bluuebunny/crossref_metadata_2025 huggingface dataset:
How China lends: a rare look into 100 debt contracts with foreign governments
Authors: Gelpern Anna , Horn Sebastian , Morris Scott , Parks Brad , Trebesch Christoph
Published: November 2022

China is the world’s largest official creditor, but we lack basic facts about the terms and conditions of its lending. Very few contracts between Chinese lenders and their government borrowers have ever been published or studied. This paper is the first systematic analysis of the legal terms of China’s foreign lending. We collect and analyse 100 contracts between Chinese state-owned entities and government borrowers in 24 developing countries in Africa, Asia, Eastern Europe, Latin America and Oceania, and compare them with those of other bilateral, multilateral and commercial creditors. Three main insights emerge. First, the Chinese contracts contain unusual confidentiality clauses that bar borrowers from revealing the terms or even the existence of the debt. Second, Chinese lenders seek advantage over other creditors, using collateral arrangements such as lender-controlled revenue accounts and promises to keep the debt out of collective restructuring (‘no Paris Club’ clauses). Third, cancellation, acceleration and stabilization clauses in Chinese contracts potentially allow the lenders to influence debtors’ domestic and foreign policies. Even if these terms were unenforceable in court, the mix of confidentiality, seniority and policy influence could limit the sovereign debtor’s crisis management options and complicate debt renegotiation. Overall, the contracts use creative design to manage credit risks and overcome enforcement hurdles, presenting China as a muscular and commercially savvy lender to the developing world.
Mathematical modeling and investigation on the role of demography and contact patterns in social distancing measures effectiveness in COVID-19 dissemination
Authors: Ridenti Marco A , Teles Lara K , Maranhão Alexandre , Teles Vladimir K
Published: November 2022

In this article, we investigate the importance of demography and contact patterns in determining the spread of COVID-19 and to the effectiveness of social distancing policies. We investigate these questions proposing an augmented epidemiological model with an age-structured model, with the population divided into susceptible (S), exposed (E), asymptomatic infectious (A), hospitalized (H), symptomatic infectious (I) and recovered individuals (R), to simulate COVID-19 dissemination. The simulations were carried out using six combinations of four types of isolation policies (work restrictions, isolation of the elderly, community distancing and school closures) and four representative fictitious countries generated over alternative demographic transition stage patterns (aged developed, developed, developing and least developed countries). We concluded that the basic reproduction number depends on the age profile and the contact patterns. The aged developed country had the lowest basic reproduction number ($R0=1.74$) due to the low contact rate among individuals, followed by the least developed country ($R0=2.00$), the developing country ($R0=2.43$) and the developed country ($R0=2.64$). Because of these differences in the basic reproduction numbers, the same intervention policies had higher efficiencies in the aged and least developed countries. Of all intervention policies, the reduction in work contacts and community distancing were the ones that produced the highest decrease in the $R0$ value, prevalence, maximum hospitalization demand and fatality rate. The isolation of the elderly was more effective in the developed and aged developed countries. The school closure was the less effective intervention policy, though its effects were not negligible in the least developed and developing countries.
Viral Genetic Determinants of Prolonged Respiratory Syncytial Virus Infection Among Infants in a Healthy Term Birth Cohort
Authors: Lawless Dylan , McKennan Christopher G , Das Suman R , Junier Thomas , Xu Zhi Ming , Anderson Larry J , Gebretsadik Tebeb , Shilts Meghan H , Larkin Emma , Rosas-Salazar Christian , Chappell James D , Fellay Jacques , Hartert Tina V
Published: November 2022

Background

Respiratory syncytial virus (RSV) is associated with acute respiratory infection. We sought to identify RSV variants associated with prolonged infection.

Methods

Among healthy term infants we identified those with prolonged RSV infection and conducted (1) a human genome-wide association study (GWAS) to test the dependence of infection risk on host genotype, (2) a viral GWAS for association with prolonged RSV infection using RSV whole-genome sequencing, (3) an analysis of all viral public sequences, (4) an assessment of immunological responses, and (5) a summary of all major functional data. Analyses were adjusted for viral/human population structure and host factors associated with infection risk.

Results

We identified p.E123K/D and p.P218T/S/L in G protein that were associated with prolonged infection (Padj = .01). We found no evidence of host genetic risk for infection. The RSV variant positions approximate sequences that could bind a putative viral receptor, heparan sulfate.

Conclusions

Using analysis of both viral and host genetics we identified a novel RSV variant associated with prolonged infection in otherwise healthy infants and no evidence supporting host genetic susceptibility to infection. As the capacity of RSV for chronicity and its viral reservoir are not defined, these findings are important for understanding the impact of RSV on chronic disease and endemicity.
Outpatient purchasing patterns of hydroxychloroquine and ivermectin in the USA and Canada during the COVID-19 pandemic: an interrupted time series analysis from 2016 to 2021
Authors: Ho Martin , Tadrous Mina , Iacono Anita , Suda Katie , Gomes Tara
Published: November 2022

Background

Hydroxychloroquine and ivermectin received widespread attention after initial studies suggested that they were effective against COVID-19. However, several of these studies were later discredited.

Objectives

We explored the impact of scientific articles, public announcements and social media posts on hydroxychloroquine and ivermectin purchases in the USA and Canada during the COVID-19 pandemic.

Methods

We conducted a retrospective, population-based time series analysis of retail hydroxychloroquine and ivermectin purchases in the USA and Canada from February 2016 through to December 2021, using IQVIA’s Multinational Integrated Data Analysis database. We fitted the purchasing rates with interventional autoregressive integrated moving average models. We used Google Trends to identify the most influential interventions to include in the models.

