bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Digital Health Diplomacy” in Global Digital Health? A call for critique and discourse
Authors: Godinho Myron Anthony , Martins Henrique , Al-Shorbaji Najeeb , Quintana Yuri , Liaw Siaw-Teng 
Published: December 2021

Abstract
Actualizing the vision of Global Digital Health is a central issue on the Global Health Diplomacy agenda. The COVID-reinforced need for accelerated digital health progress will require political structures and processes to build a foundation for Global Digital Health. Simultaneously, Global Health Diplomacy uses digital technologies in its enactment. Both phenomena have driven interest in the term “Digital Health Diplomacy.” A review of the literature revealed 2 emerging but distinct definitions that have been published very recently, each with its associated discourse and practice. This multiplicity of ideas demonstrates the myriad ways in which global digital and political systems are becoming increasingly entangled. Untangling these, this paper proposes and discusses 3 dimensions of Digital Health Diplomacy: “Diplomacy for digital health,” “Digital health for diplomacy,” and “Digital health in diplomacy.” It calls upon digital health professionals, diplomats, political and social scientists, epidemiologists, and clinicians to discuss, critique, and advance this emerging domain.
Frequency analysis of δ Scuti stars towards the Galactic bulge
Authors: Netzel H , Pietrukowicz P , Soszyński I , Wrona M 
Published: December 2021

ABSTRACT
We have performed a frequency analysis of 10 092 δ Scuti-type stars detected in the fourth phase of the Optical Gravitational Lensing Experiment towards the Galactic bulge, which is the most numerous homogeneous sample of δ Scuti stars observed so far. The main goal was to search for stars pulsating in at least two radial modes simultaneously. We have found 3083 candidates for such stars, which is the largest set obtained to date. Among them, 2655 stars pulsate in two radial modes, 414 stars pulsate in three radial modes, and 14 stars pulsate in four radial modes at the same time. We report the identification of 221 δ Scuti stars pulsating in the fundamental mode, first overtone, and third overtone simultaneously. We show the most populated Petersen and Bailey diagrams and discuss statistical properties of the identified frequencies based on this numerous sample. Additionally, we present theoretical predictions of period ratios for δ Scuti stars pulsating in overtones from the fourth to the seventh.
Pairing of single mutations yields obligate Cre-type site-specific recombinases
Authors: Hoersten Jenna , Ruiz-Gómez Gloria , Lansing Felix , Rojo-Romanos Teresa , Schmitt Lukas Theo , Sonntag Jan , Pisabarro M Teresa , Buchholz Frank 
Published: December 2021

Abstract
Tyrosine site-specific recombinases (SSRs) represent a versatile genome editing tool with considerable therapeutic potential. Recent developments to engineer and evolve SSRs into heterotetramers to improve target site flexibility signified a critical step towards their broad utility in genome editing. However, SSR monomers can form combinations of different homo- and heterotetramers in cells, increasing their off-target potential. Here, we discover that two paired mutations targeting residues implicated in catalysis lead to simple obligate tyrosine SSR systems, where the presence of all distinct subunits to bind as a heterotetramer is obligatory for catalysis. Therefore, only when the paired mutations are applied as single mutations on each recombinase subunit, the engineered SSRs can efficiently recombine the intended target sequence, while the subunits carrying the point mutations expressed in isolation are inactive. We demonstrate the utility of the obligate SSR system to improve recombination specificity of a designer-recombinase for a therapeutic target in human cells. Furthermore, we show that the mutations render the naturally occurring SSRs, Cre and Vika, obligately heteromeric for catalytic proficiency, providing a straight-forward approach to improve their applied properties. These results facilitate the development of safe and effective therapeutic designer-recombinases and advance our mechanistic understanding of SSR catalysis.
CBMS-1 Targeting amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas
Authors: Ohba Shigeo , Hirayama Akiyoshi , Hitachi Keisuke , Yamaguchi Hisateru , Teranishi Takao , Mukherjee Joydeep , Pieper Russell , Hirose Yuichi 
Published: December 2021

