bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B46: CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb Repressive complex 2 via a H3K27M-like mechanism
Authors: Piunti Andrea , Smith Edwin , Morgan Marc , Ugarenko Michal , Khaltyan Natalia , Helmin Kathryn , Ryan Caila , Murray David , Rickels Ryan , Yilmaz Bahar , Rendleman Emily , Savas Jeffrey , Singer Benjamin , Bulun Serdar , Shilatifard Ali
Published: August 2020

Dysregulation of Polycomb Repressive Complex 2 (PRC2) function is a common feature of many cancer types, including both solid and hematologic malignancies. A number of chromosomal translocations involving Polycomb group proteins have been identified; however, the molecular function of these fusion proteins remains largely unexplored. Here we characterize two endometrial stromal sarcoma (ESS) associated fusion proteins: JAZF1-SUZ12 and MBTD1-CXORF67. We identify JAZF1 as a previously unreported subunit of the NuA4 complex, which when fused to SUZ12 creates a bridge between the NuA4 and PRC2 complexes. Intriguingly, the MBTD1-CXORF67 fusion binds to PRC2 and leads to strongly reduced levels of the PRC2 catalytic products H3K27me2/3. We demonstrate that this inhibitory function is mediated by the CXORF67 half of the fusion protein. Because of this striking property, we propose a new gene name: CATACOMB (CATalytic Antagosnist of polyCOMB; official gene name: EZHIP). We map CATACOMB’s inhibitory function to a short, highly conserved region and identify a single methionine residue essential for diminution of H3K27me2/3 levels. Remarkably, the amino acid sequence surrounding this critical methionine resembles that of the oncogenic histone H3 lysine-27-to-methionine (H3K27M) mutation found in high-grade pediatric gliomas. Finally, we show CATACOMB expression is silenced through DNA methylation and upon treatment with DNA demethylating agents, CATACOMB is expressed, binds to PRC2, and antagonizes its catalytic activity. In conclusion, we have identified an endogenous inducible gene, CATACOMB, which can regulate the catalytic activity of PRC2 and propose that such mechanism of regulation of histone modifications through the expression of antagonistic subunits may also exist for other histone-modifying enzyme complexes.

Citation Format: Andrea Piunti, Edwin Smith, Marc Morgan, Michal Ugarenko, Natalia Khaltyan, Kathryn Helmin, Caila Ryan, David Murray, Ryan Rickels, Bahar Yilmaz, Emily Rendleman, Jeffrey Savas, Benjamin Singer, Serdar Bulun, Ali Shilatifard. CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb Repressive complex 2 via a H3K27M-like mechanism [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B46.
Abstract B49: Modeling a pathogenic SAMD9 mutation in human induced pluripotent stem cells
Authors: Schwartz Jason R. , Connelly Jon P. , Pruett-Miller Shondra M. , Klco Jeffery M.
Published: August 2020

Germline mutations in SAMD9 are the molecular determinants of some pedigrees with familial monosomy 7 and myelodysplastic syndrome (MDS) (OMIM 252270), MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy), and other nonsyndromic pediatric MDS. Mutations identified thus far have been associated with decreased growth of hematopoietic stem and progenitor cells (HSPCs) and bone marrow hypocellularity. Previous studies suggest that the wild-type function of SAMD9 is growth restrictive; therefore, the mutations identified in pediatric MDS have been deemed gain-of-function (GoF), given the exaggerated antiproliferative phenotype demonstrated in overexpression systems within nonhematopoietic cell lines, most commonly HEK-293T. To date, no model systems are available to study the impact of these mutations in their endogenous locus, a locus known to be induced by inflammatory stimuli, namely interferon (IFN). Here we report our development, using CRISPR/Cas9 genomic engineering, of two separate isogenic human induced pluripotent stem cell (iPSC) lines, derived from a non-neoplastic iPSC line (BJFF.6), containing a known pathogenic SAMD9 mutation (c.3406G>C; p.E1136Q), which we previously identified in a family with monosomy 7 and MDS. From this mutated iPSC line we are able to successfully differentiate hematopoietic precursors and myeloid cells that contain a pathogenic SAMD9 mutation. Using our novel pediatric MDS model system, we demonstrate that in the presence of IFN, viability of HSPCs (CD34+) and differentiated myeloid cells (CD13+) is significantly decreased when the SAMD9 p.E1136Q mutation is present (CD34+; WT=16.7% vs Mut=11.5% (p=0.05), CD13+; WT=22.6% vs. Mut=3.5% (p<0.0001)). Furthermore, we show that the genomically engineered SAMD9 locus of our iPSC-derived CD34+ and CD13+ cells remains robustly responsive to IFN stimulation. The basal level of SAMD9 expression is higher in differentiated myeloid cells than in HSPCs, a finding consistent with expression levels within normal hematopoiesis. These data suggest that we have a SAMD9 mutant pediatric MDS model system that provides a plentiful source of cells in which the effect of specific mutations on hematopoietic differentiation, proliferation, and viability may be investigated.

