Publications by authors named "Takuya Matsui"

49 Publications

Robotic open-thoracotomy-view approach using vertical port placement and confronting monitor setting.

Interact Cardiovasc Thorac Surg 2021 May 11. Epub 2021 May 11.

Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.

Objectives: Robotic lung resections (RLRs) are conventionally performed using look-up views of the thorax from the caudal side. To conduct RLR with views similar to those in open thoracotomy, we adopted a vertical port placement and confronting upside-down monitor setting, which we called robotic 'open-thoracotomy-view approach'. We herein present our experience of this procedure.

Methods: We retrospectively reviewed 58 patients who underwent RLR (43 with lobectomy; 15 with segmentectomy) with 3-arm open-thoracotomy-view approach using the da Vinci Surgical System between February 2019 and October 2020. The patient cart was rolled in from the left cranial side of the patient regardless of the side to be operated on. Robotic ports were vertically placed along the axillary line, and 2 confronting monitors and 2 assistants were positioned on each side of the patient. The right-side monitor, which was set up for the left-side assistant to view, projected the upside-down image of the console surgeon's view.

Results: All procedures were safely performed. The median duration of surgery and console operation was 215 and 164 min, respectively. Emergency conversion into thoracotomy and severe morbidities did not occur, and the median postoperative hospitalization duration was 3 days. In all procedures, the console surgeon and 2 assistants had direct 'bird-eye' views of the cranially located intrathoracic structures and instrument tips, which are sometimes undetectable with the conventional look-up view.

Conclusions: The open-thoracotomy-view approach setting is a possible option for RLR. It offers natural thoracotomy views and can circumvent some of the known limitations of the conventional procedure.
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http://dx.doi.org/10.1093/icvts/ivab033DOI Listing
May 2021

Type A thymoma with simultaneous solitary intrapulmonary metastasis: A case report.

Thorac Cancer 2021 Jun 7;12(12):1923-1926. Epub 2021 May 7.

Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

A 79-year-old woman was referred to our facility because of an abnormal chest shadow. Chest computed tomography (CT) showed a solitary right middle lung nodule with a maximum diameter of 3 mm and anterior mediastinal nodule with a maximum diameter of 21 mm. The lung nodule was suspected of being a primary lung cancer rather than a metastatic tumor because there were no primary malignant tumors, apart from an anterior mediastinal tumor visible on diagnostic imaging, including F fluorodeoxyglucose-positron emission tomography, and a solitary lung nodule. Partial lung resection by video-assisted thoracoscopic surgery (VATS) was performed, and the intraoperative frozen section of the tumor tissue resulted in a diagnosis of carcinoid tumor. As a result, right middle lobectomy by VATS was performed. The final histological diagnosis of the permanent specimen was intrapulmonary type A thymoma. VATS thymectomy was performed three months later. The histological diagnosis was type A thymoma with intrapulmonary metastasis (Masaoka stage IVb). Additional therapy was not performed because complete resection was achieved. Follow-up CT was performed once every six months after the operation. The patient has been followed up for one year without any further recurrence.
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http://dx.doi.org/10.1111/1759-7714.13975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201543PMC
June 2021

Kawasaki Disease Shock Syndrome in Japan and Comparison With Multisystem Inflammatory Syndrome in Children in European countries.

Front Pediatr 2021 19;9:625456. Epub 2021 Mar 19.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan.

Multisystem inflammatory syndrome in children (MIS-C) is a severe Kawasaki-like illness that was first linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in European countries in the spring of 2020 and has been suggested to have overlap with Kawasaki disease shock syndrome (KDSS). There are few reports of MIS-C from Asia. This observational study aimed to identify the clinical features in children presenting with KDSS in Japan over a 5-year period and to summarize similarities and differences between KDSS and MIS-C. We retrospectively collected data on patient characteristics, clinical signs and symptoms, treatment, and prognosis including coronary artery abnormalities (CAAs), which were compared with data of patients with KDSS worldwide and patients with MIS-C from a review. KDSS was identified in 6 (1.1%) of 552 patients with Kawasaki disease (KD) treated at a single institution in Japan between 2015 and 2020 (1 in 2020). In patients with KDSS in Japan or worldwide vs. patients with MIS-C, KDSS was more likely to have a diagnosis of complete KD (100, 70 vs. 6.3%), a higher incidence of CAAs (50, 65 vs. 11%), and a greater requirement for vasoactive agonists (67, 67 vs. 43%) because of circulatory shock (100, 50 vs. 26%). Both KDSS and MIS-C had good prognosis (mortality 0, 6.7 vs. 1.7%). Although KDSS in Japan and MIS-C show some overlap in clinical symptoms, they are unlikely to be the same disease entity. KDSS is more likely to have a cardiovascular phenotype with CAAs and requires treatment with cardiovascular agents.
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http://dx.doi.org/10.3389/fped.2021.625456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017212PMC
March 2021

Four new isoflavones from and their antiproliferative effects.

Nat Prod Res 2021 Feb 24:1-6. Epub 2021 Feb 24.

School of Sports and Health Science, Tokai Gakuen University, Miyoshi, Aichi, Japan.

