Publications by authors named "Takeshi Endo"

137 Publications

An association analysis between hypertension, dementia, and depression and the phases of pre-sarcopenia to sarcopenia: A cross-sectional analysis.

PLoS One 2021 22;16(7):e0252784. Epub 2021 Jul 22.

Center for Community-Based Healthcare Research and Education (CoHRE), Shimane University, Shimane, Japan.

Sarcopenia is intricately related to aging associated diseases, such as neuropsychiatric disorders, oral status, and chronic diseases. Dementia and depression are interconnected and also related to sarcopenia. The preliminary shift from robust to sarcopenia (i.e., pre-sarcopenia) is an important albeit underdiscussed stage and is the focus of this study. Identifying factors associated with pre-sarcopenia may lead to sarcopenia prevention. To separately examine the effects of dementia and depression on pre-sarcopenia/sarcopenia, we conducted multiple analyses. This cross-sectional study used health checkup data from a rural Japanese island. The participants were aged 60 years and above, and the data included muscle mass, gait speed, handgrip strength, oral status (teeth and denture), chronic diseases (e.g., hypertension), dementia (cognitive assessment for dementia, iPad Version), and depression (self-rating depression scale). A total of 753 older adult participants were divided into the sarcopenia (n = 30), pre-sarcopenia (n = 125), and robust (n = 598) groups. An ordered logit regression analysis indicated that age and depression were positively correlated with sarcopenia, while hypertension was negatively associated with it. A multiple logistic regression analysis between the robust and pre-sarcopenia groups showed significant associations between the same three variables. Depression was associated with pre-sarcopenia, but not dementia. There was also a significant association between hypertension and pre-sarcopenia. Further research is needed to reveal whether the management of these factors can prevent sarcopenia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252784PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297796PMC
July 2021

Endoscopic anisakis removal induced anterior cutaneous nerve entrapment syndrome.

BMJ Case Rep 2021 Feb 19;14(2). Epub 2021 Feb 19.

General Medicine Center, Shimane University Hospital, Izumo, Shimane, Japan

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http://dx.doi.org/10.1136/bcr-2020-241455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896586PMC
February 2021

Narrow pelvic inlet plane area and obesity as risk factors for anastomotic leakage after intersphincteric resection.

World J Gastrointest Surg 2020 Oct;12(10):425-434

Department of Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo 157-0066, Japan.

Background: Intersphincteric resection (ISR) has been increasingly used as the ultimate sphincter-preserving procedure in extremely low rectal cancer. The most critical complication of this technique is anastomotic leakage. The incidence rate of anastomotic leakage after ISR has been reported to range from 5.1% to 20%.

Aim: To investigate risk factors for anastomotic leakage after ISR based on clinicopathological variables and pelvimetry.

Methods: This study was conducted at Department of Colorectal Surgery, Japanese Red Cross Medical Center, Tokyo, Japan, with a total of 117 patients. We enrolled 117 patients with extremely low rectal cancer who underwent laparotomic and laparoscopic ISRs at our hospital. We conducted retrospective univariate and multivariate regression analyses on 33 items to elucidate the risk factors for anastomotic leakage after ISR. Pelvic dimensions were measured using three-dimensional reconstruction of computed tomography images. The optimal cutoff value of the pelvic inlet plane area that predicts anastomotic leakage was determined using a receiver operating characteristic (ROC) curve.

Results: We observed anastomotic leakage in 10 (8.5%) of the 117 patients. In the multivariate analysis, we identified high body mass index (odds ratio 1.674; 95% confidence interval: 1.087-2.58; = 0.019) and smaller pelvic inlet plane area (odds ratio 0.998; 95% confidence interval: 0.997-0.999; = 0.012) as statistically significant risk factors for anastomotic leakage. According to the receiver operating characteristic curves, the optimal cutoff value of the pelvic inlet plane area was 10074 mm. Narrow pelvic inlet plane area (≤ 10074 mm) predicted anastomotic leakage with a sensitivity of 90%, a specificity of 85.9%, and an accuracy of 86.3%.

Conclusion: Narrow pelvic inlet and obesity were independent risk factors for anastomotic leakage after ISR. Anastomotic leakage after ISR may be predicted from a narrow pelvic inlet plane area (≤ 10074 mm).
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http://dx.doi.org/10.4240/wjgs.v12.i10.425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642346PMC
October 2020

M-Ras is Muscle-Ras, Moderate-Ras, Mineral-Ras, Migration-Ras, and Many More-Ras.

Authors:
Takeshi Endo

Exp Cell Res 2020 12 29;397(1):112342. Epub 2020 Oct 29.

