On-Surface Fabrication toward Polar 2D Macromolecular Crystals.

Polar 2D macromolecular structures have attracted significant attention because of their ferroelectricity and ferro-magnetism. However, it is challenging to synthesize them experimentally because dipoles or spins of these macromolecules tend to cancel each other. So far, there has been no successful strategy for assembling macromolecules in a unidirectional manner, achieving stereoregular polymerization on metal surfaces, and creating polar 2D polymer crystals. Recent progress in molecular assembly, on-surface polymer synthesis, and direct control of molecules using electric field applications provides an opportunity to develop such strategies. In this regard, we first review past studies on chiral and achiral molecular assembly, on-surface polymer synthesis, and orientation control of polar molecules. Then, we discuss our newly developed approach called "vectorial on-surface synthesis", which is based on "dynamic chirality" of compass precursors, stereoselective polymerization, and favorable interchain interactions originating from CH-π interactions. Finally, we conclude with a prospective outlook.

Deceptive orbital confinement at edges and pores of carbon-based 1D and 2D nanoarchitectures.

The electronic structure defines the properties of graphene-based nanomaterials. Scanning tunneling microscopy/spectroscopy (STM/STS) experiments on graphene nanoribbons (GNRs), nanographenes, and nanoporous graphene (NPG) often determine an apparent electronic orbital confinement into the edges and nanopores, leading to dubious interpretations such as image potential states or super-atom molecular orbitals. We show that these measurements are subject to a wave function decay into the vacuum that masks the undisturbed electronic orbital shape. We use Au(111)-supported semiconducting gulf-type GNRs and NPGs as model systems fostering frontier orbitals that appear confined along the edges and nanopores in STS measurements. DFT calculations confirm that these states originate from valence and conduction bands. The deceptive electronic orbital confinement observed is caused by a loss of Fourier components, corresponding to states of high momentum. This effect can be generalized to other 1D and 2D carbon-based nanoarchitectures and is important for their use in catalysis and sensing applications.

Manifold dynamic non-covalent interactions for steering molecular assembly and cyclization.

Deciphering rich non-covalent interactions that govern many chemical and biological processes is crucial for the design of drugs and controlling molecular assemblies and their chemical transformations. However, real-space characterization of these weak interactions in complex molecular architectures at the single bond level has been a longstanding challenge. Here, we employed bond-resolved scanning probe microscopy combined with an exhaustive structural search algorithm and quantum chemistry calculations to elucidate multiple non-covalent interactions that control the cohesive molecular clustering of well-designed precursor molecules and their chemical reactions. The presence of two flexible bromo-triphenyl moieties in the precursor leads to the assembly of distinct non-planar dimer and trimer clusters by manifold non-covalent interactions, including hydrogen bonding, halogen bonding, C-H⋯π and lone pair⋯π interactions. The dynamic nature of weak interactions allows for transforming dimers into energetically more favourable trimers as molecular density increases. The formation of trimers also facilitates thermally-triggered intermolecular Ullmann coupling reactions, while the disassembly of dimers favours intramolecular cyclization, as evidenced by bond-resolved imaging of metalorganic intermediates and final products. The richness of manifold non-covalent interactions offers unprecedented opportunities for controlling the assembly of complex molecular architectures and steering on-surface synthesis of quantum nanostructures.

Achievements and challenges of the Sakigake designation system in Japan.

The Sakigake designation system (Sakigake) has been launched to encourage the pioneered development of innovative new medical products for the effective treatment of severe illness in Japan, which allows leveraging the several advantages in prioritized consultation, rapid review, premium drug pricing and extended data-protection period. We retrospectively analysed the Sakigake products including drugs and regenerative medical products to clarify the achievements and the future issues in this system. From April 2015 to August 2020 (the first 5-year trial period of Sakigake), 37 products were designated, and 10 of those were approved in Japan in which 7 new active substances achieved the first-in-world approvals. Oncology, neurology and cardiovascular disease were the major therapeutic areas, and those 3 accounted for 75.7% of all products. Sakigake achieved some first-in-world approvals by the Pharmaceuticals and Medical Devices Agency/the Ministry of Health, Labor and Welfare of innovative new medical products, although in some therapeutic areas, there remains room in stimulating drug development.

