bluuebunny/crossref_metadata_2025 huggingface dataset:
On weak Ikeda–Nakayama rings
Authors: Van Thuyet Le , Diallo Abdoul Djibril , Diop Papa Cheikhou , Quynh Truong Cong
Published: September 2024

A ring [Formula: see text] is called a left Ikeda–Nakayama ring (briefly, left IN-ring) if [Formula: see text] for all left ideals [Formula: see text] and all left ideals [Formula: see text] of [Formula: see text]. A ring [Formula: see text] is a called a left [Formula: see text]-ring if [Formula: see text] for all finitely generated semisimple left ideals [Formula: see text] and all left ideals [Formula: see text] of [Formula: see text]. It is clear that a left [Formula: see text] ring must be left [Formula: see text]. Right [Formula: see text]-rings can be defined similarly. It is shown that a left [Formula: see text]-ring may not be right [Formula: see text] and a left [Formula: see text] ring may not be left [Formula: see text]. One of the aims of this paper is to investigate left [Formula: see text]-rings satisfying additional conditions. We show that this weak injectivity property is useful in obtaining semiperfect rings. Moreover, we give several new characterizations of [Formula: see text] rings and [Formula: see text] rings via [Formula: see text]-rings. Finally, left [Formula: see text], [Formula: see text]-rings were considered.
Nonlinear mixed ∗-Jordan n-derivations on ∗-algebras
Authors: Siddeeque Mohammad Aslam , Bhat Raof Ahmad , Shikeh Abbas Hussain
Published: September 2024

Let [Formula: see text] be a ∗-algebra with unity [Formula: see text] and a nontrivial projection [Formula: see text]. In this paper, it is shown that if a map [Formula: see text] satisfies [Formula: see text] for all [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] for all [Formula: see text], where [Formula: see text], then [Formula: see text] is an additive ∗-derivation. Moreover, we shall call such a map [Formula: see text], a nonlinear mixed ∗-Jordan [Formula: see text]-derivation. As applications, we will characterize nonlinear mixed ∗-Jordan [Formula: see text]-derivation in standard operator algebras and von Neumann algebras.
Thallium enrichment mechanism and geological significance of the Xiangquan thallium deposit in Anhui Province, China
Authors: Guo Zhijuan , Xu Renting , Song Yuntao , Han Wei , Kong Mu , Fan Yang
Published: September 2024

The discovery of the independent thallium (Tl) deposit in Xiangquan, Anhui Province, provides an example for the study of the enrichment and mineralization of the highly dispersed rare metal element Tl. In this paper, a range of methods are used to characterize the enrichment, depletion, migration and occurrence state of Tl in different types of rocks and ores: lithogeochemistry; electron microprobe and principal component analysis; and exploring the significance of geochemical anomalies on the geological indication of Tl deposit formation. The results show that Tl is mainly distributed in silicified rocks of the Ordovician Lunshan Formation, and its average content is 307.08 

μ

g g
–1
. The contents of As, Sb, S, Fe
2
O
3
and Tl in wall rocks, altered rocks and ores are significantly correlated, indicating a close relationship with Tl accumulation. The geochemical characteristics confirm that pyrite in the study area originates from submarine hot-water deposition. The main carrier of Tl is pyrite of hydrothermal sedimentary origin, in which Tl occurs as isomorphs in fine grains of pyrite. Tl mineralization may be accompanied by silicification, and the metallogenic environment is in a relative oxidation state. The mineralization process results in the geochemical differentiation of elements. Under the influence of tectonic and low-temperature hydrothermal activities, ore-forming elements migrate to structurally favourable conditions for mineralization to occur. This study provides a basis for further understanding the mechanisms of co-enrichment and separation of Tl and guidance for Tl mineral exploration.
Decoding Debugging Instruction: A Systematic Literature Review of Debugging Interventions
Authors: Yang Stephanie , Baird Miles , O’Rourke Eleanor , Brennan Karen , Schneider Bertrand
Published: September 2024

Students learning computer science frequently struggle with debugging errors in their code. These struggles can have significant downstream effects—negatively influencing how students assess their programming ability and contributing to their decision to drop out of CS courses. However, debugging instruction is often an overlooked topic, and instructors report feeling unaware of effective approaches to teach debugging. Within the literature, research on the topic is sporadic, and though there are rigorous and insightful studies to be found, there is a need to synthesize instructional approaches for debugging. In this article, we review research from 2010 to 2022 on debugging interventions. We summarize the common pedagogical approaches for learning and categorize how these target specific cognitive and non-cognitive debugging skills, such as self-efficacy and emotion regulation. We also present a summary of assessment methods and their outcomes in order to discuss intervention efficacy and directions for further research. Our sample displays a diverse variety of debugging interventions and pedagogical approaches, ranging from games to unplugged activities. An evaluation of article results also presents encouraging findings, revealing several interventions that improved debugging accuracy and learning. Still, we notice gaps in interventions addressing non-cognitive debugging skills and observe limited success in guiding students toward adopting systematic debugging strategies. The review concludes with a discussion of future directions and implications for researchers and instructors in the field.
Creative Writing and Expository Writing. Flip Sides of the Same Coin?
Authors: Yaffe Philip
Published: September 2024

Each "Communication Corner" essay is self-contained; however, they build on each other. For best results, before reading this essay exercise, go to the first essay "How an Ugly Duckling Became a Swan," and then read each succeeding essay.

