bluuebunny/crossref_metadata_2025 huggingface dataset:
Igg-Dependent Hydrolysis of Myelin Basic Protein of Patients with Different Courses of Schizophrenia
Authors: Parshukova Daria A. , Smirnova Liudmila P. , Kornetova Elena G. , Semke Arkadiy V. , Buneva Valentina N. , Ivanova Svetlana A.
Published: August 2020

The level hydrolysis of myelin basic protein (MBP) by IgG in patients with schizophrenia was studied depending on the clinical features and course of the disease. The patients were grouped according to type of schizophrenia and type of disease course. We found that IgGs isolated and purified from sera of schizophrenia patients’ blood hydrolyses human MBP, and the level of this hydrolysis significantly exceeds that of healthy individuals. Detection of protease activity corresponding only to intact IgGs in polyacrylamide gel fragments, together with data of gel filtration of antibodies under conditions of “acid shock” (concordance of optical density profile of IgG with profile of MBP-hydrolyzing activity) and with the absence of any other proteins and bands in gradient SDS-PAGE and in PVDF membrane provides direct evidence that the IgGs from the schizophrenia patients have MBP-hydrolyzing activity. The antibodies-specific proteolytic activity of patients with acute schizophrenia (1.026 [0.205; 3.372] mg MBP/mg IgG/h) significantly exceeds the activity of IgG in patients in remission (0.656 [0.279; 0.873] mg MBP/mg IgG/h) and in healthy individuals (0.000 [0.00; 0.367] mg MBP/mg IgG/h). When comparing the specific activity in patients with different types of disease course, we have found that patients with a continuous course of paranoid schizophrenia (1.810 [0.746; 4.101 mg MBP/mg IgG/h]) had maximal activity values. It can be assumed that the increase in the activity of MBP-hydrolyzing antibodies is due to the activation of humoral immunity in acute schizophrenia.
A Hierarchical Attention Recommender System Based on Cross-Domain Social Networks
Authors: Zhao Rongmei , Xiong Xi , Zu Xia , Ju Shenggen , Li Zhongzhi , Li Binyong
Published: August 2020

Search engines and recommendation systems are an essential means of solving information overload, and recommendation algorithms are the core of recommendation systems. Recently, the recommendation algorithm of graph neural network based on social network has greatly improved the quality of the recommendation system. However, these methods paid far too little attention to the heterogeneity of social networks. Indeed, ignoring the heterogeneity of connections between users and interactions between users and items may seriously affect user representation. In this paper, we propose a hierarchical attention recommendation system (HA-RS) based on mask social network, combining social network information and user behavior information, which improves not only the accuracy of recommendation but also the flexibility of the network. First, learning the node representation in the item domain through the proposed Context-NE model and then the feature information of neighbor nodes in social domain is aggregated through the hierarchical attention network. It can fuse the information in the heterogeneous network (social domain and item domain) through the above two steps. We propose the mask mechanism to solve the cold-start issues for users and items by randomly masking some nodes in the item domain and in the social domain during the training process. Comprehensive experiments on four real-world datasets show the effectiveness of the proposed method.
A Joint Dynamic Pricing, Advertising, and Production Model with Inventory-Level-Dependent Goodwill
Authors: Wang Yongzhao , Wei Liqun , Zhang Jianxiong
Published: August 2020

Inventory level has a significant impact on the goodwill of products to customers, which seldom becomes the focus of previous studies. In this paper, joint dynamic pricing, advertising, and production decision-making problem is investigated, where the demand rate depends on sales price and goodwill. The inventory and backlog as well as advertisement are considered as goodwill-building factors. The optimal dynamic pricing, advertising, and production policies are derived by using Pontryagin’s maximum principle. Numerical examples are provided to demonstrate the obtained results, and sensitivity analysis of main system parameters is carried out to obtain some managerial insights. We find that when the initial goodwill is relatively high, the firm’s profit first decreases and then increases with respect to the impact intensity of inventory on goodwill; otherwise, the firm always benefits from a higher impact intensity of inventory on goodwill. Furthermore, the optimal production and advertising policies are complementary caused by the feature of inventory-dependent goodwill.
A Review of the Dermatological Manifestations of Coronavirus Disease 2019 (COVID-19)
Authors: Marraha Farah , Al Faker Ibtissam , Gallouj Salim
Published: August 2020

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has affected 210 countries and territories around the world. The virus has spread rapidly, and the disease is still extending up to now. The pathophysiology for SARS-CoV-2 has not been well elucidated, and diverse hypotheses to date have been proposed. Initially, no skin manifestations were observed among patients with COVID-19, but recently a few cases have been described. In this review, we discuss these various cutaneous manifestations and skin problems related to personal protective equipment, as well as different cutaneous anti-COVID-19 drug-associated reactions. We also focus on the currently proposed managements of these rare manifestations.
Emotional Interactive Simulation System of English Speech Recognition in Virtual Context
Authors: Li Dan
Published: August 2020

