Nature Medicine - AOP - nature.com science feeds Nature Medicine is the premier journal for biomedical research. Respected internationally for the quality of its papers on areas ranging from infectious disease to cancer and neurodegeneration, Nature Medicine aims to bridge the gap between basic research and medical advances and is consistently ranked the number one journal by the Institute of Scientific Investigation in the Medicine, Research and Experimental category. http://www.nature.com/nm/current_issue/ Nature Publishing Group en © Nature Publishing Group Nature Medicine 1078-8956 1546-170X © Nature Publishing Group permissions@nature.com Nature Medicine http://www.nature.com/includes/rj_globnavimages/nm_logo.gif http://www.nature.com/nm/ A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome http://feeds.nature.com/~r/nm/rss/aop/~3/A_qnH2DQGn0/nm.2063 In individuals with 5q– syndrome, deletion within chromosome 5q is associated with hematological abnormalities. Jillian Barlow et al. now create an animal model of the disease using chromosomal engineering to remove a corresponding region of the mouse genome. The resulting hematological abnormalities resemble those in the human disease, and the authors provide genetic evidence that p53 activation contributes to the disease process. Advertisment

A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome

Nature Medicine. doi:10.1038/nm.2063

Authors: Jillian L Barlow, Lesley F Drynan, Duncan R Hewett, Luke R Holmes, Silvia Lorenzo-Abalde, Alison L Lane, Helen E Jolin, Richard Pannell, Angela J Middleton, See Heng Wong, Alan J Warren, James S Wainscoat, Jacqueline Boultwood & Andrew N J McKenzie

]]> A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome Jillian L Barlow Lesley F Drynan Duncan R Hewett Luke R Holmes Silvia Lorenzo-Abalde Alison L Lane Helen E Jolin Richard Pannell Angela J Middleton See Heng Wong Alan J Warren James S Wainscoat Jacqueline Boultwood Andrew N J McKenzie doi:10.1038/nm.2063 Nature Medicine 2009-11-22 Nature Medicine 2009-11-22 10.1038/nm.2063 http://dx.doi.org/10.1038/nm.2063 Article http://dx.doi.org/10.1038/nm.2063 A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6–dependent B cell lymphomas http://feeds.nature.com/~r/nm/rss/aop/~3/y1rlLWKfnxI/nm.2059 By taking advantage of the direct interaction between heat shock protein 90 (Hsp90) and the transcriptional repressor Bcl-6, a purine-derived inhibitor of Hsp90 selectively kills diffuse large B cell lymphomas that depend on the expression of Bcl-6 for their survival. A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6–dependent B cell lymphomas

Nature Medicine. doi:10.1038/nm.2059

Authors: Leandro C Cerchietti, Eloisi C Lopes, Shao Ning Yang, Katerina Hatzi, Karen L Bunting, Lucas A Tsikitas, Alka Mallik, Ana I Robles, Jennifer Walling, Lyuba Varticovski, Rita Shaknovich, Kapil N Bhalla, Gabriela Chiosis & Ari Melnick

]]> A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6–dependent B cell lymphomas Leandro C Cerchietti Eloisi C Lopes Shao Ning Yang Katerina Hatzi Karen L Bunting Lucas A Tsikitas Alka Mallik Ana I Robles Jennifer Walling Lyuba Varticovski Rita Shaknovich Kapil N Bhalla Gabriela Chiosis Ari Melnick doi:10.1038/nm.2059 Nature Medicine 2009-11-22 Nature Medicine 2009-11-22 10.1038/nm.2059 http://dx.doi.org/10.1038/nm.2059 Article http://dx.doi.org/10.1038/nm.2059 Enhanced tonic GABAA inhibition in typical absence epilepsy http://feeds.nature.com/~r/nm/rss/aop/~3/5c2jtBeKCDo/nm.2058 Contrary to the widely held view that impaired γ-aminobutyric acid (GABA)-mediated neurotransmission underlies epileptic activity, extrasynaptic GABA-dependent thalamocortical inhibition caused by reduced GABA uptake is reported to be increased in diverse models of absence seizures. Enhanced tonic GABAA inhibition in typical absence epilepsy

Nature Medicine. doi:10.1038/nm.2058

Authors: David W Cope, Giuseppe Di Giovanni, Sarah J Fyson, Gergely Orbán, Adam C Errington, Magor L Lőrincz, Timothy M Gould, David A Carter & Vincenzo Crunelli

