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Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion–positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion–positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion–positive cancer.

Figure S1. Chemical structure, Figure S2. Kinase selectivity, Figure S3. PK, Figure S4. Inhibition of proliferation and induction of apoptosis in vivo, Figure S5. TP53 sequencing, Table S2. Crystallographic data collection, Table S3. Genes changed by 1 uM CH7057288 treatment, Table S4. Upstream regulators, Table S5. The Caco-2 permeability assay

Cell line information and sensitivity to CH7057288 in high-throughput assay systems.

Our Japanese industry and university project group at Aoyama Gakuin University carried out two types of development and demonstration classes as part of new educational programs to create human resources focused on future strategy design over several years. In response to social issues related to SDGs and the circular economy (CE) that may arise in the future, new human resources who can formulate SDG/CE business scheme documents to solve these social issues are called “business producers.” New educational methods that combine both project-based learning (PBL) and active learning (AL) to create business producers were developed to accommodate hybrid group work exercises. Specifically, educational digital transformation (DX) technology was integrated to ensure a flexible response to the new normal following COVID-19. As prerequisites to develop the four types of human resources that make up the SDGs/CE business scheme, the learning of theories and mechanisms pertinent to the various advanced technologies is desirable. These new human resources equipped with specialized knowledge and practical skills are called “system creators.” A practical hands-on training program to enhance the skills of the system creators through future strategy design was created to cover the following subjects: IoT and platform services, as well as metaverse experiences.

Our Japanese industry-university project group from Aoyama Gakuin University investigated and studied new educational programs to cultivate “future strategy design” human resources over several years. The purpose of this research paper is to describe two types of educational programs. The first program proposes the system creator, which is capable of new product design and innovative management that uses advanced technologies such as IoT, AI, and augmented and virtual reality. The second program proposes the business producer that is capable of platform service business modeling, product development and strategy, and customer service. The characteristics of these programs involve to apply new educational methods to combine project based learning (PBL) and active learning.

Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion–positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion–positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion–positive cancer.

Applications and prospects of Computational Fluid Dynamics (CFD) for wind engineering fields are described from the viewpoint of a researcher at a construction company. First, CFD applications for environmental tasks are introduced. Predicting the pedestrian wind environment was one of the earliest examples that was put into practical use. Since then, CFD has been extended to applications such as predicting the dust dispersion from construction sites. These predictions are based on the Reynolds Averaged Navier-Stokes Simulation (RANS) turbulence model. Another model, Large Eddy Simulation (LES), is used to predict high-temperature exhaust gas flows inside the urban canopy, where the unsteady flow field affects the scalar transport phenomena. The area where the use of LES is most expected is in the field of wind force evaluation. For this purpose, the generation of time-dependent inflow boundary conditions is indispensable. Accordingly, the generation methods are introduced, and prediction examples are explained. Further, the prediction examples of the peak wind pressure around a complex-shaped building and the wind force evaluation for a base isolated building are exhibited. These results prove that the result of proper execution of CFD is equivalent to that of a wind tunnel experiment. In addition, as an exploratory study example, a prediction of wind pressure distribution brought by a tornado-like swirling flow is illustrated. Finally, future prospects in using CFD are discussed.

Purpose: Pelvic adhesions inhibit follicular growth and ovum transport, causing female infertility. In this report, we describe successful ovum pick-up (OPU) during adhesiotomy in a woman with severe adhesions that prevented transvaginal OPU. Subsequently, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) were attempted after transport of cumulus-oocyte complexes (COCs). Materials and methods: Clinical examination revealed a chocolate cyst on the patient's left ovary. Her right ovary was adherent to the posterior part of the uterus. COCs were harvested during adhesiotomy and stored at 37°C in a 1.5-ml tube containing Sperm Washing Medium. The tube was transported to our clinic using hot gel bags and a portable infant incubator. Immediately upon arrival, IVF and ICSI were performed. On day 7, two ICSI-derived blastocysts were cryopreserved. Two months later, these blastocysts were transferred to the patient's uterus. Results: The patient conceived, and a normal, healthy boy...

Eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3, [developing code: ED-71]), a new osteoporosis treatment drug that was recently approved in Japan, is a best-in-class drug in the class of calcitriol (1α,25-dihydroxyvitamin D3) and its prodrug alfacalcidol (1α-hydroxyvitamin D3), which have been used to treat osteoporosis for 30 years. In a comparative Phase III clinical study with alfacalcidol in osteoporosis patients, eldecalcitol demonstrated superior efficacy in the endpoints of increment of bone mineral density and reduction of bone fracture with equivalent safety to alfacalcidol. Eldecalcitol was discovered by searching synthetic analogs of calcitriol and alfacalcidol, and its main structural characteristic is having the 3-hydroxypropoxy group at the 2β-position. This review discusses why introducing the group leads to excellent efficacy and safety in osteoporosis treatment and elucidates the functional roles of the 3-hydroxypropoxy group. Briefly, the functional roles of the group are, first, realizing the metabolism switching in which eldecalcitol shows resistance to CYP24A1 and is metabolized in the liver; second, increasing the affinity to the serum carrier protein and prolonging the half-life to 53h; and third, stabilizing the eldecalcitol-receptor complex. Taken together, these functional roles of the 3-hydroxypropoxy group are beneficial in osteoporosis treatment. This review attempts to give a detailed account of the mode of action of eldecalcitol by clarifying these multifunctional roles of the 3-hydroxypropoxy group from the medicinal chemist's perspective.

The endometrial condition is a significant factor for successful pregnancy. To regulate endometrial function in fertility treatment, prednisolone (PSL) is administered for suppression of increased natural killer cells and stimulation of endometrium embryo transfer (SEET) to enhance communication between embryo and maternal tissues. We attempted to improve the endometrial condition by PSL administration and SEET during frozen–thawed blastocyst transfer (FBT). Patients took PSL (5 mg) 3 times daily for 3 days after ovulation during the FBT cycle. To analyse effects of PSL combined with SEET, we determined rates of chemical pregnancy, clinical pregnancy, foetal heart movement (FHM) and live birth. Rates of chemical pregnancy, clinical pregnancy and FHM were significantly higher in the PSL(+)/SEET(+) (57.7%, 50.0% and 46.2%, respectively) and PSL(+)/SEET(-) (53.3%, 46.7% and 46.7%, respectively) groups than in the PSL(-)/SEET(+) (30.3%, 18.2% and 18.2%, respectively) and PSL(-)/SEET(-) (22.4%, 22.4% and 18.4%; P = 0.0043, 0.0081 and 0.0055, respectively) groups. The live birth rate was significantly higher in the PSL(+)/SEET(+) group than in the PSL(+)/SEET(-), PSL(-)/SEET(+) and PSL(-)/SEET(-) groups (42.3%, 26.7%, 18.2% and 12.2%, respectively; P = 0.0237). PSL combined with SEET may be a useful adjunct to assisted reproductive technology in women who repeatedly fail to conceive by infertility treatment.

In order to apply Computational Fluid Dynamics (CFD) techniques to estimate pollutant dispersion in urban areas, it is important to assess the performance of numerical models used to estimate these...

Maternal age is a significant factor in infertility treatment. Ovarian function and oocyte quality decrease with age, whereas the frequency of chromosomal abnormalities increases. In this study, improvement of oocyte quality and ovarian function were attempted using a herbal medicine comprising 7 crude drugs:Angelicae radix,Rehmanniae radix,Plantaginis semen,Lonicerae flos,Carthami flos,Ginseng radix, andCucurbita moschata Duch. Thirty-one women who repeatedly failed to conceive by intracytoplasmic sperm injection took the herbal medicine before breakfast and dinner from the start of menstrual cycle in the ovum pickup cycle. Average patient age was 38.5 ± 0.7 years, and the average ovum pickup frequency on the first dosage day was 7.9 ± 1.5. To analyze the effects of herbal medicine intake, the number of recovered and mature oocytes, their morphology and physical qualities, as well as the rates of fertilization, oocyte development, and pregnancy was compared before and after intake. The recovered and mature oocyte numbers, oocyte morphology and physical qualities, and fertilization rate were not significantly different before and after drug intake. However, the oocyte development rate was significantly higher(58.0%) after herbal medicine intake than before (32.5%; p = 0.0003). Moreover, the successful pregnancy rate was significantly higher after intake than before (6.9% versus 0%; p = 0.0111). Herbal medicine may constitute a useful adjunct to assisted reproductive technology in women.

The purpose of this paper is to investigate turbulence effects on characteristics of local severe suction on side face of a three-dimensional square cylinder by LES. The behavior of conical vortices associated with local suctions at the angle of the attack =0, and glancing angle are focused on. First, the computed results for distribution of the pressure coefficients are validated through comparison with the experimental data. Next, using the computed results, the effects of inflow turbulence on the high peak suctions and flow characteristics are examined. As a result, high peak suctions occur associated with wake characteristics and flow reattachment characteristics affected by the large scale fluctuation of oncoming turbulence.

