bluuebunny/crossref_metadata_2025 huggingface dataset:
They will hate us for this: effects of media coverage on Islamist terror attacks on Muslims’ perceptions of public opinion, perceived risk of victimization, and behavioral intentions
Authors: Zerback Thomas , Karadas Narin
Published: November 2022

While research has intensively studied the effects of media coverage of Islamist terror on non-Muslims, our knowledge about how it affects Muslims themselves is still limited. Following Sikorski et al. (2017), we distinguish between undifferentiated and differentiated news on Islamist terror, i.e., news reports that explicitly establish or deny a link between Muslims or Islam and Islamist terror. In a 1 × 4 randomized experiment, we exposed N = 423 German Muslims to four different news conditions (terror differentiated, terror undifferentiated, criminal act, and a control group). Our results show that Muslims infer a negative picture of public opinion toward their group from news articles about Islamist terror, with stronger effects for undifferentiated depictions. Moreover, this notion leads to an increased perceived risk for the ingroup to fall victim to xenophobic violence. A strong German national identity attenuated the effects, whereas Muslim identity had no moderating effect.
Urine Exosomal bkv-miR-B1-5p and BK Virus Nephropathy in Kidney Transplant Recipients
Authors: Jung Su Woong , Cho Won-Hee , Seo Jung-Woo , Kim Yang-Gyun , Moon Ju-Young , Kim Jin Sug , Kim Chan-Duck , Chung Byung Ha , Park Jae Berm , Kim Yeong Hoon , Lee Sang-Ho
Published: November 2022

Background

Urine exosomal bkv-miR-B1-5p is associated with BK virus (BKV) nephropathy (BKVN); however, its posttransplantation changes and predictability for BKVN have not been determined in kidney transplant recipients (KTRs).

Methods

Urine exosomal bkv-miR-B1-5p and urine and plasma BKV DNA were measured at 2 weeks and 3, 6, and 12 months posttransplant in 83 KTRs stratified into biopsy-proven or presumptive BKVN, BKV viruria, and no evidence of BKV reactivation. Joint model, multivariable Cox model and receiver operating characteristic curve (ROC) were used to investigate the association of each assay with the following events: a composite of biopsy-proven or presumptive BKVN, and biopsy-proven BKVN.

Results

Urine exosomal bkv-miR-B1-5p and urine and plasma BKV DNA showed similar posttransplant time-course changes. Joint models incorporating serial values demonstrated significant associations of all assays with the events, and Cox analyses using single time point values at 2 weeks posttransplant showed that only urine exosomal bkv-miR-B1-5p was significantly associated with the events, although it did not outperform urine BKV DNA in ROC analyses.

Conclusions

Urine exosomal bkv-miR-B1-5p was associated with BKVN as were urine and plasma BKV DNA loads on serial follow-up, and might have potential as a predictive marker for BKVN during the early posttransplant period.

Clinical Trials Registration

Clinical Research Information Service (https://cris.nih.go.kr/cris/), KCT0001010.
The impact of outsourcing bed-based aged care services on quality of care: A multisite observational study
Authors: Horne-Thompson Anne , Khalil Hanan , Harding Katherine , Kane Richard , Taylor Nicholas F
Published: November 2022

Background

Outsourcing health-care services has become popular globally, provided by both profit and non-for-profit organizations with varying degrees of quality. To date, few published studies have evaluated the quality of care in health services using outsourcing.

Objective

The purpose of this study was to determine if there were differences in quality of care (effectiveness, safety and patient experience) for a Transition Care Program designed to improve older people’s independence and confidence after a hospital stay, when provided within a public health network compared to being outsourced to private facilities.

Methods

For clients discharged to a residential Transition Care Program operating across three sites from a large health service network (n = 1546), an audit of medical records was completed. Site 1 remained within the public health service (internally managed), whereas Sites 2 and 3 involved outsourcing to residential aged care facilities. The main outcome measures were discharge destination, length of stay and number of falls. Client demographics were analysed descriptively, and inferential statistics for continuous data and negative binomial regression for event data were used to examine differences between the sites.

Results

There were differences in quality of care between the internally and outsourced managed sites. One outsourced site discharged a smaller proportion to rehabilitation (P = 0.003) compared to the other two sites. There were differences in length of stay between the three sites. The length of stay was a mean of 4.8 days less at Site 1 (internally managed) (95% Confidence Interval (CI) 0.5 to 9.1) than Site 2 and 4.6 days less (95% CI 1.2 to 8.1) than Site 3. For those discharged to permanent residential care, the length of stay was 9.4 days less at the internal site than Site 2 (95% CI 3.5 to 15.2) and 7.0 days less than Site 3 (95% CI 1.9 to 12). Additionally, a lower rate of falls was recorded at Site 1 (internally managed) compared to Site 2 (outsourced) (incidence rate ratio = 0.44 (95% CI 0.32 to 0.60), P < 0.001).

Conclusion

An internally managed Transition Care Program in a public health network was associated with better quality of care outcomes compared to outsourced services.
Seeking status and ontological security in hierarchy: Korea in the historical East Asian order
Authors: Min In Young
Published: November 2022

This article argues that secondary states in international hierarchy pursue distinctive strategies to define and secure their identities. When and why do they adopt strategy of socialization and emulation? When and why do they prioritize security of identity even at the expense of physical security? To address these questions, I empirically examine the relationships between Korea and imperial China during the Ming and Qing dynasties. I ask why Chosŏn Korea chose to voluntarily subordinate to the Ming, and why it risked its survival during the period of obvious power transition with the rise of the Qing. I develop a theory of secondary states’ identity-seeking based on social identity theory and ontological security studies. Theoretically, it suggests a new mechanism in which secondary states’ status-seeking generates a lock-in effect through deep socialization. Empirically, it adds to the growing literature on historical East Asian international relations by explicitly theorizing secondary states’ quest for identity.
Nuclear Weapons and Low-Level Military Conflict
Authors: Lee Kyung Suk , Kim James D , Jin Hwalmin , Fuhrmann Matthew
Published: November 2022

