Stem Cell Research for the Treatment of Malignant Glioma

Glioblastoma is the most aggressive brain tumor. Gene therapies, such as cytokine-based, suicide gene, and oncolytic virus therapies, are different types of treatments from chemotherapy such as using temozolomide as a standard treatment. However, overall survival was not prolonged in some clinical trials because of the low efficiency of gene transduction and viral infection. Neural stem cells (NSCs) have tumor trophic migratory capacity and can be cellular delivery vehicles of cytokines, suicide genes, and oncolytic virus. NSCs can be differentiated from embryonic stem cells. In addition, mesenchymal stem cells can be another cellular delivery vehicle. Recently, induced pluripotent stem cells (iPSCs) have been established. iPSCs are multipotent; hence, they can efficiently differentiate to NSCs and can possibly overcome ethical and practical issues in clinical application. In this study, current topics about stem cell therapy for malignant glioma are reviewed

Precocious activation of APC/C-Cdh1 at pre-anaphase causes genome instability

Faithful chromosome segregation and thereby accurate gene transmission are crucial for all organisms. Until proper attachment of the mitotic spindle to the kinetochore is established, the ubiquitin ligase (E3) Cdc20-activated APC/C (anaphase promoting complex/cyclosome) is repressed by the spindle assembly checkpoint (SAC) and sister chromatin cohesion is protected. Mutants defective in SAC fail to arrest at metaphase even in the presence of damaged microtubules. Interestingly, a similar phenomenon occurs in yeast cells defective in Bub2, a negative factor of the mitotic exit network (MEN), which is required for telophase onset, although its precise molecular mechanism is unknown. Here, we show that chromosome missegregation occurs frequently in bub2∆ cells in the presence of damaged microtubules. The loss of Bub2 caused precocious activation of APC/C-Cdh1/Hct1 at pre-anaphase, leading to securin degradation and then separase-mediated cohesin cleavage. Overexpression of CDH1 and CDC14, encoding Cdc14 phosphatase, at pre-anaphase similarly caused chromosome missegregation. Thus, sequential activation of APC/C-Cdc20 and then APC/C-Cdh1 is critical for precise chromosome segregation and precocious activation of APC/C-Cdh1 at pre-anaphase causes genomic instability. Since degradation of human securin is also mediated by APC/C-Cdc20 and APC/C-Cdh1, this study predicts that precocious activation APC/C-Cdh1 in human cells similarly causes genomic instability, and thereby cell death or tumorigenesis

Triethylamine Enables Catalytic Generation of Oxidopyrylium Ylides for [5+2] Cycloadditions with Alkenes: An Efficient Entry to 8-Oxabicyclo[3.2.1]octane Frameworks

An efficient method for the preparation of a range of 8-oxabicyclo[3.2.1]octane derivatives including synthetic intermediates of natural products is described, in which triethylamine effectively catalyzes [5+2] cycloaddition reactions between oxidopyrylium ylides and alkenes. This method can be applied not only to intermolecular cycloadditions with various alkenes but also to intramolecular cycloadditions. The key finding is that the combined use of organic bases having appropriate basicity and oxidopyrylium ylide precursors bearing a suitable leaving group facilitates the base-assisted generation of oxidopyrylium ylides in a catalytic manner.ArticleADVANCED SYNTHESIS & CATALYSIS.360(12):2377-2381(2018)journal articl

Presenilin-2 Mutation Causes Early Amyloid Accumulation and Memory Impairment in a Transgenic Mouse Model of Alzheimer's Disease