Department of Biology, Graduate School of Science, Chiba University, 1-33 Yayoicho, Inageku, Chiba, Chiba 263-8522, Japan. Electronic address:

The Ras family of small GTPases comprises about 36 members in humans. M-Ras is related to classical Ras with regard to its regulators and effectors, but solely constitutes a subfamily among the Ras family members. Although classical Ras strongly binds Raf and highly activates the ERK pathway, M-Ras less strongly binds Raf and moderately but sustainedly activates the ERK pathway to induce neuronal differentiation. M-Ras also possesses specific effectors, including RapGEFs and the PP1 complex Shoc2-PP1c, which dephosphorylates Raf to activate the ERK pathway. M-Ras is highly expressed in the brain and plays essential roles in dendrite formation during neurogenesis, in contrast to the axon formation by R-Ras. M-Ras is also highly expressed in the bone and induces osteoblastic differentiation and transdifferentiation accompanied by calcification. Moreover, M-Ras elicits epithelial-mesenchymal transition-mediated collective and single cell migration through the PP1 complex-mediated ERK pathway activation. Activating missense mutations in the MRAS gene have been detected in Noonan syndrome, one of the RASopathies, and MRAS gene amplification occurs in several cancers. Furthermore, several SNPs in the MRAS gene are associated with coronary artery disease, obesity, and dyslipidemia. Therefore, M-Ras carries out a variety of cellular, physiological, and pathological functions. Further investigations may reveal more functions of M-Ras.
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http://dx.doi.org/10.1016/j.yexcr.2020.112342DOI Listing
December 2020

Well-Defined Construction of Functional Macromolecular Architectures Based on Polymerization of Amino Acid Urethanes.

Biomedicines 2020 Aug 29;8(9). Epub 2020 Aug 29.

Department of Applied Chemistry, Faculty of Science and Engineering, Kindai University, Kowakae 3-4-1, Higashi Osaka, Osaka 577-8502, Japan.

Polypeptide synthesis was accomplished using the urethane derivatives of amino acids as monomers, which can be easily prepared, purified, and stored at ambient temperature without the requirement for special precautions. The urethanes of amino acids are readily synthesized by the N-carbamoylation of onium salts of amino acids using diphenyl carbonate (DPC). The prepared urethanes are then efficiently cyclized to produce amino acid N-carboxyanhydrides (NCAs). Thereafter, in the presence of primary amines, the ring-opening polymerization (ROP) of NCAs is initiated using the amines, to yield polypeptides with controlled molecular weights. The polypeptides have propagating chains bearing reactive amino groups and initiating chain ends endowed with functional moieties that originate from the amines. Aiming to benefit from these interesting characteristics of the polypeptide synthesis using the urethanes of amino acids, various macromolecular architectures containing polypeptide components have been constructed and applied as biofunctional materials in highly efficient antifouling coatings against proteins and cells, as biosensors for specific molecules, and in targeted drug delivery.
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http://dx.doi.org/10.3390/biomedicines8090317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555150PMC
August 2020

Charcot Arthropathy of the Shoulder Joint in a Patient with Guillain-Barré Syndrome: A Case Report.

JBJS Case Connect 2020 Jan-Mar;10(1):e0530

Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.

Case: A 53-year-old woman presented with Charcot arthropathy of the shoulder joint secondary to residual sensory neuropathy of Guillain-Barré syndrome, which was accompanied by swollen shoulder and restricted range of motion of the right shoulder. We performed a reverse shoulder arthroplasty (RSA). The range of motion had improved 15 months postoperatively, and there was no postoperative complication after RSA.

Conclusion: Clinicians should be aware that Guillain-Barré syndrome can cause Charcot arthropathy of the shoulder joint. RSA is regarded as a useful treatment, although careful follow-up is needed.
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http://dx.doi.org/10.2106/JBJS.CC.19.00530DOI Listing
January 2021

Real Clinical Practice in ALK-rearranged NSCLC Patients: A Retrospective Observational Study.

Anticancer Res 2020 Feb;40(2):957-964

Division of Respiratory Medicine, Ryugasaki Saiseikai Hospital, Ryugasaki, Japan.

Background/aim: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation.

Patients And Methods: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a population of three million people.

Results: There were 129 ALK rearranged NSCLC patients. Among them, 103 patients including 40 recurrent disease cases received ALK-tyrosine kinase inhibitors (TKI) and chemotherapy. Our treatment results were comparable to previously reported clinical trials and clinical practice studies. First-line alectinib, treatment sequence of ALK-TKI followed by another ALK-TKI, and pemetrexed-containing chemotherapy contributed to the outcome of treatment.

Conclusion: By arrangement of treatment such as treatment sequence of ALK-TKI and chemotherapy regimen, it might be possible to obtain a treatment outcome almost equivalent to those of clinical trials even in real clinical practice.
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http://dx.doi.org/10.21873/anticanres.14029DOI Listing
February 2020

Dominant-negative antagonists of the Ras-ERK pathway: DA-Raf and its related proteins generated by alternative splicing of Raf.

Authors:
Takeshi Endo

Exp Cell Res 2020 02 13;387(2):111775. Epub 2019 Dec 13.

Department of Biology, Graduate School of Science, Chiba University, 1-33 Yayoicho, Inageku, Chiba, Chiba 263-8522, Japan. Electronic address:

The Ras-ERK pathway regulates a variety of cellular and physiological responses, including cell proliferation, differentiation, morphogenesis during animal development, and homeostasis in adults. Deregulated activation of this pathway leads to cellular transformation and tumorigenesis as well as RASopathies. Several negative regulators of this pathway have been documented. Each of these proteins acts at particular points of the pathway, and they exert specific cellular and physiological functions. Among them, DA-Raf1 (DA-Raf), which is a splicing isoform of A-Raf and contains the Ras-binding domain but lacks the kinase domain, antagonizes the Ras-ERK pathway in a dominant-negative manner. DA-Raf induces apoptosis, skeletal myocyte differentiation, lung alveolarization, and fulfills tumor suppressor functions by interfering with the Ras-ERK pathway. After the findings of DA-Raf, several kinase-domain-truncated splicing variants of Raf proteins have also been reported. The family of these truncated proteins represents the concept that alternative splicing can generate antagonistic proteins to their full-length counterparts.
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http://dx.doi.org/10.1016/j.yexcr.2019.111775DOI Listing
February 2020

Severe fever with thrombocytopenia syndrome complicated with subdural hematoma: A rare case and literature review.

