bluuebunny/crossref_metadata_2025 huggingface dataset:
A Research of Stereo-Selective Synthesis of Silica-based Amphiphilic Janus Particles
Authors: Wang Shichao
Published: December 2021

Because Janus particles with specific asymmetric nanostructures can be fixed in the oil phase or water respectively, they are more suitable for Pickering emulsion stability. Furthermore, the complete separation of hydrophobic and hydrophobic regions makes adjusting the hydrophobic/hydrophobic region ratio possible by changing the volume ratio. In this study, the preparations of three asymmetric silicon-based amphiphilic Janus nanoparticles are introduced. The methods used are consecutive immobilization, seed emulsion polymerization, and selective encapsulation, respectively. Complete compartmentalization of hydrophilic and hydrophobic domains was realized by anchoring silica with nucleation site, seed emulsion polymerization, or surface charge repulsion. In addition, these nanoparticles can be easily functionalized, bringing new research opportunities to applications in catalysis, adsorption, separation and biomedicine.
Trace Scandium addition on the strength and thermal stability of TiB2 particles reinforced Al-4.5 Cu composites
Authors: Zhang Yunliang , Yu Wentao , Wang Xinliang , Xue Yanqing
Published: December 2021

Strategies employed for developing ultrahigh strength and scalable ductile particles reinforced aluminium-copper matrix composites (AMCs) are highly desirable and grandly challenging. In the present paper, the Scandium (Sc) micro-alloying TiB2 particles reinforced Al-4.5 Cu composites were successfully fabricated by the optimized salt-metal reaction method. The observed microstructures displayed that Sc addition could remarkably ameliorate the dispersion of TiB2 particles, enlarge equiaxed α-Al grain zone and refine the grains on the basis of TiB2 heterogeneous nucleation. In particular, for the 0.4 wt.% Sc microalloyed 5%TiB2/Al-4.5Cu composites, more than a 20 %, 87 %, and 118 % increase in the ultimate tensile strength (UTS), fracture strain elongation (%) and microhardness (HV), respectively were found with respect to the 3 %TiB2/Al-4.5Cu composites at room temperature (298K). The improved mechanical properties of strength-ductility synergy were mainly thanks to the homogeneous distribution of TiB2 particles and modification of Al2Cu phase. Moreover, proper Sc also enhanced the elevated-temperature mechanical properties of the composites with the aid of the accelerated precipitation of θ′ phase and much lower coarsens rate.
The Effect of 3D Printing Process Parameters on the Mechanical Properties of PLA Parts
Authors: Xu Jiangmin , Xu Fan , Gao Ge
Published: December 2021

Taking the PLA molded by FDM as the research object, the influence of various process parameters on mechanical properties is investigated through comparative experiments, which provides reference and help for the promotion and application of FDM molding technology. During the molding process, the PLA material undergoes the process of melting to solidification, thus the performance of the molded part is worse than the original due to thermal shrinkage and other reasons. To improve the quality and mechanical properties of the molded parts, the experiment is designed using an orthogonal test method in parallel with nine different sets of process parameters (layer thickness, build direction, filling speed, and infill density, etc.). Ultimately, the mechanical properties of PLA are tested and the results are analyzed respectively to determine the main factors affecting the mechanical properties and their optimal level combination. Among them, fill rate is the crucial factor in compressive property, while build direction has a significant effect on surface roughness, tensile property and bending property.
The Research on Anti-DC current Transformer of Dual Iron Core Structure with Air Gap
Authors: Lin Zhongai , Zhang Xingyi , Tang Biao , Shen Feng
Published: December 2021