Citation Format: Jason R. Schwartz, Jon P. Connelly, Shondra M. Pruett-Miller, Jeffery M. Klco. Modeling a pathogenic SAMD9 mutation in human induced pluripotent stem cells [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B49.
Abstract B51: Adaptation to oncogene-induced metabolic stress by MondoA (MLXIP) drives common acute lymphoblastic leukemia (cALL) malignancy
Authors: Sipol Alexandra , Hameister Erik , Petry Andreas , Görlach Agnes , Ruland Jürgen , Richter Guenther , Burdach Stefan , Sorensen Poul
Published: August 2020

MondoA (also known as MLXIP, MAX-like protein X interacting protein) is a metabolic stress sensor and a proglycolytic transcription factor potentially involved in metabolic addiction features of leukemia and the Warburg effect. MondoA dimerizes with MLX within the MYC interactome and promotes longevity in C. elegans (Johnson et al., 2014). The MYC interactome comprises the MYC/MAX/MNT/MLX/MLXIP transcription factor network: Its key players MYC, MNT and MLXIP differentially mediate proliferation, differentiation, or metabolism by heterodimerization with MAX or MLX. We previously described MondoA to promote malignancy of common precursor B-cell acute lymphoblastic leukemia (cALL). MondoA knockdown (MKD) in cALL cell lines in xenografted mice reduced the number of leukemic blasts (Sipol, 2014). Here we report that MondoA high expression was observed in ALL subtypes with no MYC overexpression. RNA-sequencing data of 132 primary ALL bone marrow samples confirmed the inverse correlation of MYC and MondoA. Interestingly, in subgroups of ALL with low MYC expression and high MondoA (cALL with BCR-ABL, cALL with TCF3-PBX, cALL with ETV6-RUNX1, and cALL with hyperdiploid karyotype), metabolic gene sets did not appear as upregulated. In contrast, cALL samples with high MYC expression and low MondoA (proB-ALL with MLL rearrangements and B-ALL with IGH-MYC fusion gene) demonstrated upregulation of pathways for oxidative phosphorylation and fatty acid metabolism in addition to targets of E2F, G2M checkpoints, and MYC targets. Using CRISPR/CAS9-mediated knockout (MKO), we demonstrate that MondoA dials down MYC-induced metabolic stress and increases leukemia stress resistance. By limiting mitochondrial pyruvate dehydrogenase (PDH) activity in PDHK1 (pyruvate dehydrogenase kinase 1)-dependent manner, MondoA decreases oxidative phosphorylation. In line with limiting effect of MondoA on oxidative phosphorylation, we observed that MondoA decreases ROS generation in B cells. In conclusion, MondoA is restricting MYC-target gene expression to promote leukemia cell survival by facilitating glycolysis and adaption to oxidative stress. MondoA limits pyruvate availability for the TCA cycle by decreasing PDH activity, thus ensuring consistent glycolytic flux, mediating the Warburg effect, and insuring integrity of leukemia metabolism and ROS balancing in response to oncogene activation.

Citation Format: Alexandra Sipol, Erik Hameister, Andreas Petry, Agnes Görlach, Jürgen Ruland, Guenther Richter, Stefan Burdach, Poul Sorensen. Adaptation to oncogene-induced metabolic stress by MondoA (MLXIP) drives common acute lymphoblastic leukemia (cALL) malignancy [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B51.
Abstract B52: Ewing sarcoma: A case study of clonal aneuploidy and DNA damage repair in pediatric cancer
Authors: Su Xiaofeng A. , Ma Duanduan , Parsons James V. , Replogle John M. , Amatruda James F. , Whittaker Charles A. , Stegmaier Kimberly , Amon Angelika
Published: August 2020

Many tumor types harbor specific chromosome gains or losses. In Ewing sarcoma (ES) chromosome 8 gain is extremely common, indicating that this trisomy drives tumorigenesis. However, in primary cells, whole chromosome gains and losses are universally detrimental. We hypothesize that gain of chromosome 8 suppresses cellular stresses associated with oncogenic transformation in ES. In this study, we induced expression of EWS-FLI1 fusion oncogene, which drives ES, in various primary human mesenchymal progenitor and fibroblast cells. We showed that expression of EWS-FLI1 results in a strong cell cycle-dependent replication stress in euploid mesenchymal progenitor cells and fibroblast cells. As a consequence, proliferation is impaired when EWS-FLI1 is expressed in these cells. However, primary fibroblast cells carrying an extra copy of chromosome 8 (trisomy 8) exhibit much less replication stress, and the impairment of proliferation was also not seen in these cells. The levels of replication-associated DNA damage are lower in the trisomy 8 cells than in the euploid cells in the presence of EWS-FLI1. Then, we applied weighted co-expression network analysis (WGCNA) to RNA sequencing data obtained from ES patient tumor tissues in combination of mouse synteny analysis. We identified multiple potential genes and regions on chromosome 8, which are beneficial to ES oncogenesis when gain of extra copies. Above all, we demonstrate that gain of chromosome 8 in Ewing sarcoma facilitates the primary mesenchymal-lineage cells to overcome certain oncogenic stresses and reduces DNA damage associated with tumorigenic processes, which is achieved by cooperative upregulation of multiple gene expression on chromosome 8.