Results

There were significant pulse increases in hydroxychloroquine purchases in March 2020 in both the USA (P < 0.0001) and Canada (P < 0.0001). For ivermectin, there were no significant changes in April 2020 in either the USA (P = 0.41) or Canada (P = 0.16); however, significant pulse increases occurred from December 2020 to January 2021 in both the USA (P = 0.0006) and Canada (P < 0.0001), as well as significant ramp increases from April to August 2021 in both the USA (P < 0.0001) and Canada (P = 0.02). The increases in ivermectin purchases were larger in the USA than in Canada.

Conclusions

Increases in hydroxychloroquine and ivermectin purchasing rates aligned with controversial scientific articles and social media posts. This highlights the importance of scientific integrity and disseminating accurate epidemiologic information during pandemics.
Impact of cartel enforcement on compliance in the chemical industry
Authors: De Stefano Gianni , Stephan Andreas
Published: November 2022

This article examines the relationship between EU cartel enforcement in the chemical industry in the period 1997–2010 and compliance measures announced in the Annual Reports of the undertakings involved. It goes on to focus on Akzo Nobel NV’s unique use of an internal amnesty programme, and the level of compliance in the industry following this period of enforcement. Its findings suggest cartel enforcement may have prompted significant investment in compliance measures, with some evidence of those measures resulting in earlier reporting in return for leniency.
Deceptively Simple: Can Urine Samples from CLIA-Waived Urine Drug Screen Devices Be Reused for Confirmatory Testing?
Authors: Pandya Vrajesh , McMillin Gwendolyn A , Young Brittany A
Published: November 2022

Background

Many low-complexity urine drug screen (UDS) devices are approved by the Food and Drug Administration as waived under Clinical Laboratory Improvement Amendments (CLIA) criteria. Labeling instructs patients to urinate directly into the device and also states that positive results should be confirmed. However, the device itself may pose a risk of drug adsorption and/or specimen contamination that could affect results in confirmatory assays if specimens are reused. Collecting urine in a separate container before performing the UDS would reclassify the test as nonwaived, negating the conveniences of a CLIA-waived test. Also, patients may be unable or unwilling to urinate in an additional container for confirmatory testing. This study examined reusing urine from a UDS device (NexScreen) for confirmatory testing.

Methods

25 patient specimens were pooled and verified to be drug-free. To evaluate drug leaching from the UDS device, 30 mL of this pool was incubated in NexScreen cups, followed by confirmatory testing. To evaluate drug adsorption, 14 representative analytes were spiked slightly over the NexScreen positivity cutoffs, followed by incubation in NexScreen cups and confirmation testing.

Results

All negative samples incubated in NexScreen cups remained negative upon confirmation testing, indicating that NexScreen test strips do not contaminate the specimen. For the drug adsorption experiment, 11 of 14 analytes had recoveries of at least 95%, whereas buprenorphine and 11-nor-9-carboxy-tetrahydrocannabinol recovered at 94% and 87%, respectively, suggesting minor adsorption. All analytes recovered above their respective confirmation cutoffs.

Conclusions

Urine aliquots from NexScreen cups may be used for confirmatory testing.
Using automated methods to detect safety problems with health information technology: a scoping review
Authors: Surian Didi , Wang Ying , Coiera Enrico , Magrabi Farah
Published: November 2022

Objective

To summarize the research literature evaluating automated methods for early detection of safety problems with health information technology (HIT).

Materials and Methods

We searched bibliographic databases including MEDLINE, ACM Digital, Embase, CINAHL Complete, PsycINFO, and Web of Science from January 2010 to June 2021 for studies evaluating the performance of automated methods to detect HIT problems. HIT problems were reviewed using an existing classification for safety concerns. Automated methods were categorized into rule-based, statistical, and machine learning methods, and their performance in detecting HIT problems was assessed. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Reviews statement.

Results

Of the 45 studies identified, the majority (n = 27, 60%) focused on detecting use errors involving electronic health records and order entry systems. Machine learning (n = 22) and statistical modeling (n = 17) were the most common methods. Unsupervised learning was used to detect use errors in laboratory test results, prescriptions, and patient records while supervised learning was used to detect technical errors arising from hardware or software issues. Statistical modeling was used to detect use errors, unauthorized access, and clinical decision support system malfunctions while rule-based methods primarily focused on use errors.

Conclusions

A wide variety of rule-based, statistical, and machine learning methods have been applied to automate the detection of safety problems with HIT. Many opportunities remain to systematically study their application and effectiveness in real-world settings.
Clinical features of CDK4/6 inhibitor-related interstitial lung disease in patients with breast cancer: a case series study
Authors: Funasaka Chikako , Naito Yoichi , Kusuhara Shota , Nakao Takehiro , Nakajima Hiromichi , Kawamoto Megumi , Baba Kaede , Mamishin Kanako , Kondoh Chihiro , Harano Kenichi , Matsubara Nobuaki , Hosono Ako , Sasaki Tomoaki , Kawasaki Toshikatsu , Mukohara Toru
Published: November 2022

Background

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the standard treatment for advanced hormone receptor-positive breast cancer. Although interstitial lung disease is a rare (1–3.3%) but serious adverse event associated with CDK4/6 inhibitors, the incidence of interstitial lung disease in Japanese patients in the real world and the risk factors of interstitial lung disease are not clear.

Methods

We retrospectively investigated the incidence of interstitial lung disease in 224 patients with advanced breast cancer who received CDK4/6 inhibitors at our hospital between 31 January 2017 and 31 January 2021. The correlation of age (>50 vs ≤50 years), presence or absence of previous history of interstitial lung disease, lung metastasis, smoking history and chest radiation with the development of interstitial lung disease was evaluated.

