A PROTAC degrader suppresses oncogenic functions of PTK6 inducing apoptosis of breast cancer cells.

Protein tyrosine kinase 6 (PTK6), a non-receptor tyrosine kinase, is an oncogenic driver in many tumor types. However, agents that therapeutically target PTK6 are lacking. Although several PTK6 kinase inhibitors have been developed, none have been clinically translated, which may be due to kinase-independent functions that compromise their efficacy.

Structure- and Property-Based Optimization of Efficient Pan-Bromodomain and Extra Terminal Inhibitors to Identify Oral and Intravenous Candidate I-BET787.

The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail -acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 () that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration.

MARCH2, a Novel Oncogene-regulated SNAIL E3 Ligase, Suppresses Triple-negative Breast Cancer Metastases.

Unlabelled: Epithelial-mesenchymal transition (EMT) in cancer promotes metastasis and chemotherapy resistance. A subset of triple-negative breast cancer (TNBC) exhibits a mesenchymal gene signature that is associated with poor patient outcomes. We previously identified PTK6 tyrosine kinase as an oncogenic driver of EMT in a subset of TNBC.

RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4.

Chromosomal translocation generates the MLL-AF4 fusion gene, which causes acute leukemia of multiple lineages. MLL-AF4 is a strong oncogenic driver that induces leukemia without additional mutations and is the most common cause of pediatric leukemia. However, establishment of a murine disease model via retroviral transduction has been difficult owning to a lack of understanding of its regulatory mechanisms.

Evaluating the daily life of child and adolescent psychiatric outpatients during temporary school closure over COVID-19 pandemic: A single-center case-control study in Japan.

This study evaluated the clinical characteristics of mental health of child and adolescent psychiatric patients during temporary school closure throughout the coronavirus 2019 (COVID-19) pandemic in Japan using the Questionnaire - Children with Difficulties (QCD) and other useful psychological rating scales. The participants were those who visited the Department of Child and Adolescent Psychiatry, Kohnodai Hospital. From those 1,463 participants, case and control groups were selected: 92 patients who visited the hospital during the temporary school closure from March 2020 to May 2020 (case group) and randomly sampled sex- and age-matched 92 patients during the pre-COVID period from April 2017 to March 2020 (control group).

A biomimetic hydrogel culture system to facilitate cardiac reprogramming.

Direct cardiac reprogramming, in which fibroblasts are converted into induced cardiomyocytes (iCMs) with cardiogenic transcription factors, may be a promising approach for myocardial regeneration. Here, we present a protocol for cardiac reprogramming using a handmade hydrogel culture system. This system can recapitulate substrate stiffness comparable to that of the native myocardium.

Organelle genome assembly uncovers the dynamic genome reorganization and cytoplasmic male sterility associated genes in tomato.

To identify cytoplasmic male sterility (CMS)-associated genes in tomato, we determined the genome sequences of mitochondria and chloroplasts in three CMS tomato lines derived from independent asymmetric cell fusions, their nuclear and cytoplasmic donors, and male fertile weedy cultivated tomato and wild relatives. The structures of the CMS mitochondrial genomes were highly divergent from those of the nuclear and cytoplasmic donors, and genes of the donors were mixed up in these genomes. On the other hand, the structures of CMS chloroplast genomes were moderately conserved across the donors, but CMS chloroplast genes were unexpectedly likely derived from the nuclear donors.

Compromised anti-tumor-immune features of myeloid cell components in chronic myeloid leukemia patients.

Chronic myeloid leukemia (CML) is a form of myeloproliferative neoplasm caused by the oncogenic tyrosine kinase BCR-ABL. Although tyrosine kinase inhibitors have dramatically improved the prognosis of patients with CML, several problems such as resistance and recurrence still exist. Immunological control may contribute to solving these problems, and it is important to understand why CML patients fail to spontaneously develop anti-tumor immunity.

Mechanical load regulates bone growth via periosteal Osteocrin.

Mechanical stimuli including loading after birth promote bone growth. However, little is known about how mechanical force triggers biochemical signals to regulate bone growth. Here, we identified a periosteal-osteoblast-derived secretory peptide, Osteocrin (OSTN), as a mechanotransducer involved in load-induced long bone growth.

Current use of attention-deficit hyperactivity disorder (ADHD) medications and clinical characteristics of child and adolescent psychiatric outpatients prescribed multiple ADHD medications in Japan.

Background/aim: Patients with attention-deficit hyperactivity disorder (ADHD) manifest symptoms of hyperactivity, impulsivity, and/or inattention. ADHD medications available in Japan are limited compared with those in Western countries. Prescribing status has not been sufficiently evaluated in clinical settings in Japan.

