Publications by authors named "Ryo Taguchi"

134 Publications

Chylothorax associated with lymphatic reflux in a thoracic duct tributary after lung cancer surgery.

Thorac Cancer 2021 Jun 21. Epub 2021 Jun 21.

Department of General Thoracic Surgery, Saitama Medical University International Medical Center, Saitama, Japan.

Chyle leaks are attributed to damage to the thoracic duct itself or its tributaries during surgery. Chylothorax after lung cancer surgery can occur due to damaged thoracic duct tributaries; however, little is known of the mechanism involved. A 71-year-old female underwent a left upper lobectomy with hilar and mediastinal lymphadenectomy for a 1.8-cm primary squamous cell carcinoma, and developed a chylothorax a day later. Catheter lymphangiography revealed high-flow chyle leaks from a damaged thoracic duct tributary, known as a bronchomediastinal lymph trunk, due to a lymphatic reflex from the thoracic duct. Subsequently, catheter embolization of the tributary repaired the chylothorax. The potential for persistent chylothorax after lung cancer surgery and successful lymphatic intervention should be noted.
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http://dx.doi.org/10.1111/1759-7714.14062DOI Listing
June 2021

An aorto-right-atrial fistula caused by infective endocarditis in a patient with an anomalous coronary artery from the opposite sinus.

Gen Thorac Cardiovasc Surg 2021 Aug 12;69(8):1251-1253. Epub 2021 May 12.

Department of Thoracic and Cardiovascular Surgery, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.

A 35-year-old man presented with an anomalous right coronary artery from the opposite Valsalva sinus. He developed an aorto-right-atrial fistula due to destructive infective endocarditis undetected during preoperative computed tomography. Intraoperative retrograde cardioplegia and direct insertion of the coronary probe demonstrated that the right coronary ostium was in the left Valsalva sinus near the left coronary ostium. The right-sided aortic root and right atrium were severely damaged. This coronary anomaly allowed us to perform a unique aortic root reconstruction without touching or injuring the right coronary artery. Two years later, the patient remains well without complications. This novel reconstruction treatment is feasible for destructive infective endocarditis in such patients.
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http://dx.doi.org/10.1007/s11748-021-01644-yDOI Listing
August 2021

Reversible dementia due to vitamin B12 deficiency in a lung cancer patient: Relevance of preoperative evaluation.

Palliat Support Care 2021 Jun;19(3):377-379

Department of Psycho-oncology, Saitama Medical University International Medical Center, Saitama, Japan.

Objective: Cognitive dysfunction has a negative effect on cancer treatment; however, in a cancer setting, specific treatments can restore cognitive function. Such conditions are known as reversible dementia, with one of these being vitamin B12 (VB12) deficiency. However, there have been no reports of VB12 deficiency identified by preoperative evaluation in cancer patients.

Method: We studied a patient who was referred to the Department of Psycho-oncology on suspicion of cognitive decline prior to lung cancer surgery. Preoperative evaluation revealed VB12 deficiency.

Results: The patient was an 82-year-old woman diagnosed with lung cancer. She also presented with cognitive decline and, therefore, was referred to the Department of Psycho-oncology for preoperative evaluation. The patient scored 19 points on a Mini-Mental State Examination (MMSE), which is indicative of cognitive decline. As the onset of symptoms occurred several months previously and they were subacute, the possibility of reversible dementia was considered. Extensive examination revealed VB12 deficiency, and VB12 replacement therapy normalized the MMSE score to 25 points before surgery.

Significance Of The Results: When cognitive decline is observed in cancer patients, it is necessary to actively evaluate the serum levels of some B vitamins, including VB12.
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http://dx.doi.org/10.1017/S1478951521000481DOI Listing
June 2021

Quantitative analysis of bending hysteresis by real-time monitoring of curvature in flexible polymeric films.

Soft Matter 2021 Apr;17(15):4040-4046

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan. and Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Ookayama, Meguro-ku, Tokyo 152-8552, Japan.

Flexibility, viscoelasticity and stress-strain relation in bending polymeric films are key factors in designing mechanically durable flexible electronic devices and soft robots. However, bending hysteresis, which appears as a precursor phenomenon of fracture and fatigue, remains unclear; no one quantitatively evaluated a bending curvature causing hysteresis. Herein, we report the bending hysteresis of polymeric films used as common substrates in flexible electronics by precisely monitoring bending curvatures. By real-time measuring curvatures of films upon bending and subsequent unbending, we have successfully determined the curvatures that cause the hysteresis. These curvatures also depend on a film thickness. Furthermore, we revealed that the occurrence of bending hysteresis is explained by bending strains that have a nonlinear relation with internal stresses. This enables us to predict strain limits that cause the bending hysteresis, based on a stress-strain curve of polymeric films.
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http://dx.doi.org/10.1039/d0sm02233kDOI Listing
April 2021

Bed Exit Action Detection Based on Patient Posture with Long Short-Term Memory.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:4390-4393

It has been known that the fall of a patient in a hospital is a serious accident. In order to prevent such accidents, we have been studying the fall prevention using image processing technology. Our previous studies have detected the patient's end sitting position with high accuracy, but have problems responding to the sitting position of patients who are eating or responding to visitors. In order to solve these problems, this paper proposes a method to detect the patient's bed exit action by analyzing the posture of the patient extracted from the image of the monocular camera by long short-term memory (LSTM). Our proposed method introduces two strategies - abstraction of input information and use of relative position information for the input time-series human images, achieving a 99.2[%] detection rate of bed exit action with a 5.7[%] false detection rate. Detecting the bed exit action with high accuracy contributes to preventing the patient from falling down. The proposed solution handles only posture information that abstracts camera images for patient privacy purposes.
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http://dx.doi.org/10.1109/EMBC44109.2020.9175619DOI Listing
July 2020

NEWS technique: easy and reliable thoracoscopic wedge resections of lung tumors.