Do nuclear weapons deter low-level military conflict? Although the political effects of nuclear weapons have been debated for more than seventy years, scholarship has yet to produce a clear answer. We design a study that reduces the risk of omitted variable bias relative to prior research. Our analysis compares the rates of conflict among eventual nuclear powers in the periods before and after they obtained an arsenal. We include two-way fixed effects to control for time-invariant state-specific confounders and address common shocks. Our findings indicate that switching from nonnuclear status to a nuclear arsenal decreases the risk of being targeted in militarized interstate disputes (MID) by nonnuclear challengers. However, when it comes to low-level conflict, nuclear powers do not appear to be deterred from instigating disputes with other nuclear-armed states. This result stands in contrast to most prior studies, which conclude that the possession of nuclear weapons increases or does not reliably decrease the risk of being targeted—even for nonnuclear challengers. Although there are clear limits to the deterrence benefits of nuclear weapons at low levels of conflict, states can reduce their vulnerability to some degree by developing a nuclear arsenal.
No Bandwidth to Self-Gift: How Feeling Constrained Discourages Self-Gifting
Authors: Rifkin Jacqueline R , Wight Kelley Gullo , Cutright Keisha M
Published: November 2022

From time, to money, to energy, many consumers are feeling more constrained than ever before. One potential solution to the pervasive feeling of constraint is self-gifting, which is the process of invoking a hedonic consumption experience with the a priori intention of boosting one’s emotional well-being. But despite being a potentially powerful tool for mood repair, are consumers effectively coping with constraint by engaging in self-gifting? And if not, what is stopping them? A correlational pilot and six studies examine the relationship between the feeling of constraint and self-gifting consumption. When consumers feel constrained, they are less (rather than more) interested in self-gifting, and this is driven by a belief that feeling constrained will hamper their ability to derive the emotional well-being benefits of self-gifting. Importantly, though, this belief is miscalibrated: resource-constrained consumers can derive substantial well-being benefits from self-gifting, relative to those feeling less constrained. The effects generalize across several sources of constraint, do not occur for non-self-gifts, and cannot be explained by feelings of deservingness or justifiability. This research advances understanding of self-gifting, affective forecasting, and consumer decision-making, yields practical recommendations to marketers of self-gifting consumption, and has important consumer implications for people seeking to boost their well-being.
Is it time to modify the Japanese Uterine Cervical Cancer Guidelines to recommend a higher dose for radio-resistant tumors?
Authors: Murakami Naoya , Okuma Kae , Takahashi Ayaka , Kato Tomoyasu , Igaki Hiroshi
Published: November 2022

Compared with the European or the United States’ uterine cervical cancer management guidelines, which aim to deliver >85 Gy EQD2 (the equivalent effective dose in 2 Gy per fraction) to the high-risk clinical target volume (CTVHR) D90 (minimal dose of 90% of the CTVHR), the dose goal of the corresponding Japanese guidelines does not recommend delivering such a high dose to the CTVHR D90. Subsequently, while the rate of late radiation-induced toxicities is reported to be much lower in the Japanese schedule, the local control rate is relatively inferior to that of clinical results reported by the IntErnational study on MRI-guided BRAchytherapy in CErvical cancer study (EMBRACE-I) in which the dose goal for CTVHR D90 was >85 Gy and showed >90% local control regardless of tumor stage. In daily clinical practice, patients with residual disease supposedly due to insufficient total dose delivery are occasionally referred to our hospital for the possibility of re-irradiation, which is not usually recommended because the risk of late severe radiation-induced toxicity is high. In this report, the authors hope to raise a discussion in our community about modifying our treatment guidelines to recommend a higher dose at least for patients with poor response.
Spatiotemporal Omics-Refining the landscape of precision medicine
Authors: Zhang Jiajun , Yin Jianhua , Heng Yang , Xie Ken , Chen Ao , Amit Ido , Bian Xiu-wu , Xu Xun
Published: November 2022

Current streamline of precision medicine uses histomorphological and molecular information to indicate individual phenotypes and genotypes to achieve optimal outcome of treatment. The knowledge of detected mutations and alteration can hardly describe molecular interaction and biological process which can finally be manifested as a disease. With molecular diagnosis revising the modalities of disease, there is a trend in precision medicine to apply multiomic and multidimensional information to decode tumors, regarding heterogeneity, pathogenesis, prognosis, etc. Emerging state-of-art spatiotemporal omics provides a novel vision for in discovering clinicopathogenesis associated findings, some of which show a promising potential to be translated to facilitate clinical practice. Here, we summarize the available spatiotemporal omic technologies and algorithms, highlight the novel scientific findings and explore potential applications in the clinical scenario. Spatiotemporal omics present the ability to provide impetus to rewrite clinical pathology and to answer outstanding clinical questions. This review emphasizes the novel vision of spatiotemporal omics to refine the landscape of precision medicine in the clinic.
ANGI-05. VASCULAR NORMALIZATION IN MURINE GLIOBLASTOMA IS CONTROLLED BY APLN-SIGNALING AND CAN BE MONITORED BY DCE-MR IMAGING IN VIVO
Authors: Kälin Roland , Barci Enio , Zhang Huabin , Topping Geoffrey , Cheng Jiying , Sühnel Sandra , Tonn Joerg-Christian , Schilling Franz , Glass Rainer
Published: November 2022

OBJECTIVE

Glioblastoma (GBM) expansion is accompanied by aberrant tumor vascularization. We demonstrated that the peptide hormone Apelin (APLN) controls GBM neo-vascularization and that the APLN-receptor antagonist Apelin-F13A improved the efficiency and reduced the invasive side effect of established antiangiogenic therapy. Here we investigated if Apelin-F13A blunts the formation of vasogenic edema, which can be monitored by MRI in vivo.

