bluuebunny/crossref_metadata_2025_split huggingface dataset:
Latina/o/x Immigrant Youth’s Motivations for Disclosing their Family-Undocumented Experiences to a Teacher(s): A Latent Transition Analysis
Authors: Kam Jennifer A , Marcoulides Katerina M , Fazio Keli Steuber , Murillo Roselia Mendez , Cornejo Monica 
Published: November 2020

AbstractUsing the revelation risk model (RRM), we examined factors that might motivate family-undocumented youth (i.e., youth who are undocumented or who have an immediate family member who is undocumented) to confide in a teacher(s). Latent transition analysis with 414 Latina/o/x 9th-12th grade students uncovered three profiles: concerned indirect revealers (i.e., moderate teacher-student relational closeness, highest perceived risk of disclosing, lowest communication efficacy, moderate indirect disclosure, low direct disclosure), relationally-close revealers (i.e., strongest teacher-student closeness, low perceived risk of disclosing, low communication efficacy, and highest moderate indirect and direct disclosure), and confident nonrevealers (i.e., moderate teacher-student closeness, lowest perceived risk of disclosing, highest communication efficacy, and lowest indirect and direct disclosure). Greater fear of deportation at Wave 1 predicted relationally-close revealers becoming concerned indirect revealers three months later. These findings identify experiences that could affect the extent to which family-undocumented youth turn to a teacher(s), which has implications for youth’s well-being.
How vocal temporal parameters develop: a comparative study between humans and songbirds, two distantly related vocal learners
Authors: Takahasi Miki , Okanoya Kazuo , Mazuka Reiko 
Published: November 2020

Abstract
Human infants acquire motor patterns for speech during the first several years of their lives. Sequential vocalizations such as human speech are complex behaviors, and the ability to learn new vocalizations is limited to only a few animal species. Vocalizations are generated through the coordination of three types of organs: namely, vocal, respiratory, and articulatory organs. Moreover, sophisticated temporal respiratory control might be necessary for sequential vocalization involving human speech. However, it remains unknown how coordination develops in human infants and if this developmental process is shared with other vocal learners. To answer these questions, we analyzed temporal parameters of sequential vocalizations during the first year in human infants and compared these developmental changes to song development in the Bengalese finch, another vocal learner. In human infants, early cry was also analyzed as an innate sequential vocalization. The following three temporal parameters of sequential vocalizations were measured: note duration (ND), inter-onset interval, and inter-note interval (INI). The results showed that both human infants and Bengalese finches had longer INIs than ND in the early phase. Gradually, the INI and ND converged to a similar range throughout development. While ND increased until 6 months of age in infants, the INI decreased up to 60 days posthatching in finches. Regarding infant cry, ND and INI were within similar ranges, but the INI was more stable in length than ND. In sequential vocalizations, temporal parameters developed early with subsequent articulatory stabilization in both vocal learners. However, this developmental change was accomplished in a species-specific manner. These findings could provide important insights into our understanding of the evolution of vocal learning.
Multiple competing RNA structures dynamically control alternative splicing in the human ATE1 gene
Authors: Kalinina Marina , Skvortsov Dmitry , Kalmykova Svetlana , Ivanov Timofei , Dontsova Olga , Pervouchine Dmitri D 
Published: November 2020

Abstract
The mammalian Ate1 gene encodes an arginyl transferase enzyme with tumor suppressor function that depends on the inclusion of one of the two mutually exclusive exons (MXE), exons 7a and 7b. We report that the molecular mechanism underlying MXE splicing in Ate1 involves five conserved regulatory intronic elements R1–R5, of which R1 and R4 compete for base pairing with R3, while R2 and R5 form an ultra-long-range RNA structure spanning 30 Kb. In minigenes, single and double mutations that disrupt base pairings in R1R3 and R3R4 lead to the loss of MXE splicing, while compensatory triple mutations that restore RNA structure revert splicing to that of the wild type. In the endogenous Ate1 pre-mRNA, blocking the competing base pairings by LNA/DNA mixmers complementary to R3 leads to the loss of MXE splicing, while the disruption of R2R5 interaction changes the ratio of MXE. That is, Ate1 splicing is controlled by two independent, dynamically interacting, and functionally distinct RNA structure modules. Exon 7a becomes more included in response to RNA Pol II slowdown, however it fails to do so when the ultra-long-range R2R5 interaction is disrupted, indicating that exon 7a/7b ratio depends on co-transcriptional RNA folding. In sum, these results demonstrate that splicing is coordinated both in time and in space over very long distances, and that the interaction of these components is mediated by RNA structure.
SL-2 Breast cancer treatment system
Authors: Toi Masakazu 
Published: November 2020

