Showing papers by "Kumamoto University published in 2019"

The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019)

Abstract: Satoshi Umemura ● Hisatomi Arima ● Shuji Arima ● Kei Asayama ● Yasuaki Dohi ● Yoshitaka Hirooka ● Takeshi Horio ● Satoshi Hoshide ● Shunya Ikeda ● Toshihiko Ishimitsu ● Masaaki Ito ● Sadayoshi Ito ● Yoshio Iwashima ● Hisashi Kai ● Kei Kamide ● Yoshihiko Kanno ● Naoki Kashihara ● Yuhei Kawano ● Toru Kikuchi ● Kazuo Kitamura ● Takanari Kitazono ● Katsuhiko Kohara ● Masataka Kudo ● Hiroo Kumagai ● Kiyoshi Matsumura ● Hideo Matsuura ● Katsuyuki Miura ● Masashi Mukoyama ● Satoko Nakamura ● Takayoshi Ohkubo ● Yusuke Ohya ● Takafumi Okura ● Hiromi Rakugi ● Shigeyuki Saitoh ● Hirotaka Shibata ● Tatsuo Shimosawa ● Hiromichi Suzuki ● Shori Takahashi ● Kouichi Tamura ● Hirofumi Tomiyama ● Takuya Tsuchihashi ● Shinichiro Ueda ● Yoshinari Uehara ● Hidenori Urata ● Nobuhito Hirawa

JCS 2018 Guideline on Diagnosis and Treatment of Acute Coronary Syndrome.

Abstract: J-STAGE Advance Publication released online March 29, 2019 Mailing address: Scientific Committee of the Japanese Circulation Society, 18F Imperial Hotel Tower, 1-1-1 Uchisaiwai-cho, Chiyoda-ku, Tokyo 100-0011, Japan. E-mail: meeting@j-circ.or.jp This document is an English version of JCS 2018 Guideline on Diagnosis and Treatment of Acute Coronary Syndrome reported at the Japanese Circulation Society Joint Working Groups performed in 2018. (Website: http://www.j-circ.or.jp/guideline/pdf/JCS2018_ kimura.pdf). *Chairperson. Refer to Appendix 1 for the details of members. Joint Working Groups: The Japanese Circulation Society, the Japanese Association for Thoracic Surgery, the Japanese Association of Cardiac Rehabilitation, the Japanese Association of Cardiovascular Intervention and Therapeutics, the Japanese College of Cardiology, the Japanese Coronary Association, the Japanese Heart Rhythm Society, the Japanese Society for Cardiovascular Surgery, the Japanese Society of Intensive Care Medicine ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp JCS 2018 Guideline on Diagnosis and Treatment of Acute Coronary Syndrome

Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids.

Abstract: Gut microbiota mediates the effects of diet, thereby modifying host metabolism and the incidence of metabolic disorders. Increased consumption of omega-6 polyunsaturated fatty acid (PUFA) that is abundant in Western diet contributes to obesity and related diseases. Although gut-microbiota-related metabolic pathways of dietary PUFAs were recently elucidated, the effects on host physiological function remain unclear. Here, we demonstrate that gut microbiota confers host resistance to high-fat diet (HFD)-induced obesity by modulating dietary PUFAs metabolism. Supplementation of 10-hydroxy-cis-12-octadecenoic acid (HYA), an initial linoleic acid-related gut-microbial metabolite, attenuates HFD-induced obesity in mice without eliciting arachidonic acid-mediated adipose inflammation and by improving metabolic condition via free fatty acid receptors. Moreover, Lactobacillus-colonized mice show similar effects with elevated HYA levels. Our findings illustrate the interplay between gut microbiota and host energy metabolism via the metabolites of dietary omega-6-FAs thereby shedding light on the prevention and treatment of metabolic disorders by targeting gut microbial metabolites.

Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment.