METHODS

To investigate the role of APLN -signaling in regulating the tightness of the tumor vasculature we performed in vivo leakage assays using Evans-Blue dye and fluorescent dextran. By confocal immunofluorescence, we characterized the maturation of the tumor vasculature with respect to pericyte-coverage and established a dynamic contrast enhanced (DCE) MR imaging protocol to follow vascular edema formation.

RESULTS

We found that Evans-Blue extravasation is significantly increased by 3-fold in APLNKO tumors compared to controls. Uptake of fluorescent Dextran by CD31+ endothelia was quantified and increased massively from 200μm2 per high magnification field (HMF) in wildtype to 3500μm2 per HMF in APLNKO tumors. Interestingly, intracerebral infusion of Apelin-F13A enhanced pericyte coverage of the tumor vasculature by 50%, decreased Evans-Blue extravasation from 25 μg/ml in controls to 8 μg/ml in treated tumors significantly and efficiently reversed the APLN-dependent vasogenic edema assessed by comparison of T2w-MRI to HE tumor volumes. To follow vasogenic edema formation in vivo, T1w 3D FLASH images were acquired every second over a 360s time course after gadolinium-based MR-contrast agent injection and demonstrated a delayed washout of the contrast in APLN-deficient GBM.

CONCLUSION

Together, our study shows that DCE-MRI can document APLN-dependent intratumoral vascular normalization and allows inspecting vasogenic edema formation in vivo. In addition to its anti-angiogenic / anti-invasive effect, Apelin-F13A can potently reduce vasogenic edema and might thus serve as a multimodal therapy for the treatment of human GBM in the future.
BIOM-04. CORRELATIVE PERFORMANCE OF CEREBROSPINAL FLUID (CSF) CIRCULATING TUMOR CELLS (CTC) AND CELL-FREE TUMOR-DERIVED DNA (CTDNA) IN LEPTOMENINGEAL METASTASES (LM) AND PARENCHYMAL BRAIN METASTASES (BM)
Authors: Diaz Maria , Reiner Anne , Huereca Claudia , Young Robert , Arcila Maria , Rosenblum Marc , Ramanathan Lakshmi , Bale Tejus , Pentsova Elena
Published: November 2022

BACKGROUND

CSF-CTC analysis through the CellSearch® platform has been studied as a diagnostic and prognostic tool for LM from solid tumors. CSF-ctDNA can be detected in LM and/or BM, with unclear significance. We aimed to evaluate CSF-CTCs and CSF-ctDNA as predictors of LM diagnosis and survival in LM and BM.

METHODS

We retrospectively reviewed charts of patients with solid tumors who underwent CSF-CTC and ctDNA evaluation from the same lumbar puncture between 2016-2021 at Memorial Sloan Kettering Cancer Center. LM was diagnosed by MRI and/or CSF cytology; CSF-ctDNA was considered “positive” if next-generation sequencing (NGS) detected ≥ 1 mutations using clinically validated thresholds. Associations with newly diagnosed LM were performed using logistic regression, and with development of LM using cause-specific competing risks models. Survival analyses were performed using Cox proportional hazards modeling from date of first CSF collection, and adjusted by LM as a time-dependent variable.

RESULTS

Out of 151 total patients, 99 had LM at the time of CSF analysis (58/99 with newly diagnosed LM, within 30 days of first CSF collection), and 52 had BM only, of which 8/52 (15%) developed LM later (median time from CSF to LM=235 days, range 57-364). CSF-CTCs and CSF-ctDNA were predictive of newly diagnosed LM (OR=1.006, 95% CI:1.002-1.01, p=0.002 for continuous CSF-CTCs; OR=3.60, 95% CI:1.65-7.87, p=0.001 for positive CSF-ctDNA). In a small cohort of patients without LM, CSF-ctDNA was almost statistically significant in predicting later development of LM (HR=4.14, 95% CI: 0.98-17.57, p=0.054) while continuous CSF-CTCs were not (HR=1.02, 95% CI: 0.99-1.04, p=0.21). In all patients, both CSF-CTCs (OR=1.004, 95% CI: 1.001-1.006, p=0.002) and CSF-ctDNA (OR=2.49, 95% CI: 1.51-4.15, p=0.0004) predicted survival.

CONCLUSION

CSF-ctDNA could predict development of LM in patients with BM. Presence of CTCs and ctDNA in CSF were associated with poor survival in patients with central nervous system metastases.
BIOM-10. CIRCULATING EXTRACELLULAR VESICLES AS A TOOL FOR DIAGNOSIS, PROGNOSIS AND MONITORING IN GLIOMA
Authors: Ricklefs Franz , Wollmann Kathrin , Maire Cecile , Drexler Richard , Westphal Manfred , Lamszus Katrin , Dührsen Lasse
Published: November 2022

OBJECTIVE

Extracellular vesicles (EVs) represent a population of lipid bilayer nanoparticles released by all cell types, including tumor cells that can serve as a noninvasive source for liquid biopsy. To date, MRI images have been the established method for monitoring treatment efficacy in brain tumor patients. We investigated the potential of pure EV count for diagnosis, prognosis, and treatment monitoring in gliomas.

METHODS

Plasma samples, differential blood counts, at multiple timepoints before and after surgery of glioblastoma patients (n=101) were collected. Follow-up samples were obtained every 3 months. Healthy donors served as controls (n=29). Plasma EVs concentration was measured by Nanoparticle Tracking Analysis (NTA). EVs were characterized by electron microscopy and imaging flow cytometry. Tumor burden was measured by MRI images. Clinical characteristics were prospectively recorderd. In addition plasma EVs from Mut3 tumor bearing mice were analysed at d3, d5, d7, d10, d12 after tumor injection (n=20). MRI images and differential blood counts were analyzed.

