DNAJA1- and conformational mutant p53-dependent inhibition of cancer cell migration by a novel compound identified through a virtual screen

Cancers are frequently addicted to oncogenic missense mutant p53 (mutp53). DNAJA1, a member of heat shock protein 40 (HSP40), also known as J-domain proteins (JDPs), plays a crucial role in the stabilization and oncogenic activity of misfolded or conformational mutp53 by binding to and preventing mutp53 from proteasomal degradation. However, strategies to deplete mutp53 are not well-established, and no HSP40/JDPs inhibitors are clinically available. To identify compounds that bind to DNAJA1 and induce mutp53 degradation, we performed an in silico docking study of ~10 million of compounds from the ZINC database for the J-domain of DNAJA1. A compound 7-3 was identified, and its analogue A11 effectively reduced the levels of DNAJA1 and conformational mutp53 with minimal effects on the levels of wild-type p53 and DNA-contact mutp53. A11 suppressed migration and filopodia formation in a manner dependent on DNAJA1 and conformational mutp53. A mutant DNAJA1 with alanine mutations at predicted amino acids (tyrosine 7, lysine 44, and glutamine 47) failed to bind to A11. Cells expressing the mutant DNAJA1 became insensitive to A11-mediated depletion of DNAJA1 and mutp53 as well as A11-mediated inhibition of cell migration. Thus, A11 is the first HSP40/JDP inhibitor that has not been previously characterized for depleting DNAJA1 and subsequently conformational mutp53, leading to inhibition of cancer cell migration. A11 can be exploited for a novel treatment against cancers expressing conformational mutp53

A Cross-Cultural Study of Value and Value Change. : (2) The Differences in Value Priorities in Terms of Survey Time, Subjects, Goal Type, and Interests Served.

本研究の目的は，調査を通じて，Schwartz&Bilsky （1987）に基づいて選定された各価値項目及び12の動機づけ領域に見られる価値優位性が，調査の対象者（教師，学生） と時期（1989，1994）によってどのように異なるかを明らかにするとともに， あわせて，価値の目標タイプ（終極的，道具的）や価値がもたらす利益（個人的，集団的，及び個人と集団の両方的） とによってもその優位性がどのように異なるかを明らかにすることである。価値項目と12の動機づけ領域の多くにおいて，調査の対象者と時期による価値優位性の差異が認められた。また， 目標タイプ，利益が明確な51の価値項目に基づいて算出した全般的な価値の重視度も，調査の対象者と時期，及び価値の目標タイプと価値がもたらす利益によって異なることが明らかになった。価値に関係する既存の調査結果と対比させて，これらの結果を考察した。This study used a value survey based on Schwartz and Bilsky\u27s (1987) 12 motivational domains to investigate the differences in value priorities for each domain across time (1989, 1994) and subject type (teachers, students). Also, the relationship between goal type (terminal, instrumental) and interests served (individualistic, collective, and both) was investigated. Differences in value priorities were found across time and subject type. Also, using a general index of 51 value items, differences were found for time, subject type, goal type, and interests served. Results from this study are compared with existing research on values

SLPI is a critical mediator that controls PTH-induced bone formation

Osteoclastic bone resorption and osteoblastic bone formation/replenishment are closely coupled in bone metabolism. Anabolic parathyroid hormone (PTH), which is commonly used for treating osteoporosis, shifts the balance from osteoclastic to osteoblastic, although it is unclear how these cells are coordinately regulated by PTH. Here, we identify a serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), as a critical mediator that is involved in the PTH-mediated shift to the osteoblastic phase. Slpi is highly upregulated in osteoblasts by PTH, while genetic ablation of Slpi severely impairs PTH-induced bone formation. Slpi induction in osteoblasts enhances its differentiation, and increases osteoblast–osteoclast contact, thereby suppressing osteoclastic function. Intravital bone imaging reveals that the PTH-mediated association between osteoblasts and osteoclasts is disrupted in the absence of SLPI. Collectively, these results demonstrate that SLPI regulates the communication between osteoblasts and osteoclasts to promote PTH-induced bone anabolism.Morimoto A., Kikuta J., Nishikawa K., et al. SLPI is a critical mediator that controls PTH-induced bone formation. Nature Communications 12, 2136 (2021); https://doi.org/10.1038/s41467-021-22402-x

Osteoclasts adapt to physioxia perturbation through DNA demethylation

Oxygen plays an important role in diverse biological processes. However, since quantitation of the partial pressure of cellular oxygen in vivo is challenging, the extent of oxygen perturbation in situ and its cellular response remains underexplored. Using two-photon phosphorescence lifetime imaging microscopy, we determine the physiological range of oxygen tension in osteoclasts of live mice. We find that oxygen tension ranges from 17.4 to 36.4 mmHg, under hypoxic and normoxic conditions, respectively. Physiological normoxia thus corresponds to 5% and hypoxia to 2% oxygen in osteoclasts. Hypoxia in this range severely limits osteoclastogenesis, independent of energy metabolism and hypoxia-inducible factor activity. We observe that hypoxia decreases ten-eleven translocation (TET) activity. Tet2/3 cooperatively induces Prdm1 expression via oxygen-dependent DNA demethylation, which in turn activates NFATc1 required for osteoclastogenesis. Taken together, our results reveal that TET enzymes, acting as functional oxygen sensors, regulate osteoclastogenesis within the physiological range of oxygen tension, thus opening new avenues for research on in vivo response to oxygen perturbation.Nishikawa K., Seno S., Yoshihara T., et al. Osteoclasts adapt to physioxia perturbation through DNA demethylation. EMBO Reports 22, e53035 (2021); https://doi.org/10.15252/embr.202153035