Results

In total, 177 cases received palbociclib, 39 cases received abemaciclib and 8 cases received both palbociclib and abemaciclib, constituting a palbociclib group (n = 185) and an abemaciclib group (n = 47). At a median observation period of 607 days, 8.0% (18/224) cases (13 definite and 5 probable cases) had interstitial lung disease; 6.5% (12/185) of palbociclib-treated and 13% (6/47) of abemaciclib-treated cases. The median time to interstitial lung disease onset was 178 (range, 14–750) days. There was no significant correlation between the background factors studied and the development of interstitial lung disease.

Conclusion

The frequency of CDK4/6 inhibitor-induced interstitial lung disease was higher than that reported in clinical trials. We did not identify any risk factors for the development of interstitial lung disease in this study, and thus, larger studies that include patient predisposition are required.
Osmoelectric siphon models for signal and water dispersal in wounded plants
Authors: Gao Yong-Qiang , Farmer Edward E
Published: November 2022

When attacked by herbivores, plants produce electrical signals which can activate the synthesis of the defense mediator jasmonate. These wound-induced membrane potential changes can occur in response to elicitors that are released from damaged plant cells. We list plant-derived elicitors of membrane depolarization. These compounds include the amino acid l-glutamate (Glu), a potential ligand for GLUTAMATE RECEPTOR-LIKE (GLR) proteins that play roles in herbivore-activated electrical signaling. How are membrane depolarization elicitors dispersed in wounded plants? In analogy with widespread turgor-driven cell and organ movements, we propose osmoelectric siphon mechanisms for elicitor transport. These mechanisms are based on membrane depolarization leading to cell water shedding into the apoplast followed by membrane repolarization and water uptake. We discuss two related mechanisms likely to occur in response to small wounds and large wounds that trigger leaf-to-leaf electrical signal propagation. To reduce jasmonate pathway activation, a feeding insect must cut through tissues cleanly. If their mandibles become worn, the herbivore is converted into a robust plant defense activator. Our models may therefore help to explain why numerous plants produce abrasives which can blunt herbivore mouthparts. Finally, if verified, the models we propose may be generalizable for cell to cell transport of water and pathogen-derived regulators.
Ecological Speciation Promoted by Divergent Regulation of Functional Genes Within African Cichlid Fishes
Authors: Carruthers Madeleine , Edgley Duncan E , Saxon Andrew D , Gabagambi Nestory P , Shechonge Asilatu , Miska Eric A , Durbin Richard , Bridle Jon R , Turner George F , Genner Martin J
Published: November 2022

Rapid ecological speciation along depth gradients has taken place repeatedly in freshwater fishes, yet molecular mechanisms facilitating such diversification are typically unclear. In Lake Masoko, an African crater lake, the cichlid Astatotilapia calliptera has diverged into shallow-littoral and deep-benthic ecomorphs with strikingly different jaw structures within the last 1,000 years. Using genome-wide transcriptome data, we explore two major regulatory transcriptional mechanisms, expression and splicing-QTL variants, and examine their contributions to differential gene expression underpinning functional phenotypes. We identified 7,550 genes with significant differential expression between ecomorphs, of which 5.4% were regulated by cis-regulatory expression QTLs, and 9.2% were regulated by cis-regulatory splicing QTLs. We also found strong signals of divergent selection on differentially expressed genes associated with craniofacial development. These results suggest that large-scale transcriptome modification plays an important role during early-stage speciation. We conclude that regulatory variants are important targets of selection driving ecologically relevant divergence in gene expression during adaptive diversification.
ANGI-03. TARGETING ANGIOGENIC PATHWAYS IN COMBINATION WITH OHSV THERAPY IN GBM
Authors: Vazquez-Arreguin Karina , Otani Yoshihiro , Rivera-Caraballo Kimberly , Guangsheng Pei , Zhongming Zhao , Kaur Balveen
Published: November 2022

Glioblastoma (GBM) is the most aggressive brain malignancy, which despite continuing worldwide efforts to develop new therapies, remains a deadly disease with limited treatment options. The asparagine hydroxylase factor inhibiting HIF (FIH1) is located in chromosome 10q24, a region often deleted in GBM, suggesting a tumor protective role. FIH1 has been implicated in GBM as an inhibitor of HIF1α-mediated transcription of VEGF-A, leading to decreased angiogenesis. We previously showed that oncolytic HSV (oHSV) infection reduces the expression FIH1 via a virus encoded miRNA. Furthermore, we have found that FIH1 also negatively regulates NOTCH signaling, which is elevated following oHSV treatment. Thus, we hypothesize that FIH1 reconstitution in tumors will block pro-tumorigenic NOTCH and HIF1α signaling. Using FIH1-overexpressing GBM cells we observed a reduction in vascular permeability, measured by intravital imaging, and decreased expression of angiogenesis markers. In vivo, combination of FIH1 overexpression with oHSV treatment resulted in enhanced survival in mice bearing intracranial GBM tumors. Furthermore, FIH1 overexpression correlated with the enrichment of genes associated with oxidative phosphorylation and ROS pathways, suggesting the potential for multi-modality therapeutic strategies.
BIOM-03. COMPREHENSIVE GENOMIC AND IMMUNE PROFILING OF NON-SMALL CELL LUNG CANCER BRAIN METASTASES REVEALS LOW TUMOR INFLAMMATION AND ELEVATED CANCER TESTIS ANTIGEN BURDEN
Authors: Seager R J , Pabla Sarabjot , Achyut B R , Nesline Mary , Kannan Geoffrey , Chenn Anjen , Zhang Shengle , Klein Roger , Conroy Jeffrey , Sausen Mark , Saini Kamal , Jensen Taylor , Reddy Prasanth , Severson Eric , Ramkissoon Shakti
Published: November 2022

BACKGROUND

Non-small cell lung cancer (NSCLC) accounts for ~50% of brain metastases. We present the genomic and immune biomarker landscape for a cohort with metastatic NSCLC to the brain.