Rationales of delay and difference in regulatory review by Japan, the USA and Europe among new drugs first approved in Japan.

AIMS: To clarify the rationales of delay or difference in the review of new drug applications among regulatory authorities for new drugs, those first approved in the world being in Japan. METHODS: Among 80 new drugs first approved in Japan from 2008 to 2019, we identified those subsequently approved in the USA or Europe. Significant delays in approval time (boxplot outliers) and the rationales for the delays were assessed among the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). RESULTS: Of the 80 Japan-first approvals, 25 and 24 were approved in the USA and Europe, respectively, and their median approval times in Japan, the USA and Europe were 285, 334 and 477 days, respectively. Significant delays were identified for pirfenidone (1806 days, FDA), alogliptin benzoate (1856 days, FDA), insulin degludec (1457 days, FDA) and romosozumab (750 days, PMDA; 994 days, FDA; 748 days, EMA). Due to concerns about cardiovascular risk, alogliptin benzoate and insulin degludec were requested for additional clinical trials by the FDA, and romosozumab required a much longer review period than the standard approval time in all three regions. CONCLUSIONS: Among the new drugs significantly delayed in approval time in Japan, the USA or Europe, there were some differences in the requirements, the participating regions and the assessment of clinical trials. The regulatory views on the cardiovascular risk also differed among the three regions. These divergences may be associated with the differences in approval histories.

Efficacy of combined bland embolization and chemoembolization for huge (≥10 cm) hepatocellular carcinoma.

INTRODUCTION: To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Twenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed. RESULTS: The tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively. CONCLUSION: Combined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.

Evolving Landscape of New Drug Approval in Japan and Lags from International Birth Dates: Retrospective Regulatory Analysis.

The Pharmaceuticals and Medical Devices Agency (PMDA) has approved hundreds of new drugs in recent years. We retrospectively analyzed the new drugs approved in Japan from 2008 to 2019, and identify the first-in-world approvals and clarify the current drug lag. The new drug and the drug lag were defined as a drug with a new active substance and a difference between the approval date in Japan and the international birth date, respectively. Among 400 new drugs approved in Japan during the last 12 years, 80 (20.0%) were first approved in Japan, and 320 were outside Japan (the United States: 202, 50.5%; Europe: 82, 20.5%; other regions: 36, 9.0%). Of these, 45 new drugs have not yet been approved outside Japan, and the remaining 355 have been globally approved in Japan and overseas. The number of new drug approvals were the largest in oncology followed by metabolic/endocrine and infectious diseases. The median drug lags (year) among all 400 new drugs and 355 new drugs with global approvals were 4.3 and 4.7 in the first tertile (2008-2011), 1.5 and 2.6 in the second tertile (2012-2015), and reduced to 1.3 and 2.2 in the third tertile (2016-2019), respectively. Substantial drug lag remains in neurology, psychiatry, and therapeutic areas where the number of new drug approvals was relatively small. Collectively, one-fifth of the new drugs approved in Japan are first-in-world approvals. Drug lag has been greatly decreased, although it still exists.

Manipulable Metal Catalyst for Nanographene Synthesis.

Performing bottom-up synthesis by using molecules adsorbed on a surface is an effective method to yield functional polycyclic aromatic hydrocarbons (PAHs) and nanocarbon materials. The intramolecular cyclodehydrogenation of hydrocarbons is a critical process in this synthesis; however, thus far, its elementary steps have not been elucidated thoroughly. In this study, we utilize the metal tip of a low-temperature noncontact atomic force microscope as a manipulable metal surface to locally activate dehydrogenation for PAH-forming cyclodehydrogenation. This method leads to the dissociation of a H atom of an intermediate to yield the cyclodehydrogenated product in a target-selective and reproducible manner. We demonstrate the metal-tip-catalyzed dehydrogenation for both benzenoid and nonbenzonoid PAHs, suggesting its universal applicability as a catalyst for nanographene synthesis.