]]> Enhanced tonic GABAA inhibition in typical absence epilepsy David W Cope Giuseppe Di Giovanni Sarah J Fyson Gergely Orbán Adam C Errington Magor L Lőrincz Timothy M Gould David A Carter Vincenzo Crunelli doi:10.1038/nm.2058 Nature Medicine 2009-11-22 Nature Medicine 2009-11-22 10.1038/nm.2058 http://dx.doi.org/10.1038/nm.2058 Article http://dx.doi.org/10.1038/nm.2058 Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury http://feeds.nature.com/~r/nm/rss/aop/~3/w6i3zMajEdc/nm.2062 Gallo and his colleagues report that commensal bacteria on the skin help to dampen inflammation caused by skin injury in mice. They show that, after wounding, necrotic cells release RNA that triggers TLR3 on keratinocytes, causing inflammatory cytokine release. Commensal bacteria in the skin suppress this inflammatory response through triggering TLR2 on the keratinocytes. Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury

Nature Medicine. doi:10.1038/nm.2062

Authors: Yuping Lai, Anna Di Nardo, Teruaki Nakatsuji, Anke Leichtle, Yan Yang, Anna L Cogen, Zi-Rong Wu, Lora V Hooper, Richard R Schmidt, Sonja von Aulock, Katherine A Radek, Chun-Ming Huang, Allen F Ryan & Richard L Gallo

]]> Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury Yuping Lai Anna Di Nardo Teruaki Nakatsuji Anke Leichtle Yan Yang Anna L Cogen Zi-Rong Wu Lora V Hooper Richard R Schmidt Sonja von Aulock Katherine A Radek Chun-Ming Huang Allen F Ryan Richard L Gallo doi:10.1038/nm.2062 Nature Medicine 2009-11-22 Nature Medicine 2009-11-22 10.1038/nm.2062 http://dx.doi.org/10.1038/nm.2062 Article http://dx.doi.org/10.1038/nm.2062 Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries http://feeds.nature.com/~r/nm/rss/aop/~3/8wIad6k3Eq8/nm.2064 Excitotoxicity mediated by over activation of glutamate receptors results in neuronal loss after ischemia. Activation of sterol regulatory element–binding protein-1 is now shown to be crucial for glutamate-mediated excitotoxic neuronal death in a mouse model of stroke. Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries

Nature Medicine. doi:10.1038/nm.2064

Authors: Changiz Taghibiglou, Henry G S Martin, Ted Weita Lai, Taesup Cho, Shiv Prasad, Luba Kojic, Jie Lu, Yitao Liu, Edmund Lo, Shu Zhang, Julia Z Z Wu, Yu Ping Li, Yan Hua Wen, Joon-Hyuk Imm, Max S Cynader & Yu Tian Wang

]]> Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries Changiz Taghibiglou Henry G S Martin Ted Weita Lai Taesup Cho Shiv Prasad Luba Kojic Jie Lu Yitao Liu Edmund Lo Shu Zhang Julia Z Z Wu Yu Ping Li Yan Hua Wen Joon-Hyuk Imm Max S Cynader Yu Tian Wang doi:10.1038/nm.2064 Nature Medicine 2009-11-22 Nature Medicine 2009-11-22 10.1038/nm.2064 http://dx.doi.org/10.1038/nm.2064 Article http://dx.doi.org/10.1038/nm.2064 Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin http://feeds.nature.com/~r/nm/rss/aop/~3/7mSXj8a58og/nm.2056 In a mouse model of Huntington's disease, synaptic activation of NMDA receptors induces the formation of huntingtin-containing inclusions, rendering neurons more resistant to death in vivo and in vitro. In contrast, stimulation of extrasynaptic NMDA receptors increases neuronal vulnerability by preventing inclusion formation. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin

Nature Medicine. doi:10.1038/nm.2056

Authors: Shu-ichi Okamoto, Mahmoud A Pouladi, Maria Talantova, Dongdong Yao, Peng Xia, Dagmar E Ehrnhoefer, Rameez Zaidi, Arjay Clemente, Marcus Kaul, Rona K Graham, Dongxian Zhang, H-S Vincent Chen, Gary Tong, Michael R Hayden & Stuart A Lipton