METHODS

We analyzed brain metastases FFPE tissue (n=137; ages 40-85y (mean 65y), 52% female, 48% male) vs. primary sites (n=5533; ages 24-100+y (mean 71y), 51% female, 49% male) for advanced or metastatic NSCLC patients with comprehensive genomic and immune biomarker profiling, including PD-L1 IHC, tumor mutational burden (TMB), Tumor Immunogenic Signature (TIGS), Cell Proliferation (CP), and Cancer Testis Antigen Burden (CTAB).

RESULTS

Genomic alteration (GA) frequency for NSCLC brain metastasis versus primary sites were similar among the most frequently mutated genes except for KRAS which was significantly higher among brain metastases (39.9% vs 25.5%, p< 0.0005). No significant differences were observed for TP53 (50.7% vs 50.2%), STK11 (11.5% vs 10.9%), CDKN2A (10.1% vs 7%), or EGFR (8.0% vs 11.5%). PD-L1 expression for all cases by IHC was not significantly different (mean TPS 29.9% vs 26.3%); however, brain metastases were more likely to be PD-L1 negative (TPS< 1%) (46.3% vs 33.3%, p< 0.005). Conversely, TMB was higher in brain metastases versus primary sites (12.9 vs 10.2 muts/MB, p< 8x10-10), with more TMB-high cases (10 muts/Mb) (57.0% vs 33.5%, p< 3x10-8). Similarly, brain metastases had a higher proportion of CTAB-high cases (68.6% vs 57.6%, p=0.01). The immune response biomarker score, TIGS, was more often weak in brain metastases (52.6% vs 34.0%, p< 9x10-6).

CONCLUSION

In NSCLC, metastatic brain lesions have a larger antigen burden, with increased TMB and CTAB, likely due to the immune privileged nature of the brain, which is reflected in the lower TIGS scores and PD-L1 positivity. Despite lower PD-L1 positivity, NSCLC brain metastases with negative PD-L1 IHC may potentially benefit from immunotherapy strategies given the high TMB and CTAB.
BIOM-05. THE HER2 FLIP: HER2 AMPLIFICATION OF TUMOR CELLS IN THE CEREBROSPINAL FLUID (CSF-TCS) OF PATIENTS WITH SOLID TUMOR LEPTOMENINGEAL METASTASIS
Authors: Kumthekar Priya , Youssef Michael , Blondin Nicholas , Azadi Amir , Piccioni David , Glantz Michael , Carillo Jose , Sharma Akanksha , Avgeropoulos Nicholas , Makar Sherif , Blouw Barbara , Natasha Anna , Fisher Deanna , Huynh Lan , Peters John , Matsutani Mariko , Sales Edgar , Sweed Nathan , Dugan Michael , Kesari Santosh
Published: November 2022

INTRODUCTION

Patients with leptomeningeal metastasis (LM) have limited treatment options and a poor outcome. However, they may benefit from targeted therapy. LM patients with HER2-positive primary breast cancer treated with IT trastuzumab demonstrated clinical benefit (Malani, 2020), and improved PFS (Figura, 2019). HER2 amplification in the primary and metastatic tumors can be divergent. Biocept’s CNSideTM is a CLIA validated test that can detect CSF tumor cells (CSF-TCs) and interrogate those cells with FISH and NGS. We analyzed HER2 amplification on CSF-TCs in LM patients with breast cancer, non-small cell lung cancer (NSCLC) and upper GI cancer.

METHODS

CSF was collected from patients with suspected or confirmed LM with breast cancer (N =134 patients), NSCLC (Nf28 patients) or upper GI cancer (Nf2 patients). CSF TCs were tested for HER2 amplification by FISH using CNSide.

RESULTS

HER2 amplification in CSF-TCs was detected in 46% (76/164) of all patients. Of the breast cancer patients, 37% (49/134) flipped HER2 status in the LM tumor, 38% (41/108) switched from a HER2 negative or equivocal primary tumor to HER2 positive CSF-TCs, and 27% (7/26) from a HER2 positive primary tumor to HER2 negative CSF-TCs. For the NSCLC patients, 50% (14/28) showed HER2 amplification on the CSF-TCs. For the upper GI cancer patients, HER2 amplification in CSF-TCs was detected in both patients, one patient had an equivocal HER2 primary tumor and HER2 positive CSF-TCs.

CONCLUSION

HER2 amplification was detected in a substantial fraction of CSF-TCs from patients with LM from breast, upper GI, and NSCL cancers. This finding may have important therapeutic (justifying the use of intra-CSF trastuzumab), prognostic (HER2 positivity in NSCLC is associated with poorer prognosis and a higher frequency of CNS metastases) and pathophysiologic implications (a potential role of HER2 amplification in the genesis of CNS metastases). Additional investigations are underway.
BIOM-34. MULTIPLEX PHENOTYPING OF EXTRACELLULAR VESICLES FOR ANALYSIS OF POTENTIAL BIOMARKERS IN GLIOBLASTOMA PATIENTS
Authors: Salviano-Silva Amanda , Wollmann Kathrin , Maire Cecile , Kolbe Katharina , Dührsen Lasse , Lamszus Katrin , Ricklefs Franz
Published: November 2022

INTRODUCTION

Extracellular vesicles (EVs) carry biological information from their cell of origin that is useful for non-invasive detection of tumor biomarkers and disease monitoring. In glioblastoma (GBM), blood circulating EVs are elevated and carry GBM-associated proteins. However, it is still challenging to analyze tumor derived EVs for translational purposes. Here, we used imaging flow cytometry (IFCM) as a robust strategy to perform phenotyping of EVs with GBM related surface markers in human plasma.