Abstract
Surgery under general anesthesia for breast cancer was performed for the first time in Japan. Hormone therapy (bilateral ovariectomy, selective estrogen receptor modulator, LHRH analog, aromatase inhibitor, selective estrogen receptor down-regulator) has been developed for more than 120 years. Radiation therapy also has a history of more than 100 years. Anti-cancer chemotherapy has a history of about 50 years. It has been about 20 years since the development of molecular-targeted therapy began, and we have succeeded in developing therapeutic methods targeting HER2, mTOR, CDK4 / 6, PARP, PI3K, etc.in breast cancer, and immunotherapy is currently the biggest topic. Breast cancer is a highly heterogenous cancer, and multidisciplinary treatment and individualized treatment are the central concepts of treatment. Recent trends in multidisciplinary treatment are measures to promote treatment escalation, and de-escalation, ‘Do More and Do Less’, to maximize treatment benefits and minimize treatment-related toxicity and quality of life reduction. On the other hand, individualization of treatment has made great progress in the last 20years with the generalization of high-standard pathological diagnosis, characterization of tumor subtypes and prediction of prognosis and therapeutic outcomes using multi-gene assay / expression profiles. Recently, it has become possible to test pathogenic variants of breast cancer-related genes such as BRCA1 / 2 in clinical practice, and it has been applied to surgery for patients with primary breast cancer, preventive resection for reducing contralateral breast cancer, and to indicate PARP inhibitor as companion diagnostics for patients with recurrent breast cancer. These current situations and prospects will be described.
SS-5 Current management of primary central nervous system lymphoma
Authors: Mishima Kazuhiko , Shirahata Mitsuaki , Adachi Junichi , Suzuki Tomonari , Uchida Eita , Nishikawa Ryo 
Published: November 2020

Abstract
Primary CNS Lymphomas (PCNSLs) is a highly aggressive malignant tumor with poor prognosis and increasing incidence in elderly patients. High-dose methotrexate (HD-MTX) followed by whole-brain radiation therapy (WBRT) improves survival in PCNSLs. Several HD-MTX–based regimens, in combination with alkylating agents and rituximab, have been developed that can achieve high and durable complete response rates in patients with newly diagnosed PCNSL. In Japan, the R-MPV regimen using rituximab, HD-MTX, procarbazine, and vincristine has been recognized as the standard treatment for initial induction for newly diagnosed PCNSL. The optimal consolidative therapy for patients with disease responsive to induction chemotherapy is not yet defined. WBRT at standard dose (30–45 Gy) has a risk of neurotoxicity. To minimize the effects of delayed neurotoxicity, high-dose chemotherapy supported by autologous stem cell transplantation, reduced dose WBRT (23.4Gy), non-myeloablative chemotherapy, and maintenance chemotherapy have been addressed in large randomized trials. Gene expression profiling has provided insights into the pathogenesis of PCNSL. Recent insight into the pathophysiology of PCNSL has led to the investigation of targeted agents in the treatment of recurrent disease. In March 2020, Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for relapsed or refractory PCNSL based on the results of the phase I/II study in Japan. Seventeen of 44 patients treated with TIR at 480 mg fasted QD, an approved dose, had overall response rate of 52.9%, median progression-free survival of 5.8 months, and time to response as short as 0.92 months. The most common adverse event at any grade was rash (32%). The skin-related disorders were manageable with appropriate skin treatments. However, greater attention and management is needed the case of more rare adverse events such as severe skin-related disorders and pneumocystis pneumonia. This lecture aims to present the recent development in treatment for PCNSL.
ES-2 Phase 3 TRIDENT Trial: Radiation and Temozolomide with or without Tumor Treating Fields in newly diagnosed glioblastoma
Authors: Nakada Mitsutoshi 
Published: November 2020