]]> Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin Shu-ichi Okamoto Mahmoud A Pouladi Maria Talantova Dongdong Yao Peng Xia Dagmar E Ehrnhoefer Rameez Zaidi Arjay Clemente Marcus Kaul Rona K Graham Dongxian Zhang H-S Vincent Chen Gary Tong Michael R Hayden Stuart A Lipton doi:10.1038/nm.2056 Nature Medicine 2009-11-15 Nature Medicine 2009-11-15 10.1038/nm.2056 http://dx.doi.org/10.1038/nm.2056 Article http://dx.doi.org/10.1038/nm.2056 Synovial fibroblasts spread rheumatoid arthritis to unaffected joints http://feeds.nature.com/~r/nm/rss/aop/~3/Zv2Lbx-e-aI/nm.2050 Rheumatoid arthritis usually begins in one joint but spreads to other joints as the disease progresses. Elena Neumann and her colleagues show that rheumatoid arthritis synovial fibroblasts (RASFs) may be key mediators of this process. They show, using a SCID mouse model, that human RASFs can migrate long distances through the bloodstream from diseased cartilage to unaffected cartilage, where they can mount a new attack. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints

Nature Medicine. doi:10.1038/nm.2050

Authors: Stephanie Lefèvre, Anette Knedla, Christoph Tennie, Andreas Kampmann, Christina Wunrau, Robert Dinser, Adelheid Korb, Eva-Maria Schnäker, Ingo H Tarner, Paul D Robbins, Christopher H Evans, Henning Stürz, Jürgen Steinmeyer, Steffen Gay, Jürgen Schölmerich, Thomas Pap, Ulf Müller-Ladner & Elena Neumann

]]> Synovial fibroblasts spread rheumatoid arthritis to unaffected joints Stephanie Lefèvre Anette Knedla Christoph Tennie Andreas Kampmann Christina Wunrau Robert Dinser Adelheid Korb Eva-Maria Schnäker Ingo H Tarner Paul D Robbins Christopher H Evans Henning Stürz Jürgen Steinmeyer Steffen Gay Jürgen Schölmerich Thomas Pap Ulf Müller-Ladner Elena Neumann doi:10.1038/nm.2050 Nature Medicine 2009-11-08 Nature Medicine 2009-11-08 10.1038/nm.2050 http://dx.doi.org/10.1038/nm.2050 Article http://dx.doi.org/10.1038/nm.2050 Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype http://feeds.nature.com/~r/nm/rss/aop/~3/Tkv_mvOz7eI/nm.2054 For myelodysplastic syndromes caused by deletion of chromosome 5q, Daniel Starczynowski et al. provide evidence that decreased expression of two miRNAs in this region—miR-145 and miR-146a—contributes to abnormal megakaryocyte differentiation and platelet production and progression of the disease to either bone marrow failure or leukemia. The authors also provide a mechanistic explanation for these effects by which loss of these two miRNAs leads to derepression of innate immune signaling. Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype

Nature Medicine. doi:10.1038/nm.2054

Authors: Daniel T Starczynowski, Florian Kuchenbauer, Bob Argiropoulos, Sandy Sung, Ryan Morin, Andrew Muranyi, Martin Hirst, Donna Hogge, Marco Marra, Richard A Wells, Rena Buckstein, Wan Lam, R Keith Humphries & Aly Karsan

]]> Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype Daniel T Starczynowski Florian Kuchenbauer Bob Argiropoulos Sandy Sung Ryan Morin Andrew Muranyi Martin Hirst Donna Hogge Marco Marra Richard A Wells Rena Buckstein Wan Lam R Keith Humphries Aly Karsan doi:10.1038/nm.2054 Nature Medicine 2009-11-08 Nature Medicine 2009-11-08 10.1038/nm.2054 http://dx.doi.org/10.1038/nm.2054 Article http://dx.doi.org/10.1038/nm.2054 Modulating hedgehog signaling can attenuate the severity of osteoarthritis http://feeds.nature.com/~r/nm/rss/aop/~3/geAeIyODuf8/nm.2055 In a new report, Benjamin Alman and his colleagues find that the morphogenic pathway activated by Hedgehog signaling is a key mediator of osteoarthritis, a condition that is marked by irreversible degeneration of the joints and with no current treatment. They also found that blockade of Hedgehog signaling prevented osteoarthritis in a mouse model, suggesting this pathway as a possible target to treat this devastating disease. Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Nature Medicine. doi:10.1038/nm.2055

