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The impact of gut and oral microbiota on the clinical outcomes of patients with oral squamous cell carcinoma (OSCC) is unknown. We compared the bacterial composition of dental plaque and feces between patients with OSCC and healthy controls (HCs). Fecal and dental plaque samples were collected from 7 HCs and 18 patients with OSCC before treatment initiation. Terminal restriction fragment-length polymorphism analysis of 16S rRNA genes was performed. Differences in bacterial diversity between the HC and OSCC groups were examined. We compared the occupancy of each bacterial species in samples taken from patients with OSCC and HCs and analyzed the correlation between PD-L1 expression in the tumor specimens and the occupancy of each bacterial species. The gut and oral microbiota of patients with OSCC were more varied than those of HCs. Porphyromonas and Prevotella were significantly more abundant in patients with OSCC than in HCs. The abundance of Clostridium subcluster XIVa in the gut microbiota of the PD-L1-positive group was significantly greater than that in the PD-L1-negative group. The oral and gut microbiomes of patients with OSCC were in a state of dysbiosis. Our results suggest the possibility of new cancer therapies targeting these disease-specific microbiomes using probiotics and synbiotics.

This study examined the thermal dehydration characteristics of CaSO 4 ∙2H 2 O in a constant-volume rotary vessel. The experiment used CaSO 4 ∙2H 2 O particles obtained from the crushed waste gypsum board. The particle size ranged from 850 to 2000 μm, and the experiment was carried out at varying rotation speeds of 1, 10, and 35 rpm, with the vessel temperature heated to 180 °C. Temperature and pressure inside the vessel were measured simultaneously using the thermocouple and the pressure sensor. The XRPD measurement analyzed the transition of CaSO 4 ∙2H 2 O after the heating of particles. The result showed that the temperature growth rate was similar for high rotation speeds of 10 and 35 rpm, while periodic temperature changes occurred at the low rotation speed of 1 rpm. A distinguishing flow pattern was observed at the low rotation speed, and the particles inside the vessel collapsed periodically downward. This particle behavior was related to the temperature distribution of the rotation speed of 1 rpm. Additionally, the pressure in the vessel increased rapidly at higher rotation speeds. This trend indicates the desorption of the crystal water of CaSO 4 ∙2H 2 O due to the increasing temperature in the case of high rotation speed. Also, the XRPD measurement results showed the appearance of CaSO 4 ∙0.5H 2 O under the higher rotation speed conditions, and the mass fraction of CaSO 4 ∙0.5H 2 O increased with the rotation speed. Overall, the present study suggests that rotation speed plays a crucial role in determining the heat conduction and heat transfer of particles in a constant-volume rotary vessel.

Fat atrophy and adipose tissue inflammation can cause the pathogenesis of metabolic symptoms in chronic kidney disease (CKD). During CKD, the serum levels of advanced oxidation protein products (AOPPs) are elevated. However, the relationship between fat atrophy/adipose tissue inflammation and AOPPs has remained unknown. The purpose of this study was to investigate the involvement of AOPPs, which are known as uremic toxins, in adipose tissue inflammation and to establish the underlying molecular mechanism. In vitro studies involved co-culturing mouse-derived adipocytes (differentiated 3T3-L1) and macrophages (RAW264.7). In vivo studies were performed using adenine-induced CKD mice and AOPP-overloaded mice. Fat atrophy, macrophage infiltration and increased AOPP activity in adipose tissue were identified in adenine-induced CKD mice. AOPPs induced MCP-1 expression in differentiated 3T3-L1 adipocytes via ROS production. However, AOPP-induced ROS production was suppressed by the presence of NADPH oxidase inhibitors and the scavengers of mitochondria-derived ROS. A co-culturing system showed AOPPs induced macrophage migration to adipocytes. AOPPs also up-regulated TNF-α expression by polarizing macrophages to an M1-type polarity, and then induced macrophage-mediated adipose inflammation. In vitro data was supported by experiments using AOPP-overloaded mice. AOPPs contribute to macrophage-mediated adipose inflammation and constitute a potential new therapeutic target for adipose inflammation associated with CKD.