J Thorac Dis 2020 Aug;12(8):4571-4577

Department of General Thoracic Surgery, Saitama Medical University International Medical Center, Saitama, Japan.

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http://dx.doi.org/10.21037/jtd-19-4020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475537PMC
August 2020

Pulmonary high-grade fetal adenocarcinoma associated with cystic airspace: A case report.

Thorac Cancer 2020 06 29;11(6):1703-1707. Epub 2020 Mar 29.

Department of Pathology, Saitama Cardiovascular and Respiratory Center, Saitama, Japan.

Lung cancers associated with cystic airspaces have a life-threatening risk of a missed or delayed diagnosis. Here, we report a case of pulmonary high-grade fetal adenocarcinoma, a rare lung carcinoma associated with cystic airspaces, as confirmed by computed tomography (CT) scan. A 73-year-old asymptomatic male with a 52-pack a year smoking habit was referred to our hospital. Lung CT showed a thin-walled cystic space with exophytic and endophytic solid nodules along the cyst wall. After surgery, histological analysis of a resected lung specimen revealed a pure high-grade fetal adenocarcinoma probably associated with emphysematous bullae in pulmonary emphysema, suggesting smoking contributed to this pure form, as well as the emphysema. In conclusion, when treating elderly men with a smoking history, physicians need to carefully examine the walls of cystic airspaces on CT for fetal adenocarcinoma. KEY POINTS: Significant findings of the study •Pulmonary high-grade fetal adenocarcinoma may be associated with emphysematous bullae manifesting as cystic air spaces as shown by computed tomography. What this study adds •When scanning by computed tomography, physicians should carefully examine the pulmonary cystic airspace walls in elderly men with a smoking history.
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http://dx.doi.org/10.1111/1759-7714.13407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262892PMC
June 2020

Bed-Exit Prediction Applying Neural Network Combining Bed Position Detection and Patient Posture Estimation.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:3208-3211

The work of a nurse involves tasks that can lead to serious accidents with a single mistake or miss, and thus nurses are exposed to high stress. In particular, injections, pre-medications, tube connections, and falling are factors that lead to serious accidents and are considered a major part of the load of nursing work. To reduce the burden of nursing work, we are working on developing a sensing system to prevent fall accidents. Because fall accidents tend to occur when elderly people, whose lower limb muscle strength has declined, go to the toilet, we use a camera image to detect the end position, which is the initial posture of the patient's landing movement. In this study, we detected the sitting position of the patient by combining the detection result of the skeletal position of the patient and the detection result of the bed position. A simulation environment was constructed and the estimation accuracy of the end sitting position of the patient was evaluated using the image captured at the scene where the patient and the nurse are active.
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http://dx.doi.org/10.1109/EMBC.2019.8857233DOI Listing
July 2019

[Coronary Artery Bypass Grafting to the Left Anterior Descending Artery via Anterior Minithoracotomy after Surgery for Acute Papillary Muscle Rupture;Report of a Case].

Kyobu Geka 2019 Dec;72(13):1081-1084

Department of Cardiovascular Surgery, Aomori City Hospital, Aomori, Japan.

We presented a case with chronic occlusion of the left anterior descending artery(LAD) after mitral valve replacement (MVR). An 80-year-old man was transferred to our hospital with a diagnosis of acute myocardial infarction. Before coronary angiography, the patient suddenly fell in a state of cardiogenic shock. Echocardiography revealed acute mitral regurgitation due to anterior papillary muscle rupture. Although emergency MVR was performed, introduction of percutaneous cardiopulmonary support (PCPS) and intraaortic balloon pumping ( IABP) was needed to come off cardiopulmonary bypass. Postoperative coronary angiography revealed chronic occlusion of LAD. The left internal thoracic artery was anastomosed to LAD via anterior minithracotomy to avoid median re-sternotomy. The postoperative course was uneventful and the cardiac function improved.
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December 2019

Primary pulmonary synovial sarcoma with calcification: A case report.

Thorac Cancer 2019 10 19;10(10):2040-2044. Epub 2019 Aug 19.

Department of General Thoracic Surgery, Saitama Medical University International Medical Center, Saitama, Japan.

The lung is the organ most commonly affected by primary synovial sarcoma. Intratumoral calcification is less common in this organ versus soft tissue. Meanwhile, the presence of calcification in a lung nodule reduces the risk of lung cancer. Here, we report a case of pulmonary synovial sarcoma which manifested as a nodule with calcification, depicted on computed tomography (CT). A 52-year-old asymptomatic male was referred to Saitama Medical University International Medical Center and CT revealed a well-defined nodule (1.8 cm), with punctate and eccentric calcification in the right lower lobe. Enhanced CT and 18F-fluorodeoxyglucose positron-emission tomography suggested a malignant tumor, and surgery was performed. Histology provided a preliminary diagnosis of monophasic spindle-cell synovial sarcoma with hyalinized collagen bands and calcifications. Genetically, the presence of the SYT-SSX2 fusion gene was consistent with the features of this disease. We conclude that primary pulmonary synovial sarcoma should be listed as a differential diagnosis for solitary pulmonary nodules with calcification.
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http://dx.doi.org/10.1111/1759-7714.13172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775223PMC
October 2019

Distinctive clinicopathological features of adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung: A retrospective study.

