Pathway bias and emergence of quasi-irreversibility in reversible reaction networks: Extension of Curtin-Hammett principle

可逆な化学反応ネットワークにおける経路選択の原理 --準不可逆性の発現--. 京都大学プレスリリース. 2023-07-21.The Curtin-Hammett principle, which works in a reaction sequence where slow irreversible reactions are connected to a fast reversible reaction, determines the product distribution depending only on the relative energy barriers of the two irreversible reactions, resulting in kinetic pathway selection. A basic question is how the reaction pathway is selected in reaction networks composed of reversible reactions to generate a metastable state. Numerical simulations of model systems where reversible elementary reactions are connected linearly to an initial reversible reaction demonstrate that a metastable state far from equilibrium is transiently produced and that its lifetime is prolonged by increasing the number of connected reversible reactions. The pathway selection in the model systems originates from quasi-irreversibility, and a similar behavior was also observed in the molecular self-assembly of a Pd₆L₄ truncated tetrahedron, which supports the idea that the emergence of quasi-irreversibility is a key general concept underlining kinetic control in reversible reaction networks

Microenvironment and radiation therapy

Dependency on tumor oxygenation is one of the major features of radiation therapy and this has led many radiation biologists and oncologists to focus on tumor hypoxia. The first approach to overcome tumor hypoxia was to improve tumor oxygenation by increasing oxygen delivery and a subsequent approach was the use of radiosensitizers in combination with radiation therapy. Clinical use of some of these approaches was promising, but they are not widely used due to several limitations. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is activated by hypoxia and induces the expression of various genes related to the adaptation of cellular metabolism to hypoxia, invasion and metastasis of cancer cells and angiogenesis, and so forth. HIF-1 is a potent target to enhance the therapeutic effects of radiation therapy. Another approach is antiangiogenic therapy. The combination with radiation therapy is promising, but several factors including surrogate markers, timing and duration, and so forth have to be optimized before introducing it into clinics. In this review, we examined how the tumor microenvironment influences the effects of radiation and how we can enhance the antitumor effects of radiation therapy by modifying the tumor microenvironment

ゲノム情報を用いた微生物生態の探究

学位の種別: 課程博士審査委員会委員 : （主査）東京大学講師 笠原 雅弘, 東京大学教授 森下 真一, 東京大学教授 鈴木 穣, 東京大学教授 妹尾 啓史, 東京大学准教授 岩崎 渉University of Tokyo(東京大学

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

Spindle checkpoint activation at meiosis I advances anaphase II onset via meiosis-specific APC/C regulation

During mitosis, the spindle assembly checkpoint (SAC) inhibits the Cdc20-activated anaphase-promoting complex/cyclosome (APC/CCdc20), which promotes protein degradation, and delays anaphase onset to ensure accurate chromosome segregation. However, the SAC function in meiotic anaphase regulation is poorly understood. Here, we examined the SAC function in fission yeast meiosis. As in mitosis, a SAC factor, Mad2, delayed anaphase onset via Slp1 (fission yeast Cdc20) when chromosomes attach to the spindle improperly. However, when the SAC delayed anaphase I, the interval between meiosis I and II shortened. Furthermore, anaphase onset was advanced and the SAC effect was reduced at meiosis II. The advancement of anaphase onset depended on a meiosis-specific, Cdc20-related factor, Fzr1/Mfr1, which contributed to anaphase cyclin decline and anaphase onset and was inefficiently inhibited by the SAC. Our findings show that impacts of SAC activation are not confined to a single division at meiosis due to meiosis-specific APC/C regulation, which has probably been evolved for execution of two meiotic divisions

Experimental demonstration of quantum teleportation of a squeezed state

Quantum teleportation of a squeezed state is demonstrated experimentally. Due to some inevitable losses in experiments, a squeezed vacuum necessarily becomes a mixed state which is no longer a minimum uncertainty state. We establish an operational method of evaluation for quantum teleportation of such a state using fidelity, and discuss the classical limit for the state. The measured fidelity for the input state is 0.85$\pm$ 0.05 which is higher than the classical case of 0.73$\pm$0.04. We also verify that the teleportation process operates properly for the nonclassical state input and its squeezed variance is certainly transferred through the process. We observe the smaller variance of the teleported squeezed state than that for the vacuum state input.Comment: 7 pages, 1 new figure, comments adde

