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101. Adiponectin Represses Colon Cancer Cell Proliferation via AdipoR1- and -R2-Mediated AMPK Activation

Author

Kim, A. Young, primary, Lee, Yun Sok, additional, Kim, Kang Ho, additional, Lee, Jae Ho, additional, Lee, Hee Kyu, additional, Jang, Su-Hwa, additional, Kim, Seong-Eun, additional, Lee, Gha Young, additional, Lee, Joo-Won, additional, Jung, Sung-Ae, additional, Chung, Hee Yong, additional, Jeong, Sunjoo, additional, and Kim, Jae Bum, additional

Published
2010
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104. Widely Tunable Grating Cavity Lasers

Author

Kwon, Oh-Kee, primary, Sim, Eundeok, additional, Kim, Kang-Ho, additional, Kim, Jong-Hoi, additional, Yun, Ho-Gyeong, additional, Kwon, O Kyun, additional, and Oh, Kwang Ryong, additional

Published
2006
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114. The Application of B-Type Natriuretic Peptide Level of the Dyspneic Patients: Differentiation Between Cor Pulmonale and Left Ventricular Dysfunction

Author

Park, Hong hoon, primary, Kim, Sehyun, additional, Choi, Jeongeun, additional, Kim, Kang Ho, additional, Cheon, Seok Cheol, additional, Lee, Jihyun, additional, Lee, Yong gu, additional, Kim, In Jae, additional, Cha, Dong Hoon, additional, Hong, Sang Bum, additional, and Lee, Ji Hyun, additional

Published
2003
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119. Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic beta-cells.

Author

Choe SS, Choi AH, Lee J, Kim KH, Chung J, Park J, Lee K, Park K, Lee I, Kim JB, Choe, Sung Sik, Choi, A Hyun, Lee, Joo-Won, Kim, Kang Ho, Chung, Jun-Jae, Park, Jiyoung, Lee, Kyeong-Min, Park, Keun-Gyu, Lee, In-Kyu, and Kim, Jae Bum

Abstract

Liver X receptor (LXR)alpha and LXRbeta play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic beta-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced beta-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in beta-cells as a possible cause of beta-cell lipotoxicity, a key step in the development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2007
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120. Chronic Activation of Liver X Receptor Induces ß-Cell Apoptosis Through Hyperactivation of Lipogenesis.

Author

Choe, Sung Sik, Choi, A Hyun, Lee, Joo-Won, Kim, Kang Ho, Chung, Jun-Jae, Park, Jiyoung, Lee, Kyeong-Min, Park, Keun-Gyu, Lee, In-Kyu, and Kim, Jae Bum

Subjects
APOPTOSIS, LIVER, FATTY acids, METABOLISM, HOMEOSTASIS, CELLS, LIPID metabolism, ISLANDS of Langerhans
Abstract

Liver X receptor (LXR)α and LXRβ play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the fiver, intestine, fat, and macrophages are well established, its role in pancreatic β-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced β-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in β-cells as a possible cause of β-cell lipotoxicity, a key step in the development of type 2 diabetes. Diabetes 56:1534-1543, 2007 [ABSTRACT FROM AUTHOR]

Published
2007
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121. Time-course analysis of DNA damage response-related genes after in vitro radiation in H460 and H1229 lung cancer cell lines

Author

Kim, Kang Ho, Yoo, Hae Yong, Joo, Kyeung Min, Jung, Yong, Jin, Juyoun, Kim, Yonghyun, Yoon, Su Jin, Choi, Seung Ho, Seol, Ho Jun, Park, Woong-Yang, and Nam, Do-Hyun

Abstract

Radiation is the most useful treatment modality for cancer patients. It initiates a series of signal cascades such as DNA damage response (DDR) signaling for repairing damaged DNA, arresting the cell cycle, and inducing cell death. Until now, few genes have been found to be regulated by radiation, which explains the molecular mechanisms of cellular responses to radiation. Although the transcriptional changes caused by radiation have been widely investigated, little is known about the direct evidence for the transcriptional control of DDR-related genes. Here, we examined the radiosensitivity of two non-small cell lung cancer cell lines (H460 and H1299), which have different p53 status. We monitored the time-dependent changes of 24 DDR-related gene expressions via microarray analysis. Based on the basal expression levels and temporal patterns, we further classified 24 DDR-related genes into four subgroups. Then, we also addressed the protein levels of several DDR-related genes such as TopBP1, Chk1 and Chk2, confirming the results of microarray analysis. Together, these results indicate that the expression patterns of DDR-related genes are associated with radiosensitivity and with the p53 statuses of H460 and H1299, which adds to the understanding of the complex biological responses to radiation.

Published
2011
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122. Ube2i deletion in adipocytes causes lipoatrophy in mice.

Author

Cox, Aaron R., Chernis, Natasha, Kim, Kang Ho, Masschelin, Peter M., Saha, Pradip K., Briley, Shawn M., Sharp, Robert, Li, Xin, Felix, Jessica B., Sun, Zheng, Moore, David D., Pangas, Stephanie A., and Hartig, Sean M.

Abstract

White adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. The absence or loss of WAT occurring through lipodystrophy and lipoatrophy contributes to the development of hepatic steatosis and insulin resistance. We previously demonstrated that sole small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ube2i represses human adipocyte differentiation. The role of Ube2i during WAT development remains unknown. To determine how Ube2i impacts body composition and energy balance, we generated adipocyte-specific Ube2i knockout mice (Ube2i a-KO ). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ube2i locus. Subsequent genetic crosses to Adipoq-Cre transgenic mice allowed deletion of Ube2i in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ube2i a-KO and littermate controls during postnatal growth. Surprisingly, Ube2i a-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period. Our results demonstrate that Ube2i expression in mature adipocytes allows WAT expansion during postnatal growth. Deletion of Ube2i in fat cells compromises and diminishes adipocyte function that induces WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ube2i during white adipocyte expansion and endocrine control of energy balance. • A new mouse model reveals that Ube2i loss in fat cells impacts body composition. • Ube2i fat-specific knockout (Ube2i a-KO ) causes fatty liver and hyperinsulinemia. • Ube2i a-KO mice develop metabolic inflexibility and cold intolerance. • Inflammation and caspase activation of cell death occur in Ube2i a-KO adipocytes. [ABSTRACT FROM AUTHOR]

Published
2021
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123. One-step splitting of a chromosome in haploid cells of Saccharomyces cerevisiaeand its effect on the cell proliferation

Author

Widianto, Donny, Mukai, Yukio, Kim, Kang-Ho, Harashima, Satoshi, and Oshima, Yasuji

Abstract

A simple method has been developed for splitting a chromosome in Saccharomyces cerevisiaeinto two replicating halves. Haploid yeast cells of an ura3mutant were transformed with a linear molecule bearing an S. cerevisiaeDNA fragment for targeted integration into a chromosome, the URA3and CEN4DNA sequences of S. cerevisiae, and a pair of inverted repeats (IRs) of the terminal 0.7 kbp of Tetrahymenaribosomal DNA (Tr). The integrated IRs of Tr ends of the molecule at a site on a chromosome in an ura3mutant cell of S. cerevisiaesubsequently resolved and the chromosome was split into two monocentric chromosomes in the Ura+transformant. Using this procedure, chromosomes XI, VIII, and II were each split into two halves, at the GCN3, YHR088, and VPS15loci, respectively. Occurrence of the split chromosomes was confirmed by examination of their electrophoretic karyotypes. Some of the clones with the split chromosomes proliferated more quickly than the parental strain.

Published
1996
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124. Rapid Disruption of Genes Specifically in Livers of Mice Using Multiplex CRISPR/Cas9 Editing.

Author

Pankowicz, Francis P., Barzi, Mercedes, Kim, Kang Ho, Legras, Xavier, Martins, Celeste Santos, Wooton-Kee, Clavia Ruth, Lagor, William R., Marini, Juan C., Elsea, Sarah H., Bissig-Choisat, Beatrice, Moore, David D., and Bissig, Karl-Dimiter

Abstract

Background & aims Despite advances in gene editing technologies, generation of tissue-specific knockout mice is time-consuming. We used CRISPR/Cas9-mediated genome editing to disrupt genes in livers of adult mice in just a few months, which we refer to as somatic liver knockouts. Methods In this system, Fah –/– mice are given hydrodynamic tail vein injections of plasmids carrying CRISPR/Cas9 designed to excise exons in Hpd ; the Hpd -edited hepatocytes have a survival advantage in these mice. Plasmids that target Hpd and a separate gene of interest can therefore be used to rapidly generate mice with liver-specific deletion of nearly any gene product. Results We used this system to create mice with liver-specific knockout of argininosuccinate lyase, which develop hyperammonemia, observed in humans with mutations in this gene. We also created mice with liver-specific knockout of ATP binding cassette subfamily B member 11, which encodes the bile salt export pump. We found that these mice have a biochemical phenotype similar to that of Abcb11 –/– mice. We then used this system to knock out expression of 5 different enzymes involved in drug metabolism within the same mouse. Conclusions This approach might be used to develop new models of liver diseases and study liver functions of genes that are required during development. [ABSTRACT FROM AUTHOR]

Published
2018
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125. Fast and secure Global-Heap for memory-centric computing.

Author

Cha, Myung-Hoon, Lee, Sang-Min, An, Baik-Song, Kim, Hong-Yeon, and Kim, Kang-Ho

Subjects
*NONVOLATILE memory, *ELECTRONIC data processing, *PSYCHOLOGICAL adaptation
Abstract

In-memory computing has been widely used to process data quickly in memory, but it is no longer able to cope with the current data explosion. This has occurred because modern computers have structural constraints in terms of both memory capacity and bandwidth, fundamentally limiting the amount of data that can be processed in memory. In order to overcome these limitations, the memory-centric computing concept was proposed, and as an attempt to make this concept feasible, nonvolatile memory, next-generation interconnects, and memory-centric operating system technologies are being actively studied. Although, however, there have been many studies of these concepts, the essential problem of both efficiently and safely using the extremely large memory space has not been completely solved. This paper proposes what is termed Global-Heap which solves the above essential problem, thus supporting the core technology of memory-centric computing. In this technology, a heap-level abstraction which can be switched very lightly between processes is provided in an application-friendly manner as a global resource. Global-Heap also provides an effective means by which safely to use this vast address space based on Intel memory protection keys. We implemented Global-Heap on Linux and developed three useful use cases applicable to data-centric applications. Our primary evaluation shows that Global-Heap enables reorganization-free hashing. In addition, Global-Heap can improve the performance of an in-memory key-value store, Redis, by at least 7.56 times, and it can reduce the running time of graph applications executed in a pipeline approach by at least 48%. [ABSTRACT FROM AUTHOR]

Published
2021
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126. Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance.