Abstract
IDH-wildtype glioma and IDH-mutant glioma have different genetical and metabolic background although their histological appearances are similar. To reveal the difference in metabolites between IDH-wildtype and IDH-mutant glioma, and to find the effective treatment targeting cancer metabolism according to the status of IDH in gliomas, two artificial cell lines made from normal human astrocyte, NHAE6E7hTERTRas (IDH-wildtype) and NHAE6E7hTERTIDHmut (IDH-mutant), were investigated. RNA-seq analysis revealed that about 10% of changed genes were involved with metabolism. Capillary electrophoresis- and ion chromatography-coupled mass spectrometry revealed that the amount of asparagine was lower in NHAE6E7hTERTRas cells compared with NHAE6E7hTERTIDHmut cells. L-asparaginase, which converts asparagine into aspartate, was more effective in former cells. L-asparaginase induced autophagy and inhibition of autophagy by 3-MA suppressed L-asparaginase-induced antitumor effect. Adding asparagine into the culture medium rescued the antitumor effect of L-asparaginase. L-asparaginase increased the expression of asparagine synthetase (ASNS) and inhibition of ASNS enhanced the antitumor effect of L-asparaginase. Metabolic assay also showed the lower amount of glutamine, glutamate and 2-oxoglutarate in NHAE6E7hTERTIDHmut cells than NHAE6E7hTERTRas cells. Inhibition of GLUD1 which converts glutamate to 2-oxoglutarate, suppressed proliferation of the cells by inducing ROS and apoptosis in NHAE6E7hTERTIDHmut cells. Exogeneous dimethyl 2-oxoglutarate rescued the cytotoxicity by GLUD1 inhibitor, suggesting decreased 2-oxoglutarate was associated with GLUD1 inhibitor-induced cytotoxicity. ROS inhibitor, NAC suppressed GLUD1 inhibitor-induced ROS, apoptosis, and cytotoxicity in NHAE6E7hTERTIDHmut cells, revealing that cytotoxicity by GLUD1 inhibitor was at least partially due to the inhibitor-induced ROS. Other IDH-wildtype glioma cells, U251 and U87 showed similar sensitivity to L-asparaginase and GLUD1 inhibitor to NHAE6E7hTERTRas, whereas U251 expressing mutant IDH1 showed similar sensitivity to GLUD1 inhibitor to NHAE6E7hTERTIDHmut, which suggested that the difference of sensitivity to each reagent was due to the status of mutant IDH. L-asparaginase and GLUD1 inhibitor will be new therapeutic options for IDH-wildtype glioma and IDH-mutant glioma, respectively.
IM-6 HVJ-E containing PD-L1 siRNA inhibits immunosuppressive activities and elicits antitumor immune responses in glioma
Authors: Sugii Narushi , Matsuda Masahide , Okumura Genki , Shibuya Akira , Ishikawa Eiichi 
Published: December 2021

Abstract
Inactivated Sendai virus particle, hemagglutinating virus of Japan-envelope (HVJ-E), is a non-replicating virus-derived vector, in which the genomic RNA of Sendai virus (HVJ) has been destroyed. HVJ-E is a promising vector that enables the highly efficient and safe introduction of enclosed molecules such as RNA into target cells. Moreover, HVJ-E provokes robust antitumoral immunity by activating natural killer (NK) cells and CD8+ T lymphocytes and their induction into the tumor periphery, and by suppressing regulatory T lymphocytes (Treg) locally in the tumor. In the present study, we investigated a novel combination of antitumor immunotherapy by the antitumor immune-activating effect of HVJ-E itself with the inhibition of tumor PD-L1 molecule expression. We confirmed that intratumoral injection of HVJ-E containing siRNA targeting PD-L1 (siPDL1/HVJ-E) inhibited tumor PD-L1 protein expression in a mouse subcutaneous tumor model using TS, a mouse glioma stem-like cell. We conducted treatment experiments in the mouse brain tumor model in three groups: control group (PBS), siNC/HVJ-E group (negative control siRNA + HVJ-E), and siPDL1/HVJ-E group. We obtained a significant prolongation of overall survival in the siPDL1/HVJ-E group. Flow cytometric analyses of brain tumor models showed that the proportions of brain-infiltrating CD8+ T lymphocytes and NK cells were significantly increased after giving siPDL1/HVJ-E; in contrast, the rate of Treg/CD4+ lymphocytes was significantly decreased in HVJ-E-treated tumors (siNC/HVJ-E and siPDL1/HVJ-E). No difference was observed in the proportions of macrophages or M2 macrophages. CD8 depletion abrogated the therapeutic effect of siPDL1/HVJ-E, indicating that CD8+ T lymphocytes mainly mediated this therapeutic effect. We believe that this non-replicating immunovirotherapy may be a novel therapeutic alternative to treat patients with glioblastoma. The full article has been published (Cancer Science. 2021 Jan;112(1):81–90).
BOT-3 Prognostic Factors of CNS Germ Cell Tumors; Molecular and Histopathological Analyses on 154 Cases from the iGCT Consortium
Authors: Takami Hirokazu , Satomi Kaishi , Fukuoka Kohei , Matsushita Yuko , Yamasaki Kai , Nakamura Taishi , Kanamori Masayuki , Tominaga Teiji , Tanaka Shota , Mukasa Akitake , Saito Nobuhito , Suzuki Tomonari , Yanagisawa Takaaki , Nakamura Hideo , Sakai Keiichi , Sugiyama Kazuhiko , Tamura Kaoru , Maehara Taketoshi , Nakada Mitsutoshi , Nonaka Masahiro , Asai Akio , Yokogami Kiyotaka , Takeshima Hideo , Iuchi Toshihiko , Kanemura Yonehiro , Kobayashi Keiichi , Nagane Motoo , Kurozumi Kazuhiko , Yoshimoto Koji , Matsuda Masahide , Matsumura Akira , Hirose Yuichi , Tokuyama Tsutomu , Kumabe Toshihiro , Narita Yoshitaka , Shibui Soichiro , Nakazato Yoichi , Nishikawa Ryo , Matsutani Masao , Ichimura Koichi 
Published: December 2021