With the development of virtual scenes, the degree of simulation and functions of virtual reality have been very complete, providing a new platform and perspective for teaching design. Firstly, the hidden Markov chain model is used to perform emotion recognition on English speech signals. English speech emotion recognition and speech semantic recognition are essentially the same. Hidden Markov style has been widely used in English speech semantic recognition. The experiments of feature extraction and pattern recognition of speech samples prove that Hidden Markovian has higher recognition rate and better recognition effect in speech emotion recognition. Secondly, combining the human pronunciation model and the hearing model, by analyzing the impact of the glottis feature on the human ear hearing-model feature, the research application of the English speech recognition emotion interactive simulation system uses the glottis feature to compensate the human ear, hearing feature is proposed by compensated English speech recognition, and emotion interaction simulation system is used in the English speech emotion experiment, which has obtained a high recognition rate and showed excellent performance.
Prooxidant Effects of Epigallocatechin-3-Gallate in Health Benefits and Potential Adverse Effect
Authors: Ouyang Jie , Zhu Kun , Liu Zhonghua , Huang Jianan
Published: August 2020

Epigallocatechin-3-gallate (EGCG) is the major polyphenolic compound present in green tea and is generally regarded as an effective antioxidant. However, its chemical reactivity makes it susceptible to generate reactive oxygen species (ROS) via autooxidation and exhibit prooxidant effects. The prooxidant actions of EGCG could play a dual role, being both beneficial and harmful. This review summarized recent research progress on (1) the anticancer, antiobesity, and antibacterial effects of EGCG and (2) the possible toxicity of EGCG. The major focus is on the involvement of prooxidant effects of EGCG and their effective doses used. Considering dosage is a crucial factor in the prooxidant effects of EGCG; further studies are required to find the appropriate dose at which EGCG could bring more health benefits with lower toxicity.
Acute-on-Chronic Liver Failure in Pregnant Patients with Chronic Hepatitis B: A Retrospective Observational Case Series Study
Authors: Wang Shiwei , Xiong Haofeng , Luo Changling , Zhao Hong , Fan Ying , Zhang Ting , Wang Lili , Wang Qi , Xie Wen
Published: August 2020

Background and Aims. Acute-on-chronic liver failure (ACLF) is common in patients with end-stage liver disease and chronic hepatitis B (CHB) or hepatitis B virus- (HBV-) related cirrhosis. To date, no uniform definition and management strategy are available for ACLF. Although a considerable number of studies on ACLF has been published, there are few reports on ACLF in pregnant women with CHB. This study retrospectively reviewed five patients who were diagnosed with ACLF during pregnancy in the past 10 years. We aimed at investigating their clinical characteristics, treatment, biochemical test results, and maternal and fetal outcomes. Results. Asthenia, anorexia, and jaundice were the main initial clinical manifestations in these patients during the second or third trimester of pregnancy. All patients received antiviral therapy. None of the pregnant women died after treatment. Patient #4 was treated with an artificial liver support system, and patients #2 and #5 underwent transfusion therapy. The acute insult in all patients was HBV DNA reactivation. Except for patient #3, who chose an actively induced vaginal delivery because of intrauterine fetal demise, the remaining four patients underwent a preterm delivery via a cesarean section. The four neonates were alive, although all were small for gestational age. Conclusion. Asthenia, anorexia, and jaundice during mid-late pregnancy should be immediately investigated. Before and during the pregnancy, hepatologists or obstetricians should actively screen pregnant women with CHB for HBV DNA status and alanine aminotransferase levels. Reactivation of HBV replication in pregnant women with CHB may lead to ACLF, especially in multiparous women. Once ACLF is diagnosed, antiviral therapy should be considered as soon as possible to protect maternal and fetal health.
Abstract A10: Constitutive HIF activity enhances T-cell antitumor immunity and memory T-cell formation in the murine adoptive cell therapy model
Authors: Lauhan Colette R. , Witherden Deborah , Liikanan Ilkka , Goldrath Ananda
Published: August 2020

Purpose: To determine if unrestrained hypoxia inducible factor (HIF) activity in CD8 T cells improves antitumor response.

Methods: CD8 T cells were isolated from von Hippel Lindau (VHL)-deficient (VHL KO) mice, which have unrepressed HIF1 and HIF2 activity, as well as from VHL/HIF1/HIF2 triple-deficient (TKO) and WT mice. Following in vitro activation, T cells were transferred to melanoma (B16) tumor-bearing mice and monitored for tumor progression and survival. In other studies, activated VHL KO and TKO CD8 cells were mixed with WT CD8 cells and transferred to B16 or adenocarcinoma (MC38) tumor-bearing mice; after 7-10 days, donor T cells were analyzed from tumors, spleens, and draining lymph nodes (LN).

