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Editorial

Let research bloom p539

doi:10.1038/nm.3879

Recent news of raids on research budgets illustrates how precarious government funding of scientific research has become. In an era of unprecedented momentum in the development of technologies and therapies for studying and treating disease, opportunities for new discoveries must not be lost due to shortsighted budgetary concerns.


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News

Updated, augmented vaccines compete with original antigenic sin pp540 - 541

Shraddha Chakradhar

doi:10.1038/nm0615-540


New consent requirements for newborn screening raise concerns pp542 - 543

Wudan Yan

doi:10.1038/nm0615-542


Microbiome models, on computers and in lab dishes, see progress pp543 - 544

Jop de Vrieze

doi:10.1038/nm0615-543


Binding time—not just affinity—gains stature in drug design p545

Wudan Yan

doi:10.1038/nm0615-545


News in Brief

Biomedical briefing pp546 - 547

doi:10.1038/nm0615-546


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News and Views

Regulation of immunopathology in hepatitis B virus infection pp548 - 549

Silvia Piconese & Vincenzo Barnaba

doi:10.1038/nm.3873

In the liver there is a fine balance between immune surveillance of blood-borne infections and regulation of immunopathology. A new study identifies a role for granulocytic myeloid-derived suppressor cells in limiting T cell–mediated immunopathology in hepatitis B virus infection.

See also: Article by Pallett et al.


Converting smooth muscle cells to macrophage-like cells with KLF4 in atherosclerotic plaques pp549 - 551

Michael E Rosenfeld

doi:10.1038/nm.3875

Atherosclerosis is the primary cause of heart attacks and strokes and is caused by a chronic inflammatory response in the coronary and carotid arteries. A new study shows that smooth muscle cells within atherosclerotic plaques can change phenotypes to become macrophage-like cells, thereby revealing the remarkable plasticity of these cells.

See also: Article by Shankman et al.


Unpleasant memories: tissue-embedded T cell memory drives skin hypersensitivity pp551 - 552

Thomas Gebhardt & Francis R Carbone

doi:10.1038/nm.3874

Tissue-resident memory T cells (TRM cells) protect against recurrent or renewed infection in barrier tissues such as skin and mucosa. A new study sheds light on the clonal origin of TRM cells and demonstrates a crucial role for tissue-embedded T cell memory in contact hypersensitivity in skin.

See also: Letter by Gaide et al.


Mutant PRPS1: a new therapeutic target in relapsed acute lymphoblastic leukemia pp553 - 554

Charles G Mullighan

doi:10.1038/nm.3876

A new study identifies recurrent mutations in the purine biosynthesis gene phosphoribosyl pyrophosphate synthetase 1 (PRPS1) in relapsed acute lymphoblastic leukemia (ALL). This work highlights the importance of this pathway in the pathogenesis of relapse and suggests an approach to predicting and circumventing resistance in ALL.

See also: Article by Li et al.


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Brief Communications

Functionally defined therapeutic targets in diffuse intrinsic pontine glioma pp555 - 559

Catherine S Grasso, Yujie Tang, Nathalene Truffaux, Noah E Berlow, Lining Liu, Marie-Anne Debily, Michael J Quist, Lara E Davis, Elaine C Huang, Pamelyn J Woo, Anitha Ponnuswami, Spenser Chen, Tessa B Johung, Wenchao Sun, Mari Kogiso, Yuchen Du, Lin Qi, Yulun Huang, Marianne Hütt-Cabezas, Katherine E Warren, Ludivine Le Dret, Paul S Meltzer, Hua Mao, Martha Quezado, Dannis G van Vuurden, Jinu Abraham, Maryam Fouladi, Matthew N Svalina, Nicholas Wang, Cynthia Hawkins, Javad Nazarian, Marta M Alonso, Eric H Raabe, Esther Hulleman, Paul T Spellman, Xiao-Nan Li, Charles Keller, Ranadip Pal, Jacques Grill & Michelle Monje

doi:10.1038/nm.3855

The study describes the use of integrative approaches to search for candidate therapeutic targets for DIPG, and the identification of an HDAC inhibitor as a potential treatment strategy


Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M pp560 - 562

Kenneth S Thress, Cloud P Paweletz, Enriqueta Felip, Byoung Chul Cho, Daniel Stetson, Brian Dougherty, Zhongwu Lai, Aleksandra Markovets, Ana Vivancos, Yanan Kuang, Dalia Ercan, Sarah E Matthews, Mireille Cantarini, J Carl Barrett, Pasi A Jänne & Geoffrey R Oxnard

doi:10.1038/nm.3854

A mutation conferring resistance to novel irreversible EGFR inhibitors is identified in cell-free plasma DNA from lung cancer patients.


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Articles

Negative feedback–defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL pp563 - 571

Benshang Li, Hui Li, Yun Bai, Renate Kirschner-Schwabe, Jun J Yang, Yao Chen, Gang Lu, Gannie Tzoneva, Xiaotu Ma, Tongmin Wu, Wenjing Li, Haisong Lu, Lixia Ding, Huanhuan Liang, Xiaohang Huang, Minjun Yang, Lei Jin, Hui Kang, Shuting Chen, Alicia Du, Shuhong Shen, Jianping Ding, Hongzhuan Chen, Jing Chen, Arend von Stackelberg, Longjun Gu, Jinghui Zhang, Adolfo Ferrando, Jingyan Tang, Shengyue Wang & Bin-Bing S Zhou

doi:10.1038/nm.3840

The authors uncover new mutations in an enzyme from the purine synthesis pathway that cause resistance to leukemia therapy, and reveal a new mechanism by which they affect drug metabolism.

See also: News and Views by Mullighan


The Cyclophilin A–CD147 complex promotes the proliferation and homing of multiple myeloma cells pp572 - 580

Di Zhu, Zhongqiu Wang, Jian-Jun Zhao, Teresa Calimeri, Jiang Meng, Teru Hideshima, Mariateresa Fulciniti, Yue Kang, Scott B Ficarro, Yu-Tzu Tai, Zachary Hunter, Douglas McMilin, Haoxuan Tong, Constantine S Mitsiades, Catherine J Wu, Steven P Treon, David M Dorfman, Geraldine Pinkus, Nikhil C Munshi, Pierfrancesco Tassone, Jarrod A Marto, Kenneth C Anderson & Ruben D Carrasco

doi:10.1038/nm.3867

Cyclophilin A, secreted by bone marrow endothelial cells, acts as a chemotactic factor for myeloma cells, which helps explain their homing to the bone marrow and suggests a potential new therapeutic strategy.


4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors pp581 - 590

Adrienne H Long, Waleed M Haso, Jack F Shern, Kelsey M Wanhainen, Meera Murgai, Maria Ingaramo, Jillian P Smith, Alec J Walker, M Eric Kohler, Vikas R Venkateshwara, Rosandra N Kaplan, George H Patterson, Terry J Fry, Rimas J Orentas & Crystal L Mackall

doi:10.1038/nm.3838

Crystal Mackall and colleagues report that antigen-independent signaling of chimeric antigen receptors (CARs) causes T cell exhaustion and reduced therapeutic efficacy of CAR T cells that can be overcome by incorporating the 4-1BB costimulatory domain into the CAR.


Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells pp591 - 600

Laura J Pallett, Upkar S Gill, Alberto Quaglia, Linda V Sinclair, Maria Jover-Cobos, Anna Schurich, Kasha P Singh, Niclas Thomas, Abhishek Das, Antony Chen, Giuseppe Fusai, Antonio Bertoletti, Doreen A Cantrell, Patrick T Kennedy, Nathan A Davies, Muzlifah Haniffa & Mala K Maini

doi:10.1038/nm.3856

Pallett et al. report that myeloid derived suppressor cells expand, home to the liver, and inhibit T cell-mediated liver damage in chronic hepatitis B virus infection.