Four new compounds (derriscandenon D (), E (), F (), G ()) and six known isoflavones (warangalone (), millewanin E (), rhynedlin A (), 6,8-diprenylgenistein (), isolupalbigenin (), isoscandinone ()) were isolated from the acetone extract of the branches of . These compounds were assayed for cell viability using the human lung carcinoma cell line A549, colorectal carcinoma cell line Colo205, epidermoid carcinoma cell line KB, the human acute lymphoblastic leukaemia cell line NALM-6, and human dermal fibroblasts. Compounds and significantly decreased the viability of KB cells, with IC values of 2.7 and 12.9 µM, respectively. In addition, compounds and reduced the mitochondrial membrane potential in KB cells. Compounds and strongly down-regulated the cell viability of cell lines KB and NALM-6, achieving IC values of 2.7 and 0.9 µM, respectively, compared with the positive control staurosporine at 1.25 and 0.01 µM, respectively.
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http://dx.doi.org/10.1080/14786419.2021.1888290DOI Listing
February 2021

Comparison of surgical outcomes between thoracoscopic anatomical sublobar resection including and excluding subsegmentectomy.

Gen Thorac Cardiovasc Surg 2021 May 2;69(5):850-858. Epub 2021 Jan 2.

Department of Thoracic Surgery, Aichi Cancer Center, 1-1 Kanokoden Chikusa-ku, Nagoya, 464-8681, Japan.

Objectives: Despite the ubiquitous utilization of anatomical sublobar resection for malignant lung tumors, the effectiveness and feasibility of subsegmentectomy remains unclear. This study therefore compared the perioperative outcomes between anatomical sublobar resection including (IS) and excluding (ES) subsegmentectomy.

Methods: Patients who had undergone anatomical sublobar resection at our institution from January 2013 to March 2019 were retrospectively reviewed. Clinicopathologic characteristics and perioperative outcomes of the IS group (n = 58) were then analyzed the compared to those of the ES group (n = 203).

Results: No statistically significant differences in age, sex, comorbidities, tumor location, preoperative pulmonary function, or tumor size on imaging were found between both groups. The IS group had significantly higher preoperative computed tomography-guided marking rates (40% vs. 18%; p < 0.01) and used significantly more staplers for intersegmental dissection than the ES group [4, interquartile range (IQR): 3-4 vs. 3, IQR: 3-4; p = 0.03]. Both groups had comparable 30-day mortality (0% vs. 0%; p > 0.99), intraoperative complications (7% vs. 10%; p = 0.61), and postoperative complications (5% vs. 8%; p = 0.58). After propensity score matching, the IS group experienced significantly lesser blood loss than the ES group (5 mL, IQR: 1-10 vs. 5 mL, IQR: 5-20; p = 0.03). Both groups experienced no local recurrence and demonstrated similar postoperative pulmonary functions after surgery.

Conclusions: IS may be a feasible and acceptable therapeutic option for malignant lung tumors. Nonetheless, future investigations are required to further validate the current findings.
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http://dx.doi.org/10.1007/s11748-020-01556-3DOI Listing
May 2021

Efficacy of Xenon Light With Indocyanine Green for Intersegmental Visibility in Thoracoscopic Segmentectomy.

J Surg Res 2021 03 3;259:39-46. Epub 2020 Dec 3.

Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan. Electronic address:

Background: We previously reported useful methods that can be implemented to identify intersegmental boundary lines (IBLs) by using an intravenous indocyanine green (ICG) fluorescence imaging system (ICG-FS) during a thoracoscopic anatomical segmentectomy (TAS). The aim of this study was to evaluate the recently released third-generation ICG-FS that features an emphasizing xenon-light source for IBL identification.

Methods: We prospectively studied cases involving 106 consecutive patients who underwent TAS. Intraoperatively, we used the third-generation ICG-FS, the conventional ICG methods (CIM) emphasizing xenon-light (CIM-X), and the spectra-A method (SAM) emphasizing xenon-light (SAM-X), for IBL identification. Furthermore, 16 of the 106 patients (15%) could be simultaneously evaluated using old-generation ICG-FSs, CIM, and SAM. All images were completely quantified for illuminance and for three colors, red, green, and blue.

Results: IBLs were successfully identified in all the patients (100%) with no adverse events. The SAM-X significantly increased the illuminance, especially in the resecting segments, compared to the CIM (39.0 versus 22.2, P < 0.01) and SAM (39.0 versus 29.3, P < 0.01), with enhanced red color compared to the CIM (33.1 versus 21.9, P < 0.01) and SAM (33.1 versus 14.0, P < 0.01). Furthermore, the SAM-X significantly increased the illuminance contrast compared to the CIM-X (34.1 versus 15.3, P < 0.01).

Conclusions: The present study suggests that the SAM-X potentially provided images with the highest visibility and colorfulness compared to the older generation ICG-FSs or CIM-X. Secure IBL identification can be more easily and safely performed using the SAM-X.
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http://dx.doi.org/10.1016/j.jss.2020.11.028DOI Listing
March 2021

Comparison of Surgical Outcomes Between Invasive Mucinous and Non-Mucinous Lung Adenocarcinoma.

Ann Thorac Surg 2020 Nov 23. Epub 2020 Nov 23.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.

Background: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of invasive lung adenocarcinoma. However, the clinical course and prognostic outcomes following IMA resection, particularly postoperative recurrence, remain unclear.