Current transformer (CT) is wildly used in electrical measurement and relay protection. In order to improve the power system stability in DC bias, the CT performance of anti-DC is necessarily to be enhanced. Based on the Jiles-Atherton theory, the magnetization characteristics of iron core with different air gap was analyzed in this paper. A simulation model was established using the Simulink toolbox, and the ratio error and angle error were investigated in different air gap length. Simulation result shows that the maximum magnetic density of iron core almost stays uncharged with the addition of air gap. Furthermore the slope of magnetization curve decreased, which leads to the increase of iron core saturation current. Current transformer with closed and air gap iron core possesses a stable measurement error in condition of severe DC bias.
Numerical analysis of heat transfer enhancement in pulsating flow pipes
Authors: En Jianfeng , Ma Ziyao , Jia Siran , Mu Jie , Gao Zhenbang
Published: December 2021

In this paper, a rectangular flow runner is used as the research object to study the influence of adding a spoiler on the wall of the flow runner on its heat transfer characteristics and flow characteristics. Using the finite element method to analyse the influence of different spoiler’s structures and parameters of the spoilers on the heat transfer characteristics and flow characteristics of the flow runner, the study found that: by the comparison of the smooth flow runner and the rectangular spoiler flow runner, the comprehensive heat exchange effect of the spoiler runner is the best when the arc is arranged in the flow runner, and the accumulation effect of impurities in the runner is the slowest.
Analysis and Research on Fracture Cause of Fixed Shaft of Torsion Arm of Wind Turbine Gearbox
Authors: Yun Feng , Zhao Xiaochun , Liu Chunyu , Liu Jun
Published: December 2021

In a wind power plant of a wind power plant limited liability company, the fixed shaft of the torsion arm of the gear box broke during the operation of a wind power generator set. In order to find out the cause of fracture, the fracture fixed shaft of torsion arm was comprehensively detected and analyzed by means of appearance morphology analysis, chemical composition analysis, mechanical properties testing, microstructure testing and fracture micro-area analysis. The results show that the main reasons for the fracture of the fixed shaft of the torsion arm of the fan gear box are as follows: improper heat treatment process of the fixed shaft of the torsion arm of the gear box causes a large amount of massive ferrite in the material structure, resulting in insufficient strength of the material; the inclusion in the material is serious, resulting in unqualified impact toughness; Shaft surface surfacing Cr - Mn stainless steel material causes the fusion zone C migration form brittle layer, at the same time the vast difference between the state of welding layer and substrate organization fusion zone caused by larger remnants stress, the embrittlement in bond layer to form the intergranular crack crack source, and in the process of the equipment operation under the action of cyclic torsional and impact load, Cracks propagate in a fatiguing manner and lead to eventual fracture.
Application of analytic hierarchy Process in abnormal vibration of Marine machinery
Authors: Zhang Junwei , Xiao Bowen , Cai Miaomiao , Fang Jiangyu , Nie Zeguang , Wang Jiaqi , Xia Mengsheng
Published: December 2021

This paper will use analytic hierarchy process to evaluate abnormal vibration of diesel engine in operation. The possible abnormal vibration factors of diesel engine in use are further analyzed to ensure the normal operation of diesel engine in use. Combined with analytic hierarchy process, the hierarchical structure model is determined, and the problems are analyzed from different angles to reduce the influence of subjective factors.
The microstructure and properties of Mo alloying layer after surface alloying treatment induced by continuous scanning electron beam process
Authors: Ren Xulong , Wang Rong , Zhang Jing , Wei Deqiang
Published: December 2021

Surface alloying by scanning electron beams can improve the microstructure and mechanical properties of steel. In this study. Four electron energy densities were selected during the alloying process: E1 = 1.5J/cm2, E2 = 2.9J/cm2, E3 = 4.5J/cm2 and E4 = 5.9J/cm2. The obtained results show that the sample surface is composed of alloying zone and heat-affected zone. The microstructure of the alloy zone is concealed acicular martensite and molybdenum carbide particles. The microhardness of this area is 1250HV. The sample treated with an energy density of 5.9J/cm2 has the least amount of wear. After alloying treatment, the microhardness and wear amount of the scanned samples are significantly improved.
Study on Mechanical Properties of crack Healing of low carbon Steel based on cyclic Phase Transformation Heat treatment
Authors: Chu Lei
Published: December 2021

