tucker Mallory , Ferreira Manuel , Cimino Patrick
Published: November 2023

Increasing efforts have focused to improve meningioma classification through various multi-omic analyses. One such recent study (Nassiri, et al, Nature, 2021) proposed an integrative molecular classification for meningiomas that included 4 molecular subtypes (MG1-4), with possible immunohistochemical surrogates for each subtype including S100B, ACADL, SCGN, and MCM2, respectively. While these immunohistochemical surrogates have been proposed for meningioma risk-stratification, their clinical utility has not been thoroughly tested. In this study, we sought to evaluate the utility of these immunohistochemical markers for risk-stratification in an independent cohort of meningioma. Tissue microarrays containing meningioma tissues were constructed, immunohistochemically stained, and blindly scored. Our cohort included n = 142 tumors (CNS WHO: 1=93, 2=45, 3=4). Median age was 49 years (range 14-80 years) with 89 female and 53 male patients. We found that MCM2 immunopositivity was a univariate marker of poor prognosis (median progression-free survival 1.2 years) when compared to negative tumors (median progression-free survival 13.0 years). The other three markers (S100B, ACADL, SCGN) were not associated with survival. MCM2 staining held up as a significantly independent (p = 0.03) poor prognostic marker on multivariate Cox proportional hazard modeling including other histopathological features: CNS WHO grade, brain invasion, mitotic index, and tumor size. Although MCM2 staining was independent of CNS WHO grade, all 4 of the CNS WHO 3 meningiomas were positive for MCM2. MCM2-positive tumors had a higher average mitotic count (6.1 mitoses/10hpf) compared to MCM2-negative tumors (1.8 mitoses/10hpf) (p = 0.0002, two-tailed t test). There was no difference between MCM2-positive and MCM2-negative meningiomas in relation to maximum tumor size (4.9cm and 4.2cm, respectively) and mean age (51.71 years and 50.34 years, respectively). In summary, in our cohort we found MCM2 immunopositive staining (surrogate marker for high-risk molecular subtype M4) to be an independently poor prognostic biomarker in meningioma when accounting for other well-established histopathological characteristics.
BIOM-56. THE PRIVATE AND RECURRING ANTIGENIC PROFILE OF MOST AGGRESIVE PEDIATRIC BRAIN TUMORS
Authors: Yang Changlin , Trivedi Vrunda , Yegorov Oleg , Mitchell Duane
Published: November 2023

BACKGROUND

Efficient immunotherapies for pediatric brain tumors face a significant challenge in identifying tumor rejection antigens. To overcome this hurdle, we utilized a comprehensive computer algorithm called the Open Reading Frame Antigen Network (O.R.A.N.).

METHODS

Our focus was on expressed epitopes, including single nucleotide variations, small indels, gene fusions, novel junctions from alternative splicing, and Tumor Associated Antigens (TAAs), for antigenic epitope predictions. To ensure uniqueness, we compared immunogenic TAA epitopes against a personalized human proteomic library, ensuring they were not shared by other expressed isoforms or genes. The immunological landscape of medulloblastoma (n = 170) and DIPG (n = 30) was explored using immune deconvolution techniques combined with single-cell RNA sequencing integration.

RESULTS

Our hypothesis was that medulloblastomas and DIPG exhibit diverse immune profiles and express genes that are rarely found in normal tissues, making them potential targets for immunotherapy. In this study, we found that most neoantigens identified in medulloblastoma patients were unique to each individual, emphasizing the need for personalized neoantigen-based therapies. Interestingly, recurring neoantigens were predominantly present in the MB SHH subgroup, while they constituted only a small fraction of putative antigens in WNT, Group 3, and Group 4 patients. On the other hand, recurring Tumor Associated Antigens (TAAs) were more frequently expressed in the latter three molecular subgroups but not in the SHH subgroup. Thus, a combination of personalized neoantigen vaccines and targeting recurring TAAs could potentially maximize the anti-tumor effects.