Abstract
Background: Germ cell tumors (GCTs) preferentially occurs in pediatric and young adult age groups. Chemo- and radiation therapies cause long-term sequelae in their later lives. We searched for clinical and histopathological features to predict the prognosis and affect treatment response, with a future goal of treatment stratification.Methods: A total of 154 GCT cases were included in the analysis. Total of 114 germinoma cases underwent measurement of tumor cell content on H-E specimen, and 82 GCT cases underwent 450K methylation analysis. 12p gain was determined on methylation-based copy number computation and FISH. Association with progression-free and overall survival (PFS/OS) was investigated. Results: The tumor cell content was widely distributed from &lt;5% to 90% in the specimens, with a median value of 50%. Patients with a higher tumor cell content (&gt;=50%) showed shorter PFS than those with a lower tumor cell content (&lt;50 %) (p=0.03). In the multivariate analysis with tumor location, tumor cell content was the sole statistically significant prognostic factor (p=0.04). 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs, particularly in cases with malignant components. The presence of 12p gain correlated with shorter PFS and OS, even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS. The 12p copy number status was shared among histological components in mixed GCTs. Whole-genome amplification was suggested by FISH.Conclusions: We found that tumor cell content significantly affected the prognosis of germinomas. 12p gain predicts the presence of malignant components of NGGCTs, and poor prognosis of the patients. Furthermore, 12p is likely to be an early event in the tumorigenesis of CNS GCT. These potentially open the possibility of leveraging these pathological and molecular factors in the future clinical trials when stratifying the treatment intensity.
STMO-7 Usefulness of NU-KNIT in retractorless surgery for malignant glioma
Authors: Yamanaka Yuji , Hongo Takeshi , Sagehashi Yuuki , Aragaki Yuta , Gobayashi Yuko 
Published: December 2021

Abstract
On the removal of the brain tumor, securing of appropriate working corridor and the maintenance of the visibility are one of the most relevant elements regardless of tumor local existence. This is unchangeable extract in these days when a support apparatus such as navigation system and the nerve monitoring was enriched, and, in the malignant glioma that a tumor border is relatively indistinct, the importance does not change either.At our hospital, I protect the access route by two folds of coating of absorbable hemostat(Surgical NU-KNIT) and neurosurgical patties (Delicot) on the removal of the malignant brain tumor in the brain deep part instead without using as possible fixed retractor for the purpose of securing of working corridor under minimum retraction and extract deep part tumor. In this way, normal real protection, wet maintenance, maintenance of the visibility by the control of the bleeding and pressure reduction of the neighborhood organization extracting are provided, and postoperative function recovery gets an early impression. About a method of the securing of working corridor at our hospital, I inspect the usefulness and limit by showing representative cases and want to have an opinion, criticism.
STMO-9 Maximal safe glioma resection using high resolution exoscope
Authors: Saito Kuniaki , Sasaki Nobuyoshi , Seiya Yosuke , Onoda Ryo , Kobayashi Keiichi , Nakatomi Hirofumi , Shiokawa Yoshiaki , Nagane Motoo 
Published: December 2021

