Publications by authors named "Masahiro Iwasaki"

58 Publications

Prediction of treatment response from the microenvironment of tumor immunity in cervical cancer patients treated with chemoradiotherapy.

Med Mol Morphol 2021 May 8. Epub 2021 May 8.

Department of Radiology, Sapporo Medical University School of Medicine, S1 W16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.

To supplement clinical decision-making in the management of cervical cancer, various prognostic factors, including tumor immune microenvironments, were examined in patients with cervical cancer treated with definitive chemoradiotherapy. We retrospectively analyzed the expression of CD8, FoxP3, HLA-1, PD-L1, and XRCC4 in 100 cases of cervical cancer. The observed tumor immune microenvironments were also classified into three types: inflamed, excluded, and cold type. Less FoxP3+ T cells and cold-type tumor were found to be poor prognostic factors in addition to non-SCC, large pre-treatment tumor volume, and three or less cycles of concurrent chemotherapy based on multivariate analysis. Cold-type tumors had significantly worse prognoses than the other two types, whereas inflamed- and excluded-type tumors showed similar 5-year disease-specific survival (P < 0.001; 0% vs. 60.3% vs. 72.3%). Radiotherapy could overcome the inhibitory immune microenvironment that occurs in excluded type. Individualized combination therapy adapted to pre-treatment tumor immunity may be necessary to improve radiotherapy outcomes in cervical cancer.
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http://dx.doi.org/10.1007/s00795-021-00290-wDOI Listing
May 2021

Anaerobic co-digestion of dairy manure and Japanese knotweed (Fallopia japonica) under thermophilic condition: Optimal ratio for biochemical methane production.

Anim Sci J 2021 Jan;92(1):e13523

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.

Anaerobic co-digestion of animal manure and lignocellulosic biomass is a potent approach for sustainable biomethane production. Co-digestion of dairy manure (DM) and Japanese knotweed (JK), which was collected from a riverbank, was investigated at five different DM-to-JK mixing ratios (100:0, 90:10, 80:20, 60:40, and 0:100; wet weight basis) under thermophilic condition. The results showed that the methane yields obtain from the co-digestion of DM and JK were much higher than that obtained from JK alone (104 ml/gVS), which indicates the synergistic effect and the benefits of co-digesting JK with DM. The highest methane yield (232 ml/gVS) was obtained from the DM-to-JK ratio of 90:10, which was 14.9% and 123.1% higher than that from DM and JK alone, respectively. It also showed the highest synergistic effect (61 ml/gVS). However, further increase in JK ratios led to the decrease in methane yield and synergistic effect. Therefore, applying the co-digestion of DM and JK at a ratio of 90:10 is recommended for biomethane production.
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http://dx.doi.org/10.1111/asj.13523DOI Listing
January 2021

Are all wines made from various grape varieties beneficial in the prevention of myocardial infarction and stroke?

Future Sci OA 2020 Nov 9;7(2):FSO649. Epub 2020 Nov 9.

Kobe Gakuin University (Professor Emeritus), Kobe 651-2180, Japan.

Aim: Epidemiologic studies support the assumption (French paradox hypothesis) that drinking red wine is beneficial in the prevention of cardiovascular diseases. Our recent works however cast doubt on such claim. Earlier we have shown that the antithrombotic activity of various fruits and vegetables mainly depends on their varieties. For this reason, several varieties of red and white grapes were tested for antithrombotic effect in animal experiments.

Results: Antithrombotic effect of 45 red and white grape varieties were assessed in the present study. Out of the 45, one red grape variety showed antithrombotic effect, while the majority of red and white grape varieties enhanced thrombosis.

Conclusion: Most red and white grape varieties enhanced thrombotic activity of blood.
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http://dx.doi.org/10.2144/fsoa-2020-0098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787155PMC
November 2020

ERα increases endometrial cancer cell resistance to cisplatin via upregulation of BAG3.

Oncol Lett 2021 Jan 9;21(1):20. Epub 2020 Nov 9.

Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo, Hokkaido 060-8543, Japan.

Endometrial cancer is a leading cause of cancer-associated mortality in women and has a poor prognosis in advanced stages. Our previous study revealed that BCL-2-associated athanogene 3 (BAG3) may contribute to enhancing cell viability through downregulation of microRNA (miR)-29b in endometrial cancer cell lines. In addition, a relationship between estrogen receptor α (ERα) and BAG3 was recently reported in several cancer cell types. The present study investigated the relationship between ERα and BAG3 in endometrial cancer cell lines. The results demonstrated that exogenous ERα overexpression enhanced BAG3 expression in the EMTOKA endometrial cancer cell line, which does not endogenously express ERα, but had no effect on BAG3 expression levels in the Ishikawa cell line, which does endogenously express ERα. In addition, ERα overexpression suppressed miR-29b expression and enhanced the expression of Mcl-1, a mediator situated downstream of BAG3, in EMTOKA cells, but not Ishikawa cells. ERα overexpression also enhanced EMTOKA, but not Ishikawa, endometrial cancer cell viability in the presence of cisplatin. These findings suggested that ERα may contribute to enhancing endometrial cancer cell resistance to anticancer agents through BAG3 overexpression.
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http://dx.doi.org/10.3892/ol.2020.12281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681203PMC
January 2021

Association between cancer immunity and treatment results in uterine cervical cancer patients treated with radiotherapy.

Jpn J Clin Oncol 2020 Oct;50(11):1290-1297

Department of Radiology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Objective: To evaluate proteins related to tumor immune response and treatment outcome from radiotherapy for uterine cervical cancer patients.

Methods: We performed a retrospective immunohistochemical staining of 81 patients with uterine cervical cancer who underwent definitive radiotherapy. We examined the expression of programmed death ligand 1, human leukocyte antigen class I, tumor-infiltrating CD8+, and forkhead box P3+ (FoxP3+) T cells in tumor tissues.

Results: In biopsy specimen, patients with a higher number of CD8+ T cells and FoxP3+ T cells had a better disease-specific survival than patients with a lower number of CD8+ T cells and FoxP3+ cells (P = 0.018 and P = 0.009). Multivariate analysis showed that equivalent dose in 2 Gy fractions (EQD2) of the minimum dose to 90% of the high-risk clinical target volume, FoxP3+ T cells and expression of human leukocyte antigen class I were significant prognostic factors. When the EQD2 is 70 Gy or more, a higher local control rate is obtained regardless of the number of CD8- or FoxP3-positive cells. When EQD2 is <70 Gy, the number of CD8-positive cells has a significant impact on treatment outcome: the recurrence rate (local recurrence rate + distant metastasis rate) was 46.2% in the group with a CD8 value of 230 or higher, whereas the recurrence rate was 75.7% in the group with a CD8 value of less than 230.