Author

Preidis, Geoffrey A., Kang Ho Kim, Moore, David D., and Kim, Kang Ho

Subjects
*NUCLEAR receptors (Biochemistry), *FARNESOID X receptor, *FATTY acid oxidation, *HOMEOSTASIS, *GLUCONEOGENESIS, *PROTEIN metabolism, *MALNUTRITION, *ANIMALS, *CELL receptors, *FATTY acids, *GENETIC disorders, *GLYCOLYSIS, *LIPID metabolism disorders, *LIVER, *METABOLISM, *MICE, *OXIDATION-reduction reaction, *PROTEINS, *RESEARCH funding
Abstract

The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance. [ABSTRACT FROM AUTHOR]

Published
2017
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127. Intracranial Hemorrhage in the TST Trial

Author

Pierre Amarenco, Jong S. Kim, Julien Labreuche, Hugo Charles, Maurice Giroud, Philippa C. Lavallée, Byung-Chul Lee, Marie-Hélène Mahagne, Elena Meseguer, Norbert Nighoghossian, Philippe Gabriel Steg, Éric Vicaut, Eric Bruckert, Pierre-Jean Touboul, Didier Leys, Yannick Béjot, Fernando Pico, Emmanuel Touzé, Gregory Ducrocq, Jérémy Abtan, Olivier Varenne, Agnes Kemmel, Fausta Syana, Manele Ledra, Tharani Nagasara, Mervette Ledjeroud, Bahous Samia, Hafirassou Hadia, Benyoub Hazare, Ikrame El Jaghouni, Nessima Yelles, Sofia Zemouri, Mervette Ladjeroud, Salim Kerai, YunJeong In, Cristina Hobeanu, Celine Guidoux, Lucie Cabrejo, Bertrand Lapergue, Candice Sabben, Jaime Gonzalez-Valcarcel, Ricardo Rigual, Gaia Sirimarco, Anna Martin-Bechet, Elena Viedma, Ioan Avram, Yves Samson, Charlotte Rosso, Sophie Crozier, Sara Leder, Anne Léger, Sandrine Deltour, Gurkan Mutlu, Marion Yger, Chiara Zavanone, Flore Baronnet, Christine Pires, Adrien Wang, Serge Evrard, Maya Tchikviladze, Frédéric Bourdain, Delphine Lopez, Laetitia Bayon de la Tour, Marie-Laure Chadenat, Duc Long Duong, Solène Genty, Catherine Hirel, Chantal Nifle, Jérôme Servan, Daniela Stanciu, Veronica Sudacevschi, Mélissa Tir, Anne-Cécile Troussière, Jennifer Yeung, Anne-Céline Zeghoudi, Ikram Tidafi-Bayou, Sylvain Lachaud, Tae-Hee Cho, Laura Mechtouff, Thomas Ritzenthaller, Laurent Derex, Carlo Albanesi, Elodie Ong, Amandine Benoit, Nadia Berhoune, Sandra Felix, Maud Esteban-Mader, Igor Sibon, Annabelle Kazadi, François Rouanet, Pauline Renou, Sabrina Debruxelles, Mathilde Poli, Sharmila Sagnier, Jean-Louis Mas, Valérie Domigo, Catherine Lamy, Eric Bodiguel, Jérôme Grimaud, Valentin Bohotin, Michael Obadia, Erwan Morvan, Gilles Rodier, Wilfried Vadot, Hilde Hénon, Charlotte Cordonnier, Frédéric Dumont, Marie Bodenant, Christian Lucas, Solène Moulin, Nelly Dequatre, Sonia Alamowitch, Jean-Paul Muresan, Thomas Drouet, Magalie Gallea, Marie-Amélie Dalloz, Stephen Delorme, Philippe Loisel, Carine Bonnin, Virginie Bernigal, Guy Victor Osseby, Marie Hervieu-BègueMarsac, Pierre Garnier, Sandrine Accassat, Magali Epinat, Jérôme Varvat, Doïna Marinescu, Aude Triquenot-Bagan, Ozlem Ozkul- Wermester, Frédéric Philippeau, Anne Vieillart, Annie Lannuzel, Alice Demoly, Valérie Wolff, Mihaela Diaconu, Marc Bataillard, Francisco Macian Montoro, Frédéric Faugeras, Laeticia Gimenez, Françoise Abdallah-Lebeau, Serge Timsit, Irina Viakhireva-Dovganyuk, Anne Tirel-Badets, François-Mathias Merrien, Philippe Goas, François Rouhart, Aurore Jourdain, Benoit Guillon, Fanny Hérissson, Mathieu Sevin-Allouet, Nathalie Nasr, Jean-Marc Olivot, Alderic Lecluse, Guillaume Marc, null Hamon, Vincent de la Sayette, Marion Apoil, Li Lin, Julien Cogez, Sophie Guettier, Olivier Godefroy, Chantal Lamy, Jean-Marc Bugnicourt, Grégory Taurin, Marc Mérienne, Julien Gere, Anne-Marie Chessak, Tarik Habet, Anna Ferrier, Nathalie Bourgois, Dominique Minier, Marie Caillier-Minier, Fabienne Contégal- Callier, Philippe Vion, Yvan Vaschalde, Mohammed El Amrani, null Emilie, Mathieu Zuber, Marie Bruandet, Claire Join- Lambert, Pierre-Yves Garcia, Isabelle Serre, Jean-Marc Faucheux, Fatia Radji, Elena Leca-Radu, Thomas Debroucker, Rodica Cumurcuc, Serkan Cakmak, Stéphane Peysson, Emmanuel Ellie, Patricia Bernady, Thierry Moulin, Paola Montiel, Eugeniu Revenco, Pierre Decavel, Elisabeth Medeiros, Myriam Bouveret, Pierre Louchart, Claudia Vaduva, Grégory Couvreur, Eric Sartori, null Alnajar-Carpentier, Michèle Levasseur, Jean-Philippe Neau, Xavier Vandamme, Isabelle Meresse, null Stantescu, Canan Ozsancak, Katell Beauvais, Pascal Auzou, Joséphine Amevigbe, Francis Vuillemet, Marie-Hélène Dugay-Arentz, Gabriela Carelli, Mikel Martinez, Marcel Maillet-Vioud, Jean-Pierre Escaillas, Stéphane Chapuis, Jean Tardy, Eric Manchon, Olivier Varnet, Yong-Jae Kim, Yoonkyung Chang, Tae-Jin Song, Jong Sung Kim, Jung-Hoon Han, Kyung Chul Noh, Eun-Jae Lee, Dong-Wha Kang, Sun Uck Kwon, Boseoung Kwon, Seongho Park, Dongwhane Lee, Hyuk Sung Kwon, Daeun Jeong, MinHwan Lee, Joonggoo Kim, Hanbin Lee, Hyo Jung Nam, Sang Hun Lee, Bum Joon Kim, Jae-kwan Cha, DaeHyun Kim, Rae Young Kim, Sang Wuk Sohn, Dong-Hyun Shim, Hyungjin Lee, Hyun-Wook Nah, Sang Min Sung, Kyung Bok Lee, Jeong Yoon Lee, Jee Eun Yoon, Eung-Gyu Kim, Jung Hwa Seo, Yong-Won Kim, Yangha Hwang, Man Seok Park, Joon-Tae Kim, Kang-Ho Choi, Hyo Suk Nam, Ji Hoe Heo, Young Dae Kim, In Gun Hwang, Hyung Jong Park, Kyoung Sub Kim, Jang Hyun Baek, Dong Beom Song, Joon Sang Yoo, Jong-Moo Park, Ohyun Kwon, Woong-Woo Lee, Jung-Ju Lee, Kyusik Kang, Byung Kun Kim, Jae-Sung Lim, Mi Sun Oh, Kyung-Ho Yu, Bora Hong, Mihoon Jang, Seyoung Jang, Jung Eun Jin, Jei Kim, Hye Seon Jeong, Keun Sik Hong, Hong Kyun Park, Yong Jin Cho, Oh Young Bang, Keun Seo, Jongwon Chung, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Asan Medical Center [Seoul, South Korea] (AMC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe Avenir. University of Burgundy, Hallym University Sacred Heart Hospital [Anyang, South Korea] (HUS2H), Hôpital Pasteur [Nice] (CHU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), Hôpital Lariboisière-Fernand-Widal [APHP], Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, Treat Stroke to Target Investigators*: Pierre-Jean Touboul, Didier Leys, Yannick Béjot, Fernando Pico, Emmanuel Touzé, Gregory Ducrocq, Jérémy Abtan, Olivier Varenne, Pierre-Jean Touboul, Agnes Kemmel, Fausta Syana, Manele Ledra, Tharani Nagasara, Mervette Ledjeroud, Bahous Samia, Hafirassou Hadia, Benyoub Hazare, Ikrame El Jaghouni, Nessima Yelles, Sofia Zemouri, Mervette Ladjeroud, Salim Kerai, YunJeong In, Cristina Hobeanu, Celine Guidoux, Lucie Cabrejo, Bertrand Lapergue, Candice Sabben, Jaime Gonzalez-Valcarcel, Ricardo Rigual, Gaia Sirimarco, Anna Martin-Bechet, Elena Viedma, Ioan Avram, Yves Samson, Charlotte Rosso, Sophie Crozier, Sara Leder, Anne Léger, Sandrine Deltour, Gurkan Mutlu, Marion Yger, Chiara Zavanone, Flore Baronnet, Christine Pires, Bertrand Lapergue, Adrien Wang, Serge Evrard, Maya Tchikviladze, Frédéric Bourdain, Delphine Lopez, Fernando Pico, Laetitia Bayon de la Tour, Marie-Laure Chadenat, Duc Long Duong, Solène Genty, Catherine Hirel, Gurkan Mutlu, Chantal Nifle, Jérôme Servan, Daniela Stanciu, Veronica Sudacevschi, Mélissa Tir, Anne-Cécile Troussière, Jennifer Yeung, Anne-Céline Zeghoudi, Ikram Tidafi-Bayou, Sylvain Lachaud, Tae-Hee Cho, Laura Mechtouff, Thomas Ritzenthaller, Laurent Derex, Carlo Albanesi, Elodie Ong, Amandine Benoit, Nadia Berhoune, Sandra Felix, Maud Esteban-Mader, Igor Sibon, Annabelle Kazadi, François Rouanet, Pauline Renou, Sabrina Debruxelles, Mathilde Poli, Sharmila Sagnier, Jean-Louis Mas, Valérie Domigo, Catherine Lamy, Eric Bodiguel, Jérôme Grimaud, Valentin Bohotin, Michael Obadia, Candice Sabben, Erwan Morvan, Gilles Rodier, Wilfried Vadot, Hilde Hénon, Charlotte Cordonnier, Frédéric Dumont, Marie Bodenant, Christian Lucas, Solène Moulin, Nelly Dequatre, Sonia Alamowitch, Jean-Paul Muresan, Thomas Drouet, Magalie Gallea, Marie-Amélie Dalloz, Stephen Delorme, Marion Yger, Yannick Béjot, Philippe Loisel, Carine Bonnin, Virginie Bernigal, Guy Victor Osseby, Marie Hervieu-BègueMarsac, Pierre Garnier, Sandrine Accassat, Magali Epinat, Jérôme Varvat, Doïna Marinescu, Aude Triquenot-Bagan, Ozlem Ozkul-Wermester, Frédéric Philippeau, Anne Vieillart, Annie Lannuzel, Alice Demoly, Valérie Wolff, Mihaela Diaconu, Marc Bataillard, Francisco Macian Montoro, Frédéric Faugeras, Laeticia Gimenez, Françoise Abdallah-Lebeau, Serge Timsit, Irina Viakhireva-Dovganyuk, Anne Tirel-Badets, François-Mathias Merrien, Philippe Goas, François Rouhart, Aurore Jourdain, Benoit Guillon, Fanny Hérissson, Mathieu Sevin-Allouet, Nathalie Nasr, Jean-Marc Olivot, Alderic Lecluse, Guillaume Marc, Hamon, Emmanuel Touzé, Vincent de la Sayette, Marion Apoil, Li Lin, Julien Cogez, Sophie Guettier, Olivier Godefroy, Chantal Lamy, Jean-Marc Bugnicourt, Grégory Taurin, Marc Mérienne, Julien Gere, Anne-Marie Chessak, Tarik Habet, Anna Ferrier, Nathalie Bourgois, Dominique Minier, Marie Caillier-Minier, Fabienne Contégal-Callier, Philippe Vion, Yvan Vaschalde, Mohammed El Amrani, Emilie, Mathieu Zuber, Marie Bruandet, Claire Join-Lambert, Pierre-Yves Garcia, Isabelle Serre, Jean-Marc Faucheux, Fatia Radji, Elena Leca-Radu, Thomas Debroucker, Rodica Cumurcuc, Serkan Cakmak, Stéphane Peysson, Emmanuel Ellie, Patricia Bernady, Thierry Moulin, Paola Montiel, Eugeniu Revenco, Pierre Decavel, Elisabeth Medeiros, Myriam Bouveret, Pierre Louchart, Claudia Vaduva, Grégory Couvreur, Eric Sartori, Alnajar-Carpentier, Michèle Levasseur, Pierre Louchart, Jean-Philippe Neau, Xavier Vandamme, Isabelle Meresse, Stantescu, Marc Bataillard, Canan Ozsancak, Katell Beauvais, Pascal Auzou, Joséphine Amevigbe, Francis Vuillemet, Marie-Hélène Dugay-Arentz, Gabriela Carelli, Mikel Martinez, Marcel Maillet-Vioud, Jean-Pierre Escaillas, Stéphane Chapuis, Jean Tardy, Eric Manchon, Olivier Varnet, Yong-Jae Kim, Yoonkyung Chang, Tae-Jin Song, Jong Sung Kim, Jung-Hoon Han, Kyung Chul Noh, Eun-Jae Lee, Dong-Wha Kang, Sun Uck Kwon, Boseoung Kwon, Seongho Park, Dongwhane Lee, Hyuk Sung Kwon, Daeun Jeong, MinHwan Lee, Joonggoo Kim, Hanbin Lee, Hyo Jung Nam, Sang Hun Lee, Bum Joon Kim, Jae-Kwan Cha, DaeHyun Kim, Rae Young Kim, Sang Wuk Sohn, Dong-Hyun Shim, Hyungjin Lee, Hyun-Wook Nah, Sang Min Sung, Kyung Bok Lee, Jeong Yoon Lee, Jee Eun Yoon, Eung-Gyu Kim, Jung Hwa Seo, Yong-Won Kim, Yangha Hwang, Man Seok Park, Joon-Tae Kim, Kang-Ho Choi, Hyo Suk Nam, Ji Hoe Heo, Young Dae Kim, In Gun Hwang, Hyung Jong Park, Kyoung Sub Kim, Jang Hyun Baek, Dong Beom Song, Joon Sang Yoo, Jong-Moo Park, Ohyun Kwon, Woong-Woo Lee, Jung-Ju Lee, Kyusik Kang, Byung Kun Kim, Jae-Sung Lim, Mi Sun Oh, Kyung-Ho Yu, Bora Hong, Mihoon Jang, Seyoung Jang, Jung Eun Jin, Jei Kim, Hye Seon Jeong, Keun Sik Hong, Hong Kyun Park, Yong Jin Cho, Oh Young Bang, Keun Seo, Jongwon Chung, and CarMeN, laboratoire