Effects of antioxidants and NO on TNF-α-induced adhesion molecule expression in human pulmonary microvascular endothelial cells

SummaryPro-inflammatory cytokines initiate the vascular inflammatory response via upregulation of adhesion molecules on the endothelium. Recent observations suggest that reactive oxygen intermediates may play a pivotal role in TNF-α signaling and upregulate gene expression. We therefore evaluated the effects of pyrrolidine dithiocarbamate (PDTC; 0.1 mM) and spermine NONOate (Sper-NO; 1mM) on adhesion molecule expression and nuclear factor kappa B (NF-κB) activation induced by TNF-α(10ng/ml) in cultured human pulmonary microvascular endothelial cells (PMVEC). Treatment of cells with TNF-α for 4h significantly induced the surface expression of E-selectin and ICAM-1. Treatment with TNF-α for 8h significantly induced the surface expression of E-selectin, ICAM-1 and VCAM-1. The upregulation of these adhesion molecules was suppressed significantly by pretreatment with PDTC or Sper-NO for 1h. 8-Bromo-cyclic GMP (1mM) had no such effect, suggesting that the NO donor's effect was non-cGMP-dependent. The mRNA expression of E-selectin, ICAM-1 and VCAM-1, and activation of NF-κB induced by TNF-α for 2h were decreased significantly by the above two pretreatments. N-acetylcysteine (10mM) and S-nitroso-N-acetylpenicillamine (1mM) had little inhibitory effects on the cell surface and mRNA expression of these adhesion molecules stimulated by TNF-α. Treatment with TNF-α for 4h enhanced HL-60 leukocyte adhesion to human PMVEC, the effect of which was inhibited significantly by pretreatment with PDTC or Sper-NO. These findings indicate that both cell surface and mRNA expression of adhesion molecules in human PMVEC induced by TNF-α are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly in part through blocking the activation of NF-κB. Although our in vitro results cannot be directly extrapolated to the in vivo situation, they suggest a potential therapeutic approach for intervention in cytokine-mediated inflammatory processes in the human lung

Multi-institutional phase II study on the safety and efficacy of dynamic tumor tracking-stereotactic body radiotherapy for lung tumors

Background and purpose: This study aimed to evaluate the safety and efficacy of dynamic tumor tracking-stereotactic body radiotherapy (DTT-SBRT) for lung tumors. Materials and methods: Patients with cStage I primary lung cancer or metastatic lung cancer with an expected range of respiratory motion of ≥10 mm were eligible for the study. The prescribed dose was 50 Gy in four fractions. A gimbal-mounted linac was used for DTT-SBRT delivery. The primary endpoint was local control at 2 years. Results: Forty-eight patients from four institutions were enrolled in this study. Forty-two patients had primary non-small-cell lung cancer, and six had metastatic lung tumors. DTT-SBRT was delivered for 47 lesions in 47 patients with a median treatment time of 28 min per fraction. The median respiratory motion during the treatment was 13.7 mm (range: 4.5–28.1 mm). The motion-encompassing method was applied for the one remaining patient due to the poor correlation between the abdominal wall and tumor movement. The median follow-up period was 32.3 months, and the local control at 2 years was 95.2% (lower limit of the one-sided 85% confidence interval [CI]: 90.3%). The overall survival and progression-free survival at 2 years were 79.2% (95% CI: 64.7%–88.2%) and 75.0% (95% CI: 60.2%–85.0%), respectively. Grade 3 toxicity was observed in one patient (2.1%) with radiation pneumonitis. Grade 4 or 5 toxicity was not observed. Conclusion: DTT-SBRT achieved excellent local control with low incidences of severe toxicities in lung tumors with respiratory motion