Conclusion: The combination of CD8 or FoxP3 with EQD2 can be potentially useful to predict the treatment results of radiotherapy for cervical cancer, leading to individualized optimal selection of treatment for cervical cancer.
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http://dx.doi.org/10.1093/jjco/hyaa149DOI Listing
October 2020

Effect of solid-liquid separation on anaerobic digestion of dairy manure in semi-continuous stirred tank reactors: Process performance and digestate characteristics.

Anim Sci J 2020 Jan-Dec;91(1):e13393

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.

The objective of this study was to investigate the effect of solid-liquid separation on anaerobic digestion of dairy manure in semi-continuous stirred tank reactors. Reactors fed with liquid fraction of dairy manure (screened liquid manure) were kept in water baths at mesophilic (Run 1) and thermophilic (Run 3) temperatures, respectively, while reactors fed with water diluted manure and kept at mesophilic (Run 2) and thermophilic (Run 4) temperatures as control reactors. The performances of reactors were compared in terms of biogas and methane production, and digestate characteristics. The methane yields obtained from screened manure were higher than those from diluted manure at both mesophilic and thermophilic temperatures, while the highest methane yield was 185 L/kg VS under thermophilic temperature. Solid-liquid separation also had improved the effect on digestate fertilizer characteristics. Among four digestates from reactors, the highest contents of nutrients, N (4.12 g/kg) and P (2.36 g/kg) were found in Run 3, while the highest content of K (3.42 g/kg) was found in Run 1. These results showed the benefits of solid-liquid separation of dairy manure on process performance and digestate characteristics.
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http://dx.doi.org/10.1111/asj.13393DOI Listing
October 2020

Potential of biogas production from manure of dairy cattle fed on natural soil supplement rich in iron under batch and semi-continuous anaerobic digestion.

Bioresour Technol 2020 Aug 6;309:123298. Epub 2020 Apr 6.

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Japan. Electronic address:

This study provides a novel method for improving the anaerobic digestion (AD) of Holstein dairy manure (HDM) by the direct addition of Mineraso (MnS), a natural soil-derived supplement, to the feed of Holstein dairy cattle (HDC). MnS is chiefly composed of approximately 69.08% FeO and was supplemented at rates of 0 (F1), 25 (F2), and 50 (F3) g/head of HDC/d for two months. The HDM was then examined for non-absorbed iron prior to the batch and semi-continuous bench AD experiments. The results revealed that MnS enhanced CH generation in F2 and F3 by 25% and 42%, respectively, in the batch experiments compared to that of F1. Additionally, the gas yield improved in F2 and F3 by 45% and 66%, respectively, over the control after 7 d in the bench experiments. Therefore, supplementing animals with MnS represents a sustainable and economic approach to enhancing CH yields.
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http://dx.doi.org/10.1016/j.biortech.2020.123298DOI Listing
August 2020

Prospects for biogas production and HS control from the anaerobic digestion of cattle manure: The influence of microscale waste iron powder and iron oxide nanoparticles.

Waste Manag 2020 Jan 11;101:141-149. Epub 2019 Oct 11.

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan. Electronic address:

Improving the quality and quantity of biogas usually requires pre-treatment to maximize methane yields and/or post-treatment to remove HS, which involves considerable energy consumption and higher costs. Therefore, this study proposes a cost-effective method for the enhanced anaerobic digestion (AD) of dairy manure (DM) without pre/post-treatment by directly adding waste iron powder (WIP) and iron oxide nanoparticles (INPs) to batch digesters. The results showed that the addition of iron in the form of microscale WIP (generated from the laser cutting of iron and steel) at concentrations of 100 mg/L, 500 mg/L, and 1000 mg/L improved methane yields by 36.99%, 39.36%, and 56.89%, respectively. In comparison, the equivalent dosages of INPs improved yields by 19.74%, 18.14%, and 21.11%, respectively. Additionally, the highest WIP dose (1000 mg/L) achieved the maximum improvement in the rate of hydrolysis (k), which was 1.25 times higher than in control reactions, and a maximum biomethane production rate (R) of 0.045 L/gVS/d according to kinetic analysis models (i.e., first-order and the Gompertz kinetic models). The rate of HS production was also significantly reduced (by 45.20%, 58.16%, and 77.24%) using the three WIP concentrations in comparison with INPs (which achieved reductions of 33.59%, 46.30%, and 53.52%, respectively). Therefore, the direct mixing of WIP with cattle manure is proposed as a practical and economical means of addressing complex and high-cost pre- and post-treatments that are otherwise required in the digestion process.
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http://dx.doi.org/10.1016/j.wasman.2019.10.003DOI Listing
January 2020

Impacts of iron oxide and titanium dioxide nanoparticles on biogas production: Hydrogen sulfide mitigation, process stability, and prospective challenges.

J Environ Manage 2019 Jun 29;240:160-167. Epub 2019 Mar 29.

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan. Electronic address:

Anaerobic digestion for biogas production is one of the most used technology for bioenergy. However, the adoption of nanoparticles still needs further studies. Therefore, this study was designed to examine the effect of metal oxide nanoparticles (MONPs) at four different concentrations in two different combinations, 20 (R1) and 100 (R2) mg/L for FeO, 100 (R3) and 500 (R4) mg/L for TiO, and a mixture of FeO and TiO at rates of 20, 500 (R5) and 100, and 500 (R6), on hydrogen sulfide (HS) mitigation, biogas, and methane (CH) yield during the anaerobic digestion of cattle manure (CM) using an anaerobic batch system. The results showed that HS production was 2.13, 2.38, 2.37, 2.51, 2.64, and 2.17 times lower than that of the control (R0), respectively, when the CM was treated by the aforementioned MONPs. Additionally, biogas and CH production were 1.09 and 1.105, 1.15 and 1.191, 1.07 and 1.097, 1.17 and 1.213, 1.10 and 1.133, and 1.13 and 1.15 times higher than those of R0 when R1, R2, R3, R4, R5, and R6 were supplemented with MONPs, respectively. The highest specific production of biogas and CH was 336.25 and 192.31 mL/gVS, respectively, which was achieved by R4 supplemented with 500 mg/L TiO NPs, while the corresponding values in the case of R0 were 286.38 and 158.55 mL/gVS.
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http://dx.doi.org/10.1016/j.jenvman.2019.03.089DOI Listing
June 2019

The survival of pathogenic bacteria and plant growth promoting bacteria during mesophilic anaerobic digestion in full-scale biogas plants.