Citation Format: Xiaofeng A. Su, Duanduan Ma, James V. Parsons, John M. Replogle, James F. Amatruda, Charles A. Whittaker, Kimberly Stegmaier, Angelika Amon. Ewing sarcoma: A case study of clonal aneuploidy and DNA damage repair in pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B52.
Abstract B54: Enhancer reprogramming by ASPSCR1-TFE3 in alveolar soft part sarcoma
Authors: Tanaka Miwa , Nakamura Takuro
Published: August 2020

Alveolar soft part sarcoma (ASPS) predominantly affects adolescents and young adults, with lower legs and buttocks as frequent primary sites. ASPS is characterized by alveolar structure of tumor cells, abundant vascularization, and frequent hematogenous metastasis. As for gene abnormality, the ASPSCR1-TFE3 (AT3) fusion is invariably observed in all ASPS cases with low genetic mutational burdens. To understand the functional roles of AT3 in ASPS development, we have generated an ex vivo mouse model for ASPS that well recapitulates its phenotypes. TFE3 belongs to the MiT/TFE (TFE3/TFEB/TFEC/MITF) gene family encoding bHLH/leucine zipper transcription factors, all of which share common DNA-binding domains and consensus DNA-binding motifs. Mutations or overexpression of MiT/TFE family genes trigger human malignancies including ASPS, renal cell carcinoma (RCC), and malignant melanoma (MM). To address whether AT3 possesses a specific potency to induce ASPS, we have generated artificial chimeras between ASPSCR1 and MiT/TFE family genes and have revealed that only TFE3 and TFEB could induce ASPS in vivo whereas the others could not. To get insights into the role of AT3 in enhancer reprogramming that affects tumor phenotypes, we investigated the epigenetic landscape of ASPS. ChIP-seq analyses of human and mouse ASPS showed frequent overlapping of AT3 DNA-binding with histone H3K27ac and H3K4me3 at target loci, indicating that AT3 frequently binds to active enhancers. Among them, canonical MiT/TFE target genes involved in the autophagy, lysosome/endosome and vesicle/protein transport, and mTOR signaling pathways were significantly enriched. Analysis of dataset from GEO revealed that these loci were common targets of MiT/TFE transcription factors activated in human ASPS, RCC, and MM. To identify the AT3-specific and/or AT3-dependent enhancer reprograming mechanism, we focused on super-enhancers (SEs) that determine the cell identity and characteristic phenotypes of ASPS, and examined its modification by AT3. Frequent association of SEs with genes for vasculogenesis and apoptosis were observed in ASPS but not in MM, and AT3 depletion in ASPS resulted in disappearance of these SEs, suggesting that AT3 contributes to chromatin remodeling to promote vasculogenesis required for its alveolar structure and growth expansion. Taken together, our study provides novel aspects on common oncogenic pathways regulated by MiT/TFE family tumor in ASPS, RCC, and MM as well as AT3-specific regulatory mechanism in ASPS, which will offer potential therapeutic targets and biomarkers.

Citation Format: Miwa Tanaka, Takuro Nakamura. Enhancer reprogramming by ASPSCR1-TFE3 in alveolar soft part sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B54.
Abstract B61: Improvement of physical activity training in childhood acute lymphoblastic leukemia survivors: New specific equation to predict the peak oxygen uptake from the six-minute walk test
Authors: Caru Maxime , Labonté Jennifer , Lemay Valérie , Drouin Simon , Bertout Laurence , Andelfinger Gregor , Alos Nathalie , Krajinovic Maja , Laverdière Caroline , Sinnett Daniel , Curnier Daniel
Published: August 2020

Purpose: The six-minute walk test (6MWT) is the most widely used test to assess the functional capacity of cancer patients. However, it is reported that the actual equations cannot accurately predict oxygen uptake (VO2 value) or walk distance (6MWD) in cancer survivors. Because of the importance for clinicians and physiologists to have a validated VO2 or 6MWD equation from the 6MWT to observe the predicted survivors’ value, we focused on the validation of a standard and specific equation to predict VO2 peak and 6MWD.

Methods: A total of 200 survivors were enrolled in this study, among whom 168 participants underwent a cardiopulmonary exercise test and a 6MWT. They also completed a physical activity questionnaire. Participants were randomly divided in two groups to predict the equations (n=118 (70%)) and to validate them (n=50 (30%)). Multiple linear regression analyses were used to determine a new prediction equation for VO2 peak and 6MWD from 6MWT. Bland and Altman methods were used to assess the accuracy.

Results: Our findings showed that without specific variables in the VO2 peak equation, the mean bias was of 2.67 mL.kg-1.min-1 and of 2.51 mL.kg-1.min-1 with specific variables. We observed a better accuracy compared to previously published equations, which reported a mean bias of 12.09 mL.kg-1.min-1. The same results were observed for the 6MWD.

Conclusion: This was the first study to predict VO2 peak and 6MWD using clinical and specific variables related to the disease. Every health care professional and exercise physiologist should use both our validated equations to provide a better adapted physical training. Our findings strengthen the need to evaluate survivors’ cardiorespiratory fitness in the care process.

Citation Format: Maxime Caru, Jennifer Labonté, Valérie Lemay, Simon Drouin, Laurence Bertout, Gregor Andelfinger, Nathalie Alos, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. Improvement of physical activity training in childhood acute lymphoblastic leukemia survivors: New specific equation to predict the peak oxygen uptake from the six-minute walk test [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B61.
Abstract B62: The need to improve exercise prescriptions to support care in pediatric oncology
Authors: Caru Maxime , Petrykey Kateryna , Samoilenko Mariia , Drouin Simon , Lemay Valérie , Kern Laurence , Romo Lucia , Beaulieu Patrick , St-Onge Pascal , Bertout Laurence , Lefebvre Geneviéve , Andelfinger Gregor , Krajinovic Maja , Laverdière Caroline , Sinnett Daniel , Curnier Daniel
Published: August 2020

Purpose: Cancer survivors’ exposure to chemotherapeutic agents leads to multiple long-term side effects with a decrease in their cardiorespiratory fitness. The first aim was to determine whether cardiorespiratory fitness and physical activity levels were lower among survivors than healthy Canadians, while the second aim was to report associations between genetic variants and cardiorespiratory fitness in survivors.

