Crystal Growth and Structural Analysis of Layered Lithium Titanium Sulfide.

Layered sulfide crystals are suitable hosts for lithium and sodium ions in batteries. In this study, new layered lithium titanium sulfide (LTS) crystals were grown in a sealed silica tube using a LiS self-flux at 800-950 °C. X-ray diffraction (XRD) analysis results indicated the formation of a new sulfide phase with higher symmetry in the Li-Ti-S system.

Efficacy and safety of avalglucosidase alfa in Japanese patients with late-onset and infantile-onset Pompe diseases: A case series from clinical trials.

Background: The efficacy and safety of avalglucosidase alfa for Pompe disease (PD) have been demonstrated in a global Phase 3 trial (COMET) in patients with late-onset PD (LOPD) and a global Phase 2 trial (Mini-COMET) in patients with infantile-onset PD (IOPD). This case series examines the individual results of three Japanese patients enrolled in these trials.

Methods: Case reports were assembled from data collected in the COMET and Mini-COMET trials.

Acceleration of Protein Degradation by 20S Proteasome-Binding Peptides Generated by In Vitro Artificial Evolution.

Although the 20S core particle (CP) of the proteasome is an important component of the 26S holoenzyme, the stand-alone 20S CP acts directly on intrinsically disordered and oxidized/damaged proteins to degrade them in a ubiquitin-independent manner. It has been postulated that some structural features of substrate proteins are recognized by the 20S CP to promote substrate uptake, but the mechanism of substrate recognition has not been fully elucidated. In this study, we screened peptides that bind to the 20S CP from a random eight-residue pool of amino acid sequences using complementary DNA display an in vitro molecular evolution technique.

T-cell receptor repertoire analysis of CD4-positive T cells from blood and an affected organ in an autoimmune mouse model.

One hallmark of some autoimmune diseases is the variability of symptoms among individuals. Organs affected by the disease differ between patients, posing a challenge in diagnosing the affected organs. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and the development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear.

Palladium-Catalyzed Synthesis of 3,6-Diaryl-1-silylfulvenes: A Promising Entry for Preparing 1,3,6-Triarylfulvenes Bearing Three Different Aryl Groups.

We developed a synthetic methodology for preparing ()-1,3,6-triarylfulvenes bearing three different aryl groups. The reaction of 1,4-diaryl-1-bromo-1,3-butadienes with silylacetylenes in the presence of a palladium catalyst produced ()-3,6-diaryl-1-silyl-fulvenes in good to excellent yields. The (isopropoxy)silylated fulvenes thus obtained were converted to ()-1,3,6-triarylfulvenes bearing different types of aryl substituents.

Safety and efficacy of avalglucosidase alfa in individuals with infantile-onset Pompe disease enrolled in the phase 2, open-label Mini-COMET study: The 6-month primary analysis report.

Purpose: Mini-COMET (NCT03019406; Sanofi) is a phase 2, open-label, ascending-dose, 3-cohort study, evaluating avalglucosidase alfa safety, pharmacokinetics, and efficacy in individuals with infantile-onset Pompe disease aged <18 years who previously received alglucosidase alfa and showed clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3).

Methods: During a 25-week primary analysis period, cohorts 1 and 2 received avalglucosidase alfa 20 and 40 mg/kg every other week, respectively, for 6 months, whereas cohort 3 individuals were randomized (1:1) to receive avalglucosidase alfa 40 mg/kg every other week or alglucosidase alfa (current stable dose) for 6 months.

Results: In total, 22 individuals were enrolled (cohort 1 [n = 6], cohort 2 [n = 5], cohort 3-avalglucosidase alfa [n = 5], and cohort 3-alglucosidase alfa [n = 6]).

Development of Gilteritinib-Based Chimeric Small Molecules that Potently Induce Degradation of FLT3-ITD Protein.