See also: News and Views by Piconese & Barnaba


Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models pp601 - 609

Mario Schiffer, Beina Teng, Changkyu Gu, Valentina A Shchedrina, Marina Kasaikina, Vincent A Pham, Nils Hanke, Song Rong, Faikah Gueler, Patricia Schroder, Irini Tossidou, Joon-Keun Park, Lynne Staggs, Hermann Haller, Sergej Erschow, Denise Hilfiker-Kleiner, Changli Wei, Chuang Chen, Nicholas Tardi, Samy Hakroush, Martin K Selig, Aleksandr Vasilyev, Sandra Merscher, Jochen Reiser & Sanja Sever

doi:10.1038/nm.3843

The small molecule Bis-T-23 targets actin polymerization to improve renal morphology and function in several mouse models of kidney injury and disease.


Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity pp610 - 618

Elise Dalmas, Amine Toubal, Fawaz Alzaid, Katrina Blazek, Hayley L Eames, Kristell Lebozec, Maria Pini, Isabelle Hainault, Emilie Montastier, Raphaël G P Denis, Patricia Ancel, Amélie Lacombe, Yin Ling, Omran Allatif, Céline Cruciani-Guglielmacci, Sébastien André, Nathalie Viguerie, Christine Poitou, Vladimir Stich, Alexandra Torcivia, Fabienne Foufelle, Serge Luquet, Judith Aron-Wisnewsky, Dominique Langin, Karine Clément, Irina A Udalova & Nicolas Venteclef

doi:10.1038/nm.3829

Deletion of the transcription factor Irf5 in macrophages leads to expansion of the subcutaneous fat depot but restriction of the visceral fat during obesity, resulting in improved insulin sensitivity


The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes pp619 - 627

Bengt-Frederik Belgardt, Kashan Ahmed, Martina Spranger, Mathieu Latreille, Remy Denzler, Nadiia Kondratiuk, Ferdinand von Meyenn, Felipe Nunez Villena, Karolin Herrmanns, Domenico Bosco, Julie Kerr-Conte, Francois Pattou, Thomas Rülicke & Markus Stoffel

doi:10.1038/nm.3862

The miR-200 family of miRNAs is upregulated in diabetes and leads to the apoptosis of pancreatic beta cells, while its knockout prevents this pathology


KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis pp628 - 637

Laura S Shankman, Delphine Gomez, Olga A Cherepanova, Morgan Salmon, Gabriel F Alencar, Ryan M Haskins, Pamela Swiatlowska, Alexandra A C Newman, Elizabeth S Greene, Adam C Straub, Brant Isakson, Gwendalyn J Randolph & Gary K Owens

doi:10.1038/nm.3866

A high percentage of smooth muscle cells in atherosclerotic lesions lose expression of smooth muscle marker proteins and acquire the phenotype of other cell types, a process of functional importance in lesion pathogenesis that is controlled by the transcription factor KLF4.

See also: News and Views by Rosenfeld


Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α pp638 - 646

Ivan D Mascanfroni, Maisa C Takenaka, Ada Yeste, Bonny Patel, Yan Wu, Jessica E Kenison, Shafiuddin Siddiqui, Alexandre S Basso, Leo E Otterbein, Drew M Pardoll, Fan Pan, Avner Priel, Clary B Clish, Simon C Robson & Francisco J Quintana

doi:10.1038/nm.3868

Metabolic changes induced by hypoxia and extracellular ATP, acting through the transcription factors HIF1-α and AHR, regulate the differentiation of type 1 regulatory (Treg1) cells.


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Letter

Common clonal origin of central and resident memory T cells following skin immunization pp647 - 653

Olivier Gaide, Ryan O Emerson, Xiaodong Jiang, Nicholas Gulati, Suzanne Nizza, Cindy Desmarais, Harlan Robins, James G Krueger, Rachael A Clark & Thomas S Kupper

doi:10.1038/nm.3860

Following skin immunization a common naïve T cell precursor gives rise to resident and central memory T cells, which mediate rapid and delayed skin immune responses, respectively.

See also: News and Views by Gebhardt & Carbone


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