RESULTS

Glioblatoma patients have a 5-fold increase of plasma EVs compared to HD; p < 0.0001). Circulating EVs counts correlated only with FLAIR hyperintensity and with no other MRI or blood-based parameter. Similar results were obtained from Mut3 tumor mice. Dichotomisation of GBM patients in EVhigh and low revealed a significant overall survival and progression free survival benefit for EVlow patients (p=0.004). After surgery, EVs decreased significantly (5-fold, p< 0.0001). A massive drop in EVs was associated with gross-total resection (p < 0.05). At the time of tumor recurrence, the number of circulating EVs increased in all patients during a follow-up (9 months).

CONCLUSION

Our findings highlight the potential of circulating EVs as a biomarker tool for diagnosis, prognosis and treatment monitoring in GBM patietns, as they seem to reflect the presence of a tumor mass and thus may assist in clinical decision making.
BIOM-12. PROLONGED RESPONSE TO THIRD-LINE TREATMENT WITH COMBINATION CCNU/TMZ IN AN MGMT METHYLATED IDH-WILDTYPE GLIOBLASTOMA
Authors: Pan Peter , Haggiagi Aya , Iwamoto Fabio
Published: November 2022

INTRODUCTION

Multiply recurrent glioblastoma suffers from poor response rates to treatment, and limited durability. We describe a case of an impressive response to third-line CCNU/TMZ.

BACKGROUND

Headaches brought a 76-year-old man to medical attention. MRI identified an enhancing right temporal mass -- path following resection demonstrated glioblastoma (IDH-wildtype, MGMT-methylated, TERT mutant; PTEN Y68H, CDKN2A/B loss, CCND3 amplification; VUS in POLE, ATM, GRIN2A, and ROS1). He received hypofractionated RT 40.05Gy/15-fractions plus 21-days concurrent TMZ 75 mg/m2, then 5-day-on / 23-day-off TMZ (150 mg/m2 cycles #1-3; 200 mg/m2 subsequent). MRI pre-cycle #6, nearly 6 months post-RT, showed increased enhancement/FLAIR consistent with local progression (POD).Second-Line: After screen-fail for clinical trial, initiated off-label regorafenib 160 mg/d, 21-days-on/7-days-off -- with partial response in enhancement at 3 weeks. With dose-reduction to 120 mg/d cycles #2-3 (for mounting fatigue), enhancement progressively worsened. Despite resuming higher 160 mg/d for cycle #4, enhancement progressed, consistent with POD.Third-Line: Given presence of MGMT promoter methylation (and extrapolating from CeTeG/NOA-09), combination CCNU 100 mg/m2 (day 1) and TMZ 100 mg/m2 (days 2-6; 8-week cycle) was started. There was improvement in enhancement/FLAIR, which continued to improve gradually through 6 cycles of CCNU/TMZ. Durability of response was surprising -- MRIs stable/improved at 15 months since starting CCNU/TMZ.

DISCUSSION

This case illustrates impressive response to CCNU/TMZ in the third-line. Delayed RT treatment effect is less likely given time elapsed from RT at initial progression (after 5 cycles of adjuvant TMZ), convincing but short-lived improvement to regorafenib (that progressively worsened through 3 more regorafenib cycles), and robust response only with CCNU/TMZ. He was also never on steroids (except post-operatively) nor bevacizumab. This suggests that improvement was mediated by antitumor effect against progressing tumor, rather than delayed RT treatment effect. MGMT methylation may have played a role in this patient's response to dual alkylator therapy.
BIOM-22. BMX EXPRESSION LEVEL IN GLIOBLASTOMA PREDICTS HYPERSENSITIVITY TO IBRUTINIB TREATMENT
Authors: Shakya Sajina , Sundar Swetha , Recinos Violette , Hubert Christopher
Published: November 2022

Glioblastoma (GBM) is the most prevalent and aggressive form of primary brain cancer and is notoriously drug and radiation resistant. The tumor recurrence and therapeutic resistance typically seen in GBM are largely driven by a small population of self-renewing, highly tumorigenic cells termed cancer stem cells (CSCs). The stem-cell-like properties of GBM CSCs are promoted, at least in part, by abnormal activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. This activation can occur through aberrant expression of bone marrow and X-linked (BMX) protein, a non-receptor tyrosine kinase that is upregulated in glioma stem cells and may be targeted by the drug ibrutinib, currently undergoing clinical trials in GBM. In contrast, BMX is not expressed in normal non-cancerous stem cells of the brain. We discovered a striking dissimilarity where a subset of our patient-derived GBM specimens are up to 100-fold more sensitive to ibrutinib than others. We investigated the mechanisms behind this hypersensitivity by analyzing the expression levels of JAK/STAT3 signaling proteins. Here we discovered that the baseline expression value of BMX prior to treatment has a strikingly high predictive value for later later response to ibrutinib, primarily explaining the variation in a specimen’s ibrutinib sensitivity. Furthermore, we found that pediatric GBM tumor models are typically BMX-low and most likely to be hypersensitive to ibrutinib compared to their adult counterparts. Ibrutinib further suppresses GBM and DIPG proliferation in CSC-rich proliferative regions of organoid models. Our data suggest the potential use of BMX as a predictive biomarker of ibrutinib sensitivity, and provide an impetus for mechanistic and preclinical investigation of ibrutinib sensitivity, particularly in pediatric disease.
BIOM-26. GENOME-WIDE SOMATIC COPY NUMBER ALTERATION SIGNATURES HAVE PROGNOSTIC IMPLICATIONS FOR ADULT ASTROCYTIC GLIOMA
Authors: Nuechterlein Nicholas , Li Beibin , Shapiro Linda , Cimino Patrick , Holland Eric
Published: November 2022

BACKGROUND

The molecular landscape of adult diffuse glioma has been extensively characterized by gene expression and DNA methylation profiling, but less attention has been paid to somatic copy number alteration (SCNA) data. This study aimed to give a rigorous, survival-focused analysis of glioma genome-wide SCNA data that builds on our previous work.