Internal tandem duplication (ITD) in the gene encoding FMS-like tyrosine kinase 3 () (FLT3-ITD) is the most frequently observed mutation in acute myeloid leukemia (AML). Currently approved FLT3 kinase inhibitors have high efficacy, but drug resistance caused by reactivation of FLT3 kinase activity is often clinically observed. In this study, we developed novel FLT3 degraders by introducing gilteritinib, an FDA-approved FLT3 inhibitor, into targeted protein degradation technology.

Development of a potent small-molecule degrader against oncogenic BRAF protein that evades paradoxical MAPK activation.

BRAF mutations are frequently observed in melanoma and hairy-cell leukemia. Currently approved rapidly accelerated fibrosarcoma (RAF) kinase inhibitors targeting oncogenic BRAF V600 mutations have shown remarkable efficacy in the clinic, but their therapeutic benefits are occasionally hampered by acquired resistance due to RAF dimerization-dependent reactivation of the downstream MAPK pathway, which is known as paradoxical activation. There is also a concern that paradoxical activation of the MAPK pathway may trigger secondary cancer progression.

Ring-Opening Fluorination of Isoxazoles.

A ring-opening fluorination of isoxazoles has been developed. Upon treatment of isoxazoles with an electrophilic fluorinating agent (Selectfluor), fluorination followed by deprotonation leads to tertiary fluorinated carbonyl compounds. This method features mild reaction conditions, good functional group tolerance, and a simple experimental procedure.

Efficacy of catheter ablation for patients with atrial fibrillation and atrial septal defect.

Introduction: Given that few studies investigated the efficacy of catheter ablation (CA) in patients with paroxysmal atrial fibrillation (AF) and atrial septal defect (ASD), this study evaluated its effectiveness in patients with paroxysmal AF and ASD.

Methods And Results: Of the 216 patients who underwent ASD device closure at two hospitals, 36 patients had paroxysmal AF. After April 2012, CA for AF was performed before ASD device closure (ASD-CA group; n = 20).

Pregnancy and Delivery in Patients With Repaired Congenital Heart Disease - A Retrospective Japanese Multicenter Study.

Background: Although advances in cardiac surgery have led to an increased number of survivors with congenital heart disease (CHD), epidemiological data regarding the pregnancies and deliveries of patients with repaired CHD are scarce.

Methods and results: In this study, we retrospectively reviewed the clinical outcomes of pregnancies and deliveries of women with repaired CHD. Overall, 131 women with repaired CHD were enrolled and there were 269 gestations.

Discovery of a novel 9-position modified second-generation anti-HCV candidate via bioconversion and semi-synthesis of FR901459.

Evidence that hepatitis C virus (HCV) utilizes cellular cyclophilin proteins in the virus replication cycle has increased attention on cyclophilin inhibitors as attractive therapeutic targets in the treatment of HCV. Previous reports have described a number of non-immunosuppressive cyclophilin inhibitors, most of which require many synthetic steps for their preparation. Sasamura et al.

Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity.

We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead . X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD cofactor.

Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer. An isozyme-selective MTHFD2 inhibitor is highly attractive for potential use in cancer treatment. Herein, we disclose a novel isozyme-selective MTHFD2 inhibitor DS44960156, with a tricyclic coumarin scaffold, which was initially discovered via high-throughput screening (HTS) and improved using structure-based drug design (SBDD).

Boron delivery for boron neutron capture therapy targeting a cancer-upregulated oligopeptide transporter.

Boron neutron capture therapy (BNCT) is a radiotherapy utilizing the neutron capture and nuclear fission reaction of B taken up into tumor cells. The most commonly used boron agent in BNCT, p-borono-l-phenylalanine (BPA), is accumulated in tumors by amino acid transporters upregulated in tumor cells. Here, by using dipeptides of BPA and tyrosine (BPA-Tyr and Tyr-BPA), we propose a novel strategy of selective boron delivery into tumor cells via oligopeptide transporter PEPT1 upregulated in various cancers.