J Gen Fam Med 2019 Nov 9;20(6):251-254. Epub 2019 Sep 9.

Department of Internal Medicine Unnan City Hospital Unnan-City Japan.

A 79-year-old woman presented with fever and general malaise. Examination revealed hepatic injury, thrombocytopenia, skin lesions, and regional lymphadenopathy; severe fever with thrombocytopenia syndrome (SFTS) was diagnosed using polymerase chain reaction. The patient developed impaired consciousness that worsened after 4 days. Magnetic resonance imaging of the head revealed a subdural hematoma in the occipital region with an uncertain onset time. As SFTS rarely causes intracranial hemorrhage, the associated risk factors are unknown. Clinicians may overlook potential intracranial hemorrhage in stuporous SFTS patients.
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http://dx.doi.org/10.1002/jgf2.273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875529PMC
November 2019

A Novel Experimental Model to Determine the Axon-Promoting Effects of Grafted Cells After Peripheral Nerve Injury.

Front Cell Neurosci 2019 28;13:280. Epub 2019 Jun 28.

Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Although peripheral nerves can regenerate, clinical outcomes after peripheral nerve injuries are not always satisfactory, especially in cases of severe or proximal injuries. Further, autologous nerve grafting remains the gold standard for the reconstruction of peripheral nerves, although this method is still accompanied by issues of donor-site morbidity and limited supply. Cell therapy is a potential approach to overcome these issues. However, the optimal cell type for promoting axon regeneration remains unknown. Here, we report a novel experimental model dedicated to elucidation of the axon-promoting effects of candidate cell types using simple and standardized techniques. This model uses rat sciatic nerves and consists of a 25 mm-long acellular region and a crush site at each end. The acellular region was made by repeated freeze/thaw procedures with liquid nitrogen. Importantly, the new model does not require microsurgical procedures, which are technically demanding and greatly affect axon regeneration. To test the actual utility of this model, red fluorescent protein-expressing syngeneic Schwann cells (SCs), marrow stromal cells, or fibroblasts were grafted into the acellular area, followed by perfusion of the rat 2 weeks later. All types of grafted cells survived well. Quantification of regenerating axons demonstrated that SCs, but not the other cell types, promoted axon regeneration with minimum variability. Thus, this model is useful for differentiating the effects of various grafted cell types in axon regeneration. Interestingly, regardless of the grafted cell type, host SCs migrated into the acellular area, and the extent of axon regeneration was strongly correlated with the number of SCs. Moreover, all regenerating axons were closely associated with SCs. These findings suggest a critical role for SCs in peripheral nerve axon regeneration. Collectively, this novel experimental model is useful for elucidating the axon-promoting effects of grafted cells and for analyzing the biology of peripheral nerve axon regeneration.
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http://dx.doi.org/10.3389/fncel.2019.00280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611175PMC
June 2019

Evidence for cell-contact factor involvement in neurite outgrowth of dorsal root ganglion neurons stimulated by Schwann cells.

Exp Physiol 2019 10 11;104(10):1447-1454. Epub 2019 Aug 11.

Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

New Findings: What is the central question of this study? Although the factors secreted from Schwann cells that promote axonal growth in the peripheral nervous system have been well studied, the effect of cell-contact factors on Schwann cells remains to be determined. What is the main finding and its importance? This study demonstrates that Schwann cells stimulate neurite outgrowth by direct contact with neurites and by secreting factors. Notably, the effect of cell-contact factors in neurite outgrowth is comparable to that of secreted factors, indicating that the identification of cell surface molecules on Schwann cells that promote neurite outgrowth could lead to development of a new therapy for peripheral nervous system injury.

Abstract: Schwann cells (SCs) play a variety of roles in the regeneration process after injury to the peripheral nervous system. The factors secreted from SCs that promote axonal growth have been well studied. However, the involvement of cell-contact factors on SCs remains to be determined. Here, we demonstrate a significant contribution of a cell-contact mechanism in the effect of SCs on promotion of neuronal outgrowth. Neurite outgrowth of adult sensory neurons from dorsal root ganglia was quantified during co-culture with adult SCs. Direct contact of SCs with neurons was eliminated by culturing SCs on an insert placed in the same well; this resulted in a 51% reduction in the length of neurite outgrowth. In addition, when dorsal root ganglion neurons were cultured on sparsely seeded SCs, neurons that made contact with SCs on their neurites had 118% longer neurites than neurons that lacked contacts with SCs. Collectively, these findings provide evidence that SCs stimulate neurite outgrowth via direct contact with neurites in addition to secreting factors. The identification of cell surface molecules on SCs that promote neurite outgrowth could lead to development of a new therapy for peripheral nervous system injury.
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http://dx.doi.org/10.1113/EP087634DOI Listing
October 2019

Height loss but not body composition is related to low back pain in community-dwelling elderlies: Shimane CoHRE study.

BMC Musculoskelet Disord 2019 May 10;20(1):207. Epub 2019 May 10.