Methods: We pathologically reevaluated 1362 lung adenocarcinoma resections performed at our institution, categorizing cases into the IMA group (72 cases) and non-IMA group (1290 cases). The IMA group was further classified into pneumonia and nodular types based on preoperative computed tomography.

Results: Overall, the IMA group had lower carcinoembryonic antigen levels (3 vs. 8 ng/mL; p < .01), fewer lymph node metastasis (4% vs. 24%; p < .01), and more KRAS mutations (56% vs. 7%; p < .01) than the non-IMA group. Although postoperative recurrence rates did not differ between both groups (32% vs. 27%; p = 0.35), lung recurrence occurred more frequently in the IMA group (83% vs. 17%; p < .01). Propensity score-matched pair analysis showed that the IMA group had fewer lymph node metastasis (3% vs. 35%; p < .01), more KRAS mutations (56% vs. 9%; p < .01), and higher intrapulmonary recurrence rate (84% vs. 31%; p < .01) than the non-IMA group. The 5-year overall survival rates did not differ between both groups (74% vs. 81%; p = 0.26). However, among patients with intrapulmonary recurrence, those in the IMA group had significantly worse prognosis than those in the non-IMA group (35% vs. 77%; p < .01).

Conclusions: Intrapulmonary recurrence, which induced significantly worse prognosis, was more likely to occur in the IMA than non-IMA group.
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http://dx.doi.org/10.1016/j.athoracsur.2020.09.042DOI Listing
November 2020

Atomic-Layer-Deposited TiO Nanolayers Function as Efficient Hole-Selective Passivating Contacts in Silicon Solar Cells.

ACS Appl Mater Interfaces 2020 Nov 22;12(44):49777-49785. Epub 2020 Oct 22.

Global Zero Emission Research Center, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan.

Titanium oxide (TiO) has recently emerged as an electron-selective passivating contact for solar cell and semiconductor device applications. The mechanism behind this function has been attributed to the lower energy barrier for electrons than holes at the TiO/semiconductor interface. Here we report an antithetic function of TiO nanolayers (∼5 nm), which were grown by atomic layer deposition (ALD) on either planar or textured crystalline silicon (Si) without a buffer layer, acting as efficient -selective contacts with excellent surface passivation. We demonstrate the proof-of-concept solar cells with power conversion efficiencies above 20% with both - and -Si absorbers. We show that the elemental composition in the TiO/Si interfacial layers (TiOSi:H and SiO:H), which can be manipulated by the ALD process and the post-treatments such as exposure to atomic hydrogen and supply of oxygen during annealing, is a key in the efficient hole extraction and surface passivation. This new hole-selective passivating contact opens opportunities for replacing the widely used heterocontacts and dielectric-passivation layers in various device applications.
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http://dx.doi.org/10.1021/acsami.0c14239DOI Listing
November 2020

Aspirin Dose and Treatment Outcomes in Kawasaki Disease: A Historical Control Study in Japan.

Front Pediatr 2020 14;8:249. Epub 2020 May 14.

Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan.

Aspirin has been used as a concomitant drug in the treatment of Kawasaki disease (KD). In recent years, there has been discussion concerning whether high-dose aspirin is appropriate for treatment in the acute phase of KD. We retrospectively investigated the incidence of coronary artery abnormalities (CAAs) and the antipyretic effect of 30 to 50 mg/kg/day aspirin, the minimum and the maximum approved doses in Japan. This was a single-center, non-randomized, retrospective, historical cohort study. Patients were routinely treated with 50 mg/kg/day aspirin (50-mg Group) between 2007 and April 2014, and with 30 mg/kg/day aspirin (30-mg Group) between May 2014 and 2016. All patients were given initial and, if necessary, subsequent intravenous immunoglobulin (IVIG) 2.0 g/kg. The primary endpoint was incidence of CAAs defined as a CA diameter with a Z score ≥2.5 at treatment week 4. The secondary endpoint was incidence of further treatment. Incidences were compared using inverse probability weighting analysis adjusting for age, sex, and risk scores. In 587 patients, there was no significant difference in incidence of CAAs (odds ratio in 30-mg Group 0.769, 95% confidence interval (CI): 0.537-1.101, = 0.151). Risk of further treatment after the first IVIG in the 30-mg Group was significantly higher than that in the 50-mg Group (odds ratio 1.379, 95% CI: 1.051-1.811, = 0.021). Although this study has some limitations, the findings suggest that aspirin 50 mg/kg/day may have no significant effect on improving incidence of CAAs compared with 30 mg/kg/day but may have a lower rate of further treatment.
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http://dx.doi.org/10.3389/fped.2020.00249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241278PMC
May 2020

Three isoflavones from Derris scandens (Roxb.) Benth and their cancer chemopreventive activity and in vitro antiproliferative effects.

Phytochemistry 2020 Jul 15;175:112376. Epub 2020 Apr 15.

School of Sport and Health Science, Tokai Gakuen University, 21-233 Nishinohora, Ukigai, Miyoshi, Aichi, 470-0207, Japan.