Abstract: Increasing lines of evidence show that the malignant behavior of cancer is not exclusively attributable to cancer cells but also radically influenced by cancerous stroma activity and controlled through various mechanisms by the microenvironment. In addition to structural components, such as the extracellular matrix, stromal cells, such as macrophages, endothelial cells, and specifically cancer-associated fibroblasts (CAFs), have attracted substantial attention over recent decades. CAFs provide routes for aggressive carcinomas and contribute to invasion and metastasis through the biochemical alteration and regulation of cancer-related pathways. However, another facet of CAFs that has been neglected by numerous studies is that CAFs might serve as a negative regulator of cancer progression under certain circumstances. The various origins of CAFs, the diverse tissues in which they reside and their interactions with different cancer cells appear to be responsible for this inconsistency. This review summarizes the latest knowledge regarding CAF heterogeneity and offers a novel perspective and a beneficial approach for obtaining an improved understanding of CAFs.

Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report

Abstract: PurposeAdult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by chronic infection with human T-lymphotropic virus type 1 with diverse clinical features and prognosis. ATL remains a challenging disease as a result of its diverse clinical features, multidrug resistance of malignant cells, frequent large tumor burden, hypercalcemia, and/or frequent opportunistic infection. In 2009, we published a consensus report to define prognostic factors, clinical subclassifications, treatment strategies, and response criteria. The 2009 consensus report has become the standard reference for clinical trials in ATL and a guide for clinical management. Since the last consensus there has been progress in the understanding of the molecular pathophysiology of ATL and risk-adapted treatment approaches.MethodsReflecting these advances, ATL researchers and clinicians joined together at the 18th International Conference on Human Retrovirology—Human T-Lymphotropic Virus and Related Retroviruses—in Tokyo...

Boosting electrochemical water splitting via ternary NiMoCo hybrid nanowire arrays

Abstract: Hydrogen production by electrochemical water splitting is a technology with the potential to meet the growing worldwide demand for sustainable and clean energy. However, the development of cost-effective catalysts to replace noble metals, such as platinum or ruthenium, remains crucial for large-scale hydrogen production. This study presents the synthesis of a transition non-noble metal-based ternary NiMoCo hybrid nanowire array as an efficient bifunctional electrocatalyst for overall water splitting in 1.0 M KOH electrolyte. The catalyst exhibits a low cell voltage of 1.56 V to achieve a water-splitting current density of 10 mA cm−2 together with long-term stability with only 5% of the initial current lost after 100 hours. X-ray absorption spectroscopy confirms that the addition of Co to the binary Ni–Mo system results in a highly mixed chemical binding state with modulated electronic structures. Density functional theory (DFT) calculations reveal that the Co atoms on the ternary alloy become catalytically active sites and facilitate adsorption of intermediates by ensuring preferable interactions between the reactants and the catalyst surface in comparison to the binary counterpart. This work provides a new direction along which to activate binary alloys to further enhance their catalytic abilities in overall water splitting.

Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial

Abstract: OBJECTIVE To investigate the efficacy, safety, and tolerability of oral semaglutide added to insulin with or without metformin. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes uncontrolled on insulin with or without metformin were randomized to oral semaglutide 3 mg (N = 184), 7 mg (N = 182), or 14 mg (N = 181) or to placebo (N = 184) in a 52-week, double-blind trial. End points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands were defined: treatment policy (effect regardless of trial product discontinuation or rescue medication) and trial product (effect assuming trial product continuation without rescue medication) in randomized patients. RESULTS Oral semaglutide was superior to placebo in reducing HbA1c (estimated treatment difference [ETD] –0.5% [95% CI –0.7, –0.3], –0.9% [–1.1, –0.7], and –1.2% [–1.4, –1.0] for 3, 7, and 14 mg, respectively; P CONCLUSIONS Oral semaglutide was superior to placebo in reducing HbA1c and body weight when added to insulin with or without metformin in patients with type 2 diabetes. The safety profile was consistent with other glucagon-like peptide 1 receptor agonists.

Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.

Abstract: AIMS To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. METHODS AND RESULTS This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat (n = 537) and non-febuxostat groups (n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively (P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592-0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562-0.987; P = 0.041). CONCLUSION Febuxostat lowers uric acid and delays the progression of renal dysfunction. REGISTRATION ClinicalTrials.gov (NCT01984749).

Improvement of image quality at CT and MRI using deep learning

Abstract: Deep learning has been developed by computer scientists. Here, we discuss techniques for improving the image quality of diagnostic computed tomography and magnetic resonance imaging with the aid of deep learning. We categorize the techniques for improving the image quality as "noise and artifact reduction", "super resolution" and "image acquisition and reconstruction". For each category, we present and outline the features of some studies.

A nationwide survey on non-B, non-C hepatocellular carcinoma in Japan: 2011–2015 update

Abstract: We previously reported that the incidence of hepatocellular carcinoma (HCC) with non-viral etiologies increased rapidly between 1991 and 2010 in Japan. To update this investigation, we enrolled patients who were initially diagnosed as having non-B, non-C HCC at participating hospitals between 2011 and 2015. In addition to the patient characteristics investigated in the previous report, we also investigated the duration of alcohol consumption. The overall survival rate was analyzed using the Kaplan–Meier method, and the hazard function against the body mass index (BMI) was plotted using cubic splines. A total of 2087 patients were enrolled. The proportion of patients with non-viral etiologies has continued to increase from 10.0% in 1991 to 32.5% in 2015. Patients were also older (median ages, 70–73 years) and more obese (median BMIs, 23.9–24.2 kg/m2), and the proportions of patients with diabetes mellitus (46.1% to 51.6%), hypertension (42.7% to 58.6%), dyslipidemia (14.6% to 22.9%), and fatty liver (24.0% to 28.8%) had all increased significantly. There was a significant inverse relationship between the duration and the amount of daily alcohol consumption. The improvement in the overall survival was relatively small, with a decreased proportion of patients under surveillance (41.3% to 31.6%). A hazard function plot showed a curve similar to that in our previous report, with a lowest hazard of ~ 26 kg/m2. The proportion of HCC patients with non-viral etiologies continues to increase in Japan. Lifetime total amount of alcohol consumption may be a risk factor.

Heart Rate Variability-Based Driver Drowsiness Detection and Its Validation With EEG

Abstract: Objective: Driver drowsiness detection is a key technology that can prevent fatal car accidents caused by drowsy driving. The present work proposes a driver drowsiness detection algorithm based on heart rate variability (HRV) analysis and validates the proposed method by comparing with electroencephalography (EEG)-based sleep scoring. Methods: Changes in sleep condition affect the autonomic nervous system and then HRV, which is defined as an RR interval (RRI) fluctuation on an electrocardiogram trace. Eight HRV features are monitored for detecting changes in HRV by using multivariate statistical process control, which is a well known anomaly detection method. Result: The performance of the proposed algorithm was evaluated through an experiment using a driving simulator. In this experiment, RRI data were measured from 34 participants during driving, and their sleep onsets were determined based on the EEG data by a sleep specialist. The validation result of the experimental data with the EEG data showed that drowsiness was detected in 12 out of 13 pre-N1 episodes prior to the sleep onsets, and the false positive rate was 1.7 times per hour. Conclusion: The present work also demonstrates the usefulness of the framework of HRV-based anomaly detection that was originally proposed for epileptic seizure prediction. Significance: The proposed method can contribute to preventing accidents caused by drowsy driving.

Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models.

