A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.

Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the for ATP.

Synthesis and anti-tumor activities in human leukemia-derived cells of polyenylpyrroles with a methyl group at the conjugated polyene terminus.

To develop novel drugs for treating T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) which are highly malignant hematological tumors, a series of analogs having a polyenylpyrrole structure of natural compounds (rumbrin and auxarconjugatin B) were synthesized and investigated their structure-activity relationships (SAR) of in vitro anti-T-ALL and anti-AML activities. We obtained three findings: (1) introduction of a methyl group at the conjugated polyene terminus enhanced anti-T-ALL activity, (2) analogs with a 3-chloropyrrole moiety had even higher selectivity for T-ALL cells, and (3) some analogs were effective against AML-derived cells. Among the studied compounds, 3-chloro-2-(8-ethoxycarbonylnona-1,3,5,7-tetraenyl) pyrrole 4e was the most promising candidate of T-ALL- and AML-treating drug.

Identification of compounds that preferentially suppress the growth of T-cell acute lymphoblastic leukemia-derived cells.

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most frequently occurring cancers in children and is associated with a poor prognosis. Here, we performed large-scale screening of natural compound libraries to identify potential drugs against T-ALL. We identified three low-molecular-weight compounds (auxarconjugatin-B, rumbrin, and lavendamycin) that inhibited the proliferation of the T-ALL cell line CCRF-CEM, but not that of the B lymphoma cell line Raji in a low concentration range.

Association between nocturnal falls and hypnotic drug use in older patients at acute care hospitals.

Purpose: Although hypnotic drug use is a known risk factor for falls, few reports have analyzed fall risk associated with individual hypnotic drugs after adjusting for confounding factors. While it is recommended that benzodiazepine receptor agonists not be prescribed for older adults, it is unknown whether melatonin receptor agonists and orexin receptor antagonists are safe in this population. Here, we aimed to assess the influence of various hypnotic drugs on fall risk in older patients admitted to acute care hospitals.

Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma.

Patients with melanoma with activating BRAF mutations (BRAF V600E/K) initially respond to combination therapy of BRAF and MEK inhibitors. However, their clinical efficacy is limited by acquired resistance, in some cases driven by amplification of the mutant BRAF gene and subsequent reactivation of the MAPK pathway. DS03090629 is a novel and orally available MEK inhibitor that inhibits MEK in an ATP-competitive manner.

Development of a deep learning method for improving diagnostic accuracy for uterine sarcoma cases.

Uterine sarcomas have very poor prognoses and are sometimes difficult to distinguish from uterine leiomyomas on preoperative examinations. Herein, we investigated whether deep neural network (DNN) models can improve the accuracy of preoperative MRI-based diagnosis in patients with uterine sarcomas. Fifteen sequences of MRI for patients (uterine sarcoma group: n = 63; uterine leiomyoma: n = 200) were used to train the models.

Revealing differences in the chemical form of zinc in brain tissue using K-edge X-ray absorption near-edge structure spectroscopy.

Zinc is a prominent trace metal required for normal memory function. Memory loss and cognitive decline during natural ageing and neurodegenerative disease have been associated with altered brain-Zn homeostasis. Yet, the exact chemical pathways through which Zn influences memory function during health, natural ageing, or neurodegenerative disease remain unknown.

Direct oral anticoagulant use and outcomes in adult patients with Fontan circulation: A multicenter retrospective cohort study.

Background: Many adult patients with Fontan circulation are treated with antithrombotic agents, including direct oral anticoagulants (DOACs). However, few studies have investigated the efficacy, feasibility, and safety of DOACs in adult patients with Fontan circulation.

Methods And Results: In this retrospective cohort study, clinical records of 139 adult patients with Fontan circulation (70 females, 50.

Relation of Reduction of Antibodies against Hepatitis B Virus to Hepatocellular Carcinoma Recurrence in the Patients with Resolved Hepatitis B Virus Infection Following Direct-acting Antiviral Therapy for Hepatitis C Virus Infection.