CONCLUSION

Medulloblastoma is a disease characterized by its heterogeneity, and current standard treatments do not adequately address this aspect. In the case of DIPG, surgical resection is not a viable option due to its diffuse and infiltrative nature within the brainstem. By leveraging the power of the immune system, cellular immunotherapy holds promise in providing more targeted and personalized treatment options for pediatric brain tumor patients.
BIOS-05. USING DATA-DRIVEN ANALYTICS TO PREDICT SURVIVAL IN PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA: THE UTILITY OF MACHINE LEARNING IN NEXT-GENERATION NEURO-ONCOLOGY PROGNOSTICATION
Authors: Brown Nolan , Kuo Cathleen , Gendreau Julian
Published: November 2023

Medulloblastoma is the most common malignant intracranial tumor affecting the pediatric population. Despite advancements in multimodal treatment over the past 2 decades yielding a >75% 5-year survival rate, children who survive often have substantial neurological and cognitive sequelae. We aimed to identify risk factors and develop a clinically friendly online calculator for prognostic estimation in pediatric medulloblastoma patients. Pediatric patients with a histopathologically confirmed diagnosis of medulloblastoma were extracted from the Surveillance Epidemiology and End RESULTS: database (2000-2019) and split into training and validation cohorts in an 80:20 ratio (Figure 1). The Cox proportional hazards model was used to identify the univariate and multivariate survival predictors. Subsequently, a calculator with those factors was developed to predict 2-, 5-, and 10-year overall survival as well as median survival months for pediatric medulloblastoma patients. The performance of the calculator was determined by discrimination, calibration, and decision curve analysis (DCA). A total of 1,739 pediatric patients with medulloblastoma met the prespecified inclusion criteria. Fourteen variables, including age, sex, race, ethnicity, median household income, county attribute, laterality, histology, anatomical location, tumor grade, tumor size, surgery status, radiotherapy, and chemotherapy, were included in the calculator (). The concordance index was 0.757 in the training cohort and 0.762 in the validation cohort, denoting clinically useful predictive accuracy. Good agreement between the predicted and observed outcomes was demonstrated by the calibration plots. The DCA curves indicated that the developed model has a good clinical prognostic benefit for pediatric medulloblastoma patients, and could aid prognostication efforts in the clinical setting. An easy-to-use prognostic calculator for a large cohort of pediatric patients with medulloblastoma was established. Future efforts should focus on improving granularity of population-based registries and externally validating the proposed calculator.
BIOS-07. SURVIVAL TIME OF GLIOBLASTOMA PATIENTS ENROLLED IN RANDOMIZED CONTROLLED TRIALS: A NEXT GENERATION META-ANALYSIS OF SURVIVAL CURVES
Authors: Hameed Farrukh , Sajjad Omar , Sathyamurthi Sam , Priyadarshini Mamindla , Klaichart Katamon , Thompson Aaliyah , Hegde Tanvi , Wang Yan , Zinn Pascal
Published: November 2023

INTRODUCTION

Glioblastoma is the most common primary malignant brain tumor and remains an incurable disease with high mortality. Randomized controlled trials (RCTs) have investigated novel therapies that have shown promise, but there have been no major additions in the treatment armamentarium in almost two decades.

OBJECTIVE

In a first study of its kind, we investigate the cumulative change in survival times over years for GBM patients by combining the survival outcome data published by multiple trials.

METHODS

A systematic database search of PubMed for GBM RCTs with significant outcomes published after 2005 was conducted. All Kaplan-Meier (KM) survival curves were analyzed. Individual patient data was extracted from the survival curves and a cumulative survival curve was generated with corresponding times calculated. The primary outcome for all included RCT was mortality at longest follow-up.