Lung Cancer 2019 03 19;129:16-21. Epub 2018 Dec 19.

Department of Respiratory Medicine, Saitama Medical University International Medical Center, Saitama, Japan.

Objectives: The aim of this study was to investigate distinguishing clinicopathological features, in addition to histological invasiveness, in adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) of the lung.

Materials And Methods: Patients with lung adenocarcinoma who underwent surgery at our hospital between 2007 and 2014 were reviewed, focusing on computed tomography (CT) images, operative procedures and clinical outcomes, histopathology, Ki-67 immunostaining, and EGFR-mutation status. EGFR mutations were examined using a peptide nucleic acid-locked nucleic acid PCR clamp method. Group comparisons were investigated by Mann-Whitney U or Fisher's exact tests.

Results: Of 629 patients with lung adenocarcinoma who underwent surgery, 91 (14%) of 103 AIS (n = 34) or MIA (n = 69) tumors were reviewed. The ratio of male to female patients with MIA compared to AIS was significantly higher (p <  0.02). Of 103 tumors, 99 (96%) were non-mucinous. By CT, 74% of AIS appeared as pure ground-glass nodules and 75% of MIAs as part-solid ground-glass nodules. Pathological tumor diameters and Ki-67 labeling index (LI) values were significantly greater for MIAs compared to AIS (p <  0.001 for both). A Ki-67 LI of ≥2.8% indicated the presence of an MIA rather than an AIS. EGFR mutations were more frequently detected in MIAs (33/69, 48%) than AIS (9/34, 26%; p =  0.055). The ratio of exon 19 deletions to exon 21 missense mutations in MIAs tended to be higher than those in AIS (p =  0.06). Patients did not experience a local recurrence or metastasis after AIS and MIAs were removed by wedge resection, segmentectomy or lobectomy. Five-year recurrence-free survival rates were 100%.

Conclusion: Despite similar surgical outcomes for AIS and MIAs, we found differences in terms of gender, tumor diameters, CT findings, Ki-67 LI and a subset of EGFR mutations, highlighting the validity of classifying the two subtypes.
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http://dx.doi.org/10.1016/j.lungcan.2018.12.020DOI Listing
March 2019

[Surgical Outcome of Sublobar Resection in High-risk Patients with Non-small Cell Lung Cancer].

Kyobu Geka 2019 Jan;72(1):17-22

Department of General Thoracic Surgery, Saitama Medical University International Medical Center, Hidaka, Japan.

Objectives: Pulmonary lobectomy is the standard surgical procedure for resectable non-small cell lung cancer (NSCLC), while sublobar resection is an important surgical alternative for high-risk patients with comorbidities. We evaluated the treatment outcome and prognostic factors of sublobar resection in high-risk patients with NSCLC.

Methods: Eighty three high-risk patients who underwent compromised sublobar resection for clinical-N0 NSCLC with a solid appearance were retrospectively reviewed. A total of 47 wedge resections and 36 segmentectomies performed.

Results: Poor pulmonary function and synchronous or metachronous multiple lung cancer were found in 56.7% and 20.5% of patients respectively, all requiring sublobar resection. There were 21 instances of tumor recurrence and 24 deaths during a mean follow-up of 1,500 days. There was no local recurrence in the segmentectomy group. The 3-year recurrence free survival (RFS) and overall survival (OS) were 72.6% and 73.8% respectively. A multivariate analysis indicated that resection type and lymphatic invasion were independent prognostic factors for RFS. In the wedge resection group, a ratio of surgical margin to clinical tumor size greater than 1 (MT ratio≥1) was an independent prognostic factor for RFS( 87.1%,p=0.001).

Conclusion: Segmentectomy leads to a favorable prognosis. MT ratio was independently associated with a longer RFS in the wedge resection group.
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January 2019

[Open Stent Graft Stenosis after Total Arch Replacement for Acute Aortic Dissection in a Patient with Right-sided Aortic Arch].

Kyobu Geka 2018 12;71(13):1068-1072

Department of Thoracic and Cardiovascular Surgery, Hirosaki University, Hirosaki, Japan.

We describe a patient with stenosis of an open stent graft during total arch replacement of a rightsided aortic arch. A 67-year-old man was transferred to our hospital with a diagnosis of acute type A (DeBakey type II) aortic dissection. Computed tomography( CT) imaging revealed concomitant rightsided aortic arch (RAA) and Kommerell diverticulum at the descending thoracic aorta. Total arch replacement was performed using an open stent graft over the Kommerell diverticulum. While closing the sternum, blood pressure of the femoral artery dropped to a level much lower than that of radial artery. Transesophageal echocardiography revealed an apparently new intimal flap in the descending thoracic aorta. Therefore, an axilla-femoral artery bypass and a femoro-femoral artery crossover bypass were performed to improve malperfusion of the visceral organs and lower extremities. CT imaging immediately after these procedures revealed stenosis at the non-stented portion of the open stent graft, which was located at the steep-angled site of the RAA. The pressure gradient between the upper and lower extremities was around 100 mmHg on the day of surgery, but it disappeared on postoperative day 4. Improved graft stenosis was confirmed by CT before discharge.
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December 2018