Subjects
Adult, Male, [SDV]Life Sciences [q-bio], Coronary Artery Disease, LDL, Young Adult, Predictive Value of Tests, Risk Factors, Secondary Prevention, Humans, cardiovascular diseases, Aged, Ischemic Stroke, Advanced and Specialized Nursing, Aged, 80 and over, Anticholesteremic Agents, Incidence, cholesterol, Anticoagulants, Cholesterol, LDL, Middle Aged, Ezetimibe, Intracranial Arteriosclerosis, [SDV] Life Sciences [q-bio], Ischemic Attack, Transient, Hypertension, Female, Neurology (clinical), atherosclerosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, Intracranial Hemorrhages
Abstract

Background and Purpose: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of Results: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38–4.04] and 2.32/1000 patient-years [95% CI, 1.61–3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01–6.31], P =0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00–5.62], P =0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. Conclusions: Targeting an LDL cholesterol of Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.

Published
2021
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128. Impact of Lower Versus Higher LDL Cholesterol Targets on Cardiovascular Events After Ischemic Stroke in Patients With Diabetes

Author

Pierre, Amarenco, Jong S, Kim, Julien, Labreuche, Hugo, Charles, Maurice, Giroud, Byung-Chul, Lee, Philippa C, Lavallée, Marie-Hélène, Mahagne, Elena, Meseguer, Norbert, Nighoghossian, Philippe Gabriel, Steg, Éric, Vicaut, Eric, Bruckert, Jongwon, Chung, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Asan Medical Center [Seoul, South Korea] (AMC), Santé Publique : épidémiologie et qualité des soins (EA 2694), Université Lille 2 - Faculté de Médecine -Centre d'Etudes et de Recherche en Informatique Médicale [Lille] (CERIM), Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hallym University Sacred Heart Hospital [Anyang, South Korea] (HUS2H), Hôpital Pasteur [Nice] (CHU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Treat Stroke to Target Investigators, Treat Stroke to Target investigators: Pierre Amarenco, Eric Bruckert, Maurice Giroud, Jong S Kim, Julien Labreuche, Byung-Chul Lee, Marie-Hélène Mahagne, Norbert Nighoghossian, Philippe Gabriel Steg, Pierre-Jean Touboul, Eric Vicaut, Didier Leys, Yannick Béjot, Philippa Lavallée, Fernando Pico, Emmanuel Touzé, Gregory Ducrocq, Jérémy Abtan, Olivier Varenne, Charles Foix, Agnes Kemmel, Fausta Syana, Manele Ledra, Tharani Nagasara, Mervette Ledjeroud, Bahous Samia, Hafirassou Hadia, Benyoub Hazare, Ikrame El Jaghouni, Nessima Yelles, Sofia Zemouri, Salim Kerai, YunJeong In, Elena Meseguer, Philippa C Lavallée, Cristina Hobeanu, Celine Guidoux, Lucie Cabrejo, Bertrand Lapergue, Candice Sabben, Jaime Gonzalez-Valcarcel, Ricardo Rigual, Gaia Sirimarco, Anna Martin-Bechet, Elena Viedma, Ioan Avram, Yves Samson, Charlotte Rosso, Sophie Crozier, Sara Leder, Anne Léger, Sandrine Deltour, Gurkan Mutlu, Marion Yger, Chiara Zavanone, Flore Baronnet, Christine Pires, Bertrand Lapergue, Adrien Wang, Serge Evrard, Maya Tchikviladze, Frédéric Bourdain, Delphine Lopez, Fernando Pico, Laetitia Bayon de la Tour, Marie-Laure Chadenat, Duc Long Duong, Solène Genty, Catherine Hirel, Chantal Nifle, Jérôme Servan, Daniela Stanciu, Veronica Sudacevschi, Mélissa Tir, Anne-Cécile Troussière, Jennifer Yeung, Anne-Céline Zeghoudi, Ikram Tidafi-Bayou, Sylvain Lachaud, Tae-Hee Cho, Laura Mechtouff, Thomas Ritzenthaller, Laurent Derex, Carlo Albanesi, Elodie Ong, Amandine Benoit, Nadia Berhoune, Sandra Felix, Maud Esteban-Mader, Igor Sibon, Annabelle Kazadi, François Rouanet, Pauline Renou, Sabrina Debruxelles, Mathilde Poli, Sharmila Sagnier, Jean-Louis Mas, Valérie Domigo, Catherine Lamy, Eric Bodiguel, Jérôme Grimaud, Valentin Bohotin, Michael Obadia, Erwan Morvan, Gilles Rodier, Wilfried Vadot, Hilde Hénon, Charlotte Cordonnier, Frédéric Dumont, Marie Bodenant, Christian Lucas, Solène Moulin, Nelly Dequatre, Sonia Alamowitch, Jean-Paul Muresan, Thomas Drouet, Magalie Gallea, Marie-Amélie Dalloz, Stephen Delorme, Marion Yger, Yannick Béjot, Philippe Loisel, Carine Bonnin, Virginie Bernigal, Guy Victor Osseby, Marie Hervieu-Bègue Marsac, Pierre Garnier, Sandrine Accassat, Magali Epinat, Jérôme Varvat, Doïna Marinescu, Aude Triquenot-Bagan, Ozlem Ozkul-Wermester, Frédéric Philippeau, Angel Olaru, Anne Vieillart, Annie Lannuzel, Alice Demoly, Valérie Wolff, Mihaela Diaconu, Marc Bataillard, Francisco Macian Montoro, Frédéric Faugeras, Laeticia Gimenez, Françoise Abdallah-Lebeau, Serge Timsit, Irina Viakhireva-Dovganyuk, Anne Tirel-Badets, François-Mathias Merrien, Philippe Goas, François Rouhart, Aurore Jourdain, Benoit Guillon, Fanny Hérissson, Mathieu Sevin-Allouet, Nathalie Nasr, Jean-Marc Olivot, Alderic Lecluse, Guillaume Marc, Marie Christine Hamon, Emmanuel Touzé, Vincent de la Sayette, Marion Apoil, Li Lin, Julien Cogez, Sophie Guettier, Olivier Godefroy, Jean-Marc Bugnicourt, Grégory Taurin, Marc Mérienne, Julien Gere, Anne-Marie Chessak, Tarik Habet, Anna Ferrier, Nathalie Bourgois, Dominique Minier, Marie Caillier-Minier, Fabienne Contégal-Callier, Philippe Vion, Yvan Vaschalde, Mohammed El Amrani, Emilie Xxx, Mathieu Zuber, Marie Bruandet, Claire Join-Lambert, Pierre-Yves Garcia, Isabelle Serre, Jean-Marc Faucheux, Fatia Radji, Elena Leca-Radu, Thomas Debroucker, Rodica Cumurcuc, Serkan Cakmak, Stéphane Peysson, Emmanuel Ellie, Patricia Bernady, Thierry Moulin, Paola Montiel, Eugeniu Revenco, Pierre Decavel, Elisabeth Medeiros, Myriam Bouveret, Pierre Louchart, Jean-Philippe Neau, Xavier Vandamme, Isabelle Meresse, Xxx Stantescu, Canan Ozsancak, Katell Beauvais, Pascal Auzou, Joséphine Amevigbe, Francis Vuillemet, Marie-Hélène Dugay-Arentz, Gabriela Carelli, Mikel Martinez, Marcel Maillet-Vioud, Jean-Pierre Escaillas, Stéphane Chapuis, Jean Tardy, Eric Manchon, Olivier Varnet, Yong-Jae Kim, Yoonkyung Chang, Tae-Jin Song, Jong Sung Kim, Jung-Hoon Han, Kyung Chul Noh, Eun-Jae Lee, Dong-Wha Kang, Sun Uck Kwon, Boseoung Kwon, Seongho Park, Dongwhane Lee, Hyuk Sung Kwon, Daeun Jeong, MinHwan Lee, Joonggoo Kim, Hanbin Lee, Hyo Jung Nam, Sang Hun Lee, Bum Joon Kim, Jae-Kwan Cha, DaeHyun Kim, Rae Young Kim, Sang Wuk Sohn, Dong-Hyun Shim, Hyungjin Lee, Hyun-Wook Nah, Sang Min Sung, Kyung Bok Lee, Jeong Yoon Lee, Jee Eun Yoon, Eung-Gyu Kim, Jung Hwa Seo, Yong-Won Kim, Yangha Hwang, Man Seok Park, Joon-Tae Kim, Kang-Ho Choi, Hyo Suk Nam, Ji Hoe Heo, Young Dae Kim, In Gun Hwang, Hyung Jong Park, Kyoung Sub Kim, Jang Hyun Baek, Dong Beom Song, Joon Sang Yoo, Jong-Moo Park, Ohyun Kwon, Woong-Woo Lee, Jung-Ju Lee, Kyusik Kang, Byung Kun Kim, Byung-Chul Lee, Jae-Sung Lim, Mi Sun Oh, Kyung-Ho Yu, Bora Hong, Mihoon Jang, Seyoung Jang, Jung Eun Jin, Jei Kim, Hye Seon Jeong, Keun Sik Hong, Hong Kyun Park, Yong Jin Cho, Oh Young Bang, Woo-Keun Seo, Jongwon Chung., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Faculté de Médecine Henri Warembourg - Université de Lille-Centre d'Etudes et de Recherche en Informatique Médicale [Lille] (CERIM), and CarMeN, laboratoire

Subjects
Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Hypercholesterolemia, Myocardial Infarction, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Text mining, Internal medicine, Diabetes mellitus, Internal Medicine, Medicine, Humans, In patient, cardiovascular diseases, Aged, Ischemic Stroke, Ldl cholesterol, business.industry, Cholesterol, LDL, Middle Aged, medicine.disease, Ezetimibe, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Diabetes Mellitus, Type 2, Ischemic stroke, Cardiology, lipids (amino acids, peptides, and proteins), Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, 030217 neurology & neurosurgery
Abstract

International audience; After an ischemic stroke with evidence of atherosclerosis, lipid-lowering treatment with a target LDL cholesterol of

Published
2021
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129. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke

Author

Amarenco P, Kim J, Labreuche J, Charles H, Abtan J, Bejot Y, Cabrejo L, Cha J, Ducrocq G, Giroud M, Guidoux C, Hobeanu C, Kim Y, Lapergue B, Lavallee P, Lee B, Lee K, Leys D, Mahagne M, Meseguer E, Nighoghossian N, Pico F, Samson Y, Sibon I, Steg P, Sung S, Touboul P, Touze E, Varenne O, Vicaut E, Yelles N, Bruckert E, Treat Stroke Target Investigators, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Asan Medical Center [Seoul], University of Ulsan, Santé Publique : épidémiologie et qualité des soins (EA 2694), Faculté de Médecine Henri Warembourg - Université de Lille-Centre d'Etudes et de Recherche en Informatique Médicale [Lille] (CERIM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Catholic University of Korea, Hôpital Foch [Suresnes], Hallym University Sacred Heart Hospital [Anyang, South Korea] (HUS2H), Soonchunhyang University [Asan], CHU Lille, Hôpital Pasteur [Nice] (CHU), Hospices Civils de Lyon (HCL), Centre Hospitalier de Versailles André Mignot (CHV), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Pusan National University Hospital, Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), GIP Cyceron (Cyceron), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, and Treat Stroke to Target Investigators: Pierre Amarenco, Eric Bruckert, Maurice Giroud, Jong S Kim, Julien Labreuche, Byung-Chul Lee, Marie-Hélène Mahagne, Norbert Nighoghossian, Philippe Gabriel Steg, Pierre-Jean Touboul, Eric Vicaut, Didier Leys, Philippa Lavallée, Gregory Ducrocq, Jérémy Abtan, Olivier Varenne, Agnes Kemmel, Fausta Syana, Manele Ledra, Tharani Nagasara, Mervette Ledjeroud, Bahous Samia, Hafirassou Hadia, Benyoub Hazare, Ikrame El Jaghouni, Nessima Yelles, Sofia Zemouri, Mervette Ladjeroud, Salim Kerai, YunJeong In, Elena Meseguer, Philippa C Lavallée, Cristina Hobeanu, Celine Guidoux, Lucie Cabrejo, Jaime Gonzalez-Valcarcel, Ricardo Rigual, Gaia Sirimarco, Anna Martin-Bechet, Elena Viedma, Ioan Avram, Yves Samson, Charlotte Rosso, Sophie Crozier, Sara Leder, Anne Léger, Sandrine Deltour, Chiara Zavanone, Flore Baronnet, Christine Pires, Bertrand Lapergue, Adrien Wang, Serge Evrard, Maya Tchikviladze, Frédéric Bourdain, Delphine Lopez, Fernando Pico, Laetitia Bayon de la Tour, Marie-Laure Chadenat, Duc Long Duong, Solène Genty, Catherine Hirel, Gurkan Mutlu, Chantal Nifle, Jérôme Servan, Daniela Stanciu, Veronica Sudacevschi, Mélissa Tir, Anne-Cécile Troussière, Jennifer Yeung, Anne-Céline Zeghoudi, Ikram Tidafi-Bayou, Sylvain Lachaud, Tae-Hee Cho, Laura Mechtouff, Thomas Ritzenthaller, Laurent Derex, Carlo Albanesi, Elodie Ong, Amandine Benoit, Nadia Berhoune, Sandra Felix, Maud Esteban-Mader, Igor Sibon, Annabelle Kazadi, François Rouanet, Pauline Renou, Sabrina Debruxelles, Mathilde Poli, Sharmila Sagnier, Jean-Louis Mas, Valérie Domigo, Catherine Lamy, Eric Bodiguel, Jérôme Grimaud, Valentin Bohotin, Michael Obadia, Candice Sabben, Erwan Morvan, Gilles Rodier, Wilfried Vadot, Hilde Hénon, Charlotte Cordonnier, Frédéric Dumont, Marie Bodenant, Christian Lucas, Solène Moulin, Nelly Dequatre, Sonia Alamowitch, Jean-Paul Muresan, Thomas Drouet, Magalie Gallea, Marie-Amélie Dalloz, Stephen Delorme, Marion Yger, Yannick Béjot, Philippe Loisel, Carine Bonnin, Virginie Bernigal, Guy Victor Osseby, Marie Hervieu-BègueMarsac, Pierre Garnier, Sandrine Accassat, Magali Epinat, Jérôme Varvat, Doïna Marinescu, Aude Triquenot-Bagan, Ozlem Ozkul-Wermester, Frédéric Philippeau, Angel Olaru, Anne Vieillart, Annie Lannuzel, Alice Demoly, Valérie Wolff, Mihaela Diaconu, Francisco Macian Montoro, Frédéric Faugeras, Laeticia Gimenez, Françoise Abdallah-Lebeau, Serge Timsit, Irina Viakhireva-Dovganyuk, Anne Tirel-Badets, François-Mathias Merrien, Philippe Goas, François Rouhart, Aurore Jourdain, Benoit Guillon, Fanny Hérissson, Mathieu Sevin-Allouet, Nathalie Nasr, Jean-Marc Olivot, Alderic Lecluse, Guillaume Marc, Emmanuel Touzé, Vincent de la Sayette, Marion Apoil, Li Lin, Julien Cogez, Sophie Guettier, Olivier Godefroy, Chantal Lamy, Jean-Marc Bugnicourt, Grégory Taurin, Marc Mérienne, Julien Gere, Anne-Marie Chessak, Tarik Habet, Anna Ferrier, Nathalie Bourgois, Dominique Minier, Marie Caillier-Minier, Fabienne Contégal-Callier, Philippe Vion, Yvan Vaschalde, Mohammed El Amrani, Mathieu Zuber, Marie Bruandet, Claire Join-Lambert, Pierre-Yves Garcia, Isabelle Serre, Jean-Marc Faucheux, Fatia Radji, Elena Leca-Radu, Thomas Debroucker, Rodica Cumurcuc, Serkan Cakmak, Stéphane Peysson, Emmanuel Ellie, Patricia Bernady, Thierry Moulin, Paola Montiel, Eugeniu Revenco, Pierre Decavel, Elisabeth Medeiros, Myriam Bouveret, Pierre Louchart, Claudia Vaduva, Grégory Couvreur, Eric Sartori, Adam Amer Alnajar-Carpentier, Michèle Levasseur, Pierre Louchart, Jean-Philippe Neau, Xavier Vandamme, Isabelle Meresse, Marc Bataillard, Canan Ozsancak, Katell Beauvais, Pascal Auzou, Joséphine Amevigbe, Francis Vuillemet, Marie-Hélène Dugay-Arentz, Gabriela Carelli, Mikel Martinez, Marcel Maillet-Vioud, Jean-Pierre Escaillas, Stéphane Chapuis, Jean Tardy, Eric Manchon, Olivier Varnet, Yong-Jae Kim, Yoonkyung Chang, Tae-Jin Song, Jong Sung Kim, Jung-Hoon Han, Kyung Chul Noh, Eun-Jae Lee, Dong-Wha Kang, Sun Uck Kwon, Boseoung Kwon, Seongho Park, Dongwhane Lee, Hyuk Sung Kwon, Daeun Jeong, MinHwan Lee, Joonggoo Kim, Hanbin Lee, Hyo Jung Nam, Sang Hun Lee, Bum Joon Kim, Jae-Kwan Cha, DaeHyun Kim, Rae Young Kim, Sang Wuk Sohn, Dong-Hyun Shim, Hyungjin Lee, Hyun-Wook Nah, Sang Min Sung, Kyung Bok Lee, Jeong Yoon Lee, Jee Eun Yoon, Eung-Gyu Kim, Jung Hwa Seo, Yong-Won Kim, Yangha Hwang, Man Seok Park, Joon-Tae Kim, Kang-Ho Choi, Hyo Suk Nam, Ji Hoe Heo, Young Dae Kim, In Gun Hwang, Hyung Jong Park, Kyoung Sub Kim, Jang Hyun Baek, Dong Beom Song, Joon Sang Yoo, Jong-Moo Park, Ohyun Kwon, Woong-Woo Lee, Jung-Ju Lee, Kyusik Kang, Byung Kun Kim, Jae-Sung Lim, Mi Sun Oh, Kyung-Ho Yu, Bora Hong, Mihoon Jang, Seyoung Jang, Jung Eun Jin, Jei Kim, Hye Seon Jeong, Keun Sik Hong, Hong Kyun Park, Yong Jin Cho, Oh Young Bang, Woo-Keun Seo, Jongwon Chung

Subjects
Adult, Male, medicine.medical_specialty, Statin, medicine.drug_class, [SDV]Life Sciences [q-bio], MEDLINE, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Brain Ischemia, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Text mining, Pharmacotherapy, Randomized controlled trial, law, Internal medicine, Humans, Medicine, cardiovascular diseases, 030212 general & internal medicine, Aged, Intention-to-treat analysis, business.industry, Cholesterol, Anticholesteremic Agents, Cholesterol, LDL, General Medicine, Middle Aged, Atherosclerosis, Ezetimibe, Intention to Treat Analysis, Stroke, chemistry, Cardiovascular Diseases, Ischemic Attack, Transient, Ischemic stroke, Drug Therapy, Combination, Female, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract

International audience; BACKGROUND: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. METHODS: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. RESULTS: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. CONCLUSIONS: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).

Published
2020
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130. Benefit of Targeting a LDL (Low-Density Lipoprotein) Cholesterol \textless70 mg/dL During 5 Years After Ischemic Stroke