Methods: Cardiorespiratory fitness (VO2peak) and moderate to vigorous physical activity (MVPA) were compared between childhood ALL survivors (N=221) and healthy Canadians (N=825). We performed whole-exome sequencing in survivors. Germline variants (both common and rare) in a selected set of trainability genes were analyzed for an association with cardiorespiratory fitness.

Results: Survivors’ VO2 peak was found to be 22% lower than healthy Canadians. The cardiorespiratory fitness level was different between survivors and healthy Canadians despite a clinically equivalent level of MVPA. Positive associations between the cardiorespiratory fitness level and trainability genes (TTN, LEPR, IGFBPI, and ENO3 genes) were reported, especially in female survivors with a low cardiorespiratory fitness level.

Conclusion: The cardiorespiratory fitness was significantly lower in survivors, which can be associated with variants in genes related to subjects’ trainability. At this time, it appears that more physical activity would be beneficial to survivors to achieve the same benefits as the healthy population. However, the optimal amount of physical activity needed to reach these benefits is not yet clear. The survivors’ responder or nonresponder status several years after the end of the treatments is unknown. This study has important implications for the field of exercise in oncology.

Citation Format: Maxime Caru, Kateryna Petrykey, Mariia Samoilenko, Simon Drouin, Valérie Lemay, Laurence Kern, Lucia Romo, Patrick Beaulieu, Pascal St-Onge, Laurence Bertout, Geneviéve Lefebvre, Gregor Andelfinger, Maja Krajinovic, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. The need to improve exercise prescriptions to support care in pediatric oncology [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B62.
Abstract B69: Epigenomics and single-cell sequencing define a developmental hierarchy in Langerhans cell histiocytosis
Authors: Halbritter Florian , Farlik Matthias , Schwentner Raphaela , Jug Gunhild , Fortelny Nikolaus , Simonitsch-Klupp Ingrid , Bauer Wolfgang , Bock Christoph , Hutter Caroline
Published: August 2020

Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a characteristic hybrid position between cancer and inflammatory disease, which makes it an attractive model for studying cancer development. Constitutive activation of the ERK signaling pathway is a common feature of LCH, but its pathogenesis remains unclear. To explore the molecular mechanisms underlying the pathophysiology of LCH and the mechanisms that might cause the characteristic clinical heterogeneity of this disease, we investigated cellular heterogeneity in primary LCH lesions. We used a multilayered approach employing immunohistochemistry, flow cytometry, single-cell RNA-sequencing, and ATAC-sequencing of biopsies obtained from different patients with LCH. Based on the single-cell RNA expression data, we identified different LCH cell populations within LCH lesions that display distinct pathway signatures, including a stem cell-like, proliferative state and different subsets with a more differentiated phenotype, including subsets similar to maturing antigen-presenting cells and a subset that could contribute to tissue destruction in LCH. Computational analysis discovered a hierarchy between these cells that suggests a directed developmental program in each tumor. We confirmed the presence of these distinct subsets using immunohistochemical analysis of different biopsies. Furthermore, using chromatin accessibility profiling in prospectively purified LCH cell subsets in combination with single-cell RNA-seq data and integrative bioinformatic analysis, we analyzed the transcription factors and gene regulatory networks that may underlie the observed developmental hierarchy in LCH lesions. This analysis reveals an intricate interplay of immune-regulatory (including JAK-STAT, AP-1, and NF-κB signaling) and developmental regulators (including epigenetic modifiers such as EP300 or KDMs) that may shape LCH cell development. Together, this study sketches a molecular portrait of LCH lesions and enables new, unprecedented insight into this disease. Moreover, it demonstrates the power of combining single-cell RNA-sequencing and epigenome profiling for dissecting complex developmental hierarchies and their regulatory underpinnings, and thus can serve as a template for the analysis of tumorigenesis beyond LCH.

Citation Format: Florian Halbritter, Matthias Farlik, Raphaela Schwentner, Gunhild Jug, Nikolaus Fortelny, Ingrid Simonitsch-Klupp, Wolfgang Bauer, Christoph Bock, Caroline Hutter. Epigenomics and single-cell sequencing define a developmental hierarchy in Langerhans cell histiocytosis [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B69.
Abstract B76: Characterizing vascular invasion in hepatoblastoma
Authors: Woodfield Sarah E. , Patel Roma H. , Ibarra Aryana M. , Zorman Barry , Badachhape Andrew , Ghaghada Ketan B. , Lopez-Terrada Dolores , Sumazin Pavel , Vasudevan Sanjeev A.
Published: August 2020