RESULTS

We identified 14 RCT which contained KM curves presenting sufficient data for individual patient survival data extraction. Survival data of a total of 2294 patients was extracted with 1396 (60.85%) patients in the treatment arms and 898 in the control arms (39.15%). Patients in the control arm received the standard care of GBM management, whereas those in the treatment arms received differing experimental regimens. After generating the cumulative survival curve, the median survival time for patients in the treatment arm was found to be 15.2 months and 11.2 months for the control arm (P < 0.0001). The two-year survival rate was 31.0% for the treatment arm and 15.6% for the control arm.

CONCLUSION

The survival times observed in GBM patients receiving the standard care of management were worse than anticipated. In general, however, overall estimates of survival among patients with GBM have improved with more patients surviving to 2 years.
CNSC-15. MITOCHONDRIA TRANSFER VIA GLIOMA-ASTROCYTE NETWORK MICROTUBES REPROGRAMS TUMOR CELLS FOR ENHANCED TUMORIGENICITY
Authors: Watson Dionysios , Bayik Defne , Storevik Simon , Moreino Shannon , Sprowls Samuel , Han Jianhua , Augustsson Mina , Lauko Adam , Palavalasa Sravya , Rosland Gro , Troike Katie , Tronstad Karl , Wang Sabrina , Sarnow Katharina , Kay Kristen , Lunavat Taral , Silver Daniel , Dayal Sahil , Joseph Justin , Mulkearns-Hubert Erin , Ystaas Lars , Deshpande Gauravi , Guyon Joris , Zhou Yadi , Magaut Capucine , Seder Juliana , Neises Laura , Williford Sarah , Meiser Johannes , Scott Andrew J , Sajjakulnukit Peter , Mears Jason , Bjerkvig Rolf , Chakraborty Abhishek , Daubon Thomas , Cheng Feixiong , Iavarone Antonio , Lyssiotis Costas , Wahl Daniel , Hjelmeland Anita , Hossain Jubayer , Miletic Hrvoje , Lathia Justin
Published: November 2023

Glioblastoma (GBM) interaction with neural cells is critical to its pathobiology. Emerging evidence suggests that GBM cells form an interconnected network with astrocytes, facilitating tumor persistence. Given reports of intercellular transfer of mitochondria in ischemic stroke and other pathologic disease states outside the CNS, we hypothesized that this network facilitates mitochondria transfer from astrocytes to GBM with protumorigenic sequelae. Employing transgenic mice and intracranial viral vector transductions in rats, we found that mitochondria transfer from the TME to GBM occurs in intracranial mouse and patient-derived xenograft models (in nude rats) of GBM. Mitochondria transfer from bone marrow-derived immune cells was minimal in bone marrow chimera mouse models of orthotopic GBM, suggesting that neural cells were the primary mitochondria donors. We confirmed this in vitro, where mouse astrocytes were the major mitochondria donors, followed by microglia and to a much smaller extent bone marrow-derived macrophages. Immortalized human astrocytes transduced with mitochondria-localized mCherry (mito-mCherry) also transferred their mitochondria to numerous patient-derived glioma stem cell (GSC) models at rates of ~5-20%, assessed by flow cytometry and confocal microscopy. Mitochondria were visualized along intercellular actin bridges, structurally resembling tumor microtubes. Blocking actin polymerization or knocking down GAP43 (previously linked to microtube formation) decreased mitochondria transfer from astrocytes to GBM in vitro. Functionally, sorted mito-mCherry+ patient-derived GSCs displayed higher mitochondrial respiration, metabolomic reprogramming and proliferation-promoting phospho-signaling. Mito-mCherry+ GBM cells were more likely to be in the proliferative G2/M phases of the cell cycle, and when sorted from co-cultures had high self-renewal (in vitro) and tumor-initiating capacity (in vivo xenograft mouse model). In ongoing work, we are investigating the role of retrograde GBM to astrocyte transfer of mitochondria by dual-color labeling of the organelle, as well as further delineating the protein machinery involved in this fundamental protumorigenic process, with the goal of identifying novel therapeutic targets.