Publications by authors named "Daisuke Yamaguchi"

101 Publications

Sorafenib Rechallenge and Sorafenib after Lenvatinib Failure in a Patient with Hepatocellular Carcinoma.

Intern Med 2021 1;60(3):403-407. Epub 2021 Feb 1.

Department of Gastroenterology and Hepatology, Kyoto Katsura Hospital, Japan.

A 70-year-old man was diagnosed with multiple lung metastases from hepatocellular carcinoma, and lenvatinib was initiated. Three months later, the response was progressive disease. Sorafenib therapy as a second-line drug was started. Three months later, the lung metastases had shrunk. After the sorafenib failure, the patient received regorafenib treatment for six months until failure. After the regorafenib failure, sorafenib rechallenge therapy as a fourth-line treatment was initiated. The sorafenib rechallenge, which continued for two months, induced a partial response. Sorafenib after lenvatinib failure and sorafenib rechallenge may be a good option, but further prospective studies are needed.
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http://dx.doi.org/10.2169/internalmedicine.5552-20DOI Listing
February 2021

Gut microbiota changes related to Helicobacter pylori eradication with vonoprazan containing triple therapy among adolescents: a prospective multicenter study.

Sci Rep 2021 Jan 12;11(1):755. Epub 2021 Jan 12.

Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan.

Currently, it is unclear whether treating Helicobacter pylori (H. pylori) infection is safe among adolescents. This study aimed to evaluate the safety of H. pylori eradication therapy by examining gut microbiota changes in adolescents 3 months after the therapy. H. pylori-infected adolescents were enrolled in this study. Their stool samples were collected at the following three time points: before treatment, 1-2 days after completion of treatment, and time of eradication successful judgment. We assessed the relative abundance, alpha-diversity, and beta-diversity of the gut microbiota and adverse events. The number of isolated Actinobacteria decreased immediately after eradication therapy in the 16 students included in the study, and it returned to pretreatment condition at the eradication judgment point. There was no change in the relative abundance at genus level. The alpha-diversity was lost immediately after eradication therapy; however, it recovered at the time of eradication judgment, and it was restored to pretreatment condition. Meanwhile, none of the participants experienced serious adverse events. H. pylori eradication therapy is safe for adolescents with respect to gut microbiota changes associated with H. pylori eradication therapy. Therefore, further long-term evaluations of gut microbiota changes following eradication therapy are warranted.
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http://dx.doi.org/10.1038/s41598-020-80802-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804423PMC
January 2021

Successful retrograde transvenous embolization under balloon occlusion for rectal arteriovenous malformation.

Clin J Gastroenterol 2021 Jan 8. Epub 2021 Jan 8.

Department of Gastroenterology, National Hospital Organization Ureshino Medical Center, Ureshino, Japan.

A 57-year-old man was admitted to our hospital because of frequent hematochezia. Colonoscopy exhibited a submucosal tumor-like lesion in the lower rectum. Abdominal contrast-enhanced computed tomography showed a rectal arteriovenous malformation (AVM) on the right side wall of the lower rectum. The feeder was the superior rectal artery, with early venous return. Embolization of the draining vein and feeding artery of the AVM with N-butyl-2-cyanoacrylate under balloon occlusion was planned. Angiography of the superior rectal artery showed the nidus in the rectum with early venous return of contrast material. The portal vein was punctured percutaneously under ultrasound guidance, and a balloon catheter advanced to the distal part of the superior rectal vein. Venography under balloon occlusion showed the outflow vein and nidus. Transvenous and transarterial nidus embolization with N-butyl-2-cyanoacrylate under balloon occlusion was then performed. Since the embolization, there have been no further episodes of bleeding. There is no established treatment for AVMs. Successful treatment requires targeting and eradication of the nidus. We successfully performed embolization therapy for a rectal AVM via a retrograde transvenous approach. This technique may be suitable for completely eradicating the nidus without the risk of embolism.
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http://dx.doi.org/10.1007/s12328-020-01335-wDOI Listing
January 2021

The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma.

Am J Cancer Res 2020 1;10(12):4399-4415. Epub 2020 Dec 1.

R&D Division, Kyowa Kirin Co., Ltd Shizuoka, Japan.

The Hippo signaling pathway regulates cell fate and organ development. In the Hippo pathway, transcriptional enhanced associate domain (TEAD) which is a transcription factor is activated by forming a complex with yes-associated protein 1 (YAP1) or transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1). Hyper-activation of YAP1/TAZ, leading to the activation of TEAD, has been reported in many cancers, including malignant pleural mesothelioma (MPM). Therefore, the YAP1/TAZ-TEAD complex is considered a novel therapeutic target for cancer treatment. However, few reports have described YAP1/TAZ-TEAD inhibitors, and their efficacy and selectivity are poor. In this study, we performed a high-throughput screening of a neurofibromin 2 (NF2)-deficient MPM cell line and a large tumor suppressor kinase 1/2 (LATS1/2)-deficient non-small-cell lung cancer cell line using a transcriptional reporter assay. After screening and optimization, K-975 was successfully identified as a potent inhibitor of YAP1/TAZ-TEAD signaling. X-ray crystallography revealed that K-975 was covalently bound to an internal cysteine residue located in the palmitate-binding pocket of TEAD. K-975 had a strong inhibitory effect against protein-protein interactions between YAP1/TAZ and TEAD in cell-free and cell-based assays. Furthermore, K-975 potently inhibited the proliferation of NF2-non-expressing MPM cell lines compared with NF2-expressing MPM cell lines. K-975 also suppressed tumor growth and provided significant survival benefit in MPM xenograft models. These findings indicate that K-975 is a strong and selective TEAD inhibitor with the potential to become an effective drug candidate for MPM therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783735PMC
December 2020

Gastrointestinal adverse reactions reduce the success rate of Helicobacter pylori eradication therapy: A multicenter prospective cohort study.