Abstract: Patient-derived xenograft (PDX) models are created by engraftment of patient tumor tissues into immunocompetent mice. Since a PDX model retains the characteristics of the primary patient tumor including gene expression profiles and drug responses, it has become the most reliable in vivo human cancer model. The engraftment rate increases with the introduction of Non-obese diabetic Severe combined immunodeficiency (NOD/SCID)-based immunocompromised mice, especially the NK-deficient NOD strains NOD/SCID/interleukin-2 receptor gamma chain(IL2Rγ)null (NOG/NSG) and NOD/SCID/Jak3(Janus kinase 3)null (NOJ). Success rates differ with tumor origin: gastrointestinal tumors acquire a higher engraftment rate, while the rate is lower for breast cancers. Subcutaneous transplantation is the most popular method to establish PDX, but some tumors require specific environments, e.g., orthotropic or renal capsule transplantation. Human hormone treatment is necessary to establish hormone-dependent cancers such as prostate and breast cancers. PDX mice with human hematopoietic and immune systems (humanized PDX) are powerful tools for the analysis of tumor–immune system interaction and evaluation of immunotherapy response. A PDX biobank equipped with patients’ clinical data, gene-expression patterns, mutational statuses, tumor tissue architects, and drug responsiveness will be an authoritative resource for developing specific tumor biomarkers for chemotherapeutic predictions, creating individualized therapy, and establishing precise cancer medicine.

Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases.

Abstract: Prostaglandins (PGs) are the major lipid mediators in animals and which are biosynthesized from arachidonic acid by the cyclooxygenases (COX-1 or COX-2) as the rate-limiting enzymes. Prostaglandin E2 (PGE2), which is the most abundantly detected PG in various tissues, exerts versatile physiological and pathological actions via four receptor subtypes (EP1-4). Non-steroidal anti-inflammatory drugs, such as aspirin and indomethacin, exert potent anti-inflammatory actions by the inhibition of COX activity and the resulting suppression of PG production. Therefore, PGE2 has been shown to exacerbate several inflammatory responses and immune diseases. Recently, studies using mice deficient in each PG receptor subtype have clarified the detailed mechanisms underlying PGE2-associated inflammation and autoimmune diseases involving each EP receptor. Here, we review the recent advances in our understanding of the roles of PGE2 receptors in the progression of acute and chronic inflammation and autoimmune diseases. PGE2 induces acute inflammation through mast cell activation via the EP3 receptor. PGE2 also induces chronic inflammation and various autoimmune diseases through T helper 1 (Th1)-cell differentiation, Th17-cell proliferation and IL-22 production from Th22 cells via the EP2 and EP4 receptors. The possibility of EP receptor-targeted drug development for the treatment of immune diseases is also discussed.

An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment

Abstract: Metastasis is a complex multistep process that involves critical interactions between cancer cells and a variety of stromal components in the tumor microenvironment, which profoundly influence the different aspects of the metastatic cascade and organ tropism of disseminating cancer cells. Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Evidence has demonstrated that ovarian cancer possesses specific metastatic tropism for the adipose-rich omentum, which has a pivotal role in the creation of the metastatic tumor microenvironment in the intraperitoneal cavity. Considering the distinct biology of ovarian cancer metastasis, the elucidation of the cellular and molecular mechanisms underlying the reciprocal interplay between ovarian cancer cells and surrounding stromal cell types in the adipose-rich metastatic microenvironment will provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer. Herein, we review the biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum by illustrating how different stromal cells concertedly contribute to the development of ovarian cancer metastasis and metastatic tropism for the omentum.