METHODS

EVs were isolated via differential ultracentrifugation from plasma of (a) 40 GBM patients, pre- and post-surgery, (b) 11matched GBM relapses and (c) 12 healthy donors (HD). EV sizes and concentrations were evaluated by NTA. EV markers (CD9,CD63 and CD81) together with glioma-related markers (integrin beta-1 [ITGB1], tenascin C [TNC], Profilin-1 [PFN1], CD44,GPNMB, SPARC, HLA-II or CD133) were analyzed by IFCM. EV percentages and objects/mL plasma were compared among the groups and correlated with clinical parameters.

RESULTS

CD9 was the predominant tetraspanin in all groups (15-96%), while CD63 had the lowest levels (0-33%) and the strongestdecrease in GBM patients after surgery (fold change [FC]=-5.4, p<0.01). Among the glioma-related markers, ITGB1 and TNC displayed the most significant differences between the analyzed groups, especially the double positives ITGB1+/CD63+and TNC+/CD63+, which decreased in patients after tumor removal (FC=-3.5 and -12, respectively; p<0.001). Meanwhile,ITGB1+/CD9+and TNC+/CD9+EVs exhibited the highest levels in GBM when compared to HD subjects (FC=8.6 and 17.4;p<0.001) and upon tumor recurrence (FC=3.7 and 10.9, respectively; p<0.01).

SUMMARY/CONCLUSION

We identified EV surface antigens with potential clinical utility as GBM biomarkers. Among them, we highlight ITGB1 and TNC as the most promising markers.
CNSC-14. ROLE OF A COLLAGEN RECEPTOR, LAIR-1, IN GLIOMA CELLS: A POTENTIAL THERAPEUTIC TARGET
Authors: Varela Maria Luisa , Comba Andrea , Syed Mohammad Faisal , Murthy Bhuvna R , Barissi Marcus N , Castro Maria , Lowenstein Pedro
Published: November 2022

Most primary brain tumors are gliomas, among which Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. GBM has a median survival of 15-18 months, and despite extensive research remains incurable. Previous work in our lab has shown the importance of Collagen I, expressed by glioma cells, in glioma growth. Employing genetically engineered mouse models (GEMM) of glioma, NPA (NRas, shP53, shATRX), we identified that Collagen 1α1 (Col1A1) plays a key role in tumor malignancy. Molecular ablation of Col1A1 extends median survival, with a reduction in migration and proliferation. However, the mechanisms underlining these changes in survival, and the receptors mediating these effects remain unknown. Several collagen receptors are present in glioma cells. LAIR-1 is a collagen receptor that was originally described as an inhibitory receptor in hematopoietic cells. Since then, it has been demonstrated that LAIR-1 plays critical roles in the immune imbalance of autoimmune diseases and cancers. There have been several studies postulating the expression of LAIR-1 in tumor cells, including non-hematopoietic tumors. These studies suggest that LAIR-1 may constitute a novel receptor that tumor cells exploit to promote tumor growth and achieve immune evasion, yet its role in glioma remains unclear. Here we describe that glioma cells express LAIR-1, and that its molecular ablation in vitro showed reduced cell proliferation. In addition, GEMM lacking LAIR-1 (NRas, shP53, shATRX, shLAIR-1) exhibit improved median survival. Our preliminary data suggest that LAIR-1 expressed in glioma cells has a role in glioma aggressiveness. Currently we are further characterizing the role of LAIR-1 in high grade gliomas, as well as its potential as a therapeutic target. We hypothesize that blocking the interaction between LAIR-1 and collagen in the tumor microenvironment may improve median survival by reducing tumor proliferation.
TMET-06. METABOLIC FATE OF OXALOACETATE IN GLIOBLASTOMA
Authors: Ijare Omkar , Baskin David , Conway David , Cash Alan , Pichumani Kumar
Published: November 2022

Oxaloacetate (OAA) inhibits the Warburg effect by reducing the glucose-derived lactate levels in human cancer cell lines. In dose ranging IC50 experiments with human hepatocellular carcinoma (HCC) cell lines, OAA inhibited cell growth in the concentration range 1.7 - 2.4 mM. Previously, we showed that in the presence of OAA, [U-13C]glucose derived lactate was reduced by 48.8% in GBM cells. OAA also increased survival in mouse models of GBM. Here, we are showing an evidence for the direct utilization of OAA by Glioblastoma (GBM) cells, using uniformly 13C-labeled oxaloacetate ([U-13C]OAA) as a metabolic tracer. Patient-derived GBM cells were grown in DMEM medium containing 11.0 mM glucose and 2.0 mM glutamine. When cells reached confluency, were treated with 4.0 mM [U-13C]OAA in the above DMEM medium. GC-MS based 13C isotopomer analysis showed that [U-13C]OAA entered the cells and get metabolized to generate distinct 13C-labeled isotopomers of aspartate, citrate, glutamate, malate and fumarate. Upon entering TCA cycle, [U-13C]OAA generated M+4 aspartate (3.0%) and citrate (3.2%), and M+3 glutamate (4.1%). During the first turn of the TCA cycle, it produced M+2 aspartate (13.9%), malate (10.5%), and fumarate (8.8%), and after multiple turns, [U-13C]OAA led to the production of the following 13C-labeled isotopomers: M+2 citrate (21.5%), M+2 glutamate (17.2%), M+1 glutamate (5.6%) and M+4 glutamate (2.2%). In addition, [U-13C]OAA also produced [U-13C]pyruvate (17.0%) through PEPCK/PK/ or malic enzyme which further generated similar amount of [U-13C]lactate (17.0%) and [U-13C]alanine (12%). These data demonstrate that GBM cells utilize [U-13C]OAA to perturb TCA cycle and glycolytic pathways, and support our previous observation that OAA-derived pyruvate lead to an increase in the total pyruvate pool and associated decrease in glycolytic flux including the glucose-derived lactate. OAA may metabolically reduce tumor growth in difficult to treat cancers.
TMET-17. NOX2-INDUCED HIGH GLYCOLYTIC ACTIVITY CONTRIBUTES TO THE GAIN OF COL5A1-MEDIATED MESENCHYMAL PHENOTYPE IN GBM
Authors: Park Youngjoon , Park Minwoo , Kim Junhyung , Ahn Juwon , Sim Jeongmin , Bang Ji-In , Heo Jinhyung , Choi Hyejeong , Cho Kyunggi , Lee Mihye , Moon Jong-Seok , Lim Jaejoon
Published: November 2022