Vision-based Bed Detection for Hospital Patient Monitoring System.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:5006-5009

In recent years, as a way to prevent patient fall-down, studies have been conducted using patient room cameras to detect the patient behavior of leaving the bed. It is very important to specify the patient bed location in the process of detecting patient behavior using camera images. In this study, we propose a method to specify the patient bed location using a monocular camera. In this proposal, we convert a camera image viewpoint into a bird's-eye view image as a preprocessing step. By using planer perspective transformation, it is possible to display the bed as a rectangular shape with a fixed ratio, even if the bed location or camera position is changed. Therefore, it is possible to detect the bed location with a high degree of accuracy by means of machine learning. The simulation experiment results confirm that the average error and standard deviation of the bed coordinates are 7.9 and 5.0 pixels, respectively; in the practical scene, we confirm that the average error and standard deviation of the bed coordinates are 12.1 and 8.2 pixels, respectively.
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http://dx.doi.org/10.1109/EMBC.2018.8513460DOI Listing
July 2018

Lipid moiety of glycosylphosphatidylinositol-anchored proteins contributes to the determination of their final destination in yeast.

Genes Cells 2018 Oct 1;23(10):880-892. Epub 2018 Oct 1.

Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.

Yeasts have two classes of glycosylphosphatidylinositol (GPI)-anchored proteins; one is transferred to the cell wall, whereas the other is retained on the plasma membrane. The lipid moieties of the GPI in Saccharomyces cerevisiae consist of either phosphatidylinositol (PI) or inositolphosphorylceramide (IPC). Cwh43p is involved in the remodeling of lipid from PI to IPC. We found that the GPI lipid moiety of Cwp2p in wild-type cells is PI. To elucidate the physiological role of the lipid remodeling by Cwh43p, we investigated the distribution of Gas1p and Cwp2p by immunoblotting and found that Gas1p with the PI-form GPI lipid moiety in cwh43∆ mutant cells tends to be localized to the cell wall, suggesting that the IPC species in the GPI lipid moiety contributes to the retention of GPI-anchored proteins on the plasma membrane. We also found that CWH43 is genetically related to TED1, which encodes a protein involved in the removal of the ethanolamine phosphate from the second mannose residue in GPI glycan moieties. We propose possible models for the physiological function of Cwh43p and Ted1p in the transfer of GPI-anchored proteins from the plasma membrane to the cell wall.
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http://dx.doi.org/10.1111/gtc.12636DOI Listing
October 2018

A case of anaplastic lymphoma kinase (ALK)-positive ciliated muconodular papillary tumor (CMPT) of the lung.

Pathol Int 2017 Feb 17;67(2):99-104. Epub 2017 Jan 17.

Department of Anatomic Pathology, Aizawa Hospital, Matsumoto, Japan.

Ciliated muconodular papillary tumor (CMPT) is a rare papillary tumor that arises in the peripheral lung fields and is associated with the proliferation of ciliate d and goblet cells and increased mucin production. We report a case of CMPT involving the rearrangement of the anaplastic lymphoma kinase (ALK) gene. The patient was an 84-year-old Japanese female who had exhibited a small nodular shadow on chest computed tomography during a regular checkup 10 years ago. She underwent a partial resection of segment S10 of the right lung. The cut surface of the surgical specimen revealed a well-circumscribed, jelly-like mass measuring 8 × 8 × 10 mm. Histologically, the tumor was composed of a mixture of ciliated, goblet, and basal cells arranged in a papillary pattern together with pools of mucin. A diagnosis of CMPT was made. The lung tumor cells were subjected to fluorescent in situ hybridization and highly sensitive immunohistochemical staining for the ALK protein, both of which produced positive results. CMPT usually follows a favorable course, but the exact nature of this tumor; i.e., whether it is benign or malignant, has not been established. This is the first reported case of an ALK-positive CMPT.
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http://dx.doi.org/10.1111/pin.12504DOI Listing
February 2017

Lipidomic Signatures and Associated Transcriptomic Profiles of Clear Cell Renal Cell Carcinoma.

Sci Rep 2016 06 30;6:28932. Epub 2016 Jun 30.

Division of Medical Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo, Japan.

Renal cell carcinoma (RCC) is the most common histological type of adult kidney cancer. In this study, we obtained lipidomic profiles of clear cell RCC (ccRCC), a major RCC subtype, by performing a lipidomic analysis of specimens of cancerous tissue and the surrounding normal renal cortex obtained from the same patients (N = 49). We also compared the lipidomic profiles with the lipogenic transcriptome of specimens of cancerous tissue and the surrounding normal renal cortex for an additional set of patient samples (N = 95). Overall, we detected 326 lipids, including phospholipids, sphingolipids, neutral lipids, and eicosanoids. The levels of more than 70% of the detected lipids were significantly different (P < 0.01, corrected by the false discovery rate). The cancerous tissue was distinguished by higher levels of ether-type phospholipids, cholesterol esters, and triacylglycerols, as well as by lower levels of phospholipids (except for phosphatidylcholines) and polyunsaturated fatty acids. Characteristic changes in the levels of mRNAs and metabolites suggested that the phosphatidylethanolamine (PE) synthesis pathway is suppressed in ccRCC and associated with cell proliferation. The present study represents the lipidomic profiles of ccRCC, which provides novel information about the metabolic changes in renal cancerous tissue and RCC pathophysiology.
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http://dx.doi.org/10.1038/srep28932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928052PMC
June 2016

Immunization of A4galt-deficient mice with glycosphingolipids from renal cell cancers resulted in the generation of anti-sulfoglycolipid monoclonal antibodies.