METHODS

Detailed survival analyses were conducted on the substructure of UMAP projections of all TCGA glioma (Nf1092), exclusively astrocytic glioma (Nf914), and exclusively IDH-wildtype glioma (Nf528). Results were validated with data from the Glioma Longitudinal Analysis Consortium (GLASS) (Nf224). Clinical factors such as age and MGMT methylation were tested in multivariate survival analyses.

RESULTS

A UMAP projection of TCGA glioma SCNA data generated three distinct clusters composed of entirely oligodendroglioma, predominantly IDH-mutant astrocytoma (C-IDHmut-astro), and predominantly IDH-wildtype glioma (C-IDHwt), respectively. For astrocytic tumors, cluster assignment was independently prognostic of IDH status (p< 0.001): TCGA IDH-mutant astrocytomas that clustered in C-IDHwt had poorer outcomes than their counterparts (p< 0.04) and IDH-wildtype tumors that clustered in C-IDHmut-astro fared better than those that did not (p< 0.01). The distribution of GLASS astrocytic tumors, which is skewed for better survival, supported our results in IDH-wildtype glioblastoma (p< 0.001, Fisher’s). Among four distinct subclusters of TCGA IDH-wildtype glioblastomas, the largest was significantly or marginally significantly negatively prognostic compared to each other cluster (p=0.048, p=0.059, p=0.027) and their combination (p=0.002). In the GLASS dataset, inclusion in the largest subcluster was also prognostic (p=0.013) and similar trends were observed between individual clusters (p=0.21, p=0.036, p=0.083). Furthermore, membership to the largest cluster was independently prognostic of MGMT methylation status and several published IDH-wildtype glioblastoma subtypes in the TCGA.

CONCLUSIONS

Unsupervised learning of genome-wide SCNA has prognostic implications for astrocytic glioma. SCNA cluster membership is independently prognostic of MGMT methylation status.
BIOM-50. THE IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF CIRCULAR RNA CIRC_63706 IN SONIC HEDGEHOG MEDULLOBLASTOMAS
Authors: Pokhrel Rudramani , Katsushima Keisuke , Stapleton Stacie , Jallo George , Raabe Eric , Eberhart Charles , Perera Ranjan
Published: November 2022

Medulloblastoma is a central nervous system tumor that develops through various genetic, epigenetic, and non-coding (nc) RNA-related mechanisms, but the roles played by ncRNAs, particularly circular RNAs (circRNAs), remain poorly defined. CircRNAs are increasingly recognized as stable noncoding RNA therapeutic targets in many cancers, but little is known about their function, subtype specificity, and therapeutic potential in medulloblastomas. To determine medulloblastoma subgroup-specific circRNAs, we subjected RNA-seq data from 175 clinical medulloblastoma samples in four subgroups (SSH, WNT, G3, and G4) to a statistical and machine learning (random forest) pipeline and identified a group of medulloblastoma specific circular RNAs. CircRNA, circ_63706 was identified as sonic hedgehog (SHH) group specific and confirmed its expression by RNA-FISH analysis in clinical tissue samples (tissue microarrays). To identify the molecular function of circ_63706, we depleted circ_63706 in DAOY and ONS76 cells and subjected them to global RNA sequencing and lipid profiling. Circ_63706 resides in the coding gene Pericentrin (PCNT), which is known to be involved in congenital disorders. When Circ_63706 gets depleted by shRNA, it shows a significant decrease in cell proliferation and invasion in SSH cells, and mice implanted with circ_63706-deleted cells showed reduced tumor growth and extended survival compared to parental cells implant. At the molecular level, we identified circ_63706-deleted cells elevated total ceramide and oxidized lipids and reduced total triglyceride (TG). Our study implicates an identification of a novel oncogenic circular RNA in the medulloblastoma subgroup SSH and establishes its potential as a future therapeutic target.
BIOM-56. MIR-497 AND 219 IN BLOOD AID MENINGIOMA CLASSIFICATIONMIR-497 AND 219 IN BLOOD AID MENINGIOMA CLASSIFICATION
Authors: Hanemann Clemens Oliver , Abdelrahman Ahmed , Adams Claire , Sahm Felix , Urbanic-Purkart Tadeja , Khalil Michael , Vergura Raffaella , Morelli Cristina
Published: November 2022

There is a need for blood biomarkers for meningioma. The role of circulating micro RNA in cancer diagnosis has been the objective of several studies. One of the extensively studied miRNA in different types of cancer is the microRNA-497 (miR-497). This study systematically evaluated miR-497 as a meningioma biomarker for disease diagnosis and classification. We studied exosomal and serum miR-497 in 74 meningioma samples (WHO grade I=25, WHO grade II=25, and WHO grade III=24), and 53 healthy controls. We also tested two different normalisers, endogenous and external, and evaluated their impact on the diagnostic value of miR-497. Another microRNA studied in meningioma is miR-219, which increased with increasing tumour grade. We combined miR-497 and miR-219 and estimated the sensitivity and specificity of the joint biomarkers to indicate meningioma grade and the relationship between miR-497 and miR-219 expression level and methylation class of meningioma. The serum and exosomal level of miR-497 distinguished meningioma from the control samples. Moreover, miR-497 was a suitable identifier for meningioma grade. When we combined miR-497 and miR-219, the efficacy of the combined biomarker was higher than miR-497 or miR-219 when used individually in meningioma classification. Both miR-497 and miR-219 showed a noticeable change with the methylation class of meningioma.
BIOS-02. CLINICAL OUTCOMES OF OVER 600 PATIENTS WITH GLIOBLASTOMA TREATED AT A CANADIAN TERTIARY CENTER IN THE PAST 15 YEARS: A COMPARATIVE ANALYSIS WITH THE PIVOTAL STUPP TRIAL
Authors: Rousseau Julien , Desforges Sara-Maude , Jabbour Gilbert , Lemieux Bernard , Lapointe Sarah , Bélanger Karl , Moumdjian Robert , Cayrol Romain , Florescu Marie , Masucci Giuseppina Laura , Berthelet France , Lemieux-Blanchard Émilie , Bahary Jean-Paul
Published: November 2022