Author

Pierre Amarenco, Jong S. Kim, Julien Labreuche, Hugo Charles, Maurice Giroud, Byung-Chul Lee, Marie-Hélène Mahagne, Norbert Nighoghossian, Philippe Gabriel Steg, Éric Vicaut, Eric Bruckert, Pierre-Jean Touboul, Didier Leys, Yannick Béjot, Philippa Lavallée, Fernando Pico, Emmanuel Touzé, Gregory Ducrocq, Jérémy Abtan, Olivier Varenne, Agnes Kemmel, Fausta Syana, Manele Ledra, Tharani Nagasara, Mervette Ledjeroud, Bahous Samia, Hafirassou Hadia, Benyoub Hazare, Ikrame El Jaghouni, Nessima Yelles, Sofia Zemouri, Mervette Ladjeroud, Salim Kerai, Yun Jeong In, Elena Meseguer, Philippa C Lavallée, Cristina Hobeanu, Celine Guidoux, Lucie Cabrejo, Bertrand Lapergue, Candice Sabben, Jaime Gonzalez-Valcarcel, Ricardo Rigual, Gaia Sirimarco, Anna Martin-Bechet, Elena Viedma, Ioan Avram, Yves Samson, Charlotte Rosso, Sophie Crozier, Sara Leder, Anne Léger, Sandrine Deltour, Gurkan Mutlu, Marion Yger, Chiara Zavanone, Flore Baronnet, Christine Pires, Adrien Wang, Serge Evrard, Maya Tchikviladze, Frédéric Bourdain, Delphine Lopez, Laetitia Bayon de la Tour, Marie-Laure Chadenat, Duc Long Duong, Solène Genty, Catherine Hirel, Chantal Nifle, Jérôme Servan, Daniela Stanciu, Veronica Sudacevschi, Mélissa Tir, Anne-Cécile Troussière, Jennifer Yeung, Anne-Céline Zeghoudi, Ikram Tidafi-Bayou, Sylvain Lachaud, Tae-Hee Cho, Laura Mechtouff, Thomas Ritzenthaller, Laurent Derex, Carlo Albanesi, Elodie Ong, Amandine Benoit, Nadia Berhoune, Sandra Felix, Maud Esteban-Mader, Igor Sibon, Annabelle Kazadi, François Rouanet, Pauline Renou, Sabrina Debruxelles, Mathilde Poli, Sharmila Sagnier, Jean-Louis Mas, Valérie Domigo, Catherine Lamy, Eric Bodiguel, Jérôme Grimaud, Valentin Bohotin, Michael Obadia, Erwan Morvan, Gilles Rodier, Wilfried Vadot, Hilde Hénon, Charlotte Cordonnier, Frédéric Dumont, Marie Bodenant, Christian Lucas, Solène Moulin, Nelly Dequatre, Sonia Alamowitch, Jean-Paul Muresan, Thomas Drouet, Magalie Gallea, Marie-Amélie Dalloz, Stephen Delorme, Philippe Loisel, Carine Bonnin, Virginie Bernigal, Guy Victor Osseby, Marie Hervieu-Bègue Marsac, Pierre Garnier, Sandrine Accassat, Magali Epinat, Jérôme Varvat, Doïna Marinescu, Aude Triquenot-Bagan, Ozlem Ozkul-Wermester, Frédéric Philippeau, Angel Olaru, Anne Vieillart, Annie Lannuzel, Alice Demoly, Valérie Wolff, Mihaela Diaconu, Marc Bataillard, Francisco Macian Montoro, Frédéric Faugeras, Laeticia Gimenez, Françoise Abdallah-Lebeau, Serge Timsit, Irina Viakhireva-Dovganyuk, Anne Tirel-Badets, François-Mathias Merrien, Philippe Goas, François Rouhart, Aurore Jourdain, Benoit Guillon, Fanny Hérissson, Mathieu Sevin-Allouet, Nathalie Nasr, Jean-Marc Olivot, Alderic Lecluse, Guillaume Marc, Vincent de la Sayette, Marion Apoil, Li Lin, Julien Cogez, Sophie Guettier, Olivier Godefroy, Chantal Lamy, Jean-Marc Bugnicourt, Grégory Taurin, Marc Mérienne, Julien Gere, Anne-Marie Chessak, Tarik Habet, Anna Ferrier, Nathalie Bourgois, Dominique Minier, Marie Caillier-Minier, Fabienne Contégal-Callier, Philippe Vion, Yvan Vaschalde, Mohammed El Amrani, Emilie, Mathieu Zuber, Marie Bruandet, Claire Join-Lambert, Pierre-Yves Garcia, Isabelle Serre, Jean-Marc Faucheux, Fatia Radji, Elena Leca-Radu, Thomas Debroucker, Rodica Cumurcuc, Serkan Cakmak, Stéphane Peysson, Emmanuel Ellie, Patricia Bernady, Thierry Moulin, Paola Montiel, Eugeniu Revenco, Pierre Decavel, Elisabeth Medeiros, Myriam Bouveret, Pierre Louchart, Claudia Vaduva, Grégory Couvreur, Eric Sartori, Eric Alnajar-Carpentier, Michèle Levasseur, Jean-Philippe Neau, Xavier Vandamme, Isabelle Meresse, null Stantescu, Canan Ozsancak, Katell Beauvais, Pascal Auzou, Joséphine Amevigbe, Francis Vuillemet, Marie-Hélène Dugay-Arentz, Gabriela Carelli, Mikel Martinez, Marcel Maillet-Vioud, Jean-Pierre Escaillas, Stéphane Chapuis, Jean Tardy, Eric Manchon, Olivier Varnet, Yong-Jae Kim, Yoonkyung Chang, Tae-Jin Song, Jung-Hoon Han, Kyung Chul Noh, Eun-Jae Lee, Dong-Wha Kang, Sun Uck Kwon, Boseoung Kwon, Seongho Park, Dongwhane Lee, Hyuk Sung Kwon, Daeun Jeong, MinHwan Lee, Joonggoo Kim, Hanbin Lee, Hyo Jung Nam, Sang Hun Lee, Bum Joon Kim, Jae-kwan Cha, DaeHyun Kim, Rae Young Kim, Sang Wuk Sohn, Dong-Hyun Shim, Hyungjin Lee, Hyun-Wook Nah, Sang Min Sung, Kyung Bok Lee, Jeong Yoon Lee, Jee Eun Yoon, Eung-Gyu Kim, Jung Hwa Seo, Yong-Won Kim, Yangha Hwang, Man Seok Park, Joon-Tae Kim, Kang-Ho Choi, Hyo Suk Nam, Ji Hoe Heo, Young Dae Kim, In Gun Hwang, Hyung Jong Park, Kyoung Sub Kim, Jang Hyun Baek, Dong Beom Song, Joon Sang Yoo, Jong-Moo Park, Ohyun Kwon, Woong-Woo Lee, Jung-Ju Lee, Kyusik Kang, Byung Kun Kim, Jae-Sung Lim, Mi Sun Oh, Kyung-Ho Yu, Bora Hong, Mihoon Jang, Seyoung Jang, Jung Eun Jin, Jei Kim, Hye Seon Jeong, Keun Sik Hong, Hong Kyun Park, Yong Jin Cho, Oh Young Bang, Woo-Keun Seo, Jongwon Chung, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Fibrose Inflammation Remodelage [Hôpitaux Universitaires Paris Nord Val de Seine] (DHU FIRE ), Hôpitaux Universitaires Paris Nord Val de Seine, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Asan Medical Center [Seoul], University of Ulsan, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB), Hallym University Sacred Heart Hospital [Anyang, South Korea] (HUS2H), Hôpital Pasteur [Nice] (CHU), Hospices Civils de Lyon (HCL), Université de Lyon, Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Royal Brompton Hospital, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Treat Stroke to Target Investigators: Pierre-Jean Touboul, Didier Leys, Yannick Béjot, Philippa Lavallée, Fernando Pico, Emmanuel Touzé, Gregory Ducrocq, Jérémy Abtan, Olivier Varenne, Pierre-Jean Touboul, Agnes Kemmel, Fausta Syana, Manele Ledra, Tharani Nagasara, Mervette Ledjeroud, Bahous Samia, Hafirassou Hadia, Benyoub