Hepatoblastoma (HB) is the most common pediatric liver malignancy, and patients with high-risk, metastatic disease have a five-year overall survival (OS) of only about 40%. Of note, HB patients with vascular invasion (VI) have a much worse OS. Our hypothesis is that HB tumors with VI possess unique clones that invade the vasculature, resulting in dissemination of disease. We injected the aggressive HepT1 cell line with confirmed CTNNB1 and NFE2L2 mutations in the livers of immunocompromised NSG mice to generate intrahepatic tumors. After 4 weeks, we had 100% take of tumors in animals. Serum human α-fetoprotein (AFP) increased with the growth of tumors. At time of death, we saw clear presence of intrahepatic VI, vena caval tumor thrombus, extrahepatic disease including within periportal lymph nodes, and lung metastasis in animals with tumors. We grew adherent and nonadherent cell lines from tumor samples, including one cell line from intrahepatic VI and one from vena caval tumor thrombus. Cells derived from VI areas had obvious differences in phenotype from cells from the primary tumor (PT). To further pursue these provocative changes between PT and VI areas, we generated two unique patient-derived xenograft (PDX) models of HB with intrahepatic implantation of PT and VI tumor samples from a nonmetastatic pretreatment extent of disease (PRETEXT) stage 4 patient. Mice harboring the VI PDX showed serum elevation of human AFP and obvious tumor with MRI. PT and VI PDX tissues expressed established HB markers nuclear Beta-catenin, Glypican-3, and AFP, resembling the primary patient sample. We also developed a novel cell line with growth of cells from a VI tumor in vitro. With both the HepT1 and PDX models, gene set enrichment transcriptomic analyses of RNA sequencing data showed clear changes in expression in aggressive tissues that invaded vessels, including significant (p<0.05) changes in pathways associated with liver damage, inflammation, and metabolism. Further exploration of these pathways and agents that target these pathways could improve outcomes for HB patients with invasive disease.

Citation Format: Sarah E. Woodfield, Roma H. Patel, Aryana M. Ibarra, Barry Zorman, Andrew Badachhape, Ketan B. Ghaghada, Dolores Lopez-Terrada, Pavel Sumazin, Sanjeev A. Vasudevan. Characterizing vascular invasion in hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B76.
Abstract IA11: Overcoming immune evasion in pediatric brain tumors
Authors: Garancher Alexandra , Suzuki Hiromichi , Haricharan Svasti , Masihi Meher B. , Rusert Jessica M. , Norris Paula S. , Carrette Florent , Romero Megan M. , Morrissy Sorana A. , Skowron Patryk , Cavalli Florence M.G. , Farooq Hamza , Ramaswamy Vijay , Morcavallo Alaide , Henderson Jacob J. , Olson James M. , Cho Yoon-Jae , Li Xiao-Nan , Chesler Louis , Marra Marco A. , Becher Oren J. , Bradley Linda M. , Ware Carl F. , Taylor Michael D. , Wechsler-Reya Robert J.
Published: August 2020

Many immunotherapies act by enhancing T-cell killing of tumor cells. Cytotoxic T cells recognize antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. Our studies suggest that medulloblastomas and high-grade gliomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. Treatment with tumor necrosis factor or lymphotoxin beta receptor agonist rescues expression of Erap1, Tap1, and MHC-I on p53 mutant tumor cells. In vivo, TNF treatment prolongs survival and markedly augments the efficacy of the immune checkpoint inhibitor anti-PD-1. These studies identify p53 as a key regulator of immune evasion in vivo and suggest that TNF could be used to enhance sensitivity of p53-mutant tumors to immunotherapy.

Citation Format: Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Meher B. Masihi, Jessica M. Rusert, Paula S. Norris, Florent Carrette, Megan M. Romero, Sorana A. Morrissy, Patryk Skowron, Florence M.G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Alaide Morcavallo, Jacob J. Henderson, James M. Olson, Yoon-Jae Cho, Xiao-Nan Li, Louis Chesler, Marco A. Marra, Oren J. Becher, Linda M. Bradley, Carl F. Ware, Michael D. Taylor, Robert J. Wechsler-Reya. Overcoming immune evasion in pediatric brain tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA11.
Abstract IA15: Tissue-agnostic development of TRK inhibitors for pediatric cancer
Authors: Laetsch Theodore W.
Published: August 2020

Fusions involving in the NTRK1, NTRK2, and NTRK3 genes that encode the TRKA, TRKB, and TRKC neurotrophin receptors (TRK fusions) occur across a wide range of cancers in children and adults. These fusions result in constitutive expression and ligand-independent activation of the TRK kinase. TRK fusions are pathognomonic for certain rare cancers, including infantile fibrosarcoma and cellular congenital mesoblastic nephroma, and occur at a lower frequency across a range of more common cancers in children including soft-tissue sarcomas, gliomas, and leukemias. Recently, larotrectinib was FDA approved for the treatment of TRK fusion solid tumors in children and adults, representing the first kinase inhibitor to receive FDA histology-agnostic approval for the treatment of cancer. This approval was based on a combined analysis of three clinical trials, including an ongoing pediatric phase 1/2 trial that demonstrated a 94% response rate in 34 children with TRK fusion-positive solid tumors. Remarkably, due to nearly concurrent development in pediatrics and adults, more than 30% of the patients with TRK fusion solid tumors treated with larotrectinib on clinical trials to date have been children. Other TRK inhibitors are also in pediatric development, including entrectinib and LOXO-195, and clinical trials of additional agents including repotrectinib are planned. Entrectinib, which also antagonizes ROS1 and ALK, was reported to induce responses in 11/11 children whose tumors harbored fusions of the TRK, ROS1 or ALK genes. LOXO-195 and repotrectinib have the potential to antagonize resistance mutations that can develop during treatment with first-generation TRK inhibitors, and we reported a 45% response rate to LOXO-195 among 20 patients enrolled to either single-patient treatment protocols or an ongoing pediatric and adult phase 1 study who harbored a TRK kinase resistance mutation. In this talk, I will review the data on the use of TRK inhibitors for TRK fusion cancers in children, discuss unanswered questions related to the use of TRK inhibitors in children and planned clinical trials designed to address these, and highlight the challenges and opportunities that arise when studying novel therapies for rare, molecularly defined diseases.