We report the design, synthesis, and biological activity of a series of compounds that exhibit potent mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) inhibition. Structural transformation of the substructures of a starting compound gave amidomethyl derivatives and sulfonylguanidine derivatives that exhibited potent inhibition of MALT1. Compound 37 had good oral bioavailability and showed anti-psoriatic activity in an imiquimod-induced psoriasis mouse model after oral administration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The awareness of healthcare practitioners concerning heated tobacco product (HTP) use risks has been evaluated; however, few studies have investigated general dental practitioners’ awareness regarding HTP-use risks. In this cross-sectional study, we investigated dentists’ awareness of the risks of smoking, particularly HTP use. A self-administered questionnaire, including eight questions on conventional cigarette and HTP smoking/using status and both knowledge and awareness of HTP-use risks, was posted to 3883 dentists belonging to the Aichi Dental Association, Japan, in August 2019. Statistical analysis was performed using the Statistical Package for Social Sciences; statistical significance was set at p < 0.05. We analyzed the data of 1317 dentists (participation rate, 41.6%). The study group included cigarette smokers (11.5%) and HTP users (8.5%), among whom 41.1% were dual users. HTP users were more likely than never smokers/users to correctly perceive HTP-use risks (p < 0.05). This study indicates that in Japan, the proportion of HTP users is higher than that of the general population. It is important to educate not only smokers/users but also never smokers/users on the risks of smoking and using HTPs. Smoking cessation, including ceasing HTP use, and aiming to quit smoking and HTP use among dentists would contribute to appropriate smoking cessation among patients., Competing Interests: The authors declare no conflicts of interest.

This study focused on the vibrating fluidized-bed-type powder feeder used in HVAF thermal spraying equipment. This feeder has been used in thermal spraying equipment and industrial applications. However, particulate materials' flow mechanism and stable transport characteristics have not been fully understood. This study experimentally investigated the fluidization characteristics, powder dispersion state, and powder transportation characteristics of Al 2 O 3 particles during vertical vibration fluidization. The material used was Al 2 O 3 particles of 2.9 μm and 3808 kg/m 3 , classified as the group C particles in the Geldart diagram. As experimental conditions, the fluidized air velocity to the bottom of the powder bed and the vibration intensity in the vertical direction changed. The critical fluidization air velocity was defined to evaluate the generating powder flow by vertical vibrating fluidization. As a result, good fluidization of the powder bed of Al 2 O 3 was obtained by the vertical vibration, as well as an airflow that was higher than the critical fluidization air velocity. Regarding powder transportation characteristics, it was clarified that the fluidized air velocity at the bottom of the powder dispersion vessel and the pressure difference from the powder dispersion vessel to the transportation part significantly affect the mass flow rate.

Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial-mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.

Background: Sarcopenia with chronic kidney disease (CKD) progression is associated with life prognosis. Oxidative stress has attracted interest as a trigger for causing CKD-related muscular atrophy. Advanced oxidation protein products (AOPPs), a uraemic toxin, are known to increase oxidative stress. However, the role of AOPPs on CKD-induced muscle atrophy remains unclear., Methods: In a retrospective case-control clinical study, we evaluated the relationship between serum AOPPs levels and muscle strength in haemodialysis patients with sarcopenia (n = 26, mean age ± SEM: 78.5 ± 1.4 years for male patients; n = 22, mean age ± SEM: 79.1 ± 1.5 for female patients), pre-sarcopenia (n = 12, mean age ± SEM: 73.8 ± 2.0 years for male patients; n = 4, mean age ± SEM: 74.3 ± 4.1 for female patients) or without sarcopenia (n = 12, mean age ± SEM: 71.3 ± 1.6 years for male patients; n = 7, mean age ± SEM: 77.7 ± 1.6 for female ). The molecular mechanism responsible for the AOPPs-induced muscle atrophy was investigated by using 5/6-nephrectomized CKD mice, AOPPs-overloaded mice, and C2C12 mouse myoblast cells., Results: The haemodialysis patients with sarcopenia showed higher serum AOPPs levels as compared with the patients without sarcopenia. The serum AOPPs levels showed a negative correlation with grip strength (P < 0.01 for male patients, P < 0.01 for female patients) and skeletal muscle index (P < 0.01 for male patients). Serum AOPPs levels showed a positive correlation with cysteinylated albumin (Cys-albumin), a marker of oxidative stress (r 2  = 0.398, P < 0.01). In the gastrocnemius of CKD mice, muscle AOPPs levels were also increased, and it showed a positive correlation with atrogin-1 (r 2  = 0.538, P < 0.01) and myostatin expression (r 2  = 0.421, P < 0.05), but a negative correlation with PGC-1α expression (r 2  = 0.405, P < 0.05). Using C2C12 cells, AOPPs increased atrogin-1 and myostatin expression through the production of reactive oxygen species via CD36/NADPH oxidase pathway, and decreased myotube formation. AOPPs also induced mitochondrial dysfunction. In the AOPPs-overloaded mice showed that decreasing running time and hanging time accompanied by increasing AOPPs levels and decreasing cross-sectional area in gastrocnemius., Conclusions: Advanced oxidation protein products contribute to CKD-induced sarcopenia, suggesting that AOPPs or its downstream signalling pathway could be a therapeutic target for the treatment of CKD-induced sarcopenia. Serum AOPPs or Cys-albumin levels could be a new diagnostic marker for sarcopenia in CKD., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