Transarterial- chemoembolization remains an effective therapy for intermediate-stage hepatocellular carcinoma with preserved liver function.

AIM: To evaluate outcomes as well as prognostic factors of transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma (HCC) with preserved liver function to determine positioning of TACE. METHODS: Of 158 treatment-naïve patients with intermediate-stage HCC who received initial TACE from February 2007 to January 2016, 113 patients met the following inclusion criteria: no combined therapy within 4 weeks after initial TACE, and Child-Pugh score under 7. Response rate and overall survival were evaluated. The prognostic factors were investigated in univariate and multivariate analyses using Cox proportional hazards models. The deterioration of liver function after repeated TACE was also evaluated. RESULTS: The response rate was 92.7% (complete response, 63.3%; partial response, 29.4%). The median survival time was 45.2 months. Survival rates at 1, 2, and 3 years were 90.4%, 77.0%, and 60.8% respectively. Age ≥ 75 years (P = 0.022), serum α-fetoprotein level ≥ 200 ng/mL (P = .010), tumor number ≥ 11 (P = 0.008), and heterogeneous enhancement on dynamic computed tomography (P = 0.024) were poor prognostic factors. The deterioration rate of Child-Pugh score and albumin-bilirubin grade was 18.5% and 12.3%, respectively, after the first TACE, 15.6% and 5.1%, respectively, after the second TACE, and 14.5% and 11.1%, respectively, after the third TACE. CONCLUSION: Superselective TACE can achieve high tumor response rates with prolonged overall survival for patients with intermediate-stage HCC with preserved liver function. Age, serum α-fetoprotein level, tumor number ≥ 11, and heterogeneous enhancement on dynamic computed tomography indicated significantly poor prognosis.

Role of Magnesium and the Effect of Surface Roughness on the Hydroxyapatite-Forming Ability of Zirconia Induced by Biomimetic Aqueous Solution Treatment.

Zirconia is a well-known bioceramic for dental and orthopedic applications due to its mechanical and aesthetic properties. However, it lacks sufficient bioactivity to bond with the living bone. This study was aimed to induce bioactivity to tetragonal zirconia polycrystal (3Y-TZP) by simple biomimetic aqueous solution treatment. First, hydrofluoric acid (HF) etching was performed to enhance the surface roughness of the 3Y-TZP surface. Then, the samples were treated with two types of aqueous solutions containing calcium and phosphate ions (Ca-P solutions); one solution additionally contained magnesium (Mg) ions and the other without Mg ions. Finally, hydroxyapatite (HAp)-forming ability was evaluated by the conventional simulated body fluid (SBF) test, and the effect of Mg ions on the adhesive strength of the HAp layer to the roughened 3Y-TZP surface was also investigated. The results concluded that there were no noticeable differences in the effect of Mg ions on the HAp-forming ability, and both types of solution treatments resulted in dense HAp formation in 1 day SBF immersion. However, incorporation of Mg ions in one of the Ca-P solutions significantly improved the adhesive strength of the HAp layer to the HF-etched 3Y-TZP substrate compared to the Ca-P solution with no Mg ions.

Bottom-Up On-Surface Synthesis of Two-Dimensional Graphene Nanoribbon Networks and Their Thermoelectric Properties.