Novel |V_{us}| Determination Using Inclusive Strange τ Decay and Lattice Hadronic Vacuum Polarization Functions.

We propose and apply a new approach to determining |V_{us}| using dispersion relations with weight functions having poles at Euclidean (spacelike) momentum which relate strange hadronic τ decay distributions to hadronic vacuum polarization (HVP) functions obtained from lattice quantum chromodynamics. We show examples where spectral integral contributions from the region where experimental data have large errors or do not exist are strongly suppressed but accurate determinations of the relevant lattice HVP combinations remain possible. The resulting |V_{us}| agrees well with determinations from K physics and three-family Cabibbo-Kobayashi-Maskawa unitarity.

Retrospective clinical study of 296 patients with mass lesions of the tongue.

To better understand the clinical features of mass lesions of the tongue, we retrospectively evaluated frequency, recurrence rate, and complications in 296 patients who had undergone surgery for such lesions. The diagnoses were fibroma (43.6%), mucous cyst (14.

Rapid detection of Candida albicans in oral exfoliative cytology samples by loop-mediated isothermal amplification.

Loop-mediated isothermal amplification (LAMP) rapidly amplifies DNA under isothermal conditions. The aim of this study was to detect Candida albicans and compare the positivity rate in the LAMP reaction with that of conventional methods for oral exfoliative cytology (EC) samples. Sixty-eight EC samples from 53 patients were subjected to LAMP analysis.

Micropore Formation of [Zn(Oxac) (Taz)]·(HO) via CO Adsorption.

As-synthesized [Zn(Oxac) (Taz)]·(HO), referred to as ZOTW, was prepared from aqueous methanol solutions of Zn(CO)(OH) and two kinds of ligands of 1,2,4-triazole (Taz) and oxalic acid (Oxac) at 453 K for 12 h. The crystal structure was determined by the Rietveld method. As-synthesized ZOTW was pretreated at 383 K and 1 mPa for t h, ZOTW(th).

Rapid and Specific Screening Assay for KRAS Oncogene Mutation by a Novel Gene Amplification Method.

Background: Epidermal growth factor receptor (EGFR) is a target of molecular therapeutics for colorectal cancer. However, mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS) gene at codons 12 and 13 attenuates the therapeutic effect of anti-EGFR therapies. Therefore, the detection of KRAS gene mutation is important for therapeutic decision-making.

Fibroblast VEGF-receptor 1 expression as molecular target in periodontitis.

Aim: Degradation of extracellular matrices is an integral part in periodontitis. For antagonizing this pathophysiological mechanism, we aimed at identifying gene expression profiles in disease progression contributing periodontitis-associated fibroblasts (PAFs) versus normal gingival fibroblasts to determine their molecular repertoire, and exploit it for therapeutic intervention.

Materials And Methods: Applying an exploratory analysis using a small number of microarrays in combination with a three dimensional (3D) in vitro culture model that incorporates some aspects of periodontitis, PAFs were initially characterized by gene-expression analyses, followed by targeted gene down-regulation and pharmacological intervention in vitro.

Bioconversion of FR901459, a novel derivative of cyclosporin A, by Lentzea sp. 7887.

FR901459, a product of the fungus Stachybotrys chartarum No. 19392, is a derivative of cyclosporin A (CsA) and a powerful immunosuppressant that binds cyclophilin. Recently, it was reported that CsA was effective against hepatitis C virus (HCV).

(10)B-NMR determination of (10)B-BPA, (10)B-BPA-fructose complex and total (10)B in blood for BNCT.

First spontaneous, noninvasive determination method of (10)B-BPA, (10)B-BPA-fructose complex, and total (10)B in blood is described. (10)B-NMR measurement with 100,000 FT accumulation enables us to obtain the result within 100min/sample. The detection limits for the simultaneous analysis were 3ppm, 3ppm and 6ppm for (10)B-BPA, (10)B-BPA-fructose complex and total (10)B respectively in this study.