Three undescribed isoflavones, derriscandenon A, B, and C, together with seven known isoflavones were isolated and structurally characterized during a study of the chemical constituents in the leaves of Derris scandens (Roxb.) Benth (Leguminosae, Fabaceae) collected in Bangladesh. The inhibitory activity of the compounds against activation of Epstein-Barr virus antigen (EBV-EA) by 12-O-tetradecanoylphorbo-13-acetate (TPA) was measured to identify possible chemopreventive agents. Mild inhibitory effects (IC 278-290 mol ratio/32 pmol TPA) against EBV-EA induction compared with curcumin (IC 341 mol ratio/32 pmol TPA) were observed for four known compounds (lupalbigenin, isopalbigenin, glyurallin, and isangustone A). Next, we focused on antitumor effects and investigated cell viability, cell proliferation, and mitochondria membrane potential by using an MTT assay, a live cell monitoring system, and fluorescence staining. Of the seven isoflavones tested for cell viability, a dose-dependent decrease in cell viability was observed for four isoflavones (derriscandenon B and C, derrubone, and glyurallin) in KB cells and two compounds (derriscandenon B and isochandaisone) in NALM6-MSH+ cells. In addition, the proliferation of KB cells was significantly inhibited by these four compounds at a concentration of 5 μM. The mitochondria membrane potentials of KB cells treated with derriscandenon C, derrubone, and glyurallin at the IC concentration were decreased by about 55%, whereas undescribed compound derriscandenon B had no effect. Our results show that some of the compounds isolated from D. scandens may be suitable as seed compounds for cancer prevention and therapy.
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http://dx.doi.org/10.1016/j.phytochem.2020.112376DOI Listing
July 2020

Characterization of N-(2,6-dimethylphenyl)hydroxylamine adducts of 2'-deoxyguanosine under weakly basic conditions.

Chemosphere 2020 Aug 20;252:126530. Epub 2020 Mar 20.

Department of Life and Environmental System Science, Graduate School of Nanobiosciences, Yokohama City University, 22-2 Seto, Kanazawa, Kanagawa, Yokohama, 236-0027, Japan. Electronic address:

Aromatic amines are a class of chemical carcinogens that are activated by cytochrome P450 enzymes to form arylhydroxylamines that are conjugated to form N-acetoxyarylamines or N-sulfonyloxyarylamines. These conjugates undergo N-O bond cleavage to become reactive nitrenium ions that may form DNA adducts. Numerous studies in the past using N-acetoxyarylamines to investigate DNA adduct formation were conducted, however, less is known in regard to DNA adduct formation directly from arylhydroxylamines - especially under conditions that mimic the physiological conditions of cells such as weakly basic conditions. In this study, 2'-deoxyguanosine (dG) was exposed to N-(2,6-dimethylphenyl)hydroxylamine (2,6-DMPHA) and N-phenylhydroxylamine (PHA) at pH 7.4 without enzymes and analyzed by liquid chromatography high resolution mass spectrometry (LC-HRMS). 2,6-DMPHA exposure resulted in the production of relatively low amounts of adducts however the identities of at least six different adducts that were formed through reactions with carbon, nitrogen and oxygen of 2'-deoxyguanosine were proposed based upon different analytical approaches including HRMS CID fragmentation and NMR analyses. Contrastively, PHA exposure under identical conditions resulted in one adduct at the C8 position. It was concluded from these results and results of theoretical calculations that nitrenium ions produced from 2,6-DMPHA were relatively more stable resulting in longer nitrenium ion lifetimes which ultimately led to greater potential for 2,6-DMPHA nitrenium ions to react with multiple sites on dG.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126530DOI Listing
August 2020

Clinicopathological Features, Surgical Outcomes, Oncogenic Status and PD-L1 Expression of Pulmonary Pleomorphic Carcinoma.

Anticancer Res 2019 Oct;39(10):5789-5795

Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.

Background/aim: Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC.

Patients And Methods: We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017.

Results: The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%).

Conclusion: A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.
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http://dx.doi.org/10.21873/anticanres.13782DOI Listing
October 2019

Formation of Bulky DNA Adducts by Non-Enzymatic Production of 1,2-Naphthoquinone-Epoxide from 1,2-Naphthoquinone under Physiological Conditions.

Chem Res Toxicol 2019 09 20;32(9):1760-1771. Epub 2019 Aug 20.

Department of Life and Environmental System Science, Graduate School of Nanobiosciences , Yokohama City University , 22-2 Seto, Kanazawa , Yokohama , Kanagawa 236-0027 , Japan.

Quinones may be formed metabolically or abiotically from environmental pollutants and polycyclic aromatic hydrocarbons (PAHs); many are recognized as toxicological intermediates that cause a variety of deleterious cellular effects including mutagenicity. The PAH--quinone, 1,2-naphthoquinone (1,2-NQ), may exert its genotoxic effects through interactions with cellular nucleophiles such as DNA, however, the mechanisms of 1,2-NQ adduct formation are still under investigation. With the aim to further understand these mechanisms, the chemical structures of adducts formed from the reaction of 2'-deoxyguanosine (dG) with 1,2-NQ under physiological conditions were investigated by liquid chromatography electrospray ionization tandem mass spectrometry and H NMR analyses. Results showed that 1,2-NQ underwent non-enzymatic oxidation to form a 1,2-NQ-epoxide which in turn formed at least four bulky adducts with dG, and these adducts were more likely to be formed under physiological conditions. A mechanism was proposed whereby hydration of 1,2-NQ to form unstable naphthohydroquinones and 2-hydroxy-1,4-naphthoquinone resulted in formation of hydrogen peroxide that oxidized 1,2-NQ. These results suggest that the genotoxicity of 1,2-NQ may not only be caused through oxidative DNA damage and adduct formation through Michael addition but also through non-enzymatic oxidative transformation of 1,2-NQ itself to form an intermediate PAH-epoxide which covalently binds to DNA.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00088DOI Listing
September 2019

JTZ-951 (enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor.