Results: Single transfer of VHL KO CD8 T cells to B16 tumor-bearing mice resulted in delayed tumor growth and prolonged survival compared to transfer of CD8 T cells from TKO or WT donors. Co-transfer of VHL KO cells with WT cells into B16 tumor-bearing mice resulted in superior accumulation of VHL KO cells in all tissues including tumors. In contrast, mixed transfer of TKO cells with WT cells to B16 tumor-bearing mice resulted in poorer accumulation of TKO cells in all tissues including tumors. VHL KO tumor-infiltrating lymphocytes (TILs) had superior expression of tissue resident memory (TRM) phenotype markers CD103 and CD69 compared to WT and TKO TILs. Similarly in the MC38 tumor model, VHL KO cells showed improved accumulation in all tissues compared to WT cells.

Conclusions: Here we demonstrate that VHL deletion in CD8 T cells results in superior efficacy in delaying tumor growth and improving recipient survival, greater accumulation in multiple solid tumor models, and increased development of the TRM phenotype. Further, TKO recipients demonstrated increased tumor growth, reduced survival, reduced TIL numbers, and absence of TRM phenotype following adoptive transfer, confirming the HIF dependency of the VHL-deletion phenotype. Taken together, these data demonstrate that T cells with constitutive HIF activity provide a more robust antitumor response. Therefore, manipulation of HIF regulation could offer new tools for enhanced T-cell efficacy in adoptive cellular therapy for solid tumors.

Citation Format: Colette R. Lauhan, Deborah Witherden, Ilkka Liikanan, Ananda Goldrath. Constitutive HIF activity enhances T-cell antitumor immunity and memory T-cell formation in the murine adoptive cell therapy model [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 A10.
Abstract A54: Parallel targeting of RAF/MEK/ERK pathway in RAS-mutant embryonal rhabdomyosarcoma
Authors: Vaseva Angelina V. , Bandyopadhyay Abhik , Pozo Vanessa Del , Goodwin Craig M. , Gautam Prson , Wennerberg Krister , Wood Kris C. , Chen Yidong , Der Channing J. , Houghton Peter J.
Published: August 2020

RAS pathway mutations are found in nearly 75% of high-risk embryonal rhabdomyosarcoma (ERMS). While RAS oncoproteins are well-established therapeutic targets for many adult human cancers, still very little is known about the role of RAS mutations in the development and maintenance of ERMS. By sequencing, we identified cell lines and PDX tumors harboring activating mutations in H- or NRAS. Further, we showed that mutant H- or NRAS was critical for the growth of all RAS-mutant ERMS cell lines and that RAF/MEK/ERK signaling pathway, but not PI3K/AKT, was mediator of RAS dependency in these cells. However, in vivo treatment of RAS-mutant ERMS xenografts with the MEK inhibitor trametinib showed modest response as compared to BRAF-mutant astrocytoma xenografts. We reasoned that similarly to other RAS-driven cancers, ERMS cells and tumors are able to acquire resistance to inhibitors of the RAF/MEK/ERK pathway. We performed drug-sensitizing pooled CRISPR library screen and identified that inhibition of ERK2 potentiated trametinib treatment. We show that combining trametinib with ERK1/2 inhibitor leads to potent synergistic ERK inhibition and ERMS tumor growth suppression.

Citation Format: Angelina V. Vaseva, Abhik Bandyopadhyay, Vanessa Del Pozo, Craig M. Goodwin, Prson Gautam, Krister Wennerberg, Kris C. Wood, Yidong Chen, Channing J. Der, Peter J. Houghton. Parallel targeting of RAF/MEK/ERK pathway in RAS-mutant embryonal rhabdomyosarcoma [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 A54.
Abstract A62: A cerebral organoid model of pediatric glioma
Authors: Ismail Amin , Balamatsias Demis
Published: August 2020

Glioblastoma is the most devastating brain cancer with dismal prognosis both in adults and children and accounts for 16% of primary brain tumors. Despite aggressive therapeutic approaches, the majority of patients die within one year after diagnosis. Current in vivo modeling of glioblastoma involves xenografts either of cultured cell lines or human biopsies transplanted into mice. These models do not faithfully recapitulate the complex biology/pathogenesis of cancer. Here we used human pluripotent embryonic stem cells (or young children fibroblast-driven induced pluripotent stem cells) to create 3D structures with histology reminiscent of human fetal brain (the so-called cerebral organoids). Cerebral organoids combine the accurate multilineage differentiation and physiology of a developing brain with the easiness of manipulation of an in vitro system. We engineered these mini-brains to develop tumors by forced expression of combinations of epigenetic and genetic hits that have previously been shown to drive pediatric glioblastoma multiform (GMB). These include the expression of a mutant histone H3 variant H3F3A (mutated at K27M or G34R) or a gain of function of a mutant form of isocitrate dehydrogenase (IDH1R132H) in combination with the loss of ATRX histone remodeling factor and/or p53 tumor suppressor. Lentiviral transfection was used to express combination of these genetic and epigenetic hits into cerebral organoids. The mutated organoids exhibited tumorigenic growth that was histologically characterized. For example, the expression of H3K27M in combination with loss of both p53 and ATRX showed a remarkable dysplasia reminiscent of primary glioblastoma. Moreover, these organoids exhibited tumor rosette structures resembling those found in ependymoma. In contrast, organoids expressing K27M alone did not show such structures. Interestingly, IDH1R132H combined with p53 and ATRX loss resulted in different tumor morphology, suggestive of a possibility to model oncogenic dependence in pediatric GBM. Cerebral organoids could also be used as a model to study tumor invasion starting with glioma stem-like cells (GSCs, which are believed to be the tumor-initiating cells in GBM). Interestingly, the GSC cell line 923 (which does not invade mouse brain in vivo) invaded and formed a focal lesion in a cocultured organoid. The organoid-based cancer model presented here carries a promising potential to uncover the initiation and pathogenesis of pediatric tumors early in the developing brain.