Helicobacter 2020 Dec 23:e12776. Epub 2020 Dec 23.

Department of Gastroenterology, International University of Health and Welfare, Okawa, Japan.

Background: The screening and treatment of Helicobacter pylori infection for all junior high students in Saga Prefecture, Japan, were started in 2016. The present study aims to evaluate the influence of adverse reactions on the success of the eradication therapy.

Methods: From 2017 to 2019, 25,006 third-grade junior high school students were tested for urinary anti-H. pylori antibodies. Positive cases were confirmed by H. pylori stool antigen tests. Of the 531 students who were found to be H. pylori-positive, 390 (358 in first-line and 32 in second-line therapy) underwent eradication therapy, and 274 (242 in first-line and 32 in second-line) students actually completed a self-reported form to rate stool consistency (based on the Bristol Stool Scale), the maximum number of bowel movements, and abdominal symptoms during the 7 days of treatment.

Results: Among the 274 students, the total of primary and secondary eradication success rates was 87% (95% confidential interval: 82.9-90.1) in intention-to-treat analysis. On days 4, 5, and 6, stool consistency was looser in the primary eradication failure group than in the success group (p < .05). Looser stool consistencies were observed in male students with abdominal pain compared to those who did not experience pain (p < .05). Abdominal pain and diarrhea were detected in 28.5% and 42.7% of the subjects, respectively. The overall incidence of other adverse events was low (n = 8/274, 2.9%), and only two students discontinued treatment because of adverse events.

Conclusions: Softening of the stool was related to the eradication failure in the junior high school students, especially in males with abdominal pain. Adverse effects did not induce discontinuation of the eradication treatment.
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http://dx.doi.org/10.1111/hel.12776DOI Listing
December 2020

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Hum Mutat 2021 Jan 11;42(1):50-65. Epub 2020 Nov 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
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http://dx.doi.org/10.1002/humu.24129DOI Listing
January 2021

Guidelines for sedation in gastroenterological endoscopy (second edition).

Dig Endosc 2021 Jan 9;33(1):21-53. Epub 2020 Dec 9.

Japanese Gastroenterological Endoscopy Society, Tokyo, Japan.

Sedation in gastroenterological endoscopy has become an important medical option in routine clinical care. Here, the Japan Gastroenterological Endoscopy Society and the Japanese Society of Anesthesiologists together provide the revised "Guidelines for sedation in gastroenterological endoscopy" as a second edition to address on-site clinical questions and issues raised for safe examination and treatment using sedated endoscopy. Twenty clinical questions were determined and the strength of recommendation and evidence quality (strength) were expressed according to the "MINDS Manual for Guideline Development 2017." We were able to release up-to-date statements related to clinical questions and current issues relevant to sedation in gastroenterological endoscopy (henceforth, "endoscopy"). There are few reports from Japan in this field (e.g., meta-analyses), and many aspects have been based only on a specialist consensus. In the current scenario, benzodiazepine drugs primarily used for sedation during gastroenterological endoscopy are not approved by national health insurance in Japan, and investigations regarding expense-related disadvantages have not been conducted. Furthermore, including the perspective of beneficiaries (i.e., patients and citizens) during the creation of clinical guidelines should be considered. These guidelines are standardized based on up-to-date evidence quality (strength) and supports on-site clinical decision-making by patients and medical staff. Therefore, these guidelines need to be flexible with regard to the wishes, age, complications, and social conditions of the patient, as well as the conditions of the facility and discretion of the physician.
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http://dx.doi.org/10.1111/den.13882DOI Listing
January 2021

Thermally tunable selective formation of self-assembled fibers into two orthogonal directions in oriented liquid-crystalline smectic templates.

Chem Commun (Camb) 2020 Sep 17;56(69):9954-9957. Epub 2020 Jul 17.

Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

We demonstrate the formation of grid-type (crossed perpendicular to each other) fibrous assemblies of low-molecular-weight gelators in aligned liquid-crystalline smectic templates. In the template of layered structures, a gelator forms oriented fibers with one directional and two orthogonal directional (grid-like) alignment depending on the order of layered structures.
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http://dx.doi.org/10.1039/d0cc01950jDOI Listing
September 2020

The Association of Depression with Type D Personality and Coping Strategies in Patients with Coronary Artery Disease.

Intern Med 2020 1;59(13):1589-1595. Epub 2020 Jul 1.

School of Health Sciences, Shinshu University, Japan.