Center for Community-Based Healthcare Research and Education (CoHRE), Shimane University, Matsue-city, Shimane, Japan.

Background: Low back pain (LBP) is a common complaint in the elderly Japanese population. Although previous studies showed that height loss was associated with LBP, it remains unclear whether LBP is associated with body composition. The objective of the present study was to investigate whether body composition and physical characteristics, including height loss, were associated with LBP.

Methods: The present study is retrospectively registered, and the participants were 2212 community-dwelling Japanese people aged over 60 years who participated in the Shimane CoHRE study in 2016. We investigated the presence of LBP, body composition parameters (muscle, fat, body weight, and bone mass), physical characteristics (body height and height loss), chronic diseases, history of fall, smoking, and drinking habits. We examined the relationships of body composition parameters and physical characteristics with point prevalence of LBP using multivariate logistic regression.

Results: The point prevalence of LBP was 43.2% in women and 39.5% in men. Logistic regression models showed that body height and body composition were not significantly associated with LBP; however, height loss was associated significantly with LBP in women and men (OR: 1.14, 95% CI: 1.08-1.20 and OR: 1.13, 95% CI: 1.06-1.21, respectively). Hypertension (OR: 1.32, 9 5% CI: 1.04-1.69) and chronic heart disease (OR: 1.57, 95% CI: 1.01-2.43) in women and history of fall (OR: 1.70, 95% CI: 1.13-2.56) and cerebrovascular disease (OR: 1.88, 95% CI: 1.05-3.34) in men were significantly associated with LBP. However, body composition was not associated with LBP in either gender.

Conclusions: The present study demonstrated that height loss, but not body composition, was related to LBP in community-dwelling elderly people. To elucidate the cause of LBP, it is important to consider the relationship with height loss.
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http://dx.doi.org/10.1186/s12891-019-2580-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511157PMC
May 2019

DA-Raf, a dominant-negative regulator of the Ras-ERK pathway, is essential for skeletal myocyte differentiation including myoblast fusion and apoptosis.

Exp Cell Res 2019 03 8;376(2):168-180. Epub 2019 Feb 8.

Department of Biology, Graduate School of Science, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan. Electronic address:

Ras-activated ERK pathway (Raf-MEK-ERK phosphorylation cascade) regulates a variety of cellular responses including cell proliferation, differentiation, survival, and apoptosis. DA-Raf1 (DA-Raf) is a splicing variant of A-Raf and contains the Ras-binding domain but lacks the kinase domain. Accordingly, DA-Raf antagonizes the Ras-ERK pathway in a dominant-negative manner. Here we show that DA-Raf plays essential roles in skeletal myocyte differentiation including myoblast fusion and in apoptosis, which are suppressed by the Ras-ERK pathway. Expression of DA-Raf was highly induced in C2C12 skeletal myocytes in a low serum concentration of differentiation condition and in NIH3T3 fibroblasts under a serum starvation apoptosis-inducing condition. Stable knockdown of DA-Raf resulted in suppression of muscle-specific gene expression, myoblast fusion, and apoptosis. In contrast, exogenous overexpression of DA-Raf prominently caused apoptosis. DA-Raf induces apoptosis by preventing ERK-RSK-mediated inhibitory phosphorylation of Bad. Although it has been reported that apoptosis triggers myoblast fusion, DA-Raf-induced apoptosis was not involved in myoblast fusion in C2C12 cells. These results imply that suppression of the Ras-ERK pathway by DA-Raf is essential for both myocyte differentiation including myoblast fusion and apoptosis but that apoptosis is not a prerequisite for myoblast fusion.
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http://dx.doi.org/10.1016/j.yexcr.2019.02.002DOI Listing
March 2019

Selective formation of a zwitterion adduct and bicarbonate salt in the efficient CO fixation by -benzyl cyclic guanidine under dry and wet conditions.

Beilstein J Org Chem 2018 23;14:2204-2211. Epub 2018 Aug 23.

Molecular Engineering Institute, Kindai University, 11-6 Kayanomori, Iizuka, Fukuoka 820-8555, Japan.

The efficient CO fixation by -benzyl cyclic guanidine was achieved by bubbling dry CO through CHCN at 25 °C for 2 h. In addition, the zwitterion adduct and bicarbonate salt were selectively prepared from under dry (in anhydrous CHCN) and wet (in CHCN containing an equimolar amount of water for ) conditions, respectively. Both compounds and were isolated as white solids and their structures were characterized in detail by elemental analysis, FTIR-ATR, solid-state NMR, TGA, and DFT calculation. These analytical results obviously revealed the formation of a zwitterion adduct and bicarbonate salt from -benzyl cyclic guanidine and CO. Especially, the zwitterion adduct of the monocyclic guanidine derivative and CO was isolated and characterized for the first time.
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http://dx.doi.org/10.3762/bjoc.14.194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122324PMC
August 2018

Surface Modification with a Catechol-Bearing Polypeptide and Sensing Applications.

Biomacromolecules 2018 07 23;19(7):3067-3076. Epub 2018 May 23.

Department of Chemistry, Faculty of Science and Letters , Istanbul Technical University , 34469 Maslak, Istanbul , Turkey.