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and exhibits extensive heterogeneity and poor prognosis with a high recurrence rate. Among the genetic alterations in GBM with different phenotypic states, a mesenchymal subtype has been associated with a worse outcome in patients with GBM. The mechanisms for the gain of the mesenchymal subtype in GBM remain unclear. Our aim was to investigate whether NOX2-induced high glycolytic activity could contribute to the gain of the mesenchymal phenotype in GBM. We revealed that NOX2-induced high glycolytic activity can induce the gain of the COL5A1-mediated mesenchymal phenotype inGBM. Our findings will provide the molecular mechanism by which NOX2 contributes to the gain of mesenchymal phenotype in GBM.
TMIC-01. STAT3 EXPRESSION IN BRAIN METASTASES FROM BREAST CANCER: CORRELATIONS WITH DIFFERENT MOLECULAR SUBTYPES AND CLINICAL OUTCOME
Authors: Pellerino Alessia , Bruno Francesco , Bertero Luca , Bellini Elisa , Beano Alessandra , Montemurro Filippo , Valiente Manuel , Rudà Roberta , Soffietti Riccardo
Published: November 2022

BACKGROUND

STAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) from breast cancer (BC) may favor a pro-metastatic environment.

MATERIAL AND METHODS

Eighty-five BM specimens from BC were identified from the biobank of Pathology Unit of University of Turin and Spanish national BrM network (RENACER). pSTAT3 expression was scored in RA of peritumoral tissue according to Priego et al. (Nat Med 2018). Clinical, molecular data, and intracranial progression (i-PFS) were retrospectively retrieved.

RESULTS

Median age was of 54 years (range 30–81). Immunohistochemistry for GFAP and pSTAT3 was feasible in 68/85 (80%). 15/68 patients (21.1%) had BM from luminal BC, 27/68 (39.7%) from HER2-positive BC, and 26/68 (39.2%) from TNBC. 56/68 (82.4%) showed positive staining of pSTAT3, of which 9/68 (13.3%) scored with 3, 26/68 (38.2%) with 2, 21/68 (30.9%%) with 1, and 12/68 (17.6%) with 0 (negative). High pSTAT3 expression (score 2-3) was observed in 17/27 (62.9%) BM from HER2-positive BC and in 15/26 (57.7%) BM from TNBC, while most of BM from luminal BC (12/15 – 80%) had low or absent pSTAT3 (score 0-1) (p=0.021). Overall i-PFS was 16 months (range 7-41): low pSTAT3 BM (score 0-1) had a median i-PFS of 21 months versus 12 months for high pSTAT3 BM (score 2-3). A shorter median i-PFS was observed in high pSTAT3 BM from TNBC (4 months) as compared with low pSTAT3 BM (11 months). Conversely, i-PFS of high pSTAT3 BM (7 months) was similar to low pSTAT3 BM (6 months) in HER2-positive BC.

CONCLUSION

pSTAT3 expression in RA of peritumoral tissue of BM from TNBC and HER2-positive BC is higher than in BM from luminal BC. Of note, patients with high pSTAT3 BM from TNBC progressed earlier in comparison with those with low pSTAT3, suggesting that pSTAT3 expression has an influence on the outcome.
TMIC-11. ASSOCIATION OF TIM-3/GAL-9 AXIS WITHNLRC4 INFLAMMASOME IN GLIOMA MALIGNANCY: TIM-3/GAL-9 INDUCE THE NLRC4 INFLAMMASOME
Authors: Sim Jeongmin , Park JeongMan , Kim Suwan , Hwang Sojung , Sung KyoungSu , Lee Jung-Eun , Yang SeungHo , Cho Kyunggi , Lee SungHwan , Moon Jong-Seok , Ahn Juwon , Lim Jaejoon
Published: November 2022

Tim-3/Gal-9 and the NLRC4 inflammasome contribute to glioma progression. However, the underlying mechanisms involved are unclear. Here, we observed that Tim-3/Gal-9 expression increased with glioma malignancy and found that Tim-3/Gal-9 regulate NLRC4 inflammasome formation and activation. Tim-3/Gal-9 and NLRC4 inflammasome-related molecule expression levels increased with WHO glioma grade, and this association was correlated with low survival. We investigated NLRC4 inflammasome formation by genetically regulating Tim-3 and its ligand Gal-9. Tim-3/Gal-9 regulation was positively correlated with the NLRC4 inflammasome, NLRC4, and caspase-1 expression. Tim-3/Gal-9 did not trigger IL-1  secretion but were strongly positively correlated with caspase-1 activity as they induced programmed cell death in glioma cells. A protein– protein interaction analysis revealed that the FYN-JAK1-ZNF384 pathways are bridges in NLRC4 inflammasome regulation by Tim-3/Gal-9. The present study showed that Tim-3/Gal-9 are associated with poor prognosis in glioma patients and induce NLRC4 inflammasome formation and activation. We proposed that a Tim-3/Gal-9 blockade could be beneficial in glioma therapy as it would reduce the inflammatory microenvironment by downregulating the NLRC4 inflammasome.
TMIC-18. ROLE OF DISCOIDIN DOMAIN RECEPTORS (DDR1/DDR2) IN SENSITIZATION OF GLIOMAS TOWARDS RADIOTHERAPY
Authors: Syed Mohammad Faisal , Comba Andrea , Varela Maria Luisa , Argento Anna , Brumley Emily , Abel Clifford , Castro Maria , Lowenstein Pedro
Published: November 2022