Background: A possible interaction of hepatitis viruses at cellular and molecular levels has been suggested. Eradication of hepatitis C virus (HCV) has been reported to induce activation of hepatitis B virus (HBV)-related liver diseases.

Materials And Methods: The present study examined association of HBV markers with recurrence of hepatocellular carcinoma (HCC) in patients with resolved HCV infection by direct-acting antiviral (DAA) therapy.

A Review of Elemental Mapping Methods to Directly Image Changes in the Homeostasis of Diffusible Ions (Na, K, Mg, Ca, Cl) Within Brain Tissue.

Diffusible ions (Na, K, Mg, Ca, Cl) are vital for healthy function of all cells, especially brain cells. Unfortunately, the diffusible nature of these ions renders them difficult to study with traditional microscopy within brain tissue sections. This mini-review examines the recent progress in the field, using direct elemental mapping techniques to study ion homeostasis during normal brain physiology and pathophysiology, through measurement of ion distribution and concentration in brain tissue sections.

Search for high-capacity oxygen storage materials by materials informatics.

Oxygen storage materials (OSMs), such as pyrochlore type CeO-ZrO (p-CZ), are used as a catalyst support for three-way catalysts in automotive emission control systems. They have oxygen storage capacity (OSC), which is the ability to release and store oxygen reversibly by the fluctuation of cation oxidation states depending on the reducing or oxidizing atmosphere. In this study, we explore high-capacity OSMs by using materials informatics (MI) combining experiments, first-principles calculations, and machine learning (ML).

CD44/CD133-Positive Colorectal Cancer Stem Cells are Sensitive to Trifluridine Exposure.

Cancer stem cells (CSCs) are involved in metastatic colorectal cancer recurrence, but no effective therapy targeting these cells is currently available. Because trifluridine (FTD)/tipiracil therapy is used for refractory colorectal cancer, we sought to determine whether FTD is effective against CSC-like cells. CD44CD133 high-expressing and other populations of human DLD-1 colon cancer cells were separately isolated through fluorescence-activated cell sorting.

Towards the Limits of Existence of Nuclear Structure: Observation and First Spectroscopy of the Isotope ^{31}K by Measuring Its Three-Proton Decay.

The most remote isotope from the proton dripline (by 4 atomic mass units) has been observed: ^{31}K. It is unbound with respect to three-proton (3p) emission, and its decays have been detected in flight by measuring the trajectories of all decay products using microstrip detectors. The 3p emission processes have been studied by the means of angular correlations of ^{28}S+3p and the respective decay vertices.

Increase in direct social care costs of Alzheimer's disease in Japan depending on dementia severity.

Aim: With the aging population, costs of direct social support for patients with Alzheimer's disease have grown and will continue to increase. The purpose of the present study was to estimate the cost of direct social support for Alzheimer's disease under long-term care insurance in Japan.

Methods: This cross-sectional study included 169 patients with Alzheimer's disease or mild cognitive impairment who visited a memory clinic and were followed over time.

Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress.

Skeletal muscle atrophy is caused by disruption in the homeostatic balance of muscle degeneration and regeneration under various pathophysiological conditions. We have previously reported that iron accumulation induces skeletal muscle atrophy a ubiquitin ligase-dependent pathway. However, the potential effect of iron accumulation on muscle regeneration remains unclear.

Elemental characterisation of the pyramidal neuron layer within the rat and mouse hippocampus.

A unique combination of sensitivity, resolution, and penetration make X-ray fluorescence imaging (XFI) ideally suited to investigate trace elemental distributions in the biological context. XFI has gained widespread use as an analytical technique in the biological sciences, and in particular enables exciting new avenues of research in the field of neuroscience. In this study, elemental mapping by XFI was applied to characterise the elemental content within neuronal cell layers of hippocampal sub-regions of mice and rats.

Simulations tackle abrupt massive migrations of energetic beam ions in a tokamak plasma.