Creative (fiction) writing and expository (non-fiction) writing have fundamentally different objectives. Creative writing seeks to amuse and entertain; expository writing seeks to inform and instruct. But while aiming at different targets, they share fundamentally important approaches and techniques. Ignoring these commonalities does serious harm to both genres.
International Guidelines for Photosensitive Epilepsy: Gap Analysis and Recommendations
Authors: Jordan J. Bern , Vanderheiden Gregg C.
Published: September 2024

People with photosensitive epilepsy may have seizures caused by flashing lights, patterns, and video sequences. Because of this, there is increasing interest among researchers, developers, and companies toward making content safer. There are five major guidelines (from the U.K., Japan, ISO, ITU, and W3C) to limit risk in different technology domains that have been created since the mid-1990s. All address similar risk factors, but they are not fully harmonized and can be confusing. Furthermore, there have been significant changes in technology since the guidelines were introduced. This article compares and clarifies the guidelines, describes risk factors that have changed (such as the reduction of risk due to display technology), gaps in our knowledge, the coverage of new technology, and new characteristics (such as the duration and synchronicity of individual flash transitions) that may need to be accounted for. The authors suggest working values for new thresholds and propose updated guidelines.
A Survey of Distributed Graph Algorithms on Massive Graphs
Authors: Meng Lingkai , Shao Yu , Yuan Long , Lai Longbin , Cheng Peng , Li Xue , Yu Wenyuan , Zhang Wenjie , Lin Xuemin , Zhou Jingren
Published: September 2024

Distributed processing of large-scale graph data has many practical applications and has been widely studied. In recent years, a lot of distributed graph processing frameworks and algorithms have been proposed. While many efforts have been devoted to analyzing these, with most analyzing them based on programming models, less research focuses on understanding their challenges in distributed environments. Applying graph tasks to distributed environments is not easy, often facing numerous challenges through our analysis, including parallelism, load balancing, communication overhead, and bandwidth. In this article, we provide an extensive overview of the current state-of-the-art in this field by outlining the challenges and solutions of distributed graph algorithms. We first conduct a systematic analysis of the inherent challenges in distributed graph processing, followed by presenting an overview of existing general solutions. Subsequently, we survey the challenges highlighted in recent distributed graph processing papers and the strategies adopted to address them. Finally, we discuss the current research trends and identify potential future opportunities.
mm-CUR: A Novel Ubiquitous, Contact-free, and Location-aware Counterfeit Currency Detection in Bundles Using Millimeter-Wave Sensor
Authors: Niaz Fahim , Zhang Jian , Zheng Yang , Khalid Muhammad , Niaz Ashfaq
Published: September 2024

Abstract: Target material sensing in non-invasive and ubiquitous contexts plays an important role in various applications. Recently, a few wireless sensing systems have been proposed for material identification. In this article, we introduce mm-CUR, A Novel Ubiquitous, Contact-free, and Location-aware Counterfeit Currency Detection in Bundles using a Millimeter-Wave Sensor. This system eliminates the need for individual note inspection and pinpoints the location of counterfeit notes within the bundle. We use Frequency Modulated Continuous Wave (FMCW) radar sensors to classify different counterfeit currency bundles on a tabletop setup. To extract informative features for currency detection from FMCW signals, we construct a Radio Frequency Snapshot (RFS) and build signal scalogram representations that capture the distinct patterns of currency received from different currency bundles. We refine the RFS by eliminating multi-path interference, and noise cancellation and apply high pass filters for mitigating the smearing effect with the continuous wavelet transform (CWT). To broaden the usage of mm-CUR, we built a transferable learning model that yields robust detection results in different scenarios. The classification results demonstrated that the proposed counterfeit currency detection system can detect counterfeit notes in 100-note bundles with an accuracy greater than 93%. Compared to the standard CNN and DNN methods, the proposed mm-CUR model showed superior performance in distinguishing each bundle data, even for a limited-size dataset.
Ultrasound technology as a tool to teach basic concepts of physiology and anatomy in undergraduate and graduate courses: a systematic review
Authors: Johnson Christopher D. , Davison Louise , Graham Emma C. , Sweeney Eva M.
Published: September 2024

This first systematic review of ultrasound use as a teaching tool in basic anatomy and physiology confirmed that students and staff believe incorporation is beneficial to learning and is highly popular. Quantitative data are scarcer but show that it is at least as effective as more conventional teaching methods and can enhance short-term recall. Good-quality studies with adequate comparisons and assessment methods are still lacking, so further work in this area is needed.
Carbon monoxide supplementation: evaluating its potential to enhance altitude training effects and cycling performance in elite athletes
Authors: Urianstad Tomas , Villanova Simone , Odden Ingvill , Hansen Joar , Mølmen Knut S. , Porcelli Simone , Rønnestad Bent R. , Cardinale Daniele A.
Published: September 2024