Anim Sci J 2019 Feb 16;90(2):297-303. Epub 2018 Dec 16.

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan.

The introduction of biogas plants is a promising way to recycle organic wastes with renewable energy production and reducing greenhouse gas. Application of anaerobic digestate as a fertilizer reduces the consumption of chemical fertilizers. In this study, the survival of pathogenic bacteria and plant growth promoting bacteria (PGPB) in two full-scale biogas plants operated at mesophilic condition were investigated. Feedstock and anaerobic digestate samples were collected from biogas plants and bacteria load in samples were detected using standard dilution plate method. Pathogenic bacteria were reduced to not detected level through mesophilic digestion tank except for Campylobacter. However, it could be reduced by 98.7% through a sterilization tank. Bacillus was detected at 8.00 and 7.81 log CFU/g dry matter in anaerobic digestates, and it was also resistant to sterilization tank. Bacillus spp. is considered to be the safe bacteria that hold remarkable abilities for promoting plant growth. The results showed that treatment at biogas plants is effective to reduce pathogenic bacteria in dairy manure, and sterilization could further reduce the sanitary risks of pathogenic bacteria relating to anaerobic digestate application. Anaerobic digestates could also be utilized as bio-fertilizer as the high load of plant growth promoting bacteria.
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http://dx.doi.org/10.1111/asj.13137DOI Listing
February 2019

Efficacy of liquid-based genetic diagnosis of endometrial cancer.

Cancer Sci 2018 Dec 26;109(12):4025-4032. Epub 2018 Oct 26.

Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo, Japan.

Although liquid-based cytology (LBC) has increased the sensitivity of cytological diagnosis of endometrial cancer (EC) compared with conventional smear cytology, the sensitivity of LBC for the detection of EC is between 70% and 96% and remains unsatisfactory. In the present study, we compared the efficacy of LBC with liquid-based genetic diagnosis (LBGDx) by amplicon sequencing of five genes including PTEN, PIK3CA, CTNNB1, KRAS, and TP53 in 48 LBC subjects who underwent endometrial screening. Consequently, LBC classified 15 samples as "positive or suspicious for malignancy" and the 15 were later confirmed as EC. However, LBC failed to identify five cases who were diagnosed as EC by additional transvaginal ultrasound and endometrial curettage, indicating that the sensitivity of cytology alone was 75% (15/20). LBGDx identified 11 pathogenic PTEN variants in 10 subjects, six PIK3CA variants in nine, three CTNNB1 variants in five, two KRAS variants in four, and three TP53 variants in three. Collectively, at least one pathogenic variant was identified in 19 subjects, which included 17 EC (15 endometrioid carcinoma and 2 endometrial carcinosarcomas), and one cervical adenocarcinoma. However, LBGDx did not identify any pathogenic mutations in three of the 20 EC, indicating that the sensitivity of LBGDx alone was 85% (17/20). Although five EC were negative for malignancy by LBC and three were negative for pathogenic mutations by LBGDx, the combination of LBC and LBGDx would successfully diagnose all 20 EC. These data suggested that LBGDx is a useful strategy to improve the sensitivity of screening of EC by LBC.
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http://dx.doi.org/10.1111/cas.13819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272085PMC
December 2018

Potential of anaerobic digestate of dairy manure in suppressing soil-borne plant disease.

Anim Sci J 2018 Oct 21;89(10):1512-1518. Epub 2018 Aug 21.

Department of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.

Frequent use of pesticides to control soil-borne plant disease leads to environmental pollution and the development of pesticide resistance in phytopathogens. Soil amendment is considered to have the potential of suppressing plant disease because of its biological properties. However, information on anaerobic digestate is limited. In this study, potential of antagonistic activities of anaerobic digestate against phytopathogens were investigated by detecting the amounts of antagonistic bacteria (Bacillus and Pseudomonas) in anaerobic digestates of dairy manure. The results showed that anaerobic digestion increased the total amounts of Bacillus and Pseudomonas in digestate. Bacillus suppressed growth of phytopathogens, while Pseudomonas did not show any antagonistic activities. These results indicated that Bacillus was an effective antagonistic bacterium in digestate against phytopathogens. Furthermore, two selected isolates, B11 (Bacillus subtilis) and B59 (Bacillus licheniformis), were applied in field experiments and showed significant reduction in percent infection of potato late blight (Phytophthora infestans). These results demonstrate the benefits of digestate in suppressing soil-borne plant diseases caused by antagonistic bacteria.
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http://dx.doi.org/10.1111/asj.13092DOI Listing
October 2018

Valorizing waste iron powder in biogas production: Hydrogen sulfide control and process performances.

J Environ Manage 2018 Feb 16;208:134-141. Epub 2017 Dec 16.

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 Japan. Electronic address:

Biogas is composed of different gases including hydrogen sulfide (HS), which is a hazardous gas that damages pipes and generators in anaerobic digestion system. The objective of this study was to control HS by waste iron powder produced by laser cutting machine in a steel and iron industry. Waste iron powder was mixed with dairy manure at a concentration between 2.0 and 20.0 g/L in batch experiments, while the concentration was varied between 1.0 and 4.0 g/L in bench experiment. In batch experiment, a reduction of up to 93% of HS was observed at waste iron powder of 2.0 g/L (T1), while the reduction was of more than 99% at waste iron powder beyond 8.0 g/L (T4 ∼ T6). The total sulfide concentration (S) increased together with waste iron powder concentration and was fitted with a quadratic equation with a maximum S of 208.0 mg/L at waste iron powder of 20.2 g/L. Waste iron powder did not have significant effect on methane yield in batch and bench experiments. However, hydrolysis rate constant was increased by almost 100%, while the lag-phase period was reduced to half in test digesters compared to that in control digester. In bench experiment, HS concentration was reduced by 89% at 2.0 g/L, while 50% at 1.0 g/L. Therefore, waste iron powder was effectively removed HS and did not affect negatively anaerobic digestion process.
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http://dx.doi.org/10.1016/j.jenvman.2017.12.012DOI Listing
February 2018

Uterine epithelioid leiomyosarcoma with c-kit expression and YWHAE gene rearrangement: a case report of a diagnostic pitfall of uterine sarcoma.