Citation Format: Theodore W. Laetsch. Tissue-agnostic development of TRK inhibitors for pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA15.
Abstract IA19: Genomic analysis of osteosarcoma: Insights into tumor evolution and therapy response
Authors: Sweet-Cordero E. Alejandro
Published: August 2020

While significant progress has been made in most other cancers to advance targeted therapy, there has been essentially no change in our approach to treatment of osteosarcoma in over 30 years. Osteosarcomas exhibit an extremely complex genome characterized by multiple copy number changes and structural alterations. Using patient-derived xenografts and primary tumors, we are employing whole-genome sequencing (WGS) and RNAseq to characterize the evolution of this disease with a goal of understanding how evolutionary constraints can identify targetable vulnerabilities. We have identified a number of potential subtypes of osteosarcoma based on copy number alterations and defined how these copy number alterations can be exploited for therapeutic benefit using a large and clinically annotated patient-derived xenograft (PDX) collection. A key current effort is to identify novel genome-informed combination therapies for this disease. To facilitate this work, we have developed a panel of cell lines derived from PDX models, which have also be characterized with regards to their genomic characteristics. We have used these cell lines to screen for response to a wide variety of drugs with the goal of matching response to specific genomic characteristics. Lastly, we are using PDX models to study the process of metastatic progression and have identified a possible role for the enzyme ENPP1 in osteosarcoma metastasis.

Citation Format: E. Alejandro Sweet-Cordero. Genomic analysis of osteosarcoma: Insights into tumor evolution and therapy response [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA19.
Abstract IA21: Blocking purine synthesis in cancer promotes response to immunotherapy
Authors: Erez Ayelet , Ruppin Eytan , Keshet Rom , Lee Joo Sang
Published: August 2020

Nucleotide imbalance promotes mutagenesis in multiple types of cancer. We have previously shown that nucleotide imbalance favoring pyrimidines leads to mutational bias, which promotes the generation of immunogenic neoantigens that respond to ICT. We now find that tumors with high purine bias demonstrate a novel asymmetric genomic signature, consisting of transversion mutations manifested at the DNA, RNA, and protein level. This metabolic alteration leads to presentation of less immunogenic neoantigens and to decreased response to immune checkpoint inhibitors independent of mutational load. Reversing the nucleotide imbalance to favor pyrimidines improves the response to immunotherapy. Our data firmly establish that beyond mutational load and tumor heterogeneity, purine/pyrimidine bias is a strong determinant of the response to immunotherapy. Importantly, our findings suggest that we can metabolically manipulate tumor mutations to improve patients’ response to immunotherapy.

Citation Format: Ayelet Erez, Eytan Ruppin, Rom Keshet, Joo Sang Lee. Blocking purine synthesis in cancer promotes response to immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA21.
Abstract IA26: The need for evidence-based survivorship care
Authors: Kremer Leontien
Published: August 2020

The 5-year survival for children with cancer has increased enormously. However, years after treatment, childhood cancer survivors are at high risk for developing health and psychosocial long-term side effects due to their previous cancer treatment. The impacts on morbidity, mortality, and society are significant. These impacts can be reduced by optimal long-term follow-up of survivors. Survivorship care that is focused on the detection of treatable disease at an early phase will improve quality of life of survivors by timely interventions. The International Guideline Harmonisation Group (ighg.org) developed evidence-based guidelines for many late effects. However, implementing these guidelines has proven challenging. The availability of follow-up care for adult survivors varies considerably, and many clinics do not offer survivorship care for adult survivors of childhood cancer. High-quality survivorship care requires a multidisciplinary care infrastructure, implementation of guidelines, and development of a survivorship care plan with a detailed summary of treatment and specific knowledge on late effects. This presentation will focus on the translation of knowledge to guidelines and the need for survivorship care.

Citation Format: Leontien Kremer. The need for evidence-based survivorship care [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA26.
The Safety and Efficacy of Primary Duct Closure without Endoscopic Nasobiliary Drainage after Laparoscopic Common Bile Duct Exploration
Authors: Yang Yan , Han Lin , Lin Da-Ning , Hu Zeng-Ji , Tu Wei , Chen Feng , Li Yong-Qiang
Published: August 2020