A novel catechol-bearing polypeptide (CtP) was synthesized and used as a component of electrochemical biosensor involving both enzymatic activity and affinity-based sensing systems. Glucose oxidase (GOx) and anti-immunoglobulin G (Anti-IgG) were selected as model biorecognition elements for the selective analysis of glucose and IgG. Step-by-step surface modifications were followed using various techniques such as cyclic voltammetry (CV) and electrochemical impedance spectrometry (EIS) as well as X-ray photoelectron spectroscopy (XPS). Additionally, contact angles were measured in order to observe surface properties. Amperometric measurements using the GOx biosensor were performed at -0.7 V by following the oxygen consumption due to the enzymatic reaction in different glucose concentrations. Affinity-based interactions via IgG sensor were monitored using the differential pulse voltammetry (DPV) technique. As the "surface design with CtP" approach employed herein is generally applicable and easily adaptable to obtain functional matrices for biomolecule immobilization, CtP-coated surfaces can be promising platforms for the fabrication of various biobased sensing systems.
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http://dx.doi.org/10.1021/acs.biomac.8b00650DOI Listing
July 2018

[A Case of Successful Treatment with Gemcitabine plus Nab-Paclitaxel Therapy for Nonresected Pancreatic Body Cancer(Stage IVb)].

Gan To Kagaku Ryoho 2018 Mar;45(3):563-565

Dept. of Surgery, Hasuda Hospital.

A 61-year-old woman was introduced for consultation with a chief complaint of frequent vomiting. CT revealed a pancreatic body cancer approximately 40mm in size; an invading stenosis from the horizontal part of the duodenum to the jejunum, superior mesenteric artery, and portal vein, splenic vein obstruction, lymphadenopathy, and some ascitic fluid. We diagnosed a passage disorder due to the invasive stenosis from the horizontal part of the duodenum of the pancreatic body cancer to the jejunum, and subsequently performed a duodenum and jejunum bypass operation. We controlled cancer pain with opioid analgesia, and S-1 monotherapy was chosen as the primary chemotherapy. A tendency to increase and the cancer pain of the tumor was aggravated when 5 courses took effect, so gemcitabine plus nab-paclitaxel(GEM plus nab-PTX)therapy was chosen as the second-line chemotherapy because of adverse Grade 3 events due to difficulties with S-1 internal use. We tapered off the opioid analgesia dosage because the cancer pain was relieved after 1 course. The imaging top indicated stable disease at the end of 5 courses, but the pain was relieved so opioid pain killers were unnecessary. Foreign continuation is under treatment with 10-course GEM plus nab-PTX therapy after initial diagnosis. Currently, the patient has undergone 5 courses of S-1 for approximately 18 months, and has achieved stable disease. The only adverse events were nausea, fatigue, Grade 1 malaise, and Grade 2 alopecia, as detected with imaging.
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March 2018

Development of a multiple-gene-loading method by combining multi-integration system-equipped mouse artificial chromosome vector and CRISPR-Cas9.

PLoS One 2018 5;13(3):e0193642. Epub 2018 Mar 5.

Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Tottori, Japan.

Mouse artificial chromosome (MAC) vectors have several advantages as gene delivery vectors, such as stable and independent maintenance in host cells without integration, transferability from donor cells to recipient cells via microcell-mediated chromosome transfer (MMCT), and the potential for loading a megabase-sized DNA fragment. Previously, a MAC containing a multi-integrase platform (MI-MAC) was developed to facilitate the transfer of multiple genes into desired cells. Although the MI system can theoretically hold five gene-loading vectors (GLVs), there are a limited number of drugs available for the selection of multiple-GLV integration. To overcome this issue, we attempted to knock out and reuse drug resistance genes (DRGs) using the CRISPR-Cas9 system. In this study, we developed new methods for multiple-GLV integration. As a proof of concept, we introduced five GLVs in the MI-MAC by these methods, in which each GLV contained a gene encoding a fluorescent or luminescent protein (EGFP, mCherry, BFP, Eluc, and Cluc). Genes of interest (GOI) on the MI-MAC were expressed stably and functionally without silencing in the host cells. Furthermore, the MI-MAC carrying five GLVs was transferred to other cells by MMCT, and the resultant recipient cells exhibited all five fluorescence/luminescence signals. Thus, the MI-MAC was successfully used as a multiple-GLV integration vector using the CRISPR-Cas9 system. The MI-MAC employing these methods may resolve bottlenecks in developing multiple-gene humanized models, multiple-gene monitoring models, disease models, reprogramming, and inducible gene expression systems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193642PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837097PMC
July 2018

Hyperbranched Triphenylamine Polymer for UltraFast Battery Cathode.

ACS Appl Mater Interfaces 2018 Feb 9;10(7):6346-6353. Epub 2018 Feb 9.

Molecular Engineering Institute, Kindai University , 11-6, Kayanomori, Iizuka, Fukuoka 820-8555, Japan.

A novel hyperbranched poly(triphenylamine) (PHTPA) was synthesized, and the electrochemical properties of this material were studied. PHTPA was synthesized by a facile method in a one-step reaction from affordable monomers. Despite all aromatic structures, PHTPA showed good solubility in several organic solvents. The battery performance test of PHTPA showed a high discharge voltage, an ultrafast charge-discharge performance of 100-300 C, and a long cycle life of more than 5000 cycles. Moreover, the addition of the PHTPA to LiFePO (LFP) improved the charge-transfer resistance and Warburg coefficient, which is related to the diffusion of lithium ions in LFP, and consequently improved the charge-discharge performance of LFP itself at a high C rate (20-100 C). This behavior is understood to be the result of the organic-inorganic charge transfer. The superior cycle performance of the PHTPA-LFP hybrid cathode was also found. PHTPA will serve as an additive for a high-performance LIB.
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http://dx.doi.org/10.1021/acsami.7b17943DOI Listing
February 2018

Reworkable Polyhydroxyurethane Films with Reversible Acetal Networks Obtained from Multifunctional Six-Membered Cyclic Carbonates.