Abstract
Background: Tumor treating fields (TTFields) is a non-invasive, regional antimitotic treatment approved as a standard-of-care for glioblastoma. In the EF-14 Phase 3 trial, TTFields (200 kHz) plus temozolomide (TMZ) significantly increased survival of patients with newly diagnosed GBM(ndGBM) without increasing systemic toxicity. TTFields-related AEs were mainly skin AEs. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of concomitant TTFields with RT and TMZ will be tested in the TRIDENT trial. Methods: TRIDENT is an international phase III randomized trial comparing standard RT/TMZ vs the triple combination of RT/TMZ with concomitant TTFields. RT is delivered through the TTFields arrays. Patients in both arms will receive maintenance TTFields/TMZ. TTFields (200 kHz) will be delivered over18 hours/day using Optune. Patients will continue TTFields treatment until second recurrence. Patients with pathologically confirmed ndGBM, over 18 years old, KPS over 70, either sex, post-surgery or biopsy, and amenable for RT/TMZ therapy will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points: progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), progression-free survival (PFS2, PFS6, PFS12); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields/RT/TMZ will significantly improve OS versus RT/TMZ. Sample size (N=950; 475/arm) will detect a HR lower than 0.8 with 5% type I error. Survival will be measured from the time of randomization until date of death. At the time of analysis, patients lost to follow-up or still on protocol follow-up will be censored at the last date known to be alive.
ANGI-03 Functional roles of CD166/activated leukocyte cell adhesion molecule (CD166/ALCAM) for glioblastoma invasion
Authors: Kijima Noriyuki , Nakagawa Tomoyoshi , Achiha Takamune , Hirayama Ryuichi , Kinoshita Manabu , Kagawa Naoki , Kishima Haruhiko 
Published: November 2020

Abstract
CD166/activated leukocyte cell adhesion molecule (CD166/ALCAM) is a transmembrane receptor, widely expressed in various tissues, and is involved in several functions such as cell adhesion, neurogenesis and angiogenesis. We have previously reported that CD166/ALCAM is expressed on glioblastoma progenitor cells and is involved in glioblastoma invasion. However, we only have analyzed the functional roles of ALCAM using glioblastoma cell lines, not using patient derived xenografts. In this study, we investigated the functional roles of CD166/ALCAM using patient derived xenografts. We established CD166/ALCAM knocked-down glioblastoma patient derived cell lines by shRNA. For in vitro analysis, we seeded control and CD166/ALCAM knocked-down glioblastoma cells on culture dishes and performed time lapse analysis to investigate cell motility. For in vivo analysis, we orthotopically injected control and CD166/ALCAM knocked-down glioblastoma cells into the immunodeficient mice. When the mice got sick due to the tumor, we dissected the mice and analyzed the difference in invasion by immunohistochemical analysis. We found that CD166/ALCAM knocked-down glioblastoma cells significantly decreased cell motility by time lapse analysis. In addition, CD166/ALCAM knocked-down glioblastoma cells suppressed cell invasion and leptomeningeal metastasis by immunohistochemical analysis from patient derived xenografts. Our results suggest that CD166/ALCAM is involved in glioblastoma invasion, thus future studies are necessary to investigate whether CD166/ALCAM could be a therapeutic target for glioblastoma.
CBMS-01 Mechanism of brain tumor malignancy caused by aging and social isolation
Authors: Yamashita Daisuke , Flanary Victoria , Yamaguchi Shinobu , Ohtsuka Yoshihiro , Ozaki Saya , Suehiro Satoshi , Inoue Akihiro , Gorospe Myriam , Nakano Ichiro , Kunieda Takeharu 
Published: November 2020