A series of nonsecosteroidal vitamin D 3 analogs with carboxylic acid were explored. Through our systematic SAR studies on the side chain moiety, compound 6b was identified as the optimal compound showing excellent vitamin D receptor (VDR) agonistic activity. Compound 6b had the diethyl group in the terminal which was bound by ( E )-olefin linker to the bisphenyl core. Calculating the volume of the side chain showed that the diethyl group in 6b filled the hydrophobic region of VDR with the ideal packing coefficient based on the 55% rule, and that this resulted in the most potent in vitro activity.

This paper presents an experimental study with a pilot hybrid microgrid system that is proposed and implemented in Tagajo campus of Tohoku Gakuin University, Japan. The developed microgrid system is designed to be able to supply power to both DC and AC loads simultaneously by renewable power sources such as PV and wind power generations, etc. Meanwhile, in case that the renewable power is insufficient to supply both these loads, a diesel generator is automatically actuated as backup power source. For the purpose of power balance and voltage stabilization, two types of energy storage devices with different response characteristics and cost, which are secondary battery and EDLC (Electrical Double-layer Capacitor) respectively, are introduced into this system. In this work, a coordinated control strategy for these energy storages were proposed and verified by a series of experimental studies with the developed hybrid microgrid system. The purpose of the experimental study addressed in this paper is to confirm the islanded operation properties of this system for stable power supply to both AC and DC loads, even in case with considerable power fluctuation of renewable sources and significant power change in loads. As a result of this study, it is illustrated that the developed hybrid microgrid and its control systems can work properly and resiliently as being designed.

Novel vitamin D3 analogs with carboxylic acid were explored, focusing on a nonsecosteroidal analog, LG190178, with a bisphenyl skeleton. From X-ray analysis of these analogs with vitamin D receptor (VDR), the carboxyl groups had very unique hydrogen bonding interactions in VDR and mimicked 1α-hydroxy group and/or 3β-hydroxy group of 1α,25-dihydroxyvitamin D3. A highly potent analog, 6a, with good in vitro activity and pharmacokinetic profiles was identified from an SAR study. Compound 6a showed significant prevention of bone loss in a rat osteoporosis model by oral administration.

Eldecalcitol [1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3, developing code: ED-71] is an analog of active vitamin D3, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] that possesses a hydroxypropoxy substituent at the 2beta-position of 1,25(OH)2D3. Eldecalcitol has potent biological effects on bone and is now in preparation for approval as a promising medicine for the treatment of osteoporosis in Japan. To explore chemical structure-biological activity relationships between eldecalcitol and related analogs, we have already synthesized 1-epi-eldecalcitol, 3-epi-eldecalcitol, and 1,3-diepi-eldecalcitol with inherent biological interests of each targeted analog and evaluated their biological responses. It has been reported that 20-epi-1,25(OH)2D3, a diastereomer of 1,25(OH)2D3 that possesses an inverted methyl substituent at the 20-position of the side chain, shows remarkably enhanced biological activities compared to parental compound, 1,25(OH)2D3. As a continuation of our modification studies on eldecalcitol, we took great interest in 20-epi-eldecalcitol and its biological responses. In this paper, the synthesis of 20-epi-eldecalcitol by the Trost coupling reaction between the A-ring fragment and the C/D-ring fragment as well as in vitro preliminary biological evaluation of 20-epi-eldecalcitol are described. In the induction of human myeloid leukemia cell (HL-60) differentiation, inhibition of the human histiocytic lymphoma cell (U937) proliferation, and increase in osteocalcin concentration in the human osteosarcoma cell (MG-63), 20-epi-eldecalcitol showed significantly enhanced activity compared to eldecalcitol.

The 2D Peierls transition in an anisotropic triangular lattice is studied from the view point of phonon softening. The model is obtained by introducing a coupling in one of the diagonal directions to the isotropic square lattice, for which the multimode Peierls phase, involving not only the nesting vector component but also other Fourier components of distortion with wave vectors parallel to the nesting vector, is predicted. The results indicate that the multimode type Peierls transition can be expected as far as the diagonal coupling is weak compared to the nearest neighbor coupling in the square lattice.