We report the discovery of a novel series of 1,5-bisphenylpyrazoles as potent MALT1 inhibitors. Structure-activity relationship exploration of a hit compound led to a potent MALT1 inhibitor. Compound 33 showed strong activity against MALT1 (IC 50 : 0.49 μM), potent cellular activity (NF-κB inhibition and inhibition of IL2 production), and high selectivity against caspase-3, -8, and -9. The results of a kinetics study suggest that compound 33 is a non-competitive inhibitor of MALT1 protein., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

An effective strategy is highly desirable for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Thioredoxin-1 (Trx), a redox-active protein that has anti-oxidative and anti-inflammatory properties, would be a candidate for this but its short half-life limits its clinical application. In this study, we examined the renoprotective effect of long-acting Trx that is comprised of human albumin and Trx (HSA-Trx) against AKI to CKD transition. AKI to CKD mice were created by renal ischemia-reperfusion (IR). From day 1 to day 14 after renal IR, the recovery of renal function was accelerated by HSA-Trx administration. On day 14, HSA-Trx reduced renal fibrosis compared with PBS treatment. At the early phase of fibrogenesis (day 7), HSA-Trx treatment suppressed renal oxidative stress, pro-inflammatory cytokine production and macrophage infiltration, thus ameliorating tubular injury and fibrosis. In addition, HSA-Trx treatment inhibited G2/M cell cycle arrest and apoptosis in renal tubular cells. While renal Trx protein levels were decreased after renal IR, the levels were recovered by HSA-Trx treatment. Together, HSA-Trx has potential for use in the treatment of AKI to CKD transition via its effects of modulating oxidative stress and inflammation.

Objectives: Genetic predisposition is reportedly involved in early-onset oral cancer, although the genetic basis of this cancer remains unclear. The major histocompatibility complex class I-related chain A (MICA) plays a crucial role in eliminating malignant tumors by activating NKG2D, the natural killer (NK) receptor. MICA polymorphism might affect its binding to NKG2D. We aimed to find whether MICA gene microsatellite polymorphism is involved in the risk of oral squamous cell carcinoma (OSCC) development in a Japanese population., Materials and Methods: We recruited 386 patients with OSCC and 103 healthy controls. Genomic DNA was analyzed by PCR for microsatellite repeat polymorphism in the transmembrane region of the MICA gene. The groups were compared for the prevalence of various alleles and their association with disease prognosis and survival., Results: We found that adolescents and young adults (AYA) with OSCC were more likely to have the MICA A5.1 homozygous genotype than healthy controls (P = 0.0001), but their survival rate was higher than with other MICA genotypes (P = 0.0185)., Conclusion: These results suggest that cancer's immune escape is facilitated by MICA's failure to activate the NK cells. MICA A5.1 homozygosity plays a role in individual susceptibility to OSCC, increasing the risk of early-onset oral cancer. However, such patients have a better prognosis than those with other MICA genotypes., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adipose tissue inflammation appears to be a risk factor for the progression of chronic kidney disease (CKD), but the effect of CKD on adipose tissue inflammation is poorly understood. The purpose of this study was to clarify the involvement of uremic toxins (indoxyl sulfate (IS), 3-indoleacetic acid, p-cresyl sulfate and kynurenic acid) on CKD-induced adipose tissue inflammation. IS induces monocyte chemoattractant protein-1 (MCP-1) expression and reactive oxygen species (ROS) production in the differentiated 3T3L-1 adipocyte. An organic anion transporter (OAT) inhibitor, an NADPH oxidase inhibitor or an antioxidant suppresses the IS-induced MCP-1 expression and ROS production, suggesting the OAT/NADPH oxidase/ROS pathway is involved in the action of IS. Co-culturing 3T3L-1 adipocytes and mouse macrophage cells showed incubating adipocytes with IS increased macrophage infiltration. An IS-overload in healthy mice increased IS levels, oxidative stress and MCP-1 expression in epididymal adipose tissue compared to unloaded mice. Using 5/6-nephrectomized mice, the administration of AST-120 suppressed oxidative stress and the expression of MCP-1, F4/80 and TNF-α in epididymal adipose tissue. These collective data suggest IS could be a therapeutic target for the CKD-related inflammatory response in adipose tissue, and that AST-120 could be useful for the treatment of IS-induced adipose tissue inflammation.