Three weeks of training at moderate altitude with exposure to low doses of CO can significantly enhance hematological adaptations in elite cyclists compared to moderate-altitude training alone. Cycling performance determinants improved more with CO inhalation at moderate altitude compared to sea-level training, whereas there were no differences in submaximal and maximal performance measures compared to moderate-altitude training alone. This study highlights the potential of CO supplementation as an effective adjunct to altitude training regimens.
Gentiopicroside Ameliorates Sepsis‐Induced Acute Lung Injury via Inhibiting Inflammatory Response
Authors: Hu Mu , Du Hangxiang , Xu Yang , Wang Yan
Published: September 2024

Sepsis is a systemic inflammatory reaction syndrome caused by infections. Acute lung injury (ALI) occurs first and most frequently in patients with sepsis. Gentiopicroside (GPS), which originates mostly from Gentiana, is classified as a secoiridoid glycosides. Terpenoid glycosides have various biological effects, including liver protection, blood glucose and cholesterol level management, and anti‐inflammatory and antitumor effects. However, presently, the biochemical foundation and mechanism of the anti‐inflammatory effects of GPS in sepsis‐induced ALI have not been explained. In the present study, we established a rat model of sepsis ALI induced by cecal ligation and puncture. This enables us to observe the effects of GPS therapy, which significantly reduced the inflammatory response (TNF‐α, IL‐1β, and IL‐6), nitrogen stress, oxidative stress, and severity of ALI at both the whole animal and molecular levels. In addition, GPS ameliorates LPS‐induced ALI via regulation of inflammatory response and cell proptosis in BEAS‐2B. This study provides a theoretical basis for treating sepsis‐induced ALI with GPS.
Esthetic Crown Lengthening Associated With Modified Lip Repositioning Surgery (Modified LipStat) in the Treatment of Excessive Gingival Display: A 6‐Year Follow‐Up Case Report
Authors: Arruda Cesar Augusto Signori , Pratto Luciano Melo , D’Agostini Derech Estevo , Schuldt Filho Guenther
Published: September 2024

Smiling expresses emotions and affects interpersonal relationships, influencing self‐esteem and social life. Nowadays, concerns about aesthetics and access to the Internet have made people more informed and demanding about treatments for gingival smile. Excessive gingival display (EGD) is caused by a variety of factors that can act alone or in combination. These factors may include altered passive eruption (APE), vertical maxillary excess, a short upper lip, and hyperactive upper lip, among other factors that cause gingival hyperplasia. In this case report, the EGD was caused by vertical maxillary excess, hypermobility of the upper lip, and APE. The proposed treatment included two procedures: the Modified Lip Repositioning Surgery (Modified LipStat) Technique, with internal sutures to attempt to restrict the traction of the upper lip elevator muscles, and Esthetic Crown Lengthening (ECL) from the right first premolar to the left first premolar for the treatment of APE. The result provided an aesthetic improvement of the smile, with harmonization in relation to the size of the teeth. The mobility of the upper lip in spontaneous smiles remained reduced up to 6 months of follow‐up; however, there was a partial relapse in the position of the upper lip during spontaneous smiling at the end of 6 years of follow‐up.
The Potential Impact of HNRNPA2B1 on Human Cancers Prognosis and Immune Microenvironment
Authors: Huang Tao , Zhu Gang , Chen Fan
Published: September 2024

HNRNPA2B1 is a member of the HNRNP family, which is associated with telomere function, mRNA translation, and splicing, and plays an important role in tumor development. To date, there have been no pan‐cancer studies of HNRNPA2B1, particularly within the TME. Therefore, we conducted a pan‐cancer analysis of HNRNPA2B1 using TCGA data. Based on datasets from TCGA, TARGET, Genotype‐Tissue Expression, and Human Protein Atlas, we employed a range of bioinformatics approaches to explore the potential oncogenic role of HNRNPA2B1. This included analyzing the association of HNRNPA2B1 expression with prognosis, tumor mutation burden (TMB), microsatellite instability (MSI), immune response, and immune cell infiltration of individual tumors. We further validated the bioinformatic findings using immunohistochemistry techniques. HNRNPA2B1 was found to be differentially expressed across most tumor types in TCGA’s pan‐cancer database and was predictive of poorer clinical staging and survival status. HNRNPA2B1 expression was also closely linked to TMB, MSI, tumor stemness, and chemotherapy response. HNRNPA2B1 plays a significant role in the TME and is involved in the regulation of novel immunotherapies. Its expression is significantly associated with the infiltration of macrophages, dendritic cells, NK cells, and T cells. Furthermore, HNRNPA2B1 is closely associated with immune checkpoints, immune‐stimulatory genes, immune‐inhibitory genes, MHC genes, chemokines, and chemokine receptors. We performed a comprehensive evaluation of HNRNPA2B1, revealing its potential role as a prognostic indicator for patients and its immunomodulatory functions.
Impact of Renal Replacement Therapy on Outcomes of Living Donor Liver Transplantation for Acute Liver Failure: A Cohort Study
Authors: Bhatti Abu Bakar Hafeez , ul Haq Nauman , Mehmood Nayyer , Hassan Danyal , Ahmed Arsalan , Malik Wasim Tariq , Zia Haseeb Haider , Salih Mohammad , Khan Nusrat Yar , Ilyas Abid , Khan Nasir Ayub
Published: September 2024

