PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase

The cytotoxicity of ionizing radiation depends on the cell cycle phase; therefore, its pharmacological manipulation, especially the induction of cell cycle arrest at the radiosensitive mitotic-phase (M-phase), has been attempted for effective radiation therapy. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that functions in mitotic progression, and is now recognized as a potential target for radiosensitization. We herein investigated whether PLK1 blockade enhanced the cytotoxic effects of radiation by modulating cell cycle phases of cancer cells using the novel small molecule inhibitor of PLK1, TAK-960. The TAK-960 treatment exhibited radiosensitizing effects in vitro, especially when it increased the proportion of M-phase cells. TAK-960 did not sensitize cancer cells to radiation when an insufficient amount of time was provided to induce mitotic arrest. The overexpression of a PLK1 mutant, PLK1-R136G&T210D, which was confirmed to cancel the TAK-960-mediated increase in the proportion of mitotic cells, abrogated the radiosensitizing effects of TAK-960. A tumor growth delay assay also demonstrated that the radiosensitizing effects of TAK-960 depended on an increase in the proportion of M-phase cells. These results provide a rational basis for targeting PLK1 for radiosensitization when considering the therapeutic time window for M-phase arrest as the best timing for radiation treatments

ファッション カラー コーディネーション ニ カンスル ケンキュウ : ヒフク シキサイ トシテノ ハイケイショク ノ エイキョウ

被服の「似合い」の判断基準のなかで被服の色は非常に重要であると考えられ、さまざまなファッションカラーコーディネーションの手法が注目されている。 ここでは、物理学的な事項から心理学的な事項までを多段階に網羅し、かつ一般的な表色系を採用した普遍的で新しいファッションコーディネートの手法の構築を最終的な目標とし、基礎研究に着手した。「似合い」の判断基準を、被服の色と着用者の肌の色におき、着用者の肌色の美しさを問うのであれば、これは理想の肌色の存在を示唆することになる。ここで考えるファッションカラーコーディネーションの手法では、これをひとつの大きな前提とする。すなわち、理想の肌色とそれとは異なった実際の肌色が存在し、これを服の色と組み合わせることにより、理想の肌色に近づけば似合う、逆に遠ざかれば似合わないと判断していると仮定する。 実験では、色彩選択プログラムを作成し、「理想の肌色」を調整法により提示することを試みた。今回の実験でも、「理想の肌色」として特定の色が認められた。また、背景色のトーンの影響としては、前報の色相の影響と同様、一般の配色に認められる同時対比効果が現れた。したがって各個人の肌色が、この「理想の肌色」に近づくような対比効果をもたらす被服の存在が示唆された

ファッション カラー コーディネーション ニ カンスル ケンキュウ パーソナル コンピュータ オ モチイタ ハダイロ ノ worm cool カン ノ ケイソク

最近では、肌の色をもとにして似合う色を見つけるというカラーコーディネートの手法が多く見受けられる。そこでは、肌の色をオークル系(O)かピンク系(P)に分け、これらを似合う色を見つけるための手がかりとしている場合が多い。しかし、肌色と呼ばれる色の範囲は、非常に狭く、これらをどのように分類できるのか、また、ウォーム・クールに分類する時に、色相だけで判断してよいのか、など、多くの疑問がある。そこで、本研究では、肌の色のウォーム・クール感について、その決定要因を調査することとした。 実験では、肌色モデルを日本色研の肌色カラーカードに求めた。暗室状態のブースの中に被験者が1人ずつ入り、縦96pixel×横96pixelの正方形に着色した9色の肌の色を一列に並べたコンピューターの画面(17inch、縦768pixel×横1024pixel)を見ながらドラッグ操作し、それぞれをウォーム-クールの順になるように、並べ替えていく。被験者は大学3、4回生の30名である。 肌の色の色相とウォーム-クールの関係では、10Rに最も近いPがウォーム、5Bに近いOがクールとなっている。従来のカラーコーディネーションの手法では、ウォームから順にO、N(ナチュラル)、Pとしている場合が多い。しかし、今回の結果では、P、N、Oの順になった。また、明度の影響は比較的大きく、色相のみに着目すると順序が異なる場合のも認められ、その重要性が明らかとなった

Lack of impact of the ALDH2 rs671 variant on breast cancer development in Japanese BRCA1/2‐mutation carriers

The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer-initiating cells in these patients usually undergo loss of the wild-type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients

UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization

Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant properties of cancer cells, gene networks triggering the HIF-1-mediated reprogramming and molecular mechanisms linking the reprogramming with radioresistance remain to be determined. Here, we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1), which we previously identified as a novel HIF-1 activator, increased the radioresistance of cancer cells by producing an antioxidant, reduced glutathione (GSH), through HIF-1-mediated metabolic reprogramming. A luciferase assay to monitor HIF-1 activity demonstrated that the overexpression of UCHL1, but not its deubiquitination activity-deficient mutant (UCHL1 C90S), upregulated HIF-1 activity by stabilizing the regulatory subunit of HIF-1 (HIF-1α) in a murine breast cancer cell line, EMT6. UCHL1 overexpression induced the reprogramming of carbohydrate metabolism and increased NADPH levels in a pentose phosphate pathway (PPP)-dependent manner. The UCHL1-mediated reprogramming elevated intracellular GSH levels, and consequently induced a radioresistant phenotype in a HIF-1-dependent manner. The pharmacological inhibition of PPP canceled the UCHL1-mediated radioresistance. These results collectively suggest that cancer cells acquire antioxidant and radioresistant phenotypes through UCHL1-HIF-1-mediated metabolic reprogramming including the activation of PPP and provide a rational basis for targeting this gene network for radiosensitization

An FD-LC-MS/MS Proteomic Strategy for Revealing Cellular Protein Networks: A Conditional Superoxide Dismutase 1 Knockout Cells

<div><p>Systems biology aims to understand biological phenomena in terms of complex biological and molecular interactions, and thus proteomics plays an important role in elucidating protein networks. However, many proteomic methods have suffered from their high variability, resulting in only showing altered protein names. Here, we propose a strategy for elucidating cellular protein networks based on an FD-LC-MS/MS proteomic method. The strategy permits reproducible relative quantitation of differences in protein levels between different cell populations and allows for integration of the data with those obtained through other methods. We demonstrate the validity of the approach through a comparison of differential protein expression in normal and conditional superoxide dismutase 1 gene knockout cells and believe that beginning with an FD-LC-MS/MS proteomic approach will enable researchers to elucidate protein networks more easily and comprehensively.</p> </div