J Am Chem Soc 2018 01 16;140(3):884-887. Epub 2018 Jan 16.

Molecular Engineering Institute, Kindai University , 11-6 Kayanomori, Iizuka, Fukuoka 820-8555, Japan.

Multifunctional 6-membered cyclic carbonates (6-CCs) comprising acetal structures have been synthesized via phosgene-free routes and utilized for the fabrication of reworkable networked poly(acetal-hydroxyurethane) (PAHU) films. Dibenzoyl-protected di(trimethylolpropane) (DTMP) reacts with multifunctional aldehydes derived from nonexpensive alcohols to afford protected multifunctional DTMPs. After deprotection, the multifunctional DTMPs can react with diphenyl carbonate to efficiently form multifunctional 6-CCs. The polyaddition of the 6-CCs and diamines effectively proceeds in DMF to give networked PAHU films with good transparency and flexibility. These films possess the reworkability based on acid-catalyzed reversibility of acetal linkages. In particular, the film fabricated using large amounts of hexa-functional 6-CCs can reform reproducibly with maintaining to some degree its mechanical properties.
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http://dx.doi.org/10.1021/jacs.7b11824DOI Listing
January 2018

Antiviral therapy for hepatitis B virus during second pregnancies.

J Obstet Gynaecol Res 2018 Mar 11;44(3):566-569. Epub 2017 Dec 11.

Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Mother-to-child transmission of the hepatitis B virus (HBV) is a major concern for infected mothers, especially after their first child has become an HBV carrier despite immunoprophylaxis. Eight mothers whose first child had become an HBV carrier despite immunoprophylaxis were referred for antiviral therapy during the subsequent pregnancy. All pregnant women were seropositive for both the hepatitis B surface antigen and hepatitis B e antigen. In the treatment group (three receiving lamivudine and two receiving tenofovir), mother-to-child transmission of the HBV was successfully prevented in all infants (5/5). On the other hand, two of three infants became HBV carriers in the untreated group. There were no significant adverse effects in either mothers or infants. Antiviral therapy using lamivudine and tenofovir during the second pregnancy successfully prevented mother-to-child transmission of the HBV for high-risk mothers.
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http://dx.doi.org/10.1111/jog.13540DOI Listing
March 2018

DA-Raf, a dominant-negative antagonist of the Ras-ERK pathway, is a putative tumor suppressor.

Exp Cell Res 2018 01 10;362(1):111-120. Epub 2017 Nov 10.

Department of Biology, Graduate School of Science, Chiba University, 1-33 Yayoicho, Inageku, Chiba, Chiba, 263-8522, Japan. Electronic address:

Activating mutations of RAS genes, particularly KRAS, are detected with high frequency in human tumors. Mutated Ras proteins constitutively activate the ERK pathway (Raf-MEK-ERK phosphorylation cascade), leading to cellular transformation and tumorigenesis. DA-Raf1 (DA-Raf) is a splicing variant of A-Raf and contains the Ras-binding domain (RBD) but lacks the kinase domain. Accordingly, DA-Raf antagonizes the Ras-ERK pathway in a dominant-negative fashion and suppresses constitutively activated K-Ras-induced cellular transformation. Thus, we have addressed whether DA-Raf serves as a tumor suppressor of Ras-induced tumorigenesis. DA-Raf(R52Q), which is generated from a single nucleotide polymorphism (SNP) in the RBD, and DA-Raf(R52W), a mutant detected in a lung cancer, neither bound to active K-Ras nor interfered with the activation of the ERK pathway. They were incapable of suppressing activated K-Ras-induced cellular transformation and tumorigenesis in mice, in which K-Ras-transformed cells were transplanted. Furthermore, although DA-Raf was highly expressed in lung alveolar epithelial type 2 (AE2) cells, its expression was silenced in AE2-derived lung adenocarcinoma cell lines with oncogenic KRAS mutations. These results suggest that DA-Raf represents a tumor suppressor protein against Ras-induced tumorigenesis.
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http://dx.doi.org/10.1016/j.yexcr.2017.11.008DOI Listing
January 2018

The Primary Result of Prospective Randomized Multicenter Trial of New Spray-Type Bio-absorbable Adhesion Barrier System (TCD-11091) Against Postoperative Adhesion Formation.

J Gastrointest Surg 2017 Oct 25;21(10):1683-1691. Epub 2017 Jul 25.

Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita, Japan.

Background: Postoperative adhesions are the major cause of postoperative complications including intestinal obstruction, infertility, and chronic pelvic pain. In order to reduce postoperative adhesions, Terumo Corporation (Tokyo, Japan) has developed an adhesion barrier system (TCD-11091) which is easy to use at the treatment site in various surgical procedures including laparoscopic surgeries. We conducted a prospective randomized single-blind study in patients who underwent laparotomy with ileostomy.