Hazare, Ikrame El Jaghouni, Nessima Yelles, Sofia Zemouri, Mervette Ladjeroud, Salim Kerai, Yun Jeong In, Elena Meseguer, Philippa C Lavallée, Cristina Hobeanu, Celine Guidoux, Lucie Cabrejo, Bertrand Lapergue, Candice Sabben, Jaime Gonzalez-Valcarcel, Ricardo Rigual, Gaia Sirimarco, Anna Martin-Bechet, Elena Viedma, Ioan Avram, Yves Samson, Charlotte Rosso, Sophie Crozier, Sara Leder, Anne Léger, Sandrine Deltour, Gurkan Mutlu, Marion Yger, Chiara Zavanone, Flore Baronnet, Christine Pires, Bertrand Lapergue, Adrien Wang, Serge Evrard, Maya Tchikviladze, Frédéric Bourdain, Delphine Lopez, Fernando Pico, Laetitia Bayon de la Tour, Marie-Laure Chadenat, Duc Long Duong, Solène Genty, Catherine Hirel, Gurkan Mutlu, Chantal Nifle, Jérôme Servan, Daniela Stanciu, Veronica Sudacevschi, Mélissa Tir, Anne-Cécile Troussière, Jennifer Yeung, Anne-Céline Zeghoudi, Ikram Tidafi-Bayou, Sylvain Lachaud, Tae-Hee Cho, Laura Mechtouff, Thomas Ritzenthaller, Laurent Derex, Carlo Albanesi, Elodie Ong, Amandine Benoit, Nadia Berhoune, Sandra Felix, Maud Esteban-Mader, Igor Sibon, Annabelle Kazadi, François Rouanet, Pauline Renou, Sabrina Debruxelles, Mathilde Poli, Sharmila Sagnier, Jean-Louis Mas, Valérie Domigo, Catherine Lamy, Eric Bodiguel, Jérôme Grimaud, Valentin Bohotin, Michael Obadia, Candice Sabben, Erwan Morvan, Gilles Rodier, Wilfried Vadot, Hilde Hénon, Charlotte Cordonnier, Frédéric Dumont, Marie Bodenant, Christian Lucas, Solène Moulin, Nelly Dequatre, Sonia Alamowitch, Jean-Paul Muresan, Thomas Drouet, Magalie Gallea, Marie-Amélie Dalloz, Stephen Delorme, Marion Yger, Yannick Béjot, Philippe Loisel, Carine Bonnin, Virginie Bernigal, Guy Victor Osseby, Marie Hervieu-Bègue Marsac, Pierre Garnier, Sandrine Accassat, Magali Epinat, Jérôme Varvat, Doïna Marinescu, Aude Triquenot-Bagan, Ozlem Ozkul-Wermester, Frédéric Philippeau, Angel Olaru, Anne Vieillart, Annie Lannuzel, Alice Demoly, Valérie Wolff, Mihaela Diaconu, Marc Bataillard, Francisco Macian Montoro, Frédéric Faugeras, Laeticia Gimenez, Françoise Abdallah-Lebeau, Serge Timsit, Irina Viakhireva-Dovganyuk, Anne Tirel-Badets, François-Mathias Merrien, Philippe Goas, François Rouhart, Aurore Jourdain, Benoit Guillon, Fanny Hérissson, Mathieu Sevin-Allouet, Nathalie Nasr, Jean-Marc Olivot, Alderic Lecluse, Guillaume Marc, Emmanuel Touzé, Vincent de la Sayette, Marion Apoil, Li Lin, Julien Cogez, Sophie Guettier, Olivier Godefroy, Chantal Lamy, Jean-Marc Bugnicourt, Grégory Taurin, Marc Mérienne, Julien Gere, Anne-Marie Chessak, Tarik Habet, Anna Ferrier, Nathalie Bourgois, Dominique Minier, Marie Caillier-Minier, Fabienne Contégal-Callier, Philippe Vion, Yvan Vaschalde, Mohammed El Amrani Emilie, Mathieu Zuber, Marie Bruandet, Claire Join-Lambert, Pierre-Yves Garcia, Isabelle Serre, Jean-Marc Faucheux, Fatia Radji, Elena Leca-Radu, Thomas Debroucker, Rodica Cumurcuc, Serkan Cakmak, Stéphane Peysson, Emmanuel Ellie, Patricia Bernady, Thierry Moulin, Paola Montiel, Eugeniu Revenco, Pierre Decavel, Elisabeth Medeiros, Myriam Bouveret, Pierre Louchart, Claudia Vaduva, Grégory Couvreur, Eric Sartori, Eric Alnajar-Carpentier, Michèle Levasseur, Pierre Louchart, Jean-Philippe Neau, Xavier Vandamme, Isabelle Meresse, Stantescu, Marc Bataillard, Canan Ozsancak, Katell Beauvais, Pascal Auzou, Joséphine Amevigbe, Francis Vuillemet, Marie-Hélène Dugay-Arentz, Gabriela Carelli, Mikel Martinez, Marcel Maillet-Vioud, Jean-Pierre Escaillas, Stéphane Chapuis, Jean Tardy, Eric Manchon, Olivier Varnet, Yong-Jae Kim, Yoonkyung Chang, Tae-Jin Song, Jung-Hoon Han, Kyung Chul Noh, Eun-Jae Lee, Dong-Wha Kang, Sun Uck Kwon, Boseoung Kwon, Seongho Park, Dongwhane Lee, Hyuk Sung Kwon, Daeun Jeong, MinHwan Lee, Joonggoo Kim, Hanbin Lee, Hyo Jung Nam, Sang Hun Lee, Bum Joon Kim, Jae-Kwan Cha, DaeHyun Kim, Rae Young Kim, Sang Wuk Sohn, Dong-Hyun Shim, Hyungjin Lee, Hyun-Wook Nah, Sang Min Sung, Kyung Bok Lee, Jeong Yoon Lee, Jee Eun Yoon, Eung-Gyu Kim, Jung Hwa Seo, Yong-Won Kim, Yangha Hwang, Man Seok Park, Joon-Tae Kim, Kang-Ho Choi, Hyo Suk Nam, Ji Hoe Heo, Young Dae Kim, In Gun Hwang, Hyung Jong Park, Kyoung Sub Kim, Jang Hyun Baek, Dong Beom Song, Joon Sang Yoo, Jong-Moo Park, Ohyun Kwon, Woong-Woo Lee, Jung-Ju Lee, Kyusik Kang, Byung Kun Kim, Jae-Sung Lim, Mi Sun Oh, Kyung-Ho Yu, Bora Hong, Mihoon Jang, Seyoung Jang, Jung Eun Jin, Jei Kim, Hye Seon Jeong, Keun Sik Hong, Hong Kyun Park, Yong Jin Cho, Oh Young Bang, Woo-Keun Seo, Jongwon Chung, and UPJV, BU Santé

Subjects
Male, medicine.medical_specialty, Statin, Time Factors, medicine.drug_class, [SDV]Life Sciences [q-bio], Brain Ischemia, LDL, chemistry.chemical_compound, Drug Delivery Systems, Ezetimibe, Internal medicine, medicine, Clinical endpoint, Humans, angiography, Myocardial infarction, Stroke, Aged, Advanced and Specialized Nursing, Cerebral infarction, Cholesterol, business.industry, Anticholesteremic Agents, informed consent, cholesterol, Cholesterol, LDL, Middle Aged, medicine.disease, stroke, [SDV] Life Sciences [q-bio], aorta, chemistry, Number needed to treat, Cardiology, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract

Background and Purpose— The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of 4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods— One thousand seventy-three French patients were assigned to Results— After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57–0.94]; P =0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% ( P =0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% ( P =0.023). The primary outcome or intracranial hemorrhage was reduced by 25% ( P =0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53–2.62]; P =0.70). Conclusions— After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875.