Diagn Pathol 2017 Mar 14;12(1):26. Epub 2017 Mar 14.

Department of Surgical Pathology, School of Medicine, Sapporo Medical University, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.

Background: Uterine sarcoma is a rare tumor that is often difficult to classify based on morphological and immunohistochemical analysis alone. Limited access to molecular biological analysis in routine practice would hinder making a definitive diagnosis.

Case Presentation: In this report, we describe a case of a mesenchymal tumor arising from the uterine cervix in a 52-year-old woman. From microscopic morphology of the resected specimen, epithelioid leiomyosarcoma, high-grade endometrial stromal sarcoma, or uterine gastrointestinal stromal tumor (GIST) were considered as differential diagnoses. The immunophenotype of the tumor featured smooth muscle differentiation and hormone receptor expression. The cell membrane and cytoplasm were positive for c-kit, although no mutation was found in the c-kit or PDGFRA gene. Fluorescence in situ hybridization (FISH) analysis revealed a relatively low frequency of YWHAE rearrangement, whereas there were few NUTM2A and NUTM2B split signals.

Conclusions: In this case, the tumor was not typical of any three of the differential diagnoses mentioned above. However, insufficient frequency of YWHAE, NUTM2A, and NUTM2B gene rearrangement and absence of mutation in both the c-kit and PDGFRA genes suggested that this tumor should be categorized as epithelioid leiomyosarcoma. This is an instructive case showing a potential diagnostic pitfall of uterine sarcoma. Comprehensive approaches including molecular biological techniques are required for definitive diagnosis.
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http://dx.doi.org/10.1186/s13000-017-0615-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348967PMC
March 2017

High-solids anaerobic mono-digestion of riverbank grass under thermophilic conditions.

J Environ Sci (China) 2017 Feb 24;52:29-38. Epub 2016 May 24.

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan. Electronic address:

The purpose of this study was to investigate the potential of high-solids anaerobic mono-digestion of riverbank grass under thermophilic conditions, focusing on the effects of the strength and the amount of inoculum. Ensiled grass was inoculated with three different inocula; inoculum from liquid anaerobic digester (LI), inoculum from dry anaerobic digester (DI), and mixture of LI and DI (MI), at feedstock-to-inoculum ratio (FIR) of 1, 2 and 4. The ensiling process of riverbank grass reduced moisture content (p>0.05), while the hemicellulose content was significantly increased from 30.88% to 35.15% (p<0.05), on dry matter basis. The highest methane production was at an FIR of 2 with MI (167L/kg VS), which was significantly higher (p<0.05) than with DI, but not significant compared to LI (p>0.05). At an FIR of 4, digesters inoculated with LI and DI failed to produce methane, whereas 135L/kg VS was obtained with MI. The kinetic studies showed that at an FIR of 1 with LI and MI, the inoculum had less of effects on the hydrolysis rate constant (0.269day and 0.245day) and methane production (135 versus 149L/kg VS); rather, it affected the lag phase. In a thermophilic HS-AD of riverbank grass, the mixture of inoculum with low and high total solids content (TS) helps increase the TS of inoculum and digestion process. An FIR of 2 was deducted to be the limit for a better startup time and higher volumetric productivity of methane.
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http://dx.doi.org/10.1016/j.jes.2016.05.005DOI Listing
February 2017

Rap1GAP inhibits tumor progression in endometrial cancer.

Biochem Biophys Res Commun 2017 04 11;485(2):476-483. Epub 2017 Feb 11.

Department of Obstetrics and Gynecology, Sapporo Medical University Hospital, South1 West16, Chuo-ku, Sapporo, Hokkaido, Japan.

Objective: Endometrioid adenocarcinoma (EAC) is a common endometrial cancer with recent dramatic increases in incidence. Previous findings indicate that Rap1GAP acts as a tumor suppressor inhibiting Ras superfamily protein Rap1 in multiple aggressive carcinomas; however, Rap1GAP expression in EAC has not been investigated. In this study, the tumor suppressing activity of Rap1GAP in EAC was explored.

Methods: EAC cell lines were used to examine Rap1GAP levels by real-time RT-PCR and western blotting and the effects of Rap1GAP on cancer cell invasion and migration. Rap1GAP expression was analyzed by immunohistochemical staining for Rap1GAP, E-cadherin in surgically resected tumors of 114 EAC patients scored according to EAC differentiation grade. Prognostic variables such as age, stage, grade, tumor size, and immunostaining for Rap1GAP, E-cadherin were evaluated using Cox regression multivariate analysis.

Results: Low Rap1GAP expression was detected in poorly differentiated EAC cells. Rap1GAP deficiency significantly accelerated while Rap1 deficiency decreased cancer cell migration and invasion. Patients with higher Rap1GAP, E-cadherin, and especially combined Rap1GAP/E-cadherin levels had better overall survival than EAC patients with no or weak expression. In addition, Rap1GAP expression was an independent prognostic factor in EAC.

Conclusions: Inhibition of Rap1GAP expression increases EAC cell migration and invasion through upregulation of Rap1. Low expression of Rap1GAP correlates with poor EAC differentiation. Our findings suggest that Rap1GAP is an important tumor suppressor with high prognostic value in EAC.
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http://dx.doi.org/10.1016/j.bbrc.2017.02.044DOI Listing
April 2017

Sodium-glucose co-transporter-2 inhibitor use and dietary carbohydrate intake in Japanese individuals with type 2 diabetes: A randomized, open-label, 3-arm parallel comparative, exploratory study.

Diabetes Obes Metab 2017 05 21;19(5):739-743. Epub 2017 Feb 21.

Yutaka Seino Distinguished Centre for Diabetes Research, Kansai Electric Power Medical Research Institute, Kobe, Japan.