Objective Depression in patients with coronary artery disease (CAD) has been a risk factor for adverse cardiovascular events. However, personality types, strategies for coping with stressors, and their associations with depression have not been fully elucidated in patients with CAD. This study explored depression in patients with CAD and examined its association with personality types and coping strategies. Methods A prospective observational study of 89 patients with CAD was conducted between August 2016 and July 2018. The presence of depression and type D personality and types of coping strategies were measured one month after percutaneous coronary intervention. A logistic regression analysis was performed to identify characteristics associated with depression. Results Generally, the incidence of depression and type D personality was 55.1% and 44.9%, respectively. The incidence of depression in patients with type D and non-type D personality was 72.5% and 40.8%, respectively. Patients with type D personality coped less frequently using a planning strategy but frequently using a responsibility-shifting strategy. A logistic regression analysis showed that the presence of depression was significantly associated with type D personality and inversely associated with a planning strategy. Conclusion The high prevalence of depression in patients with CAD was associated with type D personality and a low rate of adoption of a planning strategy. Specific coping interventions in patients with CAD with type D personality may be potential targets for improving coping skills and preventing the development of depression.
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http://dx.doi.org/10.2169/internalmedicine.3803-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402968PMC
October 2020

A Relatively Small Gradient of Extracellular pH Directs Migration of MDA-MB-231 Cells In Vitro.

Int J Mol Sci 2020 Apr 7;21(7). Epub 2020 Apr 7.

Graduate School of Advanced Health Sciences, Saga University, Honjyo Machi 1, Saga 840-8502, Japan.

Hematogenous tumor metastasis begins with the invasion and spread of primary tumor cells in the local tissue leading to intravasation. We hypothesized that tumor cells might actively migrate toward intratumor vessels with the extracellular metabolic gradient acting as a guiding cue. Here, we determined in vitro whether the extracellular gradient of pH can act as a cue for directional migration in MDA-MB-231 cells. Cell migration was determined by the wound-healing assay under gradients of extracellular pH (~0.2 units/mm) and oxygen concentration (~6% O/mm) that were produced by a microfluidic device, gap cover glass (GCG). Without GCG, the migration of cells was spatially homogeneous; the same number of cells migrated to the rectangular wound space from the left and right boundaries. In contrast, when GCG generated pH/O gradients across the wound space, the number of cells migrating to the wound space from the boundary with higher pH/O values was considerably decreased, indicating a preferential movement of cells toward the region of higher pH/O in the gradient. The addition of hepes in the extracellular medium abolished both the extracellular pH gradient and the directional cell migration under GCG. We conclude that relatively small gradients of pH in the extracellular medium compared to those found in Na/H exchanger-driven cell migration were sufficient to guide MDA-MB-231 cells. The directional cell migration as guided by the metabolic gradient could effectively elevate the probability of intravasation and, ultimately, hematogenous metastasis.
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http://dx.doi.org/10.3390/ijms21072565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177698PMC
April 2020

Thyroid Dysfunction Related to the Antiangiogenic VEGFR2-Binding Monoclonal Antibody Ramucirumab: A Series of 14 Cases and a Descriptive Study.

Biol Pharm Bull 2020 ;43(4):752-756

Department of Pharmacy, Shiga University of Medical Science Hospital.

Hypothyroidism is a well-established toxicity of small-molecule anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors. However, its association with anti-VEGF biologics is uncertain. The aim of this study was to investigate the incidence, time course, clinical features, and severity of thyroid dysfunction in patients receiving ramucirumab (an antiangiogenic VEGF receptor 2-binding monoclonal antibody). After retrospectively reviewing electronic medical records from September 2015 to December 2018 at Kyoto-Katsura Hospital, we identified 38 patients who received ramucirumab and had thyroid function testing available to review (case series). We also evaluated the change of thyroid-stimulating hormone (TSH) level during ramucirumab chemotherapy in 16 out of 38 patients who were regularly confirmed TSH (descriptive study). A total of 14 (36.8%) patients developed thyroid dysfunction (TSH >10 mU/L) after ramucirumab chemotherapy. Thyroid autoantibodies were detected in one of the 10 patients (10.0%) who were tested for thyroid autoantibodies. The median time to onset of thyroid dysfunction after ramucirumab initiation was 275 (range, 63-553) days. Levothyroxine replacement was needed in 10 (71.4%) patients. Sixteen patients had thyroid function regularly monitored; the mean TSH level was significantly increased after ramucirumab chemotherapy compared with that at baseline (10.7 ± 10.0 mU/L vs. 4.1 ± 2.8 mU/L; p < 0.01). Our findings indicate that ramucirumab can result in thyroid dysfunction. We propose that thyroid function testing should be performed regularly to detect hypothyroidism and guide its management in patients receiving ramucirumab chemotherapy.
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http://dx.doi.org/10.1248/bpb.b19-01071DOI Listing
November 2020

Shear-induced liquid-crystalline phase transition behaviour of colloidal solutions of hydroxyapatite nanorod composites.

Nanoscale 2020 Jun 30;12(21):11468-11479. Epub 2020 Mar 30.

Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.

Liquid-crystalline (LC) bio-inspired materials based on colloidal nanoparticles with anisotropic morphologies such as sheets, plates, rods and fibers were used as functional materials. They show stimuli-responsive behaviour under mechanical force and in electric and magnetic fields. Understanding the effects of external stimuli on the structures of anisotropic colloidal particles is important for the development of highly ordered structures. Recently, we have developed stimuli-responsive hydroxyapatite (HAP)-based colloidal LC nanorods that are environmentally-friendly functional materials. In the present study, the ordering behaviour of HAP nanorod dispersions, which show LC states, has been examined using in situ small-angle neutron scattering and rheological measurements (Rheo-SANS) under shearing force. The structural analyses and dynamic viscosity observations provided detailed information about the effects of shear force on the structural changes of HAP nanorods in DO dispersion. The present Rheo-SANS measurements unraveled three kinds of main effects of the shear force: the enhancement of interactions between the HAP nanorods, the alignment of HAP nanorods to the shear flow direction, and the formation and disruption of HAP nanorod assemblies. Simultaneous analyses of dynamic viscosity and structural changes revealed that the HAP nanorod dispersions exhibited distinctive rheological properties accompanied by their ordered structural changes.
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http://dx.doi.org/10.1039/c9nr10996jDOI Listing
June 2020

Effect of probiotics during vonoprazan-containing triple therapy on gut microbiota in Helicobacter pylori infection: A randomized controlled trial.