Published
2020
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131. More than carriers, orosomucoids are key metabolic modulators.

Author

Heo MJ, Cheon I, and Kim KH

Abstract

Orosomucoids (ORMs) have historically been considered as carriers involved in drug and lipid delivery. However, recent studies indicate ORM2 as a hepatokine involved in metabolic regulation. Here, we highlight the functions of ORM2 in controlling metabolic health and disease, focusing on its newly discovered regulatory mechanisms., Competing Interests: Declaration of interests All authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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132. Hepatic Nuclear Receptors in Cholestasis-to-Cholangiocarcinoma Pathology.

Author

Cheon I, Kim M, Kim KH, and Ko S

Abstract

Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. We explore their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, we introduce available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discuss the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease., Competing Interests: Disclosure Statement None declared., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
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133. Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury.

Author

Yang Y, Xu L, Atkins C, Kuhlman L, Zhao J, Jeong JM, Wen Y, Moreno N, Kim KH, An YA, Wang F, Bynon S, Villani V, Gao B, Brombacher F, Harris R, Eltzschig HK, Jacobsen E, and Ju C

Subjects
Animals, Mice, Liver pathology, Liver metabolism, Liver blood supply, Hepatocytes metabolism, Interleukin-13 metabolism, Adoptive Transfer, Mice, Inbred C57BL, Heparin-binding EGF-like Growth Factor metabolism, Heparin-binding EGF-like Growth Factor genetics, Liver Regeneration physiology, Reperfusion Injury metabolism, Interleukin-4 metabolism, Eosinophils metabolism, Macrophages metabolism
Abstract

Objective: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair., Design: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf)., Result: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury., Conclusion: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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134. Inhibition of acid rock drainage with iron-silicate or phosphate film: in rainy and submerged environments.

Author

Kang CU, Kang J, Kim KH, Lee JH, Park SS, Kim SJ, and Jo H

Subjects
Acid Rain, Sulfides chemistry, Hydrogen Peroxide chemistry, Ferric Compounds chemistry, Silicates chemistry, Iron chemistry, Phosphates chemistry, Oxidation-Reduction
Abstract

Iron phosphate-based coating and iron silicate-based coating were used to inhibit the oxidation of sulfide minerals in rainy and submerged environments. The inhibiting effectiveness of coating agents on the oxidation of iron sulfide minerals was investigated using pyrite and rock samples resulting from acid drainage. The film formed with both surface-coating agents was identified by pyrite surface analysis. It was also confirmed that the formation of coatings varies depending on the crystallographic orientation. The inhibitory effects under rainy and submerged conditions were investigated using column experiments. Submerged conditions accelerated deterioration compared to that under rainy conditions. Iron phosphate coating had a significantly better oxidation-inhibitory effect (84.86-98.70%) than iron silicate coating (56.80-92.36%), and at a concentration of 300 mM, H + elution was inhibited by more than 90% throughout the experiment. Furthermore, methods for effective film formation were investigated in terms of producing Fe 3+ ; (1) application of coating agents mixed with oxidant (H 2 O 2 ), (2) application of coating agent after the use of the oxidant. In a rainy environment, applying iron phosphate-based coating using the sequential method showed oxidation inhibition effects for cycles 1-9, whereas applying the mixed material showed effects for cycles 9-13. The use of a surface-coating agent after applying an oxidant did not inhibit oxidation. The surface coating agent and the oxidizing agent should be applied as a mixture to form a film., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Published
2024
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135. Updates on the Immune Cell Basis of Hepatic Ischemia-Reperfusion Injury.

Author

Heo MJ, Suh JH, Poulsen KL, Ju C, and Kim KH

Subjects
Humans, Inflammation, Killer Cells, Natural, Macrophages, Liver, Reperfusion Injury
Abstract

Liver ischemia-reperfusion injury (IRI) is the main cause of organ dysfunction and failure after liver surgeries including organ transplantation. The mechanism of liver IRI is complex and numerous signals are involved but cellular metabolic disturbances, oxidative stress, and inflammation are considered the major contributors to liver IRI. In addition, the activation of inflammatory signals exacerbates liver IRI by recruiting macrophages, dendritic cells, and neutrophils, and activating NK cells, NKT cells, and cytotoxic T cells. Technological advances enable us to understand the role of specific immune cells during liver IRI. Accordingly, therapeutic strategies to prevent or treat liver IRI have been proposed but no definitive and effective therapies exist yet. This review summarizes the current update on the immune cell functions and discusses therapeutic potentials in liver IRI. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.

Published
2023
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136. Coagulopathy in Malnourished Mice Is Sexually Dimorphic and Regulated by Nutrient-Sensing Nuclear Receptors.

Author

Preidis GA, Soni KG, Suh JH, Halder T, Kim KH, Choi JM, Li F, Devaraj S, Conner ME, Coarfa C, Jung SY, and Moore DD

Abstract

Liver dysfunction, including coagulopathy, is a prominent feature of protein-energy malnutrition. To identify mechanisms underlying malnutrition-associated coagulopathy, we administered a low-protein low-fat diet to lactating dams and examined hepatic transcription and plasma coagulation parameters in young adult weanlings. Malnutrition impacted body composition to a greater extent in male versus female mice. Transcriptional profiles suggested opposing effects of nutrient-sensing nuclear receptors, namely induction of peroxisome proliferator-activated receptor α (PPARα) targets and repression of farnesoid-X-receptor (FXR) targets. Coagulopathy with decreased synthesis of fibrinogen-α (FGA) and factor 11 (F11) was observed in malnourished male animals but not female animals. In primary mouse hepatocytes, FXR agonist increased and PPARα agonist decreased Fga and F11 messenger RNA expression. Nuclear receptor DNA response elements were identified in the Fga and F11 gene regulatory regions, and opposing effects of FXR and PPARα were confirmed with luciferase assays. Unexpectedly, hepatic PPARα protein was markedly depleted in malnourished male liver and was not enriched on Fga or F11 response elements. Rather, there was loss of FXR binding at these response elements. Reduced PPARα protein was associated with loss of hepatocyte peroxisomes, which are necessary for bile acid biosynthesis, and with decreased concentrations of bile acids that function as FXR ligands, most notably the FXR agonist chenodeoxycholic acid. Conclusion : Malnutrition impairs growth and liver synthetic function more severely in male mice than in female mice. Malnourished male mice are coagulopathic and exhibit decreased hepatocyte peroxisomes, FXR agonist bile acids, FXR binding on Fga and F11 gene regulatory elements, and coagulation factor synthesis. These effects are absent in female mice, which have low baseline levels of PPARα, suggesting that nutrient-sensing nuclear receptors regulate coagulation factor synthesis in response to host nutritional status in a sex-specific manner., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Published
2020
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137. Epigenome environment interactions accelerate epigenomic aging and unlock metabolically restricted epigenetic reprogramming in adulthood.

Author

Treviño LS, Dong J, Kaushal A, Katz TA, Jangid RK, Robertson MJ, Grimm SL, Ambati CSR, Putluri V, Cox AR, Kim KH, May TD, Gallo MR, Moore DD, Hartig SM, Foulds CE, Putluri N, Coarfa C, and Walker CL

Subjects
Animals, DNA Methylation drug effects, DNA Methylation genetics, Early Growth Response Protein 1 genetics, Endocrine Disruptors toxicity, Epigenesis, Genetic drug effects, Epigenesis, Genetic genetics, Epigenomics methods, Female, Gene-Environment Interaction, Genome-Wide Association Study, Male, Rats, Epigenome genetics
Abstract

Our early-life environment has a profound influence on developing organs that impacts metabolic function and determines disease susceptibility across the life-course. Using a rat model for exposure to an endocrine disrupting chemical (EDC), we show that early-life chemical exposure causes metabolic dysfunction in adulthood and reprograms histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature. This epigenomic reprogramming persists long after the initial exposure, but many reprogrammed genes remain transcriptionally silent with their impact on metabolism not revealed until a later life exposure to a Western-style diet. Diet-dependent metabolic disruption was largely driven by reprogramming of the Early Growth Response 1 (EGR1) transcriptome and production of metabolites in pathways linked to cholesterol, lipid and one-carbon metabolism. These findings demonstrate the importance of epigenome:environment interactions, which early in life accelerate epigenomic aging, and later in adulthood unlock metabolically restricted epigenetic reprogramming to drive metabolic dysfunction.

Published
2020
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138. Protective role of cardiac-specific overexpression of caveolin-3 in cirrhotic cardiomyopathy.