In the late 1990s, fusion scientists at the Japanese tokamak JT-60U discovered abrupt large-amplitude events during beam-driven deuterium plasma experiments. A large spike in the magnetic fluctuation signal followed by a drop in the neutron emission rate indicates that energetic ions abruptly migrate out of the plasma core during an intense burst of Alfvén waves that lasts only 0.3 ms.

Interindividual Differences in the Expression of ATP-Binding Cassette and Solute Carrier Family Transporters in Human Skin: DNA Methylation Regulates Transcriptional Activity of the Human ABCC3 Gene.

The identification of drug transporters expressed in human skin and interindividual differences in gene expression is important for understanding the role of drug transporters in human skin. In the present study, we evaluated the expression of ATP-binding cassette (ABC) and solute carrier (SLC) transporters using human skin tissues. In skin samples, ABCC3 was expressed at the highest levels, followed by SLCO3A1, SLC22A3, SLC16A7, ABCA2, ABCC1, and SLCO2B1.

Ouabain exerts cytoprotection by diminishing the intracellular K(+) concentration increase caused by distinct stimuli in human leukemic cells.

Objectives: We tested if modulation of cytosolic K(+) levels by ouabain, an inhibitor of Na(+) /K(+) -ATPase, exerts cytoprotection against distinct stressful stimuli in human leukemic cells.

Methods: The cytosolic K(+) , Na(+) or Ca(2+) levels and the cytotoxicity were evaluated by flow cytometry.

Key Findings: Various cytotoxic chemicals and ultraviolet irradiation induced cell death and increased intracellular concentrations of K(+) , Na(+) or Ca(2+) .

Effect of a reduction of the atlanto-axial angle on the cranio-cervical and subaxial angles following atlanto-axial arthrodesis in rheumatoid arthritis.

Purpose: We retrospectively investigated the radiographic findings in patients with atlanto-axial subluxation (AAS) due to rheumatoid arthritis, and clarified the effect of reduction of the atlanto-axial angle (AAA) on the cranio-cervical and subaxial angles.

Methods: Forty-one patients, consisting of 29 females and 12 males, with AAS treated by surgery were reviewed. The average patient age at surgery was 61.

Crystal structure and complexation and fluorescence behaviors of 1,4-bis (9-anthracenylmethyl) piperazine.

The crystal structure of the photoinduced electron transfer (PET) fluoroionophore (3) was clarified by X-ray crystallographic analysis. A molecule 3 sits on a center of symmetry such that two anthracene ring systems are in an anti conformation with respect to one another across the piperazine ring. Intermolecular C-H···π and π···π interactions are observed.

Crystal structure and fluorescence behavior of N,N'-bis (1-naphthylmethyl)-diazonia-18-crown-6 diisothiocyanate.

N,N'-bis (1-naphthylmethyl)-diaza-18-crown-6 (1) showed weak emissions, suggesting that photoinduced electron transfer (PET) from the amine group to the excited naphthalene occurs. The PET fluoroionophore (1) was found to display unique photophysical properties in the presence of a guest cation. Single crystals of the HNCS salt of 1 were grown from 1 and NH(4)SCN.

Controllable adsorption and ideal H-aggregation behaviors of phenothiazine dyes on the tungsten oxide nanocolloid surface.

The monomer-aggregate equilibrium of four phenothiazine (PN) dyes, containing thionine (TH), methylene blue (MB), new methylene blue (NMB), and 1,9-dimethylmethylene blue (DMB), in the tungsten(VI) oxide (WO(3)) nanocolloid solution has been investigated by means of UV-vis spectroscopy. Addition of PN dye into the WO(3) nanocolloid solution brought about significant changes in the absorption spectrum, suggesting the formation of H-type (face-to-face fashion) trimer on the WO(3) nanocolloid surface. The adsorptivity of PN dyes onto the WO(3) nanocolloid surface was diminished by the raising the ionic strength, indicating the evidence of the electrostatic interaction between cationic PN dye and negatively charged WO(3) nanocolloids.