Glioblastoma is the most common malignant primary central nervous system tumor in adults and is associated with a poor prognosis. The benefit of adding concomitant followed by adjuvant temozolomide to radiotherapy after maximal safe resection was demonstrated by Stupp and colleagues in 2005 and has since remained the standard of care. This regimen conferred a statistically significant benefit with a 2-year survival rate of 26.5% compared to 10.4% in patients treated with radiotherapy alone. Our primary goal was to retrospectively assess the clinical outcomes of patients with glioblastoma treated at our institution over the past 15 years by comparing the overall survival (OS) and progression-free survival (PFS) from our cohort to data from the pivotal trial. Our secondary objective was to create a comprehensive database with clinical and pathological information in order to identify predictive and prognostic factors. We reviewed the clinical records of patients treated for glioblastoma from January 2005 to November 2019 at our center. We extracted data on survival and calculated OS and PFS using the Kaplan-Meier method. 617 patient charts were reviewed, out of which 17 were excluded because of missing data. The remaining 600 patients were included. Baseline demographic information was similar to that of the Stupp cohort, with the exception of a larger proportion of patients aged 50 or above (76% versus 69%, respectively). The median OS at our center was 14.3 months, 95% confidence interval [12.8-15.2], which was comparable to that of the original trial (14.6 months [13.2-16.8]). PFS was better in our cohort at 6 months (74.2% [70.7-77.7] versus 53.9% [48.1-59.6]) and 12 months (36.3% [32.5-40.2] versus 26.9% [21.8-32.1]), and comparable thereafter. Our study confirms that the data from the Stupp trial are reproducible in a Canadian academic center setting. Our database will allow us to explore potentially new predictive factors.
CNSC-01. THE GENE LANDSCAPE OF LUNG ADENOCARCINOMA PATIENTS WITH PROGRESSIVE DISEASE OF LEPTOMENINGE
Authors: Yang Hainan , Wen Lei , Zhou Caicun
Published: November 2022

BACKGROUND

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide a better prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the outcome of leptomeningeal metastasis (LM) remains poor. In addition, due to limited access to intracranial tumour tissue, gene alterations associated with leptomeningeal metastasis from lung adenocarcinoma (LM-LUAD) are unclear.

METHODS

Forty-five patients with LM-LUAD from May 2019 to June 2021 in Guangdong Sanjiu Brain Hospital were enrolled in this study. Seventy-five percent (34/45) of patients with LM harbored EGFR mutations, and patients with progressive disease (PD) of LM had 3rd-generation EGFR-TKI therapy and were defined as Cohort 1; those without 3rd-generation EGFR-TKI therapy were defined as Cohort 2. Next-generation targeted panel sequencing (NGS) was performed in each cerebrospinal fluid (CSF) sample of the two cohorts, and 9/45 LM-LUAD patients had matched plasma (PLA).

RESULTS

The common gene alterations discovered in the CSF of LM-LUAD were EGFR mutation (34/45, 75%), TP53 (25/45, 56%), CDKN2A (9/45, 20%), ALK (7/45, 16%), CTNNB1 (6/45, 13%), MET (5/45, 11%), APC (4/45, 9%), FGF4 (4/45, 9%), FGF3 (4/45, 9%), ERBB2 (4/45, 9%), and PIK3CG (4/45, 9%). Cooccurring mutations of TP53 and EGFR were found in 49% (22/45) of patients and correlated with poor prognosis. CDKN2A was identified in 20% (9/45) of patients and presented slightly shorter overall survival (OS) than those without (7.1 versus 8.8 months, p=0.2). Cohort 1 had more genes associated with poor prognosis, consisting of CDK4, CDKN2A, PIK3CG, or PIK3CA, and YES1 and MET were more likely to be detected in cohort 2. The alteration of EGFR was comparable between CSF and matched PLA. Incidences of gene alterations such as CDK4, CDKN2A, MET, SOX2, JAK2, BRAF, and PIK3CG were more likely to be identified in CSF. All mutant allele frequencies (MAF) were much higher in CSF than in matched PLA.
CNSC-09. THE NEUROENDOCRINE FACTOR VGF IS NECESSARY FOR THE MAINTENANCE OF THE TUMOR STEM CELL POPULATION IN GLIOBLASTOMA
Authors: Kundu Somanath , Venskus Abigail , Quiruz Lee , Longo John , Longo Sharon , Walker Jamie , Richardson Timothy , Viapiano Mariano
Published: November 2022