Despite the promising role of renal replacement therapy (RRT) in acute liver failure (ALF), high‐risk patients need liver transplantation and remain at risk for death due to cerebral complications. The objective of this study was to report outcomes of living donor liver transplantation (LDLT) for ALF with perioperative RRT. This was a single‐center retrospective cohort study. Out of 1167 LDLTs, 24 patients had ALF and met the King’s College criteria for transplantation. They were categorized into no‐RRT (n = 13) and RRT (n = 11) groups. We looked at 1‐year posttransplant survival in these patients. The median serum ammonia level at the time of transplant in the no‐RRT and RRT groups was 259.5 mcg/dL (222.7–398) and 70.6 mcg/dL (58.1–92.6) (p = 0.005). In the RRT group, serum ammonia level < 100 mcg/dL was achieved in all patients. Seven (53.8%) patients in the no‐RRT group and 11/11 (100%) in the RRT group were extubated and regained full consciousness after LDLT (p = 0.013). The 90‐day mortality was 6/13 (46.1%) and 2/11 (18.1%) (p = 0.211). There was no brainstem herniation‐related mortality in the RRT group, that is, 5/13 (38.4%) and 0/11 (0%) (p = 0.030). The 1‐year posttransplant survival was also significantly higher in the RRT group (p = 0.031). The use of RRT lowers serum ammonia levels and might reduce posttransplant mortality due to brainstem herniation.
Supplementary Data from A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: White Brian S. , Woo Xing Yi , Koc Soner , Sheridan Todd , Neuhauser Steven B. , Wang Shidan , Evrard Yvonne A. , Chen Li , Foroughi pour Ali , Landua John D. , Mashl R. Jay , Davies Sherri R. , Fang Bingliang , Raso Maria Gabriela , Evans Kurt W. , Bailey Matthew H. , Chen Yeqing , Xiao Min , Rubinstein Jill C. , Sanderson Brian J. , Lloyd Michael W. , Domanskyi Sergii , Dobrolecki Lacey E. , Fujita Maihi , Fujimoto Junya , Xiao Guanghua , Fields Ryan C. , Mudd Jacqueline L. , Xu Xiaowei , Hollingshead Melinda G. , Jiwani Shahanawaz , Acevedo Saul , Davis-Dusenbery Brandi N. , Robinson Peter N. , Moscow Jeffrey A. , Doroshow James H. , Mitsiades Nicholas , Kaochar Salma , Pan Chong-xian , Carvajal-Carmona Luis G. , Welm Alana L. , Welm Bryan E. , Govindan Ramaswamy , Li Shunqiang , Davies Michael A. , Roth Jack A. , Meric-Bernstam Funda , Xie Yang , Herlyn Meenhard , Ding Li , Lewis Michael T. , Bult Carol J. , Dean Dennis A. , Chuang Jeffrey H.
Published: September 2024

Supplementary Tables
A First-in-Human Study of Cinrebafusp Alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies
Authors: Piha-Paul Sarina , Olwill Shane A. , Hamilton Erika , Tolcher Anthony , Pohlmann Paula , Liu Stephen V. , Wurzenberger Cornelia , Hasenkamp Laura-Carolin , Hansbauer Eva-Maria , Shroff Rachna , Hurvitz Sara , Krishnamurthy Anuradha , Patnaik Amita , Hahn Noah , Kumar Raman , Duerr Manuela , Zettl Markus , Aviano Kayti , Matis Louis , Bruns Ingmar , Ku Geoffrey
Published: September 2024

Purpose:

4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, NK cells, and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibody-like bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies.

Patients and Methods:

This was a multicenter dose-escalation study involving patients with HER2-positive malignancies who received prior treatment. The study assessed the safety and efficacy of cinrebafusp alfa across various dose levels. Patients were assigned to different cohorts, and antitumor responses were evaluated. The study aimed to determine the MTD and to observe any clinical activity at different dose levels.

Results:

Of 40 evaluable patients in the “active dose” efficacy cohorts, five showed an antitumor response, resulting in an overall response rate of 12.5% and a disease-control rate of 52.5%. Clinical activity was observed at the 8 and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with grade ≤2 infusion-related reactions being the most frequent treatment-related adverse event. MTD was not reached during the study.

Conclusions:

Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies.

See related commentary by Eguren-Santamaría et al., p. 231
Abstract A005 TP53 variant clusters stratify the Li-Fraumeni spectrum and reveal an osteosarcoma-prone subgroup
Authors: Fischer Nicholas W. , Laverty Brianne , Alon Noa , Montellier Emilie , Hainaut Pierre , Maxwell Kara N. , Kratz Christian P. , Malkin David
Published: September 2024

Li-Fraumeni syndrome (LFS) has recently been redefined as a ‘spectrum’ cancer predisposition disorder to reflect its broad phenotypic heterogeneity. The wide functional gradient associated with different TP53 variants is thought to contribute to LFS heterogeneity, although it is still poorly understood and there is an unmet clinical need for risk stratification strategies. Leveraging p53 mutagenesis datasets, we performed an unsupervised cluster analysis that revealed five TP53 variant clusters with unique structural and functional consequences. Classifying variant carriers according to these clusters stratified cancer onset and survival using discovery and validation cohorts, and exposed important clinical characteristics to consider for patient management. In particular, we identified a subgroup of monomeric TP53 variant carriers prone to osteosarcoma, along with a cluster associated with less “LFS-like” phenotypes enriched in carriers with no history of cancer. Our classification of TP53 variants demonstrates the existence of a wide TP53-heritable cancer susceptibility spectrum and provides a new framework to delineate carriers toward personalized patient care.