Graphene, the one-atom-thick two-dimensional (2D) carbon material, has attracted tremendous interest in both academia and industry due to its outstanding electrical, mechanical, and thermal properties. For electronic applications, the challenging task is to make it as a semiconductor. The bottom-up synthesis of semiconducting one-dimensional (1D) nanometer-wide graphene strips, namely, graphene nanoribbons (GNRs), has attracted much attention owing to its promising electronic, optical, and magnetic properties. In this regard, we report the fabrication of cove-type 2D GNR networks (GNNs) via the interconnection of 1D self-assembled GNRs on the surface of Au(111). The cove-type 2D GNRs networks (GNNs) were fabricated from the GNR, 5-CGNR-1-1, synthesized using the precursor of DBSP. Annealing of high-density self-assembled GNRs on the surface of Au(111) through two-zone chemical vapour deposition (2Z CVD) successfully generated a 2D interconnected structure with high yield via the fusion and ladder coupling reactions of GNR chains. In order to validate the later fusion reaction, we have also synthesized the GNR, 7-AGNR-1-1, using the precursor of DBBA. The GNNs, which consist of hybridized metallic-like and semiconducting GNRs, are a new class of carbon-based materials. Further, we applied this material for thermoelectric (TE) applications and found a very low cross-plane thermal conductivity of 0.11 Wm-1 K-1 , which is one of the lowest value among the carbon-based materials as well as inorganic semiconductors, while maintaining the cross-plane electrical conductivity of 188 S m-1 .

Development of Repeatable Microcatheter Access Port for Intra-arterial Therapy of Liver Cancer.

PURPOSE: To develop an implantable port in which a microcatheter can be inserted for a combination therapy of repeated transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) for advanced liver cancer. MATERIALS AND METHODS: The design of a currently used implantable port was modified. A funnel part was constructed in the port. The septum was punctured by a 20-gauge indwelling needle, and 2.0-Fr non-tapered microcatheter was inserted into the port. In the in vitro studies, the advance of a microcatheter out of the funnel part was evaluated via seven different septum puncture sites. A 5-Fr indwelling catheter connected to the port was placed in a vascular model, and a microcatheter catheterization was evaluated. In an in vivo study, the port-catheter system was implanted in the hepatic artery in a pig. A microcatheter was percutaneously inserted through the port into the hepatic arterial branches, and embolization was performed. RESULTS: In the in vitro studies, the microcatheter was smoothly advanced out of the port and catheterizations into the hepatic arteries were successful via all septum puncture sites. In the in vivo study, repeated selective embolization through the port was successfully conducted on 7, 14 and 21 days after the implantation. CONCLUSION: The developed implantable port can be used for repeated catheter insertion into the hepatic artery. The combination of repeated TACE and HAIC could be possible using this device.

(Poly)terephthalates with Efficient Blue Emission in the Solid State.

We prepared dimethyl and diaryl 2,5-dialkoxytere-phthalates from dimethyl 2,5-dihydroxyterephthalate in good-to-high yields via alkylation or a sequence of alkylation, hydrolysis, chlorination, and condensation. The absorption spectra of the dialkoxyterephthalates contain a small band at 332-355 nm, which could be assigned to intramolecular charge-transfer transition from the alkoxy to alkoxycarbonyl groups on the basis of theoretical calculations using density functional theory. The dialkoxyterephthalates exhibited blue fluorescence with moderate-to-excellent quantum yields not only in solution but also in the solid state, such as a poly(methyl methacrylate) (PMMA) film and a powder. The solid-state quantum yields of the diisopropoxy-substituted terephthalates were similar or considerably higher than those of the dimethoxy-substituted counterparts. Copolymerization of 2,5-diisopropoxyterephthaloyl chloride and 1,4-butanediol with or without terephthaloyl chloride gave brilliantly blue fluorescent polymers, whose quantum yields were 0.72 and 0.71 in toluene and 0.46 and 0.40 in the neat film, respectively. Furthermore, white emission was achieved when a fluorescent yellow 2,5-diaminoterephthalate was doped into the thin film of the blue fluorescent polymer at 0.4 wt %.

Electrostatic Repulsion-Induced Desorption of Dendritic Viologen-Arranged Molecules Anchored on a Gold Surface through a Gold-Thiolate Bond Leading to a Tunable Molecular Template.