Note: This abstract was not presented at the conference.

Citation Format: Amin Ismail, Demis Balamatsias. A cerebral organoid model of pediatric glioma [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 A62.
Abstract A68: Optical coherence tomography improves subclinical retinoblastoma management
Authors: Soliman Sameh E. , VandenHooven Cynthia , MacKeen Leslie , Gallie Brenda
Published: August 2020

Purpose: Optical coherence tomography (OCT) improved retinal assessment that is comparable to histopathologic sections. In retinoblastoma, OCT was reported to detect fovea-tumor relation, diagnose subclinical (new, residual and recurrent tumors), and suspect tumor spread into the optic nerve. We hypothesized that strategic incorporation of OCT into retinoblastoma management will improve outcomes and managing retinoblastoma at the subclinical level (clinically undetectable) provides means for less treatment burden.

Methods: A single-center, noncomparative retrospective review of all eyes with subclinical retinoblastoma was conducted. Any eye that had an OCT-guided procedure, whether diagnostic or therapeutic, utilizing OCT software was included. OCT-guided management included projecting embedded OCT software tools (scan cube size and direction, multiple scan frames, localizing and measuring vertical and horizontal calipers, enhanced depth imaging frames, and/or red free fundus photograph) on a separate colored fundus image to guide management to improve visual, life, and eye salvage outcomes.

Results: We used OCT-guided strategies in 83 children (114 eyes). Diagnostic strategies included posterior pole screening for invisible retinoblastoma (37 eyes), topographic localization of invisible tumors (15 eyes) or subclinical recurrence (29 tumors), topographic localization of fovea-tumor relation (31 eyes), and mapping of potential choroidal or optic nerve invasion to determine subsequent management (2 eyes each). Therapeutic strategies included laser photocoagulation for perifoveal residual (26) and invisible (11) tumors and verification of photocoagulation adequacy for invisible (11) new and recurrent (11) tumors. These procedures were scored for their influence to changed therapy.

Conclusion: Detailed OCT assessment improves retinoblastoma management and facilitates precision therapy to preserve vital visual structures (e.g., the center of vision), detect subtle subclinical tumors (new or recurrent), allow administration and adequacy of laser treatment, and map subclinical high-risk features. Developing OCT-guided strategies with full technical description facilitates reproducibility and allows precision therapy to be a reality.

Citation Format: Sameh E. Soliman, Cynthia VandenHooven, Leslie MacKeen, Brenda Gallie. Optical coherence tomography improves subclinical retinoblastoma management [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 A68.
Abstract B21: Childhood Cancer Molecular Map (C2M2) to define medulloblastoma heterogeneity and predict treatment response
Authors: Yeerna Huwate , Briggs Benjamin , Rusert Jessica , Chavez Lukas , Mesirov Jill , Wechsler-Reya Robert , Tamayo Pablo
Published: August 2020

Background: Medulloblastoma is a heterogenous group of tumors that collectively are the most common malignant brain tumor of childhood. Advances in treatment are required as one third of patients die from the disease, and those who survive suffer severe long-term side effects from therapy. The ability to sequence entire genome, methylome, and transcriptome of tumors provides the opportunity to identify underlying drivers of malignancy, predict treatment response, and develop novel therapies. A lack of reproducibility when comparing identified genetic mutations with treatment response is challenging because a single genetic change does not reflect the cellular state of a cancer cell in its entirety, which is expressing a multitude of genes. Computational methods allow for the creation of mapping systems that may more accurately describe the cellular state and thereby predict treatment response.

Objective: We used Childhood Cancer Molecular Map (C2M2) to define medulloblastoma heterogeneity and predict treatment response using patient-derived xenografts (PDX).

Methods: RNA transcription abundance from medulloblastoma samples published by Cho et al. were used to create C2M2. This was accomplished by analyzing the distribution of transcriptional abundance for each gene across all samples in order to select the genes that display the most asymmetric and non-Gaussian behavior. This delineated a “context score” for each gene, emphasizing those over- and underexpressed, allowing for the creation of a unique signature to model cellular states. The medulloblastoma samples from Cho et al. were then plotted onto the map based upon their RNA transcriptional abundance signatures, creating clusters of similar cellular states. Likewise, RNA transcription abundance from 20 PDX samples, for which drug response was known, was then mapped.