Citation Format: Nicholas W. Fischer, Brianne Laverty, Noa Alon, Emilie Montellier, Pierre Hainaut, Kara N. Maxwell, Christian P. Kratz, David Malkin. TP53 variant clusters stratify the Li-Fraumeni spectrum and reveal an osteosarcoma-prone subgroup [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A005.
Abstract A012 Unravelling the role of METTL1 in Myc driven pediatric cancers using CRISPR Cas13d
Authors: Liu Pei Y. , He Steven , Mayoh Chelsea , Salib Alice , De Weck Antoine , Ekert Paul G.
Published: September 2024

METTL1 is an RNA methyltransferase which catalyzes N7-methylguanosine (m7G) methylation on various RNAs, particularly on tRNAs. METTL1 has been reported to be amplified and/or overexpressed and high expression correlates with poor patient prognosis in different types of adult cancers. Our ZERO Childhood Cancer Program focuses on identifying and validating potential new drug targets and developing novel therapies for clinical use. ZERO has sequenced the whole genome and transcriptome in over 500 high-risk pediatric tumors and found that METTL1 gene copy number and gene expression are significantly higher in a subset of high-grade glioma, neuroblastoma, diffuse midline glioma and fusion positive rhabdomyosarcoma. Analysis of the publicly available SEQC microarray dataset showed that high METTL1 expression correlates with poor outcomes in MYCN amplified neuroblastoma patients. We validated the functional roles of METTL1 gene amplification and overexpression in a few pediatric cancer cell line models using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Cas13d knockdown system, in dual lentiviral constructs. We found that knocking down METTL1 significantly decreased METTL1 amplified neuroblastoma and rhabdomyosarcoma cell viability and colony formation but not in METTL1 non-amplified neuroblastoma and rhabdomyosarcoma cells. Gene Set Enrichment Analysis from RNA sequencing data revealed that knocking down METTL1 resulted in a decrease in Myc target gene expression, and an increased in apoptosis, interferon alpha response and p53 pathway hallmarks. Western blot analysis confirmed that knocking down METTL1 led to a decrease in the MCL-1 antiapoptotic protein expression and an increase in the proapoptotic protein expression such as cleaved PARP and caspase 3. Taken together, our data demonstrate that METTL1 is a potential therapeutic target in METTL1 amplified pediatric cancers.

Citation Format: Pei Y. Liu, Steven He, Chelsea Mayoh, Alice Salib, Antoine De Weck, Paul G. Ekert. Unravelling the role of METTL1 in Myc driven pediatric cancers using CRISPR Cas13d [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A012.
Abstract A022 Characterizing the cell of origin of Ewing sarcoma
Authors: Vasileva Elena , Arata Claire , Crump Gage , Amatruda James
Published: September 2024

Ewing sarcoma (ES) is a malignant bone and soft tissue tumor that affects children, adolescents, and young adults. ES is characterized by the presence of a driver fusion oncogene, most frequently EWSR1-FLI1. The cell of origin of Ewing sarcoma and the mechanisms of EWSR1-FLI1-driven cell transformation are the subjects of long-standing debates, largely due to the absence of a representative mouse model. Previous reports have suggested that bone-marrow mesenchyme or/and neural crest cells may serve as potential cells of origin for Ewing sarcoma. These hypotheses have never been tested in vivo, as the EWSR1-FLI1 fusion causes severe developmental toxicity in most cell types. To address these questions, we developed a stable model enabling controlled expression of the human EWSR1-FLI1 oncofusion specifically in neural crest cells. Using this model, we demonstrated that expression of human EWSR1-FLI1 oncofusion in neural crest cells can lead to their transformation and the development of tumors in vivo. Here we applied innovative single-cell transcriptomic, genetic, and high-resolution imaging approaches to characterize cells giving rise to EWSR1-FLI1 driven tumors in zebrafish model of Ewing sarcoma. EWSR1-FLI1 hindered the normal differentiation of neural crest cells into glial and neuronal lineages. Instead, EWSR1-FLI1 strongly reprogrammed neural crest cells by upregulating the expression of mesodermal regulators, including the key mesodermal regulator tbxta (Brachyury or T) transcription factor. tbxta/TBXT expression was maintained in subset of zebrafish and human Ewing sarcomas. Our model provides a mechanism by which a neural crest cell population can be transformed to Ewing sarcoma, a malignancy with predominant mesenchymal features. Taken together, these findings shed light on the cellular and molecular mechanisms underlying Ewing sarcoma development and provide valuable insights into its pathogenesis.