Glycoconj J 2016 Apr 16;33(2):169-80. Epub 2016 Feb 16.

Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-0065, Japan.

In this study, we immunized Gb3/CD77 synthase gene (A4galt) knockout (KO) mice with glycosphingolipids (GSLs) extracted from 3 renal cell cancer (RCC) cell lines to raise monoclonal antibodies (mAbs) reactive with globo-series GSLs specifically expressed in RCCs. Although a number of mAbs reactive with globo-series GSLs were generated, they reacted with both RCC cell lines and normal kidney cells. When we analyzed recognized antigens by mAbs that were specifically reactive with RCC, but not with normal kidney cells at least on the cell surface, many of them turned out to be reactive with sulfoglycolipids. Eight out of 11 RCC-specific mAbs were reactive with SM2 alone, and the other 3 mAbs were more broadly reactive with sulfated glycolipids, i.e. SM3 and SM4 as well as SM2. In the immunohistochemistry, these anti-sulfoglycolipids mAbs showed RCC-specific reaction, with no or minimal reaction with adjacent normal tissues. Thus, immunization of A4galt KO mice with RCC-derived GSLs resulted in the generation of anti sulfated GSL mAbs, and these mAbs may be applicable for the therapeutics for RCC patients.
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http://dx.doi.org/10.1007/s10719-016-9654-6DOI Listing
April 2016

Effect of N-Phenylanthranilic Acid Scaffold Nonsteroidal Anti-inflammatory Drugs on the Mitochondrial Permeability Transition.

Biol Pharm Bull 2016 ;39(2):278-84

Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science.

Hepatotoxicity is a known side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, the effects of N-phenylanthranilic acid (NPA) scaffold NSAIDs on rat liver mitochondria were examined. Mefenamic acid (MEF, 200 µM) induced mitochondrial swelling, which was inorganic phosphate (Pi)-dependent and suppressed by cyclosporin A (CsA, 2.5 µM), similar to calcium-induced swelling. Mitochondrial swelling was also observed following the addition of 200 µM flufenamic acid (FLU), meclofenamic acid (MCL), and tolfenamic acid (TOL). Less swelling was observed with the addition of 200 µM diclofenac (DIC) or NPA. Diphenylamine (DPA)-induced swelling occurred in a Pi-independent manner and was not sensitive to CsA. The mechanism by which DPA interacted with the mitochondrial inner membrane differed from those of the other NPA scaffold NSAIDs. The addition of 50 µM MEF, MCL, TOL, and FLU had uncoupling effects in mitochondrial inner membrane. These NSAIDs dose-dependently obstructed electron transport in the respiratory chain. NSAIDs are known to have various dynamic structures, and the solvation free energies (dGWs: an index of stereo-hydrophobicity) of the conformers obtained were determined using a molecular orbital analysis. The relationship between the dynamic structures and swelling induced by NPA scaffold NSAIDs was also examined.
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http://dx.doi.org/10.1248/bpb.b15-00717DOI Listing
November 2016

The role of group IIF-secreted phospholipase A2 in epidermal homeostasis and hyperplasia.

J Exp Med 2015 Oct 5;212(11):1901-19. Epub 2015 Oct 5.

Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan CREST, Japan Agency for Medical Research and Development (AMED) and Japan Science and Technology Agency (JST), Tokyo 100-0004, Japan

Epidermal lipids are important for skin homeostasis. However, the entire picture of the roles of lipids, particularly nonceramide lipid species, in epidermal biology still remains obscure. Here, we report that PLA2G2F, a functionally orphan-secreted phospholipase A2 expressed in the suprabasal epidermis, regulates skin homeostasis and hyperplasic disorders. Pla2g2f(-/-) mice had a fragile stratum corneum and were strikingly protected from psoriasis, contact dermatitis, and skin cancer. Conversely, Pla2g2f-overexpressing transgenic mice displayed psoriasis-like epidermal hyperplasia. Primary keratinocytes from Pla2g2f(-) (/-) mice showed defective differentiation and activation. PLA2G2F was induced by calcium or IL-22 in keratinocytes and preferentially hydrolyzed ethanolamine plasmalogen-bearing docosahexaenoic acid secreted from keratinocytes to give rise to unique bioactive lipids (i.e., protectin D1 and 9S-hydroxyoctadecadienoic acid) that were distinct from canonical arachidonate metabolites (prostaglandins and leukotrienes). Ethanolamine lysoplasmalogen, a PLA2G2F-derived marker product, rescued defective activation of Pla2g2f(-/-) keratinocytes both in vitro and in vivo. Our results highlight PLA2G2F as a previously unrecognized regulator of skin pathophysiology and point to this enzyme as a novel drug target for epidermal-hyperplasic diseases.
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http://dx.doi.org/10.1084/jem.20141904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612087PMC
October 2015

Characterization of hepatic lipid profiles in a mouse model with nonalcoholic steatohepatitis and subsequent fibrosis.

Sci Rep 2015 Aug 20;5:12466. Epub 2015 Aug 20.

Division of Medical Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.