Eur J Pharmacol 2019 Sep 10;859:172532. Epub 2019 Jul 10.

Division of Nephrology and Endocrinology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

JTZ-951 (enarodustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor. JTZ-951 has inhibitory activities on human HIF-prolyl hydroxylase 1-3, but not on various receptors or enzymes. In Hep3B cells, JTZ-951 increased HIF-1α and HIF-2α protein levels, erythropoietin (EPO) mRNA levels, and EPO production. In normal rats, after a single oral dose of JTZ-951, the hepatic and renal EPO mRNA levels and plasma EPO concentrations were also increased. In 5/6-nephrectomized rats, repeated oral doses of JTZ-951 once daily or intermittent dosing showed the erythropoiesis stimulating effect. The administration of JTZ-951 at a high dose increased plasma vascular endothelial growth factor (VEGF) levels; however, retinal VEGF mRNA levels and the retinal vascular permeability were not changed. Finally, we evaluated the effect of JTZ-951 in a colorectal cancer cell-inoculated mouse model. Although JTZ-951 at a high dose increased the plasma VEGF, it had no effect on tumor growth. In summary, JTZ-951 induces erythropoiesis without affecting VEGF function. Therefore, it is expected that JTZ-951 will be a new oral candidate that increases and maintains hemoglobin concentrations in renal anemia patients.
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http://dx.doi.org/10.1016/j.ejphar.2019.172532DOI Listing
September 2019

Acrofolione A and B, acetophenone dimers from Acronychia pendunculata, induce an apoptotic effect on human NALM-6 pre-B cell leukaemia cells.

J Pharm Pharmacol 2019 Mar 25;71(3):348-361. Epub 2018 Oct 25.

School of Sports and Health Science, Tokai Gakuen University, Miyoshi, Aichi, Japan.

Objectives: We investigated the apoptotic activities of acrofolione A (1) and B (2) isolated from Acronychia pedunculata against a human pre-B cell leukaemia cell line (NALM-6) to explore the apoptosis-related signalling molecules targeted by 1 and 2.

Methods: The apoptosis effects of 1 and 2 in NALM-6 cells were investigated by TUNEL staining, annexin V, mitochondria membrane potential and caspase 3/7 activity. We carried out a protein array to explore the signalling molecules involved in apoptosis comprehensively.

Key Findings: Acrofolione A (1) suppressed the growth of NALM-6, K562 and HPB-ALL cells (IC 16.7 ± 1.9, 17.9 ± 0.3 and 10.1 ± 0.2 μm, respectively) more effectively than acrofolione B (2). Both compounds time-dependently increased the number of NALM-6 cells with abnormal nuclei, and increased the number of annexin V-positive cells and decreased the mitochondrial membrane potential of NALM-6 cells. Acrofolione A (1) markedly elevated caspase 3/7 activity and increased the number of TUNEL-positive cells. Cells treated with either compound showed enhanced expression of cleaved PARP and cleaved caspase 3 and 7, and reduced survivin protein levels.

Conclusions: Acrofolione A (1) and B (2) may be useful in the treatment of various types of leukaemia.
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http://dx.doi.org/10.1111/jphp.13035DOI Listing
March 2019

Spontaneous regression of lung squamous cell carcinoma with synchronous mediastinal progression: A case report.

Thorac Cancer 2018 12 11;9(12):1778-1781. Epub 2018 Oct 11.

Division of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.

Spontaneous regression (SR) of cancer implies the partial or complete disappearance of malignant disease without or with adequate medical treatment. Typically, SR of cancer is a sporadic event, especially in non-small cell lung cancer (NSCLC). Although the underlying mechanism of SR remains unknown, stimulation of an immunological response has been proposed. Herein, we report the case of a 56-year-old woman exhibiting SR of NSCLC with a mediastinal disease. Despite regression of the primary site after a lung biopsy, simultaneous progression of mediastinal lymph node metastasis occurred. Specimens obtained by surgical resection pathologically confirmed both primary and metastatic sites. Reportedly, primary and metastatic tumors shrink synchronously in SR of metastatic NSCLCs. Thus, the fact that the SR of NSCLC can present inconsistent development in primary and metastatic sites should be considered, and direct intervention is recommended if physicians diagnose this phenomenon.
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http://dx.doi.org/10.1111/1759-7714.12892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275820PMC
December 2018

Simultaneous resections of left lung cancer and esophageal schwannoma using video-assisted thoracoscopic surgery: A case report.

Asian J Endosc Surg 2019 Jul 30;12(3):348-353. Epub 2018 Aug 30.

Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan.