Abstract
INTRODUCTION: Maximal safe glioma resection should be achieved using neuronavigation, electrophysiological monitoring, fluorescence visual system, and so on. Heads-up surgery with exoscope is suitable for the multimodal glioma surgery because multi-monitors come in our sights simultaneously. We introduce our glioma surgery using a latest exoscope and neuronavigation system. METHODS: We attempted maximal safe resection for the patients with high grade glioma using 3D/4K exoscope with 5-ALA-induced fluorescence, neuronavigation, and electrophysiological monitoring or awake mapping. An extent of resection, morbidity, and postoperative infarction were retrospectively reviewed. RESULTS: Twenty-one patients (age 26–79, male 11/female 10, glioblastoma 10/lower grade glioma 11, general anesthesia 16/awake craniotomy 5) underwent exoscopic tumor removal. Neuronavigation and electrophysiological monitoring were displayed in sub-monitors close to the main screen. Navigation could be recognized continuously using electromagnetic navigation technology. Intraoperative fluorescence was observed in 100% of the tumor with gadolinium enhancement. Surrounding structures such as white matter, vessels and nerves were clearly visualized under blue light. Supra-total resection or gross total resection was achieved in 8 (80%) of the patients with glioblastoma. Surgical morbidity included hemiparesis in 1 (4.8%) patient, hemianopsia in 1 (4.8%) patient. Postoperative infarction was observed in 2 (9.5%) patients, which was significantly lower compared to 23 of 77 (29.9%) patients with glioblastoma who underwent tumor resection with fluorescence-equipped microscope (p&lt;0.05). CONCLUSION: High resolution exoscope surgery is effective for patients undergoing glioma surgery with respect to higher extent of resection and lower ischemic complication. Further studies are needed to assess direct comparisons between exoscope and microscope glioma resection.
MPC-1 DNA methylome analysis suggested the presence of “true” IDH-wildtype lower-grade gliomas
Authors: Satomi Kaishi , Fujimoto Kenji , Arita Hideyuki , Yamasaki Kai , Matsushita Yuko , Nakamura Taishi , Miyakita Yasuji , Umehara Toru , Kobayashi Keiichi , Tamura Kaoru , Tanaka Shota , Higuchi Fumi , Okita Yoshiko , Kanemura Yonehiro , Fukai Junya , Sakamoto Daisuke , Uda Takehiro , Maehara Taketoshi , Nagane Motoo , Nishikawa Ryo , Suzuki Hiroyoshi , Shibuya Makoto , Komori Takashi , Narita Yoshitaka , Ichimura Koichi 
Published: December 2021

Abstract
Background: There will be significant changes in the diagnosis of IDH-wildtype adult-type gliomas in the upcoming 5th edition of the WHO Classification of Central Nervous System Tumours. IDH-wildtype lower grade gliomas (IDHwt LGGs) that harbor molecular features of glioblastoma (EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7+/10-), or TERT promoter mutations) will be diagnosed as glioblastomas (GBMs), while IDH-wildtype astrocytomas will not be included as a separate tumor type. However, IDHwt LGGs are a very heterogeneous group of tumors, and further investigation is warranted particularly in those without molecular features of glioblastoma. To elucidate the biology of IDHwt LGGs, we analyzed DNA methylation profile and survival time. Materials and Methods: Of the 724 adult-type diffuse glioma samples from a multi-institutional study, 64 IDHwt LGG, including 54 without any of molecular features of GBM and 10 with PDGFRA amplification or TERT promoter mutation, were examined using Infinium MethylationEPIC BeadChip. The raw data files (IDAT files) were analyzed by the web-based DNA methylation classifier provided by DKFZ (MolecularNeuropathology.org) or by R (Version 4.0.4) using the minfi (1.34.0) and Rtsne (0.15) packages. [Result] Twenty-three out of 54 IDHwt LGGs matched known methylation classes using the DKFZ methylation classifier. In t-Distributed Stochastic Neighbor Embedding clustering analysis, 20 cases formed a cluster within the methylation class family glioblastoma, IDH-wildtype, mainly subclass RTK I (“GBM” cluster). Another 29 IDHwt LGGs formed an independent cluster (“LGG” cluster) separate from any of the existing reference groups near but not overlapping with several subtypes of pediatric-type lower grade gliomas. The “LGG” cluster cases had significantly longer overall survival than the “GBM” cluster cases. Discussion: Methylation profiling showed that IDHwt LGGs without molecular features of GBM were heterogeneous group of tumors. Our data suggested the presence of “true” IDHwt LGGs with intermediate prognosis.
MPC-4 Malignant transformation of diffuse low-grade gliomas: systematic review and meta-analysis
Authors: Nakasu Satoshi , Nakasu Yoko 
Published: December 2021

