Drug Repositioning for the Treatment of Glioma: Current State and Future Perspective

Gliomas are the most common primary brain tumors. Among them, glioblastoma (GBM) possesses the most malignant phenotype. Despite the current standard therapy using an alkylating anticancer agent, temozolomide, most patients with GBM die within 2 years. Novel chemotherapeutic agents are urgently needed to improve the prognosis of GBM. One of the solutions, drug repositioning, which broadens the indications of existing drugs, has gained attention. Herein, we categorize candidate agents, which are newly identified as therapeutic drugs for malignant glioma into 10 classifications based on these original identifications. Some drugs are in clinical trials with hope. Additionally, the obstacles, which should be overcome in order to accomplish drug repositioning as an application for GBM and the future perspectives, have been discussed

Dynamical Excimer Formation in Rigid Carbazolophane via Charge Transfer State

Formation dynamics of intramolecular excimer in dioxa[3.3](3, 6)carbazolophane (CzOCz) was studied by time-resolved spectroscopic methods and computational calculations. In the ground state, the most stable conformer in CzOCz is the anti-conformation where two carbazole rings are in antiparallel alignment. No other isomers were observed even after the solution was heated up to 150 °C, although three characteristic isomers were found by the molecular mechanics calculation: the first is the anti-conformer, the second is the syn-conformer where two carbazole rings are stacked in the same direction, and the third is the int-conformer where two carbazole rings are aligned in an edge-to-face geometry. Because of the anti-conformation, the interchromophoric interaction in CzOCz is negligible in the ground state. Nonetheless, the intramolecular excimer in CzOCz was dynamically formed in an acetonitrile (MeCN) solution, indicating strong interchromophoric interaction and the isomerization from the anti- to syn-conformation in the excited state. The excimer formation in CzOCz is more efficient in polar solvents than in less polar solvents, suggesting the contribution of the charge transfer (CT) state to the excimer formation. The stabilization in the excited state is discussed in terms of molecular orbital interaction between two carbazole rings. The solvent-polarity-induced excimer formation is discussed in terms of the CT character in the int-conformation

Radiofrequency Ablation with the Real-Time Virtual Sonography System for Treating Hepatocellular Carcinoma Difficult to Detect by Ultrasonography

Radiofrequency ablation has been applied to treat hepatocellular carcinoma, with favorable therapeutic outcomes. Nevertheless, practitioners have approached radiofrequency ablation with some reluctance due to the difficulty of identifying isoechoic tumors and recurrent tumors. The aim of the present study is to investigate the efficacy of Real-time Virtual Sonography to treat hepatocellular carcinoma difficult to detect by conventional ultrasonography. Real-time Virtual Sonography is a system generating multiplanar reconstruction images in real-time using the Hitachi medico EUB-8500 equipped with a probe. The system included following components: 1) digital imaging and communications in medicine (DICOM) data from dynamic CT, 2) a magnetic field generator to match the multiplanar reconstruction image on the monitor and the actual ultrasonography image, 3) the cross section with the tumor displayed as a multiplanar reconstruction image. Total twenty-five nodules of twenty-one patients underwent radiofrequency ablation monitored by Real-time Virtual Sonography. All nodules difficult to detect via conventional ultrasonography were clearly visualized in real-time. The average nodule diameter was 2.4 ± 1.6 cm, and punctures and coagulation were performed an average of 2.2 and 3 times per session. Dynamic CT after session confirmed effective coagulation of each nodule. In conclusion, this study demonstrates that the present system is capable of effectively and accurately treating tumors difficult to detect by conventional ultrasonography

Diffusion-weighted MR imaging in gynecologic cancers

Diffusion-weighted imaging (DWI) reflects changes in proton mobility caused by pathological alterations of tissue cellularity, cellular membrane integrity, extracellular space perfusion, and fluid viscosity. Functional imaging is becoming increasingly important in the evaluation of cancer patients because of the limitations of morphologic imaging. DWI is being applied to the detection and characterization of tumors and the evaluation of treatment response in patients with cancer. The advantages of DWI include its cost-effectiveness and brevity of execution, its complete noninvasiveness, its lack of ionizing radiation, and the fact that it does not require injection of contrast material, thus enabling its use in patients with renal dysfunction. In this article, we describe the clinical application of DWI to gynecological disorders and its diagnostic efficacy therein