Helicobacter 2020 Jun 24;25(3):e12690. Epub 2020 Mar 24.

Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.

Background: Probiotics are beneficial to patients with Helicobacter pylori infections by modulating the gut microbiota. Biofermin-R (BFR) is a multiple antibiotic-resistant lactic acid bacteria preparation of Enterococcus faecium 129 BIO 3B-R and is effective in normalizing the gut microbiota when used in combination with antibiotics. This study aimed to determine the effect of BFR in combination with vonoprazan (VPZ)-based therapy on gut microbiota.

Methods: Patients with positive urinary anti-H pylori antibody test (primary test) and fecal H pylori antigen test (secondary test) were examined. Patients in group 1 (BFR ) received VPZ (20 mg twice daily), amoxicillin (750 mg twice daily), and clarithromycin (400 mg twice daily) for 7 days. Patients in group 2 (BFR ) received BFR (3 tablets/day) for 7 days, in addition to the aforementioned treatments. Following treatment, the relative abundance, α-diversity, and β-diversity of gut microbiota were assessed.

Results: Supplementation with BFR prevented the decrease in a-diversity after eradication therapy (Day 7). β-diversity was similar between groups. The incidence rate of diarrhea was non-significantly higher in the BFR than in the BFR group (73.1% vs 56.5%; P = .361). Stool consistency was comparable in the BFR group on Days 7 and 1 (3.86 ± 0.95 vs 3.86 ± 1.46; P = .415).

Conclusion: Biofermin-R combined with VPZ-based therapy resulted in higher microbial α-strain diversity and suppressed stool softening during H pylori eradication therapy.
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http://dx.doi.org/10.1111/hel.12690DOI Listing
June 2020

An Investigation of Nine Patients with Gastrointestinal Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors.

Digestion 2020 4;101(1):60-65. Epub 2019 Dec 4.

International University of Health and Welfare Graduate School, Fukuoka, Japan.

Introduction/aims: Immune checkpoint inhibitors (ICIs) sometimes cause immune-related adverse events (irAEs), of which there is little information in the literatures. The objective of this study was to characterize the clinical features of gastrointestinal irAEs (GI irAEs).

Materials And Methods: From a total of 250 patients who were administered anti-PD-1 antibodies (nivolumab and pembrolizumab), we retrospectively identified 9 patients with grade 2 or higher GI irAE based on medical records. Patient characteristics, clinical features, imaging and pathological findings, and treatment course were evaluated.

Results: Grade 2 or higher GI irAEs were observed in 9 (3.6%) patients. Of the 9 patients who experienced GI irAE, 8 were male, and mean age was 63.2 years. Five patients received nivolumab and 4 received pembrolizumab. The GI irAEs observed were diarrhea in 7 patients and bloody stool in 2 patients. Grade 2 GI irAEs were identified in 3 patients and grade 3 GI irAEs in 6 patients. The average time from ICI administration to the onset of GI irAEs was 22.2 weeks (range 7-56 weeks) for nivolumab and 19.7 weeks (range 11-28 weeks) for pembrolizumab. Endoscopic findings showed ulcerative colitis-like findings in 3 of 7 patients, and pathological examination revealed crypt epithelial cell apoptosis in 6 of 7 patients. Eight of the 9 patients received steroids, and 2 patients received infliximab additionally. All GI irAEs were manageable.

Conclusions: Because of the lack of specific clinical, imaging, and pathological findings, information of ICI use was indispensable for diagnosis. Although GI irAEs are controllable by steroid and infliximab, further studies regarding management strategy will be needed.
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http://dx.doi.org/10.1159/000504647DOI Listing
August 2020

Colorectal endoscopic mucosal resection with submucosal injection of epinephrine versus hypertonic saline in patients taking antithrombotic agents: propensity-score-matching analysis.

BMC Gastroenterol 2019 Nov 19;19(1):192. Epub 2019 Nov 19.

Department of Internal Medicine, Saga Medical School, Saga, Japan.

Background: Endoscopic mucosal resection (EMR) to remove colon polyps is increasingly common in patients taking antithrombotic agents. The safety of EMR with submucosal saline injection has not been clearly demonstrated in this population.

Aims: The present study aimed to evaluate the efficacy and safety of submucosal injection of saline-epinephrine versus hypertonic saline in colorectal EMR of patients taking antithrombotic agents.

Methods: This study enrolled 204 patients taking antithrombotic agents among 995 consecutive patients who underwent colonic EMR from April 2012 to March 2018 at Ureshino Medical Center. Patients were divided into two groups according to the injected solution: saline-epinephrine or hypertonic (10%) saline (n = 102 in each group). Treatment outcomes and adverse events were evaluated in each group and risk factors for immediate and post-EMR bleeding were investigated.