Abstract
The rise in population aging worldwide is causing an unparalleled increase in death from many cancers, including glioblastoma (GBM). In advanced countries, the number of elderly people living alone is increasing due to the rapid aging of the population and the socialization of nuclear families. Here, we explored the impact of aging and social isolation on GBM tumorigenesis. In normal brain tissue, aging promoted pathways related to cytokines and inflammation, which were further promoted by social isolation. In tumor tissues, the expression of neuron/synapse-related genes was significantly reduced in aged mice, and their expression was further reduced by social isolation. In addition, the survival period of aged mice was significantly shorter than that of young mice, and the survival period was further shortened by social isolation, which was characteristic of males. This phenomenon was the same in humans, and the survival period in the young group was significantly longer than that in the elderly group, and in the elderly group, the survival period was shortened in the male elderly group living alone. Our data indicate that social isolation contributes to the highly aggressive GBM by the shift to neuro-inflammation in the elderly brain.
CBMS-02 Phosphoglycerate mutase 1 (PGAM1) controls DNA damage repair via regulation of WIP1 activity
Authors: Ohba Shigeo , Johannessen Tor-Christian , Chatla Kamalakar , Yang Xiaodong , Hirose Yuichi , Pieper Russell , Mukherjee Joydeep 
Published: November 2020

Abstract
Phosphoglycerate Mutase 1 (PGAM1) is overexpressed in different forms of cancer and has been suggested to have additional functions beyond its role in metabolism. We here report that PGAM1 is overexpressed in GBMs and indirectly regulates activation of ATM, Chk1 and Chk2 but not ATR, thereby increasing the efficiency of DNA damage repair and resistance to radiation (IR) and temozolomide (TMZ) treatment. Genetic suppression of PGAM1 in multiple GBM cell lines resulted in decrease proliferation, apoptosis and colony formation after radiation and temozolomide treatment compared to parental cells. Moreover, parental cells demonstrated DNA damage (gH2AX foci) whereas isogenic PGAM1 knockdown cells exhibited no DNA damage repair activation and a significant increase in sub-G0 apoptotic cells that expressed annexin-V, cleaved caspase-3 and cleaved PARP-1. Mechanistically, suppression of PGAM1 expression inhibited phosphorylation of ATM at s1981 and the subsequent downstream phosphorylation of Chk2 and cdc25C. Moreover, PGAM1 co-immunoprecipitated with WIP1, a phosphatase reported to bind and dephosphorylate ATM, Chk1, and Chk2. Cytoplasmic binding of WIP1 with PGAM1 prevented nuclear localization of WIP1, leaving ATM and its downstream substrates phosphorylated, which is required for DNA damage repair activity. Consistent with these observations, mice intracranially implanted with PGAM1 knockdown GBM cells and treated with TMZ and IR had longer survival than similarly treated mice implanted with matched control cells. These results therefore define PGAM1 as an activator of DNA damage repair pathway and link tumor metabolism to drug response in GBM.
CBMS-09 Intercellular communication at glioblastoma stem cell niches
Authors: Hide Takuichiro , Shirakawa Yuki , Jono Hirofumi , Shibahara Ichiyo , Inukai Madoka , Shinojima Naoki , Mukasa Akitake , Kumabe Toshihiro 
Published: November 2020

Abstract
Glioblastoma multiforme (GBM) contains heterogenous population of cells including a small population of GBM stem cells (GSCs), which potentially cause therapeutic resistance and tumor recurrence. GSCs harbored in special microenvironments, such as perinecrotic niche, perivascular niche, border niche. However, the mechanisms underlying the pathogenesis and maintenance of GSCs remain largely unknown. Stemness and chemo-radioresistance was promoted by not only additional mutation, but also microenvironment of GBM cells. Previously, we had reported that growth factors and cytokines secreted by oligodendrocyte lineage cells and macrophages/microglia induce stemness and chemo-radioresistance into GBM cells. Recently, Ito et al. reported that incorporation of ribosomes and ribosomal proteins into somatic cells promoted lineage trans-differentiation toward multipotency. Ribosomal proteins exist intra- and extracellularly. There is a possibility that ribosomal proteins promote stemness into cancer cells, we focused on 40S ribosomal protein S6 (RPS6), which is related to cell proliferation in lung and pancreatic cancer, but not reported in GBM. RPS6 was significantly upregulated in high-grade glioma. SiRNA-mediated RPS6 knock-down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and stemness marker expression, such as Nestin and Sox2. RPS6 overexpression enhanced the tumorsphere potential of GSCs. Moreover, RPS6 expression was significantly correlated with SOX2 expression in different glioma grades. Immunohistochemistry data indicated that RPS6 was predominant detected at GSC niches, concurrently with the data from IVY GAP databases. Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC-predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemo-radioresistance and GBM recurrence. These results suggested that intercellular communications through growth factors, cytokines, and ribosomes are regarded as new treatment targets of GBM.
CBMS-12 Pro renin receptor antibody regulates glioblastoma stemness
Authors: Fujimori Takeshi , Oagawa Daisuke , Kanda Takahiro , Suzuki Kenta , Shibayama Saki , Miyake Keisuke , Nishiyama Akira , Tamiya Takashi 
Published: November 2020