Analysis for the units of regional geography on UK’s geography textbook: The case study of “Geog 4th edition”

In Britain, the volume of “Regional Geography” was decreased in “the National Curriculum”. The aim of this paper is to cralify the contents of “Regional Geography” in Britain. We analyzed the geographical school textbook “Geog 4th edition” by Oxfor University Press. We find that “Geog” has only 2 or 3 case studies in each grade. The students don’t learn all of the world in geographical class. That is because it is important to learn the geographical skill

A Novel Function of Noc2 in Agonist-Induced Intracellular Ca2+ Increase during Zymogen-Granule Exocytosis in Pancreatic Acinar Cells

Noc2, a putative Rab effector, contributes to secretory-granule exocytosis in neuroendocrine and exocrine cells. Here, using two-photon excitation live-cell imaging, we investigated its role in Ca2+-dependent zymogen granule (ZG) exocytosis in pancreatic acinar cells from wild-type (WT) and Noc2-knockout (KO) mice. Imaging of a KO acinar cell revealed an expanded granular area, indicating ZG accumulation. In our spatiotemporal analysis of the ZG exocytosis induced by agonist (cholecystokinin or acetylcholine) stimulation, the location and rate of progress of ZG exocytosis did not differ significantly between the two strains. ZG exocytosis from KO acinar cells was seldom observed at physiological concentrations of agonists, but was normal (vs. WT) at high concentrations. Flash photolysis of a caged calcium compound confirmed the integrity of the fusion step of ZG exocytosis in KO acinar cells. The decreased ZG exocytosis present at physiological concentrations of agonists raised the possibility of impaired elicitation of calcium spikes. When calcium spikes were evoked in KO acinar cells by a high agonist concentration: (a) they always started at the apical portion and traveled to the basal portion, and (b) calcium oscillations over the 10 µM level were observed, as in WT acinar cells. At physiological concentrations of agonists, however, sufficient calcium spikes were not observed, suggesting an impaired [Ca2+]i-increase mechanism in KO acinar cells. We propose that in pancreatic acinar cells, Noc2 is not indispensable for the membrane fusion of ZG per se, but instead performs a novel function favoring agonist-induced physiological [Ca2+]i increases

既存薬剤Pentamidineによる新規抗グリオーマ幹細胞療法の基礎基盤構築

金沢大学附属病院Glioblastoma remains a primary malignant brain tumor with a poor prognosis. In glioblastoma, some cancer cells called glioma stem cells are contribute to resistant to radiation and chemotherapy. In this study, we analyzed to identify new therapeutic agents for glioblastoma, focusing on glioma stem cells, by application of drug repositioning Through the screening for 1,300 existing drugs using glioma stem cells, finally we identified pentamidine, anti-protozoal drug as promising anti-glioma agent. Pentamidine was found to inhibit proliferation, arrest cell cycle, and induce apoptosis.膠芽腫（こうがしゅ）は未だに予後不良の原発性悪性脳腫瘍である。特に膠芽腫においてグリオーマ幹細胞と呼ばれる細胞が一部存在し、放射線や化学療法に抵抗性を持つことが問題となっている。今回我々は既存の薬剤を応用することで、膠芽腫、特にグリオーマ幹細胞に対する新規治療薬を見出す研究を行った。約1300種類の既存薬剤から、グリオーマ幹細胞に対して抗腫瘍効果を示した抗真菌薬ペンタミジンの膠芽腫に対する基礎研究を行った。ペンタミジンが増殖抑制、細胞周期の停止およびアポトーシスの誘導効果を占めすことを見出した。研究課題/領域番号:20K17956, 研究期間(年度):2020-04-01 – 2022-03-31出典：研究課題「既存薬剤Pentamidineによる新規抗グリオーマ幹細胞療法の基礎基盤構築」課題番号20K17956（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-20K17956/20K17956seika/）を加工して作