Esophageal schwannomas are extremely rare esophageal submucosal tumors. Herein, we report a case of simultaneous resection of left lung cancer and an esophageal schwannoma with video-assisted thoracoscopic surgery. An asymptomatic 74-year-old woman received a diagnosis of an esophageal submucosal tumor during the preoperative assessment of a left lung cancer. The esophageal submucosal tumor arose in the left wall of the lower esophagus, and the patient was diagnosed as having a schwannoma by endoscopic ultrasound-guided fine needle aspiration. She underwent video-assisted thoracoscopic surgery for the simultaneous removal of both tumors. Her postoperative course was uneventful. Thoracoscopic surgery is less invasive than thoracotomy, and this allowed the patient to undergo simultaneous operations for two tumors.
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http://dx.doi.org/10.1111/ases.12643DOI Listing
July 2019

Video-assisted thoracoscopic bisegmentectomies for double primary lung cancers in a patient with situs inversus totalis.

Gen Thorac Cardiovasc Surg 2018 Nov 18;66(11):671-674. Epub 2018 Apr 18.

Division of Thoracic Surgery, Kariya-Toyota General Hospital, Sumiyoshi-cho 5-15, Kariya-shi, Aichi, 448-8505, Japan.

Situs inversus totalis (SIT) is a rare anomaly. A limited number of reports document surgery for lung cancer in patients with SIT. We report the case of a 68-year-old man with SIT who underwent video-assisted thoracoscopic bisegmentectomies for synchronous double primary lung cancers. Preoperative evaluation of the pulmonary vessels and bronchus by three-dimensional computed tomography (CT) was unavailable owing to the patient's renal function disorder. However, the procedure was safely completed by adequate anatomic identification and careful operative manipulation based on plain CT study. His postoperative course was uneventful, and no recurrence has been observed 3 years after surgery.
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http://dx.doi.org/10.1007/s11748-018-0926-xDOI Listing
November 2018

Discovery of JTZ-951: A HIF Prolyl Hydroxylase Inhibitor for the Treatment of Renal Anemia.

ACS Med Chem Lett 2017 Dec 20;8(12):1320-1325. Epub 2017 Nov 20.

Chemical Research Laboratories, Biological Pharmacological Research Laboratories, Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π-π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and by improving cell permeability led to the discovery of JTZ-951 (compound ), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound was selected as a clinical candidate.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733278PMC
December 2017

Inhibitory effects of low-intensity pulsed ultrasound sonication on the proliferation of osteosarcoma cells.

Oncol Lett 2017 Sep 23;14(3):3071-3076. Epub 2017 Jun 23.

Department of Orthopaedic Surgery, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.

To date, there is limited data on the biological effects of low-intensity pulsed ultrasound (LIPUS) on primary malignant bone tumors. The purpose of the present study was to investigate the antitumor effects of LIPUS on osteosarcoma cells. The effects of LIPUS on cell viability, induction of apoptosis, mitochondrial membrane potential and intracellular signaling molecules in the LM8 osteosarcoma cell line were investigated. LIPUS inhibited cell viability (P=0.0022) and mitochondrial membrane potential (P=0.0019) in LM8 cells. Flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed significantly higher numbers of apoptotic (P<0.0001) and necrotic cells (P=0.0091) compared with cells without treatment. LIPUS treatment significantly increased phosphorylated Akt (P<0.0001) and IκBα (P=0.0001) levels, and reduced phosphorylated mitogen-activated protein kinase 7 (P<0.0001) and phosphorylated checkpoint kinase 1 (P=0.0008) levels. These results suggest that LIPUS is a non-invasive adjuvant therapy that is able to inhibit cellular proliferation in osteosarcoma cells.
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http://dx.doi.org/10.3892/ol.2017.6472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588165PMC
September 2017

Anti-cell proliferation effect of naphthoquinone dimers isolated from Plumbago zeylanica.

Nat Prod Res 2018 Sep 20;32(18):2127-2132. Epub 2017 Aug 20.

d School of Sport and Health Science , Tokai Gakuen University , Miyoshi , Japan.

Study of the chemical constituents of the roots of Plumbago zeylanica L. collected in Taiwan led to the isolation and identification of a new naphthoquinone dimer, plumzeylanone (1), along with eight known compounds (2-9). Nine naphthoquinones isolated from this plant were assayed for cell growth inhibition activity using NALM-6 (human B cell precursor leukaemia), A549 (human lung adenocarcinoma), Colo205 (human colorectal adenocarcinoma) and KB (human epidermoid carcinoma). Plumzeylanone (1), a novel plumbagin dimer, suppressed cell proliferation in only NALM-6 cells (IC 3.98 μM). However, maritinone (9) showed strong inhibition of cell growth in all cell lines tested (0.12 < IC < 9.06 μM). This compound appeared to affect the cell cycle.
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http://dx.doi.org/10.1080/14786419.2017.1366476DOI Listing
September 2018

Four New Xanthones from Cratoxylum cochinchinense and Their In Vitro Antiproliferative Effects.

Planta Med 2017 Jun 3;83(9):812-818. Epub 2017 Feb 3.

School of Sport and Health Science, Tokai Gakuen University, Miyoshi, Japan.