Abstract
While malignant transformation of diffuse low-grade glioma (LGG) is a critical event affecting the patient survival, the incidence and related factors have been inconsistent in the literature. According to the PRISMA guideline, we systematically reviewed articles from 2009, meta-analyzed the incidence of malignant transformation and clarified factors related to the transformation. Forty-one articles were included in this study (n = 7122). We identified two definitions of malignant transformation: histologically proven (Htrans) and clinically defined (Ctrans). The malignant transformation rate curves in Htrans and Ctrans were almost in parallel when calculated from the results of meta-regression by the mean follow-up time. The true transformation rate was supposed to lie between the two curves, namely about 40% at the 10-year mean follow-up. Risk of malignant transformation was evaluated by the hazard ratio (HR). Pooled HRs were significantly higher in tumors with a larger pre- and postoperative tumor volume, lower degree of resection and notable preoperative contrast enhancement on magnetic resonance imaging than in others. Oligodendroglial histology and IDH mutation (IDHm) with 1p/19q codeletion (Codel) also significantly reduced the HRs. Using Kaplan-Meier curves from 8 studies with molecular data, we extracted data and calculated the 10-year malignant progression free survival (10yMPFS). The 10yMPFS in patients with IDHm without Codel was 30.4% (95% confidence interval (95%CI) [22.2–39.0]) in Htrans and 38.3% (95%CI [32.3–44.3]) in Ctrans, and that with IDHm with Codel was 71.7% (95%CI [61.7–79.5]) in Htrans and 62.5% (95%CI [55.9–68.5]) in Ctrans. The effect of adjuvant radiotherapy or chemotherapy could not be determined.
NI-3 Magnetic resonance relaxometry for tumor cell density imaging for glioma: An exploratory study via 11C-methionine PET and its validation via stereotactic tissue sampling
Authors: Kinoshita Manabu , Uchikoshi Masato , Tateishi Souichiro , Miyazaki Shohei , Sakai Mio , Ozaki Tomohiko , Asai Katsunori , Fujita Yuya , Matsuhashi Takahiro , Kanemura Yonehiro , Shimosegawa Eku , Hatazawa Jun , Nakatsuka Shinichi , Kishima Haruhiko , Nakanishi Katsuyuki 
Published: December 2021

Abstract
Objective: While visualization of non-enhancing tumors for glioma is crucial for planning the most appropriate surgical or non-surgical treatment of the disease, current MRI cannot achieve this goal. This study aims to test the hypothesis that quantitative and diffusion MRI can estimate tumor burden with the brain.
Materials and Methods: Study 1: Ten patients who have undergone Methionine PET (Met-PET), quantitative MRI (qMRI), and diffusion MRI (DWI) were included for analysis. A cut-off of a tumor-to-normal ratio (T/Nr) 1.5 was set on Met-PET, and the values from qMRI and DWI were compared. Study 2: Seventy-nine stereo-tactically sampled tissues from 22 glioma patients were correlated with Met-PET, qMRI, and DWI measurements regarding tumor cell density.
qMRI acquisition: Imaging was performed on either a 1.5 or 3 T MR scanner (Prisma or Aera; Siemens Healthcare, Erlangen, Germany). T1-relaxometry was achieved by first acquiring MP2RAGE images, then converting those images into T1-relaxation time maps. At the same time, T2-relaxometry was achieved by first acquiring multi-echo T2-weighted images and then converting those images into T2-relaxation time maps, with both relaxometries performed via Bayesian inference modeling (Olea Nova+; Canon Medical Systems, Tochigi, Japan).
Results: Study 1 revealed that regions of 1850ms &lt; T1-relaxation time &lt; 3200ms and 115ms &lt; T2-relaxation time &lt; 225ms tended to be Met-PET T/Nr &gt; 1.5. DWI was not useful to separate areas between low and high Met-PET.
Study 2 showed that regions of 1850ms &lt; T1-relaxation time &lt; 3200ms showed high tumor cell density than other areas (p=0.04).
Conclusions: Our results supported the hypothesis that qMRI is useful for predicting the tumor load within the brain among glioma patients. T1-relaxation time was notably useful for this means. On the other hand, ADC measured from DWI was limited for tumor load prediction.