Citation Format: Elena Vasileva, Claire Arata, Gage Crump, James Amatruda. Characterizing the cell of origin of Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A022.
Abstract A030 Secondary malignancies after radiotherapy treatment of pediatric cancer patients in Egypt over a six-year period
Authors: Sackett Charlotte L. , Zaghloul Mohamed S , Aldesouky Ahmed , Soliman Amr S , Teasdale Chloe A.
Published: September 2024

Background: Pediatric cancer survivors are at risk of developing secondary malignant neoplasms (SMNs) due to exposure to prior treatment modalities, including radiotherapy (RT). We conducted a retrospective cohort study to examine whether initial RT dose was associated with a greater risk of developing SMNs among pediatric cancer patients in Egypt. Methods: We identified patients (8 days-18 years at enrollment in care) who had received RT for treating primary cancer at Children’s Cancer Hospital (CCHE) in Cairo, Egypt, between 2009 and 2015. Patients were classified into two exposure groups based on the median initial RT course dosage, where ≤3600 centrigray (cGy) and >3600 cGy were considered low and high RT exposure, respectively. The cumulative incidence of SMN accounting for the competing risk of death was compared by initial RT dose using the cumulative incidence function, and multivariable sub-distributional hazard (SHR) models were fitted to compare the hazards of SMN for children with low vs high initial RT dose. Results: Of the 3,132 patients included in this study, 60.1% were male and the median age at enrollment in care was 6.2 years (interquartile range: 3.5-10.7). Approximately half (50.6%) of the patients received a low initial RT dose. The cumulative incidence of SMN at 11.1 years was 3.05% (95% CI 1.15-5.93%) overall and 3.92% (95% CI 1.19-9.39%) and 2.01% (95% CI 0.77-4.38%) for low and high RT dose patients, respectively. Children who received high initial RT doses did not have higher hazards of developing SMN in bivariable (SHR 0.55, 95% CI 0.32-1.75) and multivariable models (aSHR 0.25, 95% CI 0.04-1.70). Conclusion: In this cohort of pediatric cancer patients in Egypt, high initial RT dose was not associated with increased hazards of SMN. Future research should extend follow-up time after the first decade following an initial cancer diagnosis to capture a more complete picture of SMN incidence. Other initiatives may include establishing national cancer registries in low- to middle-income countries to better track longitudinal cancer data in these populations.

Citation Format: Charlotte L. Sackett, Mohamed S Zaghloul, Ahmed Aldesouky, Amr S Soliman, Chloe A. Teasdale. Secondary malignancies after radiotherapy treatment of pediatric cancer patients in Egypt over a six-year period [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A030.
Abstract A038 Plasma exosome concentrations in healthy canines and dogs with osteosarcoma
Authors: Magstadt Jaron M. , Labé Courtney H. , Wojtysiak Meagan , DuVal Kyle , Khammanivong Ali , Mills Lauren J. , Winter Amber , Feiock Caitlin , Reid Kelly , Lewellen Mitzi , Spector Logan G. , Weigel Brenda J. , Modiano Jaime F. , Makielski Kelly M.
Published: September 2024

Canine osteosarcoma is a common disease that shares many clinical and biological features with human osteosarcoma. We have previously demonstrated the potential of using mRNA signatures derived from exosome cargo to detect minimal residual disease in dogs undergoing treatment for osteosarcoma. Our goal is to continue exploring the potential of exosomes in cancer diagnosis and treatment by understanding how exosomes contribute to the biology of osteosarcoma. For this study, we compared exosome concentrations in the plasma of 26 healthy dogs and 29 dogs with various cancers, including 8 dogs with osteosarcoma. Dogs with cancer had higher exosome concentrations than the healthy dogs (p=0.0007), as did the subset of dogs with osteosarcoma. Specifically, the average exosome concentration in the samples from healthy dogs was 5x1011 (+/-2.72x1011) particles/mL, with a normal distribution ranging from 7.22x1010 to 1x1012, whereas the average exosome concentration in the samples from dogs with osteosarcoma was 1.14x1012 (+/-1.41x1012) particles/mL, with a non-parametric distribution ranging from 1.16x1011 to 4.4x1012. Ongoing work includes expanding the data set with archival samples, as well as evaluating potential relationships between exosome concentrations and disease-free survival in dogs with osteosarcoma. In conclusion, the difference in plasma exosome concentrations between healthy dogs and dogs with osteosarcoma, and specifically the heterogeneous distribution of exosomes in the plasma of dogs with osteosarcoma suggests that this could be one feature used in combination with analyses of exosome cargo to aid in prognosis and manage treatment of patients with osteosarcoma.

Citation Format: Jaron M. Magstadt, Courtney H. Labé, Meagan Wojtysiak, Kyle DuVal, Ali Khammanivong, Lauren J. Mills, Amber Winter, Caitlin Feiock, Kelly Reid, Mitzi Lewellen, Logan G. Spector, Brenda J. Weigel, Jaime F. Modiano, Kelly M. Makielski. Plasma exosome concentrations in healthy canines and dogs with osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A038.
Abstract A047 Synergy between polarized dendritic cells, radiation and PD-1 blockade in effective treatment of rhabdomyosarcoma
Authors: Gupta Ajay , Connors Eoghan , Moser Michael , Gillard Bryan , Kokolus Katie , Basse Per , Kalinski Pawel
Published: September 2024