A major factor that contributes to the unchecked growth and recurrence of glioblastoma (GBM) tumors is the presence of a heterogeneous population of GBM stem-like cells (GSCs) that continuously replenish the tumor mass. Targeting strategies against this key cell population have rarely considered the trophic signals from peritumoral neural cells, which can protect the tumor cells during therapy and therefore promote recurrence. Here, we have focused on the little-known secreted factor VGF and its derived neuropeptides, which are largely restricted to the CNS and mediate paracrine communication between neural cells. We analyzed over 200 tissue specimens and cultured GBM cells, demonstrating that VGF is upregulated in malignant gliomas and expressed in GSCs of different subtypes, although it is markedly reduced in differentiated GBM cells. More importantly, we detected VGF expression in peritumoral astrocytes, even though this neuroendocrine factor has never been described in glial cells in normal brain. Co-culture experiments and scRNAseq data from clinical tumors confirmed that VGF is expressed in tumor-associated astrocytes, suggesting that these cells are a paracrine source of VGF in GBM. Accordingly, purified exogenous VGF increased the proliferation of GSCs and rescued GSC viability when the tumor cells were treated with the chemotherapeutic temozolomide. Moreover, purified VGF decreased the expression of inflammatory cytokines in activated macrophages, suggesting that this factor may also contribute to local immunosuppression in gliomas. Conversely, knockdown of VGF in GSCs was sufficient to decrease their viability, self-renewal, and expression of stemness-related genes. At the molecular level, VGF increased intracellular calcium and Akt/mTOR signaling in GSCs, suggesting a possible G protein coupled receptor-mediated mechanism of action. Taken together, our results explore for the first time the role of brain-derived VGF in GBM progression, highlighting the importance of disrupting the communication between the tumor and its microenvironment to achieve long-term anti-tumor efficacy.
CNSC-13. TUMOR INFILTRATION OF GAMMA-DELTA T CELLS IN GLIOBLASTOMA
Authors: Juran Vilem , Piskacek Martin , Tomandlova Marie , Sova Marek , Smrcka Martin , Kazda Tomas , Vybihal Vaclav , Fadrus Pavel , Knight Andrea
Published: November 2022

Gamma-delta (γδ) T cells are innate immunity effector lymphocytes with known prominent anti-tumor reactivity against aggressive glioblastoma (GBM). However, therapeutic approaches have had limited success due to the protective blood-brain-barrier and the immunosuppressive GBM tumor microenvironment. In this study, we determined Vδ1 a Vδ2 γδ T cell populations in peripheral blood and paired tumor tissue samples in patients (n=40) following the resection and throughtout the therapy follow-up. Tumor samples were processed using enzymatic kits and gentleMACSTM Dissociator (Miltenyi Biotec Inc.) and tumor-infiltrating γδ T lymphocytes (TILs) were analyzed by flow cytometry.We found infiltration of both intratumoral CD3+ γδ T cell subsets in 68% tumor samples. We detected Vδ1 γδ T cells in the range 0-0.8% (median 0.26%). Majority of GBM patients presented the Vδ2 subset among TILs in the range 0-13.8% (median 1.5%). Functional studies showed prominent cytotoxicity of magnetically sorted Vδ1 a Vδ2 γδ T cells against GBM cell lines and more importantly against primary tumors. Detailed phenotypic profiling and single-cell sequencing of Vδ2 γδ T cells is currently underway. Next, we identified the EphA2 receptor as one of the targets for tumor-reactive Vδ1 γδ T cells. Specifically, we found that blocking of EphA2 expression resulted in significant inhibition of GBM killing mediated by Vδ1 γδ T cells. Furthermore, Luminex xMAP technology identified significantly elevated levels of stress ligand MICA and check-point inhibitor ligands PD-L1 (B7-H1, CD274) and B7-H3 (CD276) and galectin-9 in patients‘ plasma samples at diagnosis compared to age-matched controls.The patient’s clinical course and therapeutic protocols will be discussed.This study was supported by Ministry of Health, Czech Republic (grant NV19-05-00410 to AK) by Ministry of Health, Czech Republic-conceptual development of research organization (FNBr, 65269705). All rights reserved.
TMET-11. QUINOLINATE PROMOTES ALTERNATIVELY ACTIVATED MACROPHAGE-INDUCED IMMUNE TOLERANCE IN GLIOBLASTOMA THROUGH THE NMDA/PPARG SIGNALING AXIS
Authors: Kesarwani Pravin , Kant Shiva , Zhao Yi , Prabhu Antony , Buelow Katie , Miller C Ryan , Chinnaiyan Prakash
Published: November 2022

There has been considerable interest in understanding the biological consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. An overwhelming majority of this work has focused on the first-step of tryptophan metabolism (kynurenine); however, this has yet to result in clinical application. Using global metabolomic profiling on >100 patient-derived brain tumors, we identified a 64-fold accumulation of quinolinate (QA), a downstream metabolic intermediate of the tryptophan pathway, in glioblastoma when compared to low-grade glioma. As several metabolites in the tryptophan pathway have been implicated in immune modulation, we sought to determine the impact of QA on the immune microenvironment. We identified the capacity of QA to strongly skew macrophage polarization towards the “pro-tumorigenic” M2-phenotype with suppressive properties, which recent studies suggest play a dominant role in the immune microenvironment in glioblastoma. Intriguingly, QA conferred an “M2-like” phenotype to M1 macrophages and microglia, attenuating their phagocytosis efficiency. We went on to systematically delineate a novel mechanism of macrophage polarization through QA-induced NMDA receptor activation and Foxo1/PPARg signaling. We then determined that tumor cells and host macrophages/microglia work in concert to complete both upstream and downstream metabolism of tryptophan, respectively, resulting in the accumulation of QA. We discovered a very strong positive feedback loop involving the expression of kynureninase (KYNU) in macrophages, an enzyme involved in the downstream metabolism of tryptophan and QA production, making this a lead candidate for targeting this pathway. As this represents a novel target and agents designed to inhibit this enzyme are not commercially available, we generated a Kynu-/- knockout mouse model. Intriguingly, consistent with in vitro data, tumors grown in Kynu-/- mice had a ~50% reduction in M2 macrophages, increased immune activation, decreased growth, and improved overall survival in two orthotopic glioblastoma models, supporting the therapeutic potential of targeting this pathway.
TMET-15. CYTOCHROME C OXIDASE MEDIATES CELLULAR IRON HOMEOSTASIS AND RADIORESISTANCE IN GLIOBLASTOMA
Authors: Ali Md Yousuf , Pullium Casey , Flor Susanne , Goswami Prabhat , Oliva Claudia , Griguer Corinne
Published: November 2022