Using ranirestat, an aldose reductase (AR) inhibitor, we investigated the relationship between sorbitol and fructose levels in the sciatic nerve and motor nerve conduction velocity (MNCV) in streptozotocin (STZ)-treated diabetic rats. Ranirestat inhibited rat and recombinant human AR with similar IC50 values and equipotently prevented sorbitol accumulation in rat erythrocytes and sciatic nerves in vitro. One week after STZ administration, sorbitol levels in rat erythrocytes and sciatic nerves significantly increased while MNCV decreased. Oral administration of ranirestat (0.03 – 1.0 mg/kg per day) for 3 weeks dose-dependently decreased the elevated sorbitol and fructose levels in the rat sciatic nerves without affecting blood glucose level. Particularly, at doses of 0.1 mg/kg per day or higher, ranirestat normalized both sorbitol and fructose levels in the sciatic nerves of STZ-treated rats. Ranirestat (0.1 – 1.0 mg/kg per day) also improved the STZ-induced decrease in MNCV in a dose-dependent manner. This improvement correlated with the decrease of sorbitol and fructose levels in the rat sciatic nerves. These findings indicate that ranirestat improves MNCV via normalization of sorbitol and fructose accumulation in the sciatic nerve. Keywords:: ranirestat, aldose reductase inhibitor, sorbitol, fructose, motor nerve conduction velocity (MNCV)

This paper discusses the unsteady characteristics of the conical vortex on a flat roof on the basis of numerical results by large eddy simulation (LES) when flow attacks oblique to the roof. There have been a number of researches regarding the pressure characteristics associated with the motion of the conical vortices. These kind of studies have been performed by wind tunnel experiments for many years. On the other hand, recent advancement of Computational Fluid Dynamic (CFD) has made it possible to easily simulate the flow characteristics around a building. So, it has been expected that CFD become a powerful tool to investigate the pressure characteristics of a building associated with the flow structure. However, the applicability of CFD to the flow around a flat roof has not reached complete understanding. First, the present LES model is validated for the prediction of the pressure characteristics on a roof for oblique flow-through comparison with the previous experimental data. Next, the unsteady motions of the conical vortex are investigated by use of a flow visualization technique.

Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. Compound 1 was discovered from focused screening of serine protease-directed compounds from our internal collection. Using parallel synthesis supported by structure-based drug design, we identified peptidemimetic FVIIa/TF inhibitors (compounds 4-11) containing L-Gln or L-Met as the P2 moiety. However, these compounds lacked the selectivity of other serine proteases in the coagulation cascade, especially thrombin. Further optimization of these compounds was carried out with a focus on the P4 moiety. Among the optimized compounds, 12b-f showed improved selectivity.

2D spin-Peierls states are investigated by using stochastic series expansion quantum Monte Carlo method. The obtained numerical data support the previous result derived through the exact diagonalization (ED) calculations for a small cluster, indicating that the lowest energy state of the square-lattice 2D spin-Peierls system is the so-called multimode spin-Peierls (MMSP) state with lattice distortions involving Fourier components having not only the nesting wave vector but also other wave vectors parallel to it, as long as the spin–lattice coupling constant exceeds a certain critical value, and that the transition between the antiferromagnetic SDW state and the MMSP state, due to the change of the spin–lattice coupling strength, is of the first order. Since the Monte Carlo method allows us to treat larger system sizes compared to the ED method, it is possible to discuss the size effect of the transition and the degeneracy among different distortion patterns.

Side-chain elongation of active vitamin D3 is acknowledged as a structural modification to enhance its cell differentiation activity; however, the comprehensive structure−activity relationship (SAR) as a result of this modification has not been reported. To clarify the SAR, we synthesized six analogs systematically elongated at the 24-position, 26,27-position, or both by methylene (normal A-ring series 1a−f) in a facile parallel solution-phase synthesis. Using parallel synthesis, we expanded the side chain-elongation study into two 19-exomethylene analog series: 19-nor-A-ring (4a−f) and 2-methylene-19-nor-A-ring (5a−f). In the 19-nor-A-ring analog series, the SAR induced by side-chain elongation was similar to the normal A-ring analog series, but in the 2-methylene-19-nor-A-ring series, the SAR was unique.

To express its biological action, active vitamin D3 (1α,25-dihydroxyvitamin D3) interacts with three proteins : vitamin D binding protein (DBP), vitamin D receptor (VDR), and CYP24A1. This article explains how eldecalcitol interacts with these three proteins to achieve its mode of action. The main feature of eldecalcitol's molecular structure is the 3-hydroxypropyloxy group (3-HP group) at the 2β-position. When interacting with DBP, eldecalcitol tightly binds to DBP via the 3-HP group and enhances systemic stability of eldecalcitol. By binding to VDR, the 3-HP group stabilizes the eldecalcitol-VDR complex, which leads to high efficacy. The 3-HP group also interferes with the binding to CYP24A1, which induces residence to CYP24A1 and liver metabolism. These protein interactions constitute the mode of action of eldecalcitol.