With the rapid development of materials, metal materials are used less and less, but at this stage, metal materials are still widely used, and iron and steel materials are the most widely used. Cracks often appear in the process of metal material processing and use, and these cracks will have a certain impact on the use of metal materials. The existence of microcracks will affect the mechanical properties of materials to some extent, but in most cases, the mechanical properties of materials will be greatly reduced, and in serious cases, metal materials will break directly in the process of use or processing. The crack healing process needed after the emergence of cracks can effectively change this situation, but so far, the research on metal crack healing is still not perfect. In this paper, taking the internal crack of low carbon steel as the object, the recovery of mechanical properties of low carbon steel by cyclic phase transformation heat treatment was studied. The results show that with the increase of the healing area, the microhardness of the area after crack healing also increases, and the tensile strength of the specimen also increases after the healing. When the healing area is similar, increasing the healing time and temperature will result in grain coarsening, resulting in the decrease of microhardness and tensile strength in the crack healing zone.
Non-kissing complexes and tau-tilting for gentle algebras
Authors: Palu Yann , Pilaud Vincent , Plamondon Pierre-Guy
Published: December 2021

We interpret the support

τ
\tau

-tilting complex of any gentle bound quiver as the non-kissing complex of walks on its blossoming quiver. Particularly relevant examples were previously studied for quivers defined by a subset of the grid or by a dissection of a polygon. We then focus on the case when the non-kissing complex is finite. We show that the graph of increasing flips on its facets is the Hasse diagram of a congruence-uniform lattice. Finally, we study its

g

\mathbf {g}

-vector fan and prove that it is the normal fan of a non-kissing associahedron.
Predicting protein stability changes upon single-point mutation: a thorough comparison of the available tools on a new dataset
Authors: Pancotti Corrado , Benevenuta Silvia , Birolo Giovanni , Alberini Virginia , Repetto Valeria , Sanavia Tiziana , Capriotti Emidio , Fariselli Piero
Published: December 2021

Predicting the difference in thermodynamic stability between protein variants is crucial for protein design and understanding the genotype-phenotype relationships. So far, several computational tools have been created to address this task. Nevertheless, most of them have been trained or optimized on the same and ‘all’ available data, making a fair comparison unfeasible. Here, we introduce a novel dataset, collected and manually cleaned from the latest version of the ThermoMutDB database, consisting of 669 variants not included in the most widely used training datasets. The prediction performance and the ability to satisfy the antisymmetry property by considering both direct and reverse variants were evaluated across 21 different tools. The Pearson correlations of the tested tools were in the ranges of 0.21–0.5 and 0–0.45 for the direct and reverse variants, respectively. When both direct and reverse variants are considered, the antisymmetric methods perform better achieving a Pearson correlation in the range of 0.51–0.62. The tested methods seem relatively insensitive to the physiological conditions, performing well also on the variants measured with more extreme pH and temperature values. A common issue with all the tested methods is the compression of the $\Delta \Delta G$ predictions toward zero. Furthermore, the thermodynamic stability of the most significantly stabilizing variants was found to be more challenging to predict. This study is the most extensive comparisons of prediction methods using an entirely novel set of variants never tested before.
Modulation of pacemaker channel function in a model of thalamocortical hyperexcitability by demyelination and cytokines
Authors: Chaudhary Rahul , Albrecht Stefanie , Datunashvili Maia , Cerina Manuela , Lüttjohann Annika , Han Ye , Narayanan Venu , Chetkovich Dane M , Ruck Tobias , Kuhlmann Tanja , Pape Hans-Christian , Meuth Sven G , Zobeiri Mehrnoush , Budde Thomas
Published: December 2021