Vibrational energy redistribution during donor-acceptor electronic energy transfer: criteria to identify subsets of active normal modes

Photoinduced electronic energy transfer in conjugated donor-acceptor systems is naturally accompanied by intramolecular vibrational energy redistributions accepting an excess of electronic energy. Herein, we simulate these processes in a covalently linked donor-acceptor molecular dyad system by using nonadiabatic excited state molecular dynamics simulations. We analyze different complementary criteria to systematically identify the subset of vibrational normal modes that actively participate on the donoracceptor (S2S1) electronic relaxation. We analyze energy transfer coordinates in terms ofstate-specific normal modes defined according to the different potential energy surfaces (PESs) involved. On one hand, we identify those vibrations that contribute the most to the direction of the main driving force on the nuclei during electronic transitions, represented by the non-adiabatic derivative coupling vector between donor and acceptor electronic states. On the other hand, we monitor normal mode transient accumulations of excess energy and their intramolecular energy redistribution fluxes. We observe that the subset of active modes varies according to the PES on which they belong and these modes experience the most significant rearrangements and mixing. Whereas the nuclear motions that promote donoracceptor energy funneling can be localized mainly on one or two normal modes of the S2 state, they become spread out across multiple normal modes of the S1 state following the energy transfer eventThis work was partially supported by CONICET, UNQ, ANPCyT (PICT-2018-2360), the Universidad Carlos III de Madrid, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 600371, el Ministerio de Economía, Industria y Competitividad (COFUND2014-51509), el Ministerio de Educación, cultura y Deporte (CEI-15-17), Banco Santander and el Ministerio de Ciencia, Innovación y Universidades (RTI2018-101020-B-I00). We also acknowledge support from the Bavarian University Centre for Latin America (BAYLAT). The work at Los Alamos National Laboratory (LANL) was supported by the Laboratory Directed Research and Development Funds (LDRD) program. This work was done in part at the Center for Nonlinear Studies (CNLS) and the Center for Integrated Nanotechnologies (CINT), a U.S. Department of Energy and Office of Basic Energy Sciences user facility, at LANL. This research used resources provided by the LANL Institutional Computing Program. Los Alamos National Laboratory is operated by Triad National Security, LLC, for the National Nuclear Security Administration of the U.S. Department of Energy. This work has received finantial support provided by the Spanish Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, UE) under Project CTQ2016-79345-P and by the Funda-ción Séneca under Project 20789/PI/18

スタチンは肺切除術後の肺腺がん患者において有益にも有害にもなりうる

京都大学0048新制・課程博士博士(医学)甲第22005号医博第4519号新制||医||1038(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 平井 豊博, 教授 松原 和夫, 教授 萩原 正敏学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Drugs Targeting p53 Mutations with FDA Approval and in Clinical Trials

Mutations in the tumor suppressor p53 (p53) promote cancer progression. This is mainly due to loss of function (LOS) as a tumor suppressor, dominant-negative (DN) activities of missense mutant p53 (mutp53) over wild-type p53 (wtp53), and wtp53-independent oncogenic activities of missense mutp53 by interacting with other tumor suppressors or oncogenes (gain of function: GOF). Since p53 mutations occur in ~50% of human cancers and rarely occur in normal tissues, p53 mutations are cancer-specific and ideal therapeutic targets. Approaches to target p53 mutations include (1) restoration or stabilization of wtp53 conformation from missense mutp53, (2) rescue of p53 nonsense mutations, (3) depletion or degradation of mutp53 proteins, and (4) induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 mutations (enhanced YAP/TAZ activities) or deletions (hyperactivated retrotransposons). This review article focuses on clinically available FDA-approved drugs and drugs in clinical trials that target p53 mutations and summarizes their mechanisms of action and activities to suppress cancer progression

Successful treatment of late onset empyema after extrapleural pneumonectomy: A case report

Treatment of post-extrapleural pneumonectomy empyema (PEPPE) is more difficult than that for post-pneumonectomy empyema for two reasons: first, a large infectious dead space remains after extrapleural pneumonectomy (EPP); and second, defects of the pericardium and diaphragm are reconstructed with artificial materials, which ideally should be removed for treatment of infection. Here, we report the case of a 56-year-old male with PEPPE that occurred long after EPP for mesothelioma. The patient was treated successfully by minimally invasive procedures of irrigation, instillation of urokinase and antibiotics, and surgical debridement without peeling off artificial materials. Keywords: Late onset empyema, Minimally invasive surgery, Extrapleural pneumonectomy, Malignant mesotheliom