Nonalcoholic steatohepatitis (NASH) is a major health problem since it often leads to hepatocellular carcinoma. However, the underlying mechanisms of NASH development and subsequent fibrosis have yet to be clarified. We compared comprehensive lipidomic profiles between mice with high fat diet (HFD)-induced steatosis and STAM mice with NASH and subsequent fibrosis. The STAM mouse is a model that demonstrates NASH progression resembling the disease in humans: STAM mice manifest NASH at 8 weeks, which progresses to fibrosis at 12 weeks, and finally develop hepatocellular carcinoma. Overall, 250 lipid molecules were detected in the liver using liquid chromatography-mass spectrometry. We found that STAM mice with NASH presented a significantly higher abundance of sphingolipids and lower levels of triacylglycerols than the HFD-fed control mice. The abundance of certain fatty acids in phospholipid side chains was also significantly different between STAM and control mice, although global levels of phosphatidylcholines and phosphatidylethanolamines were comparable. Finally, increase in levels of acylcarnitines and some diacylglycerols was observed in STAM mice toward the fibrosis stage, but not in age-matched control mice. Our study provides insights into the lipid status of the steatotic, NASH, and fibrotic liver that would help elucidate the molecular pathophysiology of NASH progression.
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http://dx.doi.org/10.1038/srep12466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542161PMC
August 2015

Preferential incorporation of shorter and less unsaturated acyl phospholipids into high density lipoprotein-like particles in the ABCA1- and ABCA7-mediated biogenesis with apoA-I.

Chem Phys Lipids 2015 Apr 7;187:1-9. Epub 2015 Feb 7.

Nutritional Health Science Research Center, Chubu University, Kasugai, Japan. Electronic address:

Molecular species of phosphatidylcholine (PC) and sphingomyelin (SPM) were globally analyzed for lipidomics in the nascent high-density lipoprotein (HDL)-like particles generated with human apolipoprotein A-I (apoA-I) form HEK293 cells where either human ATP binding cassette transporter (ABC) A1 or ABCA7 was transfected and overexpressed. SPM/PC ratio was higher in the ABCA1-mediated HDL than ABCA7-mediated HDL likely being related to their cholesterol content, while it was less than the ratio in the cell membrane in either case. Molecular species composition of hydrocarbon chain moiety in each phospholipid in the HDL largely reflected that in the cells the lipoprotein originated in, without remarkable difference between ABCA1 and ABCA7. Further analysis, however, revealed apparent preference for the molecules with shorter hydrocarbon chain length for both PC and SPM in their relative incorporation into HDL by ABCA1 and ABCA7. Likewise, it was in favor for less-unsaturated hydrocarbon chains of PC while this preference was not apparent for SPM. The results are consistent with the view that assembly of HDL particles with extracellular apoA-I is primarily with the cellular phospholipid molecules being regulated in part by their physicochemical nature.
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http://dx.doi.org/10.1016/j.chemphyslip.2015.01.005DOI Listing
April 2015

Sterylglucoside catabolism in Cryptococcus neoformans with endoglycoceramidase-related protein 2 (EGCrP2), the first steryl-β-glucosidase identified in fungi.

J Biol Chem 2015 Jan 31;290(2):1005-19. Epub 2014 Oct 31.

From the Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan,

Cryptococcosis is an infectious disease caused by pathogenic fungi, such as Cryptococcus neoformans and Cryptococcus gattii. The ceramide structure (methyl-d18:2/h18:0) of C. neoformans glucosylceramide (GlcCer) is characteristic and strongly related to its pathogenicity. We recently identified endoglycoceramidase-related protein 1 (EGCrP1) as a glucocerebrosidase in C. neoformans and showed that it was involved in the quality control of GlcCer by eliminating immature GlcCer during the synthesis of GlcCer (Ishibashi, Y., Ikeda, K., Sakaguchi, K., Okino, N., Taguchi, R., and Ito, M. (2012) Quality control of fungus-specific glucosylceramide in Cryptococcus neoformans by endoglycoceramidase-related protein 1 (EGCrP1). J. Biol. Chem. 287, 368-381). We herein identified and characterized EGCrP2, a homologue of EGCrP1, as the enzyme responsible for sterylglucoside catabolism in C. neoformans. In contrast to EGCrP1, which is specific to GlcCer, EGCrP2 hydrolyzed various β-glucosides, including GlcCer, cholesteryl-β-glucoside, ergosteryl-β-glucoside, sitosteryl-β-glucoside, and para-nitrophenyl-β-glucoside, but not α-glucosides or β-galactosides, under acidic conditions. Disruption of the EGCrP2 gene (egcrp2) resulted in the accumulation of a glycolipid, the structure of which was determined following purification to ergosteryl-3β-glucoside, a major sterylglucoside in fungi, by mass spectrometric and two-dimensional nuclear magnetic resonance analyses. This glycolipid accumulated in vacuoles and EGCrP2 was detected in vacuole-enriched fraction. These results indicated that EGCrP2 was involved in the catabolism of ergosteryl-β-glucoside in the vacuoles of C. neoformans. Distinct growth arrest, a dysfunction in cell budding, and an abnormal vacuole morphology were detected in the egcrp2-disrupted mutants, suggesting that EGCrP2 may be a promising target for anti-cryptococcal drugs. EGCrP2, classified into glycohydrolase family 5, is the first steryl-β-glucosidase identified as well as a missing link in sterylglucoside metabolism in fungi.
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http://dx.doi.org/10.1074/jbc.M114.616300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294470PMC
January 2015

[Tumors of the diaphragm, diagnosis and surgical treatment].

Kyobu Geka 2014 Oct;67(11):982-9

Department of General Thoracic Surgery, Saitama Medical University International Medical Center, Hidaka, Japan.