Results: C2M2 identified ten cellular states for medulloblastoma by which to define patient samples: SHH DNA repair, SHH glutamate signaling, SHH RNA repair, WNT, Photoreceptor and MYC (in which Group 3 medulloblastoma falls), Neuronal migration, Neuronal MAPK activation and Axonal (in which Group 4 medulloblastoma falls), and Homeobox activation. PDX samples for which drug response was known clustered similarly onto the map.

Conclusion: C2M2 using RNA transcriptional abundance from medulloblastoma samples could be used to predict drug response.

Citation Format: Huwate Yeerna, Benjamin Briggs, Jessica Rusert, Lukas Chavez, Jill Mesirov, Robert Wechsler-Reya, Pablo Tamayo. Childhood Cancer Molecular Map (C2M2) to define medulloblastoma heterogeneity and predict treatment 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 B21.
Abstract B23: EWS-FLI1 partners with EWSR1 to regulate transcription in Ewing sarcoma
Authors: Ahmed Nasiha , Schwartz Jacob
Published: August 2020

Transcription factors are important regulators in normal cell proliferation and cancer. Ewing sarcoma is a pediatric bone cancer driven by a translocation between two transcription factor genes, EWSR1 and FLI1, leading to the expression of an aberrant transcription factor, EWS-FLI1. While FLI1 is not expressed, constitutive expression of EWSR1 is retained in Ewing sarcoma cells. However, very little is known about the effect of wild-type EWSR1 on EWS-FLI1 transcriptional activity. EWSR1 and EWS-FLI1 coimmunoprecipitate in a complex together in Ewing sarcoma cells and HEK293T cells. RNA-sequencing in Ewing sarcoma cells revealed a pool of genes coregulated by EWS-FLI1 and EWSR1. Furthermore, loss of EWSR1 in Ewing sarcoma cells inhibits anchorage-independent growth. Taken together, this suggests EWSR1 may play a key role in the transcriptional activity of EWS-FLI1 in Ewing sarcoma biology.

Citation Format: Nasiha Ahmed, Jacob Schwartz. EWS-FLI1 partners with EWSR1 to regulate transcription in Ewing 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 B23.
Abstract B59: Cardiometabolic complications after pediatric cancer: Associations with chemotherapeutic agents and body-mass-index fluctuations
Authors: Belanger Veronique , Warin Alexandre , Tonova Elitsa , Bouchard Isabelle , Meloche Caroline , Curnier Daniel , Sultan Serge , Laverdiere Caroline , Sinnett Daniel , Marcil Valerie
Published: August 2020

Introduction: Survivors of childhood cancer are at risk of cardiometabolic complications including dyslipidemia, obesity, insulin resistance, and hypertension. In addition, children undergoing chemotherapy often suffer from substantial side effects including rapid weight gain, transient hypertension, and elevated blood glucose and lipids. However, little is known about the cardiometabolic health of children shortly after cancer treatment. This study aims to describe the cardiometabolic profile of children after treatment and to study the factors associated with these complications.

Methods: Participants were recruited at Sainte-Justine UHC in Montreal as part of the VIE Program (Valorization, Implication, Education). Cardiometabolic health was assessed with biochemical, clinical, and anthropometric measures. Data on treatment (diagnosis, chemotherapeutic agents, and doses) were obtained from medical files.

Results: Evaluations were performed on 71 participants (45% boys; median age: 9.8 years; 42% with acute lymphoblastic leukemia; median time since last treatment: 1.4 years, range: 0.2-3.5 years). Our assessment showed that 28% had hypertension, 27% were obese, 19% had altered glucose metabolism, and 33% had dyslipidemia. The risk of having dyslipidemia was associated with higher age [relative risk (RR): 1.28, 95%CI: 1.14-1.44, P<0.01] and body mass index (BMI) (RR: 1.76, 95%CI: 1.11-2.78, P=0.02). Participants who increased their BMI during treatment were at higher risk of obesity (RR: 3.01, 95%CI: 1.44-6.29, P<0.01). The increase of BMI during treatment was associated with exposure to glucocorticoids (coefficient β: 0.56, 95%CI: 0.13-0.98, P=0.01) and to methotrexate (coefficient β: 0.73, 95%CI: 0.34-1.11, P<0.01).

Conclusion: We found important alterations of children’s cardiometabolic profile shortly after the end of cancer treatment. Increased BMI during and after treatment and exposure to corticosteroids and methotrexate were factors associated with cardiometabolic health. This stresses the importance of maintaining a favorable nutritional status during cancer therapy. Early nutritional interventions promoting sustainable healthy eating habits may contribute to limit cardiometabolic complications in the short and long term.