Results: There were no differences between groups in patient or polyp characteristics. The main antithrombotic agents were low-dose aspirin, warfarin, and clopidogrel. Propensity-score matching created 80 matched pairs. Adjusted comparisons between groups showed similar en bloc resection rates (95.1% with saline-epinephrine vs. 98.0% with hypertonic saline). There were no significant differences in adverse events (immediate EMR bleeding, post-EMR bleeding, perforation, or mortality) between groups. Multivariate analyses revealed that polyp size over 10 mm was associated with an increased risk of immediate EMR bleeding (odds ratio 12.1, 95% confidence interval 2.0-74.0; P = 0.001).

Conclusions: Two tested solutions in colorectal EMR were considered to be both safe and effective in patients taking antithrombotic agents.
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http://dx.doi.org/10.1186/s12876-019-1114-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862827PMC
November 2019

Ultrafast isomerization-induced cooperative motions to higher molecular orientation in smectic liquid-crystalline azobenzene molecules.

Nat Commun 2019 Sep 13;10(1):4159. Epub 2019 Sep 13.

Department of Chemistry & Biotechnology, School of Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.

The photoisomerization of molecules is widely used to control the structure of soft matter in both natural and synthetic systems. However, the structural dynamics of the molecules during isomerization and their subsequent response are difficult to elucidate due to their complex and ultrafast nature. Herein, we describe the ultrafast formation of higher-orientation of liquid-crystalline (LC) azobenzene molecules via linearly polarized ultraviolet light (UV) using ultrafast time-resolved electron diffraction. The ultrafast orientation is caused by the trans-to-cis isomerization of the azobenzene molecules. Our observations are consistent with simplified molecular dynamics calculations that revealed that the molecules are aligned with the laser polarization axis by their cooperative motion after photoisomerization. This insight advances the fundamental chemistry of photoresponsive molecules in soft matter as well as their ultrafast photomechanical applications.
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http://dx.doi.org/10.1038/s41467-019-12116-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744564PMC
September 2019

Structural colour using organized microfibrillation in glassy polymer films.

Nature 2019 06 19;570(7761):363-367. Epub 2019 Jun 19.

Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, Japan.

The formation of microscopic cavities and microfibrils at stress hotspots in polymers is typically undesirable and is a contributor to material failure. This type of stress crazing is accelerated by solvents that are typically weak enough not to dissolve the polymer substantially, but which permeate and plasticize the polymer to facilitate the cavity and microfibril formation process. Here we show that microfibril and cavity formation in polymer films can be controlled and harnessed using standing-wave optics to design a periodic stress field within the film. We can then develop the periodic stress field with a weak solvent to create alternating layers of cavity and microfibril-filled polymers, in a process that we call organized stress microfibrillation. These multi-layered porous structures show structural colour across the full visible spectrum, and the colour can be tuned by varying the temperature and solvent conditions under which the films are developed. By further use of standard lithographic and masking tools, the organized stress microfibrillation process becomes an inkless, large-scale colour printing process generating images at resolutions of up to 14,000 dots per inch on a number of flexible and transparent formats.
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http://dx.doi.org/10.1038/s41586-019-1299-8DOI Listing
June 2019

Propofol Sedation in the Endoscopy Room versus Operation Room during Endoscopic Submucosal Dissection for Gastric Tumors: A Propensity Score-Matching Analysis.

Digestion 2020 24;101(4):450-457. Epub 2019 May 24.

Department of Internal Medicine, Saga Medical School, Saga, Japan.

Background/aims: The present study was performed to compare the safety of sedation with propofol during endoscopic submucosal dissection (ESD) for gastric tumors under sedation in the endoscopy room by an endoscopist versus sedation in the operation room by an anesthesiologist.

Methods: In total, 638 patients with gastric tumors who underwent ESD from January 2011 to August 2017 at Ureshino Medical Center and Saga Medical Center Koseikan were retrospectively reviewed. The patients were divided into 2 groups: those who underwent ESD in the endoscopy room (Group E, n = 532) and those who underwent ESD in the operation room (Group O, n = 106). Propensity score matching was applied for evaluation. The treatment outcome of ESD and the adverse events of sedation during ESD (desaturation, hypotension, bradycardia, and arrhythmia) were compared between the 2 groups to consider the safety of ESD.

Results: The propensity score-matching analysis created 82 matched pairs. Adjusted comparisons between Groups E and O showed similar treatment outcomes of ESD for gastric tumors. There were no significant differences in the treatment outcomes, anesthesia time, and mean propofol dose between the 2 groups. With respect to adverse events, desaturation occurred more often in Group E than Group O (18.3 vs. 3.7%, respectively; p = 0.005). There were no significant differences in other adverse events (hypotension, bradycardia, and arrhythmia) between the 2 groups.

Conclusion: Sedation with propofol in the operation room might be required to ensure safer application of ESD for gastric tumors. However, a decrease in the desaturation rate was the only disadvantage of sedation in the endoscopy room.
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http://dx.doi.org/10.1159/000500874DOI Listing
May 2019

Nicotinamide phosphoribosyltransferase is a molecular target of potent anticancer agents identified from phenotype-based drug screening.

Sci Rep 2019 05 23;9(1):7742. Epub 2019 May 23.

R&D Planning Department, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1-9-2, Ote-machi, Chiyoda-ku, Tokyo, 100-0004, Japan.