In order to clarify the pathophysiological role of presenilin-2 (PS2) carrying the Volga German Kindred mutation (N141I) in a conventional mouse model of Alzheimer's disease (AD) expressing amyloid precursor protein (APP) with the Swedish mutation (Tg2576 line), we generated a double transgenic mouse (PS2Tg2576) by crossbreeding the PS2 mutant with Tg2576 mice. Here, we demonstrate that the PS2 mutation induced the early deposition of amyloid β-protein (Aβ) at 2-3 months of age and progressive accumulation at 4-5 months of age in the brains of the mutant mice. The PS2 mutation also accelerated learning and memory impairment associated with Aβ accumulation at 4-5 months of age in Tg2576 mice. These results suggest that the PS2 mutation causes early cerebral amyloid accumulation and memory dysfunction. PS2Tg2576 mice are a suitable mouse model for studying amyloid-lowering therapies

Efficient generation of an oxidopyrylium ylide using a Pd catalyst and its [5+2] cycloadditions with several dipolarophiles

An efficient method for the generation of an oxidopyrylium ylide from 6-acetoxy-6-acetoxymethyl-2H-pyran-3(6H)-one using a Pd catalyst and [5+2] cycloadditions of the resulting ylide are described. Among substituted styrene derivatives as dipolarophiles, electron-rich styrenes showed higher yield (up to 80%). The [5+2] cycloaddition reactions can also be applied to exo-methylene cyclic compounds, and an improved method for the synthesis of polygalolide intermediate has been demonstrated.ArticleCHEMICAL COMMUNICATIONS.54(9):1109-1112(2018)journal articl

Identifying Suspicious Regions of Covid-19 by Abnormality-Sensitive Activation Mapping

This paper presents a fully-automated method for the identification of suspicious regions of a coronavirus disease (COVID-19) on chest CT volumes. One major role of chest CT scanning in COVID-19 diagnoses is identification of an inflammation particular to the disease. This task is generally performed by radiologists through an interpretation of the CT volumes, however, because of the heavy workload, an automatic analysis method using a computer is desired. Most computer-aided diagnosis studies have addressed only a portion of the elements necessary for the identification. In this work, we realize the identification method through a classification task by using a 2.5-dimensional CNN with three-dimensional attention mechanisms. We visualize the suspicious regions by applying a backpropagation based on positive gradients to attention-weighted features. We perform experiments on an in-house dataset and two public datasets to reveal the generalization ability of the proposed method. The proposed architecture achieved AUCs of over 0.900 for all the datasets, and mean sensitivity $0.853 \pm 0.036$ and specificity $0.870 \pm 0.040$. The method can also identify notable lesions pointed out in the radiology report as suspicious regions.Comment: 10 pages, 3 figure

APC/C-Cdh1-dependent anaphase and telophase progression during mitotic slippage

<p>Abstract</p> <p>Background</p> <p>The spindle assembly checkpoint (SAC) inhibits anaphase progression in the presence of insufficient kinetochore-microtubule attachments, but cells can eventually override mitotic arrest by a process known as mitotic slippage or adaptation. This is a problem for cancer chemotherapy using microtubule poisons.</p> <p>Results</p> <p>Here we describe mitotic slippage in yeast <it>bub2Δ </it>mutant cells that are defective in the repression of precocious telophase onset (mitotic exit). Precocious activation of anaphase promoting complex/cyclosome (APC/C)-Cdh1 caused mitotic slippage in the presence of nocodazole, while the SAC was still active. APC/C-Cdh1, but not APC/C-Cdc20, triggered anaphase progression (securin degradation, separase-mediated cohesin cleavage, sister-chromatid separation and chromosome missegregation), in addition to telophase onset (mitotic exit), during mitotic slippage. This demonstrates that an inhibitory system not only of APC/C-Cdc20 but also of APC/C-Cdh1 is critical for accurate chromosome segregation in the presence of insufficient kinetochore-microtubule attachments.</p> <p>Conclusions</p> <p>The sequential activation of APC/C-Cdc20 to APC/C-Cdh1 during mitosis is central to accurate mitosis. Precocious activation of APC/C-Cdh1 in metaphase (pre-anaphase) causes mitotic slippage in SAC-activated cells. For the prevention of mitotic slippage, concomitant inhibition of APC/C-Cdh1 may be effective for tumor therapy with mitotic spindle poisons in humans.</p