Citation Format: Veronique Belanger, Alexandre Warin, Elitsa Tonova, Isabelle Bouchard, Caroline Meloche, Daniel Curnier, Serge Sultan, Caroline Laverdiere, Daniel Sinnett, Valerie Marcil. Cardiometabolic complications after pediatric cancer: Associations with chemotherapeutic agents and body-mass-index fluctuations [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 B59.
Abstract IA01: Pediatric neuro-oncology: What’s next?
Authors: Pfister Stefan M.
Published: August 2020

Based on recent discoveries and data integration in genomics and epigenomics, a lot more is known about the biology of childhood brain tumors today when compared to a decade ago. This has vastly benefitted brain tumor diagnostics, including classification and some predictive and prognostic biomarkers. Yet the gap between this newly defined diagnostic gold standard and routine clinical implementation largely remains to be bridged. Additionally, the cell of origin for a majority of brain tumor entities remains elusive. The increased granularity of understanding intertumor heterogeneity also comes with the challenge of accounting for this heterogeneity in our therapeutic approaches. Ever-smaller patient groups and, on the other hand, an ever-increasing portfolio of potentially available drugs, require a paradigm shift in how we run and evaluate preclinical and clinical trials. Academically rewarding proof-of-concept studies that are typically well published, which certainly have a different purpose and thus lack the rigor of thorough preclinical filtering (because they typically embark on one or two “representative” models, which certainly does not cover the heterogeneity of a disease by any means), should no longer be regarded “sufficient preclinical evidence” to justify a clinical trial. Thus, novel incentives and funding models for this “less academically attractive,” but highly patient-relevant studies need to be explored. Phase I trials just with the purpose of dose finding should not be carried without a path forward into efficacy testing. Drugs with no evidence for brain penetration should not “just” be tried in patients with brain tumors without even making the best effort to understand brain and tumor penetrance. Academic work-up of biologic material from every single patient being enrolled on a trial should be mandatory rather than “nice to have.” Hereditary cancer predisposition should no longer be ignored when it comes to treatment stratification. Reimbursement models for “next-generation diagnostics,” preclinical phase I and phase II studies, and academic clinical trials (focusing on combinations rather than monotherapies in end-stage disease) have to shift from traditional third-party funding to alternative funding models. If we do not manage to address this paradigm shift, high-risk brain tumor patients may still mostly die from their disease 10 years from now.

Citation Format: Stefan M. Pfister. Pediatric neuro-oncology: What’s next? [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 IA01.
Abstract IA03: Medulloblastoma predisposition according to molecular subgroup: The usual suspects and beyond
Authors: Northcott Paul A.
Published: August 2020

Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses, and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5-6% of all MB patients. The incidence of genetic predisposition to MB varied according to patient age and molecular subgroup status, with up to 25% of childhood SHH-MB patients predicted to harbor pathogenic germline variation. These estimates only account for known cancer predisposition genes, and ongoing studies designed to investigate unknown pathogenic events in the germline of MB patients have implicated novel MB predisposition genes. This presentation aims to summarize these recent insights into genetic predisposition to MB and contextualize these findings with their associated clinical implications.

Citation Format: Paul A. Northcott. Medulloblastoma predisposition according to molecular subgroup: The usual suspects and beyond [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 IA03.
Abstract IA20: Neuronal activity promotes proliferation of normal and neoplastic glial cells
Authors: Monje Michelle
Published: August 2020

Neuronal activity regulates the proliferation and differentiation of oligodendrocyte precursor cells during development and in adulthood. In the healthy brain, this results in activity-regulated plasticity of myelination and subsequent modulation of neural circuit function evident in oligodendrogenesis-dependent behavioral changes. The robust mitogenic effect of neuronal activity on normal neural precursor and oligodendroglial precursor cells, a putative cellular origin of pediatric high-grade gliomas (HGG), suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote proliferation in this devastating group of childhood brain cancers. Using in vivo and in situ optogenetic techniques together with patient-derived high-grade glioma cell cultures and xenograft models, we have demonstrated that neuronal activity similarly promotes proliferation and growth of both pediatric and adult high-grade glioma subtypes. Crucial mechanisms mediating activity-regulated high-grade glioma growth include secretion of Brain Derived Neurotrophic Factor (BDNF) and the synaptic protein neuroligin-3 (NLGN3), which induces multiple oncogenic signaling pathways together with robust changes in synaptic gene expression in glioma cells. Nlgn3 is necessary for the growth of high-grade glioma xenografts in the mouse brain, and NLGN3 expression levels in human HGG negatively correlate with patient overall survival. Thus, neuronal activity not only modulates the structure and function of the brain’s myelinated infrastructure, but neurons also play an important role in the brain tumor microenvironment, with activity-regulated secretion of NLGN3 emerging as an unexpected and therapeutically targetable mechanism underlying axon-glioma interactions and promoting neuronal activity-regulated cancer growth.