Background: Primary duct closure (PDC) after laparoscopic common bile duct exploration (LCBDE) has been widely applied for choledocholithiasis. However, there has been controversy over the placement of endoscopic nasobiliary drainage (ENBD) during operation. To date, few studies compare the clinical effect of PDC without and with ENBD. The aim of this study was to assess the safety and efficacy of PDC without ENBD for choledocholithiasis. Methods: From January 2016 to December 2018, a total of 164 patients meeting the inclusion criteria were enrolled and divided into group A (undergone LCBDE + PDC without ENBD, 81 cases) and group B (undergone LCBDE + PDC with ENBD, 83 cases) in this study. The intraoperative conditions and postoperative complications were compared between the 2 groups. Results: In group A, the time of operation, postoperative first flatus, extubation, antibiotics, and discharge were shorter than in group B (t = −17.775, p = 0.000; t = −7.649, p = 0.000; t = −5.807, p = 0.000; t = −9.247, p = 0.000; t = −9.322, p = 0.000, respectively). Furthermore, intraoperative blood loss was less (t = −2.199, p = 0.029) and hospital costs were lower (t = −6.685, p = 0.000). However, there was no significant difference in postoperative complications between the 2 groups (p > 0.05). Conclusions: In patients who meet the screening criteria, PDC without ENBD after LCBDE is safe and effective and worthy of clinical application.
Effects of Inhibition of Nitric Oxide Synthase on Muscular Arteries During Exercise: Nitric Oxide Does Not Contribute to Vasodilation During Exercise or in Recovery
Authors: O'Gallagher Kevin , Shabeeh Husain , Munir Shahzad , Roomi Ali , Jiang Benyu , Guilcher Antoine , Brett Sally , Chowienczyk Philip
Published: August 2020

Background

Basal release of nitric oxide (
NO
) from the vascular endothelium regulates the tone of muscular arteries and resistance vasculature. Effects of
NO
on muscular arteries could be particularly important during exercise when shear stress may stimulate increased
NO
synthesis.

Methods and Results

We investigated acute effects of
NO
synthase inhibition on exercise hemodynamics using

N
G

‐monomethyl‐
l
‐arginine (
l
‐
NMMA
), a nonselective
NO
synthase ‐inhibitor. Healthy volunteers (n=10, 5 female, 19–33 years) participated in a 2‐phase randomized crossover study, receiving
l
‐
NMMA
(6 mg/kg, iv over 5 minutes) or placebo before bicycle exercise (25–150 W for 12 minutes). Blood pressure, cardiac output (measured by dilution of soluble and inert tracers) and femoral artery diameter were measured before, during, and after exercise. At rest,
l
‐
NMMA
reduced heart rate (by 16.2±4.3 bpm relative to placebo,
P
<0.01), increased peripheral vascular resistance (by 7.0±1.4 mmHg per L/min,
P
<0.001), mean arterial blood pressure (by 8.9±3.5 mmHg,
P
<0.05), and blunted an increase in femoral artery diameter that occurred immediately before exercise (change in diameter: 0.14±0.04 versus 0.32±0.06 mm after
l
‐
NMMA
and placebo,
P
<0.01). During/after exercise
l
‐
NMMA
had no significant effect on peripheral resistance, cardiac output, or on femoral artery diameter.

Conclusions

These results suggest that
NO
plays little role in modulating muscular artery function during exercise but that it may mediate changes in muscular artery tone immediately before exercise.
Relationship Between Depressive Symptoms and Health Status in Peripheral Artery Disease: Role of Sex Differences
Authors: Jelani Qurat‐ul‐ain , Mena‐Hurtado Carlos , Burg Matthew , Soufer Robert , Gosch Kensey , Jones Philip G. , Spertus John A. , Safdar Basmah , Smolderen Kim G.
Published: August 2020

Background

The association of depressive symptoms with health status in peripheral artery disease (PAD) is understudied. No reports of differential impact on women have been described.

Methods and Results

The PORTRAIT (Patient‐Centered Outcomes Related to Treatment Practices in Peripheral Artery Disease Investigating Trajectories) registry enrolled 1243 patients from vascular specialty clinics with new or worsening PAD symptoms. Depressive symptoms were assessed at baseline and 3 months using the 8‐Item Patient Health Questionnaire (score ≥10 indicating clinically relevant depressive symptoms). Disease‐specific and generic health status were measured by Peripheral Artery Questionnaire and EQ‐5D Visual Analogue Scale at baseline and 3, 6, and 12 months. An adjusted general linear model for repeated measures was constructed for baseline and 3‐, 6‐, and 12‐month health status outcomes by depressive symptoms at baseline. Differences by sex were tested with interaction effects. The mean age was 67.6±9.4 years with 38% (n=470) women. More women than men (21.1% versus 12.9%;
P
<0.001) presented with severe depressive symptoms. In the adjusted model, patients with depressive symptoms had worse health status at each time point (all
P
<0.0001). Results were similar for EQ‐5D Visual Analogue Scale scores. The magnitude in 1‐year change in health status scores did not differ by sex. Depressive symptoms explained 19% of the association between sex differences in 1‐year Peripheral Artery Questionnaire summary scores.