Phenotypic screening in drug discovery has been revived with the expectation of providing promising lead compounds and drug targets and improving the success rate of drug approval. However, target identification remains a major bottleneck in phenotype-based drug discovery. We identified the lead compounds K542 and K405 with a selective inhibition of cell viability against sphingosine-1-phosphate lyase 1 (SGPL1)-transduced ES-2 cells by phenotypic screening. We therefore performed an in vivo pharmacological examination and observed the antitumor activity of K542 in an HT-1080 tumor-bearing mouse xenograft model. SGPL1 was expected to be a therapeutic target in some cancers, suggesting that these lead molecules might be promising candidates; however, their mechanisms of action still remain unexplained. We therefore synthesized the affinity probe Ind-tag derived from K542 and identified the proteins binding to Ind-tag via a pull-down experiment. Proteomics and biochemical analyses revealed that the target molecule of these lead compounds was Nicotinamide phosphoribosyltransferase (NAMPT). We established K542-resistant DLD-1 and HT-1080 cells, and genetic analyses of these cells identified a missense mutation in the NAMPT-encoding gene. This enzymatic experiment clearly showed that K393 exerts enzymatic inhibition against NAMPT. These proteomics, genetics and biochemical analyses clarified that compounds K542 and K405 were NAMPT inhibitors.
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http://dx.doi.org/10.1038/s41598-019-43994-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533267PMC
May 2019

Modeling and Validation of Vertical Direction Force Estimation with a Three-Dimensional Force Measurement Instrument Based on a Zero-Compliance Mechanism.

Sensors (Basel) 2019 Feb 15;19(4). Epub 2019 Feb 15.

Department of Mechanical Engineering, Saitama University, Saitama 338-8570, Japan.

The principle of a zero-compliance mechanism was used to develop a three-dimensional force measurement instrument. In each axis, the point of force is suspended by a zero-compliance mechanism. A vertical axis force estimation operation imitates the structure of a double series magnetic suspension system. An electromagnet directly controls the movement of the first suspended object (floator), which is denoted as a detection point, and indirectly controls the motion of the second floator, which is denoted as a point of force. Indirect control of the point of force is executed by the attractive force of a permanent magnet that is fixed to the bottom part of the detection point. To achieve zero-compliance, a Proportional-Integral-Derivative (PID) control is applied to the point of force, and to make the system stable, a Proportional-Derivative (PD) control is also applied to the detection point. In such suspension conditions, when force is exerted on the point of force, the displacement of the second floator is regulated to maintain its primary position while the detection point displaces in proportion to the applied force. Thus, a zero-compliance condition is maintained at the point of force, and the external force is measured from the linear displacement of the detection point. To restrict the motions of the detection point and the point of force in translation only, they are supported with leaf springs. This paper presents the modeling of the vertical direction force measurement operation of the developed three-axis force estimation instrument, and the theoretical analyses were validated by experiments of force measurement in both the millinewton and micronewton ranges.
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http://dx.doi.org/10.3390/s19040799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412571PMC
February 2019

New insertion method of transnasal ileus tube for small bowel obstruction: Anterior balloon method.

PLoS One 2018 21;13(11):e0207099. Epub 2018 Nov 21.

Department of Internal Medicine, Saga Medical School, Saga, Japan.

Background: Small bowel obstruction (SBO) is usually caused by postoperative adhesions and malignant disease, and decompression is effective for SBO. Our previous case report suggested that a new transnasal ileus tube insertion method, the anterior balloon method (ABM), could achieve decompression for adhesive SBO.

Aims: The study aimed to investigate the effectiveness of a new method for inserting transnasal ileus tubes in patients with SBO.

Methods: Altogether, 134 patients with small bowel obstruction treated from January 2011 to December 2017 were reviewed. The patients were categorized into two groups: those with the new method that inserts an anterior balloon (ABM group: 52 patients, 2014-2017) versus those with the ordinary insertion method (OIM group: 82 patients, 2011-2014).

Results: The patients' characteristics and symptoms on admission were similar in the ABM and OIM groups. Adhesions were the main cause of ileus in the two groups. The insertion time duration was significantly shorter in the ABM group than in OIM group (28.4 ± 9.1 vs. 33.5 ± 13.0 min; p = 0.01). The ABM group also had significantly longer tubes than OIM group (222.4 ± 32.2 vs. 157.4 ± 31.7 cm; p < 0.001), which resulted in a significantly shorter time until clinical symptoms were relieved in ABM group. There were no significant differences in adverse events between the two groups.

Conclusions: The ABM group had shorter insertion duration and longer tubes than those of OIM group. The ABM might become a preferred therapeutic choice to achieve decompression in patients with SBO.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207099PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248956PMC
April 2019

Lower Rebleeding Rate after Endoscopic Band Ligation than Endoscopic Clipping of the Same Colonic Diverticular Hemorrhagic Lesion: A Historical Multicenter Trial in Saga, Japan.

Intern Med 2019 Mar 17;58(5):633-638. Epub 2018 Oct 17.

Department of Internal Medicine, Saga Medical School, Japan.

Objective This historical control study was performed to evaluate i) the rebleeding rate of bleeding colon diverticula treated with endoscopic band ligation (EBL) versus endoscopic clipping (EC) and ii) risk factors for rebleeding of diverticula initially treated by endoscopic hemostasis. Methods From January 2010 to December 2012, 68 patients were treated with EC, and from January 2013 to August 2016, 67 patients were treated with EBL. All patients in each group were followed up for one year to check for rebleeding. Results The rebleeding rate was lower in the EBL group (7 of 67, 10%) than in the EC group (21 of 68, 31%; p<0.01). This difference was mainly due to the lower rebleeding rate from the same hemorrhagic diverticulum initially treated by hemostasis (EBL: 4 of 67, 6%; EC: 15 of 68, 22%; p<0.01). The time span until rebleeding in the EBL group was ≤1 week. A multivariate analysis indicated that bleeding from the diverticula on the right side of the colon was a high-risk factor for rebleeding from the diverticula (odds ratio, 4.48; 95% confidence interval, 1.22-16.46; p=0.02). Conclusion The low rebleeding rate in the EBL group was attributed to the low degree of rebleeding from the same diverticulum, indicating that EBL was superior to EC in preventing rebleeding of an initially treated diverticulum.
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http://dx.doi.org/10.2169/internalmedicine.1473-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443565PMC
March 2019

Higher frequency of upper gastrointestinal symptoms in healthy young Japanese females compared to males and older generations.