The study of the chemical constituents of branches and twigs of collected in Singapore led to the isolation and structural elucidation of four new xanthones, named cratoxanthone A (), B (), C (), and D (), together with six known xanthones (-) and one known dihydroanthracenone (). Eight xanthones (including and ) and were tested for their antiproliferative activity in three human carcinoma cell lines (lung adenocarcinoma A549, colorectal carcinoma Colo205, and epidermoid carcinoma KB) and a human acute lymphoblastic leukemia B cell line (NALM-6), and the mitochondrial membrane potential was determined in KB cells. New xanthones and attenuated NALM-6 cell proliferation with IC values of 17.78 and 8.27 µM, respectively. Furthermore, KB cells treated with these compounds had significantly decreased mitochondrial membrane potentials. Notably, the proliferation of A549 cells was specifically inhibited by , but not the xanthones.
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http://dx.doi.org/10.1055/s-0043-102510DOI Listing
June 2017

Pulsed Electromagnetic Field Stimulation Promotes Anti-cell Proliferative Activity in Doxorubicin-treated Mouse Osteosarcoma Cells.

In Vivo 2017 01;31(1):61-68

Department of Orthopaedic Surgery, Aichi Medical University School of Medicine Nagakute, Aichi, Japan.

Aim: We aimed to investigate the synergistic effects of pulsed electromagnetic field (PEMF) and doxorubicin therapy in a mouse osteosarcoma cell line (LM8 cells) in vitro.

Materials And Methods: The effects of PEMF (5 mT, 200 Hz) of different durations and doxorubicin on the proliferative activity of LM8 cells were measured by the MTT assay. Apoptotic-related factors such as cell-cycle phase, mitochondrial membrane potential, and caspase 3/7 activity were investigated using 4',6-diamidino-2-phenylindole staining and apoptosis kits. Identification of intracellular signaling molecules induced by the combination was comprehensively explored using a stress and apoptosis-related protein array kit.

Results: PEMF enhanced the inhibition of cell proliferation mediated by doxorubicin but did not affect the cell cycle, mitochondrial membrane potential, or doxorubicin-induced G/M arrest. The combination of PEMF and doxorubicin altered a few signaling molecules. PEMF tended to reduce the doxorubicin-induced decrease of phosphorylated BAD, while reducing the increased expression of total IĸB and phosphorylated-CHK1 induced by doxorubicin.

Conclusion: Our results indicate that combination of PEMF and doxorubicin could be a novel chemotherapeutic strategy.
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http://dx.doi.org/10.21873/invivo.11026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354149PMC
January 2017

Effects of bright light exposure during daytime on peripheral clock gene expression in humans.

Int J Biometeorol 2017 Jun 17;61(6):1133-1138. Epub 2016 Dec 17.

Department of Physiology, Aichi Medical University, Nagakute, Aichi, 480-1195, Japan.

Light is the strongest synchronizer controlling circadian rhythms. The intensity and duration of light change throughout the year, thereby influencing body weight, food preferences, and melatonin secretion in humans and animals. Although the expression of clock genes has been examined using human samples, it currently remains unknown whether bright light during the daytime affects the expression of these genes in humans. Therefore, we herein investigated the effects of bright light exposure during the daytime on clock gene expression in the hair follicular and root cells of the human scalp. Seven healthy men (20.4 ± 2.2 years old; 172.3 ± 5.8 cm; 64.3 ± 8.5 kg; BMI 21.7 ± 3.1 kg/m, mean ± SD) participated in this study. Subjects completed 3-day experimental sessions twice in 1 month during which they were exposed to bright and dim light conditions. The mRNA expression of Per1-3, Cry1-2, Rev-erb-α (Nr1d1), Rev-erb-β (Nr1d2), and Dec1 was analyzed using branched DNA probes. No significant changes were observed in the expression of Per1, Per2, Per3, Cry1, Cry2, Rev-erb-α (Nr1d1), or Dec1 following exposure to bright light conditions. However, the expression of Rev-erb-β (Nr1d2) tended to be stronger under bright light than dim light conditions. These results suggest that the bright light stimulus did not influence the expression of clock genes in humans. Long-lasting bright light exposure during the daytime may be required to change the expression of clock genes in humans.
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http://dx.doi.org/10.1007/s00484-016-1294-9DOI Listing
June 2017

Single-step enrichment of basophils from human peripheral blood by a novel method using a Percoll density gradient.

J Sep Sci 2016 Aug;39(15):3062-71

Bioseparation Technology Laboratory, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

We have developed a novel continuous flow-through cell separation method using a Percoll density gradient. This method can continuously separate a large number of cells into five fractions according to their densities. To apply this method to the separation of basophils, Percoll density gradients were modified to improve basophil enrichment. When a set of Percoll density gradients was prepared (1.071, 1.075, 1.080, 1.084, and 1.090 g/mL) the basophils in a healthy volunteer were enriched by an average of 23.1 and 63.5% at Percoll densities of 1.075 (fraction 3) and 1.080 g/mL (fraction 4), respectively. On average, the yield of basophils was 1.66 × 10(5) cells in fraction 3 and 1.61 × 10(5) cells in fraction 4 from 9 mL of peripheral blood. The expression of CD203c (cluster of differentiation 203c) on separated basophils was upregulated by anti-immunoglobulin E stimulation similar to basophils in whole blood. Histamine release induced by calcium ionophore was also observed in the separated basophils. The present method will be useful for basophil enrichment since it preserves their function without using counterflow elutriation and immunological reagents, and this method will be effective as a preparative separation for cell purification by flow cytometry.
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http://dx.doi.org/10.1002/jssc.201600329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974159PMC
August 2016

Acetophenones Isolated from Acronychia pedunculata and their Anti-proliferative Activities.