A consensus is yet to be reached regarding the exact prevalence of epileptic seizures or epilepsy in multiple sclerosis (MS). In addition, the underlying pathophysiological basis of the reciprocal interaction among neuroinflammation, demyelination, and epilepsy remains unclear. Therefore, a better understanding of cellular and network mechanisms linking these pathologies is needed. Cuprizone-induced general demyelination in rodents is a valuable model for studying MS pathologies. Here, we studied the relationship among epileptic activity, loss of myelin, and pro-inflammatory cytokines by inducing acute, generalized demyelination in a genetic mouse model of human absence epilepsy, C3H/HeJ mice. Both cellular and network mechanisms were studied using in vivo and in vitro electrophysiological techniques. We found that acute, generalized demyelination in C3H/HeJ mice resulted in a lower number of spike–wave discharges, increased cortical theta oscillations, and reduction of slow rhythmic intrathalamic burst activity. In addition, generalized demyelination resulted in a significant reduction in the amplitude of the hyperpolarization-activated inward current (Ih) in thalamic relay cells, which was accompanied by lower surface expression of hyperpolarization-activated, cyclic nucleotide-gated channels, and the phosphorylated form of TRIP8b (pS237-TRIP8b). We suggest that demyelination-related changes in thalamic Ih may be one of the factors defining the prevalence of seizures in MS.
Worldwide diversity, association potential, and natural selection in the superimposed taste genes, CD36 and GNAT3
Authors: Ramirez Vicente A , Wooding Stephen P
Published: December 2021

CD36 and GNAT3 mediate taste responses, with CD36 acting as a lipid detector and GNAT3 acting as the α subunit of gustducin, a G protein governing sweet, savory, and bitter transduction. Strikingly, the genes encoding CD36 and GNAT3 are genomically superimposed, with CD36 completely encompassing GNAT3. To characterize genetic variation across the CD36-GNAT3 region, its implications for phenotypic diversity, and its recent evolution, we analyzed from ~2,500 worldwide subjects sequenced by the 1000 Genomes Project (1000GP). CD36-GNAT3 harbored extensive diversity including 8,688 single-nucleotide polymorphisms (SNPs), 414 indels, and other complex variants. Sliding window analyses revealed that nucleotide diversity and population differentiation across CD36-GNAT3 were consistent with genome-wide trends in the 1000GP (π = 0.10%, P = 0.64; FST = 9.0%, P = 0.57). In addition, functional predictions using SIFT and PolyPhen-2 identified 60 variants likely to alter protein function, and they were in weak linkage disequilibrium (r2 < 0.17), suggesting their effects are largely independent. However, the frequencies of predicted functional variants were low (P¯ = 0.0013), indicating their contributions to phenotypic variance on population scales are limited. Tests using Tajima’s D statistic revealed that pressures from natural selection have been relaxed across most of CD36-GNAT3 during its recent history (0.39 < P < 0.67). However, CD36 exons showed signs of local adaptation consistent with prior reports (P < 0.035). Thus, CD36 and GNAT3 harbor numerous variants predicted to affect taste sensitivity, but most are rare and phenotypic variance on a population level is likely mediated by a small number of sites.
Temporal Dynamics of Anti–Type 1 Interferon Autoantibodies in Patients With Coronavirus Disease 2019
Authors: Shaw Elana R , Rosen Lindsey B , Cheng Aristine , Dobbs Kerry , Delmonte Ottavia M , Ferré Elise M N , Schmitt Monica M , Imberti Luisa , Quaresima Virginia , Lionakis Michail S , Notarangelo Luigi D , Holland Steven M , Su Helen C
Published: December 2021