Esophagus 2018 04 19;15(2):83-87. Epub 2017 Dec 19.

Departments of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

Background: The aim of this study was to evaluate the differences in upper gastrointestinal symptoms between generations and genders in relatively healthy Japanese subjects.

Methods: Altogether, 4086 healthy Japanese male and female (M/F) adults (M/F: 2244/1842) were analyzed. Among them, 3505 subjects (M/F: 1922/1583) were underwent a routine medical checkup at one of five hospitals in Saga, Japan from January 2013 to December 2013. The others were 581 (M/F: 322/259) healthy young volunteers at the Saga Medical School from April 2007 to March 2013. The participants were asked to complete the frequency scale for the symptoms of gastroesophageal reflex disease (FSSG) questionnaire, undergo upper gastrointestinal endoscopy, and submit to a rapid urease test to diagnose Helicobacter pylori infection. Among the 4086 subjects, the 2414 who had no H. pylori infection and no positive endoscopic findings were enrolled in the study.

Results: Subjects' average age was 46.9 ± 12.2 years, with males' and females' ages being almost equivalent. The total FSSG score were high in females compared to males (P < 0.01) and decreased significantly with aging (P < 0.05). Among the generations, FSSG scores were the highest for those 20-29 years old, and they were significantly decreased with ageing in both males and females (P < 0.05).

Conclusion: The FSSG score was significantly higher in healthy Japanese females than in males, and the scores decreased with aging.
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http://dx.doi.org/10.1007/s10388-017-0598-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884897PMC
April 2018

Prognostic and Predictive Value of HER2 Amplification in Patients With Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2018 09 19;17(3):198-205. Epub 2018 May 19.

Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. Electronic address:

Purpose: To evaluate a prognostic and predictive value of HER2 amplification in patients with metastatic colorectal cancer (mCRC).

Patients And Methods: Patients with mCRC who underwent surgical resection of the primary tumor and who received best supportive care with or without palliative chemotherapy between 2005 and 2015 were included. HER2 immunohistochemistry was performed using formalin-fixed, paraffin-embedded primary tumor specimens. HER2 amplification was confirmed by fluorescence in-situ hybridization. The RAS and BRAF mutations were centrally assessed using a PCR-based method. Patients were divided into 4 subgroups: R (RAS mutant), B (BRAF mutant), H (wild-type RAS/BRAF with HER2 amplification), and W (wild-type RAS/BRAF without HER2 amplification). Overall survival (OS) and progression-free survival of anti-epidermal growth factor receptor (EGFR) therapy were assessed.

Results: Among 370 eligible patients, data of 359 were successfully analyzed. Fifteen tumors harbored HER2 amplifications, including 4 tumors with concomitant RAS mutation (group R). The number of patients in groups R, B, H, and W was 204, 13, 11, and 131, respectively. The median OS was 27.4 months, and the median follow-up time was 63.2 months. The median OS for groups R, B, H, and W was 24.0, 14.2, 19.9, and 39.1 months, respectively. The number of patients who received anti-EGFR therapy in groups R, B, H, and W was 17, 4, 5, and 49, respectively. Progression-free survival of anti-EGFR therapy was significantly shorter in groups R, B, and H than in group W.

Conclusion: HER2 amplification was predictive of anti-EGFR therapy response and appeared to be prognostic in mCRC patients.
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http://dx.doi.org/10.1016/j.clcc.2018.05.006DOI Listing
September 2018

Tuning the Gas Selectivity of Tröger's Base Polyimide Membranes by Using Carboxylic Acid and Tertiary Base Interactions.

ChemSusChem 2018 Aug 10;11(16):2744-2751. Epub 2018 Jul 10.

Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, 606-8501, Kyoto, Japan.

Polyimide-based materials provide attractive chemistries for the development of gas-separation membranes. Modification of inter- and intra-chain interactions is a route to improve the separation performance. In this work, copolyimides with Tröger's base (TB) monomers are designed and synthesized. In particular, a series of copolyimides is synthesized with different contents of carboxylic acid groups (0-50 wt %) to alter the inter- and intra-chain interactions and enhance the basicity of the TB-polyimides. A detailed thermal and structural analysis is provided for the new copolyimides. Gas permeation data reveal a tunable trend in separation performance with increasing carboxylic acid group content. Importantly, this is one of the few examples of copolyimide membranes materials that show enhanced plasticization resistance to high-pressure gas feeds through physical cross-linking.
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http://dx.doi.org/10.1002/cssc.201801002DOI Listing
August 2018

Thermal stability and conformation of DNA and proteins under the confined condition in the matrix of hydrogels.

Mol Biol Rep 2018 Aug 6;45(4):403-411. Epub 2018 Apr 6.

Department of Nanobiochemistry, Faculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.