We investigated the adsorption and desorption behavior of self-assembled monolayers (SAMs) on gold derived from dendritic viologen-arranged molecules with an ω-mercaptodecyl group (A n, n (dendritic generation) = 0-3) at the apex of the dendritic structure in polar solvents. The adsorption of the dendritic molecules occurred quickly and saturated within a few minutes in an acetonitrile/ethanol (1/1, v/v) mixture at a concentration of 2 mM. Atomic force microscopy images of the SAMs showed flat surfaces regardless of the dendritic generation because the peripheral viologen units were closely packed at the surface of the molecular layer. Individual A3 molecules immobilized on the substrate were observed by scanning tunneling microscopy measurements of a mixed SAM with decanethiol. The desorption behaviors of dendritic molecules from the A n-SAMs in several solvents such as water were also investigated. The spontaneous desorption of the A n-SAM occurred more rapidly than that of a conventional n-alkanethiol SAM. However, the desorption was inhibited by adding electrolytes such as NaNO3 due to the shielding effect on the electrostatic repulsion between the dendritic molecules. These results indicate that the surface density of the dendritic molecules can be controlled through the desorption.

Orientation and Electronic Structures of Multilayered Graphene Nanoribbons Produced by Two-Zone Chemical Vapor Deposition.

The orientation and electronic structure of multilayered graphene nanoribbons with an armchair-edge (AGNRs) were determined by low-temperature scanning tunneling microscopy in this study. The orientation of AGNRs was found to be an edge-on structure when positioned as a top layer, while previous reports showed a face-on structure for monolayered AGNRs on Au(111). According to density functional theory calculations, AGNRs in a top layer preferentially form as edge-on structures rather than face-on structures due to the balance of CH-π and π-π interactions between AGNRs. Scanning tunneling spectroscopy and density functional theory calculations revealed that the electronic structures of multilayered AGNRs are similar to those in a gas-phase due to the lack of interaction between AGNRs and the Au(111) substrate. The observation of AGNRs in mutilayers might suggest the conformation-assisted mechanism of dehydrogenation when there is no contact with the Au(111) substrate.

Strain-induced skeletal rearrangement of a polycyclic aromatic hydrocarbon on a copper surface.

Controlling the structural deformation of organic molecules can drive unique reactions that cannot be induced only by thermal, optical or electrochemical procedures. However, in conventional organic synthesis, including mechanochemical procedures, it is difficult to control skeletal rearrangement in polycyclic aromatic hydrocarbons (PAHs). Here, we demonstrate a reaction scheme for the skeletal rearrangement of PAHs on a metal surface using high-resolution noncontact atomic force microscopy. By a combination of organic synthesis and on-surface cyclodehydrogenation, we produce a well-designed PAH-diazuleno[1,2,3-cd:1',2',3'-fg]pyrene-adsorbed flatly onto Cu(001), in which two azuleno moieties are highly strained by their mutual proximity. This local strain drives the rearrangement of one of the azuleno moieties into a fulvaleno moiety, which has never been reported so far. Our proposed thermally driven, strain-induced synthesis on surfaces will pave the way for the production of a new class of nanocarbon materials that conventional synthetic techniques cannot attain.

Wide graphene nanoribbons produced by interchain fusion of poly(p-phenylene) via two-zone chemical vapor deposition.

Wide graphene nanoribbons (GNRs) were fabricated via two-zone chemical vapor deposition using 4,4''-dibromo-p-terphenyl as the precursor. Densely packed arrays of poly(p-phenylene) produced on Au(111) using this method could be converted into wide GNRs via interchain fusion by thermal annealing. The field-effect transistor prepared from these GNRs exhibited an excellent on/off current ratio of 1.6 ± 0.6 × 103.

Clinical features and treatment outcomes of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV): A retrospective analysis of 235 patients from a nationwide survey in Japan.