Introduction: Clinical effectiveness of immune checkpoint inhibitor (ICI) therapy depends on tumor-infiltrating cytotoxic T lymphocytes (CTLs) resulting in the need for new tools to convert “cold” tumors which lack CTLs, into CTL-infiltrated “hot” tumors. Radiation therapy (RT) is known to modulate the solid tumor microenvironment (TME) and induce a systemic immune response via enhanced tumor antigen release, production of type I interferons (IFN), intratumoral attraction and activation of DCs, and enhanced tumor recognition by natural killer (NK) cells. Thus, local irradiation of a tumor can be advantageous for both the local treatment of a tumor as well as the prevention of distant metastases. Since previous studies have shown that RT can synergize with ICI and that IL-12 producing DCs administered intratumorally also impart a clinical advantage with ICI, we tested if ST-αDC1s, a DC type designed to produce high levels of IL-12 and CTL-attracting chemokines, can enhance the combination of RT plus anti-PD-1 therapy of mouse rhabdomyosarcoma. Methods: Mice (10-15 mice per group) were inoculated with syngeneic orthotopic (gastrocnemius) M3-9-M rhabdomyosarcoma. At day 13, when tumors reached ∼200 mm3, animals started RT with single fraction of 6 Gy (225 peak kVp) using the Precision X-Rad 320 irradiator. Four doses of anti-PD-1 treatment were given on days 13, 15, 18, and 20. ST-αDC1s were given intratumorally either early (Day 13) or late (Day 20). Surviving animals were challenged with 2.5x higher number of cancer cells on day 90-100 and followed for evidence of tumor recurrence. Results: Anti-PD1 treatment alone was not effective. Control groups receiving PBS injection or anti-PD-1 alone had no survivors at day 90, with most animals succumbing to tumors within 4 weeks. RT alone improved the outcomes, yielding 15% of day-90 survivors (2/13 animals). RT plus anti-PD-1 treatment increased the fraction of survivors to 54% (7/13 animals) , while RT plus anti-PD-1 and early ST-αDC1 treatment resulted in 70% of survivors (7/10 animals). Late ST-αDC1 treatment did not enhance the survival beyond the RT plus anti-PD1 combination. The correlative studies and rechallenge studies will be presented.

Citation Format: Ajay Gupta, Eoghan Connors, Michael Moser, Bryan Gillard, Katie Kokolus, Per Basse, Pawel Kalinski. Synergy between polarized dendritic cells, radiation and PD-1 blockade in effective treatment of rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A047.
Abstract A057 Molecular iodine reduces the invasiveness of neuroblastoma xenografts in zebrafish
Authors: Juvera-Avalos Edgar R. , Orizaga-Osti Gustavo , Delgado-González Evangelina , Aceves Carmen
Published: September 2024

Neuroblastoma (NB) is one of childhood´s most common extra-cranial solid tumors, with 90 % of the cases occurring in those <5 years of age. NB is highly heterogeneous, with variable biological and clinical characteristics; it exhibits spontaneous or induced regression processes (low-risk NB) up to highly invasive capacities and drug-resistance tumors (high-risk NB). High-risk NB overexpresses the N-MYC gene associated with invasion and chemoresistance. On the other hand, molecular iodine (I2) exerts antiproliferative and differentiation effects on cancer cells. Our previous studies have shown that I2 synergizes the neurodifferentiator effect of all-trans-retinoic acid in low-risk (SN-K-AS) and the antiproliferative and apoptotic action of cyclophosphamide in high-risk (SK-N-BE2) neuroblastoma cell lines. The cellular mechanisms include the activation of antioxidant pathways (Nrf2) and the overexpression of the peroxisome proliferator-activated receptor gamma (PPARγ). I2 can exert its effects through the activation of PPARγ, and this in turn downregulates the expression of chemoresistance genes (TrkB, MDR1, N-MYC). The aim of the present work is to analyze the effect of I2 on the invasive capacity of SK-N-BE2 both in vitro (wound healing assay) and in vivo (zebrafish model). NB cells were cultured in DMEM/F12 (1:1) medium with and without I2 400 mM for 96 hours. Wound assay was analyzed after 24 hours, whereas 400 to 600 cells labeled with Fast DiI (4 mg/mL) were injected into the perivitelline space of zebrafish larvae 2 days post fertilization. Cancer cell dissemination to the caudal vein plexus was analyzed with a fluorescence Nikon Eclipse E-600 microscope (10X/0.30 magnification) after 72 hours. Data show that I2-pretreated SK-N-BE2 cells exhibit a decrease in migration capacity in vitro (control 59.5 ± 8.5, I2 65.0± 9.4 p<0.6) and a clear and significant inhibition in vivo (control 7.6 ± 4.6, I2 4.8± 3.8 p< 0.0015). Analysis of the genetic expression (qRT-PCR) shows that I2 induces PPARγ and decreases N-MYC and TrkB expression through an apparent PPARγ independent pathway at 96 hours. The establishment of NB PPARγ knock-out cells and evaluation of the I2 effect in tumoral angiogenesis on transgenic zebrafish (Fli1: EGFP) is currently under progress. Acknowledgments The authors are grateful for the technical support of Luis Roberto Rodríguez Ortiz, Nydia Hernandez Ríos, and Martín García Servín. This work was supported by PAPIIT-UNAM IN202322, and CONAHCYT scholarship 862245.