Binding levels and neutralization activity of anti–type 1 interferon autoantibodies peaked during acute coronavirus disease 2019 and markedly decreased thereafter. Most patients maintained some ability to neutralize type 1 interferon into convalescence despite lower levels of binding immunoglobulin G. Identifying these autoantibodies in healthy individuals before the development of critical viral disease may be challenging.
Next-Generation Sequencing–Based Analysis of Urine Cell-Free mtDNA Reveals Aberrant Fragmentation and Mutation Profile in Cancer Patients
Authors: Zhou Kaixiang , Liu Yang , Yuan Qing , Lai Dong , Guo Shanshan , Wang Zhenni , Su Liping , Zhang Huanqin , Wang Xiangxu , Guo Wenjie , Ji Xiaoying , Gu Xiwen , Huang Qichao , Guo Xu , Xing Jinliang
Published: December 2021

Background

Many studies have demonstrated the high efficacy of cell-free nuclear DNA in cancer diagnostics. Compared to nuclear DNA, mitochondrial DNA (mtDNA) exhibits distinct characteristics, including multiple copies per cell and higher mutation frequency. However, the potential applicability of cell-free mtDNA (cf-mtDNA) in plasma and urine remains poorly investigated.

Methods

Here, we comprehensively analyzed the fragmentomic and mutational characteristics of cf-mtDNA in urine and plasma samples from controls and cancer patients using next-generation sequencing.

Results

Compared to plasma cf-mtDNA, urine cf-mtDNA exhibited increased copy numbers and wider spread in fragment size distributions. Based on 2 independent animal models, urine cf-mtDNA originated predominantly from local shedding and transrenal excretion. Further analysis indicated an enhanced fragmentation of urine cf-mtDNA in renal cell carcinoma (RCC) and colorectal cancer (CRC) patients. Using the mtDNA sequence of peripheral blood mononuclear cells for reference, the mutant fragments were shorter than wild-type fragments in urine cf-mtDNA. Size selection of short urine cf-mtDNA fragments (<150 bp) significantly enhanced the somatic mutation detection. Our data revealed remarkably different base proportions of fragment ends between urine and plasma cf-mtDNA that also were associated with fragment size. Moreover, both RCC and CRC patients exhibited significantly higher T-end and lower A-end proportions in urine cf-mtDNA than controls. By integrating the fragmentomic and mutational features of urine cf-mtDNA, our nomogram model exhibited a robust efficacy for cancer diagnosis.

Conclusions

Our proof-of-concept findings revealed aberrant fragmentation and mutation profiles of urine cf-mtDNA in cancer patients that have diagnostic potential.
Excessive Apoptosis in Ulcerative Colitis: Crosstalk Between Apoptosis, ROS, ER Stress, and Intestinal Homeostasis
Authors: Wan Yue , Yang Lei , Jiang Shu , Qian Dawei , Duan Jinao
Published: December 2021

Ulcerative colitis (UC), an etiologically complicated and relapsing gastrointestinal disease, is characterized by the damage of mucosal epithelium and destruction of the intestinal homeostasis, which has caused a huge social and economic burden on the health system all over the world. Its pathogenesis is multifactorial, including environmental factors, genetic susceptibility, epithelial barrier defect, symbiotic flora imbalance, and dysregulated immune response. Thus far, although immune cells have become the focus of most research, it is increasingly clear that intestinal epithelial cells play an important role in the pathogenesis and progression of UC. Notably, apoptosis is a vital catabolic process in cells, which is crucial to maintain the stability of intestinal environment and regulate intestinal ecology. In this review, the mechanism of apoptosis induced by reactive oxygen species and endoplasmic reticulum stress, as well as excessive apoptosis in intestinal epithelial dysfunction and gut microbiology imbalance are systematically and comprehensively summarized. Further understanding the role of apoptosis in the pathogenesis of UC may provide a novel strategy for its therapy in clinical practices and the development of new drugs.
“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

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

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

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

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

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

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 <5% to 90% in the specimens, with a median value of 50%. Patients with a higher tumor cell content (>=50%) showed shorter PFS than those with a lower tumor cell content (<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

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

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<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

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

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

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 < T1-relaxation time < 3200ms and 115ms < T2-relaxation time < 225ms tended to be Met-PET T/Nr > 1.5. DWI was not useful to separate areas between low and high Met-PET.