References: Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Inema I, Miller SE, Bieri G, Zuchero JB, Barres BA, Woo PJ, Vogel H, Monje M. Neuronal activity promotes adaptive oligodendrogenesis and myelination in the mammalian brain. Science 2014;344 (6183):487; 344:1252304. Venkatesh HS, Johung T, Caretti V, Noll A, Tang Y, Nagaraja S, Gibson EM, Mount CW, Pollepalli J, Mitra SS, Woo PJ, Malenka RM, Vogel H, Bredel M, Mallick P, Monje M. Neuronal activity promotes glioma growth through neuroligin-3 secretion, Cell 2015;161(4):803-16. Venkatesh HS, Tam LT, Woo PJ, Nagaraja S, Gillespe SM, Lennon J, Ni J, Duveau DY, Morris PJ, Zhao JJ, Thomas CJ, Monje M. Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma, Nature 2017;549:533-37.

Citation Format: Michelle Monje. Neuronal activity promotes proliferation of normal and neoplastic glial 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 IA20.
Abstract IA22: Tumor cells highjack diverse cellular processes to maintain redox balance
Authors: Zhang Hai-Feng , El Naggar Amal M. , Cheng Hongwei , Li Wei , Dimitrov Dimiter S. , Sorensen Poul H.
Published: August 2020

In aggressive sarcomas such as Ewing sarcoma (EwS) and osteosarcoma (OS), the single most powerful predictor of poor outcome is metastatic disease, highlighting the critical need to identify new factors driving metastasis in these diseases. Metastasis is widely regarded as a very inefficient process, likely due to diverse stress forms that can potentially cull premetastatic cancer cells during the metastatic cascade, including hypoxia in primary tumors, anoikis stress in the circulation, and increased oxidative stress at distant organs prior to colonization. Adaptation to such conditions requires rapid stress-alleviating plasticity to confer fitness for metastatic progression, but mechanisms remain elusive. Studies in our laboratory indicate that mitigation of oxidative stress, not only during local invasion at the primary tumor site but also in the circulation during dissemination, and potentially as part of colonization at distant sites, is critical for childhood sarcoma metastatic capacity. Indeed, EwS and OS cells appear to utilize many different strategies to maintain redox balance, such as the induction of antioxidant pathways involving NRF2 or through other mechanisms such as alterations in amino acid transporter systems to facilitate production of glutathione and other antioxidants via amino acid metabolism. Some of these pathways are transcriptionally regulated, such as by direct activation of EWS-ETS fusion targets, while others are regulated through rapid translational activation by pioneer translation factors such as YB-1. Examples of each of these processes will be discussed.

Citation Format: Hai-Feng Zhang, Amal M. El Naggar, Hongwei Cheng, Wei Li, Dimiter S. Dimitrov, Poul H. Sorensen. Tumor cells highjack diverse cellular processes to maintain redox balance [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 IA22.
Abstract IA23: Lessons from a rare childhood cancer syndrome on replication repair deficiency and hypermutation
Authors: Tabori Uri Y.
Published: August 2020

In order to divide, cells need to replicate their DNA. Replication is done by DNA polymerase epsilon and delta (POLE and POLD1) and creates thousands of mistakes per each replication cycle. The major components safeguarding our genome against such mutations are the proofreading capacity of both polymerases and the mismatch repair (MMR) genes. Germline mutations in either POLE or the MMR genes result in the most aggressive childhood cancer syndromes with high penetrance of cancers during childhood with the hallmark of extreme hypermutation. Data from the International Replication Repair Deficiency (RRD) Consortium reveal that this phenomenon is not restricted to the rare cancer syndrome and affects 5% of childhood cancers throughout many tissues. Hypermutation is observed in up to 10% of recurrent childhood cancers and 20% of adult cancers. Recent data reveal that there are a variety of mutational signatures that are associated with each cause of RRD and hypermutation. These mutations can be traced to the germline or previous therapy. Furthermore, signatures are not restricted to SNV but can be observed by insertions and deletions in microsatellites. Animal models of RRD shed new light on the process of tumorigenesis and mutation progression in RRD cancers and their impact on inter- and intratumoral heterogeneity. Together, these data provide an Achilles heel to these tumors where immunotherapy and combinations can improve survival for patients with germline RRD and children with RRD hypermutant cancers. Novel biomarkers of response to immunotherapy provide insight into the patterns of immune and tumor interactions in these patients.

Citation Format: Uri Y. Tabori. Lessons from a rare childhood cancer syndrome on replication repair deficiency and hypermutation [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 IA23.
Abstract IA28: Tumor uniformity
Authors: Behjati Sam
Published: August 2020

Intra- and intertumor heterogeneity has emerged as a near-universal feature of human cancer. The definition of heterogeneity has advanced our understanding of various biologic and clinical challenges. At the same time, however, it distracts from unifying features of tumor that may lend themselves as universal targets. Here, I outline some observations from single-cell RNA sequencing experiments of childhood and adult cancers that indicate that transcriptional cellular identity transcends intra- and intertumor heterogeneity. Accordingly, the cellular transcriptome may in some cases represent a tumor-overarching target.