Primary tumors of the diaphragm are very rare, and we often have difficulties in preoperative diagnosis and accurate evaluation of invasion. We experienced 3 surgical cases of tumor of diaphragm:primary mucinous adenocarcinoma, metastatic gastrointestinal stromal tumor, and mesothelioma. Besides computed tomography (CT) and conventional magnetic resonance imaging(MRI), respiratory dynamic cine magnetic resonance imaging (cine MRI) was performed. Cine MRI was acquired using steady state free precession (SSFP) sequence, and about 80 consecutive images of the same slice were taken while a patient breathed deeply. In all cases, cine MRI showed lack of tumor movement along the diaphragm during respiration. During surgery, we found that tumor was originated from diaphragm and there was no adhesion to other organs. Securing a sufficient margin, we resected tumor including the diaphragm. Since the defect of diaphragm was from 4 to 5cm in short diameter, we could close the diaphragm by direct suture. Cine MRI could provide useful information concerning discrimination between diaphragmatic and para-diaphragmatic tumor.
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October 2014

Novel lysophospholipid acyltransferase PLAT1 of Aurantiochytrium limacinum F26-b responsible for generation of palmitate-docosahexaenoate-phosphatidylcholine and phosphatidylethanolamine.

PLoS One 2014 4;9(8):e102377. Epub 2014 Aug 4.

Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka, Japan; Bio-Archtechture Center, Kyushu University, Fukuoka, Japan.

N-3 polyunsaturated fatty acids (PUFA), such as docosahexaenoic acid (DHA, 22:6n-3), have been reported to play roles in preventing cardiovascular diseases. The major source of DHA is fish oils but a recent increase in the global demand of DHA and decrease in fish stocks require a substitute. Thraustochytrids, unicellular marine protists belonging to the Chromista kingdom, can synthesize large amounts of DHA, and, thus, are expected to be an alternative to fish oils. DHA is found in the acyl chain(s) of phospholipids as well as triacylglycerols in thraustochytrids; however, how thraustochytrids incorporate DHA into phospholipids remains unknown. We report here a novel lysophospholipid acyltransferase (PLAT1), which is responsible for the generation of DHA-containing phosphatidylcholine and phosphatidylethanolamine in thraustochytrids. The PLAT1 gene, which was isolated from the genomic DNA of Aurantiochytrium limacinum F26-b, was expressed in Saccharomyces cerevisiae, and the FLAG-tagged recombinant enzyme was characterized after purification with anti-FLAG affinity gel. PLAT1 shows wide specificity for donor substrates as well as acceptor substrates in vitro, i.e, the enzyme can adopt lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine and lysophosphatidylinositol as acceptor substrates, and 15:0/16:0-CoA and DHA-CoA as donor substrates. In contrast to the in vitro experiment, only lysophosphatidylcholine acyltransferase and lysophosphatidylethanolamine acyltransferase activities were decreased in plat1-knockout mutants, resulting in a decrease of 16:0-DHA-phosphatidylcholine (PC) [PC(38:6)] and 16:0-DHA-phosphatidylethanolamine (PE) [PE(38:6)], which are two major DHA-containing phospholipids in A. limacinum F26-b. However, the amounts of other phospholipid species including DHA-DHA-PC [PC(44:12)] and DHA-DHA-PE [PE(44:12)] were almost the same in plat-knockout mutants and the wild-type. These results indicate that PLAT1 is the enzyme responsible for the generation of 16:0-DHA-PC and 16:0-DHA-PE in the thraustochytrid.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102377PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121067PMC
November 2015

The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity.

Cell Metab 2014 Jul 5;20(1):119-32. Epub 2014 Jun 5.

Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan; CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. Electronic address:

Metabolic disorders, including obesity and insulin resistance, have their basis in dysregulated lipid metabolism and low-grade inflammation. In a microarray search of unique lipase-related genes whose expressions are associated with obesity, we found that two secreted phospholipase A2s (sPLA2s), PLA2G5 and PLA2G2E, were robustly induced in adipocytes of obese mice. Analyses of Pla2g5(-/-) and Pla2g2e(-/-) mice revealed distinct roles of these sPLA2s in diet-induced obesity. PLA2G5 hydrolyzed phosphatidylcholine in fat-overladen low-density lipoprotein to release unsaturated fatty acids, which prevented palmitate-induced M1 macrophage polarization. As such, PLA2G5 tipped the immune balance toward an M2 state, thereby counteracting adipose tissue inflammation, insulin resistance, hyperlipidemia, and obesity. PLA2G2E altered minor lipoprotein phospholipids, phosphatidylserine and phosphatidylethanolamine, and moderately facilitated lipid accumulation in adipose tissue and liver. Collectively, the identification of "metabolic sPLA2s" adds this gene family to a growing list of lipolytic enzymes that act as metabolic coordinators.
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http://dx.doi.org/10.1016/j.cmet.2014.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079757PMC
July 2014

Very-long-chain polyunsaturated fatty acids accumulate in phosphatidylcholine of fibroblasts from patients with Zellweger syndrome and acyl-CoA oxidase1 deficiency.

Biochim Biophys Acta 2014 Apr 10;1841(4):610-9. Epub 2014 Jan 10.

Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Fukuoka 812-8581, Japan. Electronic address:

Peroxisomes are subcellular organelles that function in multiple anabolic and catabolic processes, including β-oxidation of very-long-chain fatty acids (VLCFA) and biosynthesis of ether phospholipids. Peroxisomal disorders caused by defects in peroxisome biogenesis or peroxisomal β-oxidation manifest as severe neural disorders of the central nervous system. Abnormal peroxisomal metabolism is thought to be responsible for the clinical symptoms of these diseases, but their molecular pathogenesis remains to be elucidated. We performed lipidomic analysis to identify aberrant metabolites in fibroblasts from patients with Zellweger syndrome (ZS), acyl-CoA oxidase1 (AOx) deficiency, D-bifunctional protein (D-BP) and X-linked adrenoleukodystrophy (X-ALD), as well as in peroxisome-deficient Chinese hamster ovary cell mutants. In cells deficient in peroxisomal biogenesis, plasmenylethanolamine was remarkably reduced and phosphatidylethanolamine was increased. Marked accumulation of very-long-chain saturated fatty acid and monounsaturated fatty acids in phosphatidylcholine was observed in all mutant cells. Very-long-chain polyunsaturated fatty acid (VLC-PUFA) levels were significantly elevated, whilst phospholipids containing docosahexaenoic acid (DHA, C22:6n-3) were reduced in fibroblasts from patients with ZS, AOx deficiency, and D-BP deficiency, but not in fibroblasts from an X-ALD patient. Because patients with AOx deficiency suffer from more severe symptoms than those with X-ALD, accumulation of VLC-PUFA and/or reduction of DHA may be associated with the severity of peroxisomal diseases.
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http://dx.doi.org/10.1016/j.bbalip.2014.01.001DOI Listing
April 2014

Hypothalamic SIRT1 prevents age-associated weight gain by improving leptin sensitivity in mice.

Diabetologia 2014 Apr 29;57(4):819-31. Epub 2013 Dec 29.

Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi-shi, Gunma, 371-8512, Japan,

Aims/hypothesis: Obesity is associated with ageing and increased energy intake, while restriction of energy intake improves health and longevity in multiple organisms; the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) is implicated in this process. Pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical for energy balance regulation, and the level of SIRT1 protein decreases with age in the ARC. In the current study we tested whether conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevents age-associated weight gain and diet-induced obesity.

Methods: We targeted Sirt1 cDNA sequence into the Rosa26 locus and generated conditional Sirt1 knock-in mice. These mice were crossed with mice harbouring either Pomc-Cre or Agrp-Cre and the metabolic variables, food intake, energy expenditure and sympathetic activity in adipose tissue of the resultant mice were analysed. We also used a hypothalamic cell line to investigate the molecular mechanism by which Sirt1 overexpression modulates leptin signalling.

Results: Conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevented age-associated weight gain; overexpression in POMC neurons stimulated energy expenditure via increased sympathetic activity in adipose tissue, whereas overexpression in AgRP neurons suppressed food intake. SIRT1 improved leptin sensitivity in hypothalamic neurons in vitro and in vivo by downregulating protein-tyrosine phosphatase 1B, T cell protein-tyrosine phosphatase and suppressor of cytokine signalling 3. However, these phenotypes were absent in mice consuming a high-fat, high-sucrose diet due to decreases in ARC SIRT1 protein and hypothalamic NAD(+) levels.

Conclusions/interpretation: ARC SIRT1 is a negative regulator of energy balance, and decline in ARC SIRT1 function contributes to disruption of energy homeostasis by ageing and diet-induced obesity.
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http://dx.doi.org/10.1007/s00125-013-3140-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940852PMC
April 2014

Inhibition of ATP citrate lyase induces triglyceride accumulation with altered fatty acid composition in cancer cells.

Int J Cancer 2014 Jul 18;135(1):37-47. Epub 2013 Dec 18.

Division of Molecular Biotherapy Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Molecular Medical Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

De novo lipogenesis is activated in most cancers and several lipogenic enzymes have been implicated as therapeutic targets. Here, we demonstrate a novel function of the lipogenic enzyme, ATP citrate lyase (ACLY), in lipid metabolism in cancer cells. ACLY depletion by small interfering RNAs caused growth suppression and/or apoptosis in a subset of cancer cell lines. To investigate the effect of ACLY inhibition on lipid metabolism, metabolome and transcriptome analysis was performed. ACLY depletion blocks the fatty acid chain elongation from C16 to C18 in triglyceride (TG), but not in other lipid classes. Meanwhile, wild-type ACLY overexpression enhanced fatty acid elongation of TG, whereas an inactive mutant ACLY did not change it. ACLY depletion-mediated blockade of fatty acid elongation was coincident with downregulation of long-chain fatty acid elongase ELOVL6, which resides in endoplasmic reticulum (ER). Paradoxically, ACLY depletion-mediated growth suppression was associated with TG accumulation. ACLY depletion downregulated the expression of carnitine palmitoyltransferase 1A, which is a mitochondrial fatty acid transporter. Consistent with this finding, metabolome analysis revealed that ACLY positively regulates the carnitine system, which plays as an essential cofactor for fatty acid transport across mitochondrial membrane. AICAR, an activator of mitochondrial fatty acid oxidation (FAO), significantly reduced ACLY depletion-mediated TG accumulation. These data indicate that inhibition of ACLY might affect both fatty acid elongation in ER and FAO in mitochondria, thereby explaining the TG accumulation with altered fatty acid composition. This phenotype may be a hallmark of growth suppression mediated by ACLY inhibition.
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http://dx.doi.org/10.1002/ijc.28652DOI Listing
July 2014
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