Authors: Alvin C Lin, Brian L Seeto, Justyna M Bartoszko, Michael A Khoury, Heather Whetstone, Louisa Ho, Claire Hsu, Amanda S Ali & Benjamin A Alman

]]> Modulating hedgehog signaling can attenuate the severity of osteoarthritis Alvin C Lin Brian L Seeto Justyna M Bartoszko Michael A Khoury Heather Whetstone Louisa Ho Claire Hsu Amanda S Ali Benjamin A Alman doi:10.1038/nm.2055 Nature Medicine 2009-11-15 Nature Medicine 2009-11-15 10.1038/nm.2055 http://dx.doi.org/10.1038/nm.2055 Letter http://dx.doi.org/10.1038/nm.2055 Comprehensive genomic access to vector integration in clinical gene therapy http://feeds.nature.com/~r/nm/rss/aop/~3/YpIVovYU37I/nm.2057 Adverse events stemming from the use of retroviral vectors in humans has prompted the search for methods predicting the fate and biological consequences of gene-modified cells after vector insertion. Methods of integration site analysis, such as linear amplification-mediated PCR (LAM-PCR), rely on use of restriction enzymes and identify only a fraction of all genomic integrants. This report describes a non–restriction enzyme–based LAM-PCR technique that provides comprehensive, unbiased integration site analysis. Comprehensive genomic access to vector integration in clinical gene therapy

Nature Medicine. doi:10.1038/nm.2057

Authors: Richard Gabriel, Ralph Eckenberg, Anna Paruzynski, Cynthia C Bartholomae, Ali Nowrouzi, Anne Arens, Steven J Howe, Alessandra Recchia, Claudia Cattoglio, Wei Wang, Katrin Faber, Kerstin Schwarzwaelder, Romy Kirsten, Annette Deichmann, Claudia R Ball, Kamaljit S Balaggan, Rafael J Yáñez-Muñoz, Robin R Ali, H Bobby Gaspar, Luca Biasco, Alessandro Aiuti, Daniela Cesana, Eugenio Montini, Luigi Naldini, Odile Cohen-Haguenauer, Fulvio Mavilio, Adrian J Thrasher, Hanno Glimm, Christof von Kalle, William Saurin & Manfred Schmidt

Retroviral vectors have induced subtle clonal skewing in many gene therapy patients and severe clonal proliferation and leukemia in some of them, emphasizing the need for comprehensive integration site analyses to assess the biosafety and genomic pharmacokinetics of vectors and clonal fate of gene-modified cells in vivo. Integration site analyses such as linear amplification–mediated PCR (LAM-PCR) require a restriction digest generating unevenly small fragments of the genome. Here we show that each restriction motif allows for identification of only a fraction of all genomic integrants, hampering the understanding and prediction of biological consequences after vector insertion. We developed a model to define genomic access to the viral integration site that provides optimal restriction motif combinations and minimizes the percentage of nonaccessible insertion loci. We introduce a new nonrestrictive LAM-PCR approach that has superior capabilities for comprehensive unbiased integration site retrieval in preclinical and clinical samples independent of restriction motifs and amplification inefficiency.

]]> Comprehensive genomic access to vector integration in clinical gene therapy Richard Gabriel Ralph Eckenberg Anna Paruzynski Cynthia C Bartholomae Ali Nowrouzi Anne Arens Steven J Howe Alessandra Recchia Claudia Cattoglio Wei Wang Katrin Faber Kerstin Schwarzwaelder Romy Kirsten Annette Deichmann Claudia R Ball Kamaljit S Balaggan Rafael J Yáñez-Muñoz Robin R Ali H Bobby Gaspar Luca Biasco Alessandro Aiuti Daniela Cesana Eugenio Montini Luigi Naldini Odile Cohen-Haguenauer Fulvio Mavilio Adrian J Thrasher Hanno Glimm Christof von Kalle William Saurin Manfred Schmidt doi:10.1038/nm.2057 Nature Medicine 2009-11-22 Nature Medicine 2009-11-22 10.1038/nm.2057 http://dx.doi.org/10.1038/nm.2057 Technical Report http://dx.doi.org/10.1038/nm.2057