Author

Kim SY, Kim KH, Schilling JM, Leem J, Dhanani M, Head BP, Roth DM, Zemljic-Harpf AE, and Patel HH

Subjects
Action Potentials, Animals, Cardiomyopathies pathology, Cardiomyopathies physiopathology, Cardiomyopathies prevention & control, Caveolin 3 genetics, Disease Models, Animal, Heart Rate, Isolated Heart Preparation, Liver Cirrhosis, Biliary chemically induced, Liver Cirrhosis, Biliary pathology, Male, Mice, Inbred C57BL, Mice, Transgenic, Myocardial Contraction, Myocardium pathology, Pyridines, Signal Transduction, Time Factors, Up-Regulation, Cardiomyopathies metabolism, Caveolin 3 metabolism, Liver Cirrhosis, Biliary metabolism, Myocardium metabolism
Abstract

Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TG neg ) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TG neg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TG neg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TG neg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TG neg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis. NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for successful liver transplantation. This study shows cardiac myocyte specific overexpression of caveolin-3 (Cav-3) provides better cardiac contractile responses and less corrected QT prolongation during adrenergic stress in a cirrhotic cardiomyopathy model, suggesting beneficial effects of Cav-3 expression in cirrhotic cardiomyopathy.

Published
2020
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139. Methyl-Sensing Nuclear Receptor Liver Receptor Homolog-1 Regulates Mitochondrial Function in Mouse Hepatocytes.

Author

Choi S, Dong B, Lin CJ, Heo MJ, Kim KH, Sun Z, Wagner M, Putluri N, Suh JM, Wang MC, and Moore DD

Subjects
Animals, Hep G2 Cells, Humans, Male, Mice, Oxidation-Reduction, S-Adenosylmethionine metabolism, S-Adenosylmethionine pharmacology, Hepatocytes metabolism, Mitochondria physiology, Phosphatidylethanolamine N-Methyltransferase physiology, Receptors, Cytoplasmic and Nuclear physiology
Abstract

Background and Aims: Liver receptor homolog-1 (LRH-1; NR5A2) is a nuclear receptor that regulates metabolic homeostasis in the liver. Previous studies identified phosphatidylcholines as potential endogenous agonist ligands for LRH-1. In the liver, distinct subsets of phosphatidylcholine species are generated by two different pathways: choline addition to phosphatidic acid through the Kennedy pathway and trimethylation of phosphatidylethanolamine through phosphatidylethanolamine N-methyl transferase (PEMT)., Approach and Results: Here, we report that a PEMT-LRH-1 pathway specifically couples methyl metabolism and mitochondrial activities in hepatocytes. We show that the loss of Lrh-1 reduces mitochondrial number, basal respiration, beta-oxidation, and adenosine triphosphate production in hepatocytes and decreases expression of mitochondrial biogenesis and beta-oxidation genes. In contrast, activation of LRH-1 by its phosphatidylcholine agonists exerts opposite effects. While disruption of the Kennedy pathway does not affect the LRH-1-mediated regulation of mitochondrial activities, genetic or pharmaceutical inhibition of the PEMT pathway recapitulates the effects of Lrh-1 knockdown on mitochondria. Furthermore, we show that S-adenosyl methionine, a cofactor required for PEMT, is sufficient to induce Lrh-1 transactivation and consequently mitochondrial biogenesis., Conclusions: A PEMT-LRH-1 axis regulates mitochondrial biogenesis and beta-oxidation in hepatocytes., (© 2019 by the American Association for the Study of Liver Diseases.)

Published
2020
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140. Metabolic dysregulation in the Atp7b -/- Wilson's disease mouse model.

Author

Wooton-Kee CR, Robertson M, Zhou Y, Dong B, Sun Z, Kim KH, Liu H, Xu Y, Putluri N, Saha P, Coarfa C, Moore DD, and Nuotio-Antar AM

Subjects
Animals, Copper-Transporting ATPases genetics, Disease Models, Animal, Female, Glucose metabolism, Hepatolenticular Degeneration genetics, Hepatolenticular Degeneration metabolism, Humans, Insulin Resistance, Liver metabolism, Male, Metabolome, Mice, Mice, Inbred C57BL, Mice, Knockout, Copper-Transporting ATPases metabolism, Hepatolenticular Degeneration enzymology
Abstract

Inactivating mutations in the copper transporter Atp7b result in Wilson's disease. The Atp7b -/- mouse develops hallmarks of Wilson's disease. The activity of several nuclear receptors decreased in Atp7b -/- mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b -/- mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography-mass spectrometry and correlated with transcriptomic data. Atp7b -/- mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, Atp7b -/- mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. Atp7b -/- mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b -/- mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b -/- mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b -/- mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in Atp7b -/- mice., Competing Interests: The authors declare no competing interest.

Published
2020
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141. Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice.

Author

Kim KH, Choi S, Zhou Y, Kim EY, Lee JM, Saha PK, Anakk S, and Moore DD

Subjects
Aging genetics, Analysis of Variance, Animals, Autophagy genetics, Cells, Cultured, Disease Models, Animal, Glucose metabolism, Hepatocytes cytology, Hepatocytes metabolism, Lipid Metabolism genetics, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Random Allocation, Fatty Acids metabolism, Gene Deletion, Gene Expression Regulation, Homeostasis genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 6 genetics, Receptors, Cytoplasmic and Nuclear genetics
Abstract

The nuclear receptors farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP; NR0B2) play crucial roles in bile acid homeostasis. Global double knockout of FXR and SHP signaling (DKO) causes severe cholestasis and liver injury at early ages. Here, we report an unexpected beneficial impact on glucose and fatty acid metabolism in aged DKO mice, which show suppressed body weight gain and adiposity when maintained on normal chow. This phenotype was not observed in single Fxr or Shp knockouts. Liver-specific Fxr/Shp double knockout mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance, and accelerated fatty acid use. In both DKO and liver-specific Fxr/Shp double knockout livers, these metabolic phenotypes were associated with altered expression of fatty acid metabolism and autophagy-machinery genes. Loss of the hepatic FXR/SHP axis reprogrammed white and brown adipose tissue gene expression to boost fatty acid usage., Conclusion: Combined deletion of the hepatic FXR/SHP axis improves glucose/fatty acid homeostasis in aged mice, reversing the aging phenotype of body weight gain, increased adiposity, and glucose/insulin tolerance, suggesting a central role of this axis in whole-body energy homeostasis. (Hepatology 2017;66:498-509)., (© 2017 by the American Association for the Study of Liver Diseases.)

Published
2017
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142. Genetically-engineered human neural stem cells with rabbit carboxyl esterase can target CNS lymphoma.

Author

Kang W, Jin J, Yang H, Seol HJ, Kim KH, Lee JI, Kim SU, Joo KM, and Nam DH

Subjects
Animals, Antineoplastic Agents, Phytogenic, Base Sequence, Bystander Effect, Camptothecin analogs & derivatives, Camptothecin pharmacology, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms pathology, DNA Primers, Humans, Irinotecan, Lymphoma drug therapy, Lymphoma pathology, Male, Mice, Mice, Inbred BALB C, Neural Stem Cells enzymology, Rabbits, Reverse Transcriptase Polymerase Chain Reaction, Carboxylesterase genetics, Central Nervous System Neoplasms therapy, Genetic Engineering, Lymphoma therapy, Neural Stem Cells cytology
Abstract

Background: Despite advances in its treatment, CNS lymphoma remains a devastating disease. Taking advantage of the tumour-tropic properties of neural stem cells (NSCs) is a novel therapeutic strategy. To apply this strategy to the treatment of CNS lymphoma, we investigated the role of NSCs expressing carboxyl esterase (HB1.F3.CE), which activates irinotecan., Materials and Methods: In order to find in vitro bystander effects of engineered NSCs, we performed cell viability assays. In vivo, the HB1.F3.CE cells were injected into the brain of mice with orthotopic CNS lymphoma. Mice were then treated with irinotecan by systemic administration., Results: The HB1.F3.CE cells significantly inhibited the growth of Raji cells with irinotecan treatment. In vivo, the HB1.F3.CE cells migrated into the tumour and significantly reduced tumour volume. In addition, survival of mice was prolonged by treatment with HB1.F3.CE and irinotecan., Conclusion: Transplantation of human NSCs encoding CE into brain, combined with irinotecan therapy, may be an effective treatment regimen for CNS lymphoma.

Published
2013

143. Melanocortin 4 receptors interact with antimicrobial frog peptide analogues.

Author

Do EU, Jo EB, Choi G, Piao LZ, Shin J, Seo MD, Kang SJ, Lee BJ, Kim KH, Kim JB, and Kim SI

Subjects
Animals, Binding, Competitive, Cell Line, Cyclic AMP metabolism, Fluorescence Polarization, Genes, Reporter, Humans, Ligands, Plant Extracts pharmacology, Ranidae, Receptor, Melanocortin, Type 4 agonists, Receptor, Melanocortin, Type 4 antagonists & inhibitors, Recombinant Proteins agonists, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins metabolism, alpha-MSH pharmacology, Antimicrobial Cationic Peptides pharmacology, Melanocyte-Stimulating Hormones pharmacology, Oligopeptides pharmacology, Receptor, Melanocortin, Type 4 metabolism, alpha-MSH analogs & derivatives
Abstract

We have developed fluorescence polarization (FP) assays of human melanocortin 4 receptor (MC4R) in 384-well microtiter plates using TAMRA-NDP-MSH as a tracer. The rank order of potency of agonists and antagonists agrees well relative to the published assays: SHU9119>MTII>NDP alphaMSH>alphaMSH. We have screened libraries of Korean plant extracts and frog peptide analogues in search of MC4R ligands using FP assays and cell-based CRE luciferase reporter assays. We report that FLGFLFKVASK, FLGWLFKVASK, FLGALFKWASK, and FLGWLFKWASK are the peptide analogues, which bind to human MC4R receptor with good affinity in vitro. FLGWLFKVASK and FLGWLFKWASK stimulated CRE-driven reporter gene via MC4R. In luciferase reporter assays, they possess the pharmacological and functional profiles of full agonists. We demonstrate the interaction of MC4R with 11-residue antimicrobial peptides derived from the Korean frog, Rana rugosa. The results suggest that MC4R interacts promiscuously with bioactive analogues of antimicrobial peptide, gaegurin-5.

Published
2006
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