This study investigated the safety and efficacy of the sodium-glucose co-transporter-2 (SGLT2) inhibitor luseogliflozin with differing carbohydrate intakes in Japanese individuals with type 2 diabetes (T2D). Participants were randomly assigned to 3 carbohydrate-adjusted meals for 14 days (days 1-14; a high carbohydrate [HC; 55% total energy carbohydrate] and high glycaemic index [HGI] meal; an HC [55% total energy carbohydrate] and low glycaemic index [LGI] meal; or a low carbohydrate [LC; 40% total energy carbohydrate] and HGI meal). All participants received luseogliflozin for the last 7 days (days 8-14), continuous glucose monitoring (CGM) before and after luseogliflozin treatment (days 5-8 and days 12-15) and blood tests on days 1, 8 and 15. Luseogliflozin significantly decreased the area under the curve and mean of CGM values in all 3 groups similarly. Fasting plasma glucose, insulin and glucagon were similar at all time points. Ketone bodies on day 15 were significantly higher in the LC-HGI group compared with the HC-HGI and HC-LGI groups. In conclusion, luseogliflozin has similar efficacy and safety in Japanese people with T2D when meals contain 40% to 55% total energy carbohydrate, but a strict LC diet on this class of drug should be avoided to prevent SGLT2 inhibitor-associated diabetic ketoacidosis.
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http://dx.doi.org/10.1111/dom.12848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412941PMC
May 2017

Reevaluation of antithrombotic fruits and vegetables: great variation between varieties.

Drug Discov Ther 2016;10(3):129-40

Kobe Gakuin University.

In the quest for prevention of atherothrombotic diseases, an antithrombotic diet may offer a promising approach. The major stumbling block in finding an effective diet is the lack of pathophysiological relevant techniques to detect potential antithrombotic effects of various diet components. Platelet function and coagulation/fibrinolysis tests currently in use do not allow assessment of global thrombotic status and their value in screening diet-components for antithrombotic effects. Recently, we combined the point-of-care shear-induced ex vivo thrombosis test (Global Thrombosis Test-GTT) with the Flow-mediated Vasodilation (FMV) in vivo test and found that the combination improved the assessment of thrombotic status in humans and could be used for screening diet-components for antithrombotic effects. In the present experiments, a combination of GTT, hemostatometry, laser-induced thrombosis tests and FMV were employed for screening. The results show that the overall antithrombotic effect is determined by the effect on thrombus formation and endogenous thrombolytic activities. This study showed a great variation in the observed antithrombotic effect between the tested varieties. Antithrombotic activities were independent from polyphenolic content or antioxidant activities. The presented experimental techniques seem to be suitable for establishing an antithrombotic diet, which may be effective in the prevention of atherothrombotic cardiovascular diseases in humans.
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http://dx.doi.org/10.5582/ddt.2016.01043DOI Listing
January 2017

Methane production from thermophilic co-digestion of dairy manure and waste milk obtained from therapeutically treated cows.

Anim Sci J 2017 Feb 12;88(2):401-409. Epub 2016 May 12.

Department of Environmental Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.

Methane production from co-digestion of dairy manure and waste milk, milk from cows treated with antibiotics for mastitis, was tested in a 2 × 4 factorial design. Four different waste milk percentages (w/w): 0% (SM), 10% (SMWM10), 20% (SMWM20) and 30% (SMWM30), were tested with two slurry percentages (w/w): 50% (A) and 25% (B) and the rest being manure at 55°C for 12 days in batch digesters. The results analyzed using a Gompertz model showed SMWM10 produced the highest methane production potential (P )/g volatile solids added followed by SM in both A and B. This P of SMWM10 in A and B was statistically non-significant (P > 0.05). More than 96% of cefazolin-resistant bacteria and 100% of multi-drug-resistant bacteria reductions were observed in all the treatments. Inclusion of waste milk at 10% in single stage digester enhances the methane production from dairy manure and could offer added benefit of waste milk treatment and disposal.
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http://dx.doi.org/10.1111/asj.12624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298021PMC
February 2017

BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer.

Int J Oncol 2016 Jul 21;49(1):402-10. Epub 2016 Apr 21.

Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo 060-8543, Japan.

Paclitaxel in combination with carboplatin improves survival among patients with susceptible ovarian cancers, but no strategy has been established against resistant ovarian cancers. BAG3 (Bcl-2-associated athanogene 3) is one of six BAG family proteins, which are involved in such cellular processes as proliferation, migration and apoptosis. In addition, expression of BAG3 with Mcl-1, a Bcl-2 family protein, reportedly associates with resistance to chemotherapy. Our aim in this study was to evaluate the functional role of BAG3 and Mcl-1 in ovarian cancer chemoresistance and explore possible new targets for treatment. We found that combined expression of BAG3 and Mcl-1 was significantly associated with a poor prognosis in ovarian cancer patients. In vitro, BAG3 knockdown in ES2 clear ovarian cancer cells significantly increased the efficacy of paclitaxel in combination with the Mcl-1 antagonist MIM1, with or without the Bcl-2 family antagonist ABT737. Moreover, BAG3 was found to positively regulate Mcl-1 levels by binding to and inhibiting USP9X. Our data show that BAG3 and Mcl-1 are key mediators of resistance to chemotherapy in ovarian cancer. In BAG3 knockdown ES2 clear ovarian cancer cells, combination with ABT737 and MIM1 enhanced the efficacy of paclitaxel. These results suggest that inhibiting BAG3 in addition to anti-apoptotic Bcl-2 family proteins may be a useful therapeutic strategy for the treatment of chemoresistant ovarian cancers.
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http://dx.doi.org/10.3892/ijo.2016.3494DOI Listing
July 2016

Meal sequence and glucose excursion, gastric emptying and incretin secretion in type 2 diabetes: a randomised, controlled crossover, exploratory trial.

Diabetologia 2016 Mar 24;59(3):453-61. Epub 2015 Dec 24.

Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, 1-5-6 Minatojimaminamimachi, Chuo-ku, Kobe, 650-0047, Japan.

Aims/hypothesis: Investigation of dietary therapy for diabetes has focused on meal size and composition; examination of the effects of meal sequence on postprandial glucose management is limited. The effects of fish or meat before rice on postprandial glucose excursion, gastric emptying and incretin secretions were investigated.