OBJECTIVE: We aimed to analyze clinical features and treatment outcomes of otitis media caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), i.e. otitis media with AAV (OMAAV). METHODS: This survey was performed between December 2013 and February 2014. The study began with a preliminary survey to 123 otolaryngology institutions in Japan to inquire about their experiences with OMAAV patients during the past 10 years, and was followed by a questionnaire survey to investigate clinical and laboratory findings. OMAAV was defined using the criteria described in the text. RESULTS: Two hundred and thirty-five patients classified as OMAAV were enrolled in this study. They were characterized as follows: (1) disease onset with initial signs/symptoms due to intractable otitis media with effusion or granulation, which did not respond to ordinary treatments such as antibiotics and insertion of tympanic ventilation tubes, followed by progressive hearing loss; (2) predominantly female (73%) and older (median age: 68 years); (3) predominantly myeloperoxidase (MPO)-ANCA-positive (60%), followed by proteinase 3 (PR3)-ANCA-positive (19%) and both ANCAs-negative (16%); (4) frequently observed accompanying facial palsy (36%) and hypertrophic pachymeningitis (28%); and (5) disease often involving lung (35%) and kidney (26%) lesions. Four factors associated with OMAAV were found to be related to an unfavorable clinical course threatening the patient's hearing and/or lives, namely facial palsy, hypertrophic pachymeningitis, both ANCAs-negative phenotype, and disease relapse. The occurrence of hypertrophic pachymeningitis was associated with facial palsy (p < 0.05), both ANCAs-negative phenotype (p < 0.001), and headache (p < 0.001). The administration of corticosteroid together with an immunosuppressant was an independent predicting factor for lack of disease relapse (odds ratio [OR] = 1.90, p = 0.03) and an improvement in hearing loss (OR =2.58, p = 0.0002). CONCLUSION: Since OMAAV has novel clinical features, the disease may be categorized as a subentity for the classification of AAV.

Homochiral polymerization-driven selective growth of graphene nanoribbons.

The surface-assisted bottom-up fabrication of graphene nanoribbons (GNRs), which consists of the radical polymerization of precursors followed by dehydrogenation, has attracted attention because of the method's ability to control the edges and widths of the resulting ribbon. Although these reactions on a metal surface are believed to be catalytic, the mechanism has remained unknown. Here, we demonstrate 'conformation-controlled surface catalysis': the two-zone chemical vapour deposition of a 'Z-bar-linkage' precursor, which represents two terphenyl units linked in a 'Z' shape, results in the efficient formation of acene-type GNRs with a width of 1.45 nm through optimized cascade reactions. These precursors exhibit flexibility that allows them to adopt chiral conformations with height asymmetry on a Au(111) surface, which enables the production of self-assembled homochiral polymers in a chain with a planar conformation, followed by dehydrogenation via a conformation-controlled mechanism. This is conceptually analogous to enzymatic catalysis and will be useful for the fabrication of new nanocarbon materials.

Pharmacokinetics and Histopathological Findings of Chemoembolization Using Cisplatin Powder Mixed with Degradable Starch Microspheres in a Rabbit Liver Tumor Model.

PURPOSE: The purpose of this study is to evaluate the pharmacokinetics and histopathological findings of transarterial chemoembolization (TACE) using cisplatin powder mixed with degradable starch microspheres (DSM) (Cis/DSM-TACE) compared with cisplatin arterial infusion (Cis-AI). MATERIALS AND METHODS: Eighteen rabbits with VX2 liver tumors were divided into two groups: Cis/DSM-TACE (n = 9) and Cis-AI (n = 9) groups. In the Cis/DSM-TACE group, a mixture of cisplatin powder and DSM was injected until stasis of hepatic arterial flow was achieved. In the Cis-AI group, cisplatin solution was infused. RESULTS: The platinum concentrations in VX2 tumors in the Cis/DSM-TACE group at 24 and 72 h were significantly elevated compared with those in the Cis-AI group (P = .016 and .019, respectively). There were no significant differences in the platinum concentrations in plasma. Histopathological examination revealed the presence of several microspheres inside the tumors at 1 h, which completely disappeared at 24 h. Tumor cell apoptosis at 1 h in the Cis/DSM-TACE group was more frequently observed compared with that in the Cis-AI group (P = .006). CONCLUSIONS: TACE using cisplatin powder mixed with DSM provides a higher drug concentration in tumors, thereby achieving stronger antitumor effects compared with arterial infusion of cisplatin solution.