Background: Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy., Methods: Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies., Results: In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway., Conclusions: AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy., Competing Interests: All authors have nothing to disclose., (Copyright © 2020 by the American Society of Nephrology.)

Conventional amide synthesis is a mainstay in discipline-spanning applications, and it is a reaction type that historically developed as a singular paradigm when considering the carbon-nitrogen bond-forming step. Umpolung amide synthesis (UmAS) exploits the unique properties of an α-halo nitroalkane in its reaction with an amine to produce an amide. The "umpolung" moniker reflects its paradigm-breaking C-N bond formation on the basis of evidence that the nucleophilic nitronate carbon and electrophilic nitrogen engage to form a tetrahedral intermediate (TI) that is an unprecedented functional group, a 1,1,1-halo-amino-nitro alkane (HANA). Studies probing HANA transience have failed to capture this (presumably) highly reactive intermediate. We report here the direct observation of a HANA, its conversion thermally to an amide functionality, and quantitative analysis of this process using computational techniques. These findings validate the HANA as a functional group common to UmAS and diverted UmAS, opening the door to its targeted use and creative manipulation., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Since the propagation of plant viruses depends on various host susceptibility factors, deficiency in them can prevent viral infection in cultivated and model plants. Recently, we identified the susceptibility factor Essential for poteXvirus Accumulation 1 (EXA1) in Arabidopsis thaliana, and revealed that EXA1-mediated resistance was effective against three potexviruses. Although EXA1 homolog genes are found in tomato and rice, little is known about which viruses depend on EXA1 for their infection capability and whether the function of EXA1 homologs in viral infection is conserved across multiple plant species, including crops. To address these questions, we generated knockdown mutants using virus-induced gene silencing in two Solanaceae species, Nicotiana benthamiana and tomato. In N. benthamiana, silencing of an EXA1 homolog significantly compromised the accumulation of potexviruses and a lolavirus, a close relative of potexviruses, whereas transient expression of EXA1 homologs from tomato and rice complemented viral infection. EXA1 dependency for potexviral infection was also conserved in tomato. These results indicate that EXA1 is necessary for effective accumulation of potexviruses and a lolavirus, and that the function of EXA1 in viral infection is conserved among diverse plant species.

G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G-protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders. A novel series of 1-(benzothiophen-7-yl)-1H-pyrazole as GPR52 agonists was designed and synthesized based on compound 1b. Compound 1b has been reported by our group as the first orally active GPR52 agonist, but high lipophilicity and poor aqueous solubility still remained as issues for candidate selection. To resolve these issues, replacement of the benzene ring at the 7-positon of compound 1b with heterocylic rings, such as pyrazole and pyridine, was greatly expected to reduce lipophilicity to levels for which calculated logD values were lower than that of compound 1b. While evaluating the pyrazole derivatives, introduction of a methyl substituent at the 3-position of the pyrazole ring led to increased GPR52 agonistic activity. Moreover, additional methyl substituent at the 5-position of the pyrazole and further introduction of hydroxy group to lower logD led to significant improvement of solubility while maintaining the activity. As a result, we identified 3-methyl-5-hydroxymethyl-1H-pyrazole derivative 17 (GPR52 EC 50  = 21 nM, E max  = 103%, logD = 2.21, Solubility at pH 6.8 = 21 μg/mL) with potent GPR52 agonistic activity and good solubility compared to compound 1b. Furthermore, this compound 17 dose-dependently suppressed methamphetamine-induced hyperlocomotion in mice., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the clinical outcome of endoscopic submucosal dissection using the Clutch Cutter (ESDCC) in older patients., Methods: We reviewed 232 consecutive patients with early gastric cancer who underwent ESDCC between June 2010 and February 2014 at Aso Iizuka Hospital. We divided patients into two groups according to age: Older patients (> 80 years, n = 64) and non-older patients (≤ 80 years, n = 168). We retrospectively compared the prevalence rates of pre-existing comorbidities, anticoagulant therapy, en bloc resection, mean duration of hospitalization, incidence of ESDCC-related complications, change in performance status (PS) before and after ESDCC, and financial cost of admission., Results: The older group comprised 64 patients with a mean age of 84.1 years, and the non-older group comprised 168 patients with a mean age of 69.5 years. Older patients had significantly more pre-existing comorbidities than did non-older patients, specifically heart disease ( P < 0.05). The en bloc resection rate in non-older patients was significantly higher than that in older patients (100% vs 95.3%, P = 0.02). There were no significant differences between the older and non-older groups in the incidence of ESDCC-related complications ( i.e ., postoperative bleeding and perforation) and the post-ESDCC change in PS. There were also no significant differences between the older and non-older groups in the mean duration of hospitalization (11.4 and 10.7 d, respectively) and financial cost of admission (657040 JPY and 574890 JPY, respectively)., Conclusion: ESDCC has a good clinical outcome in older patients., Competing Interests: Conflict-of-interest statement: Kazuya Akahoshi and Hidefumi Akahane (Fujifilm) have applied for a patent in Europe for the CC described in this article. Japan, China, and the United States have already granted patents.