Methods: The experiment was a single centre, randomised controlled crossover, exploratory trial conducted in an outpatient ward of a private hospital in Osaka, Japan. Patients with type 2 diabetes (n = 12) and healthy volunteers (n = 10), with age 30-75 years, HbA1c 9.0% (75 mmol/mol) or less, and BMI 35 kg/m(2) or less, were randomised evenly to two groups by use of stratified randomisation, and subjected to meal sequence tests on three separate mornings; days 1 and 2, rice before fish (RF) or fish before rice (FR) in a crossover fashion; and day 3, meat before rice (MR). Pre- and postprandial levels of glucose, insulin, C-peptide and glucagon as well as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide were evaluated. Gastric emptying rate was determined by (13)C-acetate breath test involving measurement of (13)CO2 in breath samples collected before and after ingestion of rice steamed with (13)C-labelled sodium acetate. Participants, people doing measurements or examinations, and people assessing the outcomes were not blinded to group assignment.

Results: FR and MR in comparison with RF ameliorated postprandial glucose excursion (AUC-15-240 min-glucose: type 2 diabetes, FR 2,326.6 ± 114.7 mmol/l × min, MR 2,257.0 ± 82.3 mmol/l × min, RF 2,475.6 ± 87.2 mmol/l × min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 1,419.8 ± 72.3 mmol/l × min, MR 1,389.7 ± 69.4 mmol/l × min, RF 1,483.9 ± 72.8 mmol/l × min) and glucose variability (SD-15-240 min-glucose: type 2 diabetes, FR 1.94 ± 0.22 mmol/l, MR 1.68 ± 0.18 mmol/l, RF 2.77 ± 0.24 mmol/l [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 0.95 ± 0.21 mmol/l, MR 0.83 ± 0.16 mmol/l, RF 1.18 ± 0.27 mmol/l). FR and MR also enhanced GLP-1 secretion, MR more strongly than FR or RF (AUC-15-240 min-GLP-1: type 2 diabetes, FR 7,123.4 ± 376.3 pmol/l × min, MR 7,743.6 ± 801.4 pmol/l × min, RF 6,189.9 ± 581.3 pmol/l × min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 3,977.3 ± 324.6 pmol/l × min, MR 4,897.7 ± 330.7 pmol/l × min, RF 3,747.5 ± 572.6 pmol/l × min [p < 0.05 for MR vs RF and MR vs FR]). FR and MR delayed gastric emptying (Time50%: type 2 diabetes, FR 83.2 ± 7.2 min, MR 82.3 ± 6.4 min, RF 29.8 ± 3.9 min [p < 0.05 for FR vs RF and MR vs RF]; healthy, FR 66.3 ± 5.5 min, MR 74.4 ± 7.6 min, RF 32.4 ± 4.5 min [p < 0.05 for FR vs RF and MR vs RF]), which is associated with amelioration of postprandial glucose excursion (AUC-15-120 min-glucose: type 2 diabetes, r = -0.746, p < 0.05; healthy, r = -0.433, p < 0.05) and glucose variability (SD-15-240 min-glucose: type 2 diabetes, r = -0.578, p < 0.05; healthy, r = -0.526, p < 0.05), as well as with increasing GLP-1 (AUC-15-120 min-GLP-1: type 2 diabetes, r = 0.437, p < 0.05; healthy, r = 0.300, p = 0.107) and glucagon (AUC-15-120 min-glucagon: type 2 diabetes, r = 0.399, p < 0.05; healthy, r = 0.471, p < 0.05). The measured outcomes were comparable between the two randomised groups.

Conclusions/interpretation: Meal sequence can play a role in postprandial glucose control through both delayed gastric emptying and enhanced incretin secretion. Our findings provide clues for medical nutrition therapy to better prevent and manage type 2 diabetes.

Trial Registration: UMIN Clinical Trials Registry UMIN000017434.

Funding: Japan Society for Promotion of Science, Japan Association for Diabetes Education and Care, and Japan Vascular Disease Research Foundation.
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http://dx.doi.org/10.1007/s00125-015-3841-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742500PMC
March 2016

Evaluation of antithrombotic effect: Importance of testing components and methodologies.

Drug Discov Ther 2015 Aug;9(4):258-66

Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University.

The beneficial antithrombotic effect of some dietary components may offer the most promising approach of prevention of cardiovascular diseases and arterial thrombosis. The major stumbling block in finding effective dietary components is the lack of physiologically relevant techniques which can detect potential antithrombotic effect in humans. The presently used platelet function and coagulation tests do not allow the assessment of global thrombotic status and their value in screening dietary components for antithrombotic effect is questionable. Most of these in vitro tests ignore the effect of flow and shear stress, thrombin generation and vascular endothelium, the major contributors to arterial thrombogenesis in humans. As a gold standard, we employed the helium-neon (He-Ne) laser-induced thrombosis test in murine carotid artery and mesenteric microvessels, as the pathomechanism of this test closely reflects arterial thrombogenesis in humans. Results obtained with laser thrombosis test were compared with various shear-induced in vitro platelet function tests which use native blood (Haemostatometry, Thrombotic Status Analyser, Global Thrombosis Test-GTT). Contribution of vascular endothelium to thrombogenesis was assessed by measuring flow-mediated vasodilation (FMV) in vivo. The combination of the two shear-induced ex vivo thrombosis tests (Haemostatometry and GTT) with FMV correlated most closely with the laser-thrombosis test. Our findings suggest that combining the commercially available point-of-care GTT with the FMV test could provide a better assessment of the overall thrombotic status than either of the two tests alone.
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http://dx.doi.org/10.5582/ddt.2015.01043DOI Listing
August 2015

Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following paclitaxel and carboplatin in patients with gynecologic cancers: A randomized, multicenter, phase-II trial.

J Obstet Gynaecol Res 2015 Oct 21;41(10):1607-13. Epub 2015 Jul 21.

Department of Gynecology and Obstetrics, Sapporo Medical University, Sapporo, Japan.

Aim: Chemotherapy-induced nausea and vomiting (CINV) can affect a patient's quality of life, leading to poor compliance with further treatments. Previous studies have provided minimal data about carboplatin-based regimens. Female sex is a known risk factor for CINV. The purpose of this study was to evaluate palonosetron plus single-dose dexamethasone (DEX) for preventing CINV caused by carboplatin plus paclitaxel combination therapy (TC regimen) in patients with gynecologic cancers.

Material And Methods: Patients were recruited for this phase-II, multicenter, randomized trial from 12 hospitals in Hokkaido, Japan. Eligible patients were women with uterine cervical, endometrial or ovarian cancer scheduled to receive conventional TC regimen or dose-dense TC regimen; 116 patients were randomly assigned to receive palonosetron in combination with 1-day DEX or 3-day DEX.