Conclusions

Women with PAD have a high burden of depressive symptoms. Depressive symptoms were associated with a strikingly worse disease‐specific health status recovery path over the year following PAD diagnosis in men and women. Developing and testing interventions to address depressive symptoms in PAD are urgently needed.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01419080.
The Poetics of Nothing: Jean Passerat’s ‘De Nihilo’ and its Legacy
Authors: White Paul
Published: August 2020

On 1 January 1582 the poet and scholar Jean Passerat (1534–1602) sent a gift to his patron Henri de Mesmes: a poem in Latin hexameters about nothing (“De nihilo”). It became a literary sensation, prompting, over the next decades, a long and varied sequence of poetic and prose responses in Latin and vernacular languages by various authors competing to out-do Passerat, and one another, in ingenuity. Why did this poem catch the imagination of so many as the sixteenth century turned into the seventeenth? This article offers the first complete account of the ‘Nothing’ phenomenon, as it passed between multiple languages, literary genres and cultural contexts. It traces its dissemination via networks linked to institutions of learning, to academies and salons, to patrons and to coteries of poets. Focusing on the French context in particular, it then goes on to argue that the literary and political significance of these texts is greater than has hitherto been recognized.
Forty-one new species of Coniceromyia Borgmeier (Diptera: Phoridae),
an identification key, and new distributional records for the species of the genus
Authors: AMENT DANILO CÉSAR , KUNG GIAR-ANN , BROWN BRIAN V.
Published: August 2020

Forty-one new species of the mostly neotropical genus Coniceromyia Borgmeier are described. The descriptions follow the methodology of recent works on the genus taxonomy and illustrate habitus, foremetatarsus, wing, hind femur, and hypopygium for each species. Unique features of some species are also illustrated, including several male features possibly related to sexual selection such as processes on different tarsomeres of the foreleg. New records for the known species are presented, as well as an identification key for the species of the genus and maps with their updated distribution. Coniceromyia brandaoi Ament & Amorim is synonymized with Coniceromyia plaumanni Borgmeier. Even though this work examined the Coniceromyia of the major collections of neotropical Phoridae, the high number of singletons and doubletons indicates that the real diversity of the genus may still be far from understood.
A new insular species of the Cyrtodactylus intermedius (Squamata: Gekkonidae) group from Cambodia with a discussion of habitat preference and ecomorphology
Authors: GRISMER L. LEE , ONN CHAN KIN , OAKS JAMIE R. , NEANG THY , SOKUN LANG , MURDOCH MATTHEW L. , STUART BRYAN L. , GRISMER JESSE L.
Published: August 2020

An integrative taxonomic analysis based on mitochondrial and morphological data recovered the population of Cyrtodactylus on Koh Rong Island, Preah Sihanouk Province, Cambodiaa as an endemic insular species belonging to the Cyrtodactylus intermedius group. This brings the number of species in the C. intermedius group to at least 10 and the number of species in Cambodia to at least seven. Species of this relatively small group vary widely in habitat preference, occurring in general, terrestrial, karstic, or granitic habitats. Ancestral character state mapping recovered a general habitat preference as the ancestral condition from which all others independently evolved even though this did not covary with morphology. The description of another new species of reptile from Cambodia continues to underscore the potentially significant amount of unrealized biodiversity in Indochina and Southeast Asia and the continued need for field surveys in unexplored or poorly explored areas.
Taxonomic evaluation of two similar bent-toed geckos Squamata: Gekkonidae: Cyrtodactylus Gray, 1827) from East Java, Indonesia
Authors: RIYANTO AWAL , FARAJALLAH ACHMAD , HAMIDY AMIR , FITRIANA YULI SULISTYA , MUNIR MISBAHUL , KURNIAWAN NIA , SMITH ERIC N.
Published: August 2020

The bent-toed geckos of the genus Cyrtodactylus are the most speciose land vertebrates of Southeast Asia (about 300 species so far) and new species continue to be recognized at a rapid rate. Within the last decade three new species were described from Java, Indonesia, C. semiadii, C. petani, and C. klakahensis. The latter two are very similar, except for differences in the precloacal depression in adult males. These two species have relatively close type localities, separated from each other by only about 50 km, and with similar habitat type and elevation. Our study aimed to evaluate the taxonomic status of C. klakahensis and C. petani using both morphological and genetic evidence. These two species are genetically similar, with a genetic divergence of only 1.5 to 1.6%. This divergence is well below the level of typically characterizes sister species of Cyrtodactylus (approximately 4% in the mitochondrial ND2 gene), and is more in line with population variation due to geographic distance. Further examination of specimens, from both type localities, showed no diagnostic morphological characters between the two species. Thus, we conclude that C. klakahensis and C. petani are conspecific, and following article 23 of the ICZN, C. klakahensis is herein considered a junior synonym of C. petani.
Considering Cumulative Social Effects of Technological Hazards and Disasters
Authors: Gill Duane , Ritchie Liesel
Published: August 2020

This article describes research designs utilized to study cumulative sociocultural and psychosocial effects of technological hazards and disasters. We apply these designs to two cases: (a) the Exxon Valdez disaster with a focus on Cordova, Alaska, and (b) the Enbridge Northern Gateway Pipeline project with a focus on the Gitga’at First Nation in Hartley Bay, British Columbia, Canada. The Exxon Valdez oil spill began in 1989 with the grounding of the supertanker on Bligh Reef in Prince William Sound, Alaska. Fisheries collapsed, key species failed to recover, and litigation languished for 19 years, creating an accumulation of impacts from the initial event. The Gitga’at First Nation serves as a case for examining cumulative effects of energy development, specifically the Enbridge Northern Gateway Pipeline project proposed in 2010. Hartley Bay’s sociocultural and psychosocial well-being are under threat from these and other ongoing development activities; they have also endured centuries of government-led subjugation. In studying each of these communities, we used mixed methods approaches that combined document review, observations, interviews, and surveys. Based on our experiences, we contend that the most effective way to examine cumulative social impacts is to employ concepts and theories drawn from existing research to support guidelines, frameworks, and methods.