Umpolung Amide Synthesis (UmAS) has emerged as a superior alternative to conventional amide synthesis methods based on carbonyl electrophiles in a range of situations, particularly when epimerization-prone couplings are prescribed. In an unanticipated development during our most recent studies, it was discovered that diacyl hydrazide products from UmAS were not formed as intermediates when using an acyl hydrazide as the amine acceptor. This resulted in a new preparation of 1,3,4-oxadiazoles from α-bromonitroalkane donors. We hypothesized that a key tetrahedral intermediate in UmAS was diverted toward a more direct pathway to the heterocycle product rather than through formation of the diacyl hydrazide, a typical oxadiazole progenitor. In studies reported here, diversion to 1,2,4-triazole products is described, a behavior hypothesized to also result from an analogous tetrahedral intermediate, but one formed from heteroaromatic hydrazine acceptors.

Aim: To evaluate the efficacy and safety of endoscopic submucosal dissection (ESD) using the clutch cutter (CC) (ESD-CC) for gastric adenoma (GA)., Methods: From June 2007 to August 2015, 122 consecutive patients with histological diagnoses of GA from specimens resected by ESD-CC were enrolled in this prospective study. The CC was used for all ESD steps (marking, mucosal incision, submucosal dissection, and hemostatic treatment), and its therapeutic efficacy and safety were assessed., Results: Both the en-bloc resection rate and the R0 resection rate were 100% (122/122). The mean surgical time was 77.4 min, but the time varied significantly according to tumor size and location. No patients suffered perforation. Post-ESD-CC bleeding occurred in six cases (4.9%) that were successfully resolved by endoscopic hemostatic treatment., Conclusion: ESD-CC is a technically efficient, safe, and easy method for resecting GA., Competing Interests: Conflict-of-interest statement: Kazuya Akahoshi and Hidefumi Akahane (FUJIFILM) have applied for the patent in Europe for the Clutch Cutter described in this article. Japan, China, and the United states have already granted the patent. The authors claim no other conflicts of interest.

G protein-coupled receptor 52 (GPR52) agonists are expected to improve the symptoms of psychiatric disorders. During exploration for a novel class of GPR52 agonists with good pharmacokinetic profiles, we synthesized 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (4u; half maximal effective concentration (EC 50 )=75nM, maximal response (E max )=122%) starting from a high-throughput screening hit 3 (EC 50 =470nM, E max =56%). The structural features of a reported GPR52 agonist were applied to 3, led to design 4-azolylbenzamides as novel GPR52 agonists. A structure-activity relationship study of 4-azolylbenzamide resulted in the design of the 1,2,4-triazole derivative 4u, which demonstrated excellent bioavailability in rats (F=53.8%). Oral administration of 4u (10mg/kg) significantly suppressed methamphetamine-induced hyperlocomotion in mice. Thus, 4u is a promising lead compound for drug discovery research of GPR52 agonists., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The design of organic compounds with nearly no gap between the first excited singlet (S 1 ) and triplet (T 1 ) states has been demonstrated to result in an efficient spin-flip transition from the T 1 to S 1 state, that is, reverse intersystem crossing (RISC), and facilitate light emission as thermally activated delayed fluorescence (TADF). However, many TADF molecules have shown that a relatively appreciable energy difference between the S 1 and T 1 states (~0.2 eV) could also result in a high RISC rate. We revealed from a comprehensive study of optical properties of TADF molecules that the formation of delocalized states is the key to efficient RISC and identified a chemical template for these materials. In addition, simple structural confinement further enhances RISC by suppressing structural relaxation in the triplet states. Our findings aid in designing advanced organic molecules with a high rate of RISC and, thus, achieving the maximum theoretical electroluminescence efficiency in organic light-emitting diodes.