Results: During the overall period, complete response (CR) was observed in 67.9% (95% confidence interval, 53.7-80.1) of patients in the 3-day DEX arm, and 60.7% (95% confidence interval, 46.8-73.5) of patients in the 1-day DEX arm; CR was significantly lower in the 1-day DEX arm if motion sickness was already present (P = 0.0370). In the severe hyperemesis gravidarum cohort, CR in the 1-day DEX arm tended to be lower than in the 3-day DEX arm.

Conclusion: Combination therapy of palonosetron and 1-day DEX was effective for subjects undergoing a TC regimen for gynecologic cancers. However, the possibility of reduced efficacy of 1-day only DEX therapy in women undergoing a TC regimen could not be refuted and requires further investigation.
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http://dx.doi.org/10.1111/jog.12748DOI Listing
October 2015

Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice: considerations for their appropriate use to avoid serious adverse events.

Expert Opin Drug Saf 2015 Jun 7;14(6):795-800. Epub 2015 Apr 7.

Kansai Electric Power Hospital, Center for Diabetes, Endocrinology and Metabolism , 2-1-7 Fukushima-ku, Osaka 553-0003 , Japan +81 6 6458 5821 ; +81 6 6458 6994 ; ;

Sodium/glucose co-transporter 2 inhibitors (SGLT2i) represent a novel class of glucose-lowering agents that lower plasma glucose levels through pharmacological inhibition of glucose reuptake from the kidney, independent of insulin secretion and action. Clinical trials of SGLT2i demonstrated therapeutic benefits on glycemic control and bodyweight in individuals with type 2 diabetes, with few cases of serious adverse events (SAEs). However, a considerable number of SAEs were reported in patients receiving SGLT2i clinically in Japan during the first 3 months of their use. These included urogenital infections, hypoglycemia and dehydration. Unexpectedly, serious skin and subcutaneous disorders, mainly reported as generalized rash or skin eruption, were prominent in patients receiving SGLT2i, but with unknown mechanisms. There is also concern for potential SAEs associated with chronic SGLT2i administration, especially in the non-obese type 2 diabetes characterized by reduced insulin secretion often seen in East Asia. Chronic SAEs may include severe hypoglycemia due to depletion of hepatic glycogen storage, acceleration of diabetes-associated sarcopenia and ketosis/ketoacidosis. The current information on acute SAEs confirms the importance of caution in the appropriate use of SGLT2i. Furthermore, careful long-term observation of patients receiving SGLT2i is essential to avoid SAEs and for better clinical use of this drug class.
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http://dx.doi.org/10.1517/14740338.2015.1034105DOI Listing
June 2015

BAG3 increases the invasiveness of uterine corpus carcinoma cells by suppressing miR-29b and enhancing MMP2 expression.

Oncol Rep 2015 May 4;33(5):2613-21. Epub 2015 Mar 4.

Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo, Japan.

Approximately 30% of uterine corpus carcinomas are diagnosed at an advanced stage and have a poor prognosis. Our previous study indicated that BCL2-associated athanogene 3 (BAG3) enhances matrix metalloproteinase-2 (MMP2) expression and binds to MMP2 to positively regulate the process of cell invasion in ovarian cancer cells. Recently, altered miRNA expression patterns were observed in several groups of patients with endometrial cancers. One of the altered miRNAs, miR-29b, reportedly reduces tumor invasiveness by suppressing MMP2 expression. Our aim in the present study was to examine the relationships among BAG3, miR-29b and MMP2 in endometrioid adenocarcinoma cells. We found that BAG3 suppresses miR-29b expression and enhances MMP2 expression, which in turn increases cell motility and invasiveness. Moreover, restoration of miR-29b through BAG3 knockdown reduced MMP2 expression, as well as cell motility and invasiveness. Collectively, our findings indicate that BAG3 enhances MMP2 expression by suppressing miR-29b, thereby increasing the metastatic potential of endometrioid adenocarcinomas.
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http://dx.doi.org/10.3892/or.2015.3831DOI Listing
May 2015

Effects of handling parameters on hydrogen sulfide emission from stored dairy manure.

J Environ Manage 2015 May 23;154:110-6. Epub 2015 Feb 23.

Graduate School of Animal and Food Hygiene, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan. Electronic address:

Hydrogen sulfide (H2S) emission from liquid manure in the process preceding field application is an important issue in fertigation systems. Given that H2S poses a significant health risk, it is important to determine the effects of different handling parameters on H2S emissions to prevent health risks to farmers. In this study, the effects of total solids (TS; 3, 5, 7, 9, and 11%) and mixing speed (100, 200, 300, and 400 rpm), duration (5, 15, 30, and 60 min), and frequency (one, two, three, and four times a day) on H2S emissions from two different dairy manures were investigated. The results indicate that the quantity of sulfur-containing substrate intake determines the potential of dairy manure to emit H2S because manure from cows fed with concentrate-based feed generates higher amounts of H2S than manure from cows fed with forage-based feed. The H2S concentration increased with TS concentration and reached a maximum of 1133 ppm at a TS of 9%; thereafter, it decreased with further increases in TS concentration. H2S emission increased with mixing speed with a peak concentration of 3996 ppm at 400 rpm. A similar trend was observed for mixing duration. However, there were no significant differences between the amounts H2S emitted at different frequencies of mixing (P > 0.05). The results indicate that mixing speed, duration, and TS are the major determinants of the quantity of H2S emitted from dairy manure. Therefore, to prevent health risks associated with H2S emission from dairy manure, it is recommended that the mixing speed and duration should be kept as low as possible, while a TS concentration of above 9% should be applied during the fertigation of dairy manure.
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http://dx.doi.org/10.1016/j.jenvman.2015.02.003DOI Listing
May 2015

Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients.

J Diabetes Complications 2015 Apr 26;29(3):413-21. Epub 2014 Dec 26.

Center for Diabetes, Endocrinology, and Metabolism, Kansai Electric Power Hospital, 2-1-7 Fukushima-ku, Osaka 553-0003, Japan. Electronic address:

Aims: Hypersecretion of glucagon and reduced insulin secretion both contribute to hyperglycemia in type 2 diabetes (T2DM). However, the relative contributions of impaired glucagon and insulin secretions in glucose excursions at the various stages of T2DM development remain to be determined.