Methods And Results: One hundred twenty-six patients were randomly assigned to TCD-11091 group (n = 62) or non-treatment group (n = 62). Patient backgrounds were similar between the groups. At the time of ileostomy closure (the second-look surgery), the observation was performed on 55 in the TCD-11091 group and 43 in the control group. The incidence of adhesions observed at the second-look surgery was significantly lower in the TCD-11091 group (52.7 versus 90.7%; p < 0.001). For the secondary endpoints, the incidence of wide extent adhesions (grade 2 or higher) was significantly reduced (38.2 versus 79.1%; p < 0.001). Regarding the severity of adhesions, the incidence of grade 2 or higher adhesions was also significantly lower in the TCD-11091 group (47.3 versus 88.4%; p < 0.001). No differences in the incidence of adverse events were found between the TCD-11091 group and the non-treatment group (85.2 versus 75.4%; p = 0.225).

Conclusions: Use of TCD-11091 was safe and associated with significantly lower incidence of adhesion and severity of adhesions compared with non-treatment procedure.
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http://dx.doi.org/10.1007/s11605-017-3503-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610222PMC
October 2017

Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome.

Acta Paediatr 2017 Nov 2;106(11):1817-1824. Epub 2017 Aug 2.

Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Aim: We evaluated combined genetic analyses with targeted next-generation sequencing (NGS), multiplex ligation probe amplification (MLPA) of Jagged1 (JAG1) genes and microarray comparative genomic hybridisation (CGH) in subjects with Alagille syndrome, incomplete clinical features of Alagille syndrome and biliary atresia.

Methods: Subjects recruited from April 2013 to December 2015 underwent a targeted NGS analysis, including JAG1 and Notch homolog 2 (NOTCH2). If no mutations were detected in JAG1 or NOTCH2, or if copy number variations were suggested by the NGS analysis, we performed an MLPA analysis of JAG1. We also performed a microarray CGH analysis with whole-exon deletion detected by the MLPA analysis.

Results: We analysed 30 subjects with Alagille syndrome, nine with incomplete Alagille syndrome and 17 with biliary atresia and detected pathogenic mutations in JAG1 or NOTCH2 in 24/30 subjects with Alagille syndrome and in 4/9 subjects with incomplete Alagille syndrome. No pathogenic mutations were detected in subjects with biliary atresia. The frequency of JAG1 mutations was as follows: single nucleotide variants (51.9%), small insertion or deletion (29.6%) and gross deletion (18.5%).

Conclusion: Combined genetic analyses achieved efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome.
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http://dx.doi.org/10.1111/apa.13981DOI Listing
November 2017

[Two Cases of Lung Metastasis from Breast Cancer Successfully Treated with Endocrine Therapy].

Gan To Kagaku Ryoho 2016 Nov;43(12):2419-2421

Dept. of Surgery, Hasuda Hospital.

We report 2 cases of lung metastasis from breast cancer that were successfully treated with endocrine therapy.Case 1 is a 69-year-old woman with cirrhosis of the liver caused by hepatitis C.She underwent surgery for left breast cancer at the age of 58, and surgery for right breast cancer at the age of 65.Four years later, she was diagnosed with lung metastasis of breast cancer.She received letrozole and the treatment was effective.Because the severity of the pleural effusion increased 3 years later, fulvestrant was subsequently administered.As a result, the patient remained in good health for 1 year.She died 5 years later.Case 2 is a 72-year-old woman who underwent right breast cancer surgery 12 years previously.She complained of respiratory discomfort as a result of right pleural effusion from lung metastasis.She was hospitalized for cancer lymphangitis that had deteriorated.The patient was immediately treated with fulvestrant and her symptoms improved significantly; the pleural effusion also disappeared.Sixteen months later, no recurrence has been observed.
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November 2016

TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation.

J Biol Chem 2017 02 12;292(8):3201-3212. Epub 2017 Jan 12.

Department of Biology, Graduate School of Science, Chiba University, Chiba 263-8522, Japan.

Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53-induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions.
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http://dx.doi.org/10.1074/jbc.M116.763318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336156PMC
February 2017

Special Issue "Ring-Opening Polymerization".

Molecules 2016 Dec 14;21(12). Epub 2016 Dec 14.

Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, Kowakae 3-4-1, Higashi-Osaka, Osaka 577-8502, Japan.

n/a.
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http://dx.doi.org/10.3390/molecules21121720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274008PMC
December 2016

A kidney injury molecule-1 (Kim-1) gene reporter in a mouse artificial chromosome: the responsiveness to cisplatin toxicity in immortalized mouse kidney S3 cells.

J Gene Med 2016 Oct;18(10):273-281

Tottori Industrial Promotion Organization, Tottori, Tottori, Japan.

Background: Kidney injury molecule-1 (Kim-1) has been validated as a urinary biomarker for acute and chronic renal damage. The expression of Kim-1 mRNA is also activated by acute kidney injury induced by cisplatin in rodents and humans. To date, the measurement of Kim-1 expression has not fully allowed the detection of in vitro cisplatin nephrotoxicity in immortalized culture cells, such as human kidney-2 cells and immortalized proximal tubular epithelial cells.

Methods: We measured the augmentation of Kim-1 mRNA expression after the addition of cisplatin using immortalized S3 cells established from the kidneys of transgenic mice harboring temperature-sensitive large T antigen from Simian virus 40.