Study 2 showed that regions of 1850ms < T1-relaxation time < 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.
NI-18 A Quantitative Analysis of Intraoperative 3T-Diffusion Tensor Imaging parameters for Functional Prediction with Motor Eloquent Glioma Patients
Authors: Kawataki Tomoyuki , Hanihara Mitsuto , Ogiwara Masakazu , Kinouchi Hiroyuki
Published: December 2021

OBJECTIVE: In motor eloquent glioma surgery, the value of intraoperative diffusion tensor (iDT) imaging was not established to preserve motor function. This study aimed to investigate a relationship between postoperative motor function and iDT imaging parameters, including fractional anisotropy (FA), mean diffusivity (MD), and shortest distance (SD) from resected tumor margin to the corticospinal tract (CST) of gliomas in motor eloquent areas. METHODS: This retrospective study enrolled 20 patients with newly diagnosed supratentorial glioma who underwent surgery and intraoperative magnetic resonance imaging at our hospital. Patients were divided into two groups (i.e., worsening and non-worsening groups) based on their manual muscle test scores before and three months after surgery. We obtained the mean FA and MD values bilaterally, along with identification of the CST and determined the ratios (the affected side / the contralateral side). The SD was measured between the CST and the resected margin of the tumor. We evaluated the quantitative analysis of these parameters related to motor functional outcomes. Moreover the correlation was measured between these parameters and the maximum reduction rate of cortical motor evoked potentials (MEPs) during surgery. RESULTS: In the worsening group (n = 5), the mean FA ratio was lower and the mean MD ratio was higher compared with the non-worsening group (n = 15; P < 0.001 and P < 0.01, respectively). Cut-off values were 0.87 for FA and 1.08 for MD. SD was 7.95 mm in the non-worsening group and 0.44 mm in the worsening group (P < 0.01). These iDT based parameters, the mean FA ratio and the SD, were well correlated with the maximum reduction rate in MEP (R = 0.72 and 0.80, respectively). CONCLUSIONS: The mean ratio of FA, MD, and SD using iDT imagings predict postoperative motor function and help in optimal surgical planning in patients with motor eloquent glioma.
NQPC-2 Cognitive function of a low-grade glioma patient treated with radiation therapy 28 years ago
Authors: Yamada Kazuki , Ideguchi Makoto , Matsutani Masao
Published: December 2021

While there are many reports that long-term survivors of low-grade glioma patients treated with radiation therapy cannot lead a healthy social life due to cognitive dysfunction, we report a low-grade glioma patient with almost normal cognitive function even after radiation therapy 28 years ago. CASE REPORT. A 64-year-old woman developed with sudden left hemiparesis and was diagnosed as a small infarction in the left corona radiata. After treated by anticoagulant therapy, she was admitted to our hospital for rehabilitation. Twenty-eight years ago, she underwent surgical resection and radiation therapy with 60 Gy for astrocytoma (WHO grade 2) in the right insular cortex. At the time of this admission, she presented with a good MMSE score of 30 points, but she couldn’t walk and her left hand was less maneuverable. After 109 days of intensive rehabilitation in our hospital, she was discharged on a cane walk, and returned to work as a gas station clerk. COGNITIVE FUNCION. We evaluated her cognitive function on TMT-A/B test, CAT (Clinical Assessment for Attention)and WAIS-4. The TMT test was normal with age adjustments. In CAT, the percentage of correct answers for the 7 constituent items was within the standard range, but in the task of evaluating the required time, a slight delay in processing speed was observed. In WAIS-4, the Full scale IQ was 98 points (normal range) including normal 3 of 4 constituent items. But, only the PSI (processing speed) of 75 point was below the standard range. CONCLUSION: We observed a slight delay in processing speed on her high-level cognitive function tests, but determined that she would be well-adapted to a familiar job in a small community. In fact, she was doing well on the job 10 months after her discharge.