Methods: The responses of glucagon and insulin as well as those of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were examined before and after ingestion of glucose or mixed meal in Japanese subjects with normal or impaired glucose tolerance (NGT and IGT) and in non-obese, untreated T2DM of short duration.

Results: In OGTT, T2DM showed a rise in glucagon at 0-30 min, unlike NGT and IGT, along with reduced insulin. In MTT, all three groups showed a rise in glucagon at 0-30 min, with that in T2DM being highest, while T2DM showed a significant reduction in insulin. Linear regression analyses revealed that glucose area under the curve (AUC)0-120 min was associated with glucagon-AUC0-30 min and insulin-AUC0-30 min in both OGTT and MTT. Total and biologically intact GIP and GLP-1 levels were similar among the three groups.

Conclusions: Disordered early phase insulin and glucagon secretions but not incretin secretion are involved in hyperglycemia after ingestion of nutrients in T2DM of even a short duration.
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http://dx.doi.org/10.1016/j.jdiacomp.2014.12.010DOI Listing
April 2015

Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion.

Cell Rep 2014 Oct 16;9(2):661-73. Epub 2014 Oct 16.

Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan; The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan. Electronic address:

Incretins, hormones released by the gut after meal ingestion, are essential for maintaining systemic glucose homeostasis by stimulating insulin secretion. The effect of incretins on insulin secretion occurs only at elevated glucose concentrations and is mediated by cAMP signaling, but the mechanism linking glucose metabolism and cAMP action in insulin secretion is unknown. We show here, using a metabolomics-based approach, that cytosolic glutamate derived from the malate-aspartate shuttle upon glucose stimulation underlies the stimulatory effect of incretins and that glutamate uptake into insulin granules mediated by cAMP/PKA signaling amplifies insulin release. Glutamate production is diminished in an incretin-unresponsive, insulin-secreting β cell line and pancreatic islets of animal models of human diabetes and obesity. Conversely, a membrane-permeable glutamate precursor restores amplification of insulin secretion in these models. Thus, cytosolic glutamate represents the elusive link between glucose metabolism and cAMP action in incretin-induced insulin secretion.
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http://dx.doi.org/10.1016/j.celrep.2014.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536302PMC
October 2014

BAG3 upregulates Mcl-1 through downregulation of miR-29b to induce anticancer drug resistance in ovarian cancer.

Gynecol Oncol 2014 Sep 30;134(3):615-23. Epub 2014 Jun 30.

Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.

Objective: Ovarian cancer is the leading cause of death from gynecologic cancer, reflecting its often late diagnosis and its chemoresistance. We identified a set of microRNAs whose expression is altered upon BAG3 knockdown. Our primary objective was to examine the relationships between BAG3, miR-29b and Mcl-1, an antiapoptotic Bcl-2 family protein, in ovarian cancer cells.

Methods: Ovarian cancer cells were cultured and their responsiveness to paclitaxel was tested. Microarray analysis was performed to identify microRNAs differentially expressed in ES2 BAG3 knockdown ovarian cancer cells and their control cells. Primary ovarian cancer tissues were obtained from 56 patients operated on for ovarian cancer. The patients' clinical and pathological data were obtained from their medical records.

Results: BAG3 knockdown increased the chemosensitivity to paclitaxel of ES2 ovarian clear cell carcinoma cells to a greater degree than AMOC2 serous adenocarcinoma cells. qRT-PCR analysis showed that miR-29b expression was significantly upregulated in primary cancer tissue expressing low levels of BAG3, as compared to tissue expressing high levels. Moreover, levels of miR-29b correlated significantly with progression-free survival. Upregulation of miR-29b also reduced levels of Mcl-1 and sensitized ES2 cells to low-dose paclitaxel.

Conclusions: BAG3 knockdown appears to downregulate expression of Mcl-1 through upregulation of miR-29b, thereby increasing the chemosensitivity of ovarian clear cell carcinoma cells. This suggests that BAG3 is a key determinant of the responsiveness of ovarian cancer cells, especially clear cell carcinoma, to paclitaxel and that BAG3 may be a useful therapeutic target for the treatment of ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2014.06.024DOI Listing
September 2014

Retrospective analysis of safety and efficacy of insulin-to-liraglutide switch in Japanese type 2 diabetes: A caution against inappropriate use in patients with reduced β-cell function.

J Diabetes Investig 2013 Nov 25;4(6):585-94. Epub 2013 Jun 25.

Division of Diabetes, Clinical Nutrition and Endocrinology Kansai Electric Power Hospital Osaka Japan.

Aims/introduction: The safety and efficacy of insulin-to-liraglutide switch in type 2 diabetes has not been studied adequately. Here, we retrospectively characterize clinical parameters that might predict insulin-to-liraglutide treatment switch without termination due to hyperglycemia, and examine the effects of switching the therapies on glycated hemoglobin (HbA1c) and bodyweight in Japanese type 2 diabetes.

Materials And Methods: Japanese type 2 diabetes patients who underwent the switch of therapy were evaluated for their clinical data including β-cell function-related indices, such as increment of serum C-peptide during glucagon stimulation test (GST-ΔCPR). HbA1c and bodyweight were analyzed in patients continuing with liraglutide after switching from insulin for 12 weeks.

Results: Of 147 patients, 28 failed in the switch due to hyperglycemia, nine failed because of other reasons and 110 continued with liraglutide for the 12-week period. Patients failing in the switch due to hyperglycemia showed longer duration and higher daily insulin dose, as well as lower GST-ΔCPR. Receiver-operating characteristic analysis showed that GST-ΔCPR of 1.34 ng/mL is a cut-off point for insulin-to-liraglutide switch without termination due to hyperglycemia. In patients continuing liraglutide for 12 weeks, the switch significantly reduced HbA1c and bodyweight with no severe hypoglycemia, irrespective of sulfonylurea co-administration, body mass index, duration and total daily insulin dose. The switch also significantly reduced the percentage of body fat and visceral fat areas.

Conclusions: Insulin-to-liraglutide switch can improve glycemic control and reduce bodyweight in Japanese type 2 diabetes patients. However, caution must be taken with the switch in patients with reduced insulin secretory capacity as predicted by GST-ΔCPR.
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http://dx.doi.org/10.1111/jdi.12111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020254PMC
November 2013