The 1,3,4-oxadiazole is an aromatic heterocycle valued for its low-lipophilicity in drug development. Substituents at the 2- and/or 5-positions can modulate the heterocycle's electronic and hydrogen bond-accepting capability, while exploiting its use as a carbonyl bioisostere. A new approach to 1,3,4-oxadiazoles is described wherein α-bromo nitroalkanes are coupled to acyl hydrazides to deliver the 2,5-disubstituted oxadiazole directly, avoiding a 1,2-diacyl hydrazide intermediate. Access to new building blocks of oxadiazole-substituted secondary amines is improved by leveraging chiral α-bromo nitroalkane or amino acid hydrazide substrates. The non-dehydrative conditions for oxadiazole synthesis are particularly notable, in contrast to alternatives reliant on highly oxophilic reagents to effect cyclization of unsymmetrical 1,2-diacyl hydrazides. The mild conditions are punctuated by the straightforward removal of co-products by a standard aqueous wash.

Background and study aims  Endoscopic snare polypectomy with prophylactic detachable snare of large pedunculated colonic polyps (PCPs) is technically demanding. To facilitate removal of such polyps, we developed endoscopic resection using the Clutch Cutter and a detachable snare (ERCCDS). This study aimed to evaluate the efficacy and safety of the procedure. Patients and methods  From April 2010 to July 2015, 14 consecutive patients who had PCPs with head > 10 mm, stalk width > 5 mm, and stalk length > 10 mm were enrolled in this single-center prospective uncontrolled study. They were treated using ERCCDS by a single endoscopist. The efficacy and safety were assessed using a database prospectively formatted from the medical records. Results  The Clutch Cutter was able to cut the distal side of the stalk an adequate distance from the detachable snare under good visual control. R0 resections were obtained in all lesions. There were no immediate or delayed complications. Conclusions  ERCCDS appears to be a safe, easy, and technically efficient method for large PCPs, although larger studies are needed to compare ERCCDS and standard resection., (© Georg Thieme Verlag KG Stuttgart · New York.)

A series of benzofuran derivatives with neuroprotective activity in collaboration with IGF-1 was discovered using a newly developed cell-based assay involving primary neural cells prepared from rat hippocampal and cerebral cortical tissues. A structure-activity relationship study identified compound 8 as exhibiting potent activity and brain penetrability. An in vitro pharmacological study demonstrated that although IGF-1 and 8 individually exhibited the neuroprotective effect, the latter acted in collaboration with IGF-1 to enhance neuroprotective activity.

Background and Study Aims: The Clutch Cutter (CC) was developed to reduce the risk of complications related to endoscopic submucosal dissection (ESD) using knives. The CC is able to grasp and coagulate and/or incise the targeted tissue using electrosurgical current, like a biopsy technique. The aim of this study was to evaluate the efficacy and safety of ESD using the CC (ESD-CC) for early gastric cancer (EGC)., Patients and Methods: From June 2007 to March 2014, 325 consecutive patients with a diagnosis of EGC were enrolled in this prospective study. They had all satisfied the Japanese gastric cancer treatment guidelines for ESD indication, namely confirmation by preliminary endoscopy, endoscopic ultrasound, and endoscopic biopsies. The CC was used for all steps of ESD (marking, circumferential marginal incision, submucosal dissection, and hemostatic treatment). The therapeutic efficacy and safety were assessed., Results: The en-bloc resection rate was 99.7 % (324/325) and the R0 resection rate was 95.3 % (310/325). The mean operating time was 97.2 minutes. Perforation during ESD-CC occurred in one case (0.3 %), which was managed with conservative medical treatment after endoscopic closure of the perforation. Post-ESD-CC bleeding occurred in 11 cases (3.4 %), which were successfully treated by endoscopic hemostatic treatment. The R0 resection rate was significantly low in tumors > 20 mm (88.9 %), and in the exclusion indication group (73.7 %). Significant differences were seen in the mean operating time, depending upon tumor size, histologic type, location, and indication criteria., Conclusions: ESD-CC is a technically efficient, safe, and easy method for resecting EGC.