Citation Format: Edgar R. Juvera-Avalos, Gustavo Orizaga-Osti, Evangelina Delgado-González, Carmen Aceves. Molecular iodine reduces the invasiveness of neuroblastoma xenografts in zebrafish [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A057.
Abstract A060 Investigating underlying efficacy and mechanism of action of the KIF11 inhibitor filanesib in Ewing and clear cell sarcomas
Authors: Walker-Mimms Hannah L. , Londono Nicole , Liao Yi , Chaudhary Neelkamal , Teng Mingxiang , Kinose Fumi , Li Xueli , Monastyrskyi Andrii , Rix Uwe , Duckett Derek
Published: September 2024

Ewing (ES) and clear cell (CCS) sarcomas are bone and soft tissue malignances and in advanced and relapsed disease overall survival rates remain dismal. For metastatic ES, five-year survival rates are between 15% and 30%. In CCS, the five-year survival rates are between 30% and 67%. Accordingly, there is a critical need for the development of novel targeted therapeutics for the treatment of these rare cancers. Both cancers are driven by fusion proteins; EWS-FLI1 in ES and EWS-ATF1 in CCS, which arise from separate chromosomal translocations: t(11;22)(q24;q12) and t(12;22)(q13;q12) respectively. Current approaches for developing new treatments focus on targeting the fusion proteins or their downstream targets. We performed a small molecule compound library screen of clinically used drugs and identified ES and CCS cells to be extremely sensitive to filanesib, a kinesin spindle protein (KIF11) inhibitor. KIF11 is known to play roles in cell cycle progression and mitotic spindle stability. Our preclinical efficacy studies demonstrated that filanesib promotes potent tumor growth inhibition in both EWS-FLI1 and EWS-ATF1 xenograft models in mice. We are currently investigating the mechanism underlying the relationship between KIF11 and EWS-FLI1 and EWS-ATF1. Prior studies have identified KIF11 within a EWS-ATF1 transcriptional complex and KIF11 has been shown to interact with the histone acetyltransferase (HAT) p300/CBP-Associated Factor (PCAF). HATs are necessary components for chromatin remodeling, which the oncogenic fusion proteins regulate. Future research directions involve elucidating the role of KIF11 in regulating the EWS-ATF1 and EWS-FlI1 transcriptional complexes. Additionally, to further improve the therapeutic response to filanesib, we are investigating potential synergistic relationships with other compounds. This work has been supported in part by the Flow Cytometry and the Molecular Genomics Cores at the H. Lee Moffitt Cancer Center & Research Institute, a comprehensive cancer center designated by the National Cancer Institute and funded in part by Moffitt’s Cancer Center Support Grant (P30-CA076292)

Citation Format: Hannah L. Walker-Mimms, Nicole Londono, Yi Liao, Neelkamal Chaudhary, Mingxiang Teng, Fumi Kinose, Xueli Li, Andrii Monastyrskyi, Uwe Rix, Derek Duckett. Investigating underlying efficacy and mechanism of action of the KIF11 inhibitor filanesib in Ewing and clear cell sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A060.
Abstract A071 Mechanisms of radiation resistance in medulloblastoma
Authors: Veo Bethany , Wang Dong , Desisto John , Vibhakar Rajeev
Published: September 2024

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children that demonstrates clinical and genomic heterogeneity. Of the four major subgroups, Group 3 tumors (MYC-MB), and particularly the 3gsubtype, exhibit high levels of MYC, high rates of metastasis, and have the worst prognosis. Despite treatment with surgery, radiation and chemotherapy, Group 3 medulloblastoma patients are more likely to develop recurrent tumors which are far more aggressive resulting in a 5-year survival rate after recurrence of 12%. Thus, there is an imperative need to examine the underlying mechanisms mediating treatment resistance. Recent evidence has identified cellular plasticity, as a major driver of therapy resistance. To investigate whether epigenetic mediated cell plasticity contributes to Myc-MB therapy response we performed Single Nuclei Multiome ATAC + Gene Expression analysis of paired primary and relapsed tumors. We identified the emergence of novel progenitor populations in resistant tumors with stem-like gene expression networks and altered chromatin accessibility. These emergent popuoations demostrated new enhancer-promoer interactions and exhibited increased metabolic reprogramming with potential for theraputic targeting. Because radiation is one of the key treatment modalities for Myc-MB, we chose to model radiation resistance in further studies. Single-cell RNA sequencing of outgrown in vivo irradiated orthotopic xenograft MB tumors showed an overall upregulation of metabolic pathways with the enhancement of genes that mediate oxidative phosphorylation and glutamate metabolism centering on wild-type IDH1 (wtIDH1), consistent with our patient data. IR-resistant cells showed altered chromatin occupancy of H3K3me3 and H3K27Ac. Disruption of IDH1 activity in IR resistant cells in vitro altered the epigenomic landscape, facilitating reversion to the pre-irradiated state. Interestingly, we observed that pluripotent genes with bivalent regions (H3K4me3 and H3K27me3) were enhanced in radiation-resistant cells and suppressed by IDH1 inhibition. Metabolic mass spectrometry reveled that metabolites from the citric acid cycle and synthesis of unsaturated fatty acids were among the main metabolically elevated molecules in radiation-resistant cells consistnat with the observed epigenomic reprograming. IDH1 inhibition reversed the metabolic reprograming and resensitized MB cells to radiation. In total our data identify a novel mechanism of radiation resistance in medulloblastoma with potential theraputic implications.

Citation Format: Bethany Veo, Dong Wang, John Desisto, Rajeev Vibhakar. Mechanisms of radiation resistance in medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A071.