Citation Format: Sam Behjati. Tumor uniformity [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 IA28.
Abstract IA31: Stalled developmental programs at the root of K27M mutant gliomas and other pediatric brain tumors
Authors: Jabado Nada
Published: August 2020

Childhood brain tumors have suspected prenatal origins. We showed that H3K27M in gliomas impairs the production and the spread of the repressive H3K27me3 mark from PRC2 high-affinity sites. Neither the recruitment of PRC2 to its nucleation sites nor the deposition of the H3K27me3 mark in the proximity of those sites was affected by the mutation. However, our findings indicate that as the marks cannot spread to establish the proper silencing landscape, further lineage specification, a major role of PRC2, is not possible, and the cell is stalled in an early epigenetic and progenitor state, indefinitely multiplying without being able to further differentiate. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >44,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 119 distinct cell populations and defined regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage, embryonal tumors with multilayered rosettes fully recapitulate a cortical neuronal lineage, atypical teratoid-rhabdoid tumors originate outside of the neuro-ectoderm, while diffuse intrinsic pontine gliomas resemble a pontine astrocytic progenitor and differentiate upon removal of driver mutation H3K27M. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies mirroring transcriptional programs of the corresponding normal lineages. We identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.

Citation Format: Nada Jabado. Stalled developmental programs at the root of K27M mutant gliomas and other 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 IA31.
Abstract PR04: Locoregionally administered B7H3-targeting CAR T cells mediate potent antitumor effects in atypical teratoid/rhabdoid tumor
Authors: Theruvath Johanna , Sotillo Elena , Graef Claus Moritz , Heitzeneder Sabine , Labanieh Louai , Majzner Robbie , Mackall Crystal
Published: August 2020

Atypical teratoid/rhabdoid tumors (ATRT) are highly malignant embryonal brain tumors, arising in very young children, and are associated with inactivation of SMARCB1. The prognosis is extremely poor. Hence new treatments are urgently needed. We show that 100% of ATRT express B7-H3 and residual SMARCA4 SWI/SNF activity drives B7-H3 expression. Further, we demonstrate that prenatal brain expresses high levels of B7-H3, but expression is absent on pediatric brain, suggesting that the cell of origin may conserve high B7-H3 expression. We recently created a 4-1BB second-generation CAR targeting B7-H3. To date, there are little data on the most efficacious route of administration of CAR T cells in malignant brain tumors. The goal of this study was to test the antitumor activity of the B7-H3 CAR in highly aggressive ATRT xenograft models and compare intracavitary (IT), intraventricular (ICV), and intravenous (IV) administration in terms of efficacy, toxicity, and persistence of CAR T cells. Locoregionally (IT and ICV) administered B7H3.BB.z-CAR T cells mediate potent antitumor effects against cerebral ATRT xenografts, with more rapid kinetics, greater potency, and diminished systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. ICV-administered CAR T cells also demonstrate robust trafficking from the CNS into the periphery, and following clearance of ATRT xenografts, ICV or IV administered B7H3.BB.z-CAR T cells mediate antigen specific protection from tumor rechallenge in the CNS or in the flank. In summary, B7H3 is a promising immune target for this largely incurable pediatric tumor. We demonstrate that CNS delivered CAR T cells cure ATRT xenografts and efficiently traffic from the CNS into the periphery and can mediate long-term immune protection from disease recurrence in the CNS or in peripheral tissues.

This abstract is also being presented as Poster A12.

Citation Format: Johanna Theruvath, Elena Sotillo, Claus Moritz Graef, Sabine Heitzeneder, Louai Labanieh, Robbie Majzner, Crystal Mackall. Locoregionally administered B7H3-targeting CAR T cells mediate potent antitumor effects in atypical teratoid/rhabdoid tumor [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 PR04.
Plasma Exchange as an Initial Treatment for Severe Bleeding Induced by Acquired Factor V Deficiency: A Case Report and Mini Literature Review
Authors: Yanagiya Ryo , Kanouchi Kazunori , Toubai Tomomi , Yamada Akane , Aizawa Keiko , Shiono Yosuke , Ito Satoshi , Ishizawa Kenichi
Published: August 2020

Acquired factor V deficiency (AFVD) is a rare autoimmune bleeding disorder. Unlike acquired hemophilia, bypass therapies with recombinant activated factor VII and activated prothrombin complex concentrates are ineffective for severe bleeding due to AFVD. Although several treatment strategies have been attempted, a standard of care for severe hemorrhage induced by AFVD is lacking. Herein, we report a case of AFVD with severe bleeding that responded to plasma exchange (PE) combined with immunosuppression. We also reviewed previously reported AFVD cases with severe hemorrhage and suggest that PE may be an effective initial treatment for AFVD-induced severe hemorrhage.