Results: A mouse Kim-1 gene luciferase reporter in conjunction with an Hprt gene reporter detected cisplatin-induced nephrotoxicity in S3 cells. These two reporter genes were contained in a mouse artificial chromosome, and two luciferases that emitted different wavelengths were used to monitor the respective gene expression. However, the Kim-1 reporter gene failed to respond to cisplatin in A9 fibroblast cells that contained the same reporter mouse artificial chromosome, suggesting cell type-specificity for activation of the reporter.

Conclusions: We report the feasibility of measuring in vitro cisplatin nephrotoxicity using a Kim-1 reporter gene in S3 cells.
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http://dx.doi.org/10.1002/jgm.2925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095820PMC
October 2016

Polypeptide with electroactive endgroups as sensing platform for the abused drug 'methamphetamine' by bioelectrochemical method.

Talanta 2016 Dec 17;161:789-796. Epub 2016 Sep 17.

Istanbul Technical University, Department of Chemistry, Faculty of Science and Letters, Istanbul, Turkey. Electronic address:

Affinity-type sensors have emerged as outstanding platforms in the detection of diagnostic protein markers, nucleic acids and drugs. Thus, these novel platforms containing antibodies could be integrated into the monitoring systems for abused drugs. Herein, we established a novel detection platform for the analysis of a common illicit drug; methamphetamine (METH). Initially, a fluorescent-labeled polypeptide (EDOT-BTDA-Pala), derived from L-alanine N-carboxyanhydride (L-Ala-NCA) via ring-opening polymerization using 4,7-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)benzo[c][1,2,5]thiadiazole-5,6-diamine (EDOT-NH-BTDA) as initiator, was employed as a glassy carbon electrode (GCE) covering host, in order to immobilize the METH-selective antibody. Prior to the examination of analytical features, GCE/EDOT-BTDA-Pala/Antibody surface was successfully characterized in the way of electrochemical (cyclic voltammetry and electrochemical impedance spectroscopy) and microscopic techniques (scanning electron microscopy and fluorescence microscopy). As for the analytical characterization, linearity and limit of detection (LOD) were found as 10-100µg/mL with an equation of y=0.0429x-0.2347, (R=0.996) and 13.07µg/mL, respectively. Moreover, sample application using artificial urine, saliva and serum samples spiked with METH (10, 25, 50µg/mL) were performed and LC-MS/MS system was used for further confirmation. The described platform can be adapted to monitor the other types of abused drugs by using suitably selected biorecognition elements.
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http://dx.doi.org/10.1016/j.talanta.2016.09.042DOI Listing
December 2016

Hepatocellular carcinoma in children and young patients with chronic HBV infection and the usefulness of alpha-fetoprotein assessment.

Cancer Med 2016 11 17;5(11):3102-3110. Epub 2016 Oct 17.

Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

The aims of the study were to elucidate the clinical characteristics of patients who developed hepatocellular carcinoma (HCC) related to persistent HBV infection since childhood and to investigate usefulness of assessing alpha-fetoprotein (AFP) in this population. A nationwide multicenter survey of children with chronic HBV infection was performed. Among 548 patients, 15 patients developed HCC at the median age of 15 years (range 9-36), including 13 males and 2 females. A case-control comparison showed that HBeAg seroconversion and liver cirrhosis were associated with the occurrence of HCC. Of the 15 HCC patients, 5 were treated with interferon and none of them responded to interferon therapy as compared with 12 of the 17 responders in the control group. Of the 15 patients, 10 died and 9 of the 10 who died never visited any medical facilities until diagnosis of HCC, while the remaining 5 surviving patients never stopped their clinic visits. The usefulness of AFP assessment was shown by the findings that AFP levels were elevated in all HCC cases, that elevations in AFP levels were detected prior to the diagnosis in the surviving patients, and that sensitivity of AFP as a diagnostic test for HCC was very high among 40 patients including our 14 and an additional 26 collected from the literature. HBeAg seroconversion and liver cirrhosis are associated with the occurrence of HCC. Regular measurement of AFP might be helpful to watch for the occurrence of HCC when following children and young patients with chronic HBV infection since childhood.
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http://dx.doi.org/10.1002/cam4.917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119965PMC
November 2016

Sporicidal performance induced by photocatalytic production of organic peroxide under visible light irradiation.

Sci Rep 2016 Sep 26;6:33715. Epub 2016 Sep 26.

Photocatalysis International Research Center, Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-0022, Japan.

Bacteria that cause serious food poisoning are known to sporulate under conditions of nutrient and water shortage. The resulting spores have much greater resistance to common sterilization methods, such as heating at 100 °C and exposure to various chemical agents. Because such bacteria cannot be inactivated with typical alcohol disinfectants, peroxyacetic acid (PAA) often is used, but PAA is a harmful agent that can seriously damage human health. Furthermore, concentrated hydrogen peroxide, which is also dangerous, must be used to prepare PAA. Thus, the development of a facile and safe sporicidal disinfectant is strongly required. In this study, we have developed an innovative sporicidal disinfection method that employs the combination of an aqueous ethanol solution, visible light irradiation, and a photocatalyst. We successfully produced a sporicidal disinfectant one hundred times as effective as commercially available PAA, while also resolving the hazards and odor problems associated with PAA. The method presented here can potentially be used as a replacement for the general disinfectants employed in the food and health industries.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036025PMC
http://dx.doi.org/10.1038/srep33715DOI Listing
September 2016
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