Nat Prod Commun 2016 Jan;11(1):83-6

Study of the chemical constituents of Acronychia pedunculata (L.) Miq. (Rutaceae) stems collected in Taiwan led to the isolation and identification of eight known and three new acetophenones, named acrophenone A (1), B (2), and C (3). Of them, acrovestone (5), acropyrone (6) and acrovestenol (7), which are dimer compounds, strikingly inhibited the proliferation of human leukemia cell lines.
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January 2016

Licarin A is a candidate compound for the treatment of immediate hypersensitivity via inhibition of rat mast cell line RBL-2H3 cells.

J Pharm Pharmacol 2015 Dec 17;67(12):1723-32. Epub 2015 Sep 17.

School of Sport and Health Science, Tokai Gakuen University, Aichi, Japan.

Objectives: We previously demonstrated that some phenylpropanoids are capable of inhibiting activated mast cells. This study evaluated the anti-allergic effects of licarin A, a neolignan isolated from various plants, on antigen-stimulated rat mast cell line.

Methods: The inhibitory effects of licarin A on histamine release, tumour necrosis factor-α (TNF-α) and prostaglandin D2 (PGD2) production, and cyclooxygenase-2 (COX-2) expression in dinitrophenyl-human serum albumin (DNP-HSA) rat basophilic leukemia cells (DNP-HSA-stimulated RBL-2H3 cells), were investigated by spectrofluorometry, ELISA and immunoblotting.

Key Findings: Licarin A significantly and dose-dependently reduced TNF-α production (IC50 12.6 ± 0.3 μm) in DNP-HSA-stimulated RBL-2H3 cells. Furthermore, the levels of PGD2 secretion in DNP-HSA-stimulated cells pretreated with licarin A were lower than those stimulated with DNP-HSA alone (positive control). Treatment with licarin A at 20 μm produced slight suppression of DNP-HSA-induced increases in COX-2 mRNA and protein levels. We identified several signalling pathways that mediated these pharmacological effects. Licarin A treatment tended to reduce phosphorylated protein kinase C alpha/beta II (PKCα/βII) and p38 mitogen-activated protein kinase (MAPK) protein levels.

Conclusions: Our results demonstrate that licarin A reduces TNF-α and PGD2 secretion via the inhibition of PKCα/βII and p38 MAPK pathways; this compound may be useful for attenuating immediate hypersensitivity.
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http://dx.doi.org/10.1111/jphp.12475DOI Listing
December 2015

Photocatalytic generation of hydrogen by core-shell WO₃/BiVO₄ nanorods with ultimate water splitting efficiency.

Sci Rep 2015 Jun 8;5:11141. Epub 2015 Jun 8.

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

Efficient photocatalytic water splitting requires effective generation, separation and transfer of photo-induced charge carriers that can hardly be achieved simultaneously in a single material. Here we show that the effectiveness of each process can be separately maximized in a nanostructured heterojunction with extremely thin absorber layer. We demonstrate this concept on WO3/BiVO4+CoPi core-shell nanostructured photoanode that achieves near theoretical water splitting efficiency. BiVO4 is characterized by a high recombination rate of photogenerated carriers that have much shorter diffusion length than the thickness required for sufficient light absorption. This issue can be resolved by the combination of BiVO4 with more conductive WO3 nanorods in a form of core-shell heterojunction, where the BiVO4 absorber layer is thinner than the carrier diffusion length while it's optical thickness is reestablished by light trapping in high aspect ratio nanostructures. Our photoanode demonstrates ultimate water splitting photocurrent of 6.72 mA cm(-2) under 1 sun illumination at 1.23 V(RHE) that corresponds to ~90% of the theoretically possible value for BiVO4. We also demonstrate a self-biased operation of the photoanode in tandem with a double-junction GaAs/InGaAsP photovoltaic cell with stable water splitting photocurrent of 6.56 mA cm(-2) that corresponds to the solar to hydrogen generation efficiency of 8.1%.
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http://dx.doi.org/10.1038/srep11141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459147PMC
June 2015

Discovery of 6-phenylpyrimido[4,5-b][1,4]oxazines as potent and selective acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors with in vivo efficacy in rodents.

J Med Chem 2014 Apr 8;57(8):3464-83. Epub 2014 Apr 8.

Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.
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http://dx.doi.org/10.1021/jm500135cDOI Listing
April 2014

Biphenyl derivatives from Garcinia schomburgkiana and the cytotoxicity of the isolated compounds.

Nat Prod Commun 2013 Sep;8(9):1265-7

Department of Medicinal Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.

Study of the chemical constituents of the stems of Garcinia schomburgkiana Pierre (Guttiferae), collected in Thailand, led to the isolation and identification of five known compounds and two new biphenyl derivatives, schomburgbiphenyl A (1) and B (2). Six phenolic compounds isolated from this plant were screened for their cell growth inhibition activity using several human leukemia cell lines. One compound, oblongifolin C (7), showed significant cytotoxic activity towards Jurkat, NALM6, K562 and HPB-ALL cells.
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September 2013