Defining the molecular mechanism(s) responsible for the adaptive radioresistance in glioblastoma (GBM) is necessary for the development of effective treatment options. The cellular labile iron pool (LIP) is very important for determining the cellular response to radiation, as it contributes to radiation-induced production of reactive oxygen species (ROS). Recently, cytochrome c oxidase (CcO), a mitochondrial heme-containing enzyme also involved in regulating ROS production, was found to be involved in GBM chemoresistance. However, the role of LIP and CcO in GBM radioresistance is not known. Herein, we tested the hypothesis that CcO-mediated alterations in the level of labile iron contribute to adaptive radioresistance. Using an in vitro model of GBM adaptive radioresistance, we found an increase in CcO activity in radioresistant cells that associated with a decrease in the cellular LIP (4.1-fold), decrease in lipid peroxidation (2-fold), and a switch in the CcO subunit 4 (COX4) isoform expression, from COX4-2 to COX4-1. Furthermore, knockdown of COX4-1 in radioresistant GBM cells decreased CcO activity and restored radiosensitivity, whereas overexpression of COX4-1 in radiosensitive cells increased CcO activity and rendered the cells radioresistant. We further observed that radioresistant cells has increased expression of mitoferrin-1, a protein that facilitates the incorporation of iron into mitochondria. Overexpression of mitoferrin-1 in glioma cells increases the activity of mitochondrial protein complexes, decreases the cellular labile iron pool (p< 0.05), and decreases the production of 4-hydroxy nonenal (4-HNE), a lipid peroxidation product. Furthermore, overexpression of mitoferrin-1 significantly increases the anchorage independent colony formation in soft agar assay (p< 0.01). Moreover, mitoferrin-1 overexpressing cells implanted orthotopically in the brain of nude mice significantly decreased survival compared to wild type (p < 0.01). These results indicate that manipulation of cellular and mitochondrial iron homeostasis may provide a strategy to improve therapeutic outcome in patients with GBM.
TMET-35. ONE CARBON AND NUCLEOTIDE METABOLISM ARE NOVEL TARGETS IN PEDIATRIC BRAINSTEM TUMORS
Authors: Mersich Ian , D'Alessandro Angelo , Desai Pankaj , Sallans Larry , Dasgupta Biplab
Published: November 2022

Diffuse intrinsic pontine glioma (DIPG) are inoperable tumors of the brainstem with no cure. The median survival of children with DIPG is less than 2 years and 5-year overall survival is only 1%. Genomic studies have identified recurrent mutations in histone H3, ACVR and TP53 genes in DIPG. However, there are still no breakthrough drug targets for DIPG. To better understand the disease biology and find new drug targets for DIPG, we recently performed joint pathway analysis of DIPG metabolites (untargeted metabolomics) and differentially expressed genes (RNAseq) relative to normal human neural stem cells. We discovered that specific enzymes of the de novo purine biosynthesis pathway (DNPB), serine synthesis and the associated and one-carbon (1C) metabolism are highly active and the most upregulated in DIPG tumors and cell lines. Gain and loss of function experiments as well as pharmacological studies indicated a mechanistic link between DIPG mutations and DNPB pathway and the dependence of DIPG cells on specific DNPB and 1C metabolism enzymes for in vitro and in vivo growth. The 1C pathway is crucial for rapidly proliferating malignant cells as it senses and regulates cellular nutrient status by allocating and cycling 1C-groups between different acceptor compounds. It controls synthesis of nucleotides, amino acids, glycogen and phosphoglyceride precursors, S-adenosylmethionine (SAM), glutathione and NADPH. Thus, besides dispensing carbon atoms it also regulates cellular epigenetic and redox status. An important carbon donor is serine which is synthesized from glucose at 3-phosphoglycerate step in glycolysis. Untargeted as well as carbon and nitrogen tracing experiments indicated large folate pools in DIPG cells that can serve as a buffer to potentially blunt antifolate therapy. Experiments are underway to understand the importance of the folate cycle in DIPG and design novel and translatable combination therapies for DIPG.
TMIC-34. INVESTIGATING THE EFFECT OF IRON IN GLIOBLASTOMA CELL POLARIZATION AND MIGRATION
Authors: Shenoy Ganesh , Palsa Kondaiah , Wade Quinn , Khunsriraksakul Chachrit , Khristov Vladimir , Slagle-Webb Becky , Lathia Justin , Wang Hong-Gang , Connor James
Published: November 2022

Glioblastoma represents one of the most difficult-to-treat malignancies as evidenced by the poor prognosis associated with a diagnosis. The ability of glioblastoma cells to diffusely infiltrate into healthy brain tissue renders complete surgical resection challenging. Consequently, a large majority of glioblastoma patients end up with recurrent disease despite receiving maximally feasible surgical resection and rigorous chemoradiation. This work examined how modulation of cellular iron levels in T98G and LN229 glioblastoma cells impacted migratory capacity. Treatment of T98G or LN229 glioblastoma cells with iron in the form of ferric ammonium citrate (FAC) resulted in significantly reduced migration as assessed by time-lapse phase contrast imaging and wound healing assays. The iron-induced reduction in migration was able to be rescued by the addition of equimolar concentrations of deferoxamine, an iron chelator. Cellular proliferation in response to the iron treatments was quantified using both optical confluence and nucleic-acid-based proliferation assays and it was found that iron treatment at the concentrations used for the migration assays (0 – 300 µM FAC) did not result in reduced proliferation. Mechanistically probing iron’s impact on cell migration revealed that addition of iron resulted in decreased expression of Cdc42, a Rho GTPase that is essential to determining cellular polarity during migration. Functional cellular polarization assays further confirmed that reduced expression of Cdc42 corresponded to reduced cellular polarization. Bioinformatic analysis of CDC42 transcripts revealed the presence of potential iron-responsive-elements that may drive the iron-induced reduction in Cdc42 expression. This work highlights the importance of iron biology in impacting glioblastoma cell phenotype and potentially glioblastoma patient outcomes.