A facile procedure for construction of the 7,8‐olefin linkage in vitamin D3 is described. Treatment of a mixture of A‐ring phosphine oxide and CD‐ring ketone in THF with lithium hexamethyldisilazide (LHMDS) at −20°C followed by gradual heating to 50°C gives the key intermediate of vitamin D3 analogs in excellent yield. This simplified procedure makes possible small‐scale synthesis benefiting the vitamin D3 analog study.

In recent studies, we have shown that the lowest energy state in a 2D square lattice SSH-type model with a half-filled electronic band is not a simple Peierls state involving only distortions with the nesting wave vector Q but complicated multimode states involving distortions with various wave vectors parallel to Q and that there are many degenerate non-equivalent distortion patterns yielding the same ground state energy. In the present work we discuss the effect of anisotropy on these multimode Peierls states. It is indicated within the pertubational treatment combined with numerical calculations that the multimode states can survive as far as the anisotropy is small. Furthermore it is pointed out that the degeneracy can be lifted by the anisotropy. These studies will shed light on the understanding of the Peierls-like behaviors of 2D materials as layered organic conductors.

The temperature dependence of the electronic diffusion coefficient in a disordered symplectic system with electron–phonon interactions is numerically calculated. Electron–phonon interactions are in...

The static and dynamical behaviors of an acoustic polaron in a quasi-one-dimensional branching-off system are studied numerically by employing Su–Schrieffer–Heeger's model extended to involve the branching-off structure. At the branching-off site, an electron is found to feel an attractive potential with the strength equal to the transfer integral between one-dimensional neighboring sites. When an acoustic polaron prepared at a site sufficiently apart from the branching-off site is set in motion by an external force towards the branching site, it is totally reflected, totally trapped or partially reflected and partially trapped at the branching site, depending on the extent of the polaron just before it reaches the branching site. It is argued that this behavior is essentially the same as that seen in a one-dimensional system with a single-site-type attractive potential. When the effective attractive potential at the branching site is cancelled out by a real repulsive site-potential, the polaron moving to...

The periodic lattice distortion BOW owing to the electron–lattice interaction and the spin density wave SDW owing to the electron–electron interaction in the two-dimensional Peierls–Hubbard model having a half-filled electronic band are studied numerically within the Hartree–Fock approximation. It is shown that the phase transition from the BOW to the SDW behaves as the first order phase transition when the on-site electron–electron interaction U is increased continuously. There is no region of U where the BOW and the SDW coexist as a uniform phase.

The phonon dispersion relations in the two-dimensional Peierls phase (Peierls insulator) are studied numerically, focusing on a two-dimensional SSH (Su–Shrieffer–Heeger) model having a half-filled ...

The discovery and structure–activity relationship of a novel series of coumarin-based TNF-α inhibitors is described. Starting from the initial lead 1a , various derivatives were prepared surrounding the coumarin core structure to optimize the in vitro inhibitory activity of TNF-α production by human peripheral blood mononuclear cells (hPBMC), stimulated by bacterial lipopolysaccharide (LPS). Selected compounds also demonstrated in vivo inhibition of TNF-α production in rats.

Peierls transition in a square lattice electron-lattice system described by a two-dimensional version of Su, Schrieffer and Heeger's model with a half-filled electronic band is numerically analyzed. The Peierls phase accompanied by multimode distortions, where lattice distortions not only with the nesting vector Q = (π,π) but also with those wave vectors parallel to Q are coexisting, is found to be the lowest Free energy state even at finite temperatures. In contrast to the Peierls phase involving only the distortion with the nesting vector, there is no gapless region along the Fermi line.

Phonon dispersion relations in a two-dimensional electron–lattice system described by a two-dimensional square-lattice version of Su–Shrieffer–Heeger's model and having a half-filled electronic band are numerically studied at non-zero temperatures. When lowering temperature from a region higher than the critical temperature of the Peierls transition, multi-mode phonon softening is confirmed; the softening modes have wave vectors parallel to the nesting vector Q =(π,π) including Q itself. Some preliminary results in the temperature region lower than the critical temperature are also reported.