Human kidney organoids: progress and remaining challenges

Abstract: Kidney organoids are regarded as important tools with which to study the development of the normal and diseased human kidney. Since the first reports of human pluripotent stem cell-derived kidney organoids 5 years ago, kidney organoids have been successfully used to model glomerular and tubular diseases. In parallel, advances in single-cell RNA sequencing have led to identification of a variety of cell types in the organoids, and have shown these to be similar to, but more immature than, human kidney cells in vivo. Protocols for the in vitro expansion of stem cell-derived nephron progenitor cells (NPCs), as well as those for the selective induction of specific lineages, especially glomerular podocytes, have also been reported. Although most current organoids are based on the induction of NPCs, an induction protocol for ureteric buds (collecting duct precursors) has also been developed, and approaches to generate more complex kidney structures may soon be possible. Maturation of organoids is a major challenge, and more detailed analysis of the developing kidney at a single cell level is needed. Eventually, organotypic kidney structures equipped with nephrons, collecting ducts, ureters, stroma and vascular flow are required to generate transplantable kidneys; such attempts are in progress. Kidney organoids have the potential to advance the field of nephrology. Here, the author discusses progress in the development of kidney organoids and describes remaining challenges to the use of these cultures for the study of kidney physiology and disease.

Pathologic Prognostic Factors in Endometrial Carcinoma (Other Than Tumor Type and Grade).

Abstract: Although endometrial carcinoma (EC) is generally considered to have a good prognosis, over 20% of women with EC die of their disease, with a projected increase in both incidence and mortality over the next few decades. The aim of accurate prognostication is to ensure that patients receive optimal treatment and are neither overtreated nor undertreated, thereby improving patient outcomes overall. Patients with EC can be categorized into prognostic risk groups based on clinicopathologic findings. Other than tumor type and grade, groupings and recommended management algorithms may take into account age, body mass index, stage, and presence of lymphovascular space invasion. The molecular classification of EC that has emerged from the Cancer Genome Atlas (TCGA) study provides additional, potentially superior, prognostic information to traditional histologic typing and grading. This classifier does not, however, replace clinicopathologic risk assessment based on parameters other than histotype and grade. It is envisaged that molecular and clinicopathologic prognostic grouping systems will work better together than either alone. Thus, while tumor typing and grading may be superseded by a classification based on underlying genomic abnormalities, accurate assessment of other pathologic parameters will continue to be key to patient management. These include those factors related to staging, such as depth of myometrial invasion, cervical, vaginal, serosal surface, adnexal and parametrial invasion, and those independent of stage such as lymphovascular space invasion. Other prognostic parameters will also be discussed. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.

Bioactive Compounds and Health Benefits of Artemisia Species

Abstract: Artemisia L. is a genus of small herbs and shrubs found in northern temperate regions. It belongs to the important family Asteraceae, one of the most numerous plant groupings, which comprises about...

Urea cycle disorders-update.

Abstract: The urea cycle is a metabolic pathway for the disposal of excess nitrogen, which arises primarily as ammonia. Nitrogen is essential for growth and life-maintenance, but excessive ammonia leads to life-threatening conditions. The urea cycle disorders (UCDs) comprise diseases presenting with hyperammonemia that arise in either the neonatal period (about 50% of cases) or later. Congenital defects of the enzymes or transporters of the urea cycle cause the disease. This cycle utilizes five enzymes, two of which, carbamoylphosphate synthetase 1 and ornithine transcarbamylase are present in the mitochondrial matrix, whereas the others (argininosuccinate synthetase, argininosuccinate lyase and arginase 1) are present in the cytoplasm. In addition, N-acetylglutamate synthase and at least two transporter proteins are essential to urea cycle function. Severity and age of onset depend on residual enzyme or transporter function and are related to the respective gene mutations. The strategy for therapy is to prevent the irreversible toxicity of high-ammonia exposure to the brain. The pathogenesis and natural course are poorly understood because of the rarity of the disease, so an international registry system and novel clinical trials are much needed. We review here the current concepts of the pathogenesis, diagnostics, including genetics and treatment of UCDs.

Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex

Abstract: Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor the accessibility of PM cholesterol remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind to one another and populate ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via their GRAM domains. They then facilitate the transport of this cholesterol via their StART-like domains. Cells that lack all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol as a result of less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate the movement of accessible PM cholesterol to the ER in order to counteract an acute increase of PM cholesterol, thereby activating non-vesicular cholesterol transport.