Glioblastoma (GBM), a high-grade glial tumor, is highly aggressive and is characterized by intra-tumoral heterogeneity and widespread infiltration, impairing therapeutic success. Our laboratory discovered dynamic multicellular fascicles of spindle-like and aligned cells with mesenchymal features called “oncostreams” inside GBM tumors that facilitate invasion into the normal brain. We found that collagen 1α1 (Col1A1) is essential for oncostream structure and function. Using in vivo intravital imaging and ex vivo explant glioma models, we established that Col1A1 suppression abolishes oncostreams, reprograms the malignant histopathological phenotype, and extends median survival in mice. However, the signaling through which collagen communicates to maintain an invasion-permissive glioma tumor microenvironment remains unclear. We propose to analyze a poorly understood collagen receptor family -the discoidin domain receptors (DDRs) - which is expressed in glioma and perivascular stromal cells. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) data suggest DDR1/DDR2 overexpression correlates with tumor progression and poor prognosis in glioma patients. Our RNA-seq data further confirm overexpression of DDRs in NPA and NPD glioma compared to the normal brain. Our preliminary data suggests that inhibiting collagen receptors DDR1 or DDR2 sensitizes glioma cells to radiotherapy (IR). DDR1 inhibition completely disrupts oncostreams` structure in the ex vivo explant glioma model. Moreover, pharmacological inhibition of DDR1 combined with irradiation significantly enhances the median survival of NPA (Nras, shP53, shATRX) tumors in an orthotopic mouse glioma model. Furthermore, we are currently testing whether inhibition of DDR1 using a genetically engineered mouse model (GEMM) of glioma called NPAD1 (Nras, shP53, shATRX, shDDR1) will show an increase in overall survival. We hypothesize that blocking collagen receptors DDR1 or DDR2 will control tumor growth, invasion and mediate anti-glioma immunity. This study will eventually uncover a novel therapeutic treatment for GBM, targeting DDR1 and DDR2 in human patients.
MODL-39. CHARACTERIZING NON-ENHANCING TUMOR USING MULTI-SHELL DIFFUSION MRI
Authors: Golkar Ehsan , Parker Drew , Brem Steven , Verma Ragini
Published: November 2022

Characterizing infiltration in the non-enhancing tumor (NET) is clinically crucial as infiltration leads to progression, and a reduction in survival times. As voxel-wise biopsy of these regions is infeasible, a non-invasive MRI-based identification of infiltration would be a significant contribution. Diffusion MRI (dMRI), with its ability to model different levels of water restriction, as is caused by infiltration and edema, is well positioned to model the NET. This is achieved via multicomparment modeling (MCM) of the dMRI where infiltration, vasogenic edema and healthy tissue (with complex fibers) form the different compartments. Current MCM approaches are either not designed for NET or rely on advanced MRI scans currently not feasible in the clinic. The simplest ball-tensor models, including Hoy 2014 using multi-shell data and FERNET 2020 for single-shell data, consists of a free water compartment that models vasogenic edema and a tensor modeling underlying tissue. These single-tensor methods cannot model complex WM fibers. Our proposed model consists of two steps. First, two bundles are fit: an isotropic bundle with two balls that model isotropic free diffusivity and restricted diffusivity, and a bundle containing stick and zeppelin, corresponding to intra-cellular and extra-cellular diffusion of axons, respectively. Next, a fiber orientation distribution (FOD) is estimated from the fitted parameters. We applied our modeling to multi-shell data from eight patients with glioblastoma, and one patient with a metastatic brain tumor. Our method produces maps corresponding to free water (CSF), restricted diffusion, intra-cellular, and extra-cellular volume fractions. Preliminary results show that restricted diffusivity map of NET comprises 46% of vasogenic metastatic edema compare to 15% of infiltrated GBM edema. In conclusion, we demonstrate that our proposed model shows promise to characterize the NET region of various brain tumors, and distinguishing tumor types. These compartments will provide invaluable radiomic features that no other modality can capture.
CSIG-09. THERAPEUTIC TARGETING OF PRENATAL PONTINE ID1 SIGNALING IN DIFFUSE MIDLINE GLIOMA
Authors: Messinger Dana , Harris Micah , Cummings Jessica , Thomas Chase , Yang Tao , Sweha Stefan , Woo Rinette , Siddaway Robert , Burkert Martin , Stallard Stefanie , Qin Tingting , Mullan Brendan , Siada Ruby , Ravindran Ramya , Niculcea Michael , Dowling Abigail , Bradin Joshua , Ginn Kevin , Gener Melissa , Dorris Kathleen , Vitanza Nicholas , Schmidt Susanne , Spitzer Jasper , Li Jiang , Filbin Mariella , Cao Xuhong , Castro Maria , Lowenstein Pedro , Mody Rajen , Chinnaiyan Arul , Desprez Pierre-Yves , McAllister Sean , Dun Matthew , Hawkins Cynthia , Waszak Sebastian , Venneti Sriram , Koschmann Carl , Yadav Viveka
Published: November 2022

Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis. The mechanism behind tumor invasion is currently not well understood. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. Whole exome, RNA, and ChIP-sequencing were performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Additional in vitro experiments were performed to determine a potential mechanism of action for CBD-mediated effects. Self-reported CBD dosing information was collected from DMG patients. We found that increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates a similar epigenetically active state at ID1 regulatory regions in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell migration, tumor growth, and to a lesser extent invasion in both murine IUE and multiple patient-derived in vivo DMG models, improving mouse survival. ID1 knockdown significantly decreases the effect of CBD on migration, tumor growth, and invasion. CBD increases reactive oxygen species production, which also affects DMG cell proliferation in a non-ID1 mediated manner. Overall, we find that H3K27M-mediated reactivation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.
RADT-05. VOLUMETRIC MODULATED ARC THERAPY CRANIOSPINAL IRRADIATION UTILIZING A VERTEBRAL BODY SPARING APPROACH: A DOSIMETRIC ANALYSIS
Authors: Matsui Jennifer , Perlow Haley , Ewing Ashlee , Cadieux Catherine , Blakaj Dukagjin , Beyer Sasha , Thomas Evan , Raval Raju , Palmer Joshua
Published: November 2022

BACKGROUND

Craniospinal irradiation (CSI) is indicated for adult patients diagnosed with leptomeningeal disease (LMD). Proton-based vertebral-body-sparing (VBS) CSI has been explored with pediatric patients to minimize hematologic toxicity; however, utilization of VBS in an adult population is limited. We hypothesize that VBS-CSI utilizing volumetric modulated arc therapy (VMAT) will effectively reduce vertebral body dose while minimizing dose to surrounding organs-at-risk (OAR) for adult patients with LMD.

METHODS

Ten adult patients with LMD received CSI, 30 Gy in 10 fractions. These patients were initially treated with a variety of VMAT and IMRT treatment techniques. These patients were then retrospectively replanned using VMAT VBS-CSI. For their VBS-CSI replan, full VMAT arcs for the brain fields matched to two spine isocenters for the upper and lower spine were created utilizing limited posterior arcs. The PTV was created with margins of 3mm uniformly around the brain contour and 7mm around the spinal canal. To further decrease the vertebral body dose, an avoid entry and exit contour was created. This structure was a margin on the PTV anteriorly designed to carve dose out of the vertebral bodies while still maintaining coverage to the PTV.

RESULTS

All 10 patients had a reduction in vertebral body dose with VMAT VBS-CSI when compared to their initial plan. The mean vertebral dose for the VBS-CSI plans had an average reduction of 33% compared to the initial plans. The mean dose to the small bowel and esophagus were reduced by 46% and 67%, respectively.

CONCLUSIONS

VBS-CSI may be utilized to minimize dose to surrounding OARs and vertebral bodies. In this study, VMAT VBS-CSI led to significant reductions in vertebral body dose while also minimizing dose to other OARs. VMAT VBS-CSI may be an acceptable alternative to proton-based VBS-CSI in an adult population with LMD. Prospective evaluation is warranted.
CTIM-01. TITLE: PHASE 1B STUDY OF AVELUMAB AND WHOLE BRAIN RADIOTHERAPY (WBRT) IN PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD): PRELIMINARY RESULTS
Authors: Pina Yolanda , Chen Ann , Arrington John A , Macaulay Rob , Tran Nam , Liu James , Mokhtari Sepideh , Li Jiannong , Law Vincent , Sahebjam Solmaz , Ahmed Kamran , Creelan Ben , Gray Jhanelle , Wallace Gerald , Evernden Brittany , Stewart Christine L , Khushalani Nikhil , Smalley Inna , Smalley Keiran , Vogelbaum Michael , Yu Michael , Forsyth Peter
Published: November 2022

BACKGROUND

LMD from systemic cancer has a dismal prognosis with median survivals of 8-10 weeks. A phase 2 trial of PD-1 inhibitor monotherapy in LMD showed median overall survival (OS) of 3.6 months (Brastianos P et al., 2020). We determined the safety/efficacy of avelumab, a PD-L1 inhibitor with WBRT in patients with LMD (NCT0371768). This combination can treat the tumor directly and increase BBB permeability (Li, 2003; Nordal, 2005) allowing the increased egress of activated T cells into the meninges/CSF.

METHODS

Patients received concurrent avelumab 800 mg IV q2 weeks for ≤ 5 cycles (unless PD or unacceptable toxicity) with WBRT 3000 cGy in 10 fractions. Primary endpoints are safety/DLTs and OS at 3 months. Secondary endpoints are CSF T-cell/cytokine profiles (scRNAseq, phosophoproteomics etc.).

RESULTS

A total of 15 patients (7 breast, 7 lung & 1 other) were enrolled (n = 13 F, ages 32-79). Pts receiving anti-PD-1/PD-1L/PD-L2/CD137,CTLA-4 therapy ≤ 6 months prior were excluded. Three of 15 patients had grade 3/4 AEs (diarrhea, lymphopenia, decreased WBC count in 3 patients). Seven patients (50%) were alive at 3 or 6 months. The estimated median follow up in 14 patients is 4.75 months (range, 0.92 – 30.05 months, 95% CI is 1.32 ~ 19.82). The median PFS is 3.75 months (95% CI = 0.85-15.16) and median OS is 6.89 months (95% CI = 1.18-14.7).

CONCLUSIONS

The combination of avelumab and WBRT is safe, well tolerated, and demonstrates encouraging activity in patients with LMD with an OS that is longer than other published series. Multiple platform interrogation of CSF (analysis underway) will determine mechanisms of LMD therapeutic/resistance effects.