Care for children's mental health during the COVID-19 pandemic in Japan.

COVID-19 causes very serious issues all over the world. In Japan, the number of new infections in Tokyo exceeded 2,000 for the first time on 7 January 2021, and the situation is becoming increasingly serious. Japan is in the midst of its third big outbreak.

Physiologically-based Pharmacokinetic (PBPK) Modelling of Transporter Mediated Drug Absorption, Clearance and Drug-drug Interactions.

Membrane transporters play an important role in intestinal absorption, distribution and clearance of drugs. Additionally transporters along with enzymes regulate tissue exposures (e.g.

Stiffness of the extracellular matrix regulates differentiation into beige adipocytes.

Beige/brite adipocytes, which express high levels of uncoupling protein 1 (UCP1) to generate heat using stored triglycerides, are induced under specific stimuli such as cold exposure in inguinal white adipose tissue (iWAT). Although extracellular microenvironments such as extracellular matrix (ECM) stiffness are known to regulate cell behaviors, including cell differentiation into adipocytes, the effect on iWAT cells is unknown. In this study, we show that rigid ECM promotes the cell spreading of iWAT-derived preadipocytes.

Current situation and challenges for mental health focused on treatment and care in Japan and the Philippines - highlights of the training program by the National Center for Global Health and Medicine.

Background And Purpose: Mental health has emerged as an important public health concern in recent years. With a high proportion of children and adolescents affected by mental disorders, it is important to ensure that they are provided with proper care and treatment. With the goal of sharing the activities and good practices on child and adolescent mental health promotion, care, and treatment in Japan and the Philippines, the National Center for Global Health and Medicine conducted a training program on the promotion of mental health focused on treatment and care in Japan and the Philippines in September and November 2019.

Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening.

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize -acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles.

Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-κB activity.

Mechanical loading plays an important role in bone homeostasis. However, molecular mechanisms behind the mechanical regulation of bone homeostasis are poorly understood. We previously reported p130Cas (Cas) as a key molecule in cellular mechanosensing at focal adhesions.

Addressing challenges in children's mental health in disaster-affected areas in Japan and the Philippines - highlights of the training program by the National Center for Global Health and Medicine.

Background And Purpose: Natural disasters such as earthquakes, typhoons, floods, and volcanic eruptions frequently occur in Republic of Philippines and mental health care for children affected by these natural disasters is a major public health concern. Aiming to train health professionals on children's mental health, to conduct a situational analysis to identify the local needs and resources for children's mental health, and to propose a mental health program for children that can be transferred from Japan to the Philippines, the National Center for Global Health and Medicine (NCGM) conducted a training program for children's mental health in disaster-affected areas in Japan and the Philippines in June, October, and December, 2017. The training was organized by NCGM for the Program for International Promotion of Japan's Healthcare Technologies and Services funded by Ministry of Health, Labour, & Welfare, Japan in relation to the Memorandum of Understanding in the Field of Healthcare between NCGM in Japan and University of the Philippines Manila, College of Public Health.

Constraint structure optimization to a specific minimum using ionization energy.

A structure optimization method with ionization energy constraint is developed to explore structures with specific ionization energy. The Levine-Coe-Martínez penalty function (J Phys Chem B 2008, 112, 405) was adopted, and the penalty function includes a predefined core-ionization energy and inner-shell ionization energy. For an S 2 reaction, isomerization of a platinum complex, a proton transfer reaction, and carbon monoxide adsorption on a palladium cluster, the present method was tested, and the targeted energy minima were obtained as designated by the input ionization energy.

Local cyclical compression modulates macrophage function and alleviates immobilization-induced muscle atrophy.

Physical inactivity gives rise to numerous diseases and organismal dysfunctions, particularly those related to aging. Musculoskeletal disorders including muscle atrophy, which can result from a sedentary lifestyle, aggravate locomotive malfunction and evoke a vicious circle leading to severe functional disruptions of vital organs such as the brain and cardiovascular system. Although the significance of physical activity is evident, molecular mechanisms behind its beneficial effects are poorly understood.

Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression.

The physical properties of the extracellular matrix (ECM), such as stiffness, are involved in the determination of the characteristics of cancer cells, including chemotherapy sensitivity. Resistance to chemotherapy is often linked to dysfunction of tumor suppressor p53; however, it remains elusive whether the ECM microenvironment interferes with p53 activation in cancer cells. Here, we show that, in MCF-7 breast cancer cells, extracellular stiffness influences p53 activation induced by the antitumor drug doxorubicin.