Spatially confined environments are seen in biological systems and in the fields of biotechnology and nanotechnology. The confinement restricts the conformational space of polymeric molecules and increasing the degree of molecular crowding. Here, we developed preparation methods for agarose and polyacrylamide gels applicable to UV spectroscopy that can evaluate the confinement effects on DNA and protein structures. Measurements of UV absorbance and CD spectra showed no significant effect of the confinement in the porous media of agarose gels on the base-pair stability of DNA polynucleotides [poly(dA)/poly(dT)] and oligonucleotides (hairpin, duplex, and triplex structures). On the other hand, a highly confined environment created by polyacrylamide gels at high concentrations increased the stability of polynucleotides while leaving that of oligonucleotides unaffected. The changes in the base-pair stability of the polynucleotides were accompanied by the perturbation of the helical conformation. The polyacrylamide gels prepared in this study were also used for the studies on proteins (lysozyme, bovine serum albumin, and myoglobin). The effects on the proteins were different from the effects on DNA structures, suggesting different nature of interactions within the gel. The experimental methods and results are useful to understand the physical properties of nucleic acids and proteins under confined conditions.
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http://dx.doi.org/10.1007/s11033-018-4174-zDOI Listing
August 2018

The Palliative Effect of Endoscopic Uncovered Self-expandable Metallic Stent Placement Versus Gastrojejunostomy on Malignant Gastric Outlet Obstruction: A Pilot Study with a Retrospective Chart Review in Saga, Japan.

Intern Med 2018 Jun 9;57(11):1517-1521. Epub 2018 Feb 9.

Department of Internal Medicine, Saga Medical School, Japan.

Objective Endoscopic self-expandable metallic stent (SEMS) placement and gastrojejunostomy (GJY) are palliative treatments for malignant gastric outlet obstruction (GOO). The aim of the present study was to compare the palliative effects of these treatments and identify predictors of a poor oral intake after treatment. Methods and Patients In total, 65 patients with GOO at multiple centers in Saga, Japan, were evaluated. Thirty-eight patients underwent SEMS placement, and 27 underwent GJY from January 2010 to December 2016. The characteristics and outcomes of the two groups were compared to detect predictors of treatment failure. Results No significant differences in the technical success, clinical success, post-treatment total protein, hospital discharge, duration from eating disability to death, or post-treatment overall survival were present between the SEMS and GJY groups. More patients in the GJY group than in the SEMS group received chemotherapy (51.4% vs. 26.3%, respectively; p=0.042). The period from treatment to the first meal was longer in the GJY group than in the SEMS group (4.5 vs. 3.0 days, respectively; p=0.013). The present study did not identify any risk factors for failure of SEMS placement. Although the stent length tended to be associated with a poor prognosis, the correlation was not statistically significant (odds ratio: 0.60, 95% confidence interval: 0.36-1.01, p=0.053). Conclusion Patients with GOO started meals more promptly after SEMS than after GJY, but the clinical outcomes were not markedly different between the SEMS and GJY groups. These findings suggest that endoscopic uncovered SEMS placement might be a feasible palliative treatment for GOO.
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http://dx.doi.org/10.2169/internalmedicine.0171-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028667PMC
June 2018

Comparison of sedation between the endoscopy room and operation room during endoscopic submucosal dissection for neoplasms in the upper gastrointestinal tract.

BMC Gastroenterol 2017 Nov 28;17(1):127. Epub 2017 Nov 28.

Department of Internal Medicine and Gastrointestinal Endoscopy, Saga Medical School, Saga, 849-8501, Japan.

Background: The present study was performed to compare the safety of sedation during endoscopic submucosal dissection (ESD) in the endoscopy room versus operation room.

Methods: In total, 297 patients with gastrointestinal tumors who underwent ESD from January 2011 to December 2016 were retrospectively reviewed. The patients were divided into two groups: those who underwent ESD in the endoscopy room without propofol (Group E) versus operation room with propofol (Group O). The patient, tumor, and procedure characteristics; adverse events; and treatment outcomes were compared between the two groups.

Results: The patient and tumor characteristics, including age (73.6 ± 8.2 vs. 72.5 ± 9.1 years), comorbidities, and tumor size and histology, were not different between Groups E and O. The ESD procedure time was comparable between Groups E and O (105.4 ± 70.4 vs. 106.5 ± 64.4 min), and the anesthesia time was equivalent (138.3 ± 78.1 vs. 148.4 ± 68.8 min). There were no significant differences in adverse events between the two groups. During the ESD procedure, desaturation occurred significantly more often in Group E than O (12.9% vs. 4.0%, P = 0.021, odds ratio: 3.53, 95% CI: 1.17-14.4). The recovery time after ESD was significantly longer in Group E than O (180 (100-360) vs. 90 (0-180) min, P < 0.001).

Conclusions: A decreased desaturation rate and shorter recovery time after ESD were the advantages of sedation in the operation room with propofol compared with sedation in the endoscopy room. These findings warrant further exploration of the advantages of safe and effective ESD for upper gastrointestinal neoplasms in the operation room.
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http://dx.doi.org/10.1186/s12876-017-0692-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704549PMC
November 2017

Effective insertion method of transnasal ileus tube for adhesive small bowel obstruction.

Dig Endosc 2018 Jan 25;30(1):120-121. Epub 2017 Oct 25.

Department of Gastroenterology, National Hospital Organization Ureshino Medical Center, Ureshino, Japan.

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http://dx.doi.org/10.1111/den.12971DOI Listing
January 2018