Abstract
Objective: Glioblastoma multiforme (GBM) is characterized by a strong self-renewal potential and poor differentiated state. We previously reported that (pro)renin receptor (PRR) was a potential target for glioma therapy by silencing the gene of PRR. Here, we have developed the monoclonal antibody of PRR and examined their effects on GBM. Materials and methods: We performed immunohistochemical analysis to detect the protein expression of PRR and SOX-2 in human sample of 56 gliomas. We used human glioma cell lines (U251MG and U87MG) and glioma stem cell line (MGG23) in vitro study. PRR antibody was designed to target the extracellular domain of the PRR with the rat lymph node method. Expression of the Wnt signaling components and stem marker (SOX-2, Oct3/4) in human glioma cell lines and glioma stem cell line treated with PRR antibody were measured using Western blotting. The effects of PRR antibody on cell proliferation, sphere formation, apoptosis, invasion were also examined. Subcutaneous xenografts with U87MG were induced in nude mice. Results: PRR expression showed a positive correlation with SOX-2 expression in glioma samples. Treatment with PRR antibody significantly reduced expression of Wnt signaling components and stem marker. We observed that PRR antibody significantly reduced cell proliferation and decreased sphere formation. Furthermore, PRR antibody suppressed invasion and induced apoptosis. In a subcutaneous U87MG xenograft model, systemic administration of the PRR antibody significantly reduced the size of the tumor volume. Conclusion: PRR has important role for the maintenance of stem cells and contribute to stem cell proliferation. PRR antibody inhibits cell proliferation and cell invasion and induces apoptosis. Treatment with PRR antibody could be an attractive therapeutic strategy for GBM.
GEN-14 Dual regulation of histone methylation by mTOR complexes drives the progression of EGFR-mutant glioblastoma
Authors: Masui Kenta , Harachi Mio , Muragaki Yoshihiro , Mischel Paul , Shibata Noriyuki 
Published: November 2020

Abstract
Trimethylation of histone H3 on lysine 27 (H3K27me3) is essential for ensuring proper gene expression and chromosomal function, and its aberration is associated with the pathogenesis of various brain tumors. However, it remains unclear how histone methylation is regulated in response to genetic mutation and intracellular metabolic status to facilitate the cancer cell survival in the most malignant IDH-wildtype glioblastoma (GBM). We herein report a novel mechanism of the specific regulation of H3K27me3 by cooperative action of two mechanistic target of rapamycin (mTOR) complexes in EGFR-mutant GBM. The level of H3K27me3 is significantly associated with the mutant EGFR signaling (EGFRvIII and EGFR amplification), and integrated analyses with histopathological, NGS and metabolome examinations revealed that both mTOR complexes (mTORC1 and mTORC2) upregulate H3K27me3 downstream of aberrant EGFR signaling. mTORC1 facilitates the protein translation of enhancer of zeste homolog 2 (EZH2), which is known as H3K27-specific methyltransferase. The other mTOR complex, mTORC2, remodels the metabolism of S-adenosylmethionine (SAM), an essential substrate for histone methylation. This synergistic mechanism causes H3K27 hypermethylation which subsequently promotes tumor cell survival both in vitro and in vivo mouse tumor model via regulation of the cell cycle-related tumor suppressor genes. The findings indicate that activated mTORC1 and mTORC2 complexes under aberrant EGFR signaling cooperatively contribute to the progression of IDH-wildtype GBM through specific epigenetic regulation, nominating them as an exploitable therapeutic target against cancer-specific epigenetics.