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Background Mutations in p53, identified in 90% of oesophageal squamous cell carcinoma (ESCC), are associated with unfavourable prognosis and chemo-resistance. APR-246 induces apoptosis by restoring transcriptional ability of mutant p53, and may be a promising therapeutic agent to overcome chemo-resistance in ESCC. Methods In ESCC cell lines differing in p53 status, we performed in vitro cell viability and apoptosis assays, evaluated reactive oxygen species (ROS) generation, and assessed signal changes by western blot after APR-246 administration with/without chemo-agent. Antitumour effects and signal changes were evaluated in in vivo experiments using xenograft and patient-derived xenograft (PDX) mouse models. Results APR-246 administration induced significant apoptosis by upregulating p73 and Noxa via ROS induction in ESCC cell lines harbouring p53 missense mutations. Moreover, APR-246 plus chemotherapy exerted combined antitumour effects in ESCC with p53 missense mutations. This effect was also mediated through enhanced ROS activity, leading to massive apoptosis via upregulation of p73 and Noxa. These findings were confirmed by xenograft and PDX models with p53 mutant ESCC. Conclusion APR-246 strongly induced apoptosis by inducing ROS activity and p73-Noxa signalling, specifically in ESCC with p53 missense mutation. This antitumour effect was further enhanced by combination with 5-FU, which we first confirmed in ESCC preclinical model.

To develop an efficient CO2 reduction catalyst, hybridizing a molecular catalyst and a porous coordination polymer (PCP) is a promising strategy because it can combine both advantages of the precise reactivity control of the former and the CO2 adsorption property of the latter. Although several PCP hybrid catalysts have been reported to date, the CO2 sorption behavior and the CO2 reduction reactivity have been investigated separately, and the CO2 enrichment during the catalysis is still unclear. We report CO2 photoreduction under different temperatures and pressures using a PCP-RuII complex hybrid catalyst. The product selectivity (CO or HCOOH) varied depending on the reaction conditions. The altered selectivity could be interpreted in terms of the CO2 capture in the micropores of a PCP.

For the first time, an NAD+-type earth-abundant metal complex [Zn(pbn)2(H2O)](ClO4)2 (1) was found to exhibit photo-induced oxidizing ability to convert various primary and secondary alcohols to the corresponding aldehyde and ketone compounds. In addition, a two-electron-reduced Zn(II) complex [Zn(pbnH-pbnH)(ClO4)2] (1red) comprising the novel C-C coupling ligand, obtained by the photo-induced oxidation of alcohols by 1, was successfully isolated and completely characterized. We clarified that the photochemical oxidation of alcohols by 1 to produce 1red proceeds via an electron transfer followed by proton transfer mechanism as elucidated by kinetic analysis on the basis of absorption spectroscopic measurements.

Stoichiometric carbon dioxide reduction to highly reduced C1 molecules, such as formic acid (2e- ), formaldehyde (4e- ), methanol (6e- ) or even most-reduced methane (8e- ), has been successfully achieved by using organosilanes, organoboranes, and frustrated Lewis Pairs (FLPs) in the presence of suitable catalyst. The development of renewable organohydride compounds could be the best alternative in this regard as they have shown promise for the transfer of hydride directly to CO2 . Reduction of CO2 by two electrons and two protons to afford formic acid by using renewable organohydride molecules has recently been investigated by various groups. However, catalytic CO2 reduction to ≥2e- -reduced products by using renewable organohydride-based molecules has rarely been explored. This Minireview summarizes important findings in this regard, encompassing both stoichiometric and catalytic CO2 reduction.

Background Immune checkpoint inhibitors have recently been widely used for advanced cancers and are known to cause ocular complications. We herein report a case developing bilateral serous retinal detachments, without ocular inflammation, after starting nivolumab treatment. Case presentation A 73-year-old man was referred to our hospital, having become aware of metamorphopsia 2 months after starting nivolumab (anti-programmed cell death protein 1 monoclonal antibody) for malignant melanoma of the nasal cavity. The initial corrected visual acuity of the right eye was 20/20, and that of the left eye was 20/16. There were no inflammatory findings in the anterior segment or the vitreous. Vitelliform lesions were found in the macular area of both ocular fundi, consistent with serous retinal detachment and subretinal deposits. Swept source optical coherence tomography showed diffuse thickening of the outer photoreceptor segment and thickening of the choroid. Two months after the initial diagnosis, multiple vitelliform lesions were noted, and the fundus findings had worsened. Indocyanine green fluorescein angiography showed delayed inflow in the peripapillary and posterior pole regions in the early phase of imaging. Fundus autofluorescence showed hyperautofluorescence consistent with most of the vitelliform lesions on color fundus photography. Conclusions Nivolumab may have impaired the pumping and phagocytosis functions of retinal pigment epithelial cells, resulting in bilateral serous retinal detachments and thickening of the photoreceptor outer segment. This is the first case report, to our knowledge, describing multiple bilateral serous retinal detachments and outer segment thickening without inflammation in a patient treated with nivolumab.

Background Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT. Methods We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines. Results TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines. Conclusion TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.

Individuals with Fanconi anemia (FA), a rare genetic bone marrow failure syndrome, have an increased risk of young‐onset head and neck squamous cell carcinomas (SCCs) and esophageal SCC. The FA DNA repair pathway is activated upon DNA damage induced by acetaldehyde, a chief alcohol metabolite and one of the major carcinogens in humans. However, the molecular basis of acetaldehyde‐induced genomic instability in SCCs of the head and neck and of the esophagus in FA remains elusive. Here, we report the effects of acetaldehyde on replication stress response in esophageal epithelial cells (keratinocytes). Acetaldehyde‐exposed esophageal keratinocytes displayed accumulation of DNA damage foci consisting of 53BP1 and BRCA1. At physiologically relevant concentrations, acetaldehyde activated the ATR‐Chk1 pathway, leading to S‐ and G2/M‐phase delay with accumulation of the FA complementation group D2 protein (FANCD2) at the sites of DNA synthesis, suggesting that acetaldehyde impedes replication fork progression. Consistently, depletion of the replication fork protection protein Timeless led to elevated DNA damage upon acetaldehyde exposure. Furthermore, FANCD2 depletion exacerbated replication abnormalities, elevated DNA damage, and led to apoptotic cell death, indicating that FANCD2 prevents acetaldehyde‐induced genomic instability in esophageal keratinocytes. These observations contribute to our understanding of the mechanisms that drive genomic instability in FA patients and alcohol‐related carcinogenesis, thereby providing a translational implication in the development of more effective therapies for SCCs., Esophageal squamous cell carcinoma (ESCC) is common in patients with Fanconi anemia (FA). Using esophageal keratinocytes, this study revealed that FANCD2, a central player of the FA DNA repair pathway, minimizes DNA replication stress in response to physiological levels of acetaldehyde, the primary metabolite of alcohol. This study suggests that FANCD2 prevents acetaldehyde‐induced genomic instability during replication to prevent ESCC.

Pachychoroid neovasculopathy (PNV) is treated with antivascular endothelial growth factor (VEGF) injection and photodynamic therapy (PDT), but no curative treatment has yet been established. We aimed to clarify the treatment results of a reduced dose of PDT for PNV. The subjects were 27 eyes of 27 patients (male:female = 20:7, mean age 58.9 years). PDT, at 2/3 of the conventional dose (2/3PDT), was administered once. The patients were then observed for one year. Eyes with polypoidal choroidal vasculopathy (PCV) were excluded. We investigated the associations among the central retinal thickness, choroidal thickness, and visual acuity changes before treatment and one, three, six and 12 months after PDT. When serous retinal detachment was increased or unchanged or new hemorrhages were observed, as compared with pretreatment findings, intravitreal injection of an anti-VEGF agent was performed. Visual acuity was significantly improved, as compared to before treatment, at three, six, and 12 months after 2/3PDT. Foveal retinal thickness was significantly decreased after versus before treatment in the 2/3PDT group (p &lt, 0.001). Foveal choroidal thickness was also significantly reduced in the 2/3PDT group (p = 0.001). Additional intravitreal anti-VEGF agent injections were administered to three patients (11%), while 24 (89%) required no additional treatment during the one-year follow-up period. For PNV without polyps, 2/3PDT appears to be effective.

Competitive reactions and formation mechanism of microstructures in Mg/Cu super-laminate composites (SLCs) during initial hydrogenation were studied. During initial hydrogenation of Mg/Cu SLCs, hydrogenation of Mg and alloying of Mg with Cu followed by hydrogenation of Mg2Cu are competitive. It is found that microstructures of Mg/Cu SLCs during initial hydrogenation have changed drastically depending on the order of hydrogenation of Mg and Mg2Cu. The microstructures of Mg/Cu SLCs after initial hydrogenation can be categorized in 3 types.

Central serous chorioretinopathy (CSC) is a disease of unknown etiology, but half-dose photodynamic therapy (hPDT) is well known to be effective for CSC. Infrared reflectance (IR) has been shown to be effective for detecting retinal pigmented epithelial and choroidal lesions, but no reports have focused on chorioretinal changes using IR images after as compared to before hPDT. This study aimed to clarify the features of IR images as well as retinal and choroidal morphological changes before and after treatment with verteporfin hPDT for CSC. We also examined prognostic factors associated with CSC treatment. This was a retrospective study that included 140 eyes of 140 patients (male/female ratio 122:18, mean age 53.4 &plusmn, 10.8 years) diagnosed with CSC who underwent hPDT in our hospital during the period from April 2015 to December 2018. We determined changes in visual acuity, therapeutic efficacy, central retinal thickness (CRT), central choroidal thickness (CCT), and IR images at one and three months after hPDT as compared to before treatment. Dry macula was defined as a complete resolution of serous retinal detachment after hPDT. History of smoking, disease duration, presence of drusen, presence of retinal pigment epithelium abnormalities, type of fluorescein angiographic leakage, and presence of choroidal vascular hyperpermeability were investigated as prognostic factors associated with treatment efficacy. CRT and CCT were measured using optical coherence tomography (Spectralis HRA-2, Heidelberg Engineering), and IR images after versus before treatment were compared using ImageJ software (version 1.52) to calculate the mean luminance for a 3 &times, 3 mm area in the macula. Compared with the values before treatment, CCT, CRT, and visual acuity showed significant improvements at one and three months after treatment, and the mean luminance of IR images was also significantly increased. Furthermore, the luminance on IR images tended to rise, though the values at one month and three months after treatment did not differ significantly. Disease duration was significantly associated with dry macula one month after treatment, and visual acuity and CRT before hPDT were both significantly related to dry macula three months after treatment. IR images tended to improve over time, from before treatment through one and three months after hPDT.

Synthesis of assumed natural (12R,13S)-enantiomers of pyriculariol (1) and dihydropyriculariol (2), phytotoxins isolated from rice blast disease fungus, Pyricularia oryzae, was achieved using Wittig reaction or microwave-assisted Stille coupling reaction as the key step. The synthesis revealed that the natural 1 and 2 are racemates. Foliar application test on a rice leaf indicated that both the salicylaldehyde core and side chain were necessary for phytotoxic activity. The fungus is found to produce optically active phytotoxins when incubated with rotary shaker, but racemic ones when cultured using an aerated jar fermenter.

Perioperative systemic inflammation induced by surgical stress elevates the risk of hematogenous cancer metastasis. This study investigated the anti-metastatic effects and mechanisms of methylprednisolone (MP) administration for surgical stress. We examined the effects of MP on the expression of adhesion molecules in human vascular endothelial cells and in a murine hepatic metastasis model under lipopolysaccharide (LPS) administration, which mimics systemic inflammation induced by surgical stress. Serum E-selectin level was measured in blood samples obtained from 32 gastric cancer patients who were randomly assigned to treat preoperatively with or without MP. The expression of E-selectin in LPS-induced vascular endothelial cells was suppressed by MP. An adhesion assay showed the number of LPS-induced adherent tumour cells was significantly lower following MP. In the in vivo study, LPS significantly elevated the number of hepatic metastases, but pretreatment with MP before LPS significantly inhibited this elevation. The LPS-induced expression of E-selectin in the vascular endothelium of the portal vein was suppressed by MP. In human clinical samples, serum E-selectin level was significantly decreased by preoperative MP. Suppression of surgically induced systemic inflammation by MP administration might prevent hematogenous cancer metastases by suppressing the induction of E-selectin expression in the vascular endothelium.

Background The intestinal epithelial barrier allows absorption of dietary nutrients and prevents passage of pathogens and toxins into the body. Severe insults have a negative impact on the intestinal environment, which may decrease intestinal barrier function and cause bacterial translocation. Bacterial translocation, which can cause infectious complications, is defined as the passage of microbes from the gastrointestinal tract across the mucosal barrier to extraintestinal sites. The aim of this study was to investigate the correlation between concentrations of preoperative fecal organic acids and the occurrence of postoperative infectious complications in patients with esophageal cancer. Methods Fifty-five patients with esophageal cancer who underwent esophagectomy were enrolled in this study. Perioperative synbiotics were administered to all patients. Perioperative clinical characteristics and concentrations of preoperative fecal organic acids were compared between patients with and without postoperative infectious complications. Results Postoperative infectious complications occurred in 10 patients. In patients with complications, the concentrations of acetic acid and propionic acid were significantly lower than in patients without complications (p = 0.044 and 0.032, respectively). The concentration of butyric acid was nonsignificantly lower in patients with complications, while the concentration of lactic acid was nonsignificantly higher. The calculated gap between the concentrations of fecal acetic acid plus propionic acid plus butyric acid minus lactic acid was significantly lower in patients with complications. Multivariate analysis revealed that a low gap between acetic acid plus propionic acid plus butyric acid minus lactic acid was an independent risk factor for postoperative infectious complications (p = 0.027). Conclusions Preoperative fecal concentrations of organic acids had a clinically important impact on the occurrence of postoperative infectious complications in patients with esophageal cancer. To reduce postoperative infectious complications, it may be useful to modulate the intestinal environment and maintain concentrations of fecal organic acids before surgery.

A RhCp* (Cp* = pentamethylcyclopentadienyl) complex bearing an NAD+/NADH-functionalized ligand, [RhCp*(pbn)Cl]Cl ([1]Cl, pbn = (2-(2-pyridyl)benzo[b]-1,5-naphthyridine)), was synthesized. The cyclic voltammogram of [1]Cl in CH3CN shows two reversible redox waves at E1/2 = −0.58 and −1.53 V (vs. the saturated calomel electrode (SCE)), which correspond to the RhIII/RhI and pbn/pbn˙− redox couples, respectively. The addition of acetic acid to the solution afforded the proton-coupled two-electron reduction of [1]Cl at −0.62 V, from which [RhCp*(pbnHH)Cl]+ was selectively generated, probably via a hydride transfer from a RhIII–hydride intermediate to the pbn ligand. Complex [1]Cl is stable under acidic conditions, whereas a methyl proton of the Cp* moiety dissociates under basic conditions. The resulting anionic methylene group attacks the para carbon of the free pyridine of pbn, accompanied by protonation of the nitrogen atom of the ligand. As a result, treatment of [1]Cl with a base produces selectively the cyclic complex [1CH]Cl, which bears a reduced pbn framework (pbnCH). [1CH]Cl forms 1 : 1 adducts with PhCOO−via hydrogen bonding. A similar adduct, formed by a Ru–pbnHH scaffold and RCOO− (R = CH3, C6H5), has been reported to react with CO2 to produce HCOO− under concomitant regeneration of Ru–pbn. The adduct of [1CH]Cl with PhCOO−, however, lacks such hydride-donor ability, due to a steric barrier in the molecular structure of [1CH]Cl, which hampers the hydride transfer.

Hybrid nanoparticles are emergent nanomaterials that combine particles with different characteristic properties to enhance their original functions or modulate their original physical or chemical properties for application in catalysis, sensing, and imaging. Fluorescent nanodiamonds (fNDs) have recently become more attractive for bioimaging because of their characteristic physicochemical properties and biocompatibility. Their wide applicability in bioimaging has been utilized in the single-particle tracking of biomolecules, local environmental sensors in cells, and stem cell tracking in tissues. However, the use of fNDs as multiscale spatial mapping probes for multiple biomolecules and cells in optical and electron microscopy techniques has been limited because of their broad fluorescence spectrum and composition of mainly light elements (C, O, H, N, etc.). On the other hand, metal nanoparticles (metal NPs) with unique photonic properties have been employed as functional labeling probes in bioimaging. The...

Background: Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood. Methods: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how EtOH exposure influences intratumoral SCC cell populations including putative cancer stem cells defined by high CD44 expression (CD44H cells). Results: Using 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we found that EtOH is metabolized via alcohol dehydrogenases to induce oxidative stress associated with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis of the majority of SCC cells within organoids. However, CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH. Importantly, inhibition of autophagy increased EtOH-mediated apoptosis and reduced CD44H cell enrichment, xenograft tumor growth, and organoid formation rate. Conclusions: This study provides mechanistic insights into how EtOH may influence SCC cells and establishes autophagy as a potential therapeutic target for the treatment of EtOH-associated SCC.

The catalytic performance of Ru-NAD-type complexes [Ru(tpy)(pbn)(CO)]2+ ([1]2+; tpy = 2,2′;6′,2″-terpyridine; pbn = 2-(pyridin-2-yl)benzo[b][1,5]naphthyridine) and the Ru-CO-bridged metallacycle [2]+ was investigated in the context of the electrochemical reduction of CO2 in H2O/CH3CN at room temperature. A controlled-potential electrolysis of [1]2+ and [2]+ afforded formate (HCOO–) as the main product, under concomitant formation of minor amounts of CO and H2. Metallacycle [2]+ showed a higher selectivity toward the formation of HCOO– than [1]2+ (HCOO–/CO for [1]2+, 2.7; HCOO–/CO for [2]+, 7). The generation of HCOO– via a catalytic hydride transfer from the NADH-type ligands of [1]2+ and [2]+ to CO2 was supported by the experimental results and a comparison with the reduction of CO2 catalyzed by [Ru(tpy)(bpy)(CO)]2+ under similar conditions. A mechanism for the catalytic reduction of CO2 by [1]2+ and [2]+ was proposed based on the experimental evidence. The thus-obtained results may help to expand the fi...

The constructions of various photochemical systems and catalysts have become a common theme in the realm of metal-catalyzed energy transformation. The biologically important redox couple β-nicotinamide adenine dinucleotide (NAD+)/1,4,β-dihydronicotinamide adenine dinucleotide (NADH) provides a reversible prototype system for the conversion of electrical to chemical energy via the reversible formation of a C–H bond centered on the nicotinamide ring representing an efficient system for numerous biological hydrogen-transfer reactions. In this short review, the first part emphasizes the need to construct operational system for the catalytic transformation of energy from viable sources due to the globally increasing demand in energy consumption. This is followed by a discussion on the redox chemistry of the NAD+/NADH reversible redox process centered on the nicotinamide ring as a representative chemical system enabling the efficient transformation of energy. Next, pioneering examples of NAD+/NADH mimics providing model systems that can perform non-enzymatic reactions based on the hydrogen (hydride) transfer ability of the model compounds are outlined. And lastly, several examples of ruthenium polypyridyl complexes having NAD+/NADH analogous ligands exhibiting excellent photo- and electrochemical properties similar to the NAD+/NADH redox couple are given. This is to demonstrate the importance of biomimetic chemistry in realizing novel strategies in the development of catalytic systems that can provide solutions in the alleviation or eradication of the world’s energy problems.

Sivelestat, a selective inhibitor of neutrophil elastase, has been reported to reduce acute lung injury associated with systemic inflammatory response syndrome (SIRS). However, no study has addressed the effect of prophylactic sivelestat administration on the postoperative course following an esophagectomy in older patients. In this retrospective study of patients aged >70 years, we performed a propensity score-matched analysis to compare short and long-term outcomes between patients who received early postoperative sivelestat administration (n = 42) and those who did not receive sivelestat (controls; n = 42) after a transthoracic esophagectomy for esophageal cancer (EC). Patient backgrounds were well balanced between the two groups. The sivelestat group showed significantly shorter SIRS durations compared to the control group (2 vs 5 days, p = 0.001). In addition, postoperative hospital stays were shorter in the sivelestat group than in the control group (26 vs 31 days, p = 0.013). Other factors did not differ between the two groups, including the reoperation rate, ICU stay, duration of mechanical ventilation, and duration of O2 supply. Postoperatively, the sivelestat group showed significantly lower heart rates than the control group (repeated-measures ANOVA, p = 0.0389) while respiratory rates, the SpO2 levels, and body temperatures did not significantly differ between the two groups. Finally, long-term survival appeared to be not different between the two groups. Sivelestat effectively stabilized postoperative vital signs and shortened SIRS durations. Thus, prophylactic sivelestat led to shorter hospital stays among older patients with EC who underwent an esophagectomy.

Purpose: The aim of this study was to clarify the 1-year outcomes of pro re nata (PRN) and bimonthly intravitreal injections of aflibercept (IVA) for typical neovascular age-related macular degeneration (tAMD) after the initial 3 monthly IVA. Methods: We conducted a prospective, interventional study. Fifty-eight treatment-naïve patients with tAMD were randomly assigned to the PRN (30 patients) or the bimonthly (28 patients) treatment group. Both groups initially received 3 monthly IVA. Visual acuity, central macular retinal thickness (CRT), and central choroidal thickness (CCT) were evaluated at 12 months. Subanalysis was performed to identify factors associated with the best-corrected visual acuity (BCVA). Results: BCVA was significantly improved only in the bimonthly group at 12 months. CRT and CCT were significantly decreased in both groups. Subanalysis showed that the only factor associated with BCVA improvement at 12 months was the existence of pigment epithelial detachment at baseline. Conclusions: BCVA showed significant improvement only in the bimonthly group but not in the PRN group at 12 months.

We report the solid-state reaction of MoO2 nanosheets, obtained from the soft-chemical delamination of Na0.9Mo2O4, into metallic Mo2C single layers that constitute a new family of versatile carbide nanosheets. This so-called pseudotopotactic reaction, i.e., conversion from nanosheet to nanosheet, is aided by the use of cationic polymers as binders for the film growth based on electrostatic self-assembly. Compared to Mo2C in the bulk form, 2D anisotropic Mo2C sheets having a larger surface-area-to-volume ratio are of significant use in potential electrochemical applications, and it is also worth noting that the thickness of Mo2C sheets can be controlled in the nanometer range by altering the stacking number of the precursor nanosheets.

Purpose To compare the findings of optical coherence tomography angiography (OCTA) with indocyanine green angiography (ICGA) in polypoidal choroidal vasculopathy (PCV) that was divided into two types: polypoidal choroidal neovascularisation (CNV) and typical PCV (type 2 PCV). Methods We studied a retrospective case series of 32 patients with treatment-naive PCV (24 men, eight women; mean age 65.4 years). PCV was categorised into polypoidal CNV (type 1 PCV) and type 2 PCV based on ICGA findings. OCTA was performed using the RTVue XR Avanti. Macular cubes (3×3 or 6×6 mm) were acquired. To evaluate the locations of polyps and branched vessel networks (BVNs), we used B-mode scan. Results OCTA clearly depicted only 17% of the type 1 PCV polyps and 46% of the type 2 PCV polyps which were detectable by ICGA. All type 1 PCV polyps detectable by OCTA were located just beneath the retinal pigment epithelium (RPE). On the other hand, type 2 PCV polyps were detected in various locations. All BVNs of type 1 PCV were located between the RPE and Bruch9s membrane on OCTA images. However, the BVNs in type 2 PCV were located mainly under the RPE, though some were located in the choroid. Conclusions Polyps of type 1 PCV were more difficult to detect with OCTA than those of type 2 PCV. Polyps of type 1 PCV were located just beneath the RPE. The BVNs of type 1 PCV were located between the RPE and Bruch9s membrane.

Background Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody–drug conjugate (ADC) targeting glypican-1 (GPC-1) as a new therapy for PDAC. Methods We evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo. Results GPC-1 was overexpressed in most primary PDAC cells and tissues. The PDAC cell lines BxPC-3 and T3M-4 strongly expressed GPC-1 relative to SUIT-2 cells. Compared with control ADC, GPC-1-ADC showed a potent antitumour effect against BxPC-3 and T3M-4, but little activity against SUIT-2 cells. In the xenograft and patient-derived tumour models, GPC-1-ADC significantly and potently inhibited tumour growth in a dose-dependent manner. GPC-1-ADC-mediated G2/M-phase cell cycle arrest was detected in the tumour tissues of GPC-1-ADC-treated mice relative to those of control-ADC-treated mice. Conclusions GPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patient-derived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer.

An NAD/NADH-functionalized ligand, benzo[b]pyrido[3,2-f][1,7]-phenanthroline (bpp), was newly synthesized. A Ru compound containing the bpp ligand, [Ru(bpp)(bpy)2](2+), underwent 2e(-) and 2H(+) reduction, generating the NADH form of the compound, [Ru(bppHH)(bpy)2](2+), in response to visible light irradiation in CH3CN/TEA/H2O (8/1/1). The UV-vis and fluorescent spectra of both [Ru(bpp)(bpy)2](2+) and [Ru(bppHH)(bpy)2](2+) resembled the spectra of [Ru(bpy)3](2+). Both complexes exhibited strong emission, with quantum yields of 0.086 and 0.031, respectively; values that are much higher than those obtained from the NAD/NADH-functionalized complexes [Ru(pbn)(bpy)2](2+) and [Ru(pbnHH)(bpy)2](2+) (pbn = (2-(2-pyridyl)benzo[b]-1.5-naphthyridine, pbnHH = hydrogenated form of pbn). The reduction potential of the bpp ligand in [Ru(bpp)(bpy)2](2+) (-1.28 V vs SCE) is much more negative than that of the pbn ligand in [Ru(pbn)(bpy)2](2+) (-0.74 V), although the oxidation potentials of bppHH and pbnHH are essentially equal (0.95 V). These results indicate that the electrochemical oxidation of the dihydropyridine moiety in the NADH-type ligand was independent of the π system, including the Ru polypyridyl framework. [Ru(bppHH)(bpy)2](2+) allowed the photoreduction of oxygen, generating H2O2 in 92% yield based on [Ru(bppHH)(bpy)2](2+). H2O2 production took place via singlet oxygen generated by the energy transfer from excited [Ru(bppHH)(bpy)2](2+) to triplet oxygen.

Purpose: The aim of this study was to clarify the characteristic findings in patients with geographic atrophy with or without hyperautofluorescent choroidal vessels within macular atrophic areas on short-wavelength fundus autofluorescence imaging. Procedures: Sixty-seven eyes of 43 consecutive patients with macular atrophic areas were divided into groups with (group 1) and without (group 2) hyperautofluorescent choroidal vessels on fundus autofluorescence imaging and then retrospectively studied using spectral-domain optical coherence tomography. Results: In group 1 (n = 21), the average subfoveal choroidal thickness was 61.5 ± 20.1 μm, and the average foveal retinal thickness was 93.0 ± 51.3 μm. On the other hand, in group 2 (n = 46), the average subfoveal choroidal thickness was 200.7 ± 83.1 μm, and the average foveal retinal thickness was 109.2 ± 58.5 μm. Although retinal thickness did not differ significantly between the two groups (p = 0.28), the difference in choroidal thickness was statistically significant (p < 0.001). Conclusions: Choroidal thinning might contribute to the hyperautofluorescence of choroidal vessels.

The combination of porphyrin as a sensitizer and a ruthenium complex as a water oxidation catalyst (WOC) is promising to exploit highly efficient molecular artificial photosynthetic systems. A covalently-linked ruthenium-based WOC–zinc porphyrin (ZnP) sensitizer dyad was assembled on a TiO2 electrode for visible-light driven water oxidation. The water oxidation activity was found to be improved in comparison to the reference systems with the simple combination of the individual WOC and ZnP as well as with ZnP solely, demonstrating the advantage of the covalent linking approach over the non-covalent one. More importantly, via vectorial multi-step electron transfer triggered by visible light, the dye-sensitized photoelectrochemical cell (DSPEC) achieved a broader PEC response in the visible region than DSPECs with conventional ruthenium-based sensitizers. Initial incident photon-to-current efficiencies of 18% at 424 nm and 6.4% at 564 nm were attained under monochromatic illumination and an external bias of � 0.2 V vs. NHE. Fast electron transfer from the WOC to the photogenerated radical cation of the sensitizer through the covalent linkage may suppress undesirable charge recombination, realizing the moderate performance of water oxidation. X-ray photoelectron spectroscopic analysis of the photoanodes before and after the DSPEC operation suggested that most of the ruthenium species exist at higher oxidation states, implying that the insufficient oxidation potential of the ZnP moiety for further oxidizing the intermediate ruthenium species at the photoanode is at least the bottleneck of the system.

The base-assisted oxidation of an aniline-Ru-quinone complex produced an anilinyl radical-Ru-semiquinone. Furthermore, base-assisted oxidation of the radical complex resulted in selective C-N bond formation through an intermolecular coupling between nitrogen and carbon atoms at the para-position of the anilinyl ligand.

Successful control over the rate of the organic hydride transfer reaction converting carbon dioxide to formate using a ruthenium NADH model complex, [Ru(bpy) 2 (pbnHH)](PF6) 2 (bpy = 2,2′-bipyridine, pbnHH = 2-(pyridin-2-yl)-5,10-dihydrobenzo[ b ][1,5]naphthyridine) has been accomplished by the tuning of the basicity of the bases. The base adduct being found to be the key compound in the carbon dioxide reduction has been fully characterized through various physicochemical methods.

The bidirectional transformation of a protein between its native water-soluble and integral transmembrane conformations is demonstrated for FraC, a hemolytic protein of the family of pore-forming toxins. In the presence of biological membranes, the water-soluble conformation of FraC undergoes a remarkable structural reorganization generating cytolytic transmembrane nanopores conducive to cell death. So far, the reverse transformation from the native transmembrane conformation to the native water-soluble conformation has not been reported. We describe the use of detergents with different physicochemical properties to achieve the spontaneous conversion of transmembrane pores of FraC back into the initial water-soluble state. Thermodynamic and kinetic stability data suggest that specific detergents cause an asymmetric change in the energy landscape of the protein, allowing the bidirectional transformation of a membrane protein.

Introduction: Heavy alcohol (EtOH) drinking and tobacco smoking increase the risk for upper digestive (e.g. oral and esophageal) squamous cell carcinomas (SCC) in individuals with polymorphic mutations in aldehyde dehydrogenase 2 (Aldh2). Mutant Aldh2E487K protein delays mitochondrial clearance of acetaldehyde, the chief metabolite of EtOH and constituents of tobacco smoke, aka a major human carcinogen. The role of Aldh2 in tumor biology remains elusive. Methods: Single cell-derived three-dimensional (3D) organoids were generated from murine oral and esophageal preneoplastic and SCC lesions carrying wild-type Aldh2WT or mutant Aldh2E487K as well as human SCC cell lines with Aldh2E487K, the latter subjected to xenograft transplantation in immunodeficient mice. 3D organoids and xenograft tumors were analyzed by morphology and flow cytometry to determine CD44, autophagy (cyto-ID), proliferation (EdU), and reactive oxygen species (ROS) following EtOH exposure ex vivo (0.1-2% EtOH) or in vivo (10% EtOH in drinking water) along with or without inhibitors of alcohol metabolism (4-methylpyrazole; 4MP, siRNA against Adh1B and Cyp2E1), and autophagy flux (chloroquine; CQ or siRNA against Atg7). Flow cytometry was performed to determine cancer stem-like cells with high CD44 expression (CD44H cells). Results: EtOH stimulated xenograft tumor growth and increased highly proliferative intratumoral CD44H cells with increased autophagy. EtOH-stimulated tumor growth and induction of CD44H cells were sharply suppressed by concurrent 4MP treatment, indicating that EtOH is directly metabolized in SCC cells to promote tumor growth via CD44H cells. These EtOH-induced effects were recapitulated in 3D organoids where Aldh2E487K augmented EtOH-mediated induction of CD44H cells and organoid formation with increased cellular atypia. EtOH induced mitochondrial superoxide and ROS-dependent autophagy activation in CD44H cells. Inhibition of autophagy prevented EtOH from enriching CD44H cells in 3D organoids, suggesting that autophagy may limit alcohol-induced oxidative stress as a cytoprotective mechanism. Conclusions: These studies provide not only mechanistic insights into the role of Aldh2 mutation in oral and esophageal SCC pathogenesis but also establish the utility of the 3D organoid system to test the functional interplay between genetic and environmental factors which may subsequently be targeted for pharmacological intervention in the setting of personalized medicine. Citation Format: Masataka Shimonosono, Takashi Kijima, Hisatsugu Maekawa, Satoshi Takada, Koji Tanaka, Varun Sahu, Manti Guha, Andres J. Klein-Szanto, J. Alan Diehl, Adam J. Bass, Anil K. Rustgi, Elizabeth Philipone, Angela J. Yoon, Hiroshi Nakagawa. Aldh2 mutation promotes oral and esophageal cancer stem cells via autophagy-mediated redox homeostasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 501.

Purpose To investigate the safety and effectiveness of intravitreal injection (IVI) of 1.25% povidone iodine (PI) followed by vitrectomy using 0.025% PI irrigation for treating endophthalmitis. Methods Prospective case series study. Nine eyes of 8 patients with postoperative or endogenous endophthalmitis treated at the Nihon University Hospital between April 2015 and October 2017 were studied. First, IVI of 0.1 mL/1.25%PI was conducted, followed by anterior chamber irrigation and vitrectomy using 0.025%PI irrigation solution. Corneal epithelial damage, anterior chamber inflammation, and vitreous inflammation were assessed and fundus examinations were performed, using a slit-lamp microscope and indirect ophthalmoscopy. A specular microscope, Goldmann perimetry, and electroretinography (ERG) were also used. Results In all but case 7, endophthalmitis resolved rapidly and good visual acuity was maintained. No adverse events were noted. Furthermore, the perioperative ERG showed improvements in the oscillatory potentials amplitudes on ERG and flicker ERG, as well as in the implicit time of the a-wave, suggesting functional recovery in the retinal outer and inner layers after therapy. Conclusions IVI of PI followed by vitrectomy was thought to be a safe and effective treatment for endophthalmitis. Translational relevance We succeeded in proving the clinical safety of IVI of PI followed by vitrectomy with PI irrigation as well as previous experimental reports. PI is available in world widely, therefore this method will be optimal treatment for endophthalmitis.

c-Met relies on CD44v6 for its activation and signaling in several cancer cell lines. However, the correlation of c-Met and CD44v6 expression and its biological significance in esophageal squamous cell carcinoma (ESCC) remains unknown. Expression of c-Met and CD44v6 was examined by immunohistochemistry (IHC) in 147 ESCC specimens. We analyzed the impact of c-Met and CD44v6 expression on clinicopathological parameters, including chemoresistance or prognosis in ESCC. High expression of c-Met and CD44v6 in cancerous lesions was identified in 49.7% and 50.3% of all patients, respectively. The c-Met-high group comprised more advanced pT and pM stages than the c-Met-low group. In addition, more patients in the c-Met-high group received neoadjuvant chemotherapy (NACT) than the c-Met-low group (64.4% vs. 43.2%, P = 0.010). On the other hand, the CD44v6-high group was associated with more advanced pT/pN stages and a poorer clinical response to NACT (response rate 53.5% vs. 77.8%, P = 0.025) than the CD44v6-low group. Double-positive immunostaining of c-Met and CD44v6 was identified in 28.6% of all cases, and multivariate analysis of overall survival (OS) identified them (hazard ratio 1.79, 95% confidence interval 1.03–3.04, P = 0.038) as independent prognostic factors in addition to pN and pM stage. c-Met/CD44v6 were associated with tumor progression or chemoresistance. Double-positive expression of c-Met and CD44v6 negatively impacted patient prognosis in ESCC, implying that c-Met and CD44v6 are candidates for targeted therapy in ESCC.

Sphingosine kinases (SPHK) are important to determine cells' fate by producing sphingosine 1-phosphate. Reportedly, exogenous SPHK2 overexpression induces cell cycle arrest or cell death. However, the regulatory mechanism of SPHK2 expression has not been fully elucidated. Here, we analyzed this issue using human colon cancer cell lines under various stress conditions. Serum depletion (FCS(-)) but not hypoxia and glucose depletion increased mRNA, protein and enzyme activity of SPHK2 but not SPHK1. In HCT116 cells mostly used, SPHK2 activity was predominant over SPHK1, and serum depletion increased both nuclear and cytoplasmic SPHK2 activity. Based on previous reports analyzing cellular response after serum depletion, the temporal changes of intracellular signaling molecules and candidate transcription factors for SPHK2 were examined using serum-depleted HCT116 cells, and performed transfection experiments with siRNA or cDNA of candidate transcription factors. Results showed that the rapid and transient JNK activation followed by CREB activation was the major regulator of increased SPHK2 transcription in FCS(-) culture. EMSA and ChIP assay confirmed the direct binding of activated CREB to the CREB binding site of 5' SPHK2 promoter region. Colon cancer cells examined continued to grow in FCS(-) culture, although mildly, while hypoxia and glucose depletion suppressed cell proliferation or induced cell death, suggesting the different role of SPHK2 in different stress conditions. Because of the unique relationship observed after serum depletion, we examined effects of siRNA for SPHK2, and found the role of SPHK2 as a growth or survival factor but not a cell proliferation inhibitor in FCS(-) culture.

Dicationic dicarbonyl [Ru(bpy)2(CO)2](2+) (bpy = 2,2'- bipyridyl) exists as equilibrium mixtures with [Ru(bpy)2(CO)(COOH)](+) and [Ru(bpy)2(CO)(CO2)](0) depending on the pH in H2O. Those three complexes work as the precursors to CO, HCOOH production, and CO2 carrier, respectively, in electro- and photochemical CO2 reduction in aqueous solutions. However, [Ru(bpy)2(CO)2](2+) loses the catalytic activity toward CO2 reduction under aprotic conditions because [Ru(bpy)2(CO)2](2+) is not regenerated from [Ru(bpy)2(CO)(CO2)](0) in the absence of proton sources. Analogous monocarbonylruthenium complexes such as [Ru(tpy)(bpy)(CO)](2+) and [Ru(bpy)2(qu)(CO)](2+) catalyze CO2 reduction in the absence and presence of proton sources. Both complexes are reproduced through oxide transfer from the corresponding Ru-CO2 to CO2 in CO2 reduction and produce the same amount of CO and CO3(2-) in the absence of proton donors. The reduction of CO2 catalyzed by polypyridylrhenium complexes in the presence of proton sources takes place via essentially the similar mechanism as that in the case of ruthenium complexes. On the other hand, CO evolution in CO2 reduction under aprotic conditions is ascribed to the dissociation of CO from a dimeric Re-C(O)OC(O)O-Re scaffold. Visible-light irradiation to a catalytic system composed of [Ru(bpy)2(CO)2](2+)/[Ru(bpy)3](2+)/Me2NH2(+)/Me2NH as the catalyst, photosensitizer, proton donor, and nucleophile in addition to the electron donor, respectively, in CO2-saturated CH3CN selectively produces N,N-dimethylformamide without concomitant CO and HCOOH formation. Structurally robust μ3-S of reduced metal-sulfur clusters provides a suitable site for reductive activation of CO2 with retention of the framework. Indeed, CO2 activated on μ3-S of [Fe6Mo2S8(SEt)3](5-) is fixed at the carbonyl carbon of thioesters trapped on a neighboring iron of the cluster, and α-keto acids are produced catalytically. Furthermore, two-electron reduction of [(CpMen)3M3S3](2+) (n = 1, M = Co; n = 5, M = Rh, Ir) creates the catalytic ability to produce oxalate through the coupling of two CO2 molecules possibly activated on μ3-S and a metal ion.

We have been proposing that there are competitive two kinds of pathways in the hydrogenation of Mg/Cu super-laminate composites. The one is that Mg reacts with Cu to form Mg2Cu and then Mg2Cu is hydrogenated to form MgH2 and MgCu2. The other is that Mg is hydrogenated and then MgH2 and Cu reacts to form MgCu2 together with H2 gas, according to a hypothesis that the reaction of MgH2 + 2Cu1⁄4MgCu2 + H2 occurs. In the present study, the reaction conditions such as pressure and temperature were investigated in order to confirm that the hypothesis is true. Well-mixed MgH2 and Cu powder was compressed to a pellet at 1.73GPa and then heated at various hydrogen pressures and temperatures. Following results were obtained from the experiments at 673K. The above-mentioned alloying accompanied by H2 emission occurs at pressures higher than 6.6MPa of H2 pressure, which is higher than lower limit for the hydrogenation of Mg2Cu. On the other hand, Mg2Cu is formed at 3.3MPa which is lower than the limit. The reaction of MgH2 with Cu also occurs at 573K in 3.3MPa H2. But it requires very long time such as 691.2 ks, although the existence of MgCu2 is confirmed in 86.1 ks of heating time in the case of Mg/Cu super-laminate composites. [doi:10.2320/matertrans.M2014426]

The [RuVO]3+ and [RuVIO]4+ generated from [RuII(NCN-Me)(bpy)(H2O)](PF6)2 play the selective role in C–H bond oxidation of 2-(pyridin-2-yl)-9,10-dihydroacridine (PADHH) and water splitting, respectively, are reported.

The proton-induced Ru-C bond variation, which was previously found to be relevant in the water oxidation, has been investigated by using cyclometalated ruthenium complexes with three phenanthroline (phen) isomers. The designed complexes, [Ru(bpy)2 (1,5-phen)](+) ([2](+)), [Ru(bpy)2 (1,6-phen)](+) ([3](+)), and [Ru(bpy)2 (1,7-phen)](+) ([4](+)) were newly synthesized and their structural and electronic properties were analyzed by various spectroscopy and theoretical protocols. Protonation of [4](+) triggered profound electronic structural change to form remote N-heterocyclic carbene (rNHC), whereas protonation of [2](+) and [3](+) did not affect their structures. It was found that changes in the electronic structure of phen beyond classical resonance forms control the rNHC behavior. The present study provides new insights into the ligand design of related ruthenium catalysts.

In sepsis, circulating free DNA (cf-DNA) is increased, and is a marker of severity and prognosis of septic patients. This study aimed to evaluate cf-DNA in a dextran sodium sulfate-induced colitis mouse model, and its clinical implications.Dynamic pathology of the cecum wall in the DSS-induced colitis mouse model was analyzed using multiphoton microscopy (MPM). Plasma cf-DNA concentrations in colitis mouse were quantified using PicoGreen dsDNA Assay Kit. Plasma cf-DNA was also measured in 123 human ulcerative colitis (UC) patients [mean age: 35.9 years (3-75 years) with 20 pediatric patients] to assess its relationships with clinical severity and Matt's grade.Real-time images of cf-DNA were detected in the colitis model. The amount of labeled cf-DNA in the circulation of the colitis mice group was significantly higher compared with that in the control group (P0.05). In human UC blood samples, plasma cf-DNA concentrations in UC patients were significantly positively correlated with the clinical severity of UC and Matt's grade (P0.05, P0.05, respectively).Using MPM, we observed and analyzed real-time images of cf-DNA in a colitis mouse model. Plasma cf-DNA is a potential non-invasive blood marker for reflecting clinical severity and mucosal damage in UC patients.

A reaction of a ruthenium(II) NAD-type complex, [Ru(tpy)(pbn)(Cl)]+ (tpy = 2,2′:6′,2′′-terpyridine; pbn = 2-(pyridin-2-yl)benzo[b][1,5]naphthyridine), with pressurized CO (2 MPa) at 150 °C in H2O selectively produced a two-electron reduced ruthenium(II)-NADH-type carbonyl complex, [Ru(tpy)(pbnHH)(CO)]2+ (pbnHH = 2-(pyridin-2-yl)-5,10-dihydrobenzo[b][1,5]naphthyridine), rather than the oxidized [Ru(tpy)(pbn)(CO)]2+ complex. Indeed, [Ru(tpy)(pbnHH)(CO)]2+ was quantitatively oxidized to [Ru(tpy)(pbn)(CO)]2+ upon treatment with one equiv. of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). The reactivity of [Ru(tpy)(pbnHH)(CO)]2+ with various bases was studied herein. Treatment of [Ru(tpy)(pbnHH)(CO)]2+ with a suitable organic base, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), resulted in the formation of a new five-membered Ru–CO-bridge metallacycle quantitatively in acetonitrile under air at room temperature. A probable mechanism was proposed for this reaction based on UV-vis, NMR, and EPR spectral studies and other experimental data. Furthermore, a reaction of the five membered Ru–CO-bridge metallacycle with NH4PF6 in CH3CN : H2O (1 : 1) under air smoothly produced another new six-membered Ru-OCO-bridge complex. A mechanism for the formation of a Ru-OCO-bridge complex was also proposed here on the basis of H2O18 experiments, DDQ treatment and other experimental data. These newly synthesized complexes appended with NAD-type ligands may have potential use as renewable hydride sources for organic reductions.

This paper describes the analysis of pore formation and detection of a single protein molecule using a large nanopore among five different pore-forming proteins. We demonstrate that the identification of appropriate pores for nanopore sensing can be achieved by classifying the channel current signals and performing noise analysis. Through these analyses, we selected a perforin nanopore from the membrane attack complex/perforin superfamily and attempted to use it to detect the granzyme B protein, a serine protease. As a result, we found that granzyme B might pass through the perforin nanopore if it adopts an unfolded structure. Our proposed analytical approach should be useful for exploring several types of nanopore as large biological nanopores other than α-hemolysin.

The selective formation of dialkyl formamides through photochemical CO2 reduction was developed as a means of utilizing CO2 as a C1 building block. Photochemical CO2 reduction catalyzed by a [Ru(bpy)2(CO)2](2+) (bpy: 2,2'-bipyridyl)/[Ru(bpy)3](2+)/Me2NH/Me2NH2(+) system in CH3CN selectively produced dimethylformamide. In this process a ruthenium carbamoyl complex ([Ru(bpy)2(CO)(CONMe2)](+)) formed by the nucleophilic attack of Me2NH on [Ru(bpy)2(CO)2](2+) worked as the precursor to DMF. Thus Me2NH acted as both the sacrificial electron donor and the substrate, while Me2NH2(+) functioned as the proton source. Similar photochemical CO2 reductions using R2NH and R2NH2(+) (R = Et, nPr, or nBu) also afforded the corresponding dialkyl formamides (R2NCHO) together with HCOOH as a by-product. The main product from the CO2 reduction transitioned from R2NCHO to HCOOH with increases in the alkyl chain length of the R2NH. The selectivity between R2NCHO and HCOOH was found to depend on the rate of [Ru(bpy)2(CO)(CONR2)](+) formation.

o-Formyl-m-hydroxycinnamic acid, the most oxidized salicylaldehyde-type phytotoxin isolated from rice blast fungus, Magnaporthe grisea, was synthesized for the first time using 5-(2,2-dimethyl-4H-1,3-benzodioxin)methanol as the starting material, and the proposed structure was confirmed.

Water oxidation, in which two water molecules undergo the coupled loss of four electrons and four protons to form an O–O bond, is one of the most appealing target reactions for molecular catalysts in view of hydrogen production by electrolytic or photolytic water splitting to cope with urgent energy and environmental problems. Inspired by a natural oxygen-evolving multinuclear manganese cluster, a number of water oxidation catalysts based on multinuclear transition-metal complexes have been developed over the last three decades. In recent years, in parallel with the discovery of mononuclear oxygen-evolving complexes, both experimental and theoretical studies have yielded important insight into O–O bond-formation pathways in these water-oxidizing complexes. In this microreview, we will present an updated view of selected current literature focusing on the working mechanism of ruthenium-based water oxidation catalysts and on the development of rationally designed ruthenium complexes that activate water at mild potentials.

We previously visualized in vivo responses to chemotherapy in a colorectal liver metastatic xenograft model using in vivo real-time and time-series intravital two-photon laser scanning microscopy (TPLSM). In this study, we established the method for evaluating the response of peritoneal xenografts to chemotherapy of metastatic gastric cancer using intravital TPLSM.Red fluorescent protein-expressing gastric cancer cells (NUGC4) were inoculated into the peritoneal cavity of green fluorescent protein nude mice.Laparotomy revealed that 2 weeks after inoculation, macroscopic peritoneal metastatic nodules were formed. The first intravital TPLSM session revealed that they were composed of red tumor cell clusters and green surrounding stroma. Paclitaxel was administered intraperitoneally after the first TPLSM three times a week for 7 days in the treatment group. At the second laparotomy, there were significantly fewer and smaller nodules in the treated mice than in the controls. The second intravital TPLSM session showed tumor cell fragmentation, swelling, and nuclear condensation in the metastatic nodules--a response to chemotherapy. There were multinuclear tumor cells in the paclitaxel-treated living mice.Our method may become a powerful tool for evaluating the efficacy of novel anti-gastric cancer drugs in a preclinical murine model with minimum interindividual variation.

Artificial photosynthesis is of great importance in the production of clean fuels such as hydrogen from sunlight and water. In such systems, water oxidation is kinetically demanding; therefore, efficient catalysts and systems for water oxidation are required. Among the artificial systems, photosynthesis has been recently developed owing to the emergence of efficient molecular catalysts for water oxidation. This Review highlights several important concepts including electron transfer and catalysis, and the representative systems of molecular systems for visible-light-driven water oxidation. In addition, the remaining challenges in this field, including the interfacial